Minimally invasive follicular thyroid cancer (MIFTC)—a consensus report of the European Society of...

REVIEWARTICLE

Minimally invasive follicular thyroid cancer(MIFTC)—a consensus report of the European Societyof Endocrine Surgeons (ESES)

Gianlorenzo Dionigi & Jean-Louis Kraimps & Kurt Werner Schmid & Michael Hermann &

Sien-Yi Sheu-Grabellus & Pierre De Wailly & Anthony Beaulieu & Maria Laura Tanda &

Fausto Sessa

Received: 18 October 2013 /Accepted: 29 October 2013 /Published online: 14 November 2013# Springer-Verlag Berlin Heidelberg 2013

AbstractBackground This paper aims to review controversies in themanagement of minimally invasive follicular thyroid carcino-ma (MIFTC) and to reach an evidence-based consensus.Method MEDLINE search of the literature was conductedusing keywords related to MIFTC. The search term wasidentified in the title, abstract, or medical subject heading.Available literature meeting the inclusion criteria were

assigned the appropriate levels of evidence and recommenda-tions in accordance with accepted international standards.Results were discussed at the 2013Workshop of the EuropeanSociety of Endocrine Surgeons devoted to MIFTC.Results Published papers on MIFTC present inadequate pow-er with a III–IV level of evidence and C grade of recommen-dation. Several issues demanded a comparison of publishedstudies from different medical reports regarding MIFTC def-inition, specimen processing, characteristics, diagnosis, prog-noses, and therapy. As a consequence, it is difficult to makevaluable statements on MIFTC with a sufficient recommen-dation rating. MIFTC diagnosis requires clearer, unequivocal,and reproducible criteria for pathologist, surgeons, and endo-crinologists to use in the management of these patients. If thedistinction between MIFTC and WIFTC cannot be made, anexpert in thyroid pathologist should be consulted.Conclusion According to published papers, the following con-clusions can be drawn. (a) Candidates for hemithyroidectomyareMIFTCwith exclusive capsular invasion, patients <45 yearsold at presentation, tumor size <40 mm, without vascularinvasion, and without any node or distant metastases. (b) Can-didates for total thyroidectomy areMIFTC in patients ≥45 yearsat presentation, tumor size ≥40 mm, vascular invasion present,positive nodes, and positive distant metastases. (c) In the ab-sence of clinical evidence for lymph node metastasis, patientswith MIFTC do not require prophylactic lymph node dissec-tion. (d) Radio iodine ablation is indicated in elderly patients(>45 years), large tumor size (>40 mm), extensive vascularinvasion, presence of distant synchronous or metachronousmetastasis, positive nodes, and if recurrence is noted atfollow-up.

Keywords Follicular thyroid carcinoma .Minimally invasivefollicular thyroid carcinoma .Widely invasive follicular

This paper was partly presented and discussed at the workshop “Surgeryof Thyroid Cancer” organized by the European Society of EndocrineSurgeons (Berlin, Germany, May 23–25, 2013).

G. Dionigi (*)1st Division of General Surgery, Department of Surgical Sciencesand Human Morphology, University of Insubria, Via Guicciardini 9,21100 Varese, Italye-mail: [email protected]

J.<L. Kraimps : P. De Wailly :A. BeaulieuDepartment of Endocrine Surgery, Jean Bernard Hospital, PoitiersUniversity, 86021 Poitiers, France

K. W. Schmid : S.<Y. Sheu-GrabellusInstitute of Pathology and Neuropathology, University HospitalEssen, University of Essen-Duisburg, Essen, Germany

M. Hermann2nd Department of General Surgery, Krankenanstalt Rudolfstiftung,1030, Juchgasse 25, Vienna, Austria

M. L. TandaDivision of Endocrinology, Department of Clinical and ExperimentalMedicine, University of Insubria, Via Guicciardini 9, 21100 Varese,Italy

F. SessaDivision of Pathology, Department of Surgical Sciences and HumanMorphology, University of Insubria, Via Guicciardini 9,21100 Varese, Italy

Langenbecks Arch Surg (2014) 399:165–184DOI 10.1007/s00423-013-1140-z

carcinoma . Histopathology . Classification . Vascularinvasion . Capsular invasion . Surgery . Diagnosis .

Prognosis . Adult . Age . Tumor size . Distant metastases .

Recurrence . Lymph nodemetastases . Radio iodine ablation .

Lymphadenectomy

Introduction

Follicular thyroid carcinoma (FTC) accounts for 10–20 % ofdifferentiated thyroid carcinomas (DTCs) [1, 2]. In 1914,Graham [3] was the first to provide a histological definitionof FTC, which originates from follicular cells [3]. Accordingto the WHO classification system [4] for the pathologicaldiagnosis and classification of FTC, the presence of capsularand/or vascular invasion or invasion of adjacent structures andthe absence of nuclear features of papillary thyroid carcinoma(PTC) defines FTC. The follicular variant of PTC is excludedbased on nuclear features of PTC [5].

In 1988, Hedinger et al. [6] differentiated FTC according tothe grade of invasion in minimally invasive (MIFTC) andwidely invasive tumors (WIFTC), and he defined the progno-sis with different recurrence and mortality rates. Patients withWIFTC present with clearly grossly invasive tumors thatshow widespread infiltration into blood vessels and/or adja-cent thyroid tissue and often lack complete encapsulation; thetumors may replace the entire lobe or extend outside thethyroid into adjacent tissues [4]. MIFTC is more difficult todiagnose. The microinvasive variety can be nearly indistin-guishable from follicular adenoma.MIFTC is diagnosed if thetumor is macroscopically well defined, encapsulated withmicroscopic but not macroscopic evidence of capsular orvascular invasion, and composed of >75 % of follicular cells[4]. The salient characteristics are encapsulated tumors thatinfiltrate the blood vessels located within or immediatelyoutside the capsule and/or penetrate the thickness of the tumorcapsule. These features of MIFTC make follicular cancersdemonstrable only on permanent histological sections [4, 7–9]

The key role of the pathologist is to determine the micro-and macroscopic differentiation and the assessment of thegrade of malignancy according to reliable criteria to determinea histological diagnosis. Hermann et al. [9] defined these twodifferent types of cancer as follows: for MIFTC, “an invasionshould be searched”, and for WIFTC “a capsule has to besearched.”

Subtyping FTC represents a way to stratify the risk of localrecurrence (LR), lymph nodal (LN), and distant metastases(DM), and the prognostic impact to create a tailored surgicalstrategy for each patient [4, 7–12]. Investigators have ob-served highly significant differences between WIFTC andMIFTC from uni- and multivariate analyses that includedclinical features (e.g., older age), outcomes (e.g., higher inci-dence of DM), pathological differences and biological

behaviors (e.g., larger tumor size, extrathyroidal extension,multifocality, lymph node metastasis, marked vascular inva-sion, tumor differentiation, more advanced stage, postopera-tive LR rate disease, and risk group classification) [1, 7–12].Compared with MIFTC, patients with WIFTC have a distinctclinical course with poorer survival rates related to thyroidcancer [1, 7, 8]. Based on a recent, large published study, therates of DM (9 %) and mortality (13 %) in patients withWIFTC were higher than in patients with MIFTC (0.5 and3 %, respectively; p <0.001) [8]. Compared with WIFTCpatients, more patients with MIFTC underwent surgery (93vs. 99 %, respectively; p <0.001) [8]. Moreover, patientsdiagnosed with MIFTC were more likely to receiveradioiodine ablation (RAI) than patients with WIFTC (53 vs.48 %; p <0.001). [8] In one study, patients in the MIFTCgroup had lower postoperative thyroglobulin levels than thosein the WIFTC group [7]. WIFTC patients have also beenshown to present more frequently with recurrent goiter disease[1, 7, 8].

Therefore, the two entities WIFTC and MIFTC may bereported separately [9–12].

The purposes of this paper are, first, to critically reviewmost relevant recent contributions to MIFTC under the scopeof evidence-based medicine; second, to analyze the clinical,pathological features and outcomes of patients with MIFTC;and third, to present a series of recommendations for therapy.

Methods

MEDLINE search of the literature was conducted using key-words related to MIFTC. An extensive review had previouslybeen performed in 2001 [13]. The search term was identifiedin the title, abstract, or medical subject heading. Referencesmeeting the inclusion criteria were also included when thenumber of patients treated was fewer than 100. Availableliterature meeting the inclusion criteria were assigned theappropriate levels of evidence and recommendations in accor-dance with accepted international standards. [14, 15]. A draftmanuscript was prepared and published on the ESEShomepage for Members' comments (http://www.eses.cc/login_eses.php). The topic was discussed in plenary sessionswith input from the Delegates at the 2013 ESES workshop inBerlin (May 23–25): Surgery of Thyroid Cancer—W3Minimally Invasive FTC .

