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Familial thyroid carcinoma: the road less travelled in thyroid pathology
Mini-symposium: endocrine pathology
Familial thyroid carcinoma: the road less travelled in thyroid pathology
Characteristics of familial thyroid carcinoma • Young age • Gender incidence equal (contrast to sporadic PTC 3:1 femaleto-male ratio) • Positive family history of thyroid cancer and/or nodules (some have positive family history of other endocrine or nonendocrine lesions) • Multifocal tumours • Bilateral tumours • Possible precursor lesions (C-cell hyperplasia)
Virginia A LiVolsi Zubair W Baloch
Abstract This paper reviews the pathologic and clinicopathologic aspects of thyroid cancers and neoplasms which occur in familial settings. The data and details of C cell lesions are reviewed and a brief overview of the molecular-morphological correlations is presented. Familial tumors of follicular derivation are also described with a review of the many syndromes associated with these lesions. These tumors which may be papillary, follicular or Hurthle cell can occur solely as thyroid neoplasms without extrathyroidal manifestations or may accompany syndromes in which the extrathyroidal lesions are of primary prognostic importance (e.g. familial adenomatous polyposis). The pathologist may play a critical role in the identification of these syndromes by recognizing particular patterns of thyroid tumors (e.g. cribriform morular variant of papillary carcinoma). These issues are reviewed in this article.
Table 1
similar tumours affecting other family members and multifocal disease.5,6
Medullary carcinoma Although tumours that today would be diagnosed as medullary carcinoma of the thyroid were seen and described in the early part of the 20th century, they were not recognized as a distinct group. They were classified as either ‘atypical adenomas’ if they were circumscribed and non-invasive, and as spindle cell carcinomas akin to anaplastic carcinomas if they were infiltrative in growth pattern. In 1951, Robert Horn described seven cases of a distinctive thyroid tumour, which on the basis of morphology illustrated in the photomicrographs are medullary carcinomas; he noted that they were clinically aggressive lesions, although the clinical course was slower than that of anaplastic cancers.7 Hazard et al, in their classical paper, used the diagnostic term ‘medullary carcinoma’; these authors do credit Horn’s description and agree with the intermediate clinical features of this tumour. All the cases in these series occurred in adults; these early papers did not indicate the possibility of an hereditary neoplastic syndrome.8 During the mid-20th century, the investigation of other factors not immediately related to the pathology of these tumours was progressing. This included the identification of C cells in the human thyroid (they had been known for decades in animals) and the discovery of the hormone calcitonin (originally termed thyrocalcitonin) by Copp.9 This hormone was noted to have the effect of lowering calcium and being an antagonist to parathyroid hormone. In 1961, a case report described the autopsy of an individual with thyroid tumours and bilateral phaeochromocytomas of the adrenal glands. The author, Sipple, has since been associated with this syndrome of multiple endocrine tumours.10 In the mid-1960s, Williams postulated (based on a few cases) that this unusual thyroid tumour, medullary carcinoma, might indeed be derived from non-follicular thyroid cells, that is the C cells, and that the new hormone might be produced by these cells in the thyroid. If so, he theorized that medullary carcinoma could produce calcitonin and this could become a diagnostic and prognostic marker for this neoplasm.11 Investigation at the more basic level was concurrently being conducted in many laboratories around the world and by linkage
Keywords C cell tumors; familial tumors; syndromic neoplasms; thyroid cancer
A majority of thyroid carcinomas are sporadic and their aetiological factors are not well established. The one factor that is associated with an increased risk for papillary thyroid carcinoma (PTC) is ionizing radiation, usually of low to intermediate dose.1 The molecular correlates of the interaction of radiation with follicular epithelial cells have been defined in part and continue to be studied. It is known that rearrangements or translocations in RET proto-oncogene (RET/PTC) are found in about one-third of sporadic papillary carcinomas,2 whereas about 45% of papillary carcinomas harbour mutations in the Braf gene.3 A minority of thyroid carcinomas are familial and these fall into two main groups: those derived from parafollicular or C cells (i.e. medullary carcinoma) and those of follicular cell origin. Certainly the understanding, both at the clinical and the molecular level, of familial medullary carcinoma and related syndromes is far ahead of our knowledge of familial follicular-derived tumours.4,5 In general, familial tumours of any organ share certain characteristics (Table 1), including young age at diagnosis,
Virginia A LiVolsi MD is Professor of Pathology and Laboratory Medicine at the Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA. Zubair W Baloch MD PhD is Professor of Pathology and Laboratory Medicine at the Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA.
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analysis; the ‘hot spot’ on chromosome 10 was implicated in tumourigenesis of medullary carcinoma. These studies led to the discovery of RET mutations in the germline of these familial cases as well as in the tumours.12 The elegance of germline genetic testing with essentially no false-positive tests has been a major advance in oncology and has served as the model to be found for many common cancers (unfortunately the genetics of common cancers has proven to be quite complex and not as easily followed as in medullary carcinoma cases). Multiple point mutations in RET can give rise to medullary carcinoma and there have now been studies that show the specific mutations can be correlated with distinct pathological features, specific patterns of organ involvement, clinical features and prognostic outcomes.13,14 Medullary thyroid carcinoma comprises fewer than 10% of all thyroid malignancies. This tumour is of great diagnostic importance because of its aggressiveness, its close association with multiple endocrine neoplasia syndromes (MEN-2A and -2B) and a relationship to C-cell hyperplasia, the putative precursor lesion. While the majority of medullary carcinomas are sporadic, about 10–20% are familial.6,15 Clinical features are similar in sporadic and familial cases who are symptomatic. Medullary carcinoma affects patients of any age, although most occur in adults at an average age of 50 years. However, in familial cases, children can be affected; also in these instances the age at diagnosis tends to be younger (mean age, about 20 years). Although sporadic medullary carcinomas are seen more commonly in women, familial cases have an equal gender ratio, since an autosomal dominant mode of inheritance is present.16 In the familial forms there are associated endocrine and/or neuroendocrine lesions, although familial medullary carcinoma alone can occur in some kindreds. Sipple syndrome (MEN type 2 or 2A) is familial and consists of medullary thyroid cancer and C-cell hyperplasia, adrenal phaeochromocytoma, adrenal medullary hyperplasia and parathyroid hyperplasia. Although most affected patients will have the complete syndrome, not every patient will manifest each of these lesions. Indeed, parathyroid disease is seen in a minority of affected families (16–25%). Mutations in RET (different from the RET translocation in papillary carcinoma) are found in the tumours and the germline of patients with familial medullary carcinomas and the MEN-2 syndromes (Table 2). Mutations in specific codons have been correlated with clinical behaviour and symptomatology in some families.17 MEN-2B consists of medullary thyroid carcinoma and C-cell hyperplasia, phaeochromocytoma and adrenal medullary hyperplasia, mucosal neuromas, gastrointestinal ganglioneuromas and musculoskeletal abnormalities. These patients may have familial disease (> 50% do); some cases arise apparently as spontaneous mutations. These patients have biologically aggressive medullary carcinoma and may succumb to metastases at an early age. MEN-2B shows similarity to von Recklinghausen disease since in neurofibromatosis similar lesions are found in the gastrointestinal tract and phaeochromocytomas are common. In MEN-2B, the tumours and germline mutations in RET are found on codon 918 – an intracellular domain of the RET oncogene.14,18,19
Syndromes associated with medullary thyroid carcinoma Clinicopathological features
MEN-2 (Sipple syndrome)
Medullary thyroid carcinoma and associated C-cell hyperplasia Adrenal phaeochromocytoma and adrenal medullary hyperplasia Parathyroid hyperplasia (adenomas) Medullary thyroid carcinoma and associated C-cell hyperplasia Adrenal phaeochromocytoma and adrenal medullary hyperplasia Neuromas of oral cavity and gastrointestinal tract Musculoskeletal abnormalities (marfanoid habitus) Eye lens abnormalities Medullary thyroid carcinoma and associated C cell hyperplasia
MEN-2B
FMTC
FMTC, familial medullary thyroid carcinoma; MEN, multiple endocrine neoplasia.
