UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl) UvA-DARE (Digital Academic Repository) Oncological outcomes for patients with well differentiated thyroid cancer Nixon, I.J. Link to publication Citation for published version (APA): Nixon, I. J. (2013). Oncological outcomes for patients with well differentiated thyroid cancer. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Download date: 17 Jun 2020
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UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl)
UvA-DARE (Digital Academic Repository)
Oncological outcomes for patients with well differentiated thyroid cancer
Nixon, I.J.
Link to publication
Citation for published version (APA):Nixon, I. J. (2013). Oncological outcomes for patients with well differentiated thyroid cancer.
General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s),other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).
Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, statingyour reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Askthe Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam,The Netherlands. You will be contacted as soon as possible.
Oncological Outcomes for Patients with Well Differentiated Thyroid Cancer
Research presented in this thesis has been performed in the department of Head and Neck Surgery and Oncology (Head: Prof. J.P. Shah), Memorial Sloan Kettering Cancer Center, New York, USA
Layout and printing by: Buijten & Schipperheijn, Amsterdam
Oncological Outcomes for Patients with Well Differentiated Thyroid
CancerACADEMISCH PROEFSCHRIFT
ter verkrijging van de graad van doctoraan de Universiteit van Amsterdamop gezag van de Rector Magnificus
prof. dr. D.C. van den Boomten overstaan van een door het college voor promoties
ingestelde commissie,in het openbaar te verdedigen in de Aula der Universiteit
op woensdag 17 september 2013, te 12:00 uur
doorIain James Nixon
geboren te Edinburgh, Verenigd Koninkrijk
Promotiecommissie
Promotores: Prof. dr. J. P. Shah Prof. dr. A.J.M. Balm
Co-promotores: Dr. I. Ganly Prof. S.G. Patel
Overige leden: Prof. dr. M.W.M. van den Brekel Prof. dr. B.L.F. van Eck-Smit Prof. dr. J. Kievit Dr. E.J.M. Nieveen van Dijkum Prof. dr. M.J. van de Vijver
Faculteit der Geneeskunde
ChaptersChapter 1. Introduction 9
Chapter 2. Changing Trends in Incidence, Histological Distribution, Clinical Management and Outcomes of Well Differentiated Thyroid Carcinoma Over Eight Decades in One Institution 23
Chapter 3. Disease-related death in patients who were considered free of macroscopic disease after initial treatment of well-differentiated thyroid carcinoma. 41
Chapter 4. Thyroid isthmusectomy for well-differentiated thyroid cancer. 53
Chapter 5. Thyroid lobectomy for treatment of well differentiated intrathyroid malignancy. 63
Chapter 6. The impact of microscopic extrathyroid extension on outcome in patients with clinical T1 and T2 well-differentiated thyroid cancer. 83
Chapter 7. Observation of Clinically Negative Central Compartment Lymph Nodes in Papillary Thyroid Carcinoma 101
Chapter 8. The Results of Selective Use of Radioactive Iodine on Survival and on Recurrence in the Management of Papillary Thyroid Cancer Based on MSKCC Risk Group Stratification. 117
Chapter 9. The Selective Use of Radioactive Iodine in Patients at Intermediate Risk from Papillary Thyroid Carcinoma 143
Chapter 10. Discussion, conclusion and future directions 157
Chapter 11. English summary 173
Chapter 12. Samenvatting en conclusies 177
Curriculum Vitae 181
Chapter 1
Introduction
10
Chapter 1 - Introduction
Thyroid malignancies include those of follicular cell origin and those arising from the C cells. Cancers of follicular cell origin are by far the most common and include papillary, follicular Hurthle cell , poorly differentiated and anaplastic carcinoma. Of these subtypes, anaplastic is rare and is known for its extremely bad prognosis and almost universally fatal outcome. Similarly, poorly differentiated carcinomas also have aggressive behaviour and relatively unfavourable outcome. The three remaining subtypes, papillary, follicular and Hurthle cell are by far the most common, constituting over 90% of thyroid malignancies, with papillary (PTC) being the most common of the three. Unlike poorly differentiated and anaplastic thyroid cancers, these three subtypes are grouped as well differentiated thyroid cancers, and generally have excellent outcomes. Although excellent outcomes are reassuring for patients and rewarding for treating clinicians, they present a problem for researchers. With less than 10% of patients expected to die of disease in 10 or more years, attempts to characterize disease outcomes, and the impact of interventions by prospective studies, would require huge patient numbers with prolonged follow up and therefore are recognized as not readily feasible [1].There is widespread observation that the incidence of WDTC is rising , and that majority of the tumors and the patients in whom they arise have a favourable outcome. In terms of risk stratifying patients with WDTC, great steps have been made towards characterizing those patients at higher risk of recurrence and death. Treatment for WDTC is controversial, both in terms of surgical and adjuvant medical approaches. In the absence of randomized controlled trials, there have been two broad approaches to assessing different treatments; single institution reviews and multi institutional database reviews. Single institutional reviews have the strength of accurate surgical, pathological, treatment and outcome data, but are limited by patient number. Multi institutional database studies provide large numbers but lack accuracy in terms of treatment, histological analysis and disease specific follow up. The absence of level I evidence to guide treatment decisions have led to great controversy amongst clinicians responsible for managing WDTC. It is against this backdrop that we chose to study WDTC.
Increasing Incidence and Changing Trends in Well Differentiated Thyroid CancerWell differentiated thyroid cancer is the most common endocrine malignancy and is increasing in incidence across the world [2-14]. This increase is being seen particularly in papillary carcinoma [15]. The reasons for this increase are unclear and probably multi-factorial. Groups have suggested that increased exposure to ionizing radiation, either due to disasters such as Chernobyl or increased incidence due to routine medical surveillance, and imaging studies, [16] may play a role. The effect of changing trends in public health may have an effect, with both obesity [17, 18] and diabetes [19] being linked with a higher risk of thyroid cancer. Not only are a greater number of cancers identified now in comparison with 4 decades ago, but the nature of the primary tumors detected has changed. Increased availability of diagnostic scanning, in particular high resolution ultrasound, has led to the discovery that high
Chapter 1 Introduction
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rates of nodularity are detectable in the thyroid glands of otherwise normal individuals [20]. When discovered, needle biopsy of such nodularity may lead to detection of otherwise occult malignancies. Many investigators feel that this increased rate of detection is the major driver in the rising incidence of WDTC, and is contributing to the significant rise in incidence of small lesions [12]. The discovery of occult disease however may not be the only factor influencing the observed changes. A recent Surveillance, Epidemiology and End Results (SEER) Database review identified not only increases in micro carcinoma, but also in larger tumors over 4 and even over 6 cms, which would not be so easily explained by increased surveillance. In addition to changes in the histological subtype, number and average size of WDTCs now detected, and the patient cohort in whom they present is also changing. Although rates are rising in all age groups, they are rising fastest in patients over the age of 45 years [21]. The impact of this change in average age remains to be seen. Women have been considered to have superior outcomes to men, however recent evidence suggests that the seemingly protective effect of gender may be lost after menopause [22]. Increasing incidence and changing patterns of both disease and patients affected by this disease, have led to great interest in WDTC and outcomes for patients who are diagnosed with this disease. Much attention has been paid to predicting outcome and the selection of appropriate therapy for these patients.
Long Term Oncological OutcomesWork from the mid 20th century did much to outline the mode of death in patient with recurrent WDTC [23, 24] However, it was not until long term studies involving large patient cohorts were reported that an idea of disease biology became apparent. The Lahey Clinic published its results in 1976, reporting mortality rates of 3% and 5% at 5 and 10 years respectively for a group of 441 patients treated for PTC [25]. Data from 576 patients treated within the US Airforce Hospitals [26, 27] suggested that with 10 years follow up only around 1% of patients would die of disease. Although rates of recurrence in this cohort were higher (15%), many of these recurrences were successfully salvaged. The Mayo Clinic experience of over 800 patients and up to 40 years follow up confirmed these findings. Less than 6% of patients in their cohort died of disease at 30 years and WDTC accounted for only 3% of overall mortality. Memorial Sloan Kettering Cancer Center reported their experience of 50 years and over 900 patients [28] with a survival of nearly 90%. Similarly promising results were published as the experience of a number of major US centers were reported throughout the 1980s and 1990s [29-32]. This US experience was reinforced by worldwide single institutional experiences, again reporting survival rates around 90% dependant on length of follow up [33, 34]. Methods of data collection in the United States including the National Cancer Database and SEER have allowed analysis of very large groups of patients treated for WDTC. In 2006 Davies et al. reviewed statistics in the SEER database and reported thyroid cancer mortality rates at 0.5 deaths per 100,000 population [12]. These rates had remained stable, despite the increase in incidence between 1973 and 2002. Similarly low rates have been reported by other groups who analyzed data at a national level [13, 35].
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Evidence reflected the excellent outcomes that could be expected for patients with WDTC. However, not all patients did so well. Some patients would suffer disease recurrence despite adequate treatment, and would go on to die of disease, prompting investigators to analyze their experience in an attempt to devise methods to predict outcome on an individual patient basis. Development of Risk Prediction SystemsWith convincing long term evidence that most patients with WDTC have an excellent prognosis, balanced with clinical experience that some patients have more aggressive disease which leads to recurrence and death, several investigators turned their attention to predicting which patients might be expected to do badly. Although an increasing percentage of patients are now detected with limited local disease, some patients do present with advanced local, regional or distant disease. The impact of patient, tumor and treatment factors has been recognized to have an effect on both outcomes. In the 1960s and 70s several reports in the literature confirmed that the cell type of origin for a thyroid cancer was crucial to outcome [36, 37]. For WDTC, in 1986 the Mayo Clinic group reported outcomes for 859 patients with papillary thyroid cancer (PTC) treated between the 1940s-1970s. Their results suggested that advanced age at diagnosis, extra thyroid extension and distant metastases were strong predictors of death. These results were replicated by a number of groups including Mazzaferri who reported on 576 patients with similar findings [26, 27]. Hay et al. from the Mayo Clinic combined the risk factors of age, tumor grade, extent of disease and size of primary lesion in to the “AGES” system for risk prediction. Stratifying patients this way allowed groups to be identified who were at low versus high risk of death. This was later refined to include completeness of surgical resection and reported as a “MACIS” score [38]. Cady et al. reviewed over 800 patients managed in the Lahey Clinic over 4 decades, and reported similar results, introducing the “AMES” system which included age, distant metastases, extra thyroid extension and size, again to stratify patients into high and low risk groups [30]. A similar group of risk factors was reported by Shah from Memorial Sloan Kettering Cancer Center [28] which gave rise to the “GAMES” system of stratification (including tumor grade on histology). They separated patients and tumors into high and low risk categories for death. They then used these 2 factors to classify cases as low, or high risk cases. They also introduced an intermediate risk group category for young patients with high risk tumor factors, and older patients with low risk tumor features. [39]. The impact of nodal metastases on mortality is limited and therefore has not been included in many of the major risk prediction systems. Early work by Cady et al. suggested that nodal metastases actually had a protective effect [40], a finding explained by the predominance of young patients in the cohort, and the association with young age and both excellent survival and higher rates of nodal metastases. Hughes et al. later showed that in patients under 45 years of age at presentation, regional metastasis was not associated with death. However, in older patient, regional disease had a significant impact on cause specific mortality [41]. The American Joint Committee on Cancer now includes N stage in stratification of patients over the age of 45 years [42].
Chapter 1 Introduction
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Many similar risk prediction tools have been published, focusing on the risk of death from WDTC [43]. To this point, no system has demonstrated clear superiority. More recently, the American Thyroid Association (ATA) published guidelines for stratifying patients by risk of recurrence [44]. The factors involved once again included the presence of distant metastases, completeness of surgical resection and the presence of extra thyroid extension or adverse histological features. Unlike previously cited systems that predict death, nodal metastases are included as conferring an intermediate risk of recurrence. As almost no patients will die of WDTC, a system designed to predict recurrence rather than death may prove to be of more clinical utility to modern day clinicians.With the ability to predict outcome for individual patients, clinicians were able to consider their therapeutic approach to patients with WDTC. The extent of primary surgery and the role of radioactive iodine (RAI) in the post operative management were scrutinized in an attempt to tailor therapy to both the disease and the patient. Evolution of the Surgical Management of Well Differentiated Thyroid Cancer – Primary DiseaseWith improvements in understanding of the biology of WDTC came attempts to optimize treatment for the condition. Several investigators, looked at the results of different therapeutic approaches and analyzed their outcomes in search of the optimal trade off between improving outcome whilst preventing side effects.Early opinions favouring conservative surgical therapy [45] were challenged by clinical series suggesting improved results for patients who underwent total thyroidectomy. Mazzaferri analyzed the outcomes of 576 patients treated in the US Air force medical service [26], finding that patients who had total thyroidectomy had lower rates of cancer related death and recurrence than those patients who underwent less than thyroidectomy. The series was updated in 1994 to include 1355 patients treated both in the US Air force and Ohio State University Hospital. Again the authors demonstrated, on multivariate analysis, a link between more aggressive primary surgery and improved outcome. This experience seemingly provided strong data in support of total thyroidectomy for all but the smallest of tumors. However, this data should be viewed with the acknowledgment of significant limitations. The multi-institutional nature of the series introduced the potential for significant heterogeneity in treatment approaches across the centers. The surgeons involved in management were based at military hospitals , and may not have had the same rigorous surgical training and experience required of modern day thyroid surgeons. Seventeen percent of patients in that report underwent either less than lobectomy or subtotal thyroidectomy, both procedures which no longer have a place in the routine management of thyroid cancer [40]. The patients were not stratified by age, histology or extent of disease. Despite these limitations, this work provided an evidence base for increased application of total thyroidectomy in the management of WDTC. In contrast to Mazzaferri’s work, Cady et al. reported the results of the Lahey Clinic in 1976 [40]. Seven hundred and ninety-two patients were operated in this single institution for WDTC. Their work suggested no improvement in survival resulting from excision of a seemingly uninvolved
14
contralateral lobe. Hay and colleagues from the Mayo Clinic analyzed their outcomes in 860 patients with PTC. They found that for patients with low risk disease, total thyroidectomy did not result in improved outcomes when compared with lobectomy [46, 47]. A matched pair analysis of older patients with disease limited to the gland who underwent total thyroidectomy versus lobectomy at Memorial Sloan Kettering Cancer Center again demonstrated no advantage of more aggressive surgery, with the authors concluding that thyroid lobectomy should be used selectively in tumors less than 4cm in size, limited to the gland and without evidence of disease in the contralateral lobe [48].The collection of data in resources such as the SEER database allowed analysis of large patient cohorts, which promised to resolve the debate on the required extent of surgical resection required. In 2007 Bilimoria et al reported outcomes for over 50000 patients recorded in the National Cancer Database (NCDB) [49]. They found that although total thyroidectomy did not affect outcome for patients with sub-centimeter disease, for all patients with primary lesions greater than 1cm, total thyroidectomy reduced recurrence and improved survival. This report was cited by the ATA, in their 2009 guidelines on the management of WDTC, which recommends that total thyroidectomy should be advised for all lesions over 1cm in size, and lobectomy reserved only for the smallest tumors in the absence of any other risk factors [44]. Although the Bilimoria study provided higher numbers than would ever have been achieved in any single institution series, significant limitations of the data are evident [50]. Detail on pre operative investigations relating to abnormalities in the contralateral lobe were not included. Completeness of surgical resection was not recorded, but is vital information, particularly when considering patients coded as with lobectomy, who would be inappropriately recorded if the contralateral lobe was found to be unresectable. No information on specific high risk histological subtypes of papillary carcinoma was included, and recurrence data was reported as locoregional, rather than separating local from nodal recurrence. Unlike single institutional series, which are able to report these important co-variables, these national level studies omit the critical data required to make the assumption that total thyroidectomy improves outcome. In contrast to the Bilimoria results, Haigh et al. used the additional data recorded in the SEER database to show that total thyroidectomy did not confer a survival advantage in either low or high risk groups using the AMES classification[51]. A similar multivariate analysis of the SEER database by Mendelsohn et al. controlling for tumor size in a cohort of over 20000 patients found no survival difference in patients who underwent total thyroidectomy rather than thyroid lobectomy [52]. Davies et al. reported similar results in an analysis of 35000 patients managed between 1973-2005, again finding no advantage in total thyroidectomy [53]. The National Thyroid Cancer Treatment Cooperative Study Group from North America reported on almost 3000 patients in 2006, and was unable to show an improved disease specific survival or disease free survival at any stage of disease based upon extent of surgery [54]. Debate over the extent of thyroid surgery required for WDTC relates in part to complications of total thyroidectomy versus lobectomy . Rates of complication for thyroid surgery are significant. A study of 5583 thyroid cases operated in the USA in 1996 for WDTC reported a post operative hypocalcemia rate of 10% and a recurrent laryngeal nerve palsy rate of around
Chapter 1 Introduction
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1% [55]. Multi-center studies from Italy and Scandinavia reported very similar findings [56, 57]. Comparing total thyroidectomy with lobectomy, both US and Italian studies have reported higher rates of hypocalcaemia, unilateral vocal cord palsy and bilateral vocal cord palsy following total thyroidectomy rather than thyroid lobectomy performed for malignancy [56, 58]. Despite these results, which represent multi-institutional results, experts in thyroid surgery report very low rates of complication following either lobectomy or total thyroidectomy [59]. This contrast supports the observation that the risk of thyroid surgery is directly related to the operating surgeon’s experience.Despite conflicting evidence about both the oncological superiority of total thyroidectomy and the surgical complications that result from bilateral surgery, there has been a steady increase in the proportion of surgeries which are total thyroidectomy in the USA [60]. Total thyroidectomy is now the procedure of choice in around 90% of patients with WDTC 1cm or greater in the USA [61]. Evolution of the Surgical Management of Well Differentiated Thyroid Cancer – Neck DissectionWhilst there is agreement that management of overt nodal metastases involves surgical resection of disease using a compartment orientated approach, the position in relation to management of the clinically N0 patient is highly controversial. Patients who have apparently intrathyroid disease enjoy excellent outcomes. Therefore, most groups have abandoned elective lateral neck dissection, as the significant potential morbidity outweighs any advantage in terms of recurrence or survival. Elective central neck dissection however, reveals nodal micrometastases up to 60% of cN0 cases [62]. This procedure can be performed safely in expert hands [63, 64] and leads to up-staging in patients over the age of 45 years [62-64]. The information gained from this additional dissection can be used to target patients for adjuvant radioactive iodine (RAI) or for administration of higher RAI doses in departments that use adjuvant RAI routinely [64]. Despite such arguments, elective central neck dissection has not been shown to improve survival or reduce recurrence rates. In contrast to arguments in favour of elective central neck dissection, there is a lack of evidence that such additional surgery results in measurable benefit. No effect on outcome, either recurrence or survival has been demonstrated by individual studies [63, 64] or the meta analysis of results [65]. Sywak at al. demonstrated lower thyroglobulin in patients who underwent prophylactic neck dissection, however this effect lost significance with time [66]. For these reasons and a lack of evidence that such procedures can be performed in a community setting without increasing morbidity from nerve injury and hypocalcemia [57], routine elective neck dissection is not supported by most major international guidelines. The current American Thyroid Association Guidelines state “prophylactic central-compartment neck dissection may be performed in patients with papillary thyroid carcinoma, especially for advanced primary tumors (T3 or T4)” [44]. In addition, they recently considered the feasibility of performing a randomized controlled trial of elective central neck dissection, determining that over 5000 patients would have to be enrolled [1]. This conclusion means the question is unlikely ever to
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be conclusively resolved, however it also highlights the fact that such elective surgery has such a small impact on outcome that surgeons must be sure that their rates of morbidity in relation to more aggressive surgery are sufficiently low to consider such a procedure. The Role of Radioactive Iodine in the Management of Well Differentiated Thyroid CancerThe role of RAI in the management of WDTC is also controversial. Recognition that RAI could be used to ablate normal thyroid tissue, and that it might have a tumoricidal effect on WDTC with seemingly low levels of side effects led to widespread use. When Mazzaferri et al. considered the effect of RAI in their early work [26], they observed significant reductions in both recurrence and mortality in patients who received RAI. Their later work further supported the position that for patients with disease over 1.5cm, those treated with RAI had improved outcomes in comparison with those selected not to receive RAI. This observation led to a recommendation by the authors that RAI should be used in all tumors over 1.5cm in size. It should be noted, however, that the same limitations that were applied to interpretation of this group’s surgical findings should be borne in mind when considering their recommendations for RAI. A significant number of patients did not undergo true total thyroidectomy. Therefore significant volumes of thyroid tissue may have been left behind, limiting application of this groups conclusions in the modern era. The work from the Mayo clinic, analyzed in 2008, suggested that for 83% of their patients, no improvement in outcome was observed despite the increase in use of RAI throughout their 6 decade experience [67]. This group therefore recommends only using RAI routinely in patients deemed to be at high risk of recurrence or death from disease. A similar outcome was reported in a multi-institutional study of around 3000 patients from North America [54]. The authors observed no benefit in RAI for patients with low stage disease, but observed improved disease free survival and disease specific survival in patients considered high risk.The American Thyroid Association included these studies in its guidelines, which currently recommend the routine use of RAI in only high risk patients, and do not support its use in the lowest risk patients (<1cm disease). For patients with intermediate risk disease (pT2 or N+) they recommend selective use based on the presence of any adverse risk factors such as previous radiation, or higher risk histologies.Whilst the benefit of RAI in lower risk patients is questionable, the potential for salivary and lacrimal side effects, and post treatment dysphagia have been demonstrated by a number of groups. This treatment related morbidity has been shown to have a negative impact on quality of life [68-72]. In addition to morbidity, RAI has also been linked with increased rates of second primary malignancies [73, 74]. Despite conflicting evidence regarding efficacy, and growing evidence of the adverse effects of treatment, use of RAI has increased significantly in the USA [67]. It is perhaps not surprising, given the state of the evidence in relation to RAI, that there is wide variation in RAI use across the USA.
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Aims and Brief Outline of this ThesisWith rates of WDTC having tripled in the US over the past 4 decades and similar trends being reported globally, the impact on international healthcare resources is significant and continues to grow. Over the past century, investigators have observed that the vast majority of patients with WDTC will not die of disease, and that with appropriate treatment, excellent outcomes can be achieved. Surgery is the mainstay of treatment, although disagreement exists over the extent of thyroidectomy .In patients presenting with metastatic or large volume disease, or for patients with evidence of extra-thyroid extension, authors agree that total thyroidectomy is the primary procedure of choice. However, epidemiological studies of WDTC suggest that such high risk cases will provide only a minority of the workload in the future. Increasingly, we are seeing low volume disease presenting in an older patient group [21]. At least two thirds of patients seen in the US today have disease limited to the thyroid [2], the majority of which will measure 2cms or less (pT1). Outcomes in this group are excellent and therefore differences in treatment effects are likely to be small. The debate over management of such low risk patients is far from resolved. Prospective randomized trials of surgical therapy are unrealistic. Recruitment and follow up would be unachievable. In the absence of such high level evidence, clinicians have looked to single institution series and multi-institutional datasets for guidance. The main drawback of single institutional studies is low patient number, whereas multi-institutional studies lack the level of detailed data required to interpret the effect of different treatment regimens on outcome.The role of RAI has also been debated, with similar concerns about the lack of high level evidence confounding a straightforward interpretation of the evidence presented. Although the routine use of RAI has been accepted for patients considered at high risk of death or recurrence, for the majority of patients, the position is less clear.
Despite (a) the increasing number of patients who present with early localized disease (b) the lack of convincing evidence that more aggressive surgery results in improved outcome in such patients (c) the lack of evidence that routine use of RAI in low risk patients is of benefit and (d) the known increase in side effects related to more aggressive surgical and medical treatment, an increasing percentage of patients are being managed with total thyroidectomy and post operative RAI. Inspite of this increasingly aggressive and potentially morbid treatment approach, no reduction in mortality rates has been observed over the past 2 decades.Memorial Sloan Kettering Cancer Center, in New York has a long tradition of thyroid cancer research. As one of the highest volume centers in the USA, the workload allows recruitment of a large patient cohort. Following previous analysis of records from 1930-1985, thyroid lobectomy is recommended in properly selected patients. A risk stratified approach to the use of RAI within our institution has also long been practiced, with RAI reserved mainly for use in high risk cases. This less aggressive approach to the management of WDTC sets our institutional practice apart from much of the world, and has given us the opportunity to update our experience with a contemporary group of patients, in regard to their outcomes
18
and the effect of therapy on both recurrence and death. In chapter 2 we compare our dataset with the previously reported cohort of patients from 1930-1985. We describe both the similarities and differences observed over 8 decades. In chapter 3 we report the mode of death now experienced in the few fatalities reported within our cohort. Chapter 4 focuses on the least aggressive oncologically sound procedure that should be considered for patients with WDTC, isthmusectomy. Chapter 5 describes the role of thyroid lobectomy in patients with disease limited to the gland, and chapter 6 extends this experience to patients considered localized, but with microscopic extra thyroid extension reported on the histopathology report. In chapter 7 we examine the outcomes of patients who had 0 nodes excised at their primary surgery (Nx), in an attempt to address the role of elective central neck surgery in such cases. Chapters 8 and 9 analyze the use of RAI in the management of WDTC, with a particular focus on those patients who can safely be considered for treatment without RAI.The aim of this thesis is to provide evidence from a large, consecutive group of patients with WDTC managed in a single major institution, which has had a relatively stable approach to the surgery, pathological reporting, adjuvant therapy and post operative follow up over many years. We focus on outcomes for patients treated in a selective manner. We assess outcomes following less than total thyroidectomy. In patients treated with total thyroidectomy, we assess outcomes for patients selected not to receive RAI.
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27. Mazzaferri, E.L. and R.L. Young, Papillary thyroid carcinoma: a 10 year follow-up report of the impact of therapy in 576 patients. Am J Med, 1981. 70(3): p. 511-8.
28. Shah, J.P., et al., Prognostic factors in differentiated carcinoma of the thyroid gland. Am J Surg, 1992. 164(6): p. 658-61.
29. DeGroot, L.J., et al., Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab, 1990. 71(2): p. 414-24.
30. Cady, B. and R. Rossi, An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery, 1988. 104(6): p. 947-53.
31. Samaan, N.A., et al., The results of various modalities of treatment of well differentiated
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32. Loh, K.C., et al., Pathological tumor-node-metastasis (pTNM) staging for papillary and follicular thyroid carcinomas: a retrospective analysis of 700 patients. J Clin Endocrinol Metab, 1997. 82(11): p. 3553-62.
33. Esik, O., et al., Survival chance in papillary thyroid cancer in Hungary: individual survival probability estimation using the Markov method. Radiother Oncol, 1997. 44(3): p. 203-12.
34. Sugitani, I., et al., A novel classification system for patients with PTC: addition of the new variables of large (3 cm or greater) nodal metastases and reclassification during the follow-up period. Surgery, 2004. 135(2): p. 139-48.
35. Nixon, I.J., et al., Thyroid isthmusectomy for well-differentiated thyroid cancer. Ann Surg Oncol, 2011. 18(3): p. 767-70.
36. Woolner, L.B., et al., Classification and prognosis of thyroid carcinoma. A study of 885 cases observed in a thirty year period. Am J Surg, 1961. 102: p. 354-87.
37. Byar, D.P., et al., A prognostic index for thyroid carcinoma. A study of the E.O.R.T.C. Thyroid Cancer Cooperative Group. Eur J Cancer, 1979. 15(8): p. 1033-41.
38. Hay, I.D., et al., Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery, 1993. 114(6): p. 1050-7; discussion 1057-8.
39. Shaha, A.R., J.P. Shah, and T.R. Loree, Risk group stratification and prognostic factors in papillary carcinoma of thyroid. Ann Surg Oncol, 1996. 3(6): p. 534-8.
40. Cady, B., et al., Changing clinical, pathologic, therapeutic, and survival patterns in differentiated thyroid carcinoma. Ann Surg, 1976. 184(5): p. 541-53.
41. Hughes, C.J., et al., Impact of lymph node metastasis in differentiated carcinoma of the thyroid: a matched-pair analysis. Head Neck, 1996. 18(2): p. 127-32.
42. Edge, S.B. and American Joint Committee on Cancer., AJCC cancer staging manual. 7th ed. 2010, New York: Springer. xiv, 648 p.
43. Sherman, S.I., et al., Prospective multicenter study of thyrois]carcinoma treatment: initial analysis of staging and outcome. National Thyroid Cancer Treatment Cooperative Study Registry Group. Cancer, 1998. 83(5): p. 1012-21.
44. Cooper, D.S., et al., Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid, 2009. 19(11): p. 1167-214.
45. Crile, G., Jr., A conservative approach to treatment of thyroid cancer. Postgrad Med, 1975. 57(7): p. 111-5.
46. Hay, I.D., et al., Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: a retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery, 1987. 102(6): p. 1088-95.
47. Hay, I.D., et al., Papillary thyroid microcarcinoma: a study of 900 cases observed in a 60-year period. Surgery, 2008. 144(6): p. 980-7; discussion 987-8.
48. Shah, J.P., et al., Lobectomy versus total thyroidectomy for differentiated carcinoma of the thyroid: a matched-pair analysis. Am J Surg, 1993. 166(4): p. 331-5.
49. Bilimoria, K.Y., et al., Extent of surgery affects survival for papillary thyroid cancer. Ann Surg, 2007. 246(3): p. 375-81; discussion 381-4.
50. Shah, J.P., Re: Extent of surgery affects papillary thyroid cancer. Ann Surg, 2008. 247(6): p. 1082-3; author reply 1083-4.
51. Haigh, P.I., D.R. Urbach, and L.E. Rotstein, Extent of thyroidectomy is not a major determinant of survival in low- or high-risk papillary thyroid cancer. Ann Surg Oncol, 2005. 12(1): p. 81-9.
52. Mendelsohn, A.H., et al., Surgery for papillary thyroid carcinoma: is lobectomy enough? Arch Otolaryngol Head Neck Surg, 2010. 136(11): p. 1055-61.
53. Davies, L. and H.G. Welch, Thyroid cancer survival in the United States: observational data from 1973 to 2005. Arch Otolaryngol Head Neck Surg, 2010. 136(5): p. 440-4.
54. Jonklaas, J., et al., Outcomes of patients with differentiated thyroid carcinoma following initial therapy. Thyroid, 2006. 16(12): p. 1229-42.
55. Hundahl, S.A., et al., Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the united states during 1996. U.S. and German Thyroid Cancer Study Group.An American College of Surgeons Commission on Cancer Patient Care Evaluation study.Cancer, 2000. 89(1): p. 202-17.
56. Rosato, L., et al., Complications of thyroid surgery: analysis of a multicentric study on 14,934 patients operated on in Italy over 5 years. World J Surg, 2004. 28(3): p. 271-6.
57. Bergenfelz, A., et al., Complications to thyroid surgery: results as reported in a database from a multicenter audit comprising 3,660 patients. Langenbecks Arch Surg, 2008. 393(5): p. 667-73.
58. Zerey, M., et al., Short-term outcomes after unilateral versus complete thyroidectomy for malignancy: a national perspective. Am Surg, 2009. 75(1): p. 20-4.
59. Clark, O.H., et al., Thyroid cancer: the case for total thyroidectomy. Eur J Cancer Clin Oncol, 1988.
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24(2): p. 305-13.60. Mitchell, I., et al., Trends in thyroid cancer
demographics and surgical therapy in the United States. Surgery, 2007. 142(6): p. 823-8; discussion 828 e1.