Criticality of published data

Several issues demanded a comparison of published studiesfrom different medical reports regarding MIFTC characteristicsand prognoses. As a consequence, it is difficult to make valu-able statements on MIFTC with a sufficient recommendation

166 Langenbecks Arch Surg (2014) 399:165–184

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rating [14, 15]. Below, we describe the criticalities that emergedfrom this review.

Definitions

A source of confusion arose from the classification of follic-ular tumors and subclassification of MIFTC. Accepted histo-logical schemes of MIFTC are useful and should be correlatedwith tumor behavior so that results regarding survival anddisease stage reported from different medical centers can becompared. However, considerable differences of opinion re-main among pathologists about the precise criteria that shouldbe used to diagnose and differentiate MIFTC and subtypes ofMIFTC from follicular adenoma and WIFTC [16–19]. Avariety of different MIFTC definitions have been describedin the literature [16–19]. The histological diagnoses ofMIFTCin earlier reports were based on the criteria determined at eachinstitution [16–19]. Therefore, the termMIFTC covers a widespectrum, including tumors with only minimal capsular inva-sion, those with vascular invasion, and tumors with minimalinvasion but distant metastases (Table 1). [20] Clinicians havesuggested that preoperative detectable distant metastasis inMIFTC is a diagnostic criterion of exclusion [13].

The Armed Forces Institute of Pathology classification stat-ed that the diagnosis of MIFTC can be made either on the basisof focal capsular invasion alone, limited vascular invasionalone, or both capsular and vascular invasion [4, 6, 21]. Otherreports proposed classifying FTC into three categories: mini-mally invasive, intermediate (moderately) invasive, and widelyinvasive [22, 23]. D'Avanzo proposed that minimally invasiveFTC should be categorized as FTCwith capsular invasion only,moderately invasive FTC should include angioinvasion with orwithout capsular invasion, and widely invasive FTC shouldinclude tumors that invade directly into adjacent parenchymaand\or other tissue [22, 23]. Baloch and LiVolsi [12] haverecommended that only those follicular lesions with capsularinvasion alone should be termed MIFTC. The College ofAmerican Pathologists does not consider MIFTC to includethose tumors with vascular invasion [26]. It remains to beshown whether Rosai's categorization of the intensity of histo-pathological vascular invasion (i.e., four or more vs. one tothree sites of invasion) [27, 28] can discriminate betweenminimally invasive and widely invasive FTC. The furthersubdivision by Neuhold, Kaserer, and Lax for the AustrianCancer manual by the Arbeitsgemeinschaft ChirurgischeOnkologie der Österreichischen Gesellschaft für Chirurgie(ACO-ASSO) in 2010 [29] has been defined in the followingway: MIFTC describes an capsulated tumor with the loss ofcontinuity of the capsule and/or limited vascular invasion (max-imum of three foci of invasion).

Moreover, certain terminology used in published papers,such as “capsular invasion” or “vascular invasion,” may bemisleading [9].

Thompson et al. [13] specified that capsular infiltration ispresent when the tumor cells are seen penetrating through thewhole capsule or, alternatively, when there is interruption ofthe capsule by tumor cells perpendicular to the direction of thecapsule fibers. This interruption is often represented as afungoid invasion of neoplastic cells in the adjacent structures,which may build a pseudocapsule and hide the capsular inva-sion by appearing as an intact capsule. An incomplete capsu-lar invasion makes it difficult to discriminate between follic-ular adenoma and carcinoma, and the differentiation maydepend on the ability and experience of the pathologist [30,31]. Some, but not all, pathologists consider only completepenetration of the capsule as indicative of capsular invasion[30, 31]. In some reports, capsule infiltration was not other-wise specified. In other studies, this infiltration was defined ascapsular invasion up to the full extent of the capsule, and/or an“extension into the capsule,” “definite capsular invasion,”“complete penetration of the capsule,” “duplication of thecapsule,” “protrusion of tumor cells outside the capsule,”and a “satellite nodule” [30, 31]. Other studies classifiedcapsular invasion by the degree of invasion (<50 or >50 %of the thickness of the capsule), by single or multiple sites, orby <4 foci or ≥4 foci [13, 26]. A broken capsule caused byfine-needle aspiration (FNA) cytology, intraoperative acciden-tal capsular breaking, or distortions due to inappropriate prep-aration of the specimen are often difficult to distinguish fromneoplastic invasion of the capsule [9]. In most of the cases,capsular invasion can only be assessed by observing multiplesections. Furthermore, the analysis of traumatized thyroidmasses with capsular defects due to surgery can be difficultand subjective [9].

Hence, the surgeon plays a relevant role in the correctdiagnosis by gently moving the thyroid and avoiding instru-mental lesions. Most importantly, a surgeon should take careto not open the capsule of the mass (which occurs frequentlyin large tumors) in cases with unfavorable neck anatomy orwhen the surgical incision is too small compared to the di-mension of the mass [9]. The surgeon should also avoidmacroscopic evaluation by cutting the mass intraoperatively,as this evaluation should be conducted by the pathologist [9].

In addition, the definition of vascular invasion is a topic ofcontroversy. Vascular invasion is identified by direct exten-sion into the vessel lumen, intravascular attached tumorthrombi, and/or tumor nests covered by endothelium [26]. Asubendothelial cluster of tumor cells in a vein, localized in thecapsule of the mass or just outside of the capsule, definesvascular invasion. Vascular invasion is sometimes not speci-fied or is defined as “vascular invasion within the lesion” and/or “vascular invasion immediately outside of the tumor cap-sule” [26]. Tumor plugs in vascular spaces within the tumormass did not qualify as vascular invasion according to thereview of Thompson et al. [13]. In others studies, vascularinvasion in MIFTC was also stratified according to a cut-off

Langenbecks Arch Surg (2014) 399:165–184 167

Tab

le1

MIFTCdefinitio

nsincluded

inmostrecentp

ublishedstudies

Author,year,paper

MIF

TC

Definition

ofMIFT

CCapsular

invasion

(CI)

CIwith

/with

out

AI≤3

Vascular

invasion

(VI)

Oncocytic

changes

Meanfollo

w-up

(years)

Death

%(n/to

tal)

GoffredoP,2013,A

nnSurg

Oncol

1.200

WHO

––

–Excluded

103.2%

(39/1.200)

ItoY,2013,Endocrino

Pathol

292

Capsularinvasion

only

Lim

itedvascular

invasion

(<4)

Extensive

vascular

invasion

(>4)

49%

(144/292)

–30

%(88/292)

17%

(50/292)

9.7(0.5–27)

2%

(7/292)

Sugino

K,2012,Thyroid

251

WHO

76%

(193/251)

–83

%(209/251)

Excluded

7.2

5.5%

(14/251)

Ban

EJ,2012,A

NZJSurg

52WHO

––

–Excluded

9.7±7.7(m

edian,7.2;

range,1–34)

7.9%

(10/127)

AsariR,2009,AnnalsofSurgery

127

WHO

––

–22

%9.0±0.4

0%

(0/89)

Huang

CC,2009,Surg

Oncol

89WHO

––

–Excluded

80%

(0/44)

HermannM,2008,Eur

Surg

(abstract)

44Capsualinvasion

CIandlim

itedvascular

invasion

(<4)

25%

(11/44)

75%

(33/44)

–Excluded

30

GhosseinRA,2006,Cancer

50Capsularinvasion

only

Lim

itedvascular

invasion

(<4)

Extensive

vascular

invasion

(>4)

78%

(39/50)

34%

(17/50)

64%

(32/50)

30%

(15/50)

14.4(0.1–38.6)

0%

(0/72)

LoCY,2005,Ann

Surg

72WHO

68%

(49)

–32

%(23)

Excluded

7.9(0.2–39)

12.6

%(12/95)

D'AvanzoA,2003,Cancer

95Minim

allyinvasive:capsularinvasiononly

Moderateinvasive:v

ascularinvasion

with

orwith

outC

I

47%

(45)

–53

%(50)

Excluded

10.8

2%

(1/52)

ChowSM

,2002,Cancer

52To

talencapsulatio

nwith

nomacroscopic

invasion

––

–Excluded

11.3(1–20.4)

0

Collin

iP,2004,Histopatology

18Capsularinvasion

only

Lim

itedvascular

invasion

(<4)

Extensive

vascular

invasion

(>4)

100%

(18/18)

88%

(16/18)

83%

(15/18)

Excluded

––


number of vascular invasions. This cut-off value was intendedto identify, calculate and compare concrete numbers of vascu-lar invasions to discriminate between WI and MIFTC. Langet al. [25] considered those cases of FTC invading fewer thanfour vessels as MIFTC and those cases invading more thanfour blood vessels (≥4) asWIFTC. In this way, Lang et al. [25]identified a subset of MIFTC patients who were at a higherrisk of relapse. Investigators then could classify MIFTC intotwo subsets according to the degree of vascular invasion:“minimally invasive” characterized by the presence of limitedvascular invasion (<4) and/or capsular invasion that follows arelatively indolent clinical course and MIFTC with extensivevascular invasion (≥4), which is regarded as a subset ofMIFTC associated with a higher risk of relapse. Goldsteinet al. [32] found no relationship between the number of foci ofvascular and capsular invasion and the occurrence of metas-tases. Regarding the size of vessels, some studies have ex-cluded “large” vessel invasion from the definition of MIFTC[32, 33]. Thompson et al. [13] classified vascular invasionaccording to vessel size as small, medium, or large, withfurther classification into single or multiple foci. Small vesselsusually were located within the capsule and were of a limitedcaliber. Medium-sized vessels without a smooth muscle walloften were located immediately adjacent to the capsule. Al-though they were present in the capsule, the large-calibervessels with smooth muscle in the vessel wall usually weredistant from the capsule [13]. In most studies, no distinctionwas made between veins, arteries, or lymphatic channels, andno histochemical or immunohistochemical studies were per-formed to identify vascular structures.

