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The occurrence of medullary thyroid carcinoma (MTC) in patients with germline RET mutation is well established, but the occasional occurrence of papillary thyroid carcinoma (PTC) in this setting remains unexplained. We report a case of synchronous MTC and PTC in a patient with germline RET mutation, and investigate the molecular pathogenesis of these two tumors. A 48-year-old man presented with cervical lymphadenopathy and was found to have metastatic MTC involving cervical and mediastinal lymph nodes. He underwent thyroidectomy and debulking of metastatic disease. The resected thyroid showed bilateral MTC and a 1-cm PTC. His lymph node metastases were predominantly MTC along with a small focus of metastatic PTC. Molecular testing using peripheral blood revealed a germline RET point mutation (Val804Met). Both tumors were analyzed for the BRAF (Val600Glu) mutation and the RET/PTC1 translocation. The PTC was positive for the BRAF mutation but negative for RET/PTC1. The MTC was negative for both abnormalities. We conclude that the MTC was caused by the germline RET mutation, while the PTC was caused by a somatic BRAF mutation. The occurrence of PTC in patients with germline RET mutations appears to be purely coincidental. [ABSTRACT FROM AUTHOR]

RET proto-oncogene (RET) mutations were proved to be related to the development of medullary thyroid carcinoma (MTC). We aimed to analyze the role of RET mutations in cervical lymph node metastasis in patients with MTC. Forty-nine patients with preoperatively diagnosed MTC by fine-needle aspiration cytology (FNAC) who underwent bilateral total thyroidectomy with cervical lymphadenectomy were included. Postoperative RET gene test and pathological analysis were performed with the surgical specimens; serum calcitonin (Ctn) and carcinoembryonic antigen (CEA) levels were tested pre- and postoperatively, to evaluate the association between RET mutations and cervical lymph node metastasis in MTC. In these 49 patients, the RET mutation rates of Exon 11, Exon 10, Exon 11&13, Exon 13, and Exon 16 were 20.4%, 4.1%, 38.8%, 22.4%, and 0%, respectively. The lymph node metastasis rates of patients with RET mutation in the central and lateral compartments were 71.4% and 64.3%, respectively, versus 28.6% and 14.3% of patients without RET mutation. The preoperative basal serum levels of Ctn (234.8 ± 188.4 vs. 44.4 ± 27.5, p < 0.01) and postoperative Ctn (49.8 ± 86.4 vs. 3.7 ± 2.2, p = 0.001) in MTC patients with RET mutations were significantly higher than those in MTC patients without RET mutation. In addition, the preoperative (50.2 ± 76.7 vs. 7.4 ± 6.8, p = 0.001) and postoperative serum levels of CEA (13.2 ± 19.5 vs. 1.3 ± 1.6, p < 0.01) in MTC patients with RET mutations were significantly higher than those in MTC patients without RET mutation (p < 0.05). RET mutation was related to cervical lymph node metastasis in patients with MTC, especially the mutation in Exon 11&13. Patients with RET mutation in Exon 11&13 might be regarded as the predictor for prophylactic ipsilateral total cervical lymphadenectomy even without clear evidence of lateral cervical lymph node metastasis. [ABSTRACT FROM AUTHOR]

Our understanding of the genomics and epigenomics of medullary thyroid carcinoma (MTC) has advanced since the initial recognition of RET as a driver of MTC tumorigenesis in familial MTC. We now have insight into the frequency and prognostic significance of specific RET mutations in sporadic MTC. For example, the most common RET mutation in sporadic MTC is the RET Met918Thr mutation, the same mutation that underlies MEN2B and a poor prognosticator. This mutation is relatively infrequent in medullary thyroid microcarcinomas but is over-represented in advanced-stage disease. RAS mutations are detected in 70% of sporadic, RET wild-type MTC. Although next-generation and whole-exome sequencing studies have shown that tumors that are wild-type for RET and RAS mutations essentially lack other recurrent mutations, additional pathways and epigenetic alterations have been implicated in MTC tumorigenesis. Increased insight into the clinical course of patients with familial MTC with specific RET mutations has guided treatment recommendations for these patients. Finally, an understanding of the genomics has informed treatment for patients with advanced MTC. In this review, we will examine the genomics and epigenomics of sporadic and familial MTC, along with the prognostic significance of molecular alterations, management of patients with germline RET mutations, and treatment strategies for MTC patients. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are characterized by development of medullary thyroid carcinoma (MTC) and caused by germline RET mutations. Patients with MEN 2A also develop pheochromocytoma and/or hyperparathyroidism (HPT). However, MEN 2A-affected individuals could display the FMTC phenotype at first clinical manifestation. To establish the correct phenotype and improve clinical management of patients affected by hereditary MTC, clinical screening, RET mutational analysis, penetrance of MTC, and genotype-phenotype correlation were performed in a large, suspected FMTC kindred of 86 individuals. Germline C634Y RET mutation was confirmed in 22 individuals, 15 of whom were thyroidectomized when high serum calcitonin levels were detected. MTC was confirmed in 12 individuals and C-cell hyperplasia in 3. HPT was detected in two patients. High penetrance of MTC at young age (79% at 30 yr of age) was found. This family was considered to be affected by FMTC for several years because MTC was the sole clinical manifestation. However, our results allowed reclassifying the family as MEN 2A, thereby improving clinical management of family members. Our findings regarding penetrance and genotype-phenotype correlation suggest that patients considered to have FMTC may in fact have MEN 2A in some kindreds. [ABSTRACT FROM AUTHOR]