61. Bilimoria, K.Y., et al., Utilization of total thyroidectomy for papillary thyroid cancer in the United States. Surgery, 2007. 142(6): p. 906-13; discussion 913 e1-2.
62. Hughes, D.T., et al., Influence of prophylactic central lymph node dissection on postoperative thyroglobulin levels and radioiodine treatment in papillary thyroid cancer. Surgery, 2010. 148(6): p. 1100-6; discussion 1006-7.
63. Popadich, A., et al., A multicenter cohort study of total thyroidectomy and routine central lymph node dissection for cN0 papillary thyroid cancer. Surgery, 2011. 150(6): p. 1048-57.
64. Hartl, D.M., et al., Optimization of staging of the neck with prophylactic central and lateral neck dissection for papillary thyroid carcinoma. Ann Surg, 2012. 255(4): p. 777-83.
65. Zetoune, T., et al., Prophylactic central neck dissection and local recurrence in papillary thyroid cancer: a meta-analysis. Ann Surg Oncol, 2010. 17(12): p. 3287-93.
66. Sywak, M., et al., Routine ipsilateral level VI lymphadenectomy reduces postoperative thyroglobulin levels in papillary thyroid cancer. Surgery, 2006. 140(6): p. 1000-5; discussion 1005-7.
67. Hay, I.D., et al., Papillary thyroid carcinoma managed at the Mayo Clinic during six decades (1940-1999): temporal trends in initial therapy and long-term outcome in 2444 consecutively treated patients. World J Surg, 2002. 26(8): p. 879-85.
68. Newkirk, K.A., et al., The role of radioactive iodine in salivary gland dysfunction. Ear Nose Throat J, 2000. 79(6): p. 460-8.
69. Alexander, C., et al., Intermediate and long-term side effects of high-dose radioiodine therapy for thyroid carcinoma. J Nucl Med, 1998. 39(9): p. 1551-4.
70. Mandel, S.J. and L. Mandel, Radioactive iodine and the salivary glands. Thyroid, 2003. 13(3): p. 265-71.
71. Almeida, J.P., et al., Late side effects of radioactive iodine on salivary gland function in patients with thyroid cancer. Head Neck, 2011. 33(5): p. 686-90.
72. Almeida, J.P., J.G. Vartanian, and L.P. Kowalski, Clinical predictors of quality of life in patients with initial differentiated thyroid cancers. Arch Otolaryngol Head Neck Surg, 2009. 135(4): p. 342-6.
73. Sawka, A.M., et al., Second primary malignancy risk after radioactive iodine treatment for thyroid cancer: a systematic review and meta-analysis. Thyroid, 2009. 19(5): p. 451-7.
74. Iyer, N.G., et al., Rising incidence of second cancers in patients with low-risk (T1N0) thyroid cancer who receive radioactive iodine therapy. Cancer, 2011. 117(19): p. 4439-46.
Chapter 2
Changing Trends in Well Differentiated
Thyroid Carcinoma Over Eight Decades
Iain J Nixon, MD, Ian Ganly, MD, PhD, Frank L. Palmer, BA, Monica Whitcher, BA, Rony Ghossein, MD, Snehal G Patel, MD, R. Michael Tuttle, MD, Ashok Shaha, MD,
Jatin P Shah, MD
Int. J Surg. 2012; 10(10): 618-23
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Abstract
IntroductionThe incidence of well differentiated thyroid cancer (WDTC) is rising in the USA. The objective of this study is to present the changes in incidence, presentation, management and outcomes of WDTC within our institution over the past 8 decades.
Methods2797 patients managed between 1932-2005 at Memorial Sloan Kettering Cancer Center were identified from our institutional database.
ResultsThere has been an increase in the number of patients managed per decade. Although the median age was 45 years, patients managed post-1985 were more likely to be over 45 years (53% versus 44%, p<0.001). The percentage of women increased from 68% to 72% (p=0.026), and the percentage of papillary carcinomas also increased, from 78% to 92%, p<0.001. An increase in early stage tumors was observed with pT1 lesions increasing from 19% to 48%. Patients in the latter cohort were less likely to have thyroid lobectomy (29% versus 72%, p<0.001). There was a significant change in the use of RRA, with 8% of the early versus 44% of the latter group receiving post-operative RRA (p<0.001). Since the introduction of risk group stratification disease specific survival (DSS) has not changed significantly. With a median follow up of 90 months, 10 year DSS rates were below 90% in the cohort managed prior to the 1970s, which rose to >95% thereafter (p<0.001).
ConclusionsOlder patients with earlier stage disease present an increasing workload for surgical oncologists. Excellent outcomes remain unchanged despite increasingly aggressive surgical and medical management.
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Introduction
Well differentiated thyroid cancer (WDTC) is rising in incidence in the USA and across the world over the past three decades (1-5). Unlike most human malignancies, WDTC has high cure rates when managed appropriately (6-8). Our understanding of the biology of this common disease and the impact of treatment on patient outcome has evolved over the past century. Over this time period, management of thyroid cancer has evolved from a wide spectrum of treatment approaches to a more standardized evidence based approach, due to improved understanding of the biological behavior of this cancer, and supported by national and international guidelines (9-11). Surgery remains the cornerstone of management of thyroid cancer with post-operative radioactive iodine administered as adjuvant treatment in selected cases based on risk of recurrence and risk of disease specific mortality.The objective of our study is to present the changing trends in the incidence, presentation, management and outcomes of WDTC within our institution over the past 8 decades.
26
Patients and Methods
Following approval by the Institutional Review Board, 2797 patients who had thyroid surgery for WDTC between 1932 and 2005 at Memorial Sloan Kettering Cancer Center, New York, were identified from our institutional database. Data collection was carried out over two separate time periods, with reports based on the initial cohort (1932-1985, n=987) published separately from the subsequent group (1986-2005, n=1810). Both cohorts were combined to produce the data presented in this manuscript. Patients with anaplastic, poorly differentiated and medullary carcinoma, as well as those who were selected as not suitable for surgery were excluded from these studies.Data collected included patient demographics, surgical details including extent of thyroid surgery, histopathological diagnosis at the time of treatment and pTNM status. Data on adjuvant radioactive iodine remnant ablation (RRA) was also collected. In-depth analysis of recurrence data have been presented previously(12). In this manuscript we present data on 10 year disease specific survival (DSS). Mode of death was determined from case notes and death certificates where available, and cross checked against the social security index for all patients. Patients who were known to have died of disease were coded as cause specific death. Those who died of other causes were censored at the time of death for DSS analysis. Patients who died during follow up, and no cause could be confirmed were considered to have died of disease if there was evidence of disease at last follow up, in order not to underestimate the effect of disease.Our institutional approach to the management of WDTC involves risk stratification using the previously reported GAMES criteria (Table 1) (13). These criteria, consider patient and tumor factors in risk stratification. This classification was designed to predict the risk of death from WDTC, rather than the risk of recurrence. Patients are considered at low risk if under the age of 45 years, and high risk if over 45 years. Tumors with more aggressive histology, which are larger than 4cms, and/or have extrathyroid extension or have distant metastases are considered high risk tumors. In contrast, well differentiated tumors that are less than 4 cms, and are intrathyroidal, and have no evidence of distant metastases are considered low risk tumors. Thus, patients above 45 years age with high risk tumors are considered in the high risk group. Patients under the age of 45, with low risk tumors are included in the low risk group. All others are included in the intermediate risk group. i.e. young patients with high risk tumors or older patients with low risk tumors. Our philosophy of management has been to advocate ipsilateral lobectomy in low risk patients with a unifocal intraglandular tumor, without any detectable abnormality in the opposite lobe. Assessment of the contralateral lobe is by intra-operative examination. Nowadays, this is supplemented with preoperative ultrasound. These patients do not receive RRA therapy. In the high risk group, a total thyroidectomy or even more extensive resection and post-operative RRA is recommended. Surgical resection of all clinically apparent disease is the mainstay of treatment and to this end extracapsular total thyroidectomy is performed with resection of strap muscles, recurrent nerve and even laryngotracheal or esophageal structures as indicated
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to ensure macroscopic surgical clearance. For intermediate risk cases, an individualized treatment decision is made based on discussion between the surgeon, endocrinologist and patient and is mainly based on tumor factors. This approach to risk stratification and treatment was adopted during the time period of the initial cohort and has remained our standard of care for subsequent decades.In terms of management of the neck, we do not perform routine elective central or lateral compartment neck dissection. The cervical nodal basins are examined clinically, ultrasonographically (in more recent years) and intra-operatively. For a clinically positive neck, with palpable node in the lateral compartment, an anatomically comprehensive, and oncologically effective selective neck dissection ( lymph nodes at levels II,III,IV and V) is carried out. If suspicious nodes are identified during surgery of the primary tumor, frozen section is used to confirm metastatic disease, and appropriate neck dissection is carried out depending on the location of the metastatic nodes. Central compartment dissection is performed only if suspicious nodes are noted during thyroidectomy and confirmed by frozen section.Statistical analysis was carried out using JMP statistical package (SAS Institute Inc. SAS Campus Drive, Cary, NC 27513) and SPSS (IBM Company Headquarters, 233 S. Wacker Drive, 11th Floor, Chicago, Illinois 60606). Variables were compared within groups using Pearson’s Chi squared test. Survival outcomes were determined using the Kaplan-Meier method. Univariate analysis was carried out by the log rank test.
28
Results
Patient, tumor and treatment characteristics of the group as a whole and stratified by the date of initial surgical management by decade are shown in Table 2. The median follow up for the overall group was 90 months (range 1-811 months). Throughout the time period studied, there has been a steady increase in the number of patients managed per decade, with 982 patients managed between 1932-1985 in comparison to 1810 patients between 1986 and 2005 (Table 2,Figure 1). The median age of the whole group was 45 years (range 4-94 years). In comparison with the earlier cohort, patients managed post 1985 were more likely to be over the age of 45 years (53% versus 44%, p<0.001).The percentage of women in the cohort increased from 68% to 72% in the more recent cohort (p=0.026), and the percentage of tumors classified as papillary carcinoma also increased from 78% to 92%, p<0.001.An increase in early stage tumors was observed during the study with pT1 lesions increasing from 19% in the early cohort to 48% in the latter cohort. For pT4 tumors, representing locally advanced tumors, we saw no increase in incidence with 8% in the early cohort and 7% in the latter cohort. Throughout the decades there has been a rise in the percentage of papillary carcinomas presenting with our institution. In the earlier cohort, around 75% of WDTC were classified a papillary carcinoma, which rose to 86% between 1986-1995 and 94% between 1996-2005. This corresponded with a fall in the percentage of follicular carcinomas from 18% to 3% over the same time period. In part, this change may be explained by changes in the definition of follicular carcinoma, with some patients now being classified as follicular variant of papillary carcinoma. The percentage of patients with pathologically positive neck nodes fell from 48% to 33% (p<0.001). The incidence of patients with distant metastasis at presentation was similar (4% in the early versus 3% in the later cohort, p=0.262). The rising age of patients resulted in an increased percentage of intermediate risk cases in the later cohort, and a reduced number of low risk cases. However, the number of cases considered high risk remained relatively constant (Table 4a). Trends in treatment revealed that patients in the later cohort were less likely to have thyroid lobectomy (29% versus 72%, p<0.001), with a corresponding increase in rates of total thyroidectomy. There was also a significant change in the use of RRA, with 8% of the pre 1985 group versus 44% of the post 1985 group receiving post-operative RRA (p<0.001). When stratified by decade, the percentage who received RRA rose from 0% in 1932-1945 to 2%, 8%, 32%, 71%, 48% and 68% by 1996-2005.By the 1970s, evidence had shown that procedures which involved less than unilateral lobectomy resulted in worse outcomes, and therefore for analysis of DSS we considered 3 groups: those managed before 1970, those managed between 1970-1986 and those managed between 1986-2005. Analysis of DSS by time period shows a significant improvement over
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time with modern day 10 year survival figures of 96.1% (Table 3). This improvement in outcome is most marked in the high risk group (Table 4b). Since the introduction of risk group stratification, and individualized treatment protocols based on such an approach (around the 1970s) DSS has not changed significantly. 10 year DSS rates were below 90% in the cohort managed prior to the 1970s, which rose to >95% thereafter (p<0.001).Analysis of factors predictive of poorer outcome for the whole group confirmed non-papillary histology, age over 45 years, the presence of distant metastasis, evidence of extrathyroid extension and size over 4cms as independent predictors on multivariate analysis (GAMES)(14). In contrast, the presence of lymph node metastases was not predictive of DSS (Table 5).
30
Discussion
Over the past century there has been a gradual change in the management of thyroid cancer. A number of major centers have published the results of institutional series spanning many decades (15, 16). The incidence and presenting features of this common disease have undergone significant changes in recent times. It is now recognized that the incidence of papillary thyroid carcinoma is rising at a faster rate than any other malignancy(17). The reasons proposed for this are contentious. There is no doubt that enhanced imaging has resulted in increased rates of detection, particularly of cancers less than 1cm in size (microcarcinomas) (3, 17). However, there has also been an increase in tumors greater than 4-6cm, suggesting that the increasing incidence may be a true increase caused by other yet unknown factors (18). Thyroid cancer is recognized as being more common in females. However, recent reports suggest the incidence in women may be increasing at a higher rate than in males (4). The incidence has also been reported to be increasing at a faster rate in older patients (17).Early reports of deaths from WDTC suggested that less than total thyroidectomy procedures resulted in less favorable oncological outcomes, and that all gross disease should be removed as part of the initial surgical procedure (19-21). Debate about the required extent of initial surgical therapy continues, with an understanding that thyroid lobectomy is a safe and effective option in low risk, unifocal, intraglandular thyroid cancers (9-11, 22) The management of the contralateral lobe in low risk cases has been long debated with evidence supporting both lobectomy alone (23, 24) and total thyroidectomy (25, 26). In the absence of prospective randomized controlled trials, this debate is unlikely to be resolved. In high risk cases, the place of total thyroidectomy is widely accepted.Over the past 8 decades at MSKCC there has been an increase in the rate of total thyroidectomy (Figure 2). High resolution ultrasound imaging in the pre-operative investigation of patients with WDTC has increased the number of contralateral thyroid nodules identified preoperatively. This, previously considered occult disease, now results in total thyroidectomy rather than thyroid lobectomy being adopted, even in low risk patients. Surgical practice has therefore gone full circle, with an initial move away from total thyroidectomy to thyroid lobectomy for selected low risk caseswith now a move back towards total thyroidectomy to excise previously occult contralateral nodular disease, regardless of its histological status.The role of RRA also remains unclear in certain situations. For low risk patients, little benefit has been demonstrated(27, 28), whereas in high risk cases the benefits are more certain(28). The therapeutic efficacy of RRA in the management of WDTC has led to a large increase in its use, even in low risk patients, at many major centers across the US(29).Our results over the past 73 years reflect the changes described above, with an increasing number of cases managed within our institution over the past 8 decades (Figure 1). Along with this volume increase, we have also observed a trend towards an older patient group (94% versus 53%, p<0.001), with a higher percentage of women represented in recent years (72% versus 68%, p=0.026) (Table 2). These trends may be due to a change in referral patterns with increased access to ultrasound in both primary care and obstetrics and gynecology practice.
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Analysis of survival of the whole group confirms our earlier reports that non-papillary histology, age over 45 years, the presence of distant metastases, extrathyroid extension, and size over 4cms are predictive of poorer DSS. The results of analysis of both patient and tumor related factors underscore the importance of risk stratification, to allow for individualization in the management of WDTC (Table 5).In terms of histopathological subtypes of WDTC, papillary thyroid carcinoma remains the most prevalent, with an increasing percentage in recent years (92% versus 78%, p<0.001). There has also been a reduction in the incidence of follicular carcinoma, from 16% to 5% (p<0.001). This is likely due to the recognition that many primary lesions previously described as follicular carcinoma are now categorized as follicular variant of papillary carcinoma. A further change in histological reporting has resulted in the recognition of poorly differentiated thyroid carcinoma. Towards the end of our study this was recognized as a separate histological entity, and was reported separately. Although we found a relatively constant rate of pT4 disease presented throughout the decades, some more recent pT4 cancers may have been recognized as poorly differentiated and therefore excluded from this analysis. In keeping with other reports, we also noted a significant increase in the number of microcarcinomas (<1cm). pT1 disease comprised 48% of the recent cohort of patients compared to 19% of the earlier cohort, p<0.001. Interestingly, nodal disease has decreased in prevalence, from 48% to 33% (p<0.001). This may be due to the increase in early T stage tumors that we now see. It may also be due to a change in neck dissection policy since our risk stratification system was introduced, with neck dissection only being carried out for clinically palpable neck disease in the past , and more recently for radiographically detected lymph node metastases. The percentage of patients presenting with evidence of distant metastases has remained constant at less than 5%, suggesting that the percentage of patients presenting with aggressive, high risk disease that is likely to affect survival has not changed dramatically over the 7 decade period.With regards to our risk stratification system (GAMES), we observed a shift of low risk cases to the intermediate risk group category (Table 4a). This is as a result of the older patient age at presentation, despite the increases in low risk tumors. Only 25% of patients in the earlier cohort underwent total thyroidectomy versus 68% in the recent cohort. In our institution, even older patients with intraglandular WDTC are selected for thyroid lobectomy. Therefore a change in overall risk stratification should have a limited effect on rates of total thyroidectomy. This change in practice therefore is likely to be multifactorial in etiology. Along with the change in risk groups, the introduction of preoperative ultrasound over this time period has resulted in more occult nodular disease in the contralateral lobe being detected. As a consequence, there has been an increase in the number of total thyroidectomies. In addition, the increased number of total thyroidectomies may also be accounted for by several international guidelines now recommending total thyroidectomy for intra-thyroid lesions over 1.5cm (9-11).Post-operative adjuvant RRA was rarely used in the early part of this study, but has become a part of therapy for 44% of cases in recent times (Figure 2). Over the past few years we have become increasingly aware of the side effects of RRA as well as the risk of second primaries. As a result, we now carefully consider the risk versus benefit ratio before recommending treatment with RRA.
32
DSS for patients managed during this study has increased significantly from below 90% to over 95% in the later years (Table 3). This improvement is in keeping with other series and demonstrates the excellent outcomes that most patients with WDTC now experience. Careful scrutiny of these figures however demonstrates that these improvements were largely achieved prior to the mid-1970s (Table 4b). It was at this time that evidence to support the surgical techniques now routinely employed was starting to appear. This is with particular reference to abandoning the practice of subtotal or near total thyroidectomyand instituting the practice of routine “extracapsular” total thyroidectomy Around this time the understanding of risk stratification was improving with several investigators presenting their own method for predicting outcome in patients with WDTC (27, 30, 31). More recently, despite the increase in the rates of total thyroidectomy and RRA, no significant improvement in DSS has been observed for a cancer which already had excellent outcomes (Figure 2). These figures are affected by the changing trends in presentation. An increased number of intermediate risk cases are now seen (Table 4a). Analysis on a risk group specific level show improvement in each time period studies (Table 4b) although overall, improved survival was more marked from the mid 1970s.Over the past 8 decades in our institution, the incidence, presentation and management of WDTC has changed considerably. Older patients with earlier stage disease present an increasing workload for our department. It is likely that the incidence of WDTC will continue to rise in the short to medium term at least. Already excellent outcomes are unlikely to be significantly improved with an ever more aggressive approach to treatment. Opportunities to improve standards of care include identifying patient groups most likely to benefit from aggressive contemporary management and at the same time developing new therapeutic strategies. Efforts must also include attempts to identify those patients who will benefit from less invasive treatment, which would reduce the potential lifelong impact that complications of therapy can have, whilst maintaining oncological outcomes and allowing focusing of resources on those patients most likely to benefit. Our efforts in clinical care in future need to be focused to reducing mortality from thyroid cancer, and in the discovery of new treatment modalities, that will create a positive impact on patients with distant metastatic disease, for whom we have little to offer at this time.
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16. Sanders LE, Cady B. Differentiated thyroid cancer: reexamination of risk groups and outcome of treatment. Arch Surg. 1998;133(4):419-25. Epub 1998/05/23.
17. Hughes DT, Haymart MR, Miller BS, Gauger PG, Doherty GM. The most commonly occurring papillary thyroid cancer in the United States is now a microcarcinoma in a patient older than 45 years. Thyroid. 2011;21(3):231-6. Epub 2011/01/28.
18. Morris LG, Myssiorek D. Improved detection does not fully explain the rising incidence of well-differentiated thyroid cancer: a population-based analysis. Am J Surg. 2010;200(4):454-61. Epub 2010/06/22.
19. Tollefsen HR, Decosse JJ, Hutter RV. Papillary Carcinoma of the Thyroid. A Clinical and Pathological Study of 70 Fatal Cases. Cancer. 1964;17:1035-44. Epub 1964/08/01.
20. Cody HS, 3rd, Shah JP. Locally invasive, well-differentiated thyroid cancer. 22 years’ experience at Memorial Sloan-Kettering Cancer Center. Am J Surg. 1981;142(4):480-3. Epub 1981/10/01.
21. McConahey WM, Hay ID, Woolner LB, van Heerden JA, Taylor WF. Papillary thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome. Mayo Clin Proc. 1986;61(12):978-96. Epub 1986/12/01.
22. Nixon IJ, Ganly I, Patel SG, et al. Thyroid lobectomy for treatment of well differentiated intrathyroid malignancy. Surgery. 2011. Epub 2011/10/18.
23. Shah JP, Loree TR, Dharker D, Strong EW. Lobectomy versus total thyroidectomy for differentiated carcinoma of the thyroid: a matched-pair analysis. Am J Surg. 1993;166(4):331-5. Epub 1993/10/01.
24. Hassanain M, Wexler M. Conservative management of well-differentiated thyroid cancer. Can J Surg. 2010;53(2):109-18. Epub 2010/03/26.
25. Barney BM, Hitchcock YJ, Sharma P, Shrieve DC, Tward JD. Overall and cause-specific survival for patients undergoing lobectomy, near-total, or total thyroidectomy for differentiated thyroid cancer. Head Neck. 2011;33(5):645-9. Epub 2010/08/06.
26. Bilimoria KY, Bentrem DJ, Ko CY, et al. Extent of surgery affects survival for papillary thyroid cancer. Ann Surg. 2007;246(3):375-81; discussion 81-4. Epub 2007/08/25.
34
27. Cady B, Rossi R. An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery. 1988;104(6):947-53. Epub 1988/12/01.
28. Mazzaferri EL. Thyroid remnant 131I ablation for papillary and follicular thyroid carcinoma. Thyroid. 1997;7(2):265-71. Epub 1997/04/01.
29. Carcangiu ML, Zampi G, Rosai J. Poorly differentiated (“insular”) thyroid carcinoma. A reinterpretation of Langhans’ “wuchernde Struma”. Am J Surg Pathol. 1984;8(9):655-68. Epub 1984/09/01.
30. Shah JP, Loree TR, Dharker D, Strong EW, Begg C, Vlamis V. Prognostic factors in differentiated carcinoma of the thyroid gland. Am J Surg. 1992;164(6):658-61. Epub 1992/12/01.
31. Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery. 1993;114(6):1050-7; discuss.
Table 1. GAMES Risk of Cause Specific Mortality Stratification
Risk Level Patient Factor Tumor Factor
Low Risk Age <45y Papillary Ca M0 No ETE Size <4cm
High Risk Age >45y Follicular Ca / Hurthle Cell Ca M1 ETE Size >4cm
Low Risk Case Low Risk Patient Low Risk Tumor
Intermediate Risk Case
Low Risk Patient High Risk Tumor
High Risk Patient Low Risk Tumor
High Risk Case High Risk Patient High Risk Tumor
Chapter 2 Changing Trends in W
ell Differentiated Thyroid Carcinom
a Over Eight D
ecades
35
Table 2. Descriptive Statistics of Whole Group and Stratification by Decade
Variable Group 1932-1945 1946-1955 1956-1965 1966-1975 1976-1985 1986-1995 1996-2005 p Value
Size of Tumor <4 cm 2228 (88%) 96.9% 0.000 Referent
>4 cm 310 (12%) 79.3% 3.713 2.521-5.469 <0.001
Micro Carcinoma <1 cm 599 (21%) 98.2% 0.000
>1 cm 2198 (79%) 92.0%
Any Extrathyroid Extension Absent 2198 (79%) 94.9% 0.000 Referent
Present 598 (21%) 85.8% 2.892 1.916-4.266 <0.001
pN Stage N0 1719 (62%) 94.0% 0.292
N1 1078 (38%) 92.1%
M Stage M0 2709 (97%) 95.1% 0.000 Referent
M1 88 (3%) 41.7% 11.307 7.452-17.157 <0.001
Risk Group Low 1030 (37%) 99.4% 0.000
Intermediate 1102 (39%) 96.0%
High 664 (24%) 78.8%
38
Figure 1. Patient numbers managed by decade
Chapter 2 Changing Trends in W
ell Differentiated Thyroid Carcinom
a Over Eight D
ecades
39
Figure 2. Percentage of patients undergoing total thyroidectomy, receiving RRA and disease specific survival by decade
Chapter 3
Disease-related death in patients who were considered free of
macroscopic disease after initial treatment of well-differentiated
thyroid carcinoma
Iain J Nixon, MD, Ian Ganly, MD, PhD, Frank L. Palmer, BA, Monica Whitcher, BA, Snehal G Patel, MD,
R. Michael Tuttle, MD, Ashok Shaha, MD, Jatin P Shah, MD.
Thyroid 2011; 21(5): 501-504
42
Abstract
BackgroundDeath from well differentiated thyroid cancer (WDTC) is rare, and over the past century there has been a trend away from local recurrence as the primary cause of death. The objective of our study was to report the cause of death from thyroid cancer in patients with well differentiated thyroid cancer treated with curative intent with surgery +/- adjuvant radioactive iodine .
MethodsAn institutional database of 1811 patients with WDTC treated surgically for WDTC between 1986-2005 was analyzed to identify 165 (9.4%) who had died. Case records were studied to determine the cause of death in each patient.
ResultsOf the 165 deaths, 17 (10%) patients were confirmed to have died of thyroid cancer and6 (4%) died of an unknown cause but had thyroid cancer present at the time of last follow up. The remaining 142 (86%) died from other causes and were considered free of thyroid cancer at their last follow up. We therefore identified only 23 cause specific deaths from the entire cohort (1.3%). Of the 17 patients known to have died of thyroid cancer, all had distant recurrence. Ninety-four percent had pulmonary metastases. Of these, 47% also had bony metastasis at the time of death. Two patients had recurrent disease in the neck at the time of death, but both also had distant disease. Of the 6 patients (4%) who died of unknown causes but had thyroid cancer at last follow up, 4 (67%) had distant disease alone, 1 (17%) had local and regional recurrence and 1 had local and distant recurrence at last follow up.
ConclusionFollowing successful resection of WDTC, we report a low disease specific death rate (1.3%). In contrast to earlier reports, death due to central compartment disease in this recent series is very rare, with metastatic disease accounting for almost all fatalities.
Chapter 3 Rapid im
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43
Introduction
Well differentiated thyroid cancer (WDTC) is curable in the majority of patients. Several large series reporting on cause-specific mortality for thyroid cancers at 10 years suggest that less than 5% of patients die of disease(1-3). Despite an increasing incidence in the USA, the mortality rate from thyroid cancer is unchanged at around 0.5 deaths per 100, 000 persons(4). The long clinical course of patients with thyroid cancer, combined with low death rates makes analysis of the specific cause of death in patients who die of thyroid cancer difficult. The objective of our study was therefore to analyze the cause of death from WDTC in patients treated with curative intent with surgery +/- adjuvant radioiodine (RAI). In this select group of patients, all patients were considered free of disease after initial treatment. The study had the advantage of analyzing a large series of patients (1811 patients with WDTC) treated at a single institution with a long period of follow up.
44
Materials and Methods
After approval from the institutional review board, and with waiver of consent, the records of a consecutive series of 1811 patients who had surgery for WDTC between 1986 and 2005 at Memorial Sloan Kettering Cancer Center (MSKCC) were reviewed. This database comprised patients who had their primary surgical treatment at MSKCC; patients who underwent initial treatment elsewhere prior to referral were excluded from the database. Of the 1811 patients, 59 patients were excluded- 2 (0.1%) due to unresectable disease at the time of surgery and a further 57 (3%) due to the presence of distant metastases at presentation. This left 1752 patients available for analysis. All these patients had no evidence of macroscopic disease in the thyroid bed or cervical lymph node basins after surgery at MSKCC. In addition, there was no evidence of distant disease on post-surgical imaging in any of these patients. As such, all patients were considered free of disease after initial treatment at MSKCC. The median follow up for this group was 99.5 months (range 4-290 months). From this group we identified 165 (9.4%) patients who have died. This represents the cohort available for study in our report.All patients were treated according to our institutional approach to the management of well differentiated thyroid cancer(5). An individualized approach to treatment is adopted, with low risk patients that present with uni-nodular disease being offered thyroid lobectomy and high risk patients or those with nodular disease in the contralateral lobe being offered total thyroidectomy. Lymph node dissection in the central and lateral compartment is undertaken only in cases where pre-operative investigations or intra-operative assessment raises the suspicion or confirms metastatic disease. Radio-iodine ablation is offered to high risk patients following total thyroidectomy. Post treatment follow up is provided by both the endocrine and surgical departments, and includes clinical examination, ultrasound scanning and thyroglobulin measurement. Throughout the study period, treatment and follow up patterns evolved with increased use of ultrasound and thyroglobulin measurement in particular.Data were collected on patient demographics, surgical details including extent of both thyroid and neck surgery, and the presence of gross extra-thyroid extension or residual disease on completion of surgery. Pathological details included tumor histology, size, and presence of extra-thyroid spread, number of nodes collected and number of positive nodes, size of positive nodes and presence of extracapsular spread. Post-operative details included use of radioiodine or external beam radiotherapy. Outcomes data included local, regional or distant recurrence. The presence of local or regional recurrence following treatment was based on cytological or histopathological evidence in disease. Distant disease was determined by imaging studies including radioiodine uptake scans and CT scans, or cytological and histopathological evidence where available. Biochemical evidence of recurrence was not accepted as definitive, as the use of thyroglobulin measurement was not routine practice during the early part of the study period. The date of death and cause of death was ascertained from hospital records, death certificates and updated from the social security death index.
Chapter 3 Rapid im
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45
Results
The entire cohort of 1752 patient had a median age of 46 years. Twenty seven percent were male and 73% were female. The T stage distribution at presentation was T1 48%, T2 19%, T3 27% and T4 6%. Sixty eight percent were considered N0 following initial treatment, 16% N1a and 16% N1b. Therefore in our thyroid cancer database one third of patients had advanced T stage at presentation and one third had positive neck disease. Of 165 patients who died, the median age at presentation of patients was 65 years (range 24-94 years). Sixty eight patients (41%) were male and 97 (59%) were female. 142 (86%) patients died of unknown cause and were considered free of thyroid cancer at their last follow up (Table 1). Twenty three patients died directly from thyroid cancer or had recurrent thyroid cancer at the time of death. Of these 23 patients, 17 (10%) patients were confirmed to have died of thyroid cancer and 6 (4%) died of an unknown cause but with thyroid cancer present at the time of last follow up- these patients are considered to have died from disease. The median survival of these 23 patients was 66 months (range 4-273 months) and the disease specific mortality was 1.3% (23/1752). The patient and tumor characteristics of these 23 patients are shown in Table 1.