Level of evidence

Most published reports are contemporaneous or historical con-trols, retrospective studies, single institutional series, or cohortstudies with <100 cases (Table 2). There is only one prospectivecollected data with retrospective analysis on MIFTC [1]. Thereare four large series onMIFTC (with more than 100 patients): areview of 251 patients by Sugino et al. [34], a study of 290cases by Ito et al. [35], the study of 127 patients by Asari et al.[1], and a study of 1,200 patients byGoffredo et al. [8]. This laststudy is an analysis from 18 different regions of USA thatrepresent 28 % of the American population (largest cohort ofMIFTC in the literature) [8]. The analysis of Goffredo et al. [8]did not include specimen revision. Some data that would beinformative, such as symptoms at presentation, medical history,patient comorbidities, radiographic studies, intent of surgery,operative reports, rates of recurrence, and pertinent serologiclaboratory values, were not analyzed because they were notcollected in the database [8].

In some reports, the small number of cases and eventsprecluded the application of statistical analysis [36–38]. T

able2

Prevalence

ofMIFTC

Author,year,paper

Type

ofstudy

Period

(years)

DTC

PTC

FTC

WIFTC

MIFTC

OverallMIFTC

GoffredoP,2013,A

nnSurg

Oncol

Retrospectiv

e10

(2000–2009)

––

5.408

78%

(4.208)

22%

(1.200)

–

Sugino

K,2012,Thyroid

Retrospectiv

e17

(1989–2006)

9.333

95.7

%(8.934)

4.3%

(399)

16.5

%(66/399)

63%

(251/399)

2.7(251/9333)

Ban

EJ,2012,A

NZJSurg

Retrospectiv

e12

(1997–2009)

––

6115

%(9/61)

85%

(52/61)

–

AsariR,2009,Annalsof

Surgery

Prospective

43(1963–2006)

––

207

38.6

%(80)

61.4

%(127)

–

Huang

CC,2009,Surg

Oncol

Retrospectiv

e30

(1977–2007)

234

62%

(145)

38%

(89)

–

LoCY,2005,Ann

Surg

Retrospectiv

e39

(1961–2000)

655

76%

(499)

24%

(156)

54%

(84)

46%

(72)

10.9

%(72/655)

D'AvanzoA,2003,

Cancer

Retrospectiv

e–

––

132

20%

(24)

80%

(95)

ChowSM

,2002,Cancer

Retrospectiv

e37

(1960–1997)

1,057

79.7

%(842)

20.3

%(215)

76%

(163)

24%

(52)

4.9%

(52/1,057)

Collin

iP,2004,Histopatology

Retrospectiv

e18

(1975–1993)

720

––

–2.5%

(18)

2.5%

Thompson

LD,2002,Cancer

Retrospectiv

e9(1974–1983)

6.501

––

––

2.89

%(188/6.501)


However, a positive element in most of these studies wasthe discrete follow-up period (mean, 10 years; range, 3–14)that allowed most of the investigators to study the naturalhistory of this neoplasm (Table 1) [1, 8, 34, 35].

Specimen review

A limitation of these studies was that it was not possible tocontrol the method of specimen processing due to the retro-spective nature of the studies [36]. Slides available from eachpatient's thyroid specimen were analyzed by reviewing pa-thologists. However, these slides were only representative ofthe entire collected thyroid specimen, and it was therefore notpossible to analyze parts of the specimen that were not initiallyfixed and stained [36]. Furthermore, the number of sectionswas not known. Multiple sections are needed to demonstratecapsular or vascular invasion. Thompson et al. [13] suggesteda generous sampling of an average of 18 sections examinedper MIFTC patient would be ideal, irrespective of the tumorsize. This number equates to approximately six sections percentimeter of tumor. Lang et al. [39] demonstrated that theassessment of criteria of malignancy for MIFTC increasedtogether with the number of analyzed sections from 2 to 8 %when only two sections were analyzed, to 50 % when eightsections were analyzed, to 97 % when ten sections wereexamined [10, 11]. The standardization of the preparation ofthe specimen is fundamental for the diagnosis ofMIFTC; for adefinitive histological examination, at least 10 sections shouldbe analyzed [10, 11].

The revision of the pathologist's assessment was sometimesentrusted to one or more pathologists (control) with or withoutblinded review; few thyroid, endocrine, or head and neckpathologists were involved. The above concept is importantbecause the interobserver variation of the definition ofMIFTCamong pathologists remains significant, and a wide range ofprevalence of MIFTC has been reported (Table 2) [31, 40]. Inaddition, having a dedicated, high volume, endocrine pathol-ogist to correctly and precisely interpret and review theMIFTC specimens has been shown to be critically important[10, 11, 31, 40].

Hurthle cell carcinomas

Hurthle cell carcinoma (HCC), a variant of FTC, is defined astumors composed predominately of oncocytic cells with fol-licular epithelial cells and mitochondria filled cytoplasms [21,41–43]. HCC occurs more often in iodine-rich areas, whereasFTC occurs more often in iodine-poor areas [21, 41–43]. HCCpresents more often after exposure to therapeutic low-doseradiation compared with FTC and is more likely to be familial[41]. HCC is also more likely than FTC to involve regionallymph nodes [41]. Only 7 % of HCCs take up radioiodine

compared with 75 % of FTCs; however, both carcinomastypically produce thyroglobulin [21, 41–43].

HCCs were initially considered follicular tumors accordingto the World Health Organization classification system [6],although others [21, 42, 43] have proposed that HCCs repre-sent a distinct entity with a different behavior and clinicalcourse. Therefore, some studies included HCC in the analysis[41], while other studies did not to avoid possible bias. [21,42, 43] Therefore, this element may complicate the evaluationof the MIFTC literature (Table 1).

Spectrum of the disease

Prevalence

FTC is more common in areas of endemic goiter [1, 44]. FTCincidence is higher in iodine-deficient than iodine sufficientregions [1, 44]. A decrease in the incidence of FTC has beenreported, most likely because of the eradication of iodinedeficiency [45]. This decrease is in contrast with the recentobservations of Goffredo et al. [8], who reported that theincidence of MIFTC among all FTCs significantly increasedfrom 16 % in the period of 2000–2004 to 26 % from 2005 to2009 (p <.001) [8]. This increase was most likely due to moreaccurate histological diagnoses, that is, the identification ofsubtype variants of FTC as MIFTC rather than follicularadenoma [4, 8].

In the Surveillance, Epidemiology, and End Results analy-sis, the race distribution of 1,189 MIFTC patients who weresurgically treated was as follows: 78 % of the patients treatedwere white patients, 11 %were black patients, and 10% of thepatients were classified as other [8]. Of 95 MIFTC patientspresented by Thompson et al. in 2001 [13], 65 % were white,4 % were African American, 5 % were Asian/Indian, and26 % were reported as unknown.

MIFTC represent a small percentage of patients who un-dergo operations. An accurate description of the actual prev-alence of surgically treated MIFTC has been presented inseveral studies (Table 2).

Sugino et al. [34] reported that between 1989 and 2006, 9,333 patients with DTC underwent initial surgical treatmentand 399 (4.3 %) of the patients had been diagnosed with FTC.After excluding patients with concomitant PTC, oxyphilic cellcarcinoma, and clear cell carcinoma, there were 317 patientswith ordinary FTC. Of these patients, 251 were diagnosedwith MIFTC. Therefore, the overall prevalence of surgicallytreated MIFTC was 2.7 % (251/9,333). Chow et al. [46]analyzed 1,057 patients with DTC over a 37-year period.Patients with a diagnosis of Hurthle cell carcinoma were notincluded. In this analysis, 80 % of the patients were diagnosedwith PTC, and 20% patients were diagnosed with FTC. Of theFTC patients, 163 (163/215, 76 %) were diagnosed with


WIFTC and 52 (52/215, 24 %) with MIFTC. Therefore, theprevalence of MIFTC was 4.9 % (52/1057) overall. Lo et al.[24] presented the complete data of 655 patients with DTCtreated from 1961 to 2000. The surgical specimens revealed156 patients with FTC, including 72 patients with MIFTC(overall incidence, 10.9 %, 72/655). In total, 188 MIFTCpatients were identified in a review of 6,501 patients(2.89 %) from the files at the Armed Forces Institute ofPathology from 1974 to 1983. [13] Finally, according toCollini et al. [37, 38], MIFTC patients represented 2.5 % of720 cases seen from 1975 to 1993.