Table 2
gland. In familial cases, multiple small nodules may be detected grossly and, rarely, lesions may be found in the isthmus. The tumours range in size from barely visible to several centimetres. Many medullary carcinomas are grossly circumscribed but some will show an infiltrative border. Rarely, gross necrosis and haemorrhage can occur.20,21 By light microscopy the typical medullary carcinoma may be circumscribed or more likely will be freely infiltrating into the surrounding thyroid. The pattern of growth is of tumour cells arranged in nests separated by varying amounts of stroma. The tumour nests are composed of round, oval or spindle-shaped cells; there often is isolated cellular pleomorphism or even multinucleated cells. The nuclei are uniform with a low nuclear-tocytoplasmic ratio (Figure 1). Intranuclear cytoplasmic inclusions are commonly noted. Mitoses can be seen. The tumour stroma characteristically contains amyloid, although this is not necessary for the diagnosis; about 25% of medullary carcinomas do not contain amyloid. Calcifications in areas of amyloid deposition are characteristically present. The tumours commonly invade lymphatics and veins.21 By immunohistochemistry medullary carcinoma will stain for cytokeratins, neuroendocrine markers (chromogranin, synaptophysin, CD56), specific markers such as calcitonin, thyroid transcription factor 1 and calcitonin gene related peptide (CGRP). All medullary carcinomas are positive for carcinoembryonic antigen and may stain for a variety of peptide hormones which may lead to clinical syndromes (e.g. adrenocorticotropic hormone (ACTH)).20,22 For the pathologist, the histology of medullary carcinoma and its precursors can be challenging. Early precursor pre-invasive or early invasive lesions can cause problems. Thus, medullary
Pathology Medullary carcinoma is usually located in the area of highest C-cell concentration, that is the lateral upper two-thirds of the
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Syndrome
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Figure 1 Medullary carcinoma showing tumour cells with amphophilic cytoplasm and eccentric nuclei arranged in solid nests. The tumour cells demonstrate expression of calcitonin by immunohistochemistry (inset).
Figure 2 Hyperplasia of C cells (parafollicular cells) highlighted by calcitonin immunohistochemistry (inset).
often large and show significant nuclear atypia, and may show features of medullary carcinoma. On the other hand, secondary C-cell hyperplasia is often only observed by immunohistochemical staining for calcitonin and quantitative analysis. The actual diagnosis of C-cell hyperplasia may therefore be made by routine histological examination for the presence of C cells by H&E stains.20,28,29 Medullary microcarcinoma can be found in glands removed prophylactically because of positive genetic testing for RET mutations. In the familial setting there is usually associated C-cell hyperplasia.23,29 Medullary microcarcinoma is also being increasingly recognized as a sporadic tumour in thyroid lobes or glands removed for benign nodules or for non-medullary cancer.30 These lesions show a rounded or focally infiltrative growth pattern, may contain amyloid and are not necessarily associated with C-cell hyperplasia (Figure 3). The glands frequently show chronic lymphocytic thyroiditis.30 In the absence of symptomatic hypercalcitoninaemia or lymph node metastases, these lesions are cured by their simple removal (and many endocrinologists equate them with papillary microcarcinomas found incidentally). It is believed by many clinicians that the finding of medullary carcinoma in any circumstance and at any age requires at least a discussion with the patient regarding RET mutation testing. Some limit this to patients under the age of 45 or 50. Obviously, the implications of finding a mutation are considerable for the patient’s family.23 The progress in the understanding of medullary carcinoma from the clinical, pathological and molecular perspectives was very rapid. Researchers around the world identified and studied families with the tumours and developed tests to identify patients at risk with early disease. Stimulation tests were developed and used to force the increased numbers of C cells to hypersecrete calcitonin; grossly normal thyroids were surgically removed and, not only were small medullary cancers found, but also areas of C-cell nodules, the so-called C-cell hyperplasia. Researchers from many institutions around the world contributed to the concept that not only could pre-invasive neoplasia be diagnosed in endocrine glands, but it could be treated in the pre-invasive phase, actually leading to cure (or more correctly prevention) of cancer and its fatal consequences.13,31
icrocarcinoma, defined as a tumour that is 1 cm or less in size m (similar to papillary microcarcinoma), can be identified by prophylactic thyroidectomy, but it may also occur as a sporadic tumour and thus not be easily identified. Often such small lesions do not have stromal amyloid and may be overlooked as cellular hyperplastic follicular nodules or mistaken for papillary microcarcinoma or even granulomatous folliculitis (palpation thyroiditis).23 The definition of C-cell hyperplasia is problematic.24,25 The lower limit of C-cell hyperplasia and the upper limit of normal C-cell mass are not clear. Various studies show C-cell clusters in adults that, taken alone, could fit into the category of C-cell hyperplasia. Clusters of C cells at autopsy in apparently endocrinologically normal individuals have been described.26 The current definition of normal C cells in the adult human thyroid is a moving target, but it is that there are isolated spindle cells in a parafollicular location and always fewer than 50 per any low power field; the C cells should never exceed 6 per any follicle.25,26 Thus C-cell hyperplasia is defined as increase in number (> 6 per follicle and >50 per low power field in the area of the thyroid gland with the greatest number of C cells (upper two-thirds of lateral lobes)), and abnormal morphology, including rounded shape and both intra- and extrafollicular localization (Figure 2). Cytological atypia is common in C cells in patients with familial medullary carcinoma.25,27 Conversely, the lower limit of medullary carcinoma and upper limit of C-cell hyperplasia is difficult to define. DeLellis et al state that C-cell hyperplasia ranges from diffuse increase to nodules of C cells replacing follicles, and once the basement membrane of the follicle is breached, medullary carcinoma should be diagnosed.24 It is not always obvious that the basement membrane has been breached.24,27 In the classical case, C-cell hyperplasia appears as multifocal areas of increased numbers of amphophilic large cells replacing follicular epithelium and also completely replacing follicles leading to nodule formation.28 One of the best ways to distinguish C-cell hyperplasia is by routine histological examination. C-cell hyperplasia associated with familial medullary carcinoma and MEN syndromes is readily observed on routine H&E stains. The cells are
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Familial non-medullary thyroid carcinoma (FNMTC) as the predominant lesion of a familial tumour syndrome5,33–35 Disorder
Chromosome location
Thyroid pathology
FPTC/PRN FNMTC with oxyphilia (TCO) FNMTC1 FNMTC FMNG with PTC
1q21 19p13.2
PTC, AN, PRN AN, PTC with oxyphilia PTC, AN PTC, AN PTC, MNG* AN, FA, PTC
2q21 19p13 14q 8p23.1-p22
AN, adenomatoid nodule; FA, follicular adenoma; FMNG, familial multinodular goitre; FPTC, familial papillary thyroid carcinoma; MNG*, multinodular goitre with cyst formation; PRN, papillary renal neoplasia; PTC, papillary thyroid carcinoma.
Figure 3 Medullary microcarcinoma (i.e. tumour measuring 1.0 cm or less) in a MEN-2B patient; tumour cells show immunoexpression of calcitonin (inset).
Table 3
These lesions will be discussed by their pattern and tumour subtype.
