Parathyroid Pathology Hyperparathyroidism and Parathyroid Tumors Diane Carlson, MD N Context.—Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient setting. Parathyroid adenomas are common, unlike other parathyroid tumors. This review presents a brief summary of current updates in parathyroid pathology. Objective.—To review parathyroid development and discuss issues in hyperparathyroidism and diagnosis of parathyroid lesions, including the application of immuno- histochemistry and molecular biology. Data Sources.—Current texts, PubMed (National Library of Medicine) articles, and Memorial Sloan-Kettering Cancer Center archives. Conclusions.—Primary hyperparathyroidism is most com- monly seen with sporadic adenomas, followed by hyperplasia, multiple adenomas, and carcinoma. Autosomal dominant familial hyperparathyroidism syndromes should be consid- ered in the evaluation of patients with parathyroid lesions, particularly in association with parathyroid carcinoma. While the incidence of parathyroid carcinoma is quite low, it is seen with a greater frequency in those patients with hyperparathy- roidism-jaw tumor syndrome. Inactivation of the tumor suppressor gene HRPT2 can be identified in a large number of parathyroid carcinomas. Hence, germline HRPT2 gene mutations may reflect unrecognized syndromic patients. (Arch Pathol Lab Med. 2010;134:1639–1644) HISTORICAL BACKGROUND In 1849 Sir Richard Owen performed an autopsy on a rhinoceros and gave the first description of the parathy- roid gland. He described it as ‘‘a small compact yellow glandular body which was attached to the thyroid at the point where the veins emerged.’’ 1 The first description of the parathyroid glands in human beings was given by Ivar Sandstro ¨m, a medical student in Uppsala, Sweden in 1880. 1,2 He suggested that these glands be named the glandulae parathyroideae. 1,2 The function of these structures was unknown at that time. In 1926, at the Massachusetts General Hospital in Boston, Edward Churchill, assisted by an intern named Oliver Cope, operated for the seventh time on the famous sea captain Charles Martell for severe primary hyperparathy- roidism (HPT). 1 An ectopic adenoma was found sub- sternally. Although the operation was successful, Captain Martell died 6 weeks postoperatively, most likely from laryngeal spasm, during a procedure to relieve ureteral obstruction secondary to stones. Ironically, 83 years later, ectopic parathyroid glands continue to be a diagnostic surgical challenge. EMBRYOGENESIS While there are generally 4 parathyroid glands, weigh- ing 30 to 40 mg each, autopsy studies have shown that 2% to 13% of healthy individuals have supernumerary parathyroid glands, most commonly with a fifth gland located in the cervical thymus. 3 Approximately 1% to 3% of people have only 3 identifiable glands and 0.6% have 6 parathyroid glands. 4 Rare reports of the presence of 7 and up to 12 parathyroid glands have been described in the literature. 3–6 The presence of ectopic parathyroid tissue has been attributed to abnormal migration during embryo- genesis. During development, at day 26, five pairs of pharyngeal pouches form. The superior parathyroids develop from the fourth pharyngeal pouch and the inferior from the third. The inferior parathyroids migrate a greater distance, and do so in conjunction with thymic tissue. Therefore, these are more likely to be found in ectopic sites. The main blood supply is the inferior thyroid artery, as well as the superior thyroid artery, directly from thyroid. ANATOMY OF THE PARATHYROID GLANDS The parathyroid glands are small (3–6 mm), brown, round to ovoid soft structures, which may be somewhat flattened or bilobed. Histologically, each gland has a thin fibrous capsule that overlies an arborizing network of adipose tissue, blood vessels, and glandular parenchyma (Figure 1). The amount of stromal fibroadipose tissue increases from puberty and continues to do so until around the fifth decade of life, accounting for approxi- mately 50% of the gland volume. 5 The adult parathyroid is composed predominantly of chief cells, as well as oxyphilic cells, which are mitochondria rich, and transi- Accepted for publication February 24, 2010. From the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York. Dr Carlson is now with the Department of Pathology, Cleveland Clinic Florida, Weston, Florida. The author has no relevant financial interest in the products or companies described in this article. Presented in part at the Surgical Pathology of Neoplastic Diseases course, Memorial Sloan-Kettering Cancer Center, New York, New York, May 18–22, 2009. Reprints: Diane Carlson, MD, Department of Pathology, Cleveland Clinic Florida, 3100 Weston Blvd, Weston, FL 33331 (e-mail: carlsod@ ccf.org). Arch Pathol Lab Med—Vol 134, November 2010 Parathyroid Pathology and Parathyroid Tumors—Carlson 1639
Transcript
Parathyroid Pathology
Hyperparathyroidism and Parathyroid Tumors
Diane Carlson, MD
N Context.—Primary hyperparathyroidism is the mostcommon cause of hypercalcemia in the outpatientsetting. Parathyroid adenomas are common, unlikeother parathyroid tumors. This review presents abrief summary of current updates in parathyroidpathology.