C cell hyperplasia is considered a precursor lesion for hereditary forms of medullary thyroid carcinoma. It has therefore been suggested as a morphological marker to distinguish hereditary from sporadic medullary thyroid carcinoma and to triage genetic testing in resource poor settings. However, numerous definitions for C cell hyperplasia have been suggested, and there is surprisingly little data regarding the number of C cells present in thyroid glands removed for conditions other than medullary carcinoma. We therefore sought to investigate the specificity of different criteria for C cell hyperplasia. We examined the number of C cells and solid cell nests (ultimobranchial body remnants) present in 118 completion thyroidectomy specimens from patients without medullary carcinoma and with no risk factors for MEN2. Morphological review was performed on all H&E-stained slides, and immunohistochemistry for calcitonin was performed on one block from each case. Solid cell nests were found in 4 (3.3%) of thyroids. Increased numbers of C cells sufficient to fulfil criteria for C cell hyperplasia were found in 5 (4.2%) to 36 (30.5%) cases depending on the criteria used. We conclude that large numbers of C cells are commonly found in thyroids not associated with medullary carcinoma. Therefore, regardless of which criteria are used, the presence of C cell hyperplasia is not a specific marker for hereditary medullary thyroid carcinoma. [ABSTRACT FROM AUTHOR]

Hyperparathyroidism and/or parathyroid hyperplasia, medullary thyroid carcinoma (MTC), and pheochromocytomas compose the hallmarks of the multiple endocrine neoplasia type 2A (MEN 2A) syndrome. Revisiting a report in 1939 of a patient with hyperparathyroidism and parathyroid hyperplasia led to a search for evidence of MEN 2A. From medical records and discussion with family members, longitudinal follow-up of the patient and her descendants was obtained. Molecular diagnostics were integrated in the care of subsequent generations. The literature on hyperparathyroidism and MEN 2A was reviewed. Children of the proband exhibited all components of MEN 2A and the RET mutation of 634 TGC>CGC. The pedigree was typical for this mutation. Papers on anthropologic studies demonstrate skeletal evidence of hyperparathyroidism in humans centuries ago. The initial report of the proband preceded the publications defining both MTC and MEN 2A. The values of in-depth family histories and genetic analyses are exemplified. [ABSTRACT FROM AUTHOR]

Composite pheochromocytomas (CP) account for only 3% of all pheochromocytomas. We analyzed the clinical, immunohistochemical, ultrastructural, DNA content, and a 634 ret mutation feature in a 56-yr-old Mexican woman with a CP localized in the right adrenal gland and associated with a blood pressure of 140/90 mmHg. Clinical symptoms were absent after surgery. The tumor showed pheochromocytoma and neuroblastoma components. This dual phenotype was supported by light microscopy and corroborated by immunohistochemistry and ultrastructural findings. Flow cytometric analysis showed that both components were diploid. A genetic mutational analysis of the ret oncogene in exon 11 showed no 634 mutation. This case demonstrates the indolent behavior of neuroblastoma associated with a sporadic-type CP in an adult patient. [ABSTRACT FROM AUTHOR]

Activating mutations of the receptor tyrosine kinase, ret, are associated with multiple endocrine neoplasia type 2A (MEN-2A). However, the mechanisms leading to tumor development are unclear. Glial-derived neurotrophic factor (GDNF) activates wild-type ret via interaction with a second receptor, GFR α-1. We have utilized GDNF to stimulate normal and neoplastic chromaffin cells in order to ask whether ret activation is mitogenic. Cells from three normal adult adrenal medullas, one sporadic pheochromocytoma, and three MEN-2A pheochromocytomas were labeled with bromodeoxyuridine (BrdU) for 12 d in the presence or absence of GDNF or nerve growth factor (NGF), which is known to stimulate neurite outgrowth, but not proliferation in human chromaffin and pheochromocytoma cell cultures. Responses to GDNF and NGF were comparable, except for two MEN-2A pheochromocytomas that responded minimally to GDNF and robustly to NGF. These tumors responded to GDNF biochemically, as measured by phosphorylation of mitogen-activated protein kineses, despite their weak morphological responses. Our findings suggest that activation of ret may not be sufficient to produce chromaffin cell hyperplasia or neoplasia directly by stimulating cell proliferation. However, the possibility that altered cell-cell or cell-substrate interactions might cause responses to become differentiative rather than proliferative in vitro has not been ruled out. We also demonstrate, for the first time, that at least some human pheochromocytomas with an MEN-2A ret mutation respond to a normal ret ligand. This responsiveness could be mediated by a remaining normal ret allele or by other mechanisms. [ABSTRACT FROM AUTHOR]

Medullary thyroid carcinoma (MTC) harbors rearranged during transfection (RET) gene and rarely RAS gene mutations. The knowledge of the type of gene mutation in MTC is important to determine the treatment of the patients and the management of their family members. Targeted next-generation sequencing with a panel of 47 genes was performed in a total of 12 cases of sporadic (9/12) and hereditary MTC (3/12). Two of three hereditary MTCs had RET/C634R mutation, while the other one harbored two RET mutations (L790F and S649L). All the sporadic MTC had RET/M918T mutation except one case with HRAS mutation. Next-generation sequencing (NGS) can provide comprehensive analysis of molecular alterations in MTC in a routine clinical setting, which facilitate the management of the patient and the family members. [ABSTRACT FROM AUTHOR]