Since the molecular events underlying medullary carcinoma in the familial setting are well known, current research is focusing on targeted therapies for this tumour. Such approaches are needed since in contrast to follicular-derived thyroid tumours, medullary carcinoma does not show uptake of radioiodine and therefore that therapeutic modality is not available to patients with medullary cancers.13
Familial papillary carcinoma Thyroid papillary carcinoma of classical or follicular variant type may occur in multiple family members. In order to be considered familial cancer, at least three first-degree relatives should be affected.41 The histology of these tumours can be no different from classical or follicular variant of papillary carcinoma with or without oxyphilia, although multifocal and bilateral lesions are found. Some series indicate that these tumours clinically behave more aggressively than sporadic tumours, including extensive lymphatic invasion, lymph node metastases and frequent recurrences.41 In some of these, chromosomal abnormalities have been found, however, specific genes need to be identified.32 Sporadic PTC has BRAF mutation in approximately 40% of cases; however, most investigators have not shown BRAF mutations in FNMTC patients. Interestingly, in a recent article by Cavaco
Follicular-derived familial tumours Far less is known about these lesions and the molecular mechanisms are poorly defined. The frequency of these tumours as familial events is not known but is estimated to be between 1% and 5% of all thyroid tumours.32 This group can be conveniently divided into two main categories: familial non-medullary thyroid carcinoma (FNMTC) as the predominant lesion of a familial tumour syndrome or associated with syndromes having extrathyroidal manifestations (Tables 3 and 4).5
Non-medullary thyroid lesions associated with familial tumour syndromes5,32,36–40 Disorder
Chromosome location
Gene
Thyroid pathology
Familial adenomatous polyposis PTEN hamartoma tumour syndrome Carney complex Werner syndrome MEN-1 MEN-2A McCune Albright syndrome Peutz-Jeghers syndrome
5q21 10q22–23 17q24 8p11–21 11q13 10q11.2 20q13.1–13.2 19p13.3
APC PTEN PRKA-R1a WRN MEN-1 RET GNAS1 LKB1
PTC-CMV PTC, FTC, AN, LT AN, FA, FTC, PTC PTC, FTC, ATC NG, FA Micro-PTC NG, FTC, FA NG, PTC
AN, adenomatoid nodule; ATC, anaplastic thyroid carcinoma; CMV, cribriform morular variant; FA, follicular adenoma; FTC, follicular thyroid carcinoma; LT, lymphocytic thyroiditis; MEN, multiple endocrine neoplasias; NG, nodular goitre; PTC, papillary thyroid carcinoma.
Table 4
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et al, BRAF mutations were detected in 41% and N-RAS mutations in 23% of PTC cases in FNMTC families.42 Therefore, further work is needed to define the role of specific genes in the FNMTC tumourigenesis. The FNMTC without oxyphilia has been mapped to chromosome location 19p13 and with oxyphilia to chromosome 19p13.2 (TCO gene). The latter may show multiple oncocytic tumours of the thyroid of which one-third are malignant. The FNMTC1 syndrome has been linked to chromosome region 2q21 and is characterized by PTC and benign thyroid nodules without an increased propensity of non-thyroidal neoplasms in kindred members. The familial PTC associated with renal papillary neoplasia (FPTC/PRN) has been mapped to chromosomal region 1q21, and includes not only PTC and the expected benign thyroid nodules, but also papillary renal neoplasia and possibly malignancies of other body sites.5,32,34,43 In familial multinodular goitre (FMNG) syndrome, which maps to 14q, some patients may develop an associated PTC. The background lesions are distinctive morphologically in that they are thinly encapsulated follicular nodules with papillary hyperplastic features. The papillae are thin and the cells lining the papillae have little cytoplasm, causing the nuclei to look enlarged. The nuclei are, however, round and darkly staining. These hyperplastic nodules have been termed ‘multiple papilloid nodules’ and differ from those seen in sporadic solitary (sometimes hyperfunctioning) papillary hyperplastic lesions.43 The latter contain cells with abundant eosinophilic cytoplasm. Recently, Cavaco et al identified a large Portuguese family with 11 members affected by nodular goitre and follicular adenomas, and five patients were affected by PTC. Linkage analysis with microsatellite markers confirmed linkage to 8q23.1–p22.44 PTC and other follicular-derived thyroid tumours can be seen in other familial syndromes (see Table 4); these include PTEN hamartoma syndrome, McCune Albright syndrome, Carney complex, Peutz–Jeghers syndrome, Werner syndrome and multiple endocrine neoplasia (MEN) syndromes.5,32,36,37,45 PTEN hamartoma tumour syndrome (PHTS) is a term which covers a series of syndromic disorders caused by germline mutations in the PTEN suppressor gene which maps to chromosome 10q. The best recognized syndrome in this group is Cowden syndrome. Patients with Cowden syndrome develop both benign and malignant tumours in the breast, endometrium and thyroid. It is estimated that about 60% of affected patients will harbour thyroid nodules, including adenomatous nodules, adenomas, follicular thyroid carcinoma (FTC) and PTC. The FTC is often associated with angioinvasion. Many of the benign nodules have oncocytic morphology, as do many of the carcinomas (Figure 4). The greater risk to the patient with the syndrome is the development of breast cancer at young age, raising the possibility that this diagnosis may lead to preventative measures in these patients. The other main syndromes with germline PTEN mutations include Bannayan–Riley–Ruvalcaba syndrome (BRRS) and Proteus syndrome. Thyroid lesions are relatively less common than in Cowden syndrome.5,32,42 Carney complex is an autosomal dominant disease, characterized by skin and mucosal pigmentation, diverse pigmented skin lesions, and non-endocrine and a variety of endocrine neoplasias (pituitary adenoma, pigmented nodular adrenal disease, Sertoli and Leydig cell tumours and thyroid tumours). The thyroid is
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Figure 4 Papillary thyroid microcarcinoma; high power (inset) shows diagnostic nuclear features of papillary thyroid carcinoma.
usually multinodular with multiple adenomatous nodules and follicular adenomas, and both PTC and FTC are present in about 15% of patients with Carney complex.5,32,38 Werner syndrome is an autosomal recessive connective tissue disease, characterized by premature aging, bilateral cataracts, grey hair and skin atrophy. Patients with this syndrome have increased risk of a variety of neoplasias, including benign thyroid lesions and an increased incidence of PTC (the only tumour present in caucasian patients and the most common tumour in Japanese patients (84%)), followed by FTC (14%) and anaplastic thyroid carcinomas (2%). This latter neoplasm occurs in this syndrome at a higher frequency as compared to the general population.5,32,36 Wermer syndrome (MENI) is characterized by tumours and underlying multifocal hyperplasias of pituitary, parathyroids and pancreatic islets, and can also show thyroid nodules. Often multifocal follicular nodules, some encapsulated and therefore morphologically follicular adenomas, are found. There does not appear to be an increase in thyroid malignancies in patients with this syndrome.5 Papillary microcarcinoma Lupoli et al reported seven cases of familial papillary thyroid microcarcinoma. Five patients showed multifocal tumours and vascular invasion was present in three patients. Local recurrence occurred in three patients and one died of pulmonary metastases. The aggressive nature of these small tumours was striking. The genetic basis has not been elucidated.46 In MEN-2A patients, papillary microcarcinoma is approximately twice as common in thyroid glands as compared with the general population. These cases usually present with multiple tumours and are likely to carry only modest clinical significance, as microscopic PTCs often remain clinically silent and affected subjects carrying germline RET mutations undergo thyroidectomy at a young age (Figure 5). It is believed that the papillary carcinomas are a true component of the syndrome in affected patients and are not attributable to the care with which these 91
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Mini-symposium: endocrine pathology
Figure 5 Benign oncocytic nodule in Cowden syndrome; high power (inset) shows cells with eosinophilic cytoplasm and prominent nucleoli.