Overall, in most published studies, almost two thirds of allFTC patients are diagnosed with MIFTC [1, 42, 43]. Howev-er, this finding is in contrast to reports by Chow et al. [46],Huang et al. [7], and Goffredo et al. [8] where approximately35 % of patients were categorized as having MIFTC, and65 % of patients were categorized as having WIFTC. Thus,the interobserver variation in the diagnosis and definition ofMIFTC used among pathologists remains significant [10, 11,31, 40] (Table 2).

Clinical manifestation

Most clinical manifestations are presented and compared withregard to the specific distribution between WIFTC andMIFTC.

MIFTC is more common in women; the female/male ratiofor individuals is 4:1. MIFTC occurs most often in youngerpatients than WIFTC. In a reported series of MIFTC patients,the median age varied between 35 and 49 years with thefollowing distribution: ≤45 years (70 %) and ≥45 years(30 %) with a range of 15–95 years [1, 7–9, 13, 16, 22–25,34–38, 41, 46].

Pediatric cases of MIFTC are rare. In general, thyroidcancer comprises 0.5–1.5 % of all childhood tumors andrepresents the most common head and neck malignant tumorin the pediatric population [47, 48]. Recently, Balachandaret al. [49] presented 42 cases of thyroid carcinomas of follic-ular cell origin in children <18 years old. There was only onecase (2.5 %) of MIFTC. Compared with adults, FTCs occur-ring in children are more aggressive, are discovered in ad-vanced stages, and are associated with higher rates of recur-rences [50–56].

Most patients with MIFTC presented with an asymptom-atic, solitary thyroid nodule (>50 %), approximately 20 % ofpatients had a dominant nodule in a multinodular goiter, whilea few (<5 %) patients had symptoms, such as hoarseness,dysphagia, and pressure in the neck. In total, about 3 % ofpatients exhibited hypothyroidism, and all other patients hadnormal thyroid activity. Less than 2 % of patients had docu-mented distant metastases prior to their initial thyroid opera-tion (a lower percentage compared to patients with WIFTC)[1, 8]. In the review by Thompson et al., patients experienced

a mass in the thyroid gland (63 %), an enlarging mass (23 %),or a diffuse enlargement of the gland that clinically resembleda goiter (8%). In addition, 8% of the patients presented duringroutine physical examination and were considered to beasymptomatic, while 2 % of the patients presented clinicallywith Graves' disease [13]. To notice that in the report of Banet al. [36], only 38 % of metastatic MIFTC presented initiallywith symptoms related to distant metastases; thus, conscien-tious identification of metastases should be considered in theperioperative work-up of these patients. The duration ofsymptoms ranged from 14 days to as long as 10 years, witha mean duration of 19.8 months. In total, about 5 % of thepatients had a radiation history exposure or tumor familiarity[13].

Tumor features

The median primary tumor size ranged from 34 to 44 mm,with a total range from 3 to 150 mm; 65–70 % of the tumorswere <40 mm, and 30–35 % of the tumors were >40 mm [1,7–9, 13, 16, 22–25, 34–38, 41, 46]. Larger tumors weresignificantly more likely to occur in older patients(>45 years) [1, 7–9, 13, 16, 22–25, 34–38, 41, 46]. Whiletumors ≤10 mm (mFTC) are common for PTC patients, thissize of tumor is unusual for FTC patients [57, 58]. In detail,the incidence of mFTC was assessed in two studies by Clericiet al. and Scheiden et al. [57, 58]. In five European cancerregistries, the annual incidence of mFTC was approximatelyone patient per one million inhabitants [57]. In the study ofScheiden et al. [58], the population of Luxembourg wasobserved for 10 years, and nine patients with an mFTC tumorof 9 mm or less were identified. The diagnosis of mFTCalways should be verified by an expert in thyroid cancerpathology [57, 58]. In fact, a diagnosis of mFTC could beverified in only four of 35 patients after a slide review of thespecimens [57].

There is no apparent side predominance of MIFTC. Ac-cording to Collini et al. [37, 38], the left lobe was affected in62 % of MIFTC cases and the right lobe in 38 % of the cases.Conversely, Thompson et al. [13] presented 95 MIFTC tu-mors; of these, 2 % were located in the isthmus, 31 % on theleft side, and 67 % on the right side.

Multifocality was found in 3–9.8 % of the studies, withmore than three MIFTC tumors reported in 2 % of the spec-imens [1, 7–9, 13, 16, 22–25, 34–38, 41, 46].

The MIFTC subtype with vascular infiltration only wasfound in 32–83 % of the tumors, penetration of the capsuleonly was observed in 25–100 % of the cases, and both cap-sular and vascular infiltration was reported in an average of85 % of the cases [1, 7–9, 13, 16, 22–25, 34–38, 41, 46].

Patients may present with coexisting thyroid pathology,both benign and malignant, in the remaining parenchyma.Thompson et al. [13] noted the presence of both macroscopic


and microscopic thyroid disease, including adenomatoid nod-ules (38%), diffuse hyperplasia (4%), lymphocytic thyroiditis(41 %), and other secondary thyroid tumors, such as PTC(22 %) and medullary carcinoma (4 %). Concomitant PTC,oxyphilic cell carcinoma or clear cell carcinoma, in MIFTCpatients was reported by Sugino et al. [34]. The PTCs wereusually microscopic and were considered to be of limitedbiologic significance [13, 34]. If more carcinomas are present,the more aggressive variant or subtype must be considered fordetermining the specific therapy and follow-up course [13,34]. The evaluation of coexisting thyroid diseases may beuseful for the final surgical deliberation (total vs. limitedsurgery).

Current diagnostic investigations

MIFTCs are difficult to diagnose based on preoperative ex-aminations and frozen sections unless distant metastases orlymph node metastases have been detected [7]. MIFTC isgenerally discovered on the definite results of a final patho-logical examination made after a hemithyroidectomy [7].

Imaging techniques

It would be helpful for surgical planning to preoperativelysuggest MIFTC using a first-step noninvasive ultrasonogra-phy (US). However, US is of limited value for the preop-erative diagnosis of MIFTC [59–61]. Investigators havereported that sonographic findings suggestive of a FTCinclude the presence of a solitary and solid hypoechoictumor with inhomogeneous internal texture, an irregularand ill-defined margin, and an absent or discontinuousperipheral sonolucent halo [60]. In addition, a folliculartumor with hypervascularity and an increased ratio of peaksystolic velocity/end-diastolic velocity, pulsatility index, orresistance index can be diagnosed as an FTC [61]. Therehave been few reports on the use of sonography to depictthe distinct characteristics of MIFTC. Shin et al. [62]compared the sonographic findings of WIFTC and MIFTCin a retrospective review. WIFTCs were distinguishablefrom MIFTCs with the use of both clinical and sonographyfindings [62]. Older age (>49 years), a tumor size >56 mm,a heterogeneous echotexture with a characteristic mulberry-like feature that appeared as a conglomeration of multiplesolid nodules, and the presence of calcifications (ring ormacrocalcifications) were frequently seen for WIFTC com-pared to MIFTC. A high sensitivity (77 %), high specificity(95 %), and accuracy (89 %) were observed for WIFTCwith two or more of these findings with a statisticallysignificant difference [62]. Gritzmann et al. [59] appliedcolor Doppler sonographic findings as a parameter for thedifferentiation of FTC. Central or chaotic vascularization in

a nodule was suggestive of FTC and was found in 50 % ofWIFTC cases and 53 % of MIFTC cases [59].

At present computed tomography scan, positon emissiontomography or magnetic resonance imaging is not useful forpreoperative detection of non metastatic MIFTC in the routineclinical practice [59–62].

Preoperative cytology

FNA cytology is a widely used diagnostic tool for theevaluation of thyroid nodules, with a high accuracy forthe detection of PTC [63]. However, FNA for a preop-erative diagnosis of FTC, and in particular MIFTC, haslimited utility [63]. The differentiation of MIFTC fromfollicular adenoma and the follicular variant of PTCusually cannot be made cytologically and requires his-topathological examination of paraffin-embedded tissue[63]. The diagnosis of MIFTC depends on nuclear mor-phological criteria and histopathological demonstrationof minimal invasion of the tumor capsule and/or vascu-lar invasion [10, 11, 27, 39, 64, 65].