Deaths Due to Thyroid Cancer (n=17)The majority of patients were over 45 years of age and had papillary thyroid carcinoma. Over 2 thirds of these patients had T3 or T4 disease at presentation and following histological analysis of excised tissues, 64% were classified as pN1b. All patients were considered either intermediate risk (29%) or high risk (71%).The site of disease at the time of death was recorded for all 17 patients. Ninety-four percent of patients had pulmonary metastases at the time of death, 47% had bone metastasis (in addition to pulmonary metastases in all but one case), and two patients (12% ) had recurrent disease in the central or lateral neck as well as pulmonary metastases at the time of death (Table 2). Thirteen patients (76%) had disease at multiple sites when they died, 3 patients (18%) had only pulmonary metastases and 1 patient (6%) had only bone metastases. No patients had disease in the neck alone when they died of disease.The cause of death in 15 patients (88%) was distant metastases alone. The remaining 2 patients (12%) died of aspiration pneumonia. Both patients had central neck recurrence associated with vocal cord palsy, and both also had pulmonary metastases (Table 3). Of the 2 patients with central neck disease and pulmonary metastases, one had unresectable local recurrence for which he received external beam radiation. This patient went on to develop a trachesophageal fistula causing a fatal aspiration pneumonia. The second patient developed a nodal central neck mass which caused paralysis of the recurrent laryngeal nerve, contributing to fatal aspiration pneumonia.
46
Deaths with Evidence of Thyroid Cancer at Last Follow Up (n=6)Six patients (4%) died of unknown causes but had evidence of recurrent thyroid cancer at the time of last follow up. Three patients (50%) had pulmonary metastases alone, one (17%) had bone metastases alone, one patient had central and lateral neck recurrence, and the remaining patient had both central neck recurrence and pulmonary metastases. Therefore 5 of the 6 patients had distant metastases at the time of death. (Table 2).
Chapter 3 Rapid im
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47
Discussion
Cause specific mortality from thyroid cancer is rare. Difficulties in analyzing this group of patients arise from the slow progression of disease requiring long periods of follow up. Despite this, a number of groups have reported on the cause of death in patients managed over the past century (6-13). In all of these studies, death due to local recurrence was an important cause. For example, Tollefsen in 1964 reported on 70 patients who died of thyroid cancer from a cohort of 700 patients(6). Of these 70 patients, 40% died of locoregional recurrence, 52% died of distant metastases and 7% a combination of local and distant recurrence. Similar results were reported by Smith et al,1988 at the Mayo clinic. In the Mayo study, there were 56 lethal papillary carcinomas from 859 patients (7%) who underwent primary treatment in the Mayo Clinic(10). Thirty six percent of these patients died of locally recurrent disease, 35% died of causes relating to pulmonary metastases. Since then, a series of more recent studies have shown a continued trend away from local recurrence and towards distant metastases as the cause of death from WDTC(10-13). The most recent series reported by Ronga et al in 2002, described 83 deaths from over 1900 patients (4%). In this series locally recurrent disease was present in 12% of cases, neck disease in 13% and pulmonary or bone metastases were present in 49%(13).Other than the Mayo group(10), previous authors have not been specific in their inclusion criteria for studies. Most groups report on consecutive series of patients treated in a single institution without mention of pre-operative staging, or previous treatment for thyroid cancer. It is likely that these series include patients who presented with recurrent disease, distant metastases and unresectable lesions that have undergone initial management prior to presentation within that institution. The objective of our study was to determine the cause of death in the select group of patients with WDTC who have been treated with curative intent with surgery and post-operative RAI and are considered to be free of disease after initial treatment. In this group of patients, we report an extremely low death rate due to thyroid cancer; only 23 patients from 1752 (1.3%). This figure reflects improvements in thyroid cancer management. However, it also reflects the selection criteria in the cohort of patients which we have studied. The most striking observation is the extremely low rate of neck recurrence as cause of death. Rather, the cause of death in the majority of patients is distant metastatic disease. In our selected surgical series, 23 patients died of disease, and all were considered either intermediate or high risk(5). At the time of death, only 4 (17%) had disease present in the central neck and in only two (9%) was central neck disease known to have contributed to the cause of death. In contrast to earlier series, distant metastases were present in all but one of the cause specific fatalities. This change in the pattern of recurrent disease is partly due to a more aggressive surgical approach to WDTC in our institution. This involves total thyroidectomy but also resection of all surrounding tissues with gross invasion including strap muscles, recurrent laryngeal nerve, trachea, esophagus and larynx in order to achieve no gross residual disease. Increased use of radioiodine in recent years in comparison to historical reports may also have contributed to this shift in disease recurrence.
48
In conclusion, following compete surgical resection of WDTC and adjuvant radioactive iodine treatment; we report a low disease specific death rate of 1.3%. In contrast to earlier reports, death due to central compartment disease is very rare. Metastatic lung disease accounts for almost all fatalities.
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References1. Mazzaferri EL, Jhiang SM 1994 Long-term impact
of initial surgical and medical therapy on papillary and follicular thyroid cancer. The American journal of medicine 97:418-428.
2. Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS 1993 Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 114:1050-1057; discussion 1057-1058.
3. Lin HW, Bhattacharyya N 2009 Survival impact of treatment options for papillary microcarcinoma of the thyroid. Laryngoscope 119:1983-1987.
4. Davies L, Welch HG 2006 Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA 295:2164-2167.
5. Shaha AR, Shah JP, Loree TR 1996 Risk group stratification and prognostic factors in papillary carcinoma of thyroid. Ann Surg Oncol 3:534-538.
6. Tollefsen HR, Decosse JJ, Hutter RV 1964 Papillary Carcinoma of the Thyroid. A Clinical and Pathological Study of 70 Fatal Cases. Cancer 17:1035-1044.
7. Silliphant WM, Klinck GH, Levitin MS 1964 Thyroid Carcinoma and Death.A Clinicopathological Study
of 193 Autopsies. Cancer 17:513-525.8. Ibanez ML, Russell WO, Albores-Saavedra J,
Lampertico P, White EC, Clark RL 1966 Thyroid carcinoma--biologic behavior and mortality. Postmortem findings in 42 cases, including 27 in which the disease was fatal. Cancer 19:1039-1052.
9. Silverberg SG, Hutter RV, Foote FW, Jr. 1970 Fatal carcinoma of the thyroid: histology, metastases, and causes of death. Cancer 25:792-802.
10. Smith SA, Hay ID, Goellner JR, Ryan JJ, McConahey WM 1988 Mortality from papillary thyroid carcinoma. A case-control study of 56 lethal cases. Cancer 62:1381-1388.
11. Kobayashi T, Asakawa H, Tamaki Y, Umeshita K, Monden M 1996 Fatal differentiated thyroid cancer. J Surg Oncol 62:123-127.
12. Kitamura Y, Shimizu K, Nagahama M, Sugino K, Ozaki O, Mimura T, Ito K, Tanaka S 1999 Immediate causes of death in thyroid carcinoma: clinicopathological analysis of 161 fatal cases. J Clin Endocrinol Metab 84:4043-4049.
13. Ronga G, Filesi M, Montesano T, Melacrinis FF, Di Nicola A, Ventroni G, Antonaci A, Vestri AR 2002 Death from differentiated thyroid carcinoma: retrospective study of a 40-year investigation. Cancer Biother Radiopharm 17:507-514.
**
50
Table 1. Patient and tumor characteristics of all deaths. Patients are stratified into those who died of thyroid cancer and those who died of other causes but with thyroid cancer at last follow up.
VariableDied of Thyroid Cancer
(n=17)n (%)
Died With Thyroid Cancer (n=6)n (%)
<45y 3 (18%) 0
>45y 14 (82%) 6 (100%)
Male 10 (59%) 2 (33%)
Female 7 (41%) 4 (67%)
Papillary Ca 15 (88%) 6 (100%)
Follicular Ca 1 (6%) 0
Hurthle Cell Ca 1 (6%) 0
T1 3 (18%) 0
T2 1 (6%) 0
T3 7 (41%) 2 (33%)
T4 6 (35%) 4 (67%)
N0 3 (18%) 0 (0%)
N1a 3 (18%) 2 (33%)
N1b 11 (64%) 4 (67%)
Low 0 (0%) 0 (0%)
Intermediate 5 (29%) 0
High 12 (71%) 6 (100%)
Thyroid Lobectomy 2 (12%) 1 (17%)
Total Thyroidectomy 15 (88%) 5 (83%)
No RAI 4 (24%) 2 (33%)
RAI 13 (76%) 4 (67 %)
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Table 2. Site of disease at the time of death in patients who died of thyroid cancer or had thyroid cancer at time of last follow up.
Site of Disease at Time of Death (n=17)Died of Thyroid cancer
(n=17)n (%)
Died with Thyroid Cancer (n=6)n (%)
Central Neck 2 (12%) 2 (33%)
Lateral Neck 2 (12%) 1 (17%)
Pulmonary Metastases 16 (94%) 5 (83%)
Bony Metastases 8 (47%) 1 (17%)
Brain Metastases 3 (18%) 0 (0%)
Hepatic Metastases 3 (18%) 0 (0%)
Mediastinal Metastases 1 (6%) 0 (0%)
Abdominal Metastases 1 (6%) 0 (0%)
Table 3. Cause of death in patients who died of thyroid cancer (n=17)
Specific Cause of Death n (%)
Pulmonary Metastases 6 (35%)
Brain Metastases 2 (12%)
Cachexia 7 (41%)
Distant Metastases and Local Recurrence 2 (12%)
Chapter 4
Thyroid Isthmusectomy for Well Differentiated Thyroid Cancer
Iain J Nixon, MD, Frank L. Palmer, BA, Monica M Whitcher, BA, Ashok R Shaha, MD, Jatin P Shah, MD, Snehal G Patel, MD, Ian Ganly, MD, PhD
Ann Surg Oncol 2011; 18(3): 767-770
54
Abstract
BackgroundThe American Thyroid Association guidelines do not mention isthmusectomy as an appropriate procedure for thyroid cancer. Despite this, a small number of patients present with lesions isolated to the thyroid isthmus, which can be excised without exploring the trachesophageal grooves or total thyroidectomy. The aim of this study was to analyse outcomes in patients treated with isthmusectomy for small well differentiated thyroid cancer (WDTC) at our institution.
MethodsNineteen patients with WDTC managed by isthmusectomy were identified from a database of 1810 patients (1%) with WDTC managed by surgery in Memorial Sloan Kettering Cancer Center, between 1986-2005. Demographic, surgical, pathological and outcomes data were analyzed.
ResultsSix patients were male and 13 female. The median age was 46 years (range 28-83 years). All patients had a solitary nodule confined to the thyroid isthmus. The median size of lesion was 1cm (range 0.4-3cm). Eighteen patients had a pathologically T1 disease (pT1), 1 patient had a pT2 lesion. Two patients had papillary carcinoma detected in peri-thyroid lymph nodes (pN1a). There were no complications of recurrent laryngeal nerve palsy or hypocalcaemia. With a median follow up of 124 months (range 53-276), the 10 year disease specific survival was 100% and 100% local and regional 10 year recurrence free survival.
ConclusionOur results suggest that isthmusectomy alone may be sufficient treatment in selected patients with small WDTC limited to the isthmus. This procedure has the benefit of avoiding dissection of the recurrent laryngeal nerve and parathyroid glands thus limiting post operative complications.
et kinase activity and Wnt activity in colon cancer.
55
Introduction
The place of thyroid isthmusectomy in the management of thyroid cancer is unclear. Neither the current American Thyroid Association1 nor the British Thyroid Association guidelines2 mention isthmusectomy as an appropriate procedure in the setting of thyroid cancer. Despite this, a small number of patients will present with malignant disease isolated to the thyroid isthmus, which can be excised without exploring the trachesophageal grooves. This approach has the attraction of reducing the potential for damage to the recurrent laryngeal nerves and parathyroid glands, as well as reducing operating time. Of the few reports in the literature on thyroid isthmusectomy3-6, most series include only small numbers of malignant lesions. Of the malignant lesions, most patients were treated with completion thyroidectomy after isthmusectomy. The aim of our study was to analyse the outcomes of patients treated with thyroid isthmusectomy alone for localized well differentiated thyroid cancer over a 20 year period at our institution. This is the largest series reporting on the role of isthmusectomy alone in the management of thyroid cancer confined to the isthmus.
56
Methods and PatientsFollowing approval by the Institutional Review Board, nineteen patients with well differentiated thyroid cancer managed by thyroid isthmusectomy alone were identified from a database of 1810 patients (1%) with well differentiated thyroid cancer managed by surgery in Memorial Sloan Kettering Cancer Center, between 1986-2005. Patients who underwent initial treatment elsewhere prior to referral or those who were considered unresectable at the time of referral were excluded. Data was extracted from the electronic medical record and entered into an Excel spreadsheet for analysis. Data was collected on patient demographics, surgical details including extent of both thyroid and neck surgery, and the presence of gross extra-thyroid extension or residual disease on completion of surgery. Pathological details included tumor histology, size, and presence of extra-thyroid extension. Outcomes data included local, regional or distant recurrence. The presence of local or regional recurrence following treatment was based on cytological or histopathological evidence of disease. Distant disease was determined by imaging studies including radioiodine uptake scans and CT scans, or cytological and histopathological evidence where available. Biochemical evidence of recurrence was not accepted as definitive, as the use of thyroglobulin measurement was not routine practice during the early part of the study period, and may be difficult to interpret in the presence of normal thyroid lobes.Statistical analysis was performed using JMP statistical package (SAS Institute Inc. SAS Campus Drive, Cary, NC 27513). Survival outcomes were analyzed using the Kaplan-Meier method.
et kinase activity and Wnt activity in colon cancer.
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Results
The clinical and pathological characteristics are shown in Table 1.
Patient and Treatment CharacteristicsSix patients were male and 13 female. The median age was 46 years (range 28-83 years). All patients had a solitary nodule confined to the thyroid isthmus. Eighteen patients (95%) were T1 and 1 patient (5%) was T2. Eighteen patients (95%) were clinically N0 and 1 patient (5%) was clinically N1b. All patients were free of distant metastases. Nine patients (47%) were first diagnosed with malignancy on pre-operative fine needle aspiration (FNA), a further 3 patients (16%) were diagnosed at frozen section in the operating room. Seven patients (37%) were diagnosed on final histopathological analysis. The 1 patient with a palpable cervical lymph node had failed to respond to chemo-radiotherapy for an oropharyngeal cancer, and had a suspicious nodule in the thyroid isthmus on CT scan, which was positive for papillary carcinoma. The cervical node was found to contain squamous cell carcinoma on histopathological analysis. This patient had isthmusectomy and modified radical neck dissection. All remaining patients underwent thyroid isthmusectomy alone. No patients received post-operative radio-iodine treatment.
PathologyIn 18 patients (95%) the diagnosis was papillary carcinoma. The remaining 1 patient (5%) had follicular carcinoma. The median size of lesion was 1cm (range 0.4-3cm). Eighteen patients had a pathologically T1 disease (pT1), 1 patient had a pT2 lesion. Two patients had papillary carcinoma detected in peri-thyroid lymph nodes, making them pN1a. In two patients the surgical margin was microscopically positive. Two patients had microscopic extra thyroid extension noted on histopathology with no evidence of extension seen during surgery.Following surgical excision 8 patients (42%) were classified as low risk, 9 as intermediate (47%) and 2 were classified as high risk (11%) using the GAMES criteria.
OutcomesThere were no complications of recurrent laryngeal nerve palsy or hypocalcaemia. One patient had a wound hematoma managed at the bedside without return to the operating room.The median follow up was 124 months (range 53-276). During this time there were no disease specific deaths (10 year disease specific survival 100%). The 10 year overall survival was 94%, one patient died at 65 months of unrelated causes. There were no regional or distant recurrences. One patient had a papillary carcinoma removed from the right thyroid lobe at 124 months by uncomplicated completion thyroidectomy. That patient was a low risk female, with a 1cm tumor without extra thyroid extension. No patient with positive margins or microscopic extra thyroid extension had a local or regional recurrence.
58
Discussion
Outcomes for patients with well differentiated thyroid cancers are excellent with 20 year survival rates of around 90%7-10. Current guidelines do not support surgical management of thyroid cancer with procedures other than thyroid lobectomy, near-total and total thyroidectomy1,2. There are no specific guidelines for management of thyroid cancers confined to the thyroid isthmus. Although the majority of thyroid nodules present within the body of the lobes, a small minority of patients will present with disease limited to the isthmus11. Lesions of the thyroid isthmus occur in less than 10% of patients presenting with thyroid cancer, and may have a higher incidence of both multifocality and capsular invasion than cancers presenting in the lobes11. If, in this situation, the nodule is solitary, confined to the isthmus without evidence of extra glandular extension, the patient may be suitable for thyroid isthmusectomy or wide field isthmusectomy. Unlike excision of a thyroid lobe, isthmusectomy does not require exploration of the trachesophageal groove or formal identification of the recurrent laryngeal nerve, which may reduce risk to the parathyroid glands and the recurrent laryngeal nerve. Although thyroid isthmusectomy is a recognised surgical procedure, few groups have reported their experience with the procedure for thyroid cancer 3-6,12. In the majority of reports in which a cancer is found after isthmusectomy, completion thyroidectomy is normally performed. Perez-Ruiz et al report a series of 31 isthmusectomies including only 1 papillary carcinoma, who proceeded to completion thyroidectomy 1 week later4. Similarly, Skilbeck et al report their experience of 9 isthmusectomies for isolated isthmic lesions with indeterminate cytology5. Two of their patients were finally diagnosed with malignancy and both patients again proceeded to completion thyroidectomy. Maser et al report on 8 patients with benign or indeterminate cytology from an isthmic nodule. Three of their patients were diagnosed with malignancy on histopathology and all went on to completion thyroidectomy3. In Sugenoya et al’s report on 19 well differentiated thyroid isthmus malignancies, four patients were treated with isthmusectomy alone and all were alive with no evidence of recurrence 20 years following surgery. This finding prompted the authors to recommend isthmusectomy as an appropriate treatment for malignant lesions of the thyroid isthmus6.We advocate isthmusectomy for an isolated lesion of the thyroid isthmus without evidence of extraglandular spread on imaging or assessment in the operating room. Using these criteria only 19 of 1811 patients (1%) were deemed suitable for isthmusectomy between 1986 and 2005. All patients in this study had clinically apparent disease limited to the thyroid isthmus. In 1 patient suspected of having metastasis to the lateral neck, the metastatic malignancy was from an aerodigestive tract primary rather than from the thyroid. With a median follow up of over 10 years, disease specific survival and both regional and distant recurrence free survival in our group was 100%. One patient died of unrelated causes during the study period. One patient developed a papillary cancer in the residual thyroid tissue and underwent uneventful completion thyroidectomy over 10 years following initial surgery. We encountered no cases of hypocalcaemia or recurrent laryngeal nerve damage.
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Using our previously published risk stratification scheme, GAMES, 58% of patients were classified as intermediate or high risk. Despite this, our results suggest that in carefully selected patients, thyroid isthmusectomy can be effective treatment for well differentiated thyroid cancer. Thyroid isthmusectomy should be reserved for selected patients with a small thyroid tumor with no major extrathyroidal extension or adherence to the surrounding structures. It should be recognized that this is not a nodulectomy, it is an oncologic procedure with wide-field isthmusectomy which encompasses all gross tumor and a surrounding portion of normal thyroid tissue. Most of these patients are low or intermediate risk thyroid cancer patients who do not require postoperative radioactive iodine ablation. The preoperative ultrasound should be reviewed carefully to ensure there is no nodularity involving either lobe of the thyroid. Postoperative follow-up is generally clinical follow-up along with sonographic evaluation and thyroid function tests, etc. In our experience, this is a sound oncologic surgical procedure for small tumors involving the isthmus of the thyroid.
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Conclusion
Our results suggest that isthmusectomy alone may be sufficient treatment in selected patients with small, well differentiated cancer limited to the thyroid isthmus. This procedure has the added benefit of avoiding dissection of the recurrent laryngeal nerve and parathyroid glands thus limiting post-operative complications of hoarseness and hypocalcaemia.
S.L. Lee, S.J. Mandel, E.L. Mazzaferri, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid, 2009. 19(11): 1167-214.
2. Watkinson, J.C. The British Thyroid Association guidelines for the management of thyroid cancer in adults.Nucl Med Commun, 2004. 25(9): 897-900.
3. Maser, C., P. Donovan, and R. Udelsman. Thyroid isthmusectomy: a rarely used but simple, safe, and efficacious operation. J Am Coll Surg, 2007. 204(3): 512-4.
4. Perez-Ruiz, L., S. Ros-Lopez, M. Gudelis, J.A. Latasa-Gimeno, C. Artigas-Marco, and A. Pelayo-Salas. Isthmectomy: a conservative operation for solitary nodule of the thyroid isthmus. Acta Chir Belg, 2008. 108(6): 699-701.
5. Skilbeck, C., A. Leslie, and R. Simo. Thyroid isthmusectomy: a critical appraisal. J Laryngol Otol, 2007. 121(10): 986-9.
6. Sugenoya, A., K. Shingu, S. Kobayashi, H. Masuda, S. Takahashi, T. Shimizu, H. Onuma, et al. Surgical strategies for differentiated carcinoma of the thyroid isthmus. Head Neck, 1993. 15(2): 158-60.
7. Hay, I.D., E.J. Bergstralh, J.R. Goellner, J.R. Ebersold, and C.S. Grant. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery, 1993. 114(6): 1050-7; discussion 1057-8.
8. Mazzaferri, E.L. and S.M. Jhiang. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer.The American journal of medicine, 1994. 97(5): 418-428.
9. Lin, H.W. and N. Bhattacharyya. Survival impact of treatment options for papillary microcarcinoma of the thyroid. Laryngoscope, 2009. 119(10): 1983-7.
10. Shaha, A.R., J.P. Shah, and T.R. Loree. Risk group stratification and prognostic factors in papillary carcinoma of thyroid. Ann Surg Oncol, 1996. 3(6): 534-8.
11. Lee, Y.S., J.J. Jeong, K.H. Nam, W.Y. Chung, H.S. Chang, and C.S. Park. Papillary carcinoma located in the thyroid isthmus. World J Surg, 2010. 34(1): 36-9.
12. Saadi, H., P. Kleidermacher, and C. Esselstyn, Jr. Conservative management of patients with intrathyroidal well-differentiated follicular thyroid carcinoma. Surgery, 2001. 130(1): 30-5.
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Table 1. Clinical and pathological characteristics
Variables N (%)
Age
<45y 9 (47%)
>45y 10 (53%)
Gender
Male 6 (32%)
Female 13 (68%)
cN Stage
N0 18 (95%)
N1b 1 (5%)(Ultimately SCC)
M Stage
M0 19 (100%)
M1 0
Histology
Papillary Ca 18 (95%)
Follicular Ca 1 (5%)
Margins
Negative 17 (89%)
Positive 2 (11%)
pT Stage
T1 18 (95%)
T2 1 (5%)
Extra Thyroid Extension
None 17 (89%)
Microscopic 2 (11%)
pN Stage
N0 17 (89%)
N1a 2 (11%)
GAMES Criteria
Low 8 (42%)
Intermediate 9 (47%)
High 2 (11%)
GAMES is the method of risk stratification used in Memorial Sloan Kettering Cancer Center10
Chapter 5
Thyroid Lobectomy for Treatment of Well Differentiated
Intrathyroid Malignancy
Iain J Nixon MD, Ian Ganly, MD, PhD, Snehal G. Patel, MD, Frank L. Palmer, BA, Monica, M. Whitcher, BA, Robert M Tuttle MD, Ashok Shaha, MD, Jatin P Shah MD
Surgery 2012; 151(4): 571-579
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Abstract
BackgroundThere remains controversy over the type of surgery appropriate for T1T2N0 well differentiated thyroid cancers (WDTC). Current guidelines recommend total thyroidectomy for all but the smallest lesions, despite previous evidence from large institutions suggesting that lobectomy provides similar excellent results. The objective of this study was to report our experience of T1T2N0 WDTC managed by either thyroid lobectomy or total thyroidectomy.
MethodsEight hundred and eighty nine patients with pT1T2 intrathyroid cancers treated surgically between 1986 and 2005 were identified from a database of 1810 patients with WDTC. Total thyroidectomy was carried out in 528 (59%) and thyroid lobectomy in 361 (41%) patients. Overall survival (OS), disease specific survival (DSS) and recurrence free survival (RFS) were determined by the Kaplan Meier method. Factors predictive of outcome by univariate and multivariate analysis were determined using the log rank test and Cox proportional hazards method respectively.
ResultsWith a median follow up of 99 months the 10 year OS, DSS and RFS for all patients were 92%, 99% and 98% respectively. Univariate analysis showed no significant difference in OS by extent of surgical resection. Multivariate analysis showed that age over 45y and male gender were independent predictors for poorer OS, whereas T stage and type of surgery were not.Comparison of the thyroid lobectomy group and the total thyroidectomy group showed no difference in local recurrence (0% for both) or regional recurrence (0% versus 0.8%, p=0.96).
ConclusionPatients with pT1T2 N0 WDTC can be safely managed by thyroid lobectomy alone.
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Introduction
The incidence of thyroid cancer is rising(1, 2), in part due to detection of incidental thyroid cancer by the increased use of radiological imaging, such as ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) in medical practice(3). This increase is mainly in low risk intrathyroidal T1T2 tumors. This has resulted in a rise in the number of thyroidectomies carried out in the USA(1-3) in addition to an increased use of adjuvant radioactive iodine therapy (RAI). This increase in total thyroidectomy operations and use of RAI has created much controversy in recent times as many groups suggest low risk patients with unilateral intrathyroidal T1T2 tumors are being over treated. There is controversy as to whether or not such patients should be managed by thyroid lobectomy alone. Over the past decade, there are several reports in the literature which provide evidence supporting thyroid lobectomy as being equivalent to total thyroidectomy in terms of survival and recurrence(4-6). However, other studies by Loh et al(7) and Mazaferi et al(8) , have reported increased recurrence in those patients managed by thyroid lobectomy. Furthermore, a recent analysis of the Surveillance Epidemiology and End Results (SEER) database by Bilimoria et al(9) also suggested increased recurrence in lobectomy patients. Indeed, the Bilimoria data was taken into account when the American Thyroid Association (ATA) published the current ATA guidelines(10) recommending total thyroidectomy for all well differentiated thyroid cancers (WDTC) over 1cm. The ATA guidelines also suggest that thyroid lobectomy be considered only if disease is limited to the thyroid gland and under 1cm in a low risk patient. The Bilimoria study however has come under criticism and as a consequence the controversy on this issue remains unresolved. The objective of our study was therefore to revisit the issue of thyroid lobectomy by examining a more contemporary dataset of WDTC patients managed at Memorial Sloan Kettering Cancer Center (MSKCC) between the years 1986 to 2005.
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Methods
Following approval by the Institutional Review Board, 889 patients (49%) who had thyroid surgery for T1T2 N0 cancer (using the 2009 AJCC staging manual(11);T1:< 2cms, T2: 2-4cms) between 1986 and 2005, were identified from our institutional database of 1810 patients treated for WDTC at MSKCC. Patients who underwent initial treatment elsewhere prior to referral or those who were considered unresectable at the time of referral were excluded.Data collected included patient demographics, surgical details including extent of thyroid surgery, the presence of gross extra-thyroid extension or residual disease on completion of surgery. Histopathological details recorded included tumor histology, size and presence of extra-thyroid extension. Post-operative treatment details recorded were use of radioactive iodine. Based on clinical and pathology features, patients were classified into low, intermediate and high risk for death according to patient and tumor factors (12). Patients were classified as low risk of death if they presented before the age of 45 years and high risk if over 45 years. Tumors were classified as high risk if staged as pT3/4, if they presented with evidence of distant metastases, or if found to be high grade. A case is classified as low risk if a low risk patient presents with a low risk tumor and high risk if a high risk patient presents with a high risk tumor. Intermediate risk patients are classified as either low risk patients with a high risk tumor, or high risk patients with a low risk tumor. All patients with distant metastases or extra thyroid extension were excluded from this analysis. Patients who present with early intrathyroid WDTC, including all patients in this cohort, are not routinely investigated pre-operatively for the presence of distant metastases. Therefore, the only patients classified as high risk were patients over the age of 45 years with follicular or Hurthle cell carcinoma, based upon capsule and vascular invasion. In the absence of nodular disease in the contralateral lobe, the recommended treatment for cases considered low risk in our institution is thyroid lobectomy, reserving total thyroidectomy for high risk cases, and those with contra lateral nodularity. Intermediate risk cases are dealt with on a case-by-case basis following informed consent.In the cohort of patients from 1986 to 2005, preoperative ultrasound was not used for assessment of the central and lateral neck nodes. The assessment of the lateral neck nodes was based on preoperative clinical examination and if enlarged,ultrasound carried out. Assessment of the central compartment for all patients was intraoperative by palpation of the central compartment lymph nodes at the time of thyroidectomy. If no palpable nodes were present in the central compartment, then no central compartment neck dissection was done. If nodes were palpable, then a central compartment neck dissection was carried out. All patients with pathological evidence of metastatic central or lateral neck disease were excluded from this analysis. Therefore, all patients in our study were N0.Outcomes data included local, regional and distant recurrence as well as details of death. Local and regional recurrence were determined by clinical examination supplemented with ultrasound. During the time period of the study from 1986 to 2005, routine use of serum thyroglobulin was not available and this was not used in follow up to assess recurrence. Similarly, annual ultrasound was not introduced into our practice until 2005. The presence of
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local or regional recurrence following treatment was based on cytological or histopathological evidence of disease. Local recurrence was defined as recurrent disease located in the operated thyroid bed confirmed by cytological sampling or histological analysis following further surgery; the development of contralateral disease following lobectomy was classified as a second primary tumor rather than a local recurrence. Regional recurrence was defined as recurrent disease found in cervical lymph nodes, confirmed again by cytological sampling or histopathology following subsequent surgical resection. Distant disease was determined by imaging studies including radioiodine uptake scans, CT scans, Positron Emission Tomography (PET) scans, or cytological and histopathological evidence where available. Disease specific outcomes were calculated using the date of last follow up with the treating surgeon or endocrinologist at MSKCC. Overall survival was calculated using records received from the patient or any physician involved in the patient’s care, then cross checked against the social security index. Details of death were determined from death certificates and hospital records where available. All patients who had evidence of active disease at the time of last follow up and died during follow up were considered to have died of disease. The median follow up for the entire patient cohort was 99 months ( range 13-291 months). Outcomes data were therefore calculated at 10 years as this represented the time point at which approximately 50% of patients were still available for follow up and 50% of patients had either been lost to follow up or died. Statistical analysis was carried out using JMP statistical package (SAS Institute Inc. SAS Campus Drive, Cary, NC 27513) and SPSS (IBM Company Headquarters, 233 S. Wacker Drive, 11th Floor, Chicago, Illinois 60606). Variables were compared within groups using Pearson’s chi squared test. Survival outcomes were analyzed using the Kaplan-Meier method. Univariate analysis was carried out by the log rank test and multivariate analysis by Cox proportional hazards method.