Figure 6 Cribriform morular variant of papillary carcinoma in familial adenomatous polyposis; high power shows typical (high power) ‘morule’ formation.
excised thyroids are assessed pathologically (entirely sectioned and examined).5,26,32
a 21-year-old male. Since the colonic adenomas and carcinomas are found in equal proportion in men and women, this female preponderance for the thyroid tumours is not explained. The clinical behaviour of these distinctive lesions is similar to classical papillary carcinoma sporadic type. The critical lesion here is the gastrointestinal manifestations that the thyroid tumour portends.
Cribriform morular variant, papillary carcinoma Occurring in familial and sporadic forms, this histologically distinctive tumour shows a prominent relationship with familial adenomatous polyposis (FAP) with or without Gardner syndrome.5,32,45,47,48 In some individuals, the FAP diagnosis is known because the patient or the family has had colonic or upper gastrointestinal adenomas or carcinomas. In other cases, the thyroid tumour is the presenting lesion which leads to the diagnosis of FAP and here the pathologist plays a crucial role in the recognition of the tumour as associated with polyposis. The thyroid tumour shows a partly papillary, partly cribriform growth pattern and prominent morular (squamoid) metaplasia. Although the lesion has been placed in the papillary tumour category, the nuclei of papillary carcinoma are incompletely developed or even absent in some cases (Figure 6). Thyroglobulin immunostaining is focal and weak; in some examples it may be absent. The squamous features and unusual appearance, as well as minimal thyroglobulin immunoreactivity, may lead some to consider a metastatic tumour to the thyroid instead of a thyroid primary. The lesions are all thyroid transcription factor positive (both TTF-1 and TTF-2). FAP and Gardner syndrome are associated with germline mutations in the APC gene. From a molecular standpoint, the thyroid tumours show germline mutations of the APC gene in exon 15. Beta-catenin staining shows reaction both in the nucleus and cytoplasm because of translocation of the gene back to the nucleus.45,47,49 In sporadic cases, in which patients are somewhat older, the tumours are solitary. The molecular signatures vary somewhat, although some reports indicate that they share the genetics of FAP-associated lesions.50 One major difference of sporadic tumours as compared to familial ones is the multifocality and bilaterality of lesions in the latter group.47 The papillary carcinomas are rare and estimated as occurring in about 2% of FAP-affected patients.40 Of further interest is that these tumours in FAP families are virtually always found in young females; however, we have personally seen a case in
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Conclusions This review describes the clinical, morphological and molecular data for the various forms of familial thyroid tumours, including those derived from C cells and those of follicular derivation. We stress the comparatively rich knowledge base for the C-cell neoplasms and the need for continued investigations of both syndromic and non-syndromic follicular tumours occurring in the family setting. ◆
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29 Albores-Saavedra JA, Krueger JE. C-cell hyperplasia and medullary thyroid microcarcinoma. Endocr Pathol 2001; 12: 365–77. 30 Guyetant S, Dupre F, Bigorgne JC, et al. Medullary thyroid microcarcinoma: a clinicopathologic retrospective study of 38 patients with no prior familial disease. Hum Pathol 1999; 30: 957–63. 31 Weinhaeusel A, Scheuba C, Lauss M, et al. The influence of gender, age, and RET polymorphisms on C-cell hyperplasia and medullary thyroid carcinoma. Thyroid 2008; 18: 1269–76. 32 Nose V. Familial non-medullary thyroid carcinoma: an update. Endocr Pathol 2008 Oct 18 Epub ahead of print. 33 Malchoff CD, Malchoff DM. Familial nonmedullary thyroid carcinoma. Cancer Control 2006; 13: 106–10. 34 Brunaud L, Zarnegar R, Wada N, et al. Chromosomal aberrations by comparative genomic hybridization in thyroid tumors in patients with familial nonmedullary thyroid cancer. Thyroid 2003; 13: 621–9. 35 Bevan S, Pal T, Greenberg CR, et al. A comprehensive analysis of MNG1, TCO1, fPTC, PTEN, TSHR, and TRKA in familial nonmedullary thyroid cancer: confirmation of linkage to TCO1. J Clin Endocrinol Metab 2001; 86: 3701–4. 36 Goto M, Miller RW, Ishikawa Y, Sugano H. Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol Biomarkers Prev 1996; 5: 239–46. 37 Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet 2008; 16: 1289–300. 38 Stratakis CA. Clinical genetics of multiple endocrine neoplasias, Carney complex and related syndromes. J Endocrinol Invest 2001; 24: 370–83. 39 Stratakis CA, Kirschner LS, Taymans SE, et al. Carney complex, Peutz-Jeghers syndrome, Cowden disease, and Bannayan-Zonana syndrome share cutaneous and endocrine manifestations, but not genetic loci. J Clin Endocrinol Metab 1998; 83: 2972–6. 40 Marsh DJ, Coulon V, Lunetta KL, et al. Mutation spectrum and genotype-phenotype analyses in Cowden disease and BannayanZonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet 1998; 7: 507–15. 41 Kraimps JL, Bouin-Pineau MH, Amati P, et al. Familial papillary carcinoma of the thyroid. Surgery 1997; 121: 715–8. 42 Cavaco BM, Batista PF, Martins C, et al. Familial non-medullary thyroid carcinoma (FNMTC): analysis of fPTC/PRN, NMTC1, MNG1 and TCO susceptibility loci and identification of somatic BRAF and RAS mutations. Endocr Relat Cancer 2008; 15: 207–15. 43 Bakhsh A, Kirov G, Gregory JW, Williams ED, Ludgate M. A new form of familial multi-nodular goitre with progression to differentiated thyroid cancer. Endocr Relat Cancer 2006; 13: 475–83. 44 Cavaco BM, Batista PF, Sobrinho LG, Leite V. Mapping a new familial thyroid epithelial neoplasia susceptibility locus to chromosome 8p23.1-p22 by high-density single-nucleotide polymorphism genome-wide linkage analysis. J Clin Endocrinol Metab 2008; 93: 4426–30. 45 Fenton PA, Clarke SE, Owen W, Hibbert J, Hodgson SV. Cribriform variant papillary thyroid cancer: a characteristic of familial adenomatous polyposis. Thyroid 2001; 11: 193–7. 46 Lupoli G, Vitale G, Caraglia M, et al. Familial papillary thyroid microcarcinoma: a new clinical entity. Lancet 1999; 353: 637–9. 47 Ng SB, Sittampalam K, Goh YH, Eu KW. Cribriform-morular variant of papillary carcinoma: the sporadic counterpart of familial adenomatous polyposis-associated thyroid carcinoma. A case report with clinical and molecular genetic correlation. Pathology 2003; 35: 42–6.