Medullary thyroid carcinoma (MTC) is a C-cell-derived epithelial neuroendocrine neoplasm. With the exception of rare examples, most are well-differentiated epithelial neuroendocrine neoplasms (also known as neuroendocrine tumors in the taxonomy of the International Agency for Research on Cancer [IARC] of the World Health Organization [WHO]). This review provides an overview and recent evidence-based data on the molecular genetics, disease risk stratification based on clinicopathologic variables including molecular profiling and histopathologic variables, and targeted molecular therapies in patients with advanced MTC. While MTC is not the only neuroendocrine neoplasm in the thyroid gland, other neuroendocrine neoplasms in the thyroid include intrathyroidal thymic neuroendocrine neoplasms, intrathyroidal parathyroid neoplasms, and primary thyroid paragangliomas as well as metastatic neuroendocrine neoplasms. Therefore, the first responsibility of a pathologist is to distinguish MTC from other mimics using appropriate biomarkers. The second responsibility includes meticulous assessment of the status of angioinvasion (defined as tumor cells invading through a vessel wall and forming tumor-fibrin complexes, or intravascular tumor cells admixed with fibrin/thrombus), tumor necrosis, proliferative rate (mitotic count and Ki67 labeling index), and tumor grade (low- or high-grade) along with the tumor stage and the resection margins. Given the morphologic and proliferative heterogeneity in these neoplasms, an exhaustive sampling is strongly recommended. Routine molecular testing for pathogenic germline RET variants is typically performed in all patients with a diagnosis of MTC; however, multifocal C-cell hyperplasia in association with at least a single focus of MTC and/or multifocal C-cell neoplasia are morphological harbingers of germline RET alterations. It is of interest to assess the status of pathogenic molecular alterations involving genes other than RET like the MET variants in MTC families with no pathogenic germline RET variants. Furthermore, the status of somatic RET alterations should be determined in all advanced/progressive or metastatic diseases, especially when selective RET inhibitor therapy (e.g., selpercatinib or pralsetinib) is considered. While the role of routine SSTR2/5 immunohistochemistry remains to be further clarified, evidence suggests that patients with somatostatin receptor (SSTR)-avid metastatic disease may also benefit from the option of 177Lu-DOTATATE peptide radionuclide receptor therapy. Finally, the authors of this review make a call to support the nomenclature change of MTC to C-cell neuroendocrine neoplasm to align this entity with the IARC/WHO taxonomy since MTCs represent epithelial neuroendocrine neoplasms of endoderm-derived C-cells. [ABSTRACT FROM AUTHOR]

Grade, based on proliferative activity and tumor necrosis, has recently been shown to be prognostic in medullary thyroid carcinoma (MTC) in multivariate analysis. The aim of this study was to evaluate the interobserver reproducibility of assessed grade in MTC. Three groups (each group included one resident/fellow and one attending pathologist) independently evaluated a cohort of 44 sporadic MTC. For each case, all available tumor slides were reviewed, and mitotic count and the presence of tumor necrosis were recorded. Ki-67 was performed, and the Ki-67 proliferative index was determined in the area of highest proliferative activity. Tumors were graded according to the recently published International Medullary Thyroid Carcinoma Grading System (IMTCGS). Kappa statistics were calculated for each individual criterion (mitotic count, Ki-67 proliferative index, and necrosis) and for assigned IMTCGS grade. For our cohort of 44 MTCs, the kappa statistic for mitotic count, Ki-67 proliferative index, and necrosis was 0.68, 0.86, and 0.89, respectively. The kappa statistic for assigned IMTCGS grade was 0.87. Our findings indicate that there was a strong level of agreement for assessment of grade in our cohort of MTC, indicating that grade as assessed by the IMTCGS is not only prognostic but also reproducible. [ABSTRACT FROM AUTHOR]

Medullary thyroid carcinoma (MTC) is a rare thyroid carcinoma with a variable clinical behavior. Potential clinical and pathological prognostic markers have been investigated, but studies are limited and controversial. In neuroendocrine neoplasms of various other sites, necrosis and proliferation (mitotic activity and/or Ki67 index) are integrated to provide a histological grade. Recently, an International Medullary Thyroid Carcinoma Grading System (IMTCGS) has been designed to define high- or low-grade MTC by combining proliferative activity and necrosis. This proposal integrates two previously published grading schemes by American (2-tiered grading, low- and high-grade MTC) and Australian authors (3-tiered grading, low-, intermediate-, and high-grade MTC). To validate the clinical role of these systems, their prognostic impact was evaluated in an independent cohort of 111 MTCs. Necrosis, which was the only parameter integrated into the 3 grading systems, proved to be individually correlate with tumor relapse, while no association was found with the proliferation (mitotic count and Ki67 index); however, by combining the different parameters according to all three grading systems, "high-grade" MTCs turned out to be significantly associated with the disease recurrence (p < 0.005) in all systems. In disease-free survival analysis, the IMTCGS stratification was the only one that demonstrated a significant impact at Cox regression analysis (p = 0.004), further confirmed by the Kaplan–Meier curves (p = 0.002). Similar findings were also reproduced when analysis was restricted to sporadic MTCs (68 cases). In conclusion, our results confirm the prognostic role of IMTCGS, supporting the importance of incorporating this information into the pathology report. However, none of the systems proved to predict the overall survival in this validation cohort. [ABSTRACT FROM AUTHOR]