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Results
A) Entire GroupThe male to female ratio was 1:5 (188 men and 701 women). The median age was 46 years (range 4-91). Eight hundred patients (90%) had papillary carcinoma, 52 patients (6%) had follicular carcinoma and 37 (4%) had Hurthle cell carcinoma. Nineteen patients were classified as having tall cell variant of papillary carcinoma. Although tall cell variant does have a slightly poorer outcome(12), we still consider this in the WDTC category. Patient, tumor and treatment details are shown in Table 1. In our group of patients, total thyroidectomy was carried out in 507 (57%) and thyroid lobectomy in 382 (43%) patients. No patients had residual gross disease on completion of the procedure. Twenty-one of the 382 patients (6%) treated with initial lobectomy had immediate completion thyroidectomy. The indications for completion thyroidectomy were patient preference in 8 cases (38%), large size of primary lesion in 4 (19%) and multicentric disease in 3 (14%). Positive margins, previous exposure to radiation and the later disproven suspicious of distant metastses were the reason for completion in 1 case each (5%). For the remaining 3 cases, the reason for completion surgery was not recorded. These patients were considered as total thyroidectomy for the purposes of outcomes analysis, leaving 528 patients (59%) coded as total thyroidectomy and 361 (41%) patients coded as thyroid lobectomy. Six-hundred and thirty-seven patients were pathologically pT1 (83%) and 252 patients were pT2 (17%). All patients had no evidence of cervical or distant metastases. Sixty-seven patients (8%) had central neck dissection, 3 had lateral neck dissection only (<0.5%) and a further 4 had central and lateral neck dissections (<0.5%) due to clinical or radiological suspicion of neck metastases. However, none of these neck dissection specimens were found to contain metastatic thyroid carcinoma. Of the 7 neck dissections that included lateral neck levels, 3 were performed when thyroid cancer co-existed with another malignancy in the lateral neck nodes (1 breast Ca, 1 malignant melanoma and 1 squamous cell carcinoma). Two had needle biopsy evidence of metastatic malignancy on outside cytology, but following lateral neck dissection, no evidence of thyroid cancer was detected on histopathological analysis. One patient had clinically suspicious nodes on intra-operative examination, however the nodes were histopathologically free of disease and in 1 patient, treated in 1993, no further pre-operative details were available. Our current departmental policy to minimize the number of neck dissection specimens that do not contain disease includes ultrasound analysis of the central and lateral nodal compartments with ultrasound guided fine needle aspiration cytology of suspicious nodes. No patients had distant metastatic disease on pre-operative staging or post-operative RAI scan. Using the MSKCC risk group stratification system, three hundred and seventy-four patients (42%) were classified as being at low risk of death, 457 (51%) as intermediate risk and 58 (7%) as high risk (due to presentation with follicular or Hurthle cell carcinoma over the age of 45 years) in accordance with our previously published risk group stratification(13). With a median follow up of 99 months (range 13-291 months) the overall survival (OS),
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disease specific survival (DSS) and recurrence free survival (RFS) at 10 years were 92%, 99% and 98% respectively (Figure 1). There were 68 deaths, but only 1 was due to thyroid cancer. There were no local recurrences in the operated thyroid bed, 6 neck recurrences and 5 distant recurrences. The 10 year local recurrence free survival (LRFS), regional recurrence free survival (RRFS) and DSS were 100%, 99% and 99% respectively. Fourteen patients (4%) who underwent thyroid lobectomy had a completion thyroidectomy at a later date due to the development of contralateral nodules. The median time to completion thyroidectomy was 69.5 months (range 6-181 months). Of these, 7 patients (50%) had a malignancy of the same histological subtype in the contralateral lobe, 2 patients (14%) had a malignancy of different histological subtype and 5 patients (36%) had benign disease. Factors predictive of overall survival by univariate analysis are shown in Table 2. Age over 45 years, male gender and stratification as intermediate/high risk patients were predictive for worse outcome. Histology and type of surgery were not significant. Multivariate analysis of male gender, age >45, T stage and surgical procedure showed that age over 45y and male gender remained independent predictors of worse overall survival (hazard ratio 3.9 and 1.9 respectively), whereas both T stage and type of surgery were not. Risk groups were not used in the multivariate analysis as they are based on groups of individual variables.
B) Lobectomy and Total Thyroidectomy GroupsPatient characteristics, tumor characteristics and outcomes stratified by type of thyroid surgery are shown in Table 3. The median age of patients was 44 years (range 4-91 years) in the lobectomy group and 48 years (range 11-85 years) in the total thyroidectomy group. As expected the lobectomy cohort had more patients under the age of 45 years (54% versus 44%, p=0.002), fewer patient with papillary cancer (86% versus 93%, p<0.001) and fewer patients treated with radioactive iodine (0.3% versus 37%, p<0.001) compared to the total thyroidectomy patients.No significant differences in 10yr OS or DSS were found between thyroid lobectomy and total thyroidectomy patients (93% vs. 92%, p=0.64 and 100% vs. 98.5% p=0.246 respectively). Table 4 shows the 10 year overall survival rates for lobectomy and total thyroidectomy groups stratified by pT stage, pathological tumor size and risk group. The 10 year survival for thyroid lobectomy and total thyroidectomy were 92% versus 89% for T1 lesions (p=0.78) and 96% versus 94% for T2 lesions (p=0.62). When we stratify overall survival by tumor size the 10 year survival for patients with tumors under 1cm, 1-2cm, 2-3cm and 3-4cms was not significantly different in patients treated with lobectomy versus total thyroidectomy ( 1cm:89% versus 93% (p=0.27); 1-2cms: 94% versus 87% (p=0.11); 2-3cms: 98% versus 94% (p=0.93) and 3-4cms: 94% versus 92% (p=0.53) respectively. Figure 2 shows Kaplan Meier plot of overall survival by surgical treatment, stratified by pT size (less than 1cm and over 1cm).The 10 year overall survival for the low, intermediate and high risk groups was also not statistically different for thyroid lobectomy versus total thyroidectomy. Low risk, 97% versus 96% (p=0.58); intermediate risk, 90% versus 85% (p=0.36) and high risk, 90% versus 96% (p=0.35) respectively.
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For recurrence, we also found no significant difference in 10 year outcomes between thyroid lobectomy and total thyroidectomy. Local recurrence was 0% in both groups and regional recurrence was 0% versus 0.8% respectively, p=0.96. The 10 year distant recurrence rate in patients treated with thyroid lobectomy was 0% versus 3% in the total thyroidectomy group. This difference may be due to the fact more patients were over 45 years of age in the total thyroidectomy cohort. In comparison with the group of patients treated with initial lobectomy, the fourteen patients who required completion thyroidectomy at a later date were similar in terms of age, gender distribution, pT stage, provision of post-operative RAI and risk group (Table 5). Only one of the 14 patients had positive margins reported on histopathology.
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Discussion
The surgical management of WDTC is based upon reports from retrospective data from both single institutional datasets and national cancer registries. It is well recognized that prospective, randomized controlled trials of therapy for thyroid cancer are impractical. The excellent survival outcome of patients would require large sample sizes and long follow up to detect the small therapeutic advantages (14).Management of WDTC confined to the gland (T1T2) forms a significant part of surgical thyroid oncological practice accounting for almost 50% of our practice. The approach to surgical management of such low risk patients within our institution is to offer thyroid lobectomy as an alternative to total thyroidectomy in properly selected low or intermediate risk patients. We currently recommend total thyroidectomy for patients with nodules in the contralateral lobe (over 0.5cm detected clinically or on ultrasound), clinically significant lymph node metastasis, gross extra thyroidal extension and evidence of distant metastasis. Increased availability of high definition pre-operative ultrasound has resulted in increased detection of contralateral nodules and this has resulted in a higher rate of total thyroidectomy carried out in recent years compared to the past (rising from 30% to around 75% over the duration of this study). Despite this trend, 362/884 (41%) of patients in this cohort were treated with thyroid lobectomy. Our management strategy is based upon evidence from our institution(4), as well as others(5, 15-17), suggesting that there is no survival improvement by total thyroidectomy over lobectomy in properly selected, low risk patients. In our first report in 1993 on a matched pair analysis of thyroid lobectomy versus total thyroidectomy patients, we reported similar outcome for low risk and intermediate risk patients with tumors up to 4cm in size(4). Since then, other authors have reported similar results. For example, Sanders et al(6) reviewed their experience of over 1000 patients and found no difference in survival or recurrence rates according to extent of surgical resection when patients who underwent biopsy alone were removed from the unilateral surgery group. A similar outcome was reported by the Mayo group; over 6 decades of management of papillary thyroid cancers at the Mayo clinic, there was no reduction in survival or increased recurrence in the lobectomy patients despite a trend towards more aggressive surgical management and increased rates of post-operative RAI during the study period(18). These results were confirmed on later analysis on risk stratified patients at the same institution(5). However, in contrast, there are other studies which have reported poorer outcome when patients are treated with thyroid lobectomy. For example, Loh et al(7) reviewed their experience of 700 patients treated at their institution over a 25 year period. They found that lobectomy or sub-total thyroidectomy resulted in increased rates of both recurrence and death compared with near total or total thyroidectomy. This analysis however included patients treated for recurrence, when treated primarily outside their institution, making interpretation of exact surgical details less accurate. They also excluded patients treated with T1N0M0 disease, who constitute a large part of oncological thyroid surgical
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practice. Mazaferri et al(8) reviewed the outcomes of over 1000 patients treated at multiple institutions and found improved recurrence and survival rates in patients who underwent more extensive surgery. This effect was found to have an independent effect on survival on multivariate analysis. This group also chose to exclude patients with lesions under 1.5 cms from the analysis. A more recent study by Bilimoria(9) reporting on a large series of patients in the SEER database reported increased recurrence rates in thyroid lobectomy patients for all size of tumors compared to total thyroidectomy patients. Indeed, this study was considered when the ATA published recommendation 26 on the extent of surgery recommended for intra-thyroid lesions over 1cm in size(10). Based on this evidence, the ATA guidelines now recommend total thyroidectomy for all lesions over 1cm and lobectomy only for lesions under 1cm in a low risk patient, which is also the recommendation of the consensus statement from the European Thyroid Cancer Taskforce(19). However, the study by Bilimoria has come under much scrutiny and has been criticized for lacking inclusion of surgical details, pathology reports and recurrence data. For example, there is no record of completeness of resection, extra-thyroid extension, or histological subtypes of papillary cancer within the group. The loco-regional recurrences were not classified into recurrence in the operated thyroid bed, the contralateral virgin lobe or recurrence in cervical lymph nodes. Other criticisms are that the data is from multiple centers, and there is no physician review of medical records. Due to this controversy and the recent evidence showing that the rise in thyroid cancer is largely in low risk patients with intrathyroidal T1T2 tumors(1, 2), we sought to revisit this topic by analyzing a more recent contemporary dataset of patients from a database of 1810 WDTC patients managed at MSKCC between the years 1985 to 2005. In contrast to the Bilimoria study, our data includes accurate surgical, pathological and outcomes data. Identification and therefore exclusion of patients with extra-thyroid spread may account for the different conclusions reached between our study and that of Bilimoria. We also included all patients with intrathyroid disease, including those with pT1 lesions.We report that for intraglandular cancers, the rates of death due to disease are below 1% over a period of 10 years in patients treated with either thyroid lobectomy or total thyroidectomy. Although for overall survival, advanced age and male gender were predictors of poor outcome in this group of patients, neither T stage, nor surgical procedure was significant on multivariate analysis. Our data shows that the extent of surgical resection did not have any impact on overall or disease specific survival. In addition, there was no difference in either local or regional recurrence in patients with intraglandular cancer under 4cms in size. We found no difference in tumors less than 1cm, in keeping with the advice in the ATA guidelines(10). In addition, despite recommendation 26 of ATA guideline(10), we found no difference in outcomes for patients with tumors over 1cm, as a whole group, or when stratified by 1-2cm, 2-3cm and 3-4cms. We did see a slightly higher rate of distant recurrence in the total thyroidectomy group; the reasons for this are unclear, but were present despite lower rates of follicular carcinoma, lower rates of post-operative RAI and longer median follow up in the lobectomy group. This may relate to the higher
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median age in the total thyroidectomy group (48 years vs. 44 years).Unlike other groups, we considered the development of malignancy in a residual thyroid lobe following contralateral thyroid lobectomy as a contralateral recurrence rather than local recurrence. In our study, 21 of the 382 patients treated with initial lobectomy had immediate completion thyroidectomy based on the results of the surgical pathology. Of the remaining 361 patients treated by thyroid lobectomy alone, only 14 patients (4%) required a completion thyroidectomy at a later date; 7 patients (2%) developed a malignancy of the same histological subtype in the contralateral lobe, 2 patients (0.7%) developed a malignancy of different histological subtype in the contralateral lobe and a further 5 patients (1.3%) had the contralateral lobe removed for benign nodules. Therefore, only 9 patients (2.7%) developed a malignancy in the contralateral lobe. This low figure is good evidence to justify the policy of lobectomy adopted in these patients. In our study we did not consider the development of the same histological subtype of cancer in the contralateral lobe as a local recurrence. However, even if we do, this would give a local recurrence rate of only 2%. Table 5 shows a comparison of patient and tumor characteristics for the lobectomy patients who did not require completion versus those who went on to have completion at a later date. We found no statistically significant difference between the groups. Therefore, there were no factors which could predict the need for completion thyroidectomy. From our data we can conclude that after thyroid lobectomy there is approximately a 6% chance of needing an immediate completion thyroidectomy but only a 4% chance of requiring completion at a later date. In addition to similar outcome, thyroid lobectomy has also been shown to result in lower complication rates in large retrospective studies. The aim of our study was to report on survival outcomes following treatment rather than surgical complication rates and as such we do not report these figures within this manuscript. However, a recent study based on the Nationwide Inpatient Sample of surgeries performed in the USA 1999 to 2003, reported significantly higher rates of hypocalcaemia (10.6% v 3.5%) unilateral vocal cord palsy (1.1% v 0.6%) and bilateral vocal cord palsy (0.4% v 0.1%) following total thyroidectomy rather than thyroid lobectomy performed for malignancy(20). An Italian study of 14,934 patients from 42 experienced endocrine surgery units reported symptomatic hypocalcaemia rates of 14% following total thyroidectomy compared with 0.4% following thyroid lobectomy. They went on to report higher rates of both unilateral and bilateral recurrent laryngeal nerve palsy, tracheotomy, hemorrhage and wound infection in the group treated with total thyroidectomy(21). Experts in thyroid surgery report low rates of complications following both lobectomy and total thyroidectomy(22). However, the studies above report significant additional morbidity related to total thyroidectomy. This conflicting evidence supports the observation that the risks of thyroid surgery are related to the surgeon’s experience of the procedure. Our data does have limitations however. Like all retrospective studies, we cannot exclude selection bias resulting from physician and patient preference. There is a trend towards total thyroidectomy in recent years due to increasing use of ultrasound, which led to
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longer median follow up in the patients treated with thyroid lobectomy. The thyroid lobectomy group was younger, which would be expected to result in improved outcomes. In contrast, the lobectomy group contained less papillary cancers and less patients receiving radioactive iodine, both of which may be expected to have a negative effect on outcomes. Despite these limitations, we can still conclude from our data that thyroid lobectomy gives similar excellent outcomes for all low risk and intermediate risk patients with intraglandular WDTC compared to total thyroidectomy. Based on these results, thyroid lobectomy is a safe alternative to total thyroidectomy for T1T2 N0 WDTC. Our current practice at MSKCC for T1T2 N0 well differentiated thyroid cancer is to have an informed discussion with the patient about the options of thyroid lobectomy versus total thyroidectomy. If the thyroid mass is a single nodule less than 4cm with no contralateral nodules in the opposite lobe, and no evidence of extrathyroidal extension, patients are given the option of thyroid lobectomy. We do not recommend central compartment neck dissection unless there are palpable nodes at the time of surgery or abnormal nodes are detected by a preoperative ultrasound.
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14. Wong JB, Kaplan MM, Meyer KB, Pauker SG. Ablative radioactive iodine therapy for apparently localized thyroid carcinoma.A decision analytic perspective. Endocrinol Metab Clin North Am 1990;19:741-60.
15. Hassanain M, Wexler M. Conservative management of well-differentiated thyroid cancer. Can J Surg 2010;53:109-18.
16. Barney BM, Hitchcock YJ, Sharma P, Shrieve DC, Tward JD. Overall and cause-specific survival for patients undergoing lobectomy, near-total, or total thyroidectomy for differentiated thyroid cancer. Head Neck 2010.
17. Chow TL, Choi CY, Lam SH. Disease control of differentiated thyroid carcinomas by hemithyroidectomy. Singapore Med J 2010;51:311-4.
18. Hay ID, Thompson GB, Grant CS, Bergstralh EJ, Dvorak CE, Gorman CA, et al. Papillary thyroid carcinoma managed at the Mayo Clinic during six decades (1940-1999): temporal trends in initial therapy and long-term outcome in 2444 consecutively treated patients. World J Surg 2002;26:879-85.
19. Pacini F, Schlumberger M, Dralle H, Elisei R, Smit JW, Wiersinga W. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 2006;154:787-803.
20. Zerey M, Prabhu AS, Newcomb WL, Lincourt AE, Kercher KW, Heniford BT. Short-term outcomes after unilateral versus complete thyroidectomy for malignancy: a national perspective. Am Surg 2009;75:20-4.
21. Rosato L, Avenia N, Bernante P, De Palma M, Gulino G, Nasi PG, et al. Complications of thyroid surgery: analysis of a multicentric study on 14,934 patients operated on in Italy over 5 years. World J Surg 2004;28:271-6.
22. Clark OH, Levin K, Zeng QH, Greenspan FS, Siperstein A. Thyroid cancer: the case for total thyroidectomy. Eur J Cancer Clin Oncol 1988;24:305-13.
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Table 1. Patient, tumor and treatment characteristics
Table 3. Patient characteristics, tumor characteristics and outcomes stratified by surgical group
VariableLobectomyn= 361 (%)
Total Thyroidectomy n= 528(%) p Value
Age
<45y 195 (54%) 230 (44%) 0.002
>45y 166 (46%) 298 (56%)
Gender
Male 82 (23%) 106 (20%) 0.345
Female 279 (77%) 422 (80%)
pT Stage
pT1 249 (69%) 388 (73%) 0.143
pT2 112 (31%) 140 (27%)
RAI
No 360 (99.7%) 333 (63%) <0.001
Yes 1 (0.3%) 195 (37%)
Pathology
Papillary Ca 310 (86%) 490 (93%) <0.001
Follicular Ca 36 (10%) 16 (3%)
Hurthle Cell Ca 15 (4%) 22 (4%)
10 yr. Local Recurrence 0 (0%) 0 (0%) 1
10 yr. Neck Recurrence 0 (0%) 5 (0.8%) 0.96
10 yr. Distant Recurrence 0 (0%) 5 (3%) 0.05
10 yr. Deaths of Any Cause 18 (7%) 27 (9%) 0.64
10 yr. Disease Specific Deaths 0 (0%) 1 (1.5%) 0.246
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Table 4. 10 year overall survival for lobectomy and total thyroidectomy groups stratified by pT, pT size and risk group.
Variable N (%)Overall 10 year Survival
p valueLobectomy Total Thyroidectomy
p T Stage
T1 632 (71%) 92% 89% 0.78
T2 252 (29%) 96% 94% 0.62
p T Size (cms)
<1 354 (40%) 89% 93% 0.27
1-2 283 (32%) 94% 87% 0.11
2-3 164 (18%) 98% 94% 0.93
3-4 88 (10%) 94% 92% 0.53
Risk Group
Low 374 (42%) 97% 96% 0.58
Intermediate 457 (51%) 90% 85% 0.36
High 58 (7%) 90% 96% 0.35
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Table 5. Characteristics of Group Treated with Lobectomy Stratified by Need for Further Surgery
VariableNo FurtherSurgery
n= 347 (%)Further Surgery
n= 14 (%)p Value
Age
<45y 186 (54%) 9 (64%) 0.759
>45y 161 (46%) 5 (36%)
Gender
Male 79 (23%) 3 (21%) 0.907
Female 268 (77%) 11 (79%)
pT Stage
pT1 240 (69%) 9 (64%) 0.700
pT2 107 (31%) 5 (36%)
RAI
No 346 (99%) 14 (100%) NS
Yes 1 (1%) 0 (0%)
Pathology
Papillary Ca 299 (86%) 13 (93%) 0.904
Follicular Ca 35 (10%) 0 (0%)
Hurthle Cell Ca 13 (4%) 1 (7%)
Risk Group
Low Risk 162 (47%) 6 (43%) 0.945
Intermediate Risk 151 (43%) 8 (57%)
High Risk 34 (10%) 0 (0%)
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Figure 1. Overall survival, disease specific survival and recurrence free survival of the entire group.
82
Figure 2. Overall Survival by Surgical Treatment, Stratified by pT size (less than 1cm and over 1cm).
Chapter 6
The Impact of Microscopic Extra Thyroid Extension on Outcome
in Patients with Clinical T1 and T2 Well Differentiated Thyroid Cancer
Iain J. Nixon, MD, Ian Ganly, MD, PhD, Snehal Patel, MD, Frank L. Palmer, BA, Monica M. Whitcher, BA, R.M. Tuttle, MD, Ashok R. Shaha, MD, Jatin P. Shah, MD
Surgery 2011; 150(6):1242-1249
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Abstract
ObjectiveThe objective of our study was to report the impact of microscopic thyroid extension (ETE) on outcome in patients with clinical T1 or T2 (cT1/cT2) well differentiated thyroid cancer (WDTC). We also wanted to determine the effect of extent of surgery and adjuvant radioactive iodine (RAI) on outcome in patients with microscopic ETE.
Patients and MethodsFrom an institutional database of 1810 previously untreated patients with WDTC, we identified 984 (54%) who had thyroid surgery for cT1/T2 N0 disease. Survival and recurrence outcomes were analyzed using the Kaplan-Meier method. Univariate analysis was carried out by the log rank test and multivariate analysis by cox regression.
ResultsWith a median follow up of 98 months (range6-291) the 10 year overall survival (OS) was 92%, disease specific survival (DSS) 99% and recurrence free survival (RFS) 98% within the entire group . The 10 year local recurrence free survival (LRFS), regional recurrence free survival (RRFS) and distant recurrence free survival (DRFS) were 100%, 99% and 99% respectively. 115 patients had microscopic ETE and were therefore upstaged to pathological T3 stage (pT3). No significant difference in 10 years DSS or RFS was found (99% versus 100%, p=0.733 and 98% versus 95%, p=0.188 respectively) on comparison of the pT1/pT2 cohort and the pT3 cohort.In the pT3 cohort there were no disease specific deaths and only 3 recurrences (all in the lateral neck). Other than male gender, no other variable, including extent of thyroid surgery and administration of RAI, were significant predictors of outcome on univariate or multivariable analysis
ConclusionOutcomes in patients with well differentiated clinically intrathyroid cancers stage T1T2N0 are excellent and not significantly affected by the finding of microscopic ETE on histopathological analysis. The extent of surgical resection and administration of post operative RAI in patients with microscopic ETE does not have an impact on survival or recurrence.
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Introduction
Both the recent American Thyroid Association1 (ATA) and British Thyroid Association Guidelines2require surgeons to base treatment decisions on operating room findings. Recommendation 26 from the 2009 ATA guidelines, for example, supports thyroid lobectomy for treatment of small intrathyroid lesions in low risk patients, and suggests total thyroidectomy for all other types of lesion. The problem for surgeons is that they must make decisions based upon the macroscopic appearance of the thyroid gland. Histopathological assessment may identify microscopic extension which would upstage a clinically T1 or T23 lesion to a pathologically T3 lesion. The objective of our study was to report the impact of microscopic extrathyroid extension (ETE) on outcome in patients with clinical stage T1 or T2 WDTC. We also wanted to determine whether or not the extent of surgery (lobectomy versus total thyroidectomy) and RAI had any impact on outcome in patients with microscopic ETE (pT3 ).
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Patients and Methods
Following approval by the Institutional Review Board, 984 (54%) patients who had thyroid surgery for intraglandular clinically T1N0 or T2N0 thyroid cancers were identified from our institutional database of 1810 patients treated for WDTC at Memorial Sloan Kettering Cancer Center between 1985-2005. Patients who underwent initial treatment elsewhere prior to referral or those who were considered unresectable at the time of referral were excluded. Data was extracted from the electronic medical record and entered into an Excel spreadsheet for analysis. Data collected included patient demographics and surgical details including extent of thyroid surgery. Histopathological details included tumor histology, size and presence of microscopic ETE. Details on adjuvant RAI were also recorded. Outcomes data included local, regional and distant recurrence as well as details of death. The presence of local or regional recurrence following treatment was based on cytological or histopathological evidence of disease. Distant disease was determined by imaging studies including radioiodine uptake scans, CT scans, PET scans, or cytological and histopathological evidence where available. Biochemical evidence of recurrence was not accepted as definitive, as the use of thyroglobulin measurement was not routine practice during the early part of the study period; in addition thyroglobulin values in lobectomy patients would not be of any value. Patient, tumor and treatment details are shown in Table 1.The median age of the group was 47 years (range 4-91 years). The male to female ratio was 1:4. Eight hundred and ninety-one patients (91%) had papillary carcinoma, 52 (5%) had follicular carcinoma and 41 (4%) had Hurthle Cell carcinoma. Three hundred and seventy-six patients (38%) had thyroid lobectomy, 574 (58%) had total thyroidectomy, 16 (2%) had isthmusectomy and 18 (2%) had subtotal thyroidectomy. Twenty-two patients who had initial thyroid lobectomy had a completion thyroidectomy and were considered as having total thyroidectomy for the purposes of this analysis. Eight hundred and sixty-nine patients (88%) had no extension on histopathological analysis (pT1/pT2), whereas 115 (12%) were pathologically upstaged to pT3 due to the presence of microscopic ETE. Seventy-six (11%) cT1 and 39 (14%) cT2 lesions were upstaged to pT3.Statistical analysis was carried out using JMP statistical package (SAS Institute Inc. SAS Campus Drive, Cary, NC 27513) and SPSS (IBM Company Headquarters, 233 S. Wacker Drive, 11th Floor, Chicago, Illinois 60606). Variables were compared within groups using Pearson’s chi squared test. Survival outcomes were analyzed using the Kaplan-Meier method. Univariate analysis was carried out by the log rank test and multivariate analysis by cox regression.
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Results
A) Entire GroupWith a median follow up of 98 months (range6-291) the 10 year overall survival (OS) was 92%, disease specific survival (DSS) 99% and recurrence free survival (RFS) 98% respectively. No patient had local recurrence, 8 had regional and 5 had distant recurrence. There were 73 deaths, only one of which was due to disease (at 101 months). The 10 year local recurrence free survival (LRFS), regional recurrence free survival (RRFS) and distant recurrence free survival (DRFS) were 100%, 99% and 99% respectively.Factors predictive of overall survival by univariate analysis are shown in Table 2. Age over 45 years at the time of thyroid surgery was the only factor predictive of worse outcome. This remained significant on multivariate analysis. Factors predictive of regional recurrence free survival by univariate analysis are shown in Table 3. Microscopic extension was the only factor predictive of worse outcome (p=0.032), although on multivariate analysis the significance of this result was less convincing (p=0.052). Of 115 patients with microscopic ETE (pT3), patients with micro carcinoma (pT size 1cm or less) had a rate of ETE of only 6% (Table 4). Those with tumors 1-2cms, 2-3cms and 3-4cms had similar rates ETE (16.4%, 15.3% and 11.7% respectively).
B) Comparison of pT3 (microscopic extension) and pT1/2 CohortsPatient characteristics and tumor characteristics stratified by microscopic extension are shown in Table 5. Compared to the pT1/pT2 group, the pT3 group had more patients over the age of 45 years (66% versus 52%, p=0.004), were more likely to receive post operative RAI (57% versus 21%, p<0.001) and were more likely to have total thyroidectomy (75% versus 56%, p=0.002).The survival statistics for the 2 cohorts stratified by microscopic extension are shown in Table 6. No significant difference in 10 year OS or DSS was found between the pT1/pT2 and pT3 groups (93% versus 88%, p=0.129 and 99% versus 100%, p=0.733 respectively). There was no significant difference in outcome between the pT1/ pT2 and pT3 groups in terms of local or distant recurrence free survival at 10 years (100% versus 100%. P=1 and 99% versus 100%, p=0.389 respectively). A significant difference was found between the intrathyroid and pT3 groups in terms of 10 year regional recurrence free survival (99% versus 95%, p=0.032).
C) The Impact of Extent of Treatment On Patients With Microscopic Extension (pT3)Patients with microscopic ETE were analyzed to determine factors predictive of outcome within this group. The characteristics of this group and 10 year recurrence free survival figures, with univariate and multivariable analyses are shown in Table 7.Of the 115 patients, the median age was 53 years (range 26-85) with a male to female ratio of 1:4. Twenty-six patients (23%) had thyroid lobectomy, with only one patient (4%) receiving post operative RAI. The remaining 86 patients (77%) had total thyroidectomy, of whom 63 (73%) also received post operative RAI. There were no disease specific deaths and only 3 recurrences within this group, all of which were in the lateral cervical lymph nodes. All 3 patients who had
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neck recurrence were treated with total thyroidectomy and post operative RAI.Univariate analysis of 10 year recurrence free survival identified male gender as a significant predictor of worse outcome (79% versus 99%, p=0.028). This was not significant on multivariate analysis. No othervariable including extent of thyroid surgery or treatment with adjuvant RAI were significant predictors of outcome on univariate or multivariable analysis. In addition, in patients who had total thyroidectomy (n=86), univariate analysis showed no significant difference in RFS between those having RAI and those who did not (100% versus 90%, p=0.290).