Frozen sections

Frozen sections analyzed to clarify a cytological diagnosisof “follicular neoplasia” are rarely able to yield positiveproof of MIFTC [66–69] but may be useful to confirm orrule out other tumor entities within a suspicious thyroidnodule [67, 70, 71]. Criteria for malignancy for folliculartumors on frozen sections are seldom documentable be-cause of the limits of this method, including samplingerrors and freezing artifacts. Improved technical supportand an increased number of slides will increase the accu-racy of frozen section diagnosis [11]. Most surgeons haveconfirmed the low value of frozen sections for the intra-operative surgical management of MIFTC. Huang et al.[7] analyzed the diagnostic role of frozen sections for FTCand for MIFTC in particular. Frozen sections obtainedduring surgery enabled the diagnosis of FTC in 113(60 %) out of 187 cases. Moreover, the WIFTC grouphad a better diagnostic rate than the MIFTC group (p<.005). In one study, frozen sections were used to obtainan accurate diagnosis for 78.9 % of WIFTC cases, where-as frozen sections confirmed the diagnosis of MIFTC inapproximately 40 % of cases [7]. Thus, over 50 % of thecases of MIFTC could not be diagnosed as having cancerduring the first thyroid operation [7]. In other reports, theintraoperative identification of tumor invasion by frozensection analysis had an accuracy of 57 % in MIFTCpatients [72]. According to Shin et al. [62], malignancywas established by frozen section analysis for 46 % ofWIFTC patients and for 38 % of MIFTC patients.


Histology

The diagnosis of MIFTC is entirely based on the histologicalexclusion of various other (benign and malignant) tumors.Appropriate diagnosis of MIFTC faces a number of features,which have to be carefully considered before arriving at aconclusive decision. The histological work-up of encapsulatedtumors with follicular cell differentiation is shown in Fig. 1.

Morphological differential diagnosis of MIFTC

For the histological investigation of (solitary) encapsulatednodules, the entire central slice should be submitted to paraffinembedding [10, 21, 141]. Each block must contain a section ofthe capsule and, if present, adjacent non-neoplastic thyroidtissue. According to this recommendation approximately6.5 cm of the capsule are available for microscopic investiga-tion if a nodule is measuring 2 cm in diameter. The suspicionfor MIFTC should be amplified by the presence of a thickenedfibrous capsule, a solid, trabecular, or microfollicular growthpattern, hypercellularity, diffuse nuclear atypia, and/or easilyrecognizable mitotic figures, although these features them-selves do not represent diagnostic criteria of MIFTC.

Distinguishing MIFTC from follicular adenoma: capsularand vascular invasion

MIFTC is a grossly encapsulated tumor (usually >1 cm) mac-roscopically indistinguishable from follicular adenoma. Thus,diagnosis of MIFTC entirely depends on the histologicaldemonstration of vascular and/or capsular invasion requiring

a thorough examination of the capsule representing the tu-mor–thyroid interface [21, 116, 121, 126, 139]. Vascularinvasion and capsular breakthrough may occur simultaneous-ly. Due to different clinical management [64, 132], it is im-portant to explicitly exclude vascular invasion if MIFTCdiagnosis is solely based on capsular breakthrough. The fol-lowing list summarizes the histological hallmarks of MIFTC[11, 116, 129]:

1. Vascular invasion (Figs. 2, 3 and 4)• Tumor plug or polyp in a subendothelial location within a

vein (not a capillary; thus, the immunohistochemicaldemonstration of endothelial cells is not necessary) in orimmediately beyond the tumor capsule.

Fig. 1 Histological work-up ofencapsulated thyroid neoplasmswith follicular cell differentiation.The diagnosis of MiFTC must bepreceded by the histologicalexclusion of encapsulated PTC(follicular variant) andencapsulated PDTC

Fig. 2 MiFTC with multiple vascular and capsular invasions (arrows) inthe tumor capsule. The tumor capsule is considerable thickened; thetumor shows a microfollicular growth pattern. HE, magnification ×25


• Vascular invasion within the tumor has no diagnostic orprognostic implication.

• The tumor cell cluster protruding into a vessel is usually,but not necessarily, covered by endothelium.

• The tumor thrombus does not necessarily have to beattached to the vessel wall.

• Tumor cell clusters without endothelial covering andfreely situated in the vessel lumen, however, most likelyrepresent artifacts (Fig. 5).

2. Capsular breakthrough (Figs. 6 and 7)• Penetration of the tumor with complete transgression of

the fibrous capsule, deflecting the collagen fibers of thecapsule.

• Contact of the tumor with the surrounding non-neoplasticthyroid tissue beyond an imaginary line drawn throughthe external contour of the capsule; in some cases the

tumor bud beyond this imaginary line is covered by a thinlayer of (probably new) fibrous tissue.

• Satellite nodule beyond the capsule with identical mor-phological features (cellularity/cytoarchitecture) to thoseof the main tumor.

• A concomitant vascular invasion is not required even ifmetastases are already present at the time of diagnosis.

• Tumor foci within the capsule are not sufficient for thediagnosis of minimally invasive FTC. They represent,most likely, tumor trapping and distortion by fibrosis.

• Fine-needle biopsy may alter the contour of the capsuleby artificial dehiscence mimicking capsular invasion; thissituation has to be carefully ruled out in cases showingold hemorrhage, stromal reparative changes, and/or gran-ulation tissue.

Fig. 3 MiFTC with normofollicular growth pattern and oncocytic dif-ferentiation. The capsule is thickened and contains foci of calcification.The arrow indicates a vascular invasion. HE, magnification ×25

Fig. 4 MiFTC with a true vascular invasion of small tumor clusters offollicular structures, which are covered by endothelium. HE, magnifica-tion ×40

Fig. 5 Capsule of a follicular neoplasm with two vessels containingsingle tumor cells and small cell clusters without endothelium coveringfreely situated in the vessel lumen, which almost certainly represent mostartifacts. HE, magnification ×20

Fig. 6 Capsular breakthrough with complete transgression of the fibrouscapsule, deflecting the collagen fibers of the capsule. HE, magnification×25


Investigating the entire capsular region of the central sliceof a given neoplasm allows usually the unequivocal identifi-cation of MIFTC with >3 vascular invasions (Fig. 2). Caseswith ≤3 vascular invasions or exclusive capsular breakthroughmay require serial sections and/or additional blocks to reach aconclusive diagnosis.

Distinguishing MIFTC from encapsulated follicular variantof PTC

Making the diagnosis of MIFTC (and adenoma) includes theexclusion of the encapsulated follicular variant of PTC; thediagnosis of the latter depends entirely on the demonstrationof the characteristic nuclear features of PTC [4]. The majorityof tumors representing the follicular variant PTC are encap-sulated, composed of small- to medium-sized follicles andcompletely lack papillary structures. The follicular variant ofPTC may cause, if the nuclear features of PTC are insuffi-ciently appreciated, severe problems in the differentiationfromMIFTC, follicular adenoma, or even multinodular goiter[11]. The prognosis of the encapsulated follicular variant ofPTC is excellent [120, 130, 138]. However, a small number ofencapsulated follicular variant PTC is displayingangioinvasiveness; these tumors tend to give rise to lung andbone metastases without concurrent lymph node metastases[113, 124, 125, 131, 144]. When compared to the convention-al type of PTC the follicular variant of PTC shows distinctlydifferent molecular alterations (low frequency of BRAFV600E mutation, lack of RET/PTC rearrangements, occur-rence of PAX8/PPARgamma rearrangements, or ras mutations[115, 118, 122, 123, 127, 133, 136, 142, 143, 145, 147, 150],which may hamper the use of PTC specific molecular markers

to support the diagnosis of PTC. In contrast, analysis of sets ofPTC-specific sets of microRNA may be helpful [140].

Distinguishing MIFTC from encapsulated PoorlyDifferentiated Thyroid Carcinoma

Poorly differentiated thyroid carcinoma (PDTC) is defined asa “follicular cell neoplasm that show limited evidence ofstructural follicular cell differentiation and occupy both mor-phologically and behaviorally an intermediate position be-tween differentiated (FTC and PTC) and undifferentiated(anaplastic) carcinomas” [4, 134]. Although recognized al-most 30 years ago as an aggressive type of thyroid carcinoma[114, 137], the diagnosis of PDTC is still not familiar to manysurgical pathologists. In the so-called Turin proposal [146], analgorithmic diagnostic approach applying uniform diagnosticcriteria of PDTCwas formulated. Occasionally, PDTCmay beentirely encapsulated; the differential diagnosis between thesetumors and MIFTC can be difficult and is primarily based onthe growth pattern (solid, trabecular, and/or insular) as well asone of the following features: a mitotic rate of >3/10 HPF,tumor necrosis, and/or so-called “convoluted” nuclei. Despitethis apparently “aggressive” morphological appearance ofPDTC, some (encapsulated) cases may lack vascular invasion.

Does MIFTC develop from follicular adenoma?