This review summarizes the changes in the 5th edition of the WHO Classification of Endocrine and Neuroendocrine Tumors that relate to the thyroid gland. The new classification has divided thyroid tumors into several new categories that allow for a clearer understanding of the cell of origin, pathologic features (cytopathology and histopathology), molecular classification, and biological behavior. Follicular cell–derived tumors constitute the majority of thyroid neoplasms. In this new classification, they are divided into benign, low-risk, and malignant neoplasms. Benign tumors include not only follicular adenoma but also variants of adenoma that are of diagnostic and clinical significance, including the ones with papillary architecture, which are often hyperfunctional and oncocytic adenomas. For the first time, there is a detailed account of the multifocal hyperplastic/neoplastic lesions that commonly occur in the clinical setting of multinodular goiter; the term thyroid follicular nodular disease (FND) achieved consensus as the best to describe this enigmatic entity. Low-risk follicular cell–derived neoplasms include non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), thyroid tumors of uncertain malignant potential, and hyalinizing trabecular tumor. Malignant follicular cell–derived neoplasms are stratified based on molecular profiles and aggressiveness. Papillary thyroid carcinomas (PTCs), with many morphological subtypes, represent the BRAF-like malignancies, whereas invasive encapsulated follicular variant PTC and follicular thyroid carcinoma represent the RAS-like malignancies. This new classification requires detailed subtyping of papillary microcarcinomas similar to their counterparts that exceed 1.0 cm and recommends not designating them as a subtype of PTC. The criteria of the tall cell subtype of PTC have been revisited. Cribriform-morular thyroid carcinoma is no longer classified as a subtype of PTC. The term "Hürthle cell" is discouraged, since it is a misnomer. Oncocytic carcinoma is discussed as a distinct entity with the clear recognition that it refers to oncocytic follicular cell–derived neoplasms (composed of > 75% oncocytic cells) that lack characteristic nuclear features of PTC (those would be oncocytic PTCs) and high-grade features (necrosis and ≥ 5 mitoses per 2 mm2). High-grade follicular cell–derived malignancies now include both the traditional poorly differentiated carcinoma as well as high-grade differentiated thyroid carcinomas, since both are characterized by increased mitotic activity and tumor necrosis without anaplastic histology and clinically behave in a similar manner. Anaplastic thyroid carcinoma remains the most undifferentiated form; squamous cell carcinoma of the thyroid is now considered as a subtype of anaplastic carcinoma. Medullary thyroid carcinomas derived from thyroid C cells retain their distinct section, and there is a separate section for mixed tumors composed of both C cells and any follicular cell–derived malignancy. A grading system for medullary thyroid carcinomas is also introduced based on mitotic count, tumor necrosis, and Ki67 labeling index. A number of unusual neoplasms that occur in the thyroid have been placed into new sections based on their cytogenesis. Mucoepidermoid carcinoma and secretory carcinoma of the salivary gland type are now included in one section classified as "salivary gland–type carcinomas of the thyroid." Thymomas, thymic carcinomas and spindle epithelial tumor with thymus-like elements are classified as "thymic tumors within the thyroid." There remain several tumors whose cell lineage is unclear, and they are listed as such; these include sclerosing mucoepidermoid carcinoma with eosinophilia and cribriform-morular thyroid carcinoma. Another important addition is thyroblastoma, an unusual embryonal tumor associated with DICER1 mutations. As in all the WHO books in the 5th edition, mesenchymal and stromal tumors, hematolymphoid neoplasms, germ cell tumors, and metastatic malignancies are discussed separately. The current classification also emphasizes the value of biomarkers that may aid diagnosis and provide prognostic information. [ABSTRACT FROM AUTHOR]

In this review, we detail the changes and the relevant features that are applied to neuroendocrine neoplasms (NENs) in the 2022 WHO Classification of Endocrine and Neuroendocrine Tumors. Using a question-and-answer approach, we discuss the consolidation of the nomenclature that distinguishes neuronal paragangliomas from epithelial neoplasms, which are divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The criteria for these distinctions based on differentiation are outlined. NETs are generally (but not always) graded as G1, G2, and G3 based on proliferation, whereas NECs are by definition high grade; the importance of Ki67 as a tool for classification and grading is emphasized. The clinical relevance of proper classification is explained, and the importance of hormonal function is examined, including eutopic and ectopic hormone production. The tools available to pathologists for accurate classification include the conventional biomarkers of neuroendocrine lineage and differentiation, INSM1, synaptophysin, chromogranins, and somatostatin receptors (SSTRs), but also include transcription factors that can identify the site of origin of a metastatic lesion of unknown primary site, as well as hormones, enzymes, and keratins that play a role in functional and structural correlation. The recognition of highly proliferative, well-differentiated NETs has resulted in the need for biomarkers that can distinguish these G3 NETs from NECs, including stains to determine expression of SSTRs and those that can indicate the unique molecular pathogenetic alterations that underlie the distinction, for example, global loss of RB and aberrant p53 in pancreatic NECs compared with loss of ATRX, DAXX, and menin in pancreatic NETs. Other differential diagnoses are discussed with recommendations for biomarkers that can assist in correct classification, including the distinctions between epithelial and non-epithelial NENs that have allowed reclassification of epithelial NETs in the spine, in the duodenum, and in the middle ear; the first two may be composite tumors with neuronal and glial elements, and as this feature is integral to the duodenal lesion, it is now classified as composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET). The many other aspects of differential diagnosis are detailed with recommendations for biomarkers that can distinguish NENs from non-neuroendocrine lesions that can mimic their morphology. The concepts of mixed neuroendocrine and non-neuroendocrine (MiNEN) and amphicrine tumors are clarified with information about how to approach such lesions in routine practice. Theranostic biomarkers that assist patient management are reviewed. Given the significant proportion of NENs that are associated with germline mutations that predispose to this disease, we explain the role of the pathologist in identifying precursor lesions and applying molecular immunohistochemistry to guide genetic testing. [ABSTRACT FROM AUTHOR]