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Discussion
Well differentiated thyroid cancer is a disease with a high cure rate and following appropriate treatment most patients can expect excellent outcomes4-12. Long term follow up is required to detect differences in outcomes which has made prospective randomized controlled trials impractical13. Current treatment recommendations are therefore based upon data from retrospective analyses of either institutional experience or national databases. In keeping with previous studies, we report excellent outcomes for patients considered to have well differentiated, clinically intrathyroid lesions (cT1/cT2), with a DSS at 10 years of 99% and LRFS, RRFS and DRFS of 100%, 99% and 99% respectively. Extra thyroid extension of thyroid cancer has been recognized as a factor predictive of poor outcome by many groups7-10, 12, 14. However, more recent analyses have suggested that microscopic ETE is of less significance than gross extension, particularly in younger patients11, 15-17.This sub-classification of ETE has been recognized by the ATA. In their recent guidleines1, patients were classified as low risk if, amongst other factors, their lesion was intrathyroid, intermediate risk if the lesion extended microscopically and high risk if there was macroscopic extension. Despite this recognition, the guideline recommends total thyroidectomy for all patients with ETE following a biopsy diagnostic for malignancy. In the current study, 984 (54%) of 1810 patients were thought to have clinical T1T2N0 lesions during surgery. Of these 984, 115 (14%) were upstaged to a pathological T3 on the basis of microscopic ETE following thyroid surgery. Although lesions of 1cm or less had a rate of extra thyroid extension of only 6%, those lesions between 1 and 4cms had similar rates of extrathyroid extension independent of size (11.7-16.4%)Patients with extra thyroid extension were more likely to be older, to receive post operative RAI and to undergo total thyroidectomy. Age over 45 years was the only independent predictor of overall survival on multivariate analysis. We have shown that for lesions considered intraglandular following surgical resection, microscopic ETE had no impact on OS, DSS, LRFS or DRFS. We did find a statistically significant difference in neck recurrence free survival between the 2 cohorts ( 99% versus 95%, p=0.031 for pT1/T2 versus pT3 lesions). Those patients with microscopic ETE had a regional recurrence rate of 5% at 10 years compared with 1% for those without. Although this difference was statistically significant it is questionable whether or not this is a meaningful clinical difference as such a small change in regional recurrence at 10 years which does not translate in to a survival advantage is unlikely to change the treatment choices of a disease management team. Despite the minimal impact that microscopic extension has on outcome, the current ATA guidelines recommend to perform total thyroidectomy and consider RAI for any lesion which is not confined to the thyroid gland. The clinician therefore may face three problematic post operative scenarios. The first follows a biopsy suggesting a low risk, well differentiated malignancy which appears to be clinically intrathyroid at surgery. If lobectomy is performed and the histopathological analysis of the specimen reveals microscopic ETE, the surgeon may consider advising completion thyroidectomy. The second scenario follows a biopsy which is
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equivocal for malignancy. Thyroid lobectomy may be performed for diagnostic and treatment purposes. If in this case the histopathological analysis confirms well differentiated thyroid cancer, and also identifies microscopic ETE, again the surgeon may consider further surgery. The third scenario is after total or completion thyroidectomy and pathology shows microscopic ETE, whether or not RAI should be given.In order to address these clinical problems we analyzed the group with ETE in more detail. There were no disease specific deaths and only 3 recurrences. The recurrences were all in the lateral cervical lymph nodes.Eighty-six of these patients had total thyroidectomy (75%), of which 63 (73%) also received post operative RAI. Twenty-six patients had thyroid lobectomy (23%), 2 patient had subtotal thyroidectomy (1.5%) and 1 patient had thyroid isthmusectomy (0.5%). We found that the extent of thyroid surgery did not affect outcome (10 year RFS of 100% versus 93% for thyroid lobectomy and total thyroidectomy respectively, p=0.766) which is potentially more significant given that a higher percentage of those patients who underwent total thyroidectomy also received post operative RAI in comparison with the thyroid lobectomy group (73% versus 4%). In addition, patients not treated with RAI did not have poorer outcome or increased recurrence compared with the RAI group. The impact of adjuvant RAI in our cohort of pT3 patients is marginal at best.The current study has the potential bias associated with retrospective analyses. The patients with ETE were older than those without, which would be expected to result in worse outcomes. They were also more likely to undergo total thyroidectomy and receive post operative RAI than the group without extension, which may be expected to improve their outcome. There may have been factors which were not recorded that led clinicians to consider the lesions treated with total thyroidectomy as higher risk, resulting in higher rates of distant metastases. The group treated with lobectomy was younger which would be expected to lead to better outcomes, and there was a trend towards total thyroidectomy in the later years, as modern ultrasound identified more contralateral nodularity than clinical examination used earlier in the study period. Despite these limitations, our data suggests that pathological upstaging of a well differentiated, clinically T1 or T2 thyroid cancer without regional or distant metastases has no impact on survival. All patients do well, with only 1 disease specific death recorded in the group as a whole . Pathological microscopic ETE had a marginal effect on regional recurrence on univariate analysis, which was not significant on multivariate analysis. Microscopic extension had no impact on all other measures of outcome. We also found that thyroid lobectomy in comparison with total thyroidectomy did not result in worse outcome for patients with microscopic ETE in terms of survival or recurrence, suggesting that a report of microscopic ETE should not automatically prompt completion thyroidectomy. In addition, patients with microscopic ETE who did not have RAI did not have increased rates of recurrence.In conclusion, outcomes in patients thought to have well differentiated clinically intrathyroid cancers (cT1/cT2) are excellent and not significantly affected by the discovery of microscopic extra thyroid extension on histopathological analysis. Irrespective of the presence or absence of microscopic extra thyroid extension, the extent of surgical resection in these low risk lesions does not have an impact on survival or recurrence.
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References
1. Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. Nov 2009;19(11):1167-1214.
2. Association BT. Guidelines for the Management of Thyroid Cancer (Second Edition). In: Physicians RCo, ed. 2 ed. Great Britain: The Lavenham Press, Suffolk; 2007:92.
4. Lin HW, Bhattacharyya N. Survival impact of treatment options for papillary microcarcinoma of the thyroid. Laryngoscope. Oct 2009;119(10):1983-1987.
5. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. The American journal of medicine. 1994;97(5):418-428.
6. Saadi H, Kleidermacher P, Esselstyn C, Jr. Conservative management of patients with intrathyroidal well-differentiated follicular thyroid carcinoma. Surgery. Jul 2001;130(1):30-35.
7. Sugitani I, Toda K, Yamamoto N, Sakamoto A, Fujimoto Y. Re-Evaluation of Histopathological Factors Affecting Prognosis of Differentiated Thyroid Carcinoma in an Iodine-Sufficient Country. World J Surg. Dec 1 2009.
8. Cady B, Rossi R. An expanded view of risk-group definition in differentiated thyroid carcinoma.Surgery. Dec 1988;104(6):947-953.
9. McConahey WM, Hay ID, Woolner LB, van Heerden JA, Taylor WF. Papillary thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome. Mayo Clin Proc. Dec 1986;61(12):978-996.
10. Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery. Dec 1993;114(6):1050-1057; discussion 1057-1058.
11. Sherman SI, Brierley JD, Sperling M, et al. Prospective multicenter study of thyrois]carcinoma treatment: initial analysis of staging and outcome. National Thyroid Cancer Treatment Cooperative Study Registry Group. Cancer. Sep 1 1998;83(5):1012-1021.
12. Shaha AR, Shah JP, Loree TR. Risk group stratification and prognostic factors in papillary carcinoma of thyroid. Ann Surg Oncol. Nov 1996;3(6):534-538.
13. Wong JB, Kaplan MM, Meyer KB, Pauker SG. Ablative radioactive iodine therapy for apparently localized thyroid carcinoma.A decision analytic perspective. Endocrinol Metab Clin North Am. Sep 1990;19(3):741-760.
14. Shaha AR, Shah JP, Loree TR. Patterns of failure in differentiated carcinoma of the thyroid based on risk groups. Head Neck. Jan 1998;20(1):26-30.
15. Andersen PE, Kinsella J, Loree TR, Shaha AR, Shah JP. Differentiated carcinoma of the thyroid with extrathyroidal extension. Am J Surg. Nov 1995;170(5):467-470.
16. Ito Y, Tomoda C, Uruno T, et al. Prognostic significance of extrathyroid extension of papillary thyroid carcinoma: massive but not minimal extension affects the relapse-free survival. World J Surg. May 2006;30(5):780-786.
17. Ito Y, Tomoda C, Uruno T, et al. Minimal extrathyroid extension does not affect the relapse-free survival of patients with papillary thyroid carcinoma measuring 4 cm or less over the age of 45 years. Surg Today. 2006;36(1):12-18.
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Table 1: Characteristics of whole group
Variable (n=984) N (%)
Age
<45y 457 (46%)
>45y 527 (54%)
Gender
Male 208 (21%)
Female 776 (79%)
cT Stage
T1 707 (72%)
T2 277 (28%)
Surgery
Lobectomy 376 (38%)
Total Thyroidectomy (22 completed) 574 (58%)
Isthmusectomy 16 (2%)
Subtotal Thyroidectomy 18 (2%)
Pathology
Papillary Ca 891 (91%)
Follicular Ca 52 (5%)
Hurthle Cell Ca 41 (4%)
Extension
None 869 (88%)
Microscopic 115 (12%)
pT Stage
T1 631 (64%)
T2 238 (24%)
T3 115 (12%)
RAI
No 733 (74%)
Yes 251 (26%)
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Table 2: Factors Predictive of Overall Free Survival in the Whole Group
Table 7. Factors predictive of recurrence in patients with microscopic extrathyroidal extension.
Variable (n=115) n (%)10 Year Recurrence
Free SurvivalUnivariate
p ValueMultivariate
p Value
Age
<45y 39 (34%) 100% 0.252 N/A
>45y 76 (66%) 93%
Gender
Female 91 (79%) 99% 0.028 Referent
Male 24 (21%) 79% NS
cT Stage
T1 76(66%) 98% 0.323 N/A
T2 39 (34%) 91%
RAI
No 50 (43%) 100% 0.106 Referent
Yes 65 (57%) 90% NS
Surgery
Lobectomy 26 (23%) 100% 0.766 N/A
Total Thyroidectomy 86 (75%) 93%
Isthmusectomy 1 (1%) 100%
Subtotal Thyroidectomy 2 (1%) 100%
Pathology
Papillary Ca 106 (92%) 95% 0.907 N/A
Follicular Ca 4 (4%) 100%
Hurthle Cell Ca 5 (4%) 100%
RAI in Total Thyroidectomy (n=86)
No 23 (37%) 100% 0.290 N/A
Yes 63 (73%) 90%
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Figure 1. Effect of surgery on 10 year recurrence free survival for pT3 patients (total thyroidectomy versus lobectomy n=115)
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Figure 2. Effect of RAI on 10 year recurrence free survival in pT3 patients having undergone total thyroidectomy (n=86)
Chapter 7
Observation of Clinically Negative Central Compartment Lymph
Nodes in Papillary Thyroid Carcinoma
Iain J. Nixon MBChB, Ian Ganly MD,PhD, Snehal G. Patel MD, Luc G. Morris MD, Frank L. Palmer BA, Dorothy Thomas BA,
R. Michael Tuttle MD, Jatin P. Shah MD,PhD1, Ashok R. Shaha MD
Surgery 2013; in press
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Abstract
IntroductionThe role of propyhlactic central neck dissection (CND) in the management of papillary thyroid cancer (PTC) is controversial. We report our experience of an observational approach to the cN0 neck in PTC.
Methods1129 patients with PTC, who had total thyroidectomy between 1986-2005 were reviewed. 470 patients were pN1, 384 had benign nodes removed (pN0) and the remaining 275 had no nodes removed (pNx). The pNx group formed the cohort for this study.
ResultsWith a median follow-up of 70 months the 10year disease specific survival was 100%. Four patients had evidence of radioactive iodine (RAI) uptake on scans performed during follow-up without diagnostic cytology. All subsequently received RAI and are considered disease-free. Three patients had biopsy proven lateral-neck recurrence and underwent neck dissection. 1 patient developed a low-level thyroglobulin suspicious for recurrence. 1 patient has a sub-centimeter level-VI node suspicious for recurrence which has been observed. Therefore, the rate of structural recurrence in the central neck was 0.4% (1/275) and the rate of reoperation on the central neck was 0%.
ConclusionOur results suggest that properly selected patients can safely be managed with observation of the central neck rather than prophylactic CND, which has a higher complication rate.
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Introduction
Papillary thyroid cancer (PTC) metastasizes often and early (1-3). However unlike most human malignancies , spread of disease to regional lymph nodes is generally not associated with poor outcome (4). However, in older patients, such regional disease predicts both recurrence and survival (5, 6). Around 20-30% of patients with PTC will present with clinically palpable nodal disease (7, 8). Such patients require total thyroidectomy and appropriate neck dissection. In contrast, occult metastasis is much more common, particularly to the central neck (9). The incidence of occult metastases has been reported to be approximately 40% (9). The impact of occult metastases on outcome is unclear. As such, there is considerable controversy about the benefit of elective central compartment neck dissection in the cN0 central neck.
Clearly, there is no evidence that elective CND results in improved survival. However, proponents of the procedure argue that removal of occult disease may reduce post operative thyroglobulin (Tg) levels (10), allow improved selection of patients for adjuvant therapy (11) and reduce recurrence rates or need for reoperation (12). On the other hand, those who do not support elective CND cite low rates of identifiable persistent or recurrent central compartment disease during short term follow up of such patients (13). In addition, in those patients who do recur, after an initial central compartment elective dissection, disease is found in areas of the central compartment which are not normally dissected in the elective procedure (14). The long term outcome of observation of the central neck in cN0 patients is unknown. The American Thyroid Association (ATA) recently considered the feasibility of a prospective study to address this question (15), and calculated that over 5000 patients would have to be recruited, making such a trial impractical.
Our institutional approach has been to perform therapeutic CND only when disease is suspected based on pre-operative examination and imaging and intra-operative evaluation of the central neck. The aim of this study is to report the long-term outcomes of a large cohort of cN0 patients with PTC who underwent total thyroidectomy and post-operative observation of the central neck, in order to determine the rates of recurrence and reoperation in these patients.
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Patients and Methods
Following approval by the Institutional Review Board, we analyzed patients with papillary thyroid carcinoma undergoing total thyroidectomy. From an institutional database of 1810 consecutive patients who underwent surgery for differentiated thyroid cancer in MSKCC, 62 were excluded with non-papillary histology, 44 had distant metastases at presentation and 575 had less than total thyroidectomy. Therefore, we identified 1129 consecutive patients with PTC, who were considered free of distant metastases and had total thyroidectomy for resectable disease between 1986 and 2005.
The whole group was stratified by nodal status. 470 patients (42%) had pathological nodal metastases (pN1), 384 (34%) had nodes removed without metastases (pN0) and the remaining 275 patients (24%) had no nodal tissue removed (Nx). Twenty-two percent of our pN0 cohort and 76% of the pN1 cohort had neck dissection, whereas he remaining patients had nodal tissue removed without formal neck dissection. The surgical details were extracted from the operative report. The pathological details were extracted from the pathology report. The group of patients who had nodes removed without formal neck dissection consists both of patients who had nodal tissue excised inadvertently as part of the total thyroidectomy, and also those who had node sampling during the procedure. In an attempt to avoid ambiguity in terms of lymph node removal, only those patients who did not undergo neck dissection, and had no nodes removed during surgery (Nx group) and so had no sampling of the central neck nodes were chosen as the study cohort.Data collected included patient demographics and surgical details including the presence of gross extra-thyroid extension. Histopathological details recorded included tumor histology, primary tumor size and presence of extra-thyroid extension. Post-operative treatment details recorded included use of RAI and post-operative structural and functional imaging.
In the cohort of patients from 1986 to 2005, ultrasound was not routinely used for pre-operative assessment of the central or lateral compartment lymph nodes. The assessment of the lateral neck nodes was based on preoperative clinical examination. Assessment of the central compartment for all patients was by intraoperative evaluation and palpation of the lymph nodes at the time of thyroidectomy. If no suspicious nodes were present in the central compartment, then no elective central compartment neck dissection was done. If suspicious nodes were noted, then a central compartment neck dissection was carried out. Frozen section of the lymph nodes was generously used. Post operative thyroid stimulating hormone (TSH) suppression is practiced for all patients, aiming for a level of between 0.1-0.5mcUnits/ml.
Outcomes data included local, regional and distant recurrence as well as details of death. In order to encompass all potential events, local, regional and distant recurrences were determined by clinical examination, ultrasound, radioiodine scan or biochemical assay with or without cytological confirmation. Local recurrence was considered as disease suspected
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or proven in the thyroid bed. Regional recurrence included disease suspected or proven in the regional lymphatics (either central or lateral with additional information on all recurrences provided). Distant recurrence included disease in any site beyond the thyroid bed and regional lymhpatics.
Disease specific outcomes were calculated using the date of last follow up with the treating surgeon or endocrinologist at MSKCC. Details of death were determined from death certificates and hospital records where available. All patients who had evidence of active structural disease at the time of last follow-up and died during follow up were considered to have died of disease. The median follow-up for the entire patient cohort was 70 months (range 1-275 months).
Initially all surgical patients were followed by the attending surgeon in MSKCC, with input from the endocrinologists and nuclear medicine physicians as required. The majority of patients are now followed by both the surgeon and endocrinologist at MSKCC, all of whom are specialized in the management of thyroid cancer. A minority of patients were followed by local endocrinologists.
During the time period of the study from 1986 to 2000, serum thyroglobulin was not routinely used to detect recurrence. Similarly, annual ultrasound was not uniformly used as a tool for detection of clinically occult recurrent disease during the majority of the study period. Both ultrasound and thyroglobulin measurement have become routine in the past 10 years for follow up of patients with PTC within our institution. A total of 114 patients (41%) underwent ultrasound examination during follow up. Of those who had ultrasound the median number of examinations during follow up was 4 (range 1-14). A total of 167 patients (61%) had Tg monitoring during follow up. Of those who had Tg monitoring, the median number of Tg levels analyzed was 6 (range 1-34). Three of the 11 recurrences (27%) were detected in patients who were operated up to 2000, the remaining 8 recurrences (78%) were detected in patients operated on after 2000.
Statistical analysis was carried out using SPSS 19 (IBM Corporation). Variables were compared within groups using Pearson’s chi squared test. Survival outcomes were analyzed using the Kaplan-Meier method. Univariate analysis was carried out by the log rank test. A p value less than 0.05 was considered significant.
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Results
The median age of the Nx group was 51 years (range 20-83 years), and 73% were female. The age distribution and year of surgery for the cohort is displayed in Figure 1 and Figure 2. pT stage was T1 in 149 patients (54%) ,T2 in 59 (21%),T3 in 61 (22%)and T4 in 6 patients (3%). One hundred and thirty-three patients (48%) were treated with adjuvant RAI based on patient and primary tumor characteristics (Table 1). Table 1 shows comparison of patient and tumor characteristics of the observed group (Nx) compared to the patients who had CND (pN0 and pN1). As expected, the patient and tumor characteristics of the Nx and pN0 patients were very similar. However, in comparison with those patients who had pN1 disease, the pNx group was more likely to be older, female and have a lower pT stage. This Nx group was less likely to receive adjuvant RAI.When stratified by the use of RAI (Table 2), those selected for RAI were more likely to be male (35% versus 19%, p<0.001) and have advanced (pT3/T4) primary tumors (39% versus 11%, p<0.001).With a median follow up of 70 months (range 1-275 months), the 10 year disease specific survival and recurrence free survival in the Nx group were 100% and 94% respectively (Figure 3). Four patients did have suspicion of recurrence in the thyroid bed on subsequent imaging. Three patients had an RAI scan which showed uptake in the central neck, either normal thyroid tissue or recurrence. All were treated with RAI, and therefore despite the absence of diagnostic cytology, these were considered local recurrences for the purposes of coding in this study. One patient had a non specific thyroid bed nodule on ultrasound which was found to be RAI avid on subsequent imaging. He was also treated with RAI and therefore coded as having local recurrence. All 4 of these patients are still alive and have subsequently been free of disease for a median follow up of 124 months (range 116-161 months). No patients within this cohort (0%) required further surgery to the central neck for recurrence to central compartment neck nodes or the thyroid bed.Five patients (5/275, 1.8%) were considered to have evidence of regional disease during follow up. Three of these had biopsy proven lateral neck disease and underwent neck dissection, one of whom also recurred in the lung. Of the remaining 2 patients 1 had a low level detectable thyroglobulin (4ng/ml) without demonstrable structural disease and 1 had a sub-centimeter level VI neck node suspicious for recurrence which has been observed. Overall therefore, only 1 patient had true nodal recurrence in the central neck (1/275, 0.4%). Two patients developed pulmonary metastases. When all patients with suspicion of disease (proven by biopsy, or suspected based upon Tg or RAI imaging) were included in the analysis, the 10 year local, regional and distant recurrence rates were 2%, 3% and 2% respectively. The staging, treatment and recurrence details of these 11 patients are shown in Table 3. The median age of this group was 60 years (range 24-76). Six patients (55%) received post operative RAI.Factors predictive or outcome are shown in Table 4. Male gender and advanced pT stage both
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showed an association with regional recurrence on univariate analysis. However, there were insufficient events to support a multivariate analysis.Those patients who did not receive RAI were found to have higher rates of recurrent local disease than those who did receive RAI (5% versus 0% at 5 years, p=0.018). All of these 4 local recurrences were characterized by a delayed RAI scan which showed residual uptake in the thyroid bed rather than any cytological or histological demonstration of disease. Of the 133 patients managed without RAI, only 1 had a structural recurrence. This patient developed disease in the lateral neck 13 years after initial thyroidectomy, which was treated with selective lateral neck dissection and post operative RAI. This patient went on to die of bronchial carcinoma at the age of 92 years.
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Discussion
Few topics in the management of PTC are as controversial as the elective management of the central neck in patients with clinically uninvolved central neck nodes. The reason that this debate remains unresolved is that outcomes in these patients are excellent (16). Deaths are rare and recurrence is uncommon. With such low potential for improving outcomes in this group, prospective randomized trials are not feasible (15). A number of factors have led to a divergence of opinions amongst experts within the field. Identification of nodal metastases in the central neck is challenging without histological analysis. Although ultrasound allows accurate identification of metastatic disease in the lateral neck, it is less useful in the central compartment when the thyroid gland is still present (17). Intra-operative clinical assessment of lymph nodes is also inaccurate (11), and can be confounded by the presence of enlarged nodes related to Hashimoto’s thyroiditis. Those who argue for elective CND highlight the high rates of histologically identified metastatic nodes within the elective CND specimens (9). The presence of this occult nodal disease contributes to an upstaging of older patients by AJCC criteria (18, 19). This in turn may influence decisions regarding adjuvant radioactive iodine (RAI) therapy in up to one third of patients (11).An argument has also been made that elective CND results in lower post operative Tg levels (10). Reducing the Tg, and by inference the burden of disease, within this patient group may improve outcome and facilitate follow up, although this finding has not been widely reproduced (11). Whether elective CND results in reduced recurrence rates is controversial. Elective CND has never been shown to improve survival. Microscopic metastases, which are present in around 40% of such patients, rarely progress to become clinically meaningful disease. Therefore, the excellent outcomes enjoyed by cN0 patients managed with surgery alone questions the clinical utility of upstaging these patients and exposing them to the side effects and associated risks of RAI. In addition, the rarity of recurrence in this patient group casts doubt on the need for additional surgery in order to facilitate post operative surveillance. Given the lack of evidence in outcome from elective CND, one must carefully weigh up any potential benefit from surgery with the potential risks associated with CND such as damage to the recurrent laryngeal nerves (RLN) and inadvertent removal of parathyroid glands resulting in hypoparathyroidism. There is no doubt that removal of tissue from the para tracheal region places the parathyroid glands and recurrent laryngeal nerve (RLN) at risk (19). Although a number of expert groups have demonstrated that elective CND can be performed with low rates of complication (9, 11), such evidence is lacking for patients managed outside centers of excellence where the majority of patients are managed.A further surgical issue relating to the role of elective CND is the impact of primary surgery on the hazards of re-operating on the central neck. Re-operation has been associated with higher rates of hypoparathyroidism and RLN injury (20), and therefore clinicians must balance the increased risks of additional primary surgery against the potential for increased risk during
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subsequent procedures for recurrent disease. Indeed, the morbidity of surgery has resulted in the ATA guidelines recommending that elective lateral neck dissection should not be performed, despite a known risk of occult disease of around 23% (9). A more subtle argument in relation to recurrent disease in the central neck is related to the exact anatomical location of recurrence Clayman et al. in their report on 210 patients who underwent surgery on the central neck for persistent or recurrent nodal disease, found that up to 60% of patients had disease dorsal to the RLN (14). Additionally, high rates of disease were reported at the inlet of the RLN, at the cricopharyngeus muscle and in relation to the vertebral artery. Because of thepotential for complications related to dissection in these areas during primary surgery , they are not routinely addressed in elective CND. Therefore elective CND may not prevent the manifestation of disease in such high risk sites.In 2006, the ATA published guidelines stating “Routine central-compartment (level VI) neck dissection should be considered for patients with PTC” (21). This statement resulted in significant controversy, due to the lack of any definitive evidence. In their most current guidelines, published in 2009, the ATA changed their recommendations:, stating “Prophylactic central-compartment neck dissection may be performed in patients with PTC, especially for advanced primary tumors (T3 or T4)”. They go on to comment that the approach to the central neck should take in to consideration surgical expertise, recognizing that in low volume units, the risk benefit ratio may favor total thyroidectomy alone with observation of the central neck. This change reflected the ongoing debate over the role of prophylactic central nodal dissection. In our study, we report on 275 cN0 patients selected for observation of the central neck. No patient died during follow up and no patients required additional surgery to the central compartment. Only 11 patients (11/275, 4%) were suspected of having recurrent disease at some point during follow up. Of these, only 1 patient had proven recurrent structural disease in the central neck (1/275, 0.4%) which currently remains under observation. Three patients developed biopsy proven disease in the lateral neck (3/275, 1%), all of who underwent lateral neck dissection. Two patients developed distant metastases (2/275, 1%). The remaining 5 patients had either the suspicion of disease in the central neck on RAI scanning which was treated with RAI and are now considered disease free (4/275, 1%) or a raised Tg without structural evidence of disease (1/275, 0.4%). Around half of this cohort received adjuvant RAI. Of the 133 patients (48%) who were managed without RAI, only 1 patient had a recurrence. Our results therefore provide compelling evidence that patients with cN0 PTC can be managed safely with observation of the central neck. Such patients undoubtedly benefit from avoidance of any iatrogenic injury to RLNs and parathyroid glands. We do recognize that our study has limitations due to the retrospective nature of the study design. Our patient group was managed over a 20 year period, and although in the early stages of the study ultrasound was not used, in later years it became a routine part of pre operative clinical assessment. It is therefore likely that an increasing number of the latter patients will have suspicious disease identified prior to surgery. If anything this strengthens our results, as even in the older patients, who were likely to have had disease which today would be identified and resected, outcomes were excellent.
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The introduction of routine serial ultrasound and Tg in the follow up of these patients has also impacted on post-operative outcomes in patients with PTC. Such studies were not available during the early stages of this study, and it is conceivable that patients lost to follow up prior to the routine use of such investigations may have harbored occult persistent nodal disease. These highly sensitive investigations have allowed the identification of increasingly low volume disease. However, whether this will result in improved patient outcomes, or simply added anxiety and side effects related to intervention is not clear. Despite this, our study adds follow-up data to more contemporary cohorts, such as that reported by Monchik et al (13). This group concluded that elective CND is not required in selected low risk patients with PTC. They report that only 1.8% of 192 patients selected not to undergo elective CND had biopsy proven persistent disease in the central compartment 4-6 months following surgery.
In conclusion, we have shown that those patients without pre- or intra-operative evidence of nodal disease, who are observed, have low rates of recurrence and excellent outcome, including regional recurrence and survival. Despite the fact that these patients are likely to have a significant rate of occult micrometastasis, such patients can safely be managed with observation rather than elective central neck dissection.
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2. Roh JL, Park JY, Park CI. Total thyroidectomy plus neck dissection in differentiated papillary thyroid carcinoma patients: pattern of nodal metastasis, morbidity, recurrence, and postoperative levels of serum parathyroid hormone. Ann Surg. 2007 Apr;245(4):604-10. PubMed PMID: 17414610. Pubmed Central PMCID: 1877043.
3. Randolph G, Duh QY, Heller KS, Livolsi VA, Mandel SJ, Steward D, et al. The Prognostic Significance of Nodal Metastases from Papillary Thyroid Carcinoma can be Stratified Based on the Size and Number of Metastatic Lymph Nodes, as Well as the Presence of Extranodal Extension ATA Surgical Affairs Committee’s Taskforce on Thyroid Cancer Nodal Surgery. Thyroid.2012 Aug 10. PubMed PMID: 22881837.
4. Cady B, Sedgwick CE, Meissner WA, Bookwalter JR, Romagosa V, Werber J. Changing clinical, pathologic, therapeutic, and survival patterns in differentiated thyroid carcinoma. Ann Surg. 1976 Nov;184(5):541-53. PubMed PMID: 984923. Pubmed Central PMCID: 1345475. Epub 1976/11/01.eng.
5. Hughes CJ, Shaha AR, Shah JP, Loree TR. Impact of lymph node metastasis in differentiated carcinoma of the thyroid: a matched-pair analysis. Head Neck. 1996 Mar-Apr;18(2):127-32. PubMed PMID: 8647677. Epub 1996/03/01.eng.
6. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009 Nov;19(11):1167-214. PubMed PMID: 19860577. Epub 2009/10/29.eng.
7. Bardet S, Malville E, Rame JP, Babin E, Samama G, De Raucourt D, et al. Macroscopic lymph-node involvement and neck dissection predict lymph-node recurrence in papillary thyroid carcinoma. Eur J Endocrinol. 2008 Apr;158(4):551-60. PubMed PMID: 18362303.
8. Gemsenjager E, Perren A, Seifert B, Schuler G, Schweizer I, Heitz PU. Lymph node surgery in papillary thyroid carcinoma. J Am Coll Surg. 2003 Aug;197(2):182-90. PubMed PMID: 12892795.
9. Hartl DM, Leboulleux S, Al Ghuzlan A, Baudin E, Chami L, Schlumberger M, et al. Optimization of staging of the neck with prophylactic central and lateral neck dissection for papillary thyroid carcinoma. Ann Surg. 2012 Apr;255(4):777-83. PubMed PMID: 22418010.
10. Popadich A, Levin O, Lee JC, Smooke-Praw S, Ro K, Fazel M, et al. A multicenter cohort study of total thyroidectomy and routine central lymph node dissection for cN0 papillary thyroid cancer.Surgery. 2011 Dec;150(6):1048-57. PubMed PMID: 22136820.
11. Hughes DT, White ML, Miller BS, Gauger PG, Burney RE, Doherty GM. Influence of prophylactic central lymph node dissection on postoperative thyroglobulin levels and radioiodine treatment in papillary thyroid cancer. Surgery. 2010 Dec;148(6):1100-6; discussion 006-7. PubMed PMID: 21134539.
12. Scheumann GF, Gimm O, Wegener G, Hundeshagen H, Dralle H. Prognostic significance and surgical management of locoregional lymph node metastases in papillary thyroid cancer. World J Surg. 1994 Jul-Aug;18(4):559-67; discussion 67-8. PubMed PMID: 7725745. Epub 1994/07/01.eng.
13. Monchik JM, Simon CJ, Caragacianu DL, Thomay AA, Tsai V, Cohen J, et al. Does failure to perform prophylactic level VI node dissection leave persistent disease detectable by ultrasonography in patients with low-risk papillary carcinoma of the thyroid? Surgery. 2009 Dec;146(6):1182-7. PubMed PMID: 19958947. Epub 2009/12/05.eng.
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15. Carling T, Carty SE, Ciarleglio MM, Cooper DS, Doherty G, Kim LT, et al. American Thyroid Association (ATA) - Design and Feasibility of a Prospective Randomized Controlled Trial of Prophylactic Central Lymph Node Dissection for Papillary Thyroid Carcinoma. Thyroid.2011 Dec 9. PubMed PMID: 22150591. Epub 2011/12/14. Eng.
16. Nixon IJ, Ganly I, Patel SG, Palmer FL, Whitcher MM, Tuttle RM, et al. Thyroid lobectomy for treatment of well differentiated intrathyroid malignancy.Surgery. 2012 Apr;151(4):571-9. PubMed PMID: 22001636. Epub 2011/10/18.eng.
17. Hwang HS, Orloff LA. Efficacy of preoperative neck ultrasound in the detection of cervical lymph node metastasis from thyroid cancer.Laryngoscope. 2011 Mar;121(3):487-91. PubMed PMID: 21344423.
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19. Bozec A, Dassonville O, Chamorey E, Poissonnet G, Sudaka A, Peyrottes I, et al. Clinical impact of cervical lymph node involvement and central neck dissection in patients with papillary thyroid carcinoma: a retrospective analysis of 368 cases. Eur Arch Otorhinolaryngol. 2011 Aug;268(8):1205-
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20. Pai SI, Tufano RP. Reoperation for recurrent/persistent well-differentiated thyroid cancer. Otolaryngol Clin North Am. 2010 Apr;43(2):353-63, ix. PubMed PMID: 20510718.
21. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2006 Feb;16(2):109-42. PubMed PMID: 16420177. Epub 2006/01/20.eng.