8 Hazard JB, Hawk WA, Crile G. Medullary (solid) carcinoma of the thyroid. A clinicopathologic entity. J Clin Endocrinol Metab 1959; 19: 152–61. 9 Copp DH. Calcitonin and parathyroid hormone. Annu Rev Pharmacol 1969; 9: 327–44. 10 Sipple JH. The association of pheochromocytoma with carcinoma of the thyroid gland. Am J Med 1961; 31: 163–6. 11 Williams ED. Histogenesis of medullary carcinoma of the thyroid. J Clin Pathol 1966; 19: 114–8. 12 Mulligan LM, Eng C, Attie T, et al. Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. Hum Mol Genet 1994; 3: 2163–7. 13 Massoll N, Mazzaferri EL. Diagnosis and management of medullary thyroid carcinoma. Clin Lab Med 2004; 24: 49–83. 14 Asa SL. How familial cancer genes and environmentally induced oncogenes have changed the endocrine landscape. Mod Pathol 2001; 14: 246–53. 15 Eng C. RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschprung’s disease. Semin Med Beth Israel Hosp Boston 1996; 335: 943–51. 16 Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 2000; 88: 1139–48. 17 Eng C. RET proto-oncogene in the development of human cancer. J Clin Oncol 1999; 17: 380–93. 18 Sheikh HA, Tometsko M, Niehouse L, et al. Molecular genotyping of medullary thyroid carcinoma can predict tumor recurrence. Am J Surg Pathol 2004; 28: 101–6. 19 Jimenez C, Habra MA, Huang SC, et al. Pheochromocytoma and medullary thyroid carcinoma: a new genotype-phenotype correlation of the RET protooncogene 891 germline mutation. J Clin Endocrinol Metab 2004; 89: 4142–5. 20 Albores-Saavedra J, LiVolsi VA, Williams ED. Medullary carcinoma. Semin Diagn Pathol 1985; 2: 137–46. 21 Evans DB, Burgess MA, Goepfert H, Gagel RF. Medullary thyroid carcinoma. Curr Ther Endocrinol Metab 1997; 6: 127–32. 22 de Lellis RA, Wolfe HJ. The pathobiology of the human calcitonin (C)-cell: a review. Pathol Annu 1981; 16: 25–52. 23 Etit D, Faquin WC, Gaz R, Randolph G, DeLellis RA, Pilch BZ. Histopathologic and clinical features of medullary microcarcinoma and C-cell hyperplasia in prophylactic thyroidectomies for medullary carcinoma: a study of 42 cases. Arch Pathol Lab Med 2008; 132: 1767–73. 24 DeLellis R, Nunnemacher G, Wolfe H. C-cell hyperplasia: an ultrastructural analysis. Lab Invest 1978; 36: 237–48. 25 Albores-Saavedra J, Monforte H, Nadji M, Morales AR. C-cell hyperplasia in thyroid tissue adjacent to follicular cell tumors. Hum Pathol 1988; 19: 795. 26 Gibson W, Peng T, Croker B. C-cell nodules in adult human thyroid: a common autopsy finding. Am J Clin Pathol 1980; 73: 347–51. 27 Komminoth P, Roth J, Saremasiani P, et al. Polysialic acid of the neural cell adhesion molecule in the human thyroid: a marker for medullary carcinoma and primary C-cell hyperplasia. An immunohistochemical study on 79 thyroid lesions. Am J Surg Pathol 1994; 18: 399. 28 Wolfe HJ, Melvin KE, Cervi-Skinner SJ, et al. C-cell hyperplasia preceding medullary thyroid carcinoma. N Engl J Med 1973; 289: 437–41.
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48 Sippel RS, Caron NR, Clark OH. An evidence-based approach to familial nonmedullary thyroid cancer: screening, clinical management, and follow-up. World J Surg 2007; 31: 924–33. 49 Chan JK, Loo KT. Cribriform variant of papillary thyroid carcinoma. Arch Pathol Lab Med 1990; 114: 622–4. 50 Subramaniam MM, Putti TC, Anuar D, et al. Clonal characterization of sporadic cribriform-morular variant of papillary thyroid carcinoma by laser microdissection-based APC mutation analysis. Am J Clin Pathol 2007; 128: 994–1001.
• C-cell hyperplasia associated with familial medullary carcinoma and MEN syndromes is readily observed on routine H&E stains • By light microscopy medullary microcarcinoma shows a rounded or focally infiltrative growth pattern, may contain amyloid and is not necessarily associated with C-cell hyperplasia. The thyroid gland frequently shows chronic lymphocytic thyroiditis • Thyroid papillary carcinoma of classical or follicular variant type may occur in multiple family members. In order to be considered familial cancer, at least three first-degree relatives should be affected • Familial non-medullary thyroid carcinoma (FNMTC) can present as the predominant lesion of a familial tumour syndrome or be associated with syndromes having extrathyroidal manifestations • Papillary thyroid carcinoma and other follicular-derived thyroid tumours can be seen in other familial syndromes; these include PTEN hamartoma syndrome, McCune Albright syndrome, Carney complex, Peutz–Jeghers syndrome, Werner syndrome and MEN syndromes
Practice points • The pathological diagnosis of medullary carcinoma is of great importance because of its aggressiveness, its close association with multiple endocrine neoplasia syndromes (MEN-2A and -2B) and a relationship to C-cell hyperplasia, the putative precursor lesion
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Familial thyroid carcinoma: the road less travelled in thyroid pathology
Characteristics of familial thyroid carcinoma • Young age • Gender incidence equal (contrast to sporadic PTC 3:1 femaleto-male ratio) • Positive family history of thyroid cancer and/or nodules (some have positive family history of other endocrine or nonendocrine lesions) • Multifocal tumours • Bilateral tumours • Possible precursor lesions (C-cell hyperplasia)
Virginia A LiVolsi Zubair W Baloch
Abstract This paper reviews the pathologic and clinicopathologic aspects of thyroid cancers and neoplasms which occur in familial settings. The data and details of C cell lesions are reviewed and a brief overview of the molecular-morphological correlations is presented. Familial tumors of follicular derivation are also described with a review of the many syndromes associated with these lesions. These tumors which may be papillary, follicular or Hurthle cell can occur solely as thyroid neoplasms without extrathyroidal manifestations or may accompany syndromes in which the extrathyroidal lesions are of primary prognostic importance (e.g. familial adenomatous polyposis). The pathologist may play a critical role in the identification of these syndromes by recognizing particular patterns of thyroid tumors (e.g. cribriform morular variant of papillary carcinoma). These issues are reviewed in this article.
Table 1
similar tumours affecting other family members and multifocal disease.5,6
Medullary carcinoma Although tumours that today would be diagnosed as medullary carcinoma of the thyroid were seen and described in the early part of the 20th century, they were not recognized as a distinct group. They were classified as either ‘atypical adenomas’ if they were circumscribed and non-invasive, and as spindle cell carcinomas akin to anaplastic carcinomas if they were infiltrative in growth pattern. In 1951, Robert Horn described seven cases of a distinctive thyroid tumour, which on the basis of morphology illustrated in the photomicrographs are medullary carcinomas; he noted that they were clinically aggressive lesions, although the clinical course was slower than that of anaplastic cancers.7 Hazard et al, in their classical paper, used the diagnostic term ‘medullary carcinoma’; these authors do credit Horn’s description and agree with the intermediate clinical features of this tumour. All the cases in these series occurred in adults; these early papers did not indicate the possibility of an hereditary neoplastic syndrome.8 During the mid-20th century, the investigation of other factors not immediately related to the pathology of these tumours was progressing. This included the identification of C cells in the human thyroid (they had been known for decades in animals) and the discovery of the hormone calcitonin (originally termed thyrocalcitonin) by Copp.9 This hormone was noted to have the effect of lowering calcium and being an antagonist to parathyroid hormone. In 1961, a case report described the autopsy of an individual with thyroid tumours and bilateral phaeochromocytomas of the adrenal glands. The author, Sipple, has since been associated with this syndrome of multiple endocrine tumours.10 In the mid-1960s, Williams postulated (based on a few cases) that this unusual thyroid tumour, medullary carcinoma, might indeed be derived from non-follicular thyroid cells, that is the C cells, and that the new hormone might be produced by these cells in the thyroid. If so, he theorized that medullary carcinoma could produce calcitonin and this could become a diagnostic and prognostic marker for this neoplasm.11 Investigation at the more basic level was concurrently being conducted in many laboratories around the world and by linkage
Keywords C cell tumors; familial tumors; syndromic neoplasms; thyroid cancer
A majority of thyroid carcinomas are sporadic and their aetiological factors are not well established. The one factor that is associated with an increased risk for papillary thyroid carcinoma (PTC) is ionizing radiation, usually of low to intermediate dose.1 The molecular correlates of the interaction of radiation with follicular epithelial cells have been defined in part and continue to be studied. It is known that rearrangements or translocations in RET proto-oncogene (RET/PTC) are found in about one-third of sporadic papillary carcinomas,2 whereas about 45% of papillary carcinomas harbour mutations in the Braf gene.3 A minority of thyroid carcinomas are familial and these fall into two main groups: those derived from parafollicular or C cells (i.e. medullary carcinoma) and those of follicular cell origin. Certainly the understanding, both at the clinical and the molecular level, of familial medullary carcinoma and related syndromes is far ahead of our knowledge of familial follicular-derived tumours.4,5 In general, familial tumours of any organ share certain characteristics (Table 1), including young age at diagnosis,
Virginia A LiVolsi MD is Professor of Pathology and Laboratory Medicine at the Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA. Zubair W Baloch MD PhD is Professor of Pathology and Laboratory Medicine at the Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA.