It is still a matter of debate whether FTC arises from pre-existing follicular adenoma or not. However, epidemiologicaland demographic data, showing that the incidence of FTCparallels that of follicular adenoma in relationship to knownenvironmental factors (e.g., dietary iodine intake) as well as

a bFig. 7 MiFTC with a satellitenodule beyond the capsule (b),which shows an identicalcytoarchitecture to this of themain tumor. A small bridge oftumor tissue connecting thesatellite with the main tumor isrevealed on a serial section (a).HE, magnification ×25


the fact that FTC affects patients with a higher mean agecompared with follicular adenoma, very strongly suggest thatFTC most likely develops from follicular adenoma in a se-quential progressive manner (linear tumor progression model)[11, 148]. This concept is also supported by the rare occur-rence of follicular “microcarcinoma” (FTC with a diameter≤1 cm) [58] as well as by the widely identical cytologicalappearance of follicular adenoma and particularly encapsulat-ed FTC. There is no evidence for alternative pathways, i.e.,that follicular adenoma and FTC arise independently fromnormal follicular cells [148]. A third model assumes thatprogression from follicular adenoma to FTC is only possiblewithin a critical time window, during which (early) adenomamay be irreversibly transformed to ultimately become FTC orafter which it remains histologically and clinically permanent-ly as an adenoma (time restricted model [148]). Molecularpathological data have additionally demonstrated an overlapof genetic alterations found both in FTC and the follicularvariant of PTC [115, 118, 122, 123, 127, 133, 136, 142, 143,145, 147, 150]; this suggests that FTC may arise from a lesionwith morphological features of PTC and vice versa.

Significance of oncocytic thyroid tumors

Oncocytes are cells rich of mitochondria with morphological,functional, and genetic abnormalities [128]. Oncocytic tumorsmay be benign (oncocytic variant of follicular adenoma) ormalignant (oncocytic variant of FTC or PTC). Oncocytes mayalso be the result of regressive changes, e.g., in nodular goiter.Oncocytic metaplasia is a diagnostic hallmark in lymphocyticthyroiditis Hashimoto or may occur after radiation therapy inGraves' disease. Tumors should be classified only as“oncocytic” if at least 75 % of cells are identified as oncocytes[4]. The criteria used in the diagnosis of oncocytic variantFTC does not differ from its nononcocytic counterpart (cap-sular/vascular invasion). Overall, the prognosis of patientswith oncocytic variant of FTC is similar to those with con-ventional FTC, but the percentage of oncocytic FTCdisplaying signs of invasiveness is higher than that occurringin tumors without oncocytic features [144].

Significance of ancillary studies (immunhistochemistryand molecular pathology)

To date, there is no immunohistochemical marker that clearlydistinguishes between follicular adenoma, MiFTC, and en-capsulated PTC (follicular variant). In cases with subtle nu-clear changes, a positive immunoreactivity of markers such asHBME-1, Galectin-3, and cytokeratin 19 may aid the diagno-sis of the follicular variant of PTC [117, 119, 135]. However,due to overlapping results between benign and malignantencapsulated tumors with follicular cell differentiation nomarker offers conclusive results. Similar to the lack of

immunohistochemical markers, there is no molecular markerthat allows a definite diagnosis of follicular adenoma,MiFTC,or the follicular variant of PTC with the except for the detec-tion of the latter by demonstration of a BRAF V600E muta-tion [149]. Specific immunohistochemical/molecular markersfor the diagnosis of MiFTC would be most desirable. How-ever, the assessment of the specificity of a given marker ishampered by the fact that each marker candidate has to berelated to its presence or absence in the respective “nodule,”the diagnosis of which was originally based on the aboveoutlined histological criteria [11].

Evaluation of variables for prognosis

Cancer-related mortality for MIFTC varied from 0 to 11 % [7,24, 40, 81, 92]. In the analysis by Goffredo et al. [8], only twoMIFTC died cancer-specific over 1,200 cases with an overallsurvival similar to that of general US population. In the studyby Huang et al. [7], neither recurrence nor cancer-specificmortality was reported [7]. Conversely, in the comprehensiveanalysis of cause specific survival (CSS) and distantmetastases-free survival (DMFS) by Sugino et al., the 10-,15-, and 20-year CSS rates were 95.2, 89.5, and 84.5 %,respectively.

Thus, DM, relapses, and deaths do occur in a low percent-age of MIFTC patients [34].

Studies have been performed to establish which clinico-pathological characteristics influence outcomes. Defined riskfactors could be used to identify patients who are at higher riskfor developing distant metastases and recurrent disease andtherefore those who would possibly need more aggressivesurgical and adjuvant treatment. Many risk factors have beentaken into account, such as gender, patient age at diagnosis,tumor features, degree of invasion into the blood vessels and/or the tumor capsule of the primary neoplasm, and the pres-ence of metastases (Table 3) [32, 33, 100, 101].

Clinical features

The age at diagnosis is a prognostic factor forMIFTC [34, 35].Young patients have good prognosis. In fact, a younger age

Table 3 Summary of prognostic factors

Clinical parameters

Age (≥45 years)

Histological parameters

Tumor size (≥40 mm)

Vascular invasion

Distant metastases

UICC stage


(<45 years old) is a significant predictor for obtaining prom-ising treatment results for MIFTC and for reduced risk for DMat diagnosis (M1) or during follow-up period (M2) [7, 13, 35].A benefit of DFS in MIFTC for patients with younger ageswas observed also by Asari et al. [1]. The results of Suginoet al. [34] of the multivariate analysis in relation to CSS andDMFS showed that age was identified as an independentsignificant prognostic factor for poorer CSS and was also asignificant factor related to DMFS in the M0 group (no distantmetastases at initial diagnosis). In addition, the results fromthe series of patients of Ito et al. and Ban et al. [35, 36] havedemonstrated similar results. The 45-year-old cut-off is com-monly employed as is used in most common staging systems[76].

As for FTC, in general, male tended to have a worseprognosis compared to their female counterparts when allother factors were equal [93]. According to this review, wedid not find a difference in outcomes for MIFTC based ongender [7, 13, 35, 36, 94, 95].

The adequacy of iodine intake is thought to be related to thebiological behavior of FTC [1, 34]. The outcomes of FTC iniodine-deficient areas have been reported to be poorer than iniodine-sufficient areas [1, 34, 94, 95]. In the report of Suginoet al. [34], the DM ratio in patients with MIFTC (22 %) wasreported to be high; however, the cumulative DMFS ratio wasalmost similar to the ratio reported in other recent reports [1,46, 91].

Tumor size

Despite using a variety of different tumor size cut-off values,the size of the tumor was associated with a difference inpatient outcomes in several studies [34, 35]. The study bySugino et al. [34] examined the prognostic factors for distantmetastasis and tumor mortality in patients with MIFTC. Aunivariate analysis of risk factors was performed, and patientswith a tumor size ≥40 mm were found to have significantlypoorer rates of distant metastasis-free survival. In the study ofSugino et al. [34], CSS was significantly poorer in the groupof patients whose primary tumor size was >40 mm. Anincrease in DFS for patients with smaller MIFTC tumorswas observed [1]. A small tumor size was a significant pre-dictor for obtaining promising treatment results in MIFTCpatients [7].

Thus, 4 cm is considered as the critical cut-off in MIFTC,and the prognosis has been shown to be worse for largerneoplasm [11, 16, 96–99]. Goldstein et al. [32] reporteddistant metastases from MIFTC for tumors with a mean di-mension of 46 mm. Machens et al. [2] demonstrated that therate of bone metastases considerably increased in tumors>40 mm. The American Thyroid Association (ATA) Guide-lines consider the dimensional cut-off of 40 mm as critical;patients with tumors >40 mm with suspect cytology should

undergo total thyroidectomy, independent of the histologyobserved on frozen sections, because of the increased risk ofmalignancy. Four centimeters is also relevant for furtherradioiodine therapy [76]. Because of the lack of data, it hasnot been demonstrated whether this limit is also appropriatefor MIFTC. Moreover, it is still debated whether conservativetherapy in cases of MIFTC should be limited for MIFTCtumors <40 mm [76].

Other authors have suggested that there is no difference inoutcome based on tumor size. In fact, Ban et al. [36] found nosignificant difference in tumor size in patients with metastaticdisease. Metastatic MIFTC (bone, lungs, and soft tissue) waspresent in 4 of the 52 patients in the review of Ban et al. [36].Of note, three of the four lesions were smaller than the averagelesion size [36].

Degree of invasion

The debate continues regarding the exact prognostic impact ofvascular invasion and specifically its relation with capsularinvasion and what constitutes extensive vascular invasion[16]. For surgical therapy, this debate reflects the possibilityof defining an individual risk profile for each patient based onhistological subtyping, even though this subdivision still mustbe standardized both in definition and in classification.