Objective.—To review parathyroid development anddiscuss issues in hyperparathyroidism and diagnosis ofparathyroid lesions, including the application of immuno-histochemistry and molecular biology.
Data Sources.—Current texts, PubMed (National Libraryof Medicine) articles, and Memorial Sloan-KetteringCancer Center archives.
Conclusions.—Primary hyperparathyroidism is most com-monly seen with sporadic adenomas, followed by hyperplasia,multiple adenomas, and carcinoma. Autosomal dominantfamilial hyperparathyroidism syndromes should be consid-ered in the evaluation of patients with parathyroid lesions,particularly in association with parathyroid carcinoma. Whilethe incidence of parathyroid carcinoma is quite low, it is seenwith a greater frequency in those patients with hyperparathy-roidism-jaw tumor syndrome. Inactivation of the tumorsuppressor gene HRPT2 can be identified in a large numberof parathyroid carcinomas. Hence, germline HRPT2 genemutations may reflect unrecognized syndromic patients.
(Arch Pathol Lab Med. 2010;134:1639–1644)
HISTORICAL BACKGROUND
In 1849 Sir Richard Owen performed an autopsy on arhinoceros and gave the first description of the parathy-roid gland. He described it as ‘‘a small compact yellowglandular body which was attached to the thyroid at thepoint where the veins emerged.’’ 1
The first description of the parathyroid glands inhuman beings was given by Ivar Sandstrom, a medicalstudent in Uppsala, Sweden in 1880.1,2 He suggested thatthese glands be named the glandulae parathyroideae.1,2 Thefunction of these structures was unknown at that time. In1926, at the Massachusetts General Hospital in Boston,Edward Churchill, assisted by an intern named OliverCope, operated for the seventh time on the famous seacaptain Charles Martell for severe primary hyperparathy-roidism (HPT).1 An ectopic adenoma was found sub-sternally. Although the operation was successful, CaptainMartell died 6 weeks postoperatively, most likely fromlaryngeal spasm, during a procedure to relieve ureteralobstruction secondary to stones. Ironically, 83 years later,ectopic parathyroid glands continue to be a diagnosticsurgical challenge.
EMBRYOGENESIS
While there are generally 4 parathyroid glands, weigh-ing 30 to 40 mg each, autopsy studies have shown that 2%to 13% of healthy individuals have supernumeraryparathyroid glands, most commonly with a fifth glandlocated in the cervical thymus.3 Approximately 1% to 3%of people have only 3 identifiable glands and 0.6% have 6parathyroid glands.4 Rare reports of the presence of 7 andup to 12 parathyroid glands have been described in theliterature.3–6 The presence of ectopic parathyroid tissue hasbeen attributed to abnormal migration during embryo-genesis. During development, at day 26, five pairs ofpharyngeal pouches form. The superior parathyroidsdevelop from the fourth pharyngeal pouch and theinferior from the third. The inferior parathyroids migratea greater distance, and do so in conjunction with thymictissue. Therefore, these are more likely to be found inectopic sites. The main blood supply is the inferior thyroidartery, as well as the superior thyroid artery, directly fromthyroid.
ANATOMY OF THE PARATHYROID GLANDS
The parathyroid glands are small (3–6 mm), brown,round to ovoid soft structures, which may be somewhatflattened or bilobed. Histologically, each gland has a thinfibrous capsule that overlies an arborizing network ofadipose tissue, blood vessels, and glandular parenchyma(Figure 1). The amount of stromal fibroadipose tissueincreases from puberty and continues to do so untilaround the fifth decade of life, accounting for approxi-mately 50% of the gland volume.5 The adult parathyroid iscomposed predominantly of chief cells, as well asoxyphilic cells, which are mitochondria rich, and transi-
Accepted for publication February 24, 2010.From the Department of Pathology, Memorial Sloan-Kettering Cancer
Center, New York, New York. Dr Carlson is now with the Department ofPathology, Cleveland Clinic Florida, Weston, Florida.