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analysis; the ‘hot spot’ on chromosome 10 was implicated in tumourigenesis of medullary carcinoma. These studies led to the discovery of RET mutations in the germline of these familial cases as well as in the tumours.12 The elegance of germline genetic testing with essentially no false-positive tests has been a major advance in oncology and has served as the model to be found for many common cancers (unfortunately the genetics of common cancers has proven to be quite complex and not as easily followed as in medullary carcinoma cases). Multiple point mutations in RET can give rise to medullary carcinoma and there have now been studies that show the specific mutations can be correlated with distinct pathological features, specific patterns of organ involvement, clinical features and prognostic outcomes.13,14 Medullary thyroid carcinoma comprises fewer than 10% of all thyroid malignancies. This tumour is of great diagnostic importance because of its aggressiveness, its close association with multiple endocrine neoplasia syndromes (MEN-2A and -2B) and a relationship to C-cell hyperplasia, the putative precursor lesion. While the majority of medullary carcinomas are sporadic, about 10–20% are familial.6,15 Clinical features are similar in sporadic and familial cases who are symptomatic. Medullary carcinoma affects patients of any age, although most occur in adults at an average age of 50 years. However, in familial cases, children can be affected; also in these instances the age at diagnosis tends to be younger (mean age, about 20 years). Although sporadic medullary carcinomas are seen more commonly in women, familial cases have an equal gender ratio, since an autosomal dominant mode of inheritance is present.16 In the familial forms there are associated endocrine and/or neuroendocrine lesions, although familial medullary carcinoma alone can occur in some kindreds. Sipple syndrome (MEN type 2 or 2A) is familial and consists of medullary thyroid cancer and C-cell hyperplasia, adrenal phaeochromocytoma, adrenal medullary hyperplasia and parathyroid hyperplasia. Although most affected patients will have the complete syndrome, not every patient will manifest each of these lesions. Indeed, parathyroid disease is seen in a minority of affected families (16–25%). Mutations in RET (different from the RET translocation in papillary carcinoma) are found in the tumours and the germline of patients with familial medullary carcinomas and the MEN-2 syndromes (Table 2). Mutations in specific codons have been correlated with clinical behaviour and symptomatology in some families.17 MEN-2B consists of medullary thyroid carcinoma and C-cell hyperplasia, phaeochromocytoma and adrenal medullary hyperplasia, mucosal neuromas, gastrointestinal ganglioneuromas and musculoskeletal abnormalities. These patients may have familial disease (> 50% do); some cases arise apparently as spontaneous mutations. These patients have biologically aggressive medullary carcinoma and may succumb to metastases at an early age. MEN-2B shows similarity to von Recklinghausen disease since in neurofibromatosis similar lesions are found in the gastrointestinal tract and phaeochromocytomas are common. In MEN-2B, the tumours and germline mutations in RET are found on codon 918 – an intracellular domain of the RET oncogene.14,18,19
Syndromes associated with medullary thyroid carcinoma Clinicopathological features
MEN-2 (Sipple syndrome)
Medullary thyroid carcinoma and associated C-cell hyperplasia Adrenal phaeochromocytoma and adrenal medullary hyperplasia Parathyroid hyperplasia (adenomas) Medullary thyroid carcinoma and associated C-cell hyperplasia Adrenal phaeochromocytoma and adrenal medullary hyperplasia Neuromas of oral cavity and gastrointestinal tract Musculoskeletal abnormalities (marfanoid habitus) Eye lens abnormalities Medullary thyroid carcinoma and associated C cell hyperplasia
MEN-2B
FMTC
FMTC, familial medullary thyroid carcinoma; MEN, multiple endocrine neoplasia.
Table 2
gland. In familial cases, multiple small nodules may be detected grossly and, rarely, lesions may be found in the isthmus. The tumours range in size from barely visible to several centimetres. Many medullary carcinomas are grossly circumscribed but some will show an infiltrative border. Rarely, gross necrosis and haemorrhage can occur.20,21 By light microscopy the typical medullary carcinoma may be circumscribed or more likely will be freely infiltrating into the surrounding thyroid. The pattern of growth is of tumour cells arranged in nests separated by varying amounts of stroma. The tumour nests are composed of round, oval or spindle-shaped cells; there often is isolated cellular pleomorphism or even multinucleated cells. The nuclei are uniform with a low nuclear-tocytoplasmic ratio (Figure 1). Intranuclear cytoplasmic inclusions are commonly noted. Mitoses can be seen. The tumour stroma characteristically contains amyloid, although this is not necessary for the diagnosis; about 25% of medullary carcinomas do not contain amyloid. Calcifications in areas of amyloid deposition are characteristically present. The tumours commonly invade lymphatics and veins.21 By immunohistochemistry medullary carcinoma will stain for cytokeratins, neuroendocrine markers (chromogranin, synaptophysin, CD56), specific markers such as calcitonin, thyroid transcription factor 1 and calcitonin gene related peptide (CGRP). All medullary carcinomas are positive for carcinoembryonic antigen and may stain for a variety of peptide hormones which may lead to clinical syndromes (e.g. adrenocorticotropic hormone (ACTH)).20,22 For the pathologist, the histology of medullary carcinoma and its precursors can be challenging. Early precursor pre-invasive or early invasive lesions can cause problems. Thus, medullary
Pathology Medullary carcinoma is usually located in the area of highest C-cell concentration, that is the lateral upper two-thirds of the
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Figure 1 Medullary carcinoma showing tumour cells with amphophilic cytoplasm and eccentric nuclei arranged in solid nests. The tumour cells demonstrate expression of calcitonin by immunohistochemistry (inset).
Figure 2 Hyperplasia of C cells (parafollicular cells) highlighted by calcitonin immunohistochemistry (inset).