This review of the familial tumor syndromes involving the endocrine organs is focused on discussing the main updates on the upcoming fifth edition of the WHO Classification of Endocrine and Neuroendocrine Tumors. This review emphasizes updates on histopathological and molecular genetics aspects of the most important syndromes involving the endocrine organs. We describe the newly defined Familial Cancer Syndromes as MAFA-related, MEN4, and MEN5 as well as the newly reported pathological findings in DICER1 syndrome. We also describe the updates done at the new WHO on the syndromic and non-syndromic familial thyroid diseases. We emphasize the problem of diagnostic criteria, mention the new genes that are possibly involved in this group, and at the same time, touching upon the role of some immunohistochemical studies that could support the diagnosis of some of these conditions. As pathologists play an important role in identifying tumors within a familial cancer syndrome, we highlight the most important clues for raising the suspicious of a syndrome. Finally, we highlight the challenges in defining these entities as well as determining their clinical outcome in comparison with sporadic tumors. Instead of the usual subject review, we present the highlights of the updates on familial cancer syndromes by answering select questions relevant to practicing pathologists. [ABSTRACT FROM AUTHOR]

Medullary carcinoma of the thyroid (MTC) occurs sporadically, or in familial forms in familial medullary thyroid carcinoma and multiple endocrine neoplasia types 2A and 2B. In the familial forms it is associated with well-characterized, germline mutations in the RET protooncogene. The mutation sites differ in MEN2A and MEN2B, and MTC develops at an earlier age and is more aggressive in MEN2B. Screening of relatives of affected individuals for such mutations can identify those at risk of developing MTC and total thyroidectomy can be carried out in the first decade of life before the development of clinical disease. Analysis of such removed thyroid glands shows abnormalities of the parafollcular C-cells in almost all cases. The abnormalities range from C-cell hyperplasia, either diffuse or nodular, to microcarcinoma and occasionally frank MTC. The abnormalities are bilateral and affects the upper two thirds of the thyroid lobes. Microcarcinomas may be visible with the naked eye, but often they are identified only on microscopy. Histopathological examination of the entire gland is essential. [ABSTRACT FROM AUTHOR]

A unilateral, apparently sporadic pheochromocytoma was removed from the right adrenal of a 73-yr-old Caucasian woman. At the time of surgery, germline DNA from the patient was not available. However, a continuous cell line (KNA) established from the tumor showed a heterozygous sequence variant TGC (cysteine) to TGG (tryptophan) in exon 10, codon 611 of the RET proto-oncogene. Subsequent genetic testing of the patient and her offspring revealed the same base-change in herself, one daughter, one son, and the only grandson, confirming hereditary disease classified as MEN2A-2. Clinical follow up of the patient revealed elevated serum calcitonin after 6 yr. Thyroidectomy was performed and revealed a small medullary thyroid carcinoma. The patient’s children thus far show no evidence of MEN2, but C-cell hyperplasia has been diagnosed in the grandson. Our serendipitous finding of a MEN2A-2 mutation in a patient with initial diagnosis of late onset, unilateral, “sporadic” pheochromocytoma would argue for routine mutation screening of even elderly patients presenting with a pheochromocytoma. [ABSTRACT FROM AUTHOR]

Follicular-patterned tumors of the thyroid in the adult population frequently harbor RAS mutations or PAX8-PPARG rearrangement, but little is known about molecular profiles in the pediatric patients with thyroid tumors, which is rare. To identify the molecular profile of pediatric follicular-patterned tumors, we enrolled 41 pediatric patients with follicular-patterned tumors from two institutions. We did next-generation sequencing using a mutation panel targeting 49 thyroid-tumor-related genes and a fusion panel targeting 88 types of thyroid-related gene fusions. We identified nonsynonymous mutations in at least one target gene in most of the tumors (28/41, 68%). Somatic DICER1 mutations (22%, n = 9) were the most common genetic alteration, followed by mutations of NRAS (15%), FGFR3 (15%), PTEN (12%), and STK11 (10%). Infrequent genetic alterations (≤ 5% of all cases) included mutations of HRAS, APC, TSHR, CTNNB1, TP53, EIF1AX, FGFR4, GNAS, RET, and SOS1, and gene fusion of THADA-IGF2BP3. DICER1 and RAS mutations were mutually exclusive. No patients had tumors related to the DICER1 syndrome or the Cowden syndrome. There was no significant difference in total mutation burden or distribution between follicular adenoma and follicular carcinoma. In the literature, the DICER1 mutation has been reported in 20 to 53% of pediatric patients with follicular-patterned tumors. In conclusion, our study reinforces the role of the DICER1 mutation in the development of pediatric thyroid tumors. Gene fusions rarely occur in pediatric follicular-patterned tumors. Mutation or gene fusion alone could not distinguish benign from malignant follicular-patterned tumors in pediatric patients. [ABSTRACT FROM AUTHOR]