The author has no relevant financial interest in the products orcompanies described in this article.
Presented in part at the Surgical Pathology of Neoplastic Diseasescourse, Memorial Sloan-Kettering Cancer Center, New York, New York,May 18–22, 2009.
Reprints: Diane Carlson, MD, Department of Pathology, ClevelandClinic Florida, 3100 Weston Blvd, Weston, FL 33331 (e-mail: [email protected]).
Arch Pathol Lab Med—Vol 134, November 2010 Parathyroid Pathology and Parathyroid Tumors—Carlson 1639
Figure 1. Normal parathyroid gland containing scattered fibroadipose tissue (hematoxylin-eosin, original magnification 320).
Figure 2. a, Actual frozen section of parathyroid adenoma demonstrates dilated follicular growth with eosinophilic colloidlike material. b, Frozensection control of 2, a (hematoxylin-eosin, original magnifications 3100 [a and b]).
Figure 3. Oxyphilic (oncocytic) adenoma. Compressed rim of normal parathyroid adjacent to eosinophilic adenoma cells (hematoxylin-eosin,original magnification 320).
Figure 4. a and b, Atypical adenoma in an 11-year-old boy with hyperparathyroidism-jaw tumor syndrome. While there is a uniform population ofcells without pleomorphism (a), a focus of tumor necrosis is present (b) (hematoxylin-eosin, original magnifications 3400 [a and b]).
1640 Arch Pathol Lab Med—Vol 134, November 2010 Parathyroid Pathology and Parathyroid Tumors—Carlson
tional oxyphilic cells, which appear to represent anintermediate phase from chief cell to oxyphilic cell.
ISSUES IN HYPERPARATHYROIDISM
The level of parathyroid hormone (PTH) is inverselyproportional to the level of calcium in the blood, which istightly regulated between 8.8 and 10.2 mg/dL (to convertto millimoles per liter, multiply by 0.25). Excessivehypercalcemia leads to cessation of PTH production.Primary hyperparathyroidism is characterized by theautonomous production of parathyroid hormone result-ing in hypercalcemia and is the most common cause ofhypercalcemia in the noninpatient setting, in peoplewithout an underlying malignancy. The current incidenceof primary hyperparathyroidism has been reported as 17.7cases per 1 000 000 persons in the United States.7 Hered-itary disorders account for approximately 10% of cases ofhyperparathyroidism.8
Most commonly with primary hyperparathyroidism,one sees sporadic adenomas (85%), followed by hyper-plasia (10%), multiple adenomas (4%), and carcinoma(1%)1,4,7,8 (Table 1). The incidence of parathyroid carcino-ma is quite low. Of 574 specimens containing parathyroidtissue and reviewed from 1999 to 2009 at Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York,there were 8 reported cases of hyperplasia, with 195adenomas, 22 atypical adenomas, and 2 carcinomas; theremaining cases consisted of parathyroid glands inciden-tally removed in part or in total with thyroid lobectomy orthyroidectomy procedures (Table 2).
Historically, patients with hyperparathyroidism havepresented with symptoms including urolithiasis, bonepain, and pathologic fractures and nonspecific symptomssuch as depression, lethargy, and vague aches and pains;hence, Walter St Goar’s classic 1957 description of ‘‘stones,bones, and abdominal groans.’’ Now, however, mostpatients are asymptomatic and identified incidentally onroutine serology.1,7
Osteitis fibrosa cystica is a markedly rare disease,present in only 2% of individuals diagnosed with primaryhyperparathyroidism, which accounts for 90% of instanc-es of the disease.1 It is the excess of PTH, stimulatingosteoclastic bone resorption, which can lead to osteitisfibrosa cystica (OFC; osteitis fibrosa; or von Recklinghau-sen disease of bone), a classic skeletal manifestation ofadvanced hyperparathyroidism. There is a loss of bonemass, with peritrabecular fibrosis and the formation ofcystlike brown tumors in and around the bone. Cysts may
be lined by osteoclasts, often with abundant hemosiderin,which led to their designation as ‘‘brown tumors.’’ Thesetumors may preferentially affect mandible or maxilla, butalso have been known to arise in other craniofacial bones,including temporal bone, nasal cavity, and the sinuses.Aside from facial bone involvement, one may see rib andpelvic bone involvement. The symptoms of the disease arethe consequences of both the general softening of thebones and hypercalcemia, and include fractures, kidneystones, nausea, anorexia, and weight loss. Before 1950,around half of the patients diagnosed with hyperparathy-roidism in the United States saw the disease progress toOFC, but with early identification techniques and im-proved treatment methods, instances of OFC in developedcountries are increasingly rare. When treatment isrequired, it normally involves addressing the underlyinghyperparathyroidism before the commencement of long-term treatment for OFC—depending on its cause andseverity, this can range from hydration and exercise tosurgical intervention. Disorders such as familial hyper-parathyroidism, multiple endocrine neoplasia type 1(MEN 1), and hyperparathyroidism-jaw tumor syndromecan, if left unchecked, result in OFC.