often large and show significant nuclear atypia, and may show features of medullary carcinoma. On the other hand, secondary C-cell hyperplasia is often only observed by immunohistochemical staining for calcitonin and quantitative analysis. The actual diagnosis of C-cell hyperplasia may therefore be made by routine histological examination for the presence of C cells by H&E stains.20,28,29 Medullary microcarcinoma can be found in glands removed prophylactically because of positive genetic testing for RET mutations. In the familial setting there is usually associated C-cell hyperplasia.23,29 Medullary microcarcinoma is also being increasingly recognized as a sporadic tumour in thyroid lobes or glands removed for benign nodules or for non-medullary cancer.30 These lesions show a rounded or focally infiltrative growth pattern, may contain amyloid and are not necessarily associated with C-cell hyperplasia (Figure 3). The glands frequently show chronic lymphocytic thyroiditis.30 In the absence of symptomatic hypercalcitoninaemia or lymph node metastases, these lesions are cured by their simple removal (and many endocrinologists equate them with papillary microcarcinomas found incidentally). It is believed by many clinicians that the finding of medullary carcinoma in any circumstance and at any age requires at least a discussion with the patient regarding RET mutation testing. Some limit this to patients under the age of 45 or 50. Obviously, the implications of finding a mutation are considerable for the patient’s family.23 The progress in the understanding of medullary carcinoma from the clinical, pathological and molecular perspectives was very rapid. Researchers around the world identified and studied families with the tumours and developed tests to identify patients at risk with early disease. Stimulation tests were developed and used to force the increased numbers of C cells to hypersecrete calcitonin; grossly normal thyroids were surgically removed and, not only were small medullary cancers found, but also areas of C-cell nodules, the so-called C-cell hyperplasia. Researchers from many institutions around the world contributed to the concept that not only could pre-invasive neoplasia be diagnosed in endocrine glands, but it could be treated in the pre-invasive phase, actually leading to cure (or more correctly prevention) of cancer and its fatal consequences.13,31
icrocarcinoma, defined as a tumour that is 1 cm or less in size m (similar to papillary microcarcinoma), can be identified by prophylactic thyroidectomy, but it may also occur as a sporadic tumour and thus not be easily identified. Often such small lesions do not have stromal amyloid and may be overlooked as cellular hyperplastic follicular nodules or mistaken for papillary microcarcinoma or even granulomatous folliculitis (palpation thyroiditis).23 The definition of C-cell hyperplasia is problematic.24,25 The lower limit of C-cell hyperplasia and the upper limit of normal C-cell mass are not clear. Various studies show C-cell clusters in adults that, taken alone, could fit into the category of C-cell hyperplasia. Clusters of C cells at autopsy in apparently endocrinologically normal individuals have been described.26 The current definition of normal C cells in the adult human thyroid is a moving target, but it is that there are isolated spindle cells in a parafollicular location and always fewer than 50 per any low power field; the C cells should never exceed 6 per any follicle.25,26 Thus C-cell hyperplasia is defined as increase in number (> 6 per follicle and >50 per low power field in the area of the thyroid gland with the greatest number of C cells (upper two-thirds of lateral lobes)), and abnormal morphology, including rounded shape and both intra- and extrafollicular localization (Figure 2). Cytological atypia is common in C cells in patients with familial medullary carcinoma.25,27 Conversely, the lower limit of medullary carcinoma and upper limit of C-cell hyperplasia is difficult to define. DeLellis et al state that C-cell hyperplasia ranges from diffuse increase to nodules of C cells replacing follicles, and once the basement membrane of the follicle is breached, medullary carcinoma should be diagnosed.24 It is not always obvious that the basement membrane has been breached.24,27 In the classical case, C-cell hyperplasia appears as multifocal areas of increased numbers of amphophilic large cells replacing follicular epithelium and also completely replacing follicles leading to nodule formation.28 One of the best ways to distinguish C-cell hyperplasia is by routine histological examination. C-cell hyperplasia associated with familial medullary carcinoma and MEN syndromes is readily observed on routine H&E stains. The cells are
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Familial non-medullary thyroid carcinoma (FNMTC) as the predominant lesion of a familial tumour syndrome5,33–35 Disorder
Chromosome location
Thyroid pathology
FPTC/PRN FNMTC with oxyphilia (TCO) FNMTC1 FNMTC FMNG with PTC
1q21 19p13.2
PTC, AN, PRN AN, PTC with oxyphilia PTC, AN PTC, AN PTC, MNG* AN, FA, PTC
2q21 19p13 14q 8p23.1-p22
AN, adenomatoid nodule; FA, follicular adenoma; FMNG, familial multinodular goitre; FPTC, familial papillary thyroid carcinoma; MNG*, multinodular goitre with cyst formation; PRN, papillary renal neoplasia; PTC, papillary thyroid carcinoma.
Figure 3 Medullary microcarcinoma (i.e. tumour measuring 1.0 cm or less) in a MEN-2B patient; tumour cells show immunoexpression of calcitonin (inset).
Table 3
These lesions will be discussed by their pattern and tumour subtype.
Since the molecular events underlying medullary carcinoma in the familial setting are well known, current research is focusing on targeted therapies for this tumour. Such approaches are needed since in contrast to follicular-derived thyroid tumours, medullary carcinoma does not show uptake of radioiodine and therefore that therapeutic modality is not available to patients with medullary cancers.13
Familial papillary carcinoma Thyroid papillary carcinoma of classical or follicular variant type may occur in multiple family members. In order to be considered familial cancer, at least three first-degree relatives should be affected.41 The histology of these tumours can be no different from classical or follicular variant of papillary carcinoma with or without oxyphilia, although multifocal and bilateral lesions are found. Some series indicate that these tumours clinically behave more aggressively than sporadic tumours, including extensive lymphatic invasion, lymph node metastases and frequent recurrences.41 In some of these, chromosomal abnormalities have been found, however, specific genes need to be identified.32 Sporadic PTC has BRAF mutation in approximately 40% of cases; however, most investigators have not shown BRAF mutations in FNMTC patients. Interestingly, in a recent article by Cavaco
Follicular-derived familial tumours Far less is known about these lesions and the molecular mechanisms are poorly defined. The frequency of these tumours as familial events is not known but is estimated to be between 1% and 5% of all thyroid tumours.32 This group can be conveniently divided into two main categories: familial non-medullary thyroid carcinoma (FNMTC) as the predominant lesion of a familial tumour syndrome or associated with syndromes having extrathyroidal manifestations (Tables 3 and 4).5
Non-medullary thyroid lesions associated with familial tumour syndromes5,32,36–40 Disorder
Chromosome location
Gene
Thyroid pathology
Familial adenomatous polyposis PTEN hamartoma tumour syndrome Carney complex Werner syndrome MEN-1 MEN-2A McCune Albright syndrome Peutz-Jeghers syndrome
5q21 10q22–23 17q24 8p11–21 11q13 10q11.2 20q13.1–13.2 19p13.3
APC PTEN PRKA-R1a WRN MEN-1 RET GNAS1 LKB1
PTC-CMV PTC, FTC, AN, LT AN, FA, FTC, PTC PTC, FTC, ATC NG, FA Micro-PTC NG, FTC, FA NG, PTC
AN, adenomatoid nodule; ATC, anaplastic thyroid carcinoma; CMV, cribriform morular variant; FA, follicular adenoma; FTC, follicular thyroid carcinoma; LT, lymphocytic thyroiditis; MEN, multiple endocrine neoplasias; NG, nodular goitre; PTC, papillary thyroid carcinoma.