Table 1: Comparison of group stratified by pN0/N1/Nx
Variable pN0 (n=384) pN1 (n=470) Nx (n=275) p Value
Neck Surgery Neck Dissection 83 (22%) 355 (76%) <0.001
Node Sampling 301 (78%) 115 (24%)
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Table 2. Demographics of the Nx Group Stratified by RAI
Variable RAI (n=133)No RAI
(n=142)p
Age <=45y 55 (41%) 54 (38%) 0.573
>45y 78 (59%) 88 (62%)
Gender Female 86 (65%) 115 (81%) 0.002
Male 47 (35%) 27 (19%)
pT T1 45 (34%) 104 (73%) <0.001
T2 36 (27%) 23 (16%)
T3 46 (35%) 15 (11%)
T4 6 (4%) 0 (0%)
Table 3. Treatment and recurrence details of patients who recurred during follow up
AgepT
StageRAI LR
Time to recurrence
RRTime to
recurrenceDR
Time to Recurrence
Total Follow
up
24 T2 No Yes 15 No No 130
44 T3 No Yes 19 No No 161
62 T1 No Yes 20 No No 116
43 T2 No Yes 35 No No 118
76 T2 No No Yes 72 No 178
38 T3 Yes No Yes 4 No 78
46 T3 Yes No Yes 13 No 126
66 T3 Yes No Yes 71 No 86
69 T3 Yes No Yes 81 Yes 57 142
60 T1 Yes No No Yes 10 59
71 T3 Yes No No Yes 62 64
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Table 4. Factors predictive of recurrence free survival for the pNx group
Variable5y Regional Recurrence
Ratep
5y Local Recurrence
Ratep
5yDistant
Recurrence Ratep
>45y 1% 1% 2%
Gender Female 0% 0.007 2% 0.921 1% 0.783
Male 3% 2% 2%
pT T1 0% 0.029 1% 0.579 1% 0.402
T2 0% 5% 0%
T3 4% 2% 3%
T4 0% 0% 0%
RAI Yes 2% 0.505 0% 0.018 0% 0.134
No 0% 5% 2%
Figure 1 Age Distribution of the Cohort by Decade
20-29 30-39 40-49 50-59 60-69 70+
Age by Decade
30%
25%
20%
15%
10%
5%
0%
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Figure 2Year of Surgery
70%
60%
50%
40%
30%
20%
10%
0 1985-1990 1991-1995 1996-2000 2001-2005
Figure 3Disease specific and recurrence free survival
Chapter 8
The Results of Selective Use of Radioactive Iodine on Survival and on Recurrence in the Management
of Papillary Thyroid Cancer
Iain J Nixon, MD, Ian Ganly, PhD, Snehal G. Patel MD, Frank L. Palmer BA, Monica M. Di Lorenzo BA, Ravinder K. Grewal MD, Steven M. Larson MD, R. Michael Tuttle MD,
Ashok Shaha, MD Jatin P Shah MD
Thyroid 2013; 23(6):683-694
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Abstract
Background: The American Thyroid Association guidelines recommend the routine use of radioactive iodine for remnant ablation (RRA) in all T3 or greater primary tumors, and selective use in patients with intrathyroidal disease greater than 1cm, or evidence of nodal metastases. The guidelines recognize that there is conflicting and inadequate data to make firm recommendations for most patients. The aim of this study was to analyze our institutional experience of the use of RRA in the management of papillary thyroid cancer (PTC), with a particular focus on outcomes for those patients selected not to receive RRA.
Methods: We retrospectively reviewed 1129 consecutive patients who underwent total thyroidectomy in Memorial Sloan Kettering Cancer Center between 1986 and 2005. 490 were pT1/T2N0, 193 pT1/T2N1 and 444 were pT3/T4. Details on recurrence and disease specific survival were recorded by the Kaplan-Meier method and compared using the log rank test.
Results: The 5 year disease specific survival and recurrence free survival in the pT1/T2N0, pT1/T2N1 and pT3/T4 were 100% and 92%, 100% and 92% and 98% and 87% respectively. Low risk patients who were managed without RRA (who tended to have limited primary disease (pT1/T2) and low volume metastatic disease in the neck (pT1/T2 N1 – less than 5 nodes, all <1cm greatest dimension) had 5 year recurrence free survival of over 97%. In the group with advanced local tumors (pT3/T4), those patients who did not receive RRA (who tended to have pT3N0 disease) had 5 year recurrence free survival of over 90%.
Conclusion: Following appropriate surgical management, the majority of patients with low risk local disease and even some patients with more advanced stage (pT3) tumors or regional metastases have low rates of recurrence and high rates of survival when managed without RRA.
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Introduction
The incidence of well differentiated thyroid cancer (WDTC) is increasing world-wide , with papillary thyroid cancer (PTC) being the most common histological subtype (1-4). Treatment involves thyroidectomy, either by total thyroidectomy or thyroid lobectomy, with removal of any metastatic lymph nodes in the central or lateral compartments of the neck. Radioactive iodine remnant ablation (RRA) after total thyroidectomy has traditionally been used routinely as adjuvant therapy in all but the lowest risk patients. The rising incidence of PTC combined with increasing use of radioactive iodine (RAI) has resulted in a significant increase in the number of patients receiving RAI (5-7). However, not all patients with thyroid cancer require RRA. The identification of patient groups who may benefit from RRA is controversial. All existing evidence on the subject is drawn from retrospective institutional series and national database studies, often spanning many decades. Results from these studies are conflicting, which is reflected in the guarded treatment recommendations provided by international guidelines on the management of WDTC (8-10). At Memorial Sloan Kettering Cancer Center (MSKCC) we have used a risk group stratification policy to select patients who are at higher risk of cause specific death. Such risk stratification aims to select appropriate treatment for each individual case. Within our institution, we have applied this approach to select patients appropriate for both conservative surgery in the form of lobectomy in low risk patients, and aggressive resections including neck dissection and laryngopharyngeral resections where appropriate in high risk cases. In addition to surgical resection , we have also used risk group stratification to identify which patients may benefit from additional therapies, such as RAI , external beam radiotherapy or systemic therapy. Although papillary microcarcinomas in young patients are widely accepted as being low risk, and therefore are not routinely offered RAI, we extend the category of low risk tumors to those which are less than 4cm and remain confined to the gland. We also consider low volume neck disease (less than 5 positive nodes, all <1cm greatest dimension) as being at low risk of death and therefore a select subset of such patients are also managed without routine RRA.The objective of our study was to examine and compare our results on survival and recurrence rates in patients who were selected not to receive RRA, by examining a contemporary dataset of patients with PTC managed by total thyroidectomy at Memorial Sloan Kettering Cancer Center (MSKCC) between the years 1986 to 2005. We also report on the overall efficacy of RRA on recurrence and survival in all patients and also on specific subgroups, namely patients with pT1T2N0 disease, patients with pT1T2N+ disease and those with locally advanced (pT3T4) disease separately. Materials and MethodsFollowing approval by the Institutional Review Board, 1129 consecutive patients who had total thyroidectomy for PTC (using the 2009 AJCC staging manual) between 1986 and 2005, were identified from our institutional database of 1810 patients treated for WDTC at MSKCC. Patients with all T stages (T1a-4) were considered for this study. Although low risk patients with limited
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local disease are offered thyroid lobectomy in the absence of high risk features or nodular disease in the contralateral lobe, around half of the patients in this cohort had limited local disease (pT1T2). Patients who underwent initial treatment elsewhere prior to referral, those who were considered unresectable at the time of referral or surgery, those treated with less than total thyroidectomy and those presenting with evidence of distant metastasis at presentation or on post-operative RAI scan (within 6 months) were excluded. As not all patients underwent post operative RAI scanning, it is possible that some patients treated without RRA may have harbored occult metastases following surgery. If discovered within 6 month, such patients were coded as M1. If they presented later than 6 month, they were coded as recurrence (Only 3 patients treated without RRA suffered distant metastases at 7, 27 and 50 months, and this factor is therefore unlikely to bias the results). Data collected included patient demographics and surgical details including the presence of gross extra-thyroid extension. Histopathological details recorded included tumor histology, primary tumor size, presence of extra-thyroid extension and presence of metastatic lymph nodes. Post-operative treatment details recorded were use of RAI. Based on clinical and histopathological features, cases were classified into low, intermediate and high risk groups for death based on the MSKCC previously published risk stratification system (Table 1a) (11, 12). Patients under the age of 45 years who present with papillary carcinomas of less than 4cm confined to the thyroid gland (intraglandular), without evidence of distant metastatic disease, are at very low risk of death, whereas patient over the age of 45 years, with extrathyroid extension (ETE), aggressive histopathology, disease over 4cm in dimension or distant metastatic disease are at higher risk. Young patients with, or older patients without, aggressive histopathological features form an intermediate risk group(13). The recent ATA guidelines provided a method of stratification based on risk of recurrence rather than death, which was also applied to this group (Table 1b) (8). Patients with fully excised disease without any of the following features-ETE, aggressive histopathology, vascular invasion or regional or distant metastases, are at low risk of recurrence. Patients with macroscopic ETE, distant metastases or incomplete tumor resection are at high risk of recurrence. All other patients represent an intermediate risk group for recurrence.In the cohort of patients from 1986 to 2005, preoperative ultrasound was not routinely used for pre-operative assessment of the central and lateral compartment lymph nodes. The assessment of the lateral neck nodes was based on preoperative clinical examination and if enlarged, ultrasound carried out. Assessment of the central compartment for all patients was intraoperative by palpation of the central compartment lymph nodes at the time of thyroidectomy. If no palpable nodes were present in the central compartment, then no elective central compartment neck dissection was done. If nodes were palpable, then a central compartment neck dissection was carried out. Due to this approach to the neck, we have coded our results as N0 when no positive nodes were excised and N1 when positive nodal disease was reported on histology. Not all patients had formal neck dissections in either the N0 or N1 group, and those who had less than 6 nodes excised (pNx) without evidence of positive disease were described as N0. Post operative thyroid stimulating hormone (TSH) suppression
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is practiced for all patients, aiming for a level of between 0.1-0.5 mcUnits/ml.Our institutional approach to selecting patients for RRA has evolved during the time period studied. All high risk patients are considered for RRA, whereas low risk patients are generally selected for management without RRA. Intermediate risk patients are offered RRA dependent on patient and tumor factors. In the mid 1980s the use of RAI was increasing nationally and also within our institution. More recently our disease management team has become increasingly selective with the intermediate risk group, limiting the use of RRA in older patients who have limited local disease, and in those young patients with low volume neck disease. Despite this general institutional approach, clinicians and patients vary in their assessment of risk and benefit and an individualized treatment approach is employed in all cases which introduces heterogeneity when analyzed retrospectively. Prior to 1999, all RAI ablations and re-treatments were done using traditional thyroid hormone withdrawal for 4-6 weeks. Since 1999, the vast majority of RAI ablations and treatments have been done using recombinant human TSH simulation. While our current recommendations call for lower RAI administered activities, for the majority of the time period of the study, RAI ablation administered activities usually were in the range of 100 mCi for remnant ablation, 150 mCi of pathological lymph node metastases were present, and 175-200 mCi if distant mets were present at diagnosis. Just as with the selection of patients for RAI remnant ablation, decisions regarding retreatment with RAI were complex, multifactorial, and varied among the treating physicians at our institution.Outcomes data included local, regional and distant recurrence as well as details of death. Local and regional recurrences were determined by clinical examination supplemented with imaging and fine needle aspiration if recurrence was suspected. During the 1980s and 1990s serum thyroglobulin was not routinely used to detect recurrence. Similarly, annual ultrasound was not uniformly used as a tool for detection of recurrent disease during the majority of the study period. Both the use of thyroglobulin monitoring and serial ultrasound have become standard practice within our institution in recent years, and now influence the further investigation of patients within this cohort.The presence of local or regional recurrence following treatment was based on cytological or histopathological confirmation of structurally identifiable disease. Local recurrence was defined as recurrent disease located in the operated thyroid bed confirmed by cytological sampling or histological analysis following further surgery. Regional recurrence was defined as recurrent disease found in cervical lymph nodes, confirmed again by cytological sampling or histopathology following subsequent surgical resection. Distant recurrence was determined by imaging studies including radioiodine uptake scans, CT scans, Positron Emission Tomography (PET) scans, or cytological and histopathological evidence where available. Not all patients in the cohort had serial measurement of TG. For this reason we did not consider isolated TG changes as recurrence. However, in current practice, patients with previously undetectable TG (<0.2) who develop detectable levels are investigated with ultrasound, fine needle aspiration of suspicious nodes or nodules and CT scanning of the neck and chest in an attempt to identify evidence of structural disease.
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Disease specific outcomes were calculated using the date of last follow up with the treating surgeon or endocrinologist at MSKCC. Details of death were determined from death certificates and hospital records where available. All patients who had evidence of active structural disease at the time of last follow-up and died during follow up were considered to have died of disease. The median follow-up for the entire patient cohort was 63 months (range 1-282 months). Outcomes data were therefore calculated at 5 years. The completeness index (ratio of expected patient follow up to observed patient follow up) was 0.83 and 0.60 at 5 and 10 years respectively. Statistical analysis was carried out using JMP statistical package (SAS Institute Inc. SAS Campus Drive, Cary, NC 27513) and SPSS (IBM Company Headquarters, 233 S. Wacker Drive, 11th Floor, Chicago, Illinois 60606). Variables were compared within groups using Pearson’s chi squared test. Survival outcomes were analyzed using the Kaplan-Meier method. Univariate analysis was carried out by the log rank test and multivariate analysis by Cox proportional hazards method. A p value less than 0.05 was considered significant.
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RESULTS
Entire GroupThe median follow up of this patient cohort was 63 months (range 1-282 months). The median age was 46 years (range 11-91 years) with a male to female ratio of 1:2.8. All patients were managed with total thyroidectomy (no patients with sub total or near total thyroidectomy) and had no evidence of macroscopic residual disease following surgery or distant metastases. Six hundred and eighty-nine patients underwent no neck dissection (61%), 94 patients (8%) had central neck dissection and 346 patients (31%) had central and lateral neck dissections. Three hundred and fifty-five patients who underwent neck dissection had evidence of nodal metastases on histopathology (81%). Six hundred and ninety-one patients (61%) received post-operative RRA. Patient, tumor and treatment details are shown in Table 2. Stratified by the administration of RRA, those receiving RRA were more likely to be male, have more advanced pT and N stage disease, and more likely to be in the high risk MSKCC and ATA groups.During follow up, 18 patients (2%) died of disease and 84 (7%) developed recurrence. Four patients recurred locally (<0.1%), 61 recurred regionally (5%) and 38 had distant recurrence (0.3%). Twenty patients were considered to have active disease at the time of last follow up. Ten of these had isolated distant metastases, 1 isolated regional and 1 isolated local recurrence. Of the remaining 8 patients, 7 had regional and distant disease and 1 had local, regional and distant disease. The 5 year disease specific (DSS) and recurrence free survival (RFS) were 99% and 92% respectively. For DSS, univariate analysis showed age over 45 years, male sex, pT stage and N positive disease (N1b worse than N1a) to be predictors of worse outcome (Table 3). The administration of RRA did not predict DSS (5yr DSS RRA 99% versus no RRA 100%, p=0.821). Due to the limited number of events (18 deaths) multivariate analysis of DSS could only be carried out with 2 variables; incorporating age and pT stage confirmed age over 45 years and pT to be independent predictors of cause specific mortality. Patients over 45 years of age were x8.9 more likely to die of disease. Patients with pT4 disease were x5.5 more likely to die compared with pT1 patients. N stage was not predictive of outcome in either a multivariate model including pT and N stage, or N stage and age over 45 years. For RFS, univariate analysis showed male sex, advanced pT stage, N positive disease and the administration of RRA to predict recurrence. Patients who had RRA had a worse 5 year RFS than those who did not (90% versus 97%, p<0.001) as predicted by the higher rate of intermediate and high risk cases in this group by ATA stratification guidelines. On multivariate analysis incorporating age, sex, pT stage, N stage and administration of RAI, only pT3, pT4 and N positive disease were found to be independent predictors of outcome. Patients with pT3 disease had a x2 fold increased risk of recurrence and patients with pT4 disease a x4.5 fold increased risk of recurrence compared to pT1 patients. Patients with N1 disease had a x3.4 fold increased risk of recurrence compared to patients without excised evidence of nodal metastases.More detailed univariate analysis of local, regional and distant recurrence free survival (LRFS, RRFS and DRFS respectively) showed that age, sex, pT stage and N stage to be important predictors of outcome (again N1b performed worse than N1a) (Table 4). RRFS and DRFS
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were worse for patients who had RRA (94% versus 99%, p<0.001 and 95% versus 99%, p=0.001 respectively). There were too few events to carry out multivariate analysis of LRFS. However, multivariate analysis of RRFS and DRFS showed that pT4 and N positive disease were independent predictors of recurrence (Table 4). Patients with pT4 disease had a 3.4 fold increased risk of regional recurrence and a 2.4 fold increased risk of distant recurrence compared to pT1 patients. Patients with N1 disease had a 3.1 fold increased risk of regional recurrence and a 3.8 fold increased risk of distant recurrence compared to N0 patients.
Recurrence in patients with T1 or T2 N0 diseaseFour hundred and ninety patients within the cohort had disease localized to the thyroid at presentation. Two hundred and eighty-two patients (58%) had nodal tissue excised (node sampling or formal neck dissection) (N0), the remaining 208 (42%) had no nodes excised (Nx). Of the 282 patients who had nodal tissue excised, 55 had formal central compartment neck dissections, 4 had lateral neck dissections and the remaining patients had delphian, perithyroidal or paratracheal node biopsies. All patients were N0 on pathological review. One hundred and seventy-eight patients had RRA (36%). Patient, tumor and treatment details are shown in Table 5a. All patients were either low or intermediate risk patients using the MSKCC and ATA classifications. In agreement with our selection criteria for RRA, the patients in the group who had RRA were more likely to be male and more likely to have T2 than T1 disease. There were no local recurrences in this sub-group and therefore no factors predictive of LRFS were identified. There were only 4 regional recurrences (4/490, 1%) and 2 distant recurrences (2/490, 2%) during follow up. The 5 year DSS was 100% and RFS was 92% in this subgroup.Stratifying by RRA, the 5 year RRFS and DRFS for patients that did not have RRA were 98% and 100% respectively. The 5 year RRFS and DRFS for patients that had RRA were 100% and 99% respectively. These differences were not statistically significant. Therefore, based on our selection criteria for RRA, patients who did not have RRA had an excellent outcome. These results support the MSKCC risk group stratification and patient selection for RRA.
Recurrence in patients with T1 or T2 N1 diseaseOne hundred and ninety-three patients had pT1 or pT2 tumors and positive cervical nodal metastases (N1). As expected, the majority of these patients had RRA as they were considered by the treating clinician to be at higher risk both for recurrence and/or death. Of the 193 patients, 142 were selected to receive RRA (74%) and 51 did not receive RRA (26%). The case records of the 51 patients who did not have RRA were examined in detail to try and elicit a reason for not giving RRA. Patient, tumor and treatment details are shown in Table 5b. These patients tended to be young and have low risk tumors using the MSKCC classification; 41 (79%) patients were <45 years of age and 40 (77%) patients were categorized as low risk with the remaining 12 patients categorized as intermediate risk of death. Seven patients were seen in conjunction with an endocrinologist and these were more likely to receive RAI ablation than patients followed by surgeons alone. A flowchart stratifying patients by thyroglobulin level, size of the largest metastatic focus in lymph node and number of positive lymph nodes is
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shown in Figure 1. Of 51 patients, 5 had a post-operative thyroglobulin less than 1, 9 had a thyroglobulin over 1 and 27 patients had no post operative thyroglobulin recorded. Of the 46 patients who did not have a undetectable thyroglobulin, 14 had the largest metastatic lymph node focus less than 1cm, in 18 patients the size of the largest node was not reported and in the reminaing 15 patients the node was over 1cm in maximum dimension. Of the 33 patients who did not have a largest metastastic node of <1cm recorded, 22 had 5 or less lymph nodes positive. This left 8 patients with greater than 5 nodes positive and metastatic focus greater than 1cm. No clear reason could be identified as to why these patients did not have RRA. The number of positive nodes was unrecorded for the remaining 2 patients.For patients with T1T2N1 disease, the 5 year DSS and RFS were 100% and 92% respectively. There was only 1 local recurrence and therefore no factors predictive of LRFS were identifiable. Table 6 shows predictors for RRFS and DRFS for this group. Of 15 regional recurrences, 13 were in the group who received RAI with only 2 in the group that did not receive RAI. The 5 year RRFS in patients who had RRA was 93% versus 100% for those who did not (p=0.263). For distant recurrence, all 5 distant recurrences occurred in patients who had RRA, giving a 5 year DRFS of 93% versus 100% (p=0.274). The ATA system for classifying recurrence in patients proved to be an effective predictor of both regional and distant recurrence in this group of patients, whereas the MSKCC system, designed to predict mortality was not (Table 6).
Recurrence in patients with T3 or T4 diseaseFour hundred and forty-four patients presented with locally advanced disease (pT3 or pT4). The median follow up in this group was 64 months (range 1-282 months). Patient, tumor and treatment details are shown in Table 5c. Of 444 patients, 276 also had N1 disease (62%). As expected, the vast majority of patients (371 patients (84%)) received adjuvant RAI. The patients who had RRA were more likely to have had N1 disease. However, a select group of 73 patients did not have RRA. Those who did not have RRA were more likely to be N0 and have T3 disease (local disease over 4cm or the presence of microscopic ETE). The 5 year DSS and RFS rates were 98% and 87% respectively. Three patients recurred locally, all of whom had RRA (Table 7). Forty two patients had regional recurrence of whom 41 (98%) had RRA. Thirty one patients had distant recurrence of whom 28 (90%) had RRA. Of the 73 patients who did not have RRA, there were no local recurrences, only 1 regional recurrence and 3 distant recurrences. This indicated that the selection criteria used for these 73 patients was adequate.The 5 year RRFS of those who had RRA was 91% versus 98% for those who did not (p=0.019). Although on univariate analysis male sex, pT4 disease and N positive disease predicted outcome, RRA did not (Table 7). On multivariate analysis pT4 disease remained an independent predictor of outcome. Patients with pT4 disease were x2.3 more likely to have regional recurrence compared with pT3 disease.The 5 year DRFS within this group was 93%. Both the presence of T4 and N1 disease were predictive of outcome on univariate and multivariate analysis. Patients with pT4 disease were
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x2.3 more likely to have distant recurrence compared to patients with pT3 disease. Patients with N1 disease were x3.7 more likely to have distant recurrence compared to patients with N0 disease. Again the RRA did not predict outcome with 93% 5 year DRFS in groups receiving and not having RRA (Table 7). The ATA system for classifying patients again proved to be an effective predictor of both regional and distant recurrence in this group of patients, whereas the MSKCC system was not (Table 6).
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Discussion
The prognosis for patients diagnosed with WDTC is usually excellent, (6, 11, 14-17). Patterns of treatment have evolved over the last 25 years, with increasing use of RAI to ablate post-operative remnant thyroid tissue (5, 6). Despite this, the evidence supporting its use is conflicting (18), particularly in those patients stratified as low risk group for death (12, 16, 17, 19, 20). Many groups have examined the role of RAI in the treatment of WDTC. Some have demonstrated improved survival in patients receiving post-operative RAI (21-23), particularly in high risk groups (14, 17, 20, 24-26). In more recent studies, other groups have found no significant differences in overall survival outcomes (6, 17, 27-29). In terms of recurrence rates following treatment, again there is disagreement between studies, with some identifying improved rates (14, 23, 24, 26) whilst others do not (6, 29). Our study focuses on patients with PTC treated with a standardized surgical approach, involving extracapsular thyroidectomy and therapeutic neck dissection to remove proven or suspicious cervical lymph node metastases. We do not practice or recommend sub total or near total thyroidectomy, when total thyroidectomy is indicated. We do not carry out elective central or lateral neck dissection, as it has not been proven to improve survival. Although we use adjuvant RAI to ablate any remnant of thyroid tissue in cases considered at higher risk of mortality(12), we are selective in the use of RRA for low and even intermediate risk cases. The objective of our study was to analyze our experience of the selective use of RRA in the management of WDTC. We recognize that PTC presents to the clinician over a spectrum ranging from patients with early stage disease which carries an excellent prognosis, to those with advanced locoregional disease in whom one can expect a worse outcome. To support the selective use of RAI in our patient cohort, we analyzed 3 subgroups- pT1T2N0, pT1T2N1 and pT3T4 sub-groups respectively. In patients presenting with disease limited to the thyroid gland (pT1T2N0), 64% of our patients (312 of 490 patients) did not receive adjuvant RAI with no detrimental impact on either DSS or RFS. This is in keeping with the findings of other groups in these low risk patients (20). It is worth remembering that we do not practice routine elective neck dissections, and it is therefore likely that many patients in this group considered to have disease confined to the thyroid in fact had occult nodal metastases of questionable clinical significance. In similar patients who had evidence of regional metastases (pT1T2N1), we chose to treat the majority of patients with RRA (74%, 142 of 193 patients). However, 51 patients were carefully selected not to have RRA. Of these patients, only 7 saw an endocrinologist. Therefore the selection of these patients was determined by surgeons with extensive experience in thyroid cancer management. These patients were mainly young under 45 years of age with low risk tumors. Analyzing these patients in more detail, 5 had a post-operative thyroglobulin less than 1. Of the remaining 46 patients, 22 had 5 or less lymph node metastases. Data reported by Leboulleux et al,2005(30), Ito et al(31) and by Sugatani et al(32) have reported that the risk of recurrence in patients with less than 5 nodes positive is 3-8% and therefore this could explain the low risk of recurrence in our patients. In addition, the size of the metastatic lymph node foci has also been reported to be predictive of recurrence (33) with the risk of regional recurrence being
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higher (32%) if the metastatic foci are greater than 1cm. In our cohort of patients, 14 of the 51 had metastatic foci less than 1cm. This left 8 patients who had greater than 5 nodes positive or metastatic foci over 1cm. We could not identify any reason for these patients not receiving RAI. However, there was no detrimental impact on either 5 year DSS or RFS. Our survival and recurrence figures therefore indicate that with careful selection, some patients with N1 disease can be treated safely without adjuvant RRA. At our institution, a highly selected group of young patients with pT1T2 tumors, less than 5 nodes positive and with microscopic deposits of cancer may be managed with observation without RRA and with careful monitoring of thyroglobulin levels and regular ultrasound.In higher risk patients with locally advanced (pT3 or pT4) disease, as expected, the majority of patients (84%, 371 of 444) were treated with RRA. Careful selection of some patients, principally those with T3 disease and N0 necks, allowed some patients not to have RRA. There was no detrimental impact on 5 year DSS or RFS thus supporting our selection process for RRA in this cohort of patients. Like all retrospective studies, this data has limitations. There is obvious physician and patient related selection bias in the decision to use RAI. However, our patients were all managed within a single tertiary referral cancer center with a fairly uniform approach to surgery, histopathological reporting, post-operative treatment and follow-up. This cannot be said for studies based mainly on the records of national databases. Despite this, our approach to the use of RRA evolved during the time period studied, which limits the conclusions we can draw from our results. Those patients managed with RRA tended to be at higher risk of recurrence, being older with more aggressive tumors. For that reason direct comparison of groups stratified by use of RRA is not reported. It should also be emphasized that all patients in this cohort were treated with extra-capsular total thyroidectomy. Sub-total thyroidectomy is rarely carried out in our institution. Our excellent outcomes may therefore be a direct result of this complete and methodical technique of thyroidectomy. It should be emphasized that such results may not occur in outside centers, which are not centers of excellence, or in cases where thyroid cancer is diagnosed incidentally after surgery for benign goiter, in countries where iodine deficiency is endemic. Our results should therefore be interpreted with caution as they only apply to centers with a similar surgical approach to our own. Follow up protocols during the time period studied were based upon clinical examination, without the routine use of thyroglobulin or annual ultrasound. Therefore most recurrences were palpable structural disease rather than sonographically identified small volume, or “biochemical” recurrence. Our data supports our selection criteria for RRA. In particular, our data illustrates that for intraglandular T1T2N0 disease, survival and recurrence are similar in the RRA and no RRA groups suggesting RRA is not required in the majority of cases. For similar patients with N1 disease, RRA is generally advocated. However, even in this group there are a highly select group of young patients with low volume neck disease who can be treated safely without RRA. For advanced stage T3 or T4 disease, a select group of T3 N0 patients can be safely managed without RRA. Our data analysis shows the accuracy of the MSKCC risk stratification system for analyzing death and also the accuracy of the ATA risk stratification system for analyzing recurrence.
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Following surgical therapy, a decision must be made between the surgeon, endocrinologist, nuclear medicine physician and patient, whether to recommend RRA. Current international guidelines recommend consideration of RRA for all tumors which are over 1cm in size, or are associated with extrathyroid extension or spread beyond the thyroid (8-10). Given the known rates of occult nodal metastasis to the central (34) and lateral neck (35), clinicians therefore may consider the use of RRA in almost all of the patients they encounter. Our data shows that select patients can be identified that can be safely managed without adjuvant RRA. We believe that this selection is important as the side effects of RAI are increasingly recognized. A number of groups have shown that iodine uptake outside thyroid tissue results in significant salivary and lacrimal dysfunction (36-39). A recent report on the effect of RAI following total thyroidectomy suggested increased rates of dysphagia in patients who received RAI (39). These late side effects have been reported to have a negative impact on quality of life scores for patients who receive high levels of RAI activity (40). Perhaps more important is the reported increased risk of second primary malignancies developing in patients treated with high levels of RAI activity, with groups reporting increased rates of salivary and hematological malignancies following RAI therapy (5, 41). It is also important to realize that the use of RRA has not been conclusively proven to reduce mortality or recurrence related to PTC in the absence of distant metastases. These patients are likely to do well following appropriate surgical management, and RRA should be considered only for the patients most likely to benefit. This study was not designed to assess the efficacy of RAI, which we believe may be beneficial in properly selected patients who present with PTC. The results of this study should not lead clinicians to reject the use of RRA in lower risk patients. However, a balance between risk and benefit must be made on an individual patient basis. We report that select patients can be managed safely without post operative RRA resulting in excellent outcomes. In conclusion, following complete tumor resection, with total thyroidectomy, the majority of patients with low risk local disease and even some patients with more advanced stage (pT3) tumors or regional metastases have low rates of recurrence and high rates of survival when managed without RRA.