Treatment of Primary Hyperparathyroidism
Intraoperative evaluation of the parathyroid gland canbe reliably performed with both touch preparation and/oractual frozen section. Accuracy is high and very frequent-ly a function of experience. Common pitfalls lie in theobservation of a predominant follicular pattern of growthor oxyphil-predominant areas mimicking oncocytic thy-roid parenchyma, be it neoplastic, hyperplastic, orreactive. Follicles may even contain eosinophilic colloid-like secretions, further complicating the evaluation (Fig-ure 2, a and b).
Generally, surgery is the mainstay of treatment ofprimary hyperparathyroidism, particularly for the patientyounger than 50 years, the symptomatic patient, and thosewho cannot be closely monitored medically.7 In the past,exploration and intraoperative identification of all 4parathyroid glands were performed. However, today,with the advent of the preoperative technetium Tc 99msestamibi scan and intraoperative PTH assays, theminimally invasive parathyroidectomy has evolved. Thesensitivity of these sestamibi scans for the detection ofadenomas is between 85% and 100%, with a highspecificity.7,9 While frozen section to obtain the weight ofthe adenomatous gland is commonly performed atMSKCC, and is a useful tool in the intraoperativeidentification of parathyroid tissue, we rarely see removalbeyond the adenoma at the time of frozen section. Rather,
Table 1. Lesions Which May Be Associated WithHyperthyroidism
a Parathyroid tissue representing portions of or total glands removed inthyroid lobectomy or thyroidectomy procedures.
Arch Pathol Lab Med—Vol 134, November 2010 Parathyroid Pathology and Parathyroid Tumors—Carlson 1641
it is the intraoperative decrease of PTH by 50% (or greater)after removal of the questionable gland that is indicativeof hyperfunctioning tissue and, hence, correlates withadenoma.4,9
PARATHYROID ADENOMA
Some studies4,5 have demonstrated that exposure toionizing radiation to the head and neck, in a dose-dependent manner, increases the risk of developingparathyroid adenomas. There is nearly a 4-fold increasein parathyroid tumors among people who were exposedto the atomic bomb in Hiroshima.4
Historically, the criteria for adenoma have generallyincluded a pushing border with an absence of intralesion-al fibroadipose tissue, complete circumscription with arim of ‘‘normal’’ parathyroid at the periphery, and anabsence of lobular growth. The current definition is nolonger purely histologic, but rather includes the effect ofgland removal, with intraoperative PTH decrease andsubsequent return to normocalcemia and long-term cure.Rare ‘‘double adenomas’’ have also been described,particularly in association with autosomal dominantendocrine disorders.
While most adenomas are composed of chief cells, asmall percentage may be oxyphilic (.90% oxyphils) andrare ‘‘water-clear’’ adenomas have also been described.Interestingly, oxyphilic adenomas are apparently morereadily detected on sestamibi scans5 (Figure 3).
Lipoadenomas are another exceedingly uncommonentity, with fewer than 50 reported cases. These wereinitially thought to be hamartomatous lesions, paradoxi-cally with an increase in stromal fat, but they have beenshown to be functional4,10; that is, these tumors have beenassociated with hyperparathyroidism and their surgicalremoval has led to normal PTH and calcium levels.