Parathyroid gland excision specimens are common and sometimes underestimated cases that many surgical pathologists encounter regularly. In the vast majority of cases, these will be spot diagnoses of sporadic primary parathyroid adenomas or, perhaps, hyperplasias commonly in the setting of renal failure. However, a small but significant number of parathyroid gland excisions may be due to heritable disease. In most cases, hereditary disease is suspected by the referring clinicians. Nevertheless, a subset of these are undetected which is significant, particularly in the setting of the multiple endocrine neoplasia (MEN), and the hyperparathyroidism jaw tumour (HPT-JT) syndromes. There have been recent advances in recognition of the morphological and immunohistochemical characteristics of these tumours and hyperplasias. While hereditary kindreds are over-represented at specialist referral centres, with awareness of the characteristic clinical and morphological features, the general surgical pathologist is frequently able to suggest the possibility of hereditary parathyroid disease. We therefore provide a succinct guide for pathologists to increase the recognition of hereditary parathyroid disease. [ABSTRACT FROM AUTHOR]

Breast cancer–associated protein 1 (BAP1) gene is a broad-spectrum tumor suppressor. Indeed, its loss of expression, due to biallelic inactivating mutations or deletions, has been described in several types of tumors including melanoma, malignant mesothelioma, renal cell carcinoma, and others. There are so far only two reports of BAP1-mutated paraganglioma, suggesting the possible involvement of this gene in paraganglioma (PGL) and pheochromocytoma (PCC) pathogenesis. We assessed BAP1 expression by immunohistochemistry (IHC) in a cohort of 56 PCC/PGL patients (and corresponding metastases, when available). Confirmatory Sanger sequencing (exons 1–17) of BAP1 has been performed in those samples which resulted negative by IHC. BAP1 nuclear expression was lost in 2/22 (9.1%) PGLs and in 12/34 (35.3%) PCCs, five of which harboring a germline mutation predisposing the development of such tumors (MENIN, MAX, SDHB, SDHD, and RET gene). Confirmatory Sanger sequencing revealed the wild-type BAP1 status of all the analyzed samples. No heterogeneity between primary and metastatic tissue was observed. This study documents that the loss of BAP1 nuclear expression is quite a frequent finding in PCC/PGL, suggesting a possible role of BAP1 in the pathogenesis of these tumors. Gene mutations do not seem to be involved in this loss of expression, at least in most cases. Other genetic and epigenetic mechanisms need to be further investigated. [ABSTRACT FROM AUTHOR]

Genetic and epigenetic alterations are associated with the progression and prognosis of medullary thyroid carcinoma (MTC). We performed whole-exome sequencing of tumor tissue from seven patients with sporadic MTC using an Illumina HiSeq 2000 sequencing system. We conducted Sanger sequencing to confirm the somatic mutations in both tumor and matched normal tissues. We applied Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis with the Database for Annotation, Visualization, and Integrated Discovery and STRING for pathway analysis. We detected new somatic mutations in the BICD2, DLG1, FSD2, IL17RD, KLHL25, PAPPA2, PRDM2, PSEN1, SCRN1, and TTC1 genes. We found a somatic mutation in the PDE4DIP gene that had previously been discovered mutated in other tumors but that had not been characterized in MTC. We investigated pathway deregulation in MTC. Data regarding 1152 MTCs were assembled from the Catalogue of Somatic Mutations in Cancer (COSMIC) and seven of our patients. Ontological analysis revealed that most of the variants aggregated in pathways that included the signaling pathways of thyroid cancer, central carbon metabolism, microRNAs in cancer, PI3K-Akt, ErbB, MAPK, mTOR, VEGF, and RAS. In conclusion, we conducted wide-ranging exome-wide analysis of the mutational spectrum of MTC in Taiwan’s population and detected novel genes with potential associations with MTC tumorigenesis and irregularities in pathways that resulted in MTC pathogenesis. [ABSTRACT FROM AUTHOR]

Gain-of-function germline mutations of the RET proto-oncogene are responsible for initiation of carcinogenesis within the thyroid gland and development of hereditary form of medullary thyroid carcinoma and MEN2 syndrome. Genotype-phenotype correlations are established for most RET mutations, but the importance of the synonymous changes in this gene remains debatable. We aimed to analyze RET gene variants in Polish population. Genetic testing for the RET gene variants was performed with standard methods in 585 people aged 1-85, including 448 patients with medullary thyroid carcinoma and 131 of their first- and second-degree relatives, as well as six patients suspected of MTC/MEN2. Besides the most frequent synonymous changes, p.Leu769Leu, p.Ser836Ser, and p.Ser904Ser, four rare changes-c.1827C>T (p.Cys609Cys), c.2364C>T (p.Ile788Ile), c.2418C>T (p.Tyr806Tyr), and c.2673G>A (p.Ser891Ser)-were found in the RET gene, in the Polish population. Two of the rare changes, p.Cys609Cys and p.Ile788Ile, had not been previously described. The frequency of molecular synonymous variants in the general population was evaluated by testing 400 anonymous blood samples of neonates. Our findings may contribute to a better understanding of the genetic diversity of the RET gene and the involvement of synonymous variants in this diversity. [ABSTRACT FROM AUTHOR]