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Table 1a. MSKCC Cause Specific Mortality Risk Classification System (GAMES)
Risk Level Patient Factor Tumor Factor
Low Risk Age <45y Papillary Ca M0 No ETE Size <4cm
High Risk Age >45y Follicular Ca / Hurthle Cell Ca M1 ETE Size >4cm
Low Risk Case Low Risk Patient Low Risk Tumor
Intermediate Risk CaseLow Risk Patient High Risk Tumor
High Risk Patient Low Risk Tumor
High Risk Case High Risk Patient High Risk Tumor
Table 1b. ATA Risk of Recurrence Stratification
Regional Metastases
Distant Metastases
Extrathyroid Extension
Surgical Resection
Aggressive Pathology
RAI Uptake Outside Thyroid Bed
Low Risk Absent Absent Absent Complete Absent Absent Only Low Risk if All are True
Intermediate Risk Present Absent Microscopic Complete Present PresentIntermediate or High Risk if Any are True
High Risk Present Macroscopic Incomplete
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Table 1a. MSKCC Cause Specific Mortality Risk Classification System (GAMES)
Risk Level Patient Factor Tumor Factor
Low Risk Age <45y Papillary Ca M0 No ETE Size <4cm
High Risk Age >45y Follicular Ca / Hurthle Cell Ca M1 ETE Size >4cm
Low Risk Case Low Risk Patient Low Risk Tumor
Intermediate Risk CaseLow Risk Patient High Risk Tumor
High Risk Patient Low Risk Tumor
High Risk Case High Risk Patient High Risk Tumor
Table 1b. ATA Risk of Recurrence Stratification
Regional Metastases
Distant Metastases
Extrathyroid Extension
Surgical Resection
Aggressive Pathology
RAI Uptake Outside Thyroid Bed
Low Risk Absent Absent Absent Complete Absent Absent Only Low Risk if All are True
Intermediate Risk Present Absent Microscopic Complete Present PresentIntermediate or High Risk if Any are True
High Risk Present Macroscopic Incomplete
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Table 2. Descriptive Statistics of Whole Group and Stratification by RRA / No RRA
Variable GroupNumber (%)
(n = 1129)No RRA (n=438)
RRA (%)(n=691)
p value
Age<45 547 (48%) 205 (47%) 342 (49%)
>45 582 (52%) 233 (53%) 349 (51%) 0.378
SexMale 301 (27%) 82 (19%) 219 (32%)
Female 828 (73%) 356 (81%) 472 (68%) <0.001
pT stage
T1 506 (45%) 303 (69%) 203 (29%)
T2 177 (16%) 60 (14%) 117 (17%)
T3 360 (32%) 60 (14%) 300 (44%)
T4 84 (7%) 13 (3%) 71 (10%)
Tx 2 (<1%) 2 (<1%) 0 <0.001
N StageN0 659 (58%) 354 (81%) 305 (44%)
N1 470 (42%) 84 (19%) 386 (56%) <0.001
MSKCC Risk Group
Low 343 (30%) 168 (38%) 175 (25%)
Intermediate 535 (47%) 228 (52%) 307 (44%)
High 251 (23%) 42 (10%) 209 (30%) <0.001
Low 462 (41%) 314 (72%) 148 (21%) <0.001
ATA Risk Group Intermediate 509 (45%) 96 (22%) 413 (60%)
High 158 (14%) 28 (6%) 130 (19%)
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Table 3. Factors predictive of Disease Specific Survival by univariate and multivariate analysis
Variable GroupNumber
(n =1129)5y
DSS10y DSS
Univariate p Value
Multivariate Analysis
HR 95% CI P
Age <45 547 (48%) 100% 100% <0.001 Referent
>45 582 (52%) 98% 94% 8.9 2.0-39.6 0.004
Sex Male 301 (27%) 98% 94% 0.037 NS
Female 828 (73%) 99% 98% Referent
pT stage T1 506 (45%) 100% 100% <0.001 Referent
T1a 284 (25%)
T1b 222 (20%)
T2 177 (16%) 100% 100% NS NS 0.977
T3 360 (32%) 100% 96% 1.7 0.4-8.6 0.496
T4 84 (7%) 94% 87% 5.5 1.2-26.1 0.030
Tx 2 (<1%) 100% 100%
N Stage N0 659 (58%) 100% 100% <0.001 Referent
N1 470 (42%) 98% 94% NS
N1a 204 (18%) 100% 97%
N1b 266 (24%) 96% 92%
MSKCC Risk Group
Low 343 (30%) 100% 100% <0.01
Intermediate 535 (47%) 100% 99%
High 251 (23%) 96% 90%
ATA Risk Group
Low 462 (41%) 100% 100% <0.001
Intermediate 509 (45%) 99% 98%
High 158 (14%) 96% 89%
RAI Yes 691 (61%) 99% 97% 0.821 NS
No 438 (39%) 100% 99% Referent
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Table 4. Factors predictive of local, regional and distant recurrence free survival by univariate analysis in whole group
Figure 1 Analysis of T1/T2N1 patients who did not receive RAI, stratified by thyroglobulin level, size of largest node and number of nodes excised.
Chapter 9
Selective Radioiodine In Intermediate Group Papillary
Thyroid Cancer
Iain J Nixon MD, Snehal G. Patel, MD, Frank L. Palmer, BA, Monica M. DiLorenzo, BA, R Michale Tuttle MD†, Ashok Shaha, MD, Jatin P Shah MD, Ian Ganly, MD, PhD.
Arch Otolaryngol Head Neck Surg. 2012;38(12):1141-6
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Abstract
ObjectiveTo describe the outcomes of selective use of RAI in patients at intermediate risk of death from papillary thyroid cancer, focusing on 2 subgroups –patients over 45 years with low risk tumors and patients under 45 years with high risk tumors.
DesignRetrospective case review.
SettingTertiary referral US cancer center.
Patients532 consecutive patients operated between 1986-2005.
InterventionsAll patients underwent total thyroidectomy, 307 also received RAI.
Main Outcome MeasuresDisease specific survival (DSS) and recurrence free survival (RFS).
ResultsOf 344 patients over 45 years with low risk tumors, 148 (43%) received RAI and 196 (57%) were selected not to receive RAI. The patient managed without RAI were more likely to be female and have pT1N0 disease. The 5 year DSS and RFS were 100% and 98% respectively. The presence of nodal metastases predicted poorer 5y RFS within this group (99% versus 91%, p=0.004).Of 188 patients under 45 years with high risk tumors, 159 (85%) received RAI and only 29 (15%) were selected not to receive RAI. The 5 year DSS and RFS for these patients were 100% and 95% respectively. The presence of nodal metastases predicted poorer 5y RFS within this group (100% versus 86%, p=0.02).
ConclusionOur study shows that the subgroup of patients who are over 45 years old, with tumors <4cm, confined to the thyroid and without nodal metastases can safely be managed without RAI.
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Introduction
The American Thyroid Association Guideline recommendation 32(b), endorses the selective use of post operative radioactive iodine (RAI) in all patients with well differentiated thyroid cancer (WDTC) greater than 1cm, and goes on to recommend the routine use of RAI in patients with advanced local disease (pT3 or pT4) irrespective of age (1). Despite these recommendations, the guideline highlights the conflicting data particularly in relation to patients with less aggressive local disease. Based on clinical and histopathological features, all WDTC cases can be classified into low, intermediate and high risk groups for death based on the MSKCC previously published risk stratification system GAMES (Table 1) (2). In this system, patients under the age of 45 years who present with papillary carcinomas of less than 4cm confined to the thyroid gland (intraglandular), without evidence of distant metastatic disease, are considered at low risk of death. Patients over the age of 45 years, with extrathyroid extension (ETE), aggressive histopathology, disease over 4cm in dimension or distant metastatic disease are at higher risk. Young patients with, or older patients without, aggressive histopathological features form an intermediate risk group(3). This intermediate risk group forms the patient cohort that our study is based upon.The Head and Neck Service in Memorial Sloan Kettering Cancer Center has long employed a selective approach to the use of RAI in these patients considered at intermediate risk of death from WDTC. Our hypothesis is that older patients with low risk tumors can safely be managed without the need for RAI. The objective of this study was to examine and compare outcomes in these intermediate risk patients stratified by the use of RAI, by examining a contemporary dataset of intermediate risk patients with PTC managed by total thyroidectomy at MSKCC between 1986-2005.
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Patients and Methods
Following approval by the Institutional Review Board, 532 consecutive patients with papillary thyroid cancer, classified as being intermediate risk (using GAMES) who had total thyroidectomy between 1986 and 2005, were identified from our institutional database of 1810 patients treated for WDTC at MSKCC. Patients who underwent initial treatment elsewhere, those who were considered unresectable at the time of referral or surgery, those treated with less than total thyroidectomy and those presenting with evidence of distant metastasis were excluded. Data collected included patient demographics and surgical details including the presence of gross extra-thyroid extension. Histopathological details recorded included tumor histology, primary tumor size, presence of extra-thyroid extension and presence of metastatic lymph nodes. Post-operative treatment details recorded were use of RAI. Ninety-seven percent of our cohort had RAI in our institution, 3% were treated outside following recommendations from MSKCC. In the cohort of patients from 1986 to 2005, ultrasound was not routinely used for pre-operative assessment of the central and lateral compartment lymph nodes. The assessment of the lateral neck nodes was based on preoperative clinical examination and if enlarged, ultrasound carried out. Assessment of the central compartment for all patients was by intraoperative evaluation and palpation of the lymph nodes at the time of thyroidectomy. If no suspicious nodes were present in the central compartment, then no elective central compartment neck dissection was done. If suspicious nodes were noted, then a central compartment neck dissection was carried out. Frozen section of the lymph nodes was generously used. Post operative thyroid stimulating hormone (TSH) suppression is practiced for all patients, aiming for a level of between 0.1-0.5mcUnits/ml.The risk of recurrence in our intermediate risk patients (using GAMES) was determined using the recent ATA guidelines (1). Patients with fully excised disease without any of the following features-ETE, aggressive histopathology, vascular invasion or regional or distant metastases, are at low risk of recurrence. Patients with macroscopic ETE, distant metastases or incomplete tumor resection are at high risk of recurrence. All other patients represent an intermediate risk risk group for recurrence. All patients within our group were retrospectively classified using this system also.Outcomes data included local, regional and distant recurrence as well as details of death. Local and regional recurrences were determined by clinical examination supplemented with imaging and fine needle aspiration if recurrence was suspected. Initially all surgical patients were followed by the attending surgeon in MSKCC, with input from the endocrinologists and nuclear medicine physicians as required. As the volume of surgical practice has increased, routine follow up of many patients has passed to the endocrinology service in MSKCC. The majority of patients are now followed by endocrinologists at MSKCC all of whom are specialized in the management of thyroid cancer. A minority of patients were followed by local endocrinologists.During the time period of the study from 1986 to 2000, serum thyroglobulin was not routinely used to detect recurrence. Similarly, annual ultrasound was not uniformly used as a tool for
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detection of recurrent disease during the majority of the study period. Both ultrasound and thyroglobulin measurement have become routine in the follow up of patients with PTC within our institution, however the presence of local or regional recurrence following treatment was based on cytological or histopathological confirmation of disease. Local recurrence was defined as recurrent disease located in the operated thyroid bed confirmed by cytological sampling or histological analysis following further surgery. Regional recurrence was defined as recurrent disease found in cervical lymph nodes, confirmed again by cytological sampling or histopathology following subsequent surgical resection. Distant recurrence was determined by imaging studies including radioiodine uptake scans, CT scans, Positron Emission Tomography (PET) scans, or cytological and histopathological evidence where available. Biochemical recurrence alone was not coded as recurrence within this dataset. Disease specific outcomes were calculated using the date of last follow up with the treating surgeon or endocrinologist at MSKCC. Details of death were determined from death certificates and hospital records where available. All patients who had evidence of active structural disease at the time of last follow-up and died during follow up were considered to have died of disease. The median follow-up for the entire patient cohort was 60 months (range 1-282 months). Outcomes data were therefore calculated at 5 years. Statistical analysis was carried out using SPSS (IBM Company Headquarters, 233 S. Wacker Drive, 11th Floor, Chicago, Illinois 60606). Variables were compared within groups using Pearson’s chi squared test. Survival outcomes were analyzed using the Kaplan-Meier method. Univariate analysis was carried out by the log rank test. A p value less than 0.05 was considered significant.
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Results
1. GAMES Intermediate Risk Patients: Over 45 years with Low Risk Tumors (n=344)There were 344 patients over the age of 45 years with low risk tumors. Within this group, 196 patients (57%) did not receive RAI. The descriptive statistics of this group are shown in Table 2. These patients were more likely to be female, have pT1 disease and be free of nodal metastases. Using the ATA risk of recurrence system, retrospective analysis shows that the vast majority of patients who were selected not to have RAI (91%) were at low risk of recurrence.With a median follow up of 51 months, the 5 year DSS and RFS were 100% and 97% respectively. The 5 year RFS was 96% versus 98% for RAI versus no RAI groups, p=0.227. Two non-RAI patients developed recurrence (both regional) whereas 6 patients treated with RAI developed recurrence (1 locoregional, 1 regional, 2 regional and distant and 2 isolated distant recurrences). Analysis of factors predictive of recurrence identified positive nodal status as significant (Table 3, 5y RFS 99% versus 91%, p=0.004). Stratifying by primary tumor size, no significant difference in DSS or RFS was found between RAI and no RAI groups: 5 year DSS for <1cm 100.0% versus 97.2%, p=0.548, 1-2cm 97.1% versus 100.0%, p=0.310 and 2-4cm 100% versus 100%, p=1.00 for RAI versus no RAI groups respectively. 2. GAMES Intermediate Risk Patients: Under 45 years with High Risk Tumors (n=188)One hundred and eighty-eight intermediate risk patients were below the age of 45 years and had pT3 or pT4 disease. The descriptive statistics of this subgroup are shown in Table 4. As expected, the vast majority of patients were treated with RAI. Only 29 patients (15%) were managed without post operative RAI. With a median follow up of 54 months, the 5 year DSS and RFS in this group were 100% and 89% respectively. The 5 year RFS was 88% versus 95% for RAI versus no RAI groups. There was 1 distant recurrence in the group selected not to receive RAI. In the group treated with RAI there were 18 recurrences (1 locoregional and distant, 10 isolated regional recurrences, 4 regional and distant and 3 isolated distant recurrences).Analysis of RFS confirmed nodal status as the only significant predictor of poor outcome within this group (5 year RFS 100% for N0 versus 86% for N+, p=0.02). Administration of RAI was not found to predict outcome (Table 5).Further analysis of the records of the 29 patients managed without RAI was carried out to determine the reason for this selection. In 3 patients, the decision was based upon a negative post operative RAI scan. Two patients chose not to receive RAI. A further 2 patients had advanced stage synchronous malignancies which influenced management. One patient was pregnant. Of the remaining 21 patients, 5 had pT3 disease without evidence of extrathyroid extension, 8 had pT3 disease with microscopic extrathyroid extension. Both of these groups were considered low risk for recurrence. Four patients had N1 disease which was low volume (<5 nodes positive and <1cm maximum size). In the remaining five patients, no cause could be found for the decision not to give RAI (Figure 1).
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Discussion
The role of RAI in the treatment of patients with PTC has changed over the decades. This is due to the recognition that RAI has associated complications (4-11) and has been reported to increase the risk of second cancers (12-15). In addition, there is controversy over its efficacy in some patients. Despite this, an increasing proportion of patients now receive RAI and there is significant variation in those rates across the USA (16).A variety of risk stratification systems are available for clinicians, however for around 30 years in our institution, treatment decisions have been based on the GAMES classification. For this reason we selected the intermediate GAMES patients as the focus of this manuscript. Current guidelines agree that for the lowest risk patients, with small primary lesions limited to the thyroid gland, RAI does not confer any survival or recurrence advantage, whereas for larger, more aggressive high risk tumors, RAI is beneficial(1, 17, 18). The role of RAI in patients deemed at intermediate risk of death (using GAMES) is less clear. In this group, there is conflicting or inadequate evidence, which is likely to contribute to the heterogeneous use of RAI in the USA. This is why we chose this patient group as the focus for this study.Following surgical therapy, a decision must be made between the surgeon, endocrinologist and patient, whether or not to proceed with RAI ablation. International guidelines recommend RAI for all tumors which are over 1cm in size, or which are associated with extrathyroid extension or have metastatic disease (1, 17, 18). Given the known high rates of occult nodal metastasis to the central (19) and lateral neck (20), clinicians therefore may consider the use of RAI in almost all patients considered at intermediate risk. Indeed in units which select only thyroid nodules over 1cm to target for fine needle aspiration, all patients diagnosed are potential candidates for RAI.
Although the side effects of RAI are of reduced severity in comparison to external beam radiotherapy to the head and neck, they are potentially long lasting and significant to the patients affected. A number of groups have shown that iodine uptake outside thyroid tissue results in significant salivary and lacrimal dysfunction (4, 6). A recent report on the effect of RAI following total thyroidectomy suggested increased rates of dysphagia in patients who received RAI (4). These late side effects have been reported to have a negative impact on quality of life scores for patients who receive high doses of RAI (8). Perhaps more important is the reported increased risk of second primary malignancies developing in patients treated with high dose RAI, with groups reporting increased rates of salivary and hematological malignancies following RAI therapy (12, 15). This improved understanding of the long term effects of RAI means that a balance between the risks and benefits of RAI must be made in treating individual patients. Due to these factors, and the limited data on the efficacy of RAI in low and intermediate risk GAMES patients, we have become more selective in the use of RAI over the last 25 years in our institution. We have practiced a selective approach to therapy, treating patients on a case-by-case basis. It is the results of this approach in relation to RAI that we present in this study. We
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present data on the 2 intermediate subgroups, low risk patients with high risk tumors and high risk patients with low risk tumors. There were 344 patients with low risk tumors (pT1/T2) in patients over the age of 45 years (Table 2). One hundred and ninety-six patients (57%) in this group were selected not to receive RAI. These patients were more likely to be female, and have smaller primary disease without evidence of regional metastases. This select group of patients had excellent 5 year DSS and RFS outcomes (100% and 98% respectively (Table 3)), showing that our selection was justified. Only 7 of these older patients (3%) with evidence of nodal disease were selected for management without RAI, as previous work from our institution has shown that survival in older patients is negatively affected by the presence of nodal disease (21). In contrast, the subgroup with high risk tumors (pT3/T4) occurring in patients under the age of 45 years received RAI in the majority of cases (84%) had RAI. Only 29 of these patients (16%) did not to receive RAI (Table 4), for reasons including pregnancy, synchronous aggressive malignancies and patient choice. The majority of patients in this group who did not receive RAI had low risk local or regional disease. The 5 year DSS and RFS of these patients was 100% and 95% respectively (Table 5). Thus using very careful selection, even a small number of young patients with high risk tumors can be managed without RAI. However, it must be emphasized that this selection requires a multidisciplinary team of surgeons and endocrinologists with a large experience. Like all retrospective studies, this data has limitations. There is obvious selection bias, both physician and patient, in the decision to use RAI. During the time period studied, both locally and nationally the use of RAI evolved towards more patients being treated, however our patients were all managed within a single tertiary referral cancer center with a fairly uniform approach to surgery, histopathological reporting, post-operative treatment and follow-up. This cannot be said for studies based mainly on the records of national databases. Median follow-up within this cohort was around 5 years, which limits the conclusions that can be drawn from survival data, as deaths may occur beyond this time point. For this reason recurrence data was also included as a surrogate endpoint. Follow up protocols during the time period studied were based upon clinical examination, without the routine use of thyroglobulin or annual ultrasound. Therefore most recurrences were palpable structural disease rather than sonographically identified small volume, or “biochemical” recurrence. Although our aim was not to assess the efficacy or RAI, and therefore we cannot draw conclusions on its effects overall. However our data can be used to identify patients who can be safely managed without RAI. These patients are over 45 years old with T1 and T2 tunors, without any adverse histological features or pathologically positive neck disease. All other intermediate risk patients should be managed with adjuvant RAI with the exception of a few highly selected young patients with limited neck disease both in number and size of affected nodes. In conclusion, as the side effects of RAI, and the long term impact on quality of life have been recognized, clinicians must now select patients appropriately for adjuvant therapy. Those cases judged to be at intermediate risk of death following surgical therapy can
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expect excellent long term outcomes. Our study shows that the subgroup of patients who are over 45 years old, with tumors <4cm, confined to the thyroid, or with limited ETE and with negative neck disease can safely be managed without RAI.
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4. Almeida JP, Sanabria AE, Lima EN, Kowalski LP. Late side effects of radioactive iodine on salivary gland function in patients with thyroid cancer. Head Neck. 2011;33(5):686-90.
5. Newkirk KA, Ringel MD, Wartofsky L, Burman KD. The role of radioactive iodine in salivary gland dysfunction. Ear Nose Throat J. 2000;79(6):460-8.
6. Alexander C, Bader JB, Schaefer A, Finke C, Kirsch CM. Intermediate and long-term side effects of high-dose radioiodine therapy for thyroid carcinoma. J Nucl Med. 1998;39(9):1551-4.
7. Mandel SJ, Mandel L. Radioactive iodine and the salivary glands.Thyroid. 2003;13(3):265-71.
8. Almeida JP, Vartanian JG, Kowalski LP. Clinical predictors of quality of life in patients with initial differentiated thyroid cancers. Arch Otolaryngol Head Neck Surg. 2009;135(4):342-6.
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10. Malpani BL, Samuel AM, Ray S. Quantification of salivary gland function in thyroid cancer patients treated with radioiodine. Int J Radiat Oncol Biol Phys. 1996;35(3):535-40.
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Table 1. GAMES Risk Stratification
Risk Level Patient Factor Tumor Factor
Low Risk Age <45y Papillary Ca M0 No ETE Size <4cm
High Risk Age >45y Follicular Ca / Hurthle Cell Ca M1 ETE Size >4cm
Low Risk Case Low Risk Patient Low Risk Tumor
Intermediate Risk CaseLow Risk Patient High Risk Tumor
High Risk Patient Low Risk Tumor
High Risk Case High Risk Patient High Risk Tumor
Table 2. Descriptive Statistics of Intermediate GAMES >45 years with Low Risk Tumors Stratified by RAI/No RAI
Variable Group Number (%)(n = 344)
No RAI(n=196)
RAI (%)(n=148) p value
GenderFemale 265 (77%) 166 (85%) 99 (67%)
<0.001Male 79 (23%) 30 (15%) 49 (33%)
pT stageT1 273 (79%) 176 (90%) 97 (66%)
<0.001T2 71 (21%) 20 (10%) 51 (34%)
Microcarcinoma< 1 cm 152 (44%) 118 (60%) 34 (23%)
<0.001> 1 cm 192 (56%) 78 (40%) 114 (77%)
pN StageN0 283 (82%) 183 (93%) 100 (67%)
<0.001N1 61 (18%) 13 (7%) 48 (33%)
ATA Risk
Low 277 (80%) 179 (91%) 98 (66%)
<0.001Intermediate 66 (19%) 17 (9%) 49 (33%)
High 1 (1%) 0 1 (1%)
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Table 3. Factors Predictive of Recurrence Free Survival in Patients >45y with Low Risk Tumors
Variable Group Number (%)(n = 344) 5y RFS Univariate p value
GenderFemale 265 (77%) 97%
0.380Male 79 (23%) 97%
pT stageT1 273 (79%) 97%
0.954T2 71 (21%) 98%
Microcarcinoma< 1 cm 152 (44%) 97%
0.411> 1 cm 192 (56%) 97%
pN StageN0 283 (82%) 99%
0.004N1 61 (18%) 91%
ATA Risk
Low 277 (80%) 99%
<0.001Intermediate 66 (19%) 94%
High 1 (1%) 100%
RAINo 196 (57%) 98%
0.227Yes 148 (43%) 96%
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Table 4. Descriptive Statistics of Intermediate GAMES <45 years with High Risk Tumors Stratified by RAI/No RAI
Variable Group Number (%)(n = 188)
No RAI(n=29)
RAI (%)(n=159) p value
GenderFemale 124 (66%) 19 (65%) 105 (66%)
0.957Male 64 (34%) 10 (35%) 54 (34%)
pT stageT3 161 (86%) 26 (90%) 135 (85%)
0.502T4 27 (14%) 3 (10%) 24 (15%)
Microcarcinoma< 1 cm 19 (10%) 2 (7%) 17 (11%)
0.533> 1 cm 169 (90%) 27 (93%) 142 (89%)
ETE
None 21 (11%) 7 (24%) 14 (9%)
0.033Microscopic 115 (61%) 13 (45%) 102 (64%)
Macroscopic 52 (28%) 9 (31%) 43 (27%)
pN StageN0 49 (26%) 13 (45%) 36 (23%)
0.012N1 139 (74%) 16 (55%) 123 (77%)
ATA Risk
Low 13 (7%) 4 (14%) 9 (6%)
0.219Intermediate 123 (65%) 16 (55%) 107 (67%)
High 52 (28%) 9 (31%) 43 (27%)
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Table 5. Factors Predictive of Recurrence Free Survival by for Patients <45 years with High Risk Tumors
Variable GroupNumber (N
=188)5y RFS (19 events) Univariate p Value
Gender Female 124 89.3%0.922
Male 64 87.3%
pT stage T3 161 89.8%0.558
T4 27 81.7%
Microcarcinoma < 1 cm 19 100%0.146
> 1 cm 169 87.6%
ETE None 21 87.5%
0.966Microscopic 115 90.3%
Macroscopic 52 85.1%
pN Stage N0 49 100%0.020
N1 139 85.5%
ATA Risk Low 13 100%
0.515Intermediate 123 88.8%
High 52 85.1%
RAI Yes 159 87.9%0.263
No 29 94.7%
Chapter 10
Discussion, conclusion and future directions
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Discussion, conclusion and future directions
With the incidence of differentiated thyroid cancer (WDTC) increasing in the US and worldwide [1-6], it is now more important than ever to be critical of understanding disease behaviour, selection of optimal treatment and outcomes of therapy. Very few patients will die of WDTC, indeed few will develop recurrent disease during follow up, and for those reasons one must consider not only oncological outcomes, but iatrogenic morbidity when deciding on therapy. The aim of this thesis was to update our understanding of the biology of WDTC, and to critically analyse the outcomes of surgery and adjuvant (RAI) radio iodine therapy.The introduction (Chapter 1) describes the changing trends in incidence of WDTC. We go on to describe the long term outcomes experienced by patients with WDTC, and put these results in historical context. The evolution of systems to predict risk of death or recurrence from WDTC are then described, as is the evolution that has occurred in the approach to both surgical and adjuvant therapy. This historical account both serves to describe the context in which our further work exists, but also highlights the areas of controversy in selecting therapy for patients with WDTC. The approach to management of the primary lesion, the regional lymphatics and selection of patients for adjuvant radiation therapy are all highly controversial, and remain unresolved topics for debate. In Chapter 2 we analyzed the experience of a single institution, tertiary care cancer center over eight decades. Institutional trends have mirrored patterns reported nationally, with an increasing volume of disease managed in each decade. In addition to the change in incidence, our patient group has aged, with older women constituting a larger percentage of the cohort in recent years. Not only has the patient group changed, but the tumors now managed are smaller with over half of the cohort harbouring pT1 disease (<2cm). In addition to the change in size observed, a greater percentage are described as papillary thyroid cancer (PTC) on histology. This is due to changes in histological definitions and also to the increased incidence of PTC reported nationwide.A change in the extent of surgery was also observed with an increase in total thyroidectomy versus thyroid lobectomy during the time period studied. This trend is in keeping with national figures, although the reasons underlying this change are complex. Undoubtedly, the introduction of high resolution ultrasound scanning has allowed clinicians to identify previously occult nodularity in the contralateral lobe, resulting in a need for total thyroidectomy. However, this is unlikely to be the sole reason for the magnitude of change observed. Interpretation of the conflicting evidence on the extent of initial surgery required for WDTC has resulted in various international guidelines [7-9]recommending total thyroidectomy for all but the smallest of primary cancers. Despite the limitations of the evidence upon which such recommendations are based, they do influence practice by impacting not only on the treating surgeon, but also the patient and the endocrinologist or nuclear medicine physician involved in the care of WDTC.Similar complex influences were also seen to affect the use of radioactive iodine (RAI) during the study, with increasing usage as RAI became readily available during the 20th century.