ATYPICAL ADENOMA
Akin to the identification of a malignant paraganglioma,parathyroid carcinoma can be a difficult diagnosis toreach. Hence, those tumors whose features are worrisome,but not diagnostic of malignancy, fall under the rubric of‘‘atypical adenoma.’’ According to Seethala et al,4 thepresence of 2 or more of the following attributes will leadto this diagnosis: incomplete invasion of the capsule,fibrous bands, pronounced trabecular growth, mitoticactivity greater than 1 per 10 high-power fields, and tumornecrosis (that is not fine-needle aspiration or infarct related)(Figure 4, a and b). There is apparently debate as towhether abnormal mitoses should be acceptable in thediagnosis of atypical adenoma; their presence shouldcertainly lead to further investigation toward the elimi-nation of malignancy.11
PARATHYROID CARCINOMA
Parathyroid carcinomas represent fewer than 4% ofcases of parathyroid disease.5 Preoperatively, the mainclinical finding in parathyroid carcinoma is high calciumand PTH levels. More frequently, patients have symp-tomatic disease and can present in hypercalcemic crisis.1
Up to 75% of patients may present with a palpable neckmass, and recurrent laryngeal nerve palsy should alert theclinician to the possibility of malignancy.12,13 While thepresence of metastatic disease to regional lymph nodes ordistant sites can confirm the diagnosis preoperatively, thediagnosis can be suggested intraoperatively on the basis of
tumor invasion into surrounding structures. Intraopera-tive examination of frozen section to establish a definitivediagnosis of carcinoma is somewhat controversial becauseof the overall difficulty of rendering the diagnosis.Histopathologic findings (in addition to those of atypicaladenoma) include a high mitotic rate and capsular,vascular, or perineural invasion2,4,5,8 (Figure 5, a throughd). Other findings such as cellular pleomorphism andatypia can also be seen, including atypical mitoses. Theseabnormal mitotic figures do appear to be a uniquehallmark, though not pathognomic, of this entity. Mortal-ity rates for parathyroid carcinomas, particularly for thosepatients with recurrence within the first 2 years postop-eratively, are high and reported to be between 46% and65%.12–14 The American Joint Committee on Cancer (AJCC)neither has staged nor has planned staging for parathy-roid carcinoma in the 7th edition of the AJCC CancerStaging Manual, because of the rarity of the condition.15
IMMUNOHISTOCHEMISTRY ANDMOLECULAR BIOLOGY
When confronted with the definitive identification of asmall fragment of tissue suspected to be parathyroid, anantibody to parathyroid hormone may be the most useful,straightforward, single antibody to use for immunohisto-chemistry analysis. The strong cytoplasmic staining ofPTH in chief cells is readily identifiable. Additionally,various low-molecular-weight cytokeratins (CKs) (eg,CK8, CK18, and CK19), and chromogranin A will beimmunoreactive.4,5,7,8,11 Adenomas, unlike normal para-thyroid tissue, express neurofilament and will also labelfor vimentin and glial fibrillary acidic protein.8 Theintensity of staining for PTH and chromogranin A hasbeen described as less intense in adenomas than in normaland hyperplastic parathyroid tissue. Of note, both CD3and CD4 have been shown to be immunoreactive withnormal and abnormal parathyroid glands; while notnecessarily of diagnostic utility, this is a valuable potentialpitfall of which to be aware.
Numerous ancillary immunohistochemical markers ofcell cycle and proliferation markers have been evaluatedin an attempt to define parathyroid neoplasia, includingMIB-1 (Ki-67), cyclin D1, p27kip1, Rb, bcl2, mdm2,calcium-sensing receptor, and gelectin-3.11,16–19 Whilemany of these are considered useful, none are definitivenor diagnostic of adenoma or other pathologic entities.Parathyroid adenomas have been shown to have rear-rangements involving the PTH locus that map to 11p15.3–15.1.4,5,18,19 These genes encode a cyclin, parathyroidadenomatosis 1, also known as cyclin D1. However, highlevels of cyclin D1 have been reported in carcinomas,adenomas, and hyperplasia. Interestingly, TP53 overex-pression has generally not been detected in parathyroidneoplasms, suggesting that this tumor suppressor genedoes not play a role in parathyroid tumorigenesis. Adecrease in mdm2 expression has been seen in tumorswith adverse histologic features. It has been proposed bysome11 that p27+, bcl2+, Ki-672, mdm2+ is unique tononmalignant neoplasms.