Methods of diagnosing malignant pheochromocytoma (PCC) or paraganglioma (PGL) are needed. However, there are no reliable histopathologic criteria to distinguish malignant PCC/PGLs. The recent genomic analysis of The Cancer Genome Atlas (TCGA) provides in-depth information enabling more accurate diagnosis of disease entities. Therefore, we investigated genomic expression differences and mutational differences of malignant PCC/PGLs with TCGA. As of December 2014, TCGA had acquired multigenomic analysis of 176 PCC/PGL samples. Clinical information, mutation status, and 20,531 gene messenger RNA (mRNA) expression dataset of normalized RNA-sequencing mRNA read counts were downloaded from TCGA, and integrated into a table. Of the 176 PCC/PGL samples in the dataset, 14 had metastasis and 162 exhibited no metastasis. mRNA expression and mutations were compared in these two groups. There were 76 males in the dataset of 176 TCGA samples. Mean age was 47.6 ± 15.2 years (19-83 years). There was no significant gender or race difference between metastatic and non-metastatic groups. mRNA expression of malignant PCC/PGLs was upregulated in five pathways of cell cycle ( BUB1, BUB1B, CCNB2, CDC2, ESPL1), calcium signaling ( CCNB2, CDC2, PRKCB1), regulation of actin cytoskeleton ( DIAPH3, FGF18, IQGAP3), gap junction ( CDC2, PRKCB1), and phosphatidylinositol ( PRKCB1, TTK). Disease-free survival rates were significantly correlated with the presence or absence of mutations, such as RP11-798G7.5, HERC2, SETD2, TGDS, TRHDE, FKBP9, and BMS1. TCGA showed differences in mRNA expression and mutations between metastatic and non-metastatic PCC/PGLs. The improved recognition of genetic causes can help to achieve proper diagnosis and provide appropriate treatment of PCC/PGL. [ABSTRACT FROM AUTHOR]

The REarranged during Transfection ( RET) proto-oncogene is a receptor tyrosine kinase involved in growth and differentiation during embryogenesis and maintenance of the urogenital and nervous systems in mammals. Distinct mutations across hotspot RET exons can cause Multiple Endocrine Neoplasia Type 2A (MEN2A) characterised by development of medullary thyroid cancer (MTC), phaeochromocytoma (PCC) and primary hyperparathyroidism (PHPT), with a strong correlation between genotype and phenotype. Here, we report a 42-year-old man presented in the clinic with a unilateral PCC, with subsequent investigations revealing a nodular and cystic thyroid gland. He proceeded to thyroidectomy, which showed bilateral C-cell hyperplasia (CCH) without evidence of MTC. His brother had neonatal Hirschsprung disease (HSCR). Genetic testing revealed the presence of a heterozygous variant of unknown significance (VUS) in the cysteine-rich region of exon 10 in the RET gene (c.1846G>C, p.E616Q), in both affected siblings and their unaffected mother. Exon 10 RET mutations are known to be associated with HSCR and MEN2. Variants in the cysteine-rich region of the RET gene, outside of the key cysteine residues, may contribute to the development of MEN2 in a less aggressive manner, with a lower penetrance of MTC. Currently, a VUS in RET cannot be used to inform clinical management and direct future care. Analysis of RET reveals a gain of function mutant phenotype for this variant, which has not previously been reported, indicating that this VUS should be considered at risk for future clinical management. [ABSTRACT FROM AUTHOR]

Medullary thyroid carcinoma (MTC) is an uncommon neuroendocrine tumor arising from the C cells in the thyroid and accounts for about 5 % of all thyroid cancers. MTC exhibits more aggressive behavior than follicular tumors, with the majority of cases presenting with lymph node metastasis. It is particularly common among patients carrying germline RET mutations with almost 100 % penetrance. Because activating RET mutations occur in over 90 % of hereditary and 40 % of sporadic MTC, clinical trials of several RET-targeting multikinase inhibitors (MKIs) have resulted in FDA approval of vandetanib and cabozantinib for the treatment of MTC. Nevertheless, in light of significant individual differences in tumor behavior and treatment responses, there has been a persistent need for research efforts to decipher the molecular events within RET-driven or non- RET-driven tumors. Recently, the gene regulatory roles of microRNAs (miRNAs) in MTC have been studied extensively. Multiple miRNA deregulations have been discovered in MTC with potential prognostic and therapeutic implications. This review provides an overview of the basic pathology of MTC and an update on recent investigational progress. [ABSTRACT FROM AUTHOR]

Non-coding (nc)RNAs are divided into small ncRNAs and long ncRNAs (lncRNAs). MicroRNAs (miRNAs) are small ncRNAS which are around 22 nucleotides in length that mediate post-transcriptional gene silencing. LncRNAs are greater than 200 bp in length. Each ncRNA can have multiple targets and can be regulated by multiple genetic factors. Because ncRNAs are not translated into proteins, they can only be detected at the nucleic acid level by in situ hybridization, by RT-PCR, or by sequencing which makes their detection more challenging in the routine pathology laboratory. A great deal of new information has accumulated about miRNAs in thyroid tissues during the past decade. Some of these studies have shown that deregulation of miRNAs may be useful in diagnostic pathology. Information about the role of lncRNA in the development of thyroid tumors is in the early stages of development, but new information is accumulating rapidly. In this review, we will discuss the recent progress in our understanding of the relationship between ncRNAs and the development of thyroid cancers and the potential uses of ncRNAs in the diagnosis and prognosis of thyroid tumors. [ABSTRACT FROM AUTHOR]