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Despite conflicting evidence regarding efficacy, nearly half of the group in this study received adjuvant RAI, particularly in the later years of the study period.In contrast to the changes observed in patients, tumors, extent of primary surgery and use of adjuvant RAI, outcomes have remained relatively constant. Since the introduction of a standardized risk stratified approach to therapy, less than 5% of patients treated died of disease within 10 years of surgery. We can therefore conclude that it is the biological behaviour of WDTC, that results in excellent oncological outcomes. Few patients will die of disease and recurrence rates are low. Following adequate surgery and histological analysis, those patients who are at higher risk of recurrence and/or death can be readily identified. For these reasons we must be critical of our therapeutic approach to this usually indolent disease. An increasingly aggressive approach to surgery and widespread use of RAI has not improved survival in this patient group, highlighting the importance of selective therapy to minimize morbidity whilst maintaining excellent outcomes. Chapter 3 further considered the interplay of disease biology and therapeutic intervention by analysing the mode of death for those patients who were considered free of disease following initial treatment for WDTC. Improvements in surgical technique, including extracapsular total thyroidectomy, (instead of subtotal or near total thyroidectomy) as the oncological procedure of choice, has had a significant impact on outcome of these patients. A disease once associated with significant rates of death secondary to central compartment recurrence , including asphyxia and haemorrhage, has now largely been eliminated. Very few patients in this series (<2%) who present with resectable locoregional disease and without evidence of distant metastases die of thyroid cancer. However, of those patients who do die of disease, instead of dying from uncontrolled central neck disease, the majority of them now die from distant metastases. Our results are in keeping with other groups’ experience [10], and underscore the need for an oncologically sound approach to WDTC both to prevent death and avoid distressing terminal events.In Chapter 4 we considered thyroid isthmusectomy for select patients with solitary small cancers confined to the isthmus.. This simple procedure avoids risk to the recurrent laryngeal nerves and parathyroid glands. Despite the surgical advantages of such an approach, the technique is not even referred to by international guidelines in the field of oncological thyroid surgery [7-9]. Despite the lack of evidence reported in the literature regarding outcomes for this procedure, targeted resection of disease limited to the thyroid isthmus is oncologically sound. It allows the resection of malignancy with negative margins in properly selected patients. Approximately 1% of our patients had isthmusectomy alone, and at 10 years no patient had local, regional or distant recurrence. Such excellent outcomes provide the evidence required to recommend isthmusectomy in a very select group of patients with limited disease, confined to the isthmus, with no evidence of nodular disease in the thyroid lobes and without nodal or distant metastatic disease. Although isthmusectomy is appropriate management for a highly select group of patients, thyroid lobectomy is usually indicated in nearly half of the patients who present with WDTC,
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confined to one lobe, with no other abnormality in the other lobe, and this was the focus of Chapter 5. Over the past 20 years, there has been a trend away from lobectomy, both in our own institution and nationally. This move is supported by a number of large studies which have suggested that patients who have tumors over 1-1.5cm have better outcomes when managed by total thyroidectomy versus more limited primary surgery [11, 12]. Unfortunately, the findings of these studies have been incorporated into international management guidelines without adequate recognition of their significant limitations [7]. The absence of detailed information on histological subtype, extra thyroid extension, completeness of resection and site of recurrence renders such analyses of multi-institutional databases insufficient to conclude that total thyroidectomy should be considered the standard of care for most patients with WDTC. More recent data from similar national sources has not supported these earlier reports [4, 13-15], and experience from single institutional series, with very detailed treatment and outcome data, have long supported the use of thyroid lobectomy in patients with unifocal disease limited to a thyroid lobe [16, 17]. Our recent data again demonstrates the excellent outcomes that can be expected following lobectomy for pT1/T2N0 disease. Such patients do not die of disease, and the extent of surgery on the thyroid gland had no impact on the low risk of recurrence within this group. Indeed, when clinical staging of T1 or T2 tumors is compared to pathological staging, an important observation has emerged. In those patients with clinically intraglandular disease( T1 or T2) who are shown to have microscopic evidence of extra thyroid extension, on pathological analysis, showed no impact on outcome , as discussed in Chapter 6. Even thyroid lobectomy in such patients was not associated with either increased incidence of recurrence or mortality. The clinical implications of this finding suggest that completion thyroidectomy is not mandatory in such patients (with microscopic extrathyroid extension) as no improvement in oncological outcome would be expected as a result of further surgery. Why should we concern ourselves with extent of surgery in the management of WDTC? Experts have demonstrated that total thyroidectomy can be performed with complication rates commensurate with thyroid lobectomy, and most patients will require post-operative thyroid stimulating hormone suppression irrespective of the extent of surgery. However, worldwide, the vast majority of thyroid surgery is not performed by by international experts, working in centers of excellence. Even if all patients were treated in such tertiary care units, the fact that a procedure can be performed with minimal collateral damage does not mean it should be done if no benefit in outcome is obtained. In contrast to the evidence from large academic units, total thyroidectomy has been reported to have higher rates of hypocalcaemia, recurrent laryngeal nerve injury and tracheostomy than lobectomy when carried out in community hospitals [18, 19]. As stated above, it has not been proven to result in benefit for low risk patients. Guidelines must take these factors into account, as they exist for the protection of patients, not only from disease but also from therapy. In addition to surgery for the primary disease there is considerable controversy over the role of elective central neck dissection, which was the focus of chapter 7. Existing evidence does not suggest that elective neck surgery results in any measurable benefit. Despite this, there is a
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high rate of occult nodal metastasis in patients who undergo elective central neck dissection. The lack of outcome benefit demonstrated my numerous groups led to the American Thyroid Association (ATA) changing its guidance on central neck dissection from a statement suggesting that it “should be considered in papillary carcinoma” to “may be performed, particularly for advanced primary tumors”. There remains intense controversy about the place of elective neck surgery in WDTC, with strong proponents of both dissection and observation. We examined outcomes for those patients who had only total thyroidectomy. Around 40% of such patients would be expected to harbour clinically occult nodal metastases. Despite that, no patient required further salvage central neck surgery. These results highlight the fact that those patients without detectable metastases in the central or lateral neck have excellent outcomes when managed by total thyroidectomy. Rates of recurrence are so low that considering more aggressive surgery in an attempt to re-stage, and therefore be even more aggressive in terms of adjuvant RAI seems unjustified. Such an approach is very likely to leave patients with side effects including nerve paralysis, hypocalcemia, dry mouth and dysphagia, when their outcome without elective central neck dissection would have been excellent anyway. Our cohort of patients was screened using clinical and intraoperative examination in the main. All patients managed today undergo ultrasound assessment of the central neck, and so higher rates of suspicious disease will be encountered. Therefore, if a patient is considered free of metastatic nodal disease following pre-operative assessment and intraoperative examination, the central neck should be left undisturbed to avoid complications whilst maintaining excellent oncological outcome. Although surgery is the mainstay of therapy, radioactive iodine (RAI) is increasingly used in the management of WDTC [20, 21]. Again controversy exists about the correct indications for selecting this relatively low morbidity treatment modality. The evidence supporting the benefit of RAI for all but the highest risk patients is conflicting. Although some groups have shown improvements in outcomes with the use of RAI [11], this has not been universal with other groups reporting that RAI has no impact on survival or recurrence rates in the majority of patients [15, 22]. Although the side effects of RAI have long been considered negligible, recent reports have demonstrated that long term changes in salivary and lacrimal gland function can result in swallowing difficulties and related changes leading to impaired quality of life [23-29]. In addition, rates of second primary malignancy have been reported to be higher in patients who receive RAI, with salivary gland malignancies , leukaemias, soft tissue tumors, as well as breast and colon cancers [20, 30].Given the conflicting evidence regarding improvements in outcome and the increasing recognition of adverse effects, current guidelines recommend the use of RAI routinely, only for high risk patients and selectively for low risk patients. Indications for selection of patients for RAI include older age, male gender, adverse histologies, vascular invasion and multifocal disease. As a result of the lack of clear indications, in addition to witnessing increasing rates of RAI use in the USA, significant variation in practice has also been described [21]. Selecting which patients should receive, and perhaps more importantly not receive RAI, following total
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thyroidectomy therefore is complex, and the issue remains unresolved. It was against this backdrop that Chapters 8 and 9 focused on the role of patient selection in the administration of RAI. As RAI use across the world increases, identifying cohorts of patients managed without RAI is increasingly difficult. However, if physicians are to consider managing patients without RAI, such evidence is crucial in order to support clinical decisions. In these chapters, we do not compare patients treated with RAI to those treated without, but instead report on specific subgroups selected for management without RAI. The aim of this approach was to allow clinicians to understand the outcomes achieved with appropriate surgery alone, when considering whether adjuvant RAI will benefit an individual patient. In Chapter 8 we consider all patients treated with total thyroidectomy within our cohort (n=1129). As expected, outcomes within this group are excellent with 5 year disease specific survival of 99% and recurrence free survival of 92%. We then analyze specific groups separately, in an attempt to provide the reader with information that can be translated from the field of research into clinical practice. We found that the majority of patients with pT1/T2N0 disease were managed without RAI during our study. Those selected for management without RAI tended to have pT1 disease rather than pT2 tumors and were more likely to be female. There were no deaths from disease within this group, and at 5 years, less than 2% of patients had recurred. These results strongly support the management of patients with disease confined to the thyroid gland without RAI, particularly women with low volume disease (the most prevalent group presenting today). Those patients who had pT1/T2N1 disease and those with more advanced primary lesions (pT3/T4) were also analysed. A minority of these patients were selected for management without RAI. They tended to be younger, have smaller primary tumors and have lower volume neck disease. With this approach to risk stratification, even a select group of higher risk patients had low rates of recurrence and excellent survival.Although our aim was not to assess the efficacy of RAI, we have shown that with appropriate patient selection, a significant number of patients can safely be managed without RAI. The majority of decision making within our cohort was based upon clinical, demographic and pathological factors. However, we have also assessed the role of post-operative thyroglobulin (Tg) levels in risk stratification for patients with WDTC [31]. Of 1129 patients treated with total thyroidectomy, 424 had a recorded undetectable Tg level post operatively. The majority of these patients were considered low or intermediate risk. No such patients died, and at 5 years recurrence rates were less than 5% irrespective of the use of RAI. Again we conclude that with adequate surgical management, and selection using clinical, pathological and biochemical factors, a significant number of patients considered at low or intermediate risk following surgery can be selected for management without RAI.
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Conclusions
Having completed this work, we must now interpret our findings and relate them to modern clinical practice. Some facts are indisputable; the incidence of thyroid cancer is rising; the vast majority of lesions now encountered are of papillary histology; increasing numbers of tumors under 1cm are detected; and clinicians increasingly recommend both total thyroidectomy and RAI for all groups of patients. What remains highly contentious is how to identify patients who will benefit from total thyroidectomy rather than thyroid lobectomy, and of those patients who undergo total thyroidectomy, who will benefit from adjuvant RAI.Once the early pioneers of clinical outcomes research in thyroid cancer had shown us that the majority of patients with WDTC had excellent outcomes [32, 33], many experts refined our understanding by identifying the factors which predicted outcome [17, 34, 35]. This work led to the development of multiple risk stratification systems. Although no one system has been universally adopted, all include similar factors – histology, age, distant metastases, extra thyroid extension and size of primary tumor, in addition to completeness of resection, post-operative thyroglobulin and nodal metastases. Such systems gave clinicians the ability to reliably predict outcome for their patients and recommend therapy based on such predictions. At a similar time, advancements in the field of imaging, and in particular the introduction of high resolution ultrasound, changed our understanding of the disease itself at presentation. High rates of contralateral thyroid nodularity and regional metastases were identified leaving clinicians with a difficult dilemma: whilst these must have been present prior to the advent of such accurate imaging, radiological abnormalities could not be ignored. So at a time when we were able to predict excellent outcomes for the vast majority of patients, the identification of clinically occult disease required surgeons to be increasingly aggressive. This change coincided with evidence that a more aggressive approach to both surgery and adjuvant therapy may result in improved outcomes. Despite the previously highlighted flaws in such research, the end result was a further drift towards more aggressive management of this generally low risk patient group. This change manifested despite evidence from multiple sources that well selected patients had excellent outcomes with a more conservative strategy. This leaves us in a position where over 90% of patients in the US who present with papillary thyroid cancer can expect to undergo total thyroidectomy [36]. Following surgery, administration of RAI is increasingly common with around half of all patients being treated, and over a third of even the lowest risk patients receiving RAI as part of their initial therapy [20], despite the lack of evidence to suggest that such treatment strategy will benefit patients. The logical conclusion is that a large percentage of patients with WDTC are being over treated. Analysis of our dataset confirms that the Memorial Sloan Kettering Cancer Center risk stratification system (GAMES, Table 1) remains a valid tool for predicting mortality in well differentiated thyroid cancer. The elements of this staging system have been validated in the work of many other institutions, which have highlighted age, distant metastases, extra thyroid extension and tumor size as independent predictors of outcome. Using the GAMES system, of 1810 patients treated over the 20 year period, 32% were low risk,
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45% were intermediate risk, leaving only 23% of cases classified as being at high risk of death. Five year disease specific survivals are 100%, 99.7% and 92% for low, intermediate and high risk groups respectively (p<0.001). Indeed, the same risk stratification system can be applied to recurrence. Local recurrence at 5 years was seen in 0% of low risk cases, 0.3% of intermediate and 1% of high risk cases (p=0.033). Regional recurrence is more common, occurring in 2% of low, 3% of intermediate and 7% of high risk cases by 5 years (p<0.001). Distant recurrence at 5 years was seen in 0.5% of low risk, 3% of intermediate and 5% of high risk cases (p<0.001) using the GAMES system.By using such an approach to risk stratification, the majority of patients presenting with WDTC can be classified as being at low or intermediate risk of recurrence or death. Almost none of these patients will die of disease, and at 5 years no more than 3% will have recurred. Such excellent outcomes highlight the need for selective therapy. Any increase in morbidity of treatment, be it more aggressive surgery or the addition of adjuvant post-operative therapy, must be weighed against the low chance of improving already excellent oncological outcomes. Although total thyroidectomy carried out by an experienced surgeon is a procedure with low morbidity, this is no excuse for unnecessary surgery. In addition, there is a demonstrable difference in complication rates between thyroid lobectomy and total thyroidectomy for patients treated in the community setting. Again, the low morbidity of RAI should not be a shield used to justify its overuse. In patients who will see no benefit, the changes in lacrimal and salivary function should not be tolerated, and even though small, the association with second primary malignancies demands clinicians be selective in their approach to prescribing RAI. The costs of such potentially excessive therapies can be counted in time, morbidity, occasional mortality and health care expense.We cannot ignore the fact that an increasing number of patients will present for surgical management of WDTC. Although some patients will continue to present with large primary tumors, high volume neck disease and distant metastases, such patients are in the minority. An increasing percentage of our workload will consist of older patients with smaller disease. By 2007 around half of patients presenting in the US had disease limited to the thyroid gland which was less than 2cm and therefore can be considered low risk [20]. With adequate surgical management, these patients have low rates of recurrence and negligible risk of dying from their disease. The present trend towards total thyroidectomy in this patient group must be critically addressed. In the absence of contralateral nodules or high risk features such as aggressive histologies, gross extra thyroid extension and high volume nodal metastases, the operation for WDTC should be extra capsular thyroid lobectomy. This provides equal oncological outcomes to total thyroidectomy without jeopardizing the contralateral central compartment. If an intrathyroid malignancy is encountered following diagnostic lobectomy, the notion that returning to remove an otherwise normal contralateral lobe is good medicine is unjustified. Although a percentage of patients (around 5% in our series) required completion thyroidectomy during follow up, over treating 95% of the patient group with no demonstrable benefit in terms of survival or recurrence should not be considered.
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In selecting patients for adjuvant RAI, only those with high risk disease should be treated routinely. Low and intermediate risk patients have extremely low recurrence rates. The majority should have been treated with thyroid lobectomy, however for patients with multicentric disease or contralateral nodularity, following total thyroidectomy, RAI is an option. Within this group, clinicians and patients must both understand that outcome without RAI is likely to be excellent, and that any potential for improvement is small. This must be balanced against the small but real side effects of therapy. Most patients therefore will not be candidates for adjuvant RAI, but will enter post-operative follow up.An argument is made that total thyroidectomy with adjuvant RAI facilitates post-operative follow up with serial thyroglobulin assessment. This rationale is flawed. In fact, if a true “extra capsular” total thyroidectomy is performed, the post operative Thyroglobulin, in a vast majority of patients is not measurable, thus negating the need for ‘routine RAI ablation’. In addition, low risk patients have such low rates of recurrence, that the idea of inflicting increased morbidity of RAI therapy, on all such patients simply to allow for post-operative TG surveillance to detect residual disease of questionable clinical significance, and without evidence that this improves outcome, is irrational. In contrast, for high risk patients who are subject to higher rates of recurrence, such post-operative monitoring is valuable, further highlighting the need for a selective approach to management. It is important to highlight the limitations of the work presented in this thesis. We do not present prospective or randomized trial data. Indeed, when the ATA considered the possibility of such high quality studies, they found that over 5000 patients would have to be enrolled prospectively and followed for 7 years [37]. This calculation explains the lack of prospective evidence in the field.Throughout our chapters we have highlighted the weaknesses of multi-institutional database studies (generated from hospital based tumor registries) which provide excellent power, but lack precision and uniformity of treatment, pathological and oncological data. Every study has strengths and weaknesses. In keeping with all retrospective studies, both physician and patient biases may have affected outcomes within our dataset. In addition, treatment approaches in terms of surgical therapy and post-operative RAI evolved during our study period. We have witnessed a trend towards total thyroidectomy and RAI within our own institution over the past 3 decades. Histological definitions also evolved between 1980 and 2005. This led to an increase in the incidence of papillary thyroid cancers, and all data presented in this thesis was based on the original interpretation of the histological material. Investigations used in both pre-operative assessment and post-operative follow up have changed, with the introduction of high definition ultrasound and serial thyroglobulin measurement. However, despite the weaknesses, our dataset has consistency in terms of surgical, endocrine and histopathological expertise. In terms of data collection, access to detailed clinical notes allowed accuracy in coding of both recurrence and survival. Due to the high volume nature of our institution we have a large patient cohort (n=1810). In comparison to national databases our study may seem underpowered. However, if such large patient cohorts are required to prove the statistical significance of an improvement related to more aggressive therapy, one
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should question the clinical significance of such an approach to treatment. It is imperative that modern day clinicians not only understand the concept of risk stratification for patients presenting with WDTC, but are able to apply such a system to their practice. Patients treated in such a manner enjoy excellent outcomes, and the vast majority will be cured without ever developing recurrence following an oncologically sound but conservative treatment regimen. This will limit the iatrogenic morbidity of excessive surgery, and limit the side effects of adjuvant RAI to those patients most likely to benefit, whilst ensuring continued excellent oncological outcomes.
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Future Directions
The rising incidence of WDTC has stimulated much interest in studying this disease. However, a number of important challenges remain. In the field of clinical research in thyroid cancer, much work remains in defining the role of selective therapy. The concept of active observation rather than surgical treatment of known thyroid cancers is being explored [38]. Such work is based on our knowledge that occult thyroid cancer is present within the normal population and has routinely been described in autopsy series without contributing to the mode of death [39-41]. Insights into the natural history of untreated disease will allow clinicians to be more accurate in the discussion of alternative strategies for the lowest risk patients parenting with incidentally discovered disease. This is currently being addressin in Japan, where Ito and colleagues are following a group of over 300 patients with PTC. Within the US, the position is more challenging, as the majority of patients will not accept such an observational policy. However, a select group of patients who agree to undergo serial ultrasound for sub centimeter primary tumors are being followed within our institution.In terms of surgical therapy, experience has shown us that in low risk patients with uninodular disease, thyroid lobectomy can be considered safe. However, with the increasing definition of ultrasound imaging, high rates of contralateral previously occult nodules are being described, fuelling a move away from lobectomy. The excellent outcomes reported following lobectomy prior to the introduction of such high resolution imaging should still be expected, but more work is required to identify which contralateral nodules can safely be left in situ without the risk of later surgery. Predictive tools have been developed that allow clinician to individualize the risk of malignancy within a specific nodule [42, 43], and prospective application of such tools to patients with contralateral nodular disease could allow selection of patients with bilateral nodular disease for unilateral surgery. Similar factors now influence post operative follow up. Intense monitoring of low risk patients with serial ultrasound and Tg assessment may be excessive, and lead to heightened patient anxiety and iatrogenic injury in the attempt to address potentially detectable but clinically insignificant residual disease. Future efforts in the field should focus on describing the natural history of post treatment, sonographically identified abnormalities. We know that rates of metastatic disease in the necks of patients with papillary thyroid cancer are high, so when occult subcentimeter nodes are identified on follow up, the need for biopsy and the role for, and timing of treatment are not clear. Salvage surgery of the central neck in particular presents a high risk to patients whilst the benefit of intervention in such cases remains unknown.When considering the role of RAI, definitive evidence of benefit for the majority of patients is still lacking. Current efforts to address this deficiency should be encouraged and expanded, to provide clinicians with the evidence required to accurately select those patients most likely to benefit from RAI, whilst sparing others the side effects of therapy [44, 45]. Advances in our understanding of the molecular biology of carcinogenesis in thyroid cancer has the potential to improve our pre-operative diagnostic abilities, impact on our risk
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prediction systems and provide targets for novel therapies in the future. Already such work is being translated into practice, with the introduction of targeted therapy for those few patients with advanced or unresectable disease [46-51]. It is likely that in future, molecular analysis of biopsy and surgical specimens will allow more accurate risk prediction, aiding in the process of selecting appropriate therapy and follow up regimes.As progress is made in the field, the need for guidelines to evolve and include such a selective approach is evident. The huge volume of research relating to thyroid cancer now being reported makes it impossible for individual clinicians to keep up. The interplay of different medical specialties highlights this issue as only when all members of the disease management team work together, can inappropriate biopsies, poorly planned surgeries, unnecessary adjuvant therapies and conflicting therapeutic strategies be avoided. In the meantime, it is beholden on clinicians to understand the concepts of risk stratification, and to be able to apply them to selection of therapy for patients with WDTC. The concept of total thyroidectomy and post operative RAI for all should be coming to an end, as we move towards the model of personalized medicine. By adopting this approach to the management of WDTC, clinicians serve the interests of their patients first and come closest to the basic medical principle :primum non nocere.
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35. Shah, J.P., et al., Prognostic factors in differentiated carcinoma of the thyroid gland. Am J Surg, 1992. 164(6): p. 658-61.
36. Bilimoria, K.Y., et al., Utilization of total thyroidectomy for papillary thyroid cancer in the United States. Surgery, 2007. 142(6): p. 906-13; discussion 913 e1-2.
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38. Ito, Y., et al., An observational trial for papillary thyroid microcarcinoma in Japanese patients. World J Surg, 2010. 34(1): p. 28-35.
39. Silverberg, S.G. and R.A. Vidone, Carcinoma of the thyroid in surgical and postmortem material. Analysis of 300 cases at autopsy and literature review. Ann Surg, 1966. 164(2): p. 291-9.
40. Harach, H.R., K.O. Franssila, and V.M. Wasenius, Occult papillary carcinoma of the thyroid. A “normal” finding in Finland.A systematic autopsy study.Cancer, 1985. 56(3): p. 531-8.
41. Solares, C.A., et al., Occult papillary thyroid carcinoma in postmortem species: prevalence at autopsy. Am J Otolaryngol, 2005. 26(2): p. 87-90.
42. Nixon, I.J., et al., Nomogram for selecting thyroid nodules for ultrasound-guided fine-needle aspiration biopsy based on a quantification of risk of malignancy. Head Neck, 2012.
43. Nixon, I.J., et al., Nomogram for predicting malignancy in thyroid nodules using clinical, biochemical, ultrasonographic, and cytologic features. Surgery, 2010. 148(6): p. 1120-7; discussion 1127-8.
44. Mallick, U., et al., Iodine or Not (IoN) for low-risk
differentiated thyroid cancer: the next UK National Cancer Research Network randomised trial following HiLo. Clin Oncol (R Coll Radiol), 2012. 24(3): p. 159-61.
45. Mallick, U., C. Harmer, and A. Hackshaw, The HiLo trial: a multicentre randomised trial of high- versus low-dose radioiodine, with or without recombinant human thyroid stimulating hormone, for remnant ablation after surgery for differentiated thyroid cancer. Clin Oncol (R Coll Radiol), 2008. 20(5): p. 325-6.
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47. Ahmed, M., et al., Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: a phase II study in a UK based population. European Journal of Endocrinology, 2011. 165(2): p. 315-322.
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51. Carr, L.L., et al., Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res, 2010. 16(21): p. 5260-8.
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Table 1. GAMES Risk Stratification
Risk Level Patient Factor Tumor Factor
Low Risk Age <45y Papillary Ca M0 No ETE Size <4cm
High Risk Age >45yFollicular Ca / Hurthle
Cell CaM1 ETE Size >4cm
Low Risk Case Low Risk Patient Low Risk Tumor
Intermediate Risk CaseLow Risk Patient High Risk Tumor
High Risk Patient Low Risk Tumor
High Risk Case High Risk Patient High Risk Tumor
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English Summary
Well differentiated thyroid cancer is increasing in incidence. Despite the fact that more patients present with disease, deaths due to disease remain stable, as this malignancy is rarely fatal. The vast majority of patients can be cured, and even those that suffer a recurrence can often still expect to be disease free following salvage therapy.This thesis analyzes the outcomes of patients who present with well differentiated thyroid cancer. We report the factors which predict outcome within this group, and the mode of death for patients who recur and die of disease. We also report the results of treatment, with a particular focus on the role of individually selective therapy. Both surgical and non surgical treatments are analyzed in an attempt to define a balanced approach to the management of patients with this generally low risk disease.The role of thyroid isthmusectomy and lobectomy are analyzed in patients with disease limited to the thyroid gland, and those patients with only microscopic spread of disease beyond the capsule of the gland. It is important to highlight that none of these patients died, irrespective of treatment modality. In addition, recurrence rates were under 5% at 10 years. With such excellent outcomes, the selection of appropriate therapy which balances rates of complication with outcomes is critical.Over the past century, our understanding of thyroid cancer has improved and initial factors which predicted poor outcome, including advanced age, type of tumor, the presences of distant metastases, extra thyroid extension or tumor size over 4cms remain valid. The US and international trend in management of thyroid cancer has been towards more aggressive surgery and adjuvant radioactive iodine therapy. Despite this, we show that in well selected patients, less aggressive surgery results in excellent outcomes. This approach is true for surgery on the thyroid, but also for surgical management of the surrounding lymph nodes. By being selective in the approach to surgery, the risk of damage to surrounding structures is minimized, without compromising oncological outcome.Although previously death from thyroid cancer was commonly due to uncontrolled disease in the central neck, modern surgical management has almost completely eradicated that problem. With a selectively aggressive approach to treatment, around 1% of patients will die, all with disease which has spread beyond the neck.Having performed surgery, selection of patients for further therapy is also crucial. In the USA there is wide variation in practice, largely because of the lack of high quality evidence to guide clinicians. There has been a general trend towards increasing use of radioactive iodine therapy, despite the lack of a strong evidence base to support that change. Our work shows that well selected patients have excellent outcomes when managed without the use of adjuvant radioactive iodine, and that features such as microscopic extra thyroid extension do not mandate the use of more aggressive therapy. Although high risk patients are known to benefit from radioactive iodine, the role of this adjuvant therapy is less clear in low to intermediate risk patients. Over the past decade, the side effects of radioactive iodine have become apparent, with around 10% of patients suffering
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from dry mouth and difficulty swallowing which interferes with long term quality of life. There is also a small increase in the rates of second cancers in patients treated with radioactive iodine. These findings highlight the importance of selecting only those patients who will benefit from a potentially morbid treatment. For patients with advanced disease and those who have disease which has spread beyond the reach of surgical resection, outcomes remain poor. Our results show that only the highest risk patients with advanced cancers (pT3/T4) are at risk of death, and that recurrence rates in lower risk patients are <10% at 5 years. Those patients who are selected for management without radioactive iodine based on patient, tumor and nodal features have excellent outcomes with no deaths and <5% recurrence rates at 5 years.The evidence we present can be used by disease management teams to support a less aggressive approach to therapy for the majority of patients who present with well differentiated thyroid cancer. By adopting a risk-adapted strategy to the selection of therapy for the majority of individual low risk patients, increased attention and resources can be focussed on those patients with high risk disease. This approach will minimize the chance of iatrogenic injury to the majority of patients, reduce costs to the health care provider and society, while optimizing oncological outcomes for all patients who present with well-differentiated thyroid cancer.
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Samenvatting en conclusies
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Samenvatting en conclusies
De incidentie van goed gedifferentieerd schildkliercarcinoom is de afgelopen decennia gestaag omhoog gegaan. Hoewel er zich meer patiënten met deze ziekte presenteren, is het aantal overledenen gelijk gebleven, omdat deze maligniteit zelden fataal is. De overgrote meerderheid van de patiënten kan genezen worden, en zelfs patiënten met recidief hebben een goede kans om ziektevrij te overleven na reïnterventie. Dit proefschrift analyseert de therapie resultaten van patiënten die zich presenteren met goed gedifferentieerd schildkliercarcinoom. We beschrijven de voorspellende factoren voor therapie falen, en de doodsoorzaken in patiënten die overlijden aan deze ziekte. We beschrijven ook de therapieresultaten, met specifieke nadruk op de rol van een risico-afhankelijke therapie keuze in individueel geselecteerde patiënten. Chirurgische en niet-chirurgische therapieën worden beiden geanalyseerd om een gebalanceerde benadering te ontwikkelen voor de behandeling van deze patiënten met meestal laag-risico schildklier carcinoom.De uitkomsten van resectie van de isthmus thyreoïdea en hemithyreoïdectomie worden geanalyseerd in patiënten met intrathyroïdaal carcinoom en patiënten met slechts microscopische extrathyroïdale uitbreiding. Het is belangrijk te benadrukken dat geen van deze patiënten overleden aan de ziekte, ongeacht de gebruikte behandelingsmodaliteit. Recidief percentages na beide behandelingen waren minder dan 5%, binnen 10 jaar. Deze uitstekende resultaten benadrukken het belang van een benadering waarbij therapiekeuze wordt gebaseerd op een afweging tussen kans op complicaties en te verwachten effectiviteit. Over de afgelopen eeuw is het inzicht in het biologisch gedrag van schildklierkanker verbeterd, en zijn de initieel beschreven prognostische factoren zoals hoge leeftijd, tumor type, metastasen op afstand, extrathyroïdale uitbreiding en tumor afmeting zeer waardevol gebleken. Totale thyreoïdectomie met postoperatieve radioactief Jodium behandeling is de algemene trend in de Verenigde Staten en daarbuiten. Toch laat onze analyse zien dat uitstekende resultaten behouden blijven met een meer conservatieve chirurgische benadering, zelfs zonder Jodium nabehandeling. Dit geldt niet alleen voor schildklierchirurgie, maar ook voor chirurgie van de omliggende lymfeklier stations. Door een initieel conservatieve chirurgische procedure is het risico op complicaties minimaal, zonder dat het oncologisch resultaat gevaar loopt. Hoewel oncontroleerbare tumorgroei in de hals in het verleden de belangrijkste doodsoorzaak van schildklierkanker was, is dit probleem door een moderne benadering van schildklier-chirurgie bijna volledig verdwenen. Door middel van een agressieve locale behandeling in een geselecteerde patiëntengroep met hoog risico schildkliercarcinoom is het over lijdensrisico door de ziekte tot ongeveer 1% teruggebracht, en blijkt dat afstandsmetastasen de belangrijkste doodsoorzaak zijn in patiënten die overlijden aan deze ziekte. Na chirurgische behandeling is de selectie van postoperatieve behandeling cruciaal. In de Verenigde Staten bestaat er een grote variatie in postoperatieve therapie keuze, voornamelijk door gebrek aan bewijs voor effectiviteit van deze behandeling. Desondanks is de wereldwijde trend een verhoging van gebruik van radioactief Jodium als nabehandeling voor patiënten met schildklierkanker. Onze analyses laten zien dat uitstekende behandelingsresultaten
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kunnen worden behouden zonder gebruik van radioactief Jodium, en dat factoren zoals microscopische extrathyroïdale uitbreiding geen indicatie zijn voor meer agressieve therapie. Hoewel radioactief Jodium behandeling duidelijk voordeel biedt in hoog-risico patiënten, is dit effect veel minder duidelijk aanwezig in patiënten met laag risico en gemiddeld risico schildklierkanker. Over de afgelopen jaren zijn de neveneffecten van radioactief Jodium beter in beeld gekomen, met bijwerkingen als droge mond, slikstoornissen en verminderde kwaliteit van leven in ongeveer 10% van de behandelde patiënten. Er bestaat ook een verhoogde kans op tweede primaire tumoren in patiënten behandeld met radioactief Jodium, en deze bevindingen benadrukken het belang van een goede patiënten selectie voor gebruik van deze therapie. Voor patiënten met vergevorderde ziekte met uitbreiding buiten de voor chirurgie bereikbare gebieden blijven de uitkomsten slecht. Onze bevindingen tonen aan dat slechts patiënten met T-stadium 3 en 4 een overlijdensrisico lopen terwijl recidief percentages in laag risico patiënten circa 10% binnen 5 jaar bedragen. Patiënten die op basis van patient-, tumor- en lymfeklier-karakteristieken geselecteerd werden voor behandeling zonder radioactief Jodium hebben uitstekende uitkomsten zonder overlijdensrisico en met recidief risico van minder dan 5% binnen 5 jaar. De resultaten van dit proefschrift kunnen worden gebruikt door multidisciplinaire behandelingsteams om te pleiten voor minder agressieve schildklierkanker behandelingen in een meerderheid van patiënten met goed gedifferentieerd schildkliercarcinoom. Door een risico-afhankelijke therapie benadering te verkiezen in de meerderheid van schildklierkanker patiënten met laag of gemiddeld risico, kan het grootste deel van de beschikbare middelen worden ingezet om verhoogde therapie intensiteit aan te bieden aan hoog-risico patiënten. Deze benadering zal de kans op therapie complicaties verminderen in het merendeel van de patiënten en de kosten van schildklierkanker behandeling verminderen, terwijl de oncologische effectiviteit van de behandeling behouden blijft voor alle patiënten met goed gedifferentieerd schildkliercarcinoom.
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Curriculum Vitae
Iain James Nixon MBChB, FRCS (ORL-HNS)
I grew up in Edinburgh, Scotland and following graduation from high school, attended medical school in Glasgow. Graduation in 1999 was followed by a 1 year internship in general medicine and general surgery in Glasgow prior to a 2 year period of basic surgical training in Peterborough, just north of London, England. Having completed this basic training, my interest in otorhinolaryngology led me to continue this training in Edinburgh. In 2004 I was accepted in to higher surgical training in the West of Scotland, a program I would graduate from in 2011. During this training program my interest in head and neck surgery developed.During this period of training, I was offered the opportunity to join the Head and Neck Service in the Department of Surgery at Memorial Sloan Kettering Cancer Center (MSKCC), New York, USA, for a 1 year research fellowship. MSKCC is one of the largest cancer centers in the USA, and this tertiary referral cancer center has an international reputation for excellence in education, research and clinical practice. The head and neck faculty within the institution comprise some of the most respected head and neck surgeons in the world, with internationally recognised expertise in the field of thyroid cancer. My first year in New York was dedicated to updating the institutional database on thyroid cancer, in addition to streamlining clinical data collection within the department. 1810 patients were included in the dataset ultimately collected and this cohort formed the basis for this thesis. Having completed data collection, I returned to the UK to complete my training prior to returning to complete a clinical fellowship within MSKCC. During this time, with the mentorship of the senior faculty within the institution, I produced a series studies describing the outcomes of patients diagnosed with well differentiated thyroid cancer. These projects have been presented locally, regionally, nationally and internationally across the US and Europe. The work culminated in peer review publication accepted by the highest impact surgical journals in the world, and constitute the papers presented in this thesis. Having completed my training in New York, I have returned to academic practice in the UK, as a consultant in general otorhinolaryngology and head and neck surgery.