Vascular invasion may be a better indication of malignancythan capsular penetration [35]. It was Warren in 1931 [102]who first emphasized the adverse prognostic value of vascularinvasion. In 1983 and 1986, Kahn and Perzin and Lang et al.[17, 33] studied a large number of FTC patients and demon-strated that the number of foci of vascular invasion was anadverse prognostic sign, even in encapsulated tumors. Ghosseinet al. [26, 41] precisely subdivided vascular invasion into twocategories: focal (<4 invasive foci) and extensive (>4 foci). Thenumber of foci of vascular invasion in the tumor capsule(intracapsular vascular invasion) and outside the tumor capsulein adjacent thyroid parenchyma (extracapsular vascular inva-sion) was also recorded. According to this study, angioinvasionwas noted in 64 % of the tumors. Extensive vascular invasion(>4 foci) was observed in 30 % of the cases. Intracapsularvascular invasion was found in all of angioinvasive tumors,and extracapsular vascular invasion was noted in 22 % of thetumors. Vascular invasion was by far the most powerful pre-dictor of recurrence (p <.0001) in patients with MIFTC, where-as capsular invasionwas not significantly associatedwith tumorrecurrence. The presence of >4 foci of vascular invasion wasfound to be strongly predictive of recurrence and a decreasedrecurrence-free survival (RFS) (p <.0001). The presence of >4foci of intracapsular vascular invasion was found to significant-ly worsen the survival time (p <.0001). A similar correlationwas found between numerous foci of extracapsular vascularinvasion (>4) and outcomes (p <.0376). Collini et al. [38] foundidentical results in encapsulated non-oncocytic MIFTC. The


study of Collini et al. showed that 65 % of relapsed cases ofMIFTC had extensive vascular invasion [38].

The above conclusions were not supported by someother studies that showed vascular invasion alone did notnegatively affect the prognosis of patients [16, 25, 27, 41].In 2000, Goldstein et al. [32] compared metastatic withnonmetastatic encapsulated follicular carcinomas (includinga mixture of oncocytic and nononcocytic variants) andreported no difference in the number of foci of capsularor vascular invasion between metastatic and nonmetastatictumors. The recent study by Sugino et al. [34] examinedthe prognostic factors for distant metastasis and tumormortality in patients with MIFTC. Distant metastases wereobserved in 12.2 % of cases with capsular invasion alone,17.9 % with vascular invasion alone, and 25 % with bothvascular and capsular invasion. No significant relationshipcould be ascertained between distant metastasis and thepresence of vascular invasion. In the report of Suginoet al. [34], the differences in the DMFS rates among thegroups with capsular invasion alone, vascular invasionalone, and both capsular and vascular invasion were notsignificant. In addition, the differences among their CSSrates were not significant [34].

Some data indicate that MIFTC with capsular invasiononly can definitely metastasize, demonstrating that these le-sions do not necessarily exhibit inactive behavior. In the seriesof Ban et al. [36] with known metastatic disease (bone, lungs,and soft tissue), patients who had had low-risk lesions, name-ly, well-differentiated, small lesions without any evidence ofvascular invasion, had similarly presented with metastaticdisease.

Finally, Jorda et al. [101] showed that tumors with thecoexistence of vascular invasion and capsular invasion had apoorer outcome than those showing only one of these features.

Presence of LN metastases

The incidence of lymph node metastasis in FTC has beenshown to be approximately 3–15 % in the literature [1, 2,7, 24, 46]. Nodal involvement in patients with follicularcarcinoma is associated with extrathyroidal extension ofthe primary tumor and is therefore a sign of advanceddisease [103–105]. In this analysis of the literature, LNmetastases were rare and present in fewer than 5 % ofMIFTC cases [16, 96, 103–105]. In the cohort of Huanget al. [7], lymph node metastasis was not noted in any ofthe MIFTC cases. However, because lymph node dissec-tion was not performed in all cases, the occurrence ofmicroscopic metastasis was not completely excluded [7].According to this review, we did not find a difference inoutcomes for MIFTC based on presence of LN metastases[7, 13, 35, 36, 94, 95].

Distant metastases

Patients diagnosed with DM <1 year after the initial surgerywere classified as M1, and patients diagnosed with DM 1 yearor more after the initial surgery were classified as M2 [1, 34,35]. The presence of DM at the time of initial diagnosis orduring follow-up had a significant negative effect on CSS andDFS [1, 24, 25, 34, 35, 106–109].

In the study of Asari et al. [1], 14 % of 127 patientspresented with distant metastases at the initial diagnosis(9.4 % M1) or during follow-up (4.7 % M2). As of a medianfollow-up time of 90 months, 21.5 % of patients in the reviewof Sugino et al. [34] had been diagnosed with distant metas-tases. In detail, 8.8 % of the distant metastases were present atthe time of the initial surgery (M1), and in the other 12.7 % ofthe patients, DM were detected during the follow-up period(M2). Overall, in this review, DM in the M2 patients weredetected at a median interval of 66 months after the initialsurgery, and the intervals ranged from 24 to 189 months [1,24, 25, 34, 35, 106–109]. Lung and/or bone were the mostfrequent sites of metastases. Other sites of the distant metas-tases were the brain, liver, and soft tissue.

In the study of Sugino et al. [34], there were significantlymore M1 patients in the group of patients who were 45 yearsor older and in the group of patients who were positive forcapsular invasion. After excluding the M1 patients, postoper-ative DM were significantly more common in the group ofpatients who were 45 years or older and in the group whoseprimary tumor size was 40 mm or larger. In detail, CSS wassignificantly poorer in the M1 group [34]. The 10-, 15-, and20-year CSS rates of the M0 patients were 97.8, 91.9, and86.8 %, respectively, whereas the 5- and 10-year CSS rates ofthe M1 patients were 83.8 and 55 %, respectively [34]. Theoutcome of the group with distant metastases at presentationwas significantly poorer than in the group without distantmetastases at presentation [34]. The 10-, 15-, and 20-yearDMFS rates were 85.8, 72.6, and 70 %, respectively, for thisgroup of patients.

Cytoplasmic oxyphilia

According to this review, we did not find a difference inoutcomes for MIFTC based on presence of cytoplasmicoxyphilia [13, 44, 110–112].Cytoplasmic oxyphilia as a prog-nostic factor in FTC is controversial in the literature [13, 44,110–112]. According to Asari, no difference in the incidenceof cytoplasmic oxyphilia was found between MIFTC andWIFTC patients [1]. Comparing patients with oxyphilic FTCto nonoxyphilic FTC, there were no statistically significantdifferences in the presence of lymph node metastases, distantmetastases, or in DFS and CSS between the groups [1]. Thus,the authors suggest using the same surgical strategy indepen-dently of the presence of cytoplasmic oxyphilia.


Staging systems

CSS and DMFS were evaluated according to the AmericanJoint Committee on Cancer/Union for International CancerControl Tumor–Node–Metastases classification staging sys-tem [34]. Stage IV was significantly related to reduced CSScompared with stages I, II, and III (p <.0001). Stages II and IIIwere significantly related to reduced CSS compared withstage I (p <.0001); however, there was no significant differ-ence between stage II and III. Furthermore, the DMFS curvesdiffered significantly among all three stages [34]. Stage IIIwas significantly related to reduced DMFS compared withstages I and II (p <.005).

Therapy

Extent of surgery

Substantial controversy exists about the extent of surgerynecessary for MIFTC patients. Some authors have recom-mended a unilateral operation, while hemithyroidectomy isgenerally performed when the preoperative diagnosis is un-clear [73, 74]. Others suggest that a more complete removal ofthe thyroid improves the overall prognosis, even for the pa-tients who are in the low-risk group, if the tumor is larger than10 mm in size [75]. Furthermore, a total thyroidectomy mayallow for the use of radioactive iodine and serum thyroglob-ulin level as a tumor marker [76]. According to the 2009revision of the ATA guidelines for the management of patientswith thyroid nodules and differentiated thyroid cancer, a totalthyroidectomy is the procedure of choice for DTC [76]. Lo-bectomy is accepted for patients with a single microcarcinomaof <10 mm or indeterminate tumor (suspicious, follicularneoplasm, or Hurthle cells neoplasms) [76].

According to some authors [7, 16, 38, 77], limited surgery(hemithyroidectomy) is considered sufficient for MIFTC withexclusive capsular invasion, patients <45 years old, tumor size<40 mm, without vascular invasion, without any node ordistant metastases because recurrence and metastases are notexpected. While candidates for total thyroidectomy (radicalsurgery) are patients ≥45 years at presentation, tumor size≥40 mm, vascular invasion present, positive nodes, and pos-itive distant metastases (Table 3) [7, 16, 38, 77]. De facto, forangio-invasive MIFTC, older age >45 year old, >40 mm intumor size, and presence of distant metastases, the results weredifferent [7, 16, 32, 34, 38, 77, 78]. A retrospective analysis ofpatients with metastatic MIFTC showed that all of thesetumors were vascular invasive [32], and the risk of distantmetastases increased along with the grade of vascular invasion[78]. In a recent Japanese study [34], 251 MIFTC patientsunderwent an initial operation as follow: 191 lobectomies, 24subtotal thyroidectomies, and 36 total thyroidectomies.