All of the syndromes listed in Table 3 are inherited in anautosomal dominant manner. The multiple endocrineneoplasia (MEN) syndromes are characterized by thehyperplastic or neoplastic proliferation of 1 or moreendocrine glands. With regard to the parathyroid glands,these patients will have hyperplasia or multiple adeno-
1642 Arch Pathol Lab Med—Vol 134, November 2010 Parathyroid Pathology and Parathyroid Tumors—Carlson
mas, the latter being more prone to recurrence orpersistence. Multiple endocrine neoplasia 1–associatedhyperparathyroidism, although a multigland disease, isoligoclonal, with a gene expression profile more similar toadenomas. The mutated tumor suppressor gene MEN1encodes a nuclear protein, menin, whose function it is tointeract with SMAD3 to suppress transforming growthfactor b.20 Parathyroid carcinoma has not been proved tobe a component of MEN 1. While nearly 90% of patientswith MEN 1 have hyperparathyroidism, only 20% to 30%of patients with MEN 2A do so.
Hyperparathyroidism-jaw tumor (HPT-JT) syndrome isan inherited disorder with incomplete penetrance. Thedisorder may be characterized by parathyroid adenoma orcarcinoma, benign fibro-osseous lesions of the mandibleor maxilla, and renal cysts or tumors. Approximately 80%
of patients have hyperparathyroidism and up to 15% ofthese patients have parathyroid carcinoma. The HRPT2gene (for ‘‘hyperparathyroidism 2’’) is a putative tumorsuppressor gene that was identified and has been mappedto 1q25–q31.12,20 The gene encodes a protein namedparafibromin for its relationship to parathyroid diseaseand fibro-osseous jaw lesions. While mutations predictedto inactivate this protein were first described in patientswith HPT-JT syndrome, inactivating mutations of HRPT2are found in nearly 70% of all parathyroid carcinomas.20 Inthe familial (ie, autosomal dominant) cases, the mutationis germline and in the sporadic cases, it has been shown tobe somatic. Up to 20% of patients with apparentlysporadic parathyroid carcinoma harbor germline HRPT2mutations and therefore represent unrecognized syndro-mic patients.20 While HPT-JT syndrome is an exceedinglyuncommon entity, with an unknown incidence or prev-alence, like MEN, it should be considered in thedifferential diagnosis for the adolescent presenting withhyperparathyroidism.
Familial isolated hyperparathyroidism is distinguishedby benign mutliglandular parathyroid disease and ab-sence of extraparathyroidal disease; it is estimated torepresent 1% of cases of primary hyperparathyroidism.
Figure 5. Parathyroid carcinoma. a, Trabecular pattern of growth. b, Widely infiltrative growth. c, Perineural invasion by parathyroid carcinoma.d, Lymphovascular invasion (hematoxylin-eosin, original magnifications 3200 [a and c], 3100 [b], and 3400 [d]).
Arch Pathol Lab Med—Vol 134, November 2010 Parathyroid Pathology and Parathyroid Tumors—Carlson 1643
While the mutated gene is not identified in many cases,there are kindreds in which either MEN1 or HRPT2 havebeen identified. This disease entity has yet to be furtherelucidated and better characterized.
CONCLUSIONS
Primary hyperparathyroidism is most commonly seenwith sporadic adenomas, followed by hyperplasia, mul-tiple adenomas, and carcinoma. At Memorial Sloan-Kettering Cancer Center, an oncologic tertiary care facility,adenomas are seen with a lower frequency than thatgenerally reported in the literature. The distinctionbetween adenoma, atypical adenoma, and carcinoma canbe murky, and one may need to consider clinical findingsin addition to the histologic appearance. There is currentlyno pathognomic immunophenotype to define neoplasia.While the incidence of parathyroid carcinoma is quite low,it is seen with a greater frequency in patients withhyperparathyroidism-jaw tumor (HPT-JT) syndrome.Hence, autosomal dominant familial hyperparathyroid-ism syndromes should be considered in the differentialdiagnosis, particularly in association with parathyroidcarcinoma. Inactivation of the tumor suppressor geneHRPT2 can be identified in a large number of parathyroidcarcinomas and therefore, germline HRPT2 gene muta-tions may reflect unrecognized syndromic patients.
References
1. Shaha AR, Shah JP. Parathyroid carcinoma: a diagnostic and therapeuticchallenge. Cancer. 1999;86(3):378–380.
2. DeLellis RA. Tumors of the Parathyroid Gland. Washington, DC: ArmedForces Institute of Pathology: 1993. Atlas of Tumor Pathology. 3rd series, fascicle 6.