The purpose of this study is to describe a case of concurrent medullary and papillary thyroid carcinoma (MTC and PTC) and cutaneous melanoma and to analyze BRAF mutation in plasma and tissues. We report the clinical history and the laboratory, imaging, and histopathological findings of a 47-year-old man affected by multinodular goiter. BRAF-mutated DNA was quantified in plasma samples and in cancer sections by quantitative real-time polymerase chain reaction (qPCR). At ultrasound examination, the dominant right nodule of the thyroid was weakly hyperechoic and hypervascularized, while the left one was hypoechoic without internal vascularization. Regional lymphadenomegalia was not detected. Basal plasma calcitonin was elevated, and the patient underwent total thyroidectomy and resection of central cervical lymph nodes. Histopathological examination identified two distinct foci of MTC and PTC and micrometastasis of well-differentiated carcinoma in one of the six resected lymph nodes. RET proto-oncogene germline mutations were not detected. Cutaneous melanoma of the thorax was subsequently diagnosed. BRAF tissue DNA was detected in PTC and melanoma but not in MTC. The cell-free plasma percentage of BRAF DNA was detected in pre-thyroidectomy peripheral blood and was drastically reduced after cancer treatments. This study confirms the occurrence of synchronous MTC and PTC and is the first evidence of the co-existence of melanoma and distinct thyroid cancers of different origin. BRAF allele was detected in PTC and melanoma but not in MTC tissues. BRAF molecular quantification in pre- and post-treatment blood supports our previous data, suggesting its possible role in diagnosis and follow-up of BRAF-positive tumors. [ABSTRACT FROM AUTHOR]

This article summarizes the major clinical, pathological, and molecular features of medullary thyroid carcinoma (MTC), based on a review of the most significant advances in our understanding of this tumor type over the last 25 years. MTC is a neuroendocrine carcinoma that shows evidence of C-cell differentiation. The tumor has a distinctive morphologic appearance, including the presence of amyloid deposits. Immunostaining for calcitonin, carcinoembryonic antigen, calcitonin gene-related peptide, and thyroid transcription factor 1 is helpful in differential diagnosis. Identification of RET mutations in familial and sporadic MTC has brought important changes in early diagnosis and treatment. Surgery remains the cornerstone of effective therapy. Understanding the molecular basis of MTC will allow identification of novel approaches for individualized treatment. [ABSTRACT FROM AUTHOR]

This study was conducted to investigate the natural history of undifferentiated thyroid carcinoma (UTC) in the iodine-deficient province of Salta, Argentina, in relation to salt iodization and health care standards. Five hundred ninety-three thyroid cancers diagnosed from 1958 to2012 were reviewed based mainly on the WHO classification and grouped into three periods, one before and two after iodine prophylaxis. The incidence of UTC was analyzed in relation to changing concentrations of potassium iodide (KI) in salt during the prophylaxis period (from 40 to 33.3 mg KI/kg salt), establishment of primary health care centers throughout the region, and use of fine needle aspiration (FNA) cytology. Twenty-nine UTCs were found in the whole series. The frequency of UTC decreased from 15.2 % (9/59 cases) in the first period to 2.6 % (10/381 cases) well after salt iodination ( x Fisher's test, p < 0.0002), and the incidence from 1.4/10/year to 0.1/10/year (Student's t test, p < 0.06), respectively. The decline of UTC after iodine prophylaxis occurred even after decreasing concentrations of KI in salt and timely coincided with the establishment of primary health care centers throughout the region and routine use of FNA. The lower rate of UTC after iodine prophylaxis in the province of Salta is mostly related to earlier detection of more differentiated thyroid tumors rather than higher salt iodization. [ABSTRACT FROM AUTHOR]

Dural metastasis from medullary thyroid carcinoma (MTC) is not well established in English literature. We present the case report of MTC with unusual clinical presentation as a dural-based mass in a 39-year-old male with no family history of multiple endocrine neoplasia syndrome. Magnetic resonance imaging showed an extra-axial dural-based mass in right frontal lobe with calvarium and soft tissue extension to the right superior orbit. Histopathology showed MTC with variegated morphology and various patterns. Thyroid mass and widespread metastases from medullary thyroid carcinoma were subsequently identified. [ABSTRACT FROM AUTHOR]

Recently, using ultrasonography, we observed that the right lobe usually is larger compared with the left thyroid lobe. Since the higher cell number in a larger right lobe may confer a higher tumor risk, we investigated the location of benign and malignant lesions to test the hypothesis of a more frequent occurrence in this lobe. In 1,001 consecutive patients with benign thyroid lesions, tumors more frequently occurred in the right lobe (+21.5%, p = 0.0022). Furthermore, in 1,277 thyroid cancer patients with 1,302 thyroid cancers, the right lobe more often harbored the tumor initially (+22.9%, p = 0.0009). Our data show a larger proportion of both benign and malignant tumors in the right thyroid lobe. [ABSTRACT FROM AUTHOR]

Medullary thyroid carcinoma (MTC) is a rare tumor and accounts for 5–10% of thyroid cancers. Tuberous sclerosis (TS) is a complex autosomal dominant neurocutaneous syndrome. In literature, a few endocrine neoplasias have been reported in association with TS, but never a case of TS associated with sporadic MTC. We describe a unique case, which has never been reported previously, of MTC associated with TS. The MTC up to today has been associated with other endocrine neoplasia, and TS increases risk of neoplasia in various organs. The case reported shows one more circumstance and suggests thyroid screening in patients with diagnosis of TS. [ABSTRACT FROM AUTHOR]

Familial thyroid cancer can arise from follicular cells (familial non-medullary thyroid carcinoma (FNMTC)) or from the calcitonin-producing C-cell (familial medullary thyroid carcinoma). This is usually a component of multiple endocrine neoplasias (MEN) IIA or IIB, or as pure familial medullary thyroid carcinoma syndrome. The genetic events in the familial C-cell-derived tumors are known and genotype–phenotype correlations are well established. In contrast, the case for a familial predisposition of non-medullary thyroid carcinoma is only now beginning to emerge. Although the majority of papillary (PTC) and follicular thyroid carcinomas (FTC) are sporadic, familial tumors account for over 5% of cases. The presence of multifocal papillary carcinoma is