Completion total thyroidectomy was performed in 46 patients(33 prophylactically and 13 for recurrent disease). Fifty-fourpatients (21.5 %) presented with distant metastases. Age(>45 years), tumor size (>40 mm), and distant metastaseswere shown to be the most powerful prognostic factors inuni- and multivariate analyses. The Mayo Clinic team [16]studied MIFTC regarding the follow-up of patients with cap-sular invasion alone or capsular invasion associated withvascular invasion. The 10-year occurrence rate for cause spe-cific mortality and distant metastases were 28 and 19 %,respectively, for patients with vascular invasion. Comparablerates for the patients with capsular invasion alone were 0 %(p =.019) and 0 % (p =.052). The determinant of cause-specific mortality was the presence of distant metastasis atdiagnosis and vascular invasion [16].

To mention that some authors [20, 24, 26, 33, 79, 80] haveshown that limited vascular invasion (<4 sites of invasion)was not associated with a worse prognosis. Asari proposed theuse of the same surgical strategy described above indepen-dently of the presence of cytoplasmic oxyphilia [1].

Lymph nodes clearance

There is wide consensus that a systematic lymphadenectomydoes not affect the prognosis in FTC patients [1, 13, 38, 46,81–86]. As recommended in the revised ATA thyroid cancerguidelines [78], prophylactic central neck dissection can beavoided for small (T1–T2), noninvasive, clinically node-negative DTC patients. For these patients, the balance of riskand benefit may favor a total thyroidectomy with close intra-operative inspection of the central compartment and compart-mental dissection only in the presence of obviously involvedlymph nodes. In addition, the recent recommendations by theGroup of Oncological Surgery of the Austrian Society ofSurgery in 2010 and the German Association of EndocrineSurgeons in 2013 were not in favor of a systematic lymphad-enectomy for FTC patients [29, 64]. Authors [87] have con-firmed that a lymphadenectomy can be avoided for most FTCtumors smaller than 40 mm; however, the evidence is weakand is based on expert opinion. In this review, lymph nodeinvolvement was rare. In summary, there is consensus to notperform a prophylactive lymphadenectomy inMIFTC [1, 7, 9,13, 16, 23, 24, 38, 39, 41, 46, 77, 88].

Metastatic MIFTC

In patients with metastases, therapy should begin with a totalthyroidectomy [73], which will allow for total body 131 Iscanning. In a study by Sugino et al. [34], post-therapeuticscintigraphy showed that 57 % of the included patients hadradioiodine uptake in their metastases. In most publishedstudies, RAI therapy after the completion of a total thyroidec-tomy was performed whenever distant metastases were


detected during the follow up period (M2) or during the initialsurgery (M1) [34]. Multiple metastases are best treated byRAI therapy and occasionally adjuvant chemotherapy or ex-ternal beam irradiation [73]. For a single demonstrable resect-able metastasis, surgical resection should be considered [73].The cycle of radioactive iodine scanning and treatment formetastatic lesions can be repeated every 6 months as appro-priate according to the patient's physiologic status and tumorresponse [73]. Moreover, patients must be managed withsuppressive therapy [34, 73]. It is not clear whether comple-tion total thyroidectomy and RAI ablation prevent the occur-rence of distant metastasis, but these procedures make itpossible to detect distant metastases at an early stage [34,76]. In a report by Sugino et al. [34], a complete responsewas observed in 3% of the patients, and a partial response wasobserved in 6 % of the patients after several courses ofradioiodine treatment. The other patients had stable or pro-gressive disease [34]. Patients with bone metastases wereusually referred for orthopedic surgery [34]. Spinal metastaticdisease and spinal cord compression were major causes ofmorbidity and mortality [34]. The treatment of metastaticdiseases of the spine required surgical decompression, recon-struction, and stabilization in addition to external radiation[34]. Patients with brain metastases were treated with gammaknife surgery, and growth control was achieved [34].

Radio Iodine Therapy

RAI is performed after a total thyroidectomy or completiontotal thyroidectomy, mainly in elderly patients (>45 years),prophylactically in patients with a large tumor size (>40 mm),extensive vascular invasion, or in patients with distant syn-chronous or metachronous metastasis and positive nodes, ifrecurrence is noted in follow-up, or if patient refuse comple-tion thyroidectomy, or complications are experienced duringinitial surgery [34, 73, 76].

According to the 2009 revision of the ATA guidelines forthe management of patients with thyroid nodules and differ-entiated cancer [76] because of the excellent outcomes aftersurgical resection alone, RAI ablation may not be necessaryfor all patients with a small FTC and only capsular invasionobserved histologically.

In Japan, the use of RAI is limited by law, and RAI ablationis used only for patients with risk factors for distant metastasis[34]. In the series by Sugino et al. [34], RAI ablation wasperformed after completion total thyroidectomy, mainly inelderly patients, or after the detection of distant metastasis.No patient who received RAI ablation died of the disease [34].

A meta-analysis by Sawka et al. [89] demonstrated thebenefit of RAI as an adjuvant treatment to lessen the rate ofrecurrence and mortality. For low tumor stages, there is still noevidence [90]. The National Thyroid Cancer Treatment Co-operative Study Group stated that RAI does not provide any

survival benefit in these cases [90]. In some series, distantmetastases and cancer-related deaths have been reported, evenin cases of MIFTC with a favorable prognosis or in patientswho underwent radioiodine therapy [1, 46]. However, theseseries were not defined according to the present histopatho-logical classification. Clear recommendations by the ATA forRAI therapy are stated for tumors with distant metastases,tumors with invasion of adjacent structures (WIFTC), andtumors >40 mm [76, 77, 91]. For tumors <40 mm, RAI maybe indicated only if other risk factors coexist [76].

Summary and recommendations

Published papers on MIFTC present inadequate power with aIII–IV level of evidence and C grade of recommendation.

Because the diagnosis of MIFTC is rarely done before theoperation or using frozen sections, a isthmolobectomy is oftenperformed.

A MIFTC diagnosis requires clearer, unequivocal, andreproducible criteria for pathologist, surgeons, and endocri-nologists to use in the management of these patients. If thedistinction between MIFTC and WIFTC cannot be made, anexpert in thyroid pathologist should be consulted.

If MIFTC is diagnosed, the health care team should discusswhat is meant exactly by the term “minimally invasive” in theparticular case under review. The histological characteristicsof MIFTC are important predictors of prognosis. It has beenproposed to subclassify MIFTC patients in vascular and cap-sular invasions. Vascular invasion have unfavorable prognosisas a distinct group. The stratification of prognostic factors forage and tumor size is sometimes arbitrary in the literature.Authors have used different cut-off limits for age and tumorsize when analyzing MIFTC prognosis. Therefore, a ratherunique and significant factor is the identification of unequiv-ocal pathological risk factor as the vascular infiltration inMIFTC. The risk of progression (local recurrence and metas-tases) of encapsulated tumors with follicular cell differentia-tion is listed in Table 4. Based on prognostic and therapeuticconsequences, pathologists should explicitly document the

Table 4 Risk of progression in encapsulated thyroid tumors of follicularcell differentiation

Encapsulated thyroid neoplasm Risk of progression

Follicular adenoma No risk

Minimally invasive (encapsulated) FTC

With capsular invasion only Minimal risk

With ≤3 vascular invasions (Very) Low risk

With >3 vascular invasions Intermediate/high risk

Encapsulated follicular variant of PTC Low risk

Encapsulated PDTC High risk


following criteria of invasion for diagnosing MIFTC in theirreport [presence/absence of capsular invasion (Figs. 6 and 7);presence/absence of vascular invasion, if present limited (≤3)or extensive (>3) foci of angioinvasion (Figs. 2, 3, and 4)]:

& Candidates for limited surgery (hemithyroidectomy):MIFTC with exclusive capsular invasion, patients<45 years old at presentation, tumor size <40 mm, withoutvascular invasion, without any node or distant metastases.

& Candidates for total thyroidectomy (radical surgery ):MIFTC in patients ≥45 years at presentation, tumor size≥40 mm, vascular invasion present, positive nodes, posi-tive distant metastases.

& In the absence of clinical evidence for lymph node metas-tasis, patients with MIFTC do not require prophylacticlymph node dissection.

& RAI is indicated in elderly patients (>45 years), largetumor size (>40 mm), extensive vascular invasion, pres-ence of distant synchronous or metachronous metastasis,positive nodes, and if recurrence is noted in follow-up.

Conflicts of interest None

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Minimally invasive follicular thyroid cancer (MIFTC)—a consensus report of the European Society of...

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