Table 4
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et al, BRAF mutations were detected in 41% and N-RAS mutations in 23% of PTC cases in FNMTC families.42 Therefore, further work is needed to define the role of specific genes in the FNMTC tumourigenesis. The FNMTC without oxyphilia has been mapped to chromosome location 19p13 and with oxyphilia to chromosome 19p13.2 (TCO gene). The latter may show multiple oncocytic tumours of the thyroid of which one-third are malignant. The FNMTC1 syndrome has been linked to chromosome region 2q21 and is characterized by PTC and benign thyroid nodules without an increased propensity of non-thyroidal neoplasms in kindred members. The familial PTC associated with renal papillary neoplasia (FPTC/PRN) has been mapped to chromosomal region 1q21, and includes not only PTC and the expected benign thyroid nodules, but also papillary renal neoplasia and possibly malignancies of other body sites.5,32,34,43 In familial multinodular goitre (FMNG) syndrome, which maps to 14q, some patients may develop an associated PTC. The background lesions are distinctive morphologically in that they are thinly encapsulated follicular nodules with papillary hyperplastic features. The papillae are thin and the cells lining the papillae have little cytoplasm, causing the nuclei to look enlarged. The nuclei are, however, round and darkly staining. These hyperplastic nodules have been termed ‘multiple papilloid nodules’ and differ from those seen in sporadic solitary (sometimes hyperfunctioning) papillary hyperplastic lesions.43 The latter contain cells with abundant eosinophilic cytoplasm. Recently, Cavaco et al identified a large Portuguese family with 11 members affected by nodular goitre and follicular adenomas, and five patients were affected by PTC. Linkage analysis with microsatellite markers confirmed linkage to 8q23.1–p22.44 PTC and other follicular-derived thyroid tumours can be seen in other familial syndromes (see Table 4); these include PTEN hamartoma syndrome, McCune Albright syndrome, Carney complex, Peutz–Jeghers syndrome, Werner syndrome and multiple endocrine neoplasia (MEN) syndromes.5,32,36,37,45 PTEN hamartoma tumour syndrome (PHTS) is a term which covers a series of syndromic disorders caused by germline mutations in the PTEN suppressor gene which maps to chromosome 10q. The best recognized syndrome in this group is Cowden syndrome. Patients with Cowden syndrome develop both benign and malignant tumours in the breast, endometrium and thyroid. It is estimated that about 60% of affected patients will harbour thyroid nodules, including adenomatous nodules, adenomas, follicular thyroid carcinoma (FTC) and PTC. The FTC is often associated with angioinvasion. Many of the benign nodules have oncocytic morphology, as do many of the carcinomas (Figure 4). The greater risk to the patient with the syndrome is the development of breast cancer at young age, raising the possibility that this diagnosis may lead to preventative measures in these patients. The other main syndromes with germline PTEN mutations include Bannayan–Riley–Ruvalcaba syndrome (BRRS) and Proteus syndrome. Thyroid lesions are relatively less common than in Cowden syndrome.5,32,42 Carney complex is an autosomal dominant disease, characterized by skin and mucosal pigmentation, diverse pigmented skin lesions, and non-endocrine and a variety of endocrine neoplasias (pituitary adenoma, pigmented nodular adrenal disease, Sertoli and Leydig cell tumours and thyroid tumours). The thyroid is
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Figure 4 Papillary thyroid microcarcinoma; high power (inset) shows diagnostic nuclear features of papillary thyroid carcinoma.
usually multinodular with multiple adenomatous nodules and follicular adenomas, and both PTC and FTC are present in about 15% of patients with Carney complex.5,32,38 Werner syndrome is an autosomal recessive connective tissue disease, characterized by premature aging, bilateral cataracts, grey hair and skin atrophy. Patients with this syndrome have increased risk of a variety of neoplasias, including benign thyroid lesions and an increased incidence of PTC (the only tumour present in caucasian patients and the most common tumour in Japanese patients (84%)), followed by FTC (14%) and anaplastic thyroid carcinomas (2%). This latter neoplasm occurs in this syndrome at a higher frequency as compared to the general population.5,32,36 Wermer syndrome (MENI) is characterized by tumours and underlying multifocal hyperplasias of pituitary, parathyroids and pancreatic islets, and can also show thyroid nodules. Often multifocal follicular nodules, some encapsulated and therefore morphologically follicular adenomas, are found. There does not appear to be an increase in thyroid malignancies in patients with this syndrome.5 Papillary microcarcinoma Lupoli et al reported seven cases of familial papillary thyroid microcarcinoma. Five patients showed multifocal tumours and vascular invasion was present in three patients. Local recurrence occurred in three patients and one died of pulmonary metastases. The aggressive nature of these small tumours was striking. The genetic basis has not been elucidated.46 In MEN-2A patients, papillary microcarcinoma is approximately twice as common in thyroid glands as compared with the general population. These cases usually present with multiple tumours and are likely to carry only modest clinical significance, as microscopic PTCs often remain clinically silent and affected subjects carrying germline RET mutations undergo thyroidectomy at a young age (Figure 5). It is believed that the papillary carcinomas are a true component of the syndrome in affected patients and are not attributable to the care with which these 91
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Figure 5 Benign oncocytic nodule in Cowden syndrome; high power (inset) shows cells with eosinophilic cytoplasm and prominent nucleoli.
Figure 6 Cribriform morular variant of papillary carcinoma in familial adenomatous polyposis; high power shows typical (high power) ‘morule’ formation.
excised thyroids are assessed pathologically (entirely sectioned and examined).5,26,32
a 21-year-old male. Since the colonic adenomas and carcinomas are found in equal proportion in men and women, this female preponderance for the thyroid tumours is not explained. The clinical behaviour of these distinctive lesions is similar to classical papillary carcinoma sporadic type. The critical lesion here is the gastrointestinal manifestations that the thyroid tumour portends.
Cribriform morular variant, papillary carcinoma Occurring in familial and sporadic forms, this histologically distinctive tumour shows a prominent relationship with familial adenomatous polyposis (FAP) with or without Gardner syndrome.5,32,45,47,48 In some individuals, the FAP diagnosis is known because the patient or the family has had colonic or upper gastrointestinal adenomas or carcinomas. In other cases, the thyroid tumour is the presenting lesion which leads to the diagnosis of FAP and here the pathologist plays a crucial role in the recognition of the tumour as associated with polyposis. The thyroid tumour shows a partly papillary, partly cribriform growth pattern and prominent morular (squamoid) metaplasia. Although the lesion has been placed in the papillary tumour category, the nuclei of papillary carcinoma are incompletely developed or even absent in some cases (Figure 6). Thyroglobulin immunostaining is focal and weak; in some examples it may be absent. The squamous features and unusual appearance, as well as minimal thyroglobulin immunoreactivity, may lead some to consider a metastatic tumour to the thyroid instead of a thyroid primary. The lesions are all thyroid transcription factor positive (both TTF-1 and TTF-2). FAP and Gardner syndrome are associated with germline mutations in the APC gene. From a molecular standpoint, the thyroid tumours show germline mutations of the APC gene in exon 15. Beta-catenin staining shows reaction both in the nucleus and cytoplasm because of translocation of the gene back to the nucleus.45,47,49 In sporadic cases, in which patients are somewhat older, the tumours are solitary. The molecular signatures vary somewhat, although some reports indicate that they share the genetics of FAP-associated lesions.50 One major difference of sporadic tumours as compared to familial ones is the multifocality and bilaterality of lesions in the latter group.47 The papillary carcinomas are rare and estimated as occurring in about 2% of FAP-affected patients.40 Of further interest is that these tumours in FAP families are virtually always found in young females; however, we have personally seen a case in
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Conclusions This review describes the clinical, morphological and molecular data for the various forms of familial thyroid tumours, including those derived from C cells and those of follicular derivation. We stress the comparatively rich knowledge base for the C-cell neoplasms and the need for continued investigations of both syndromic and non-syndromic follicular tumours occurring in the family setting. ◆
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• C-cell hyperplasia associated with familial medullary carcinoma and MEN syndromes is readily observed on routine H&E stains • By light microscopy medullary microcarcinoma shows a rounded or focally infiltrative growth pattern, may contain amyloid and is not necessarily associated with C-cell hyperplasia. The thyroid gland frequently shows chronic lymphocytic thyroiditis • Thyroid papillary carcinoma of classical or follicular variant type may occur in multiple family members. In order to be considered familial cancer, at least three first-degree relatives should be affected • Familial non-medullary thyroid carcinoma (FNMTC) can present as the predominant lesion of a familial tumour syndrome or be associated with syndromes having extrathyroidal manifestations • Papillary thyroid carcinoma and other follicular-derived thyroid tumours can be seen in other familial syndromes; these include PTEN hamartoma syndrome, McCune Albright syndrome, Carney complex, Peutz–Jeghers syndrome, Werner syndrome and MEN syndromes
Practice points • The pathological diagnosis of medullary carcinoma is of great importance because of its aggressiveness, its close association with multiple endocrine neoplasia syndromes (MEN-2A and -2B) and a relationship to C-cell hyperplasia, the putative precursor lesion
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