3. Gomes EM, Nunes RC, Lacativa PG, et al. Ectopic and extranumeraryparathyroid glands location in patients with hyperparathyroidism secondary toend stage renal disease. Acta Cir Bras. 2007;22(2):105–109.
4. Seethala RR, Virji MA, Ogilvie JB. Pathology of the parathyroid glands. In:Leon Barnes, ed. Surgical Pathology of the Head and Neck. Vol III. New York,NY: Informa Health Care; 2009:1429–1472.
5. Heffess CS. Embryology, anatomy, and histology. In: Wenig B. Atlas ofHead and Neck Pathology. 2nd ed. 2008. China: Saunders Elsevier; 2008:1012–1028.
6. Uno N, Tominaga Y, Matsuoka S, et al. Incidence of parathyroid glandslocated in thymus in patients with renal hyperparathyroidism. World J Surg.2008;32(11):2516–2519.
7. DeLellis RA, Williams ED. Tumors of the thyroid and parathyroid. DeLellisRA, Lloyd RV, Heitz PU, Eng C, eds. Pathology and Genetics of Tumours ofEndocrine Organs. Lyon, France: IARC Press; 2004: 49–56, 228–229. WorldHealth Organization Classification of Tumours. vol 8.
8. Rosai J. Parathyroid glands. In: Rosai J. Rosai and Ackerman’s SurgicalPathology. 9th ed. New York, NY: Mosby; 2004:595–619.
9. Judson BL, Shaha AR. Nuclear imaging and minimally invasive surgeryin the management of hyperparathyroidism. J Nucl Med. 2008;49(11):1813–1818.
10. Seethala RR, Ogilvie JB, Carty SE, Barnes EL, Yim JH. Parathyroidlipoadenomas and lipohyperplasias: clinicopathologic correlations. Am J SurgPathol. 2008; 32(12):1854–1867.
11. Stojadinovic A, Hoos A, Nissan A, et al. Parathyroid neoplasms: clinicalhistopathological, and tissue microarray-based molecular analysis. Hum Pathol.2003;34(1):54–64.
12. Okamoto T, Iihara M, Obara T, Tsukada T. Parathyroid carcinoma:etiology, diagnosis, and treatment. World J Surgery. 2009;33(11):2343–2354.
13. Sinha S, Sinha A, McPherson GA. Synchronous sporadic carcinoma andprimary hyperplasia of the parathyroid glands: a case report and review of theliterature. Int J Surg Pathol. 2006;14(4):336–339.
14. Erickson LA, Jin L, Papotti M, Lloyd RV. Oxyphil parathyroid carcinomas:a clinicopathologic and immunohistochemical study of 10 cases. Am J SurgPathol. 2002;26(3):344–399.
16. Hadar T, Sheyero J, Yaniv E, Ram E, Shyili I, Koren R. Experssion of p53,Ki-67 and Bcl-2 in parathyroid adenoma and residual normal tissue. PatholOncol Res. 2005;11(1):45–49.
17. Naccarato AG, Marocci C, Miccoli P, et al. Bcl-2, p53, and MIB-1expression in normal and neoplastic parathyroid tissues. J Endocrinol Invest.1998;21(3):136–141.
18. Szende B, Farid P, Vegso G, Perner F, Kopper L. Apoptosis and p53, Bcl-2,and Bax gene expression in parathyroid glands of patients with hyperparathy-roidism. Pathol Oncol Res. 2004;10(2):98–103.
19. Wang W, Johansson H, Kyasnicka T, Farnebo LO, Grimelius L. Detectionof apoptotic cells and expression of Ki-67, Bcl-2, p53 oncoproteins in humanparathyroid adenoma. APMIS. 1996;104(11):789–796.
20. Simonds WF, Robbins CM, Agarwal SK, Hendy GN, Carpten JD, Marx SJ.Familial isolated hyperparathyroidism is rarely caused by germline mutation sinHRPT2, the gene for the hyperparathyroid-jaw tumor syndrome. J Clin EndocrinolMetab. 2004;89(1):96–102.
1644 Arch Pathol Lab Med—Vol 134, November 2010 Parathyroid Pathology and Parathyroid Tumors—Carlson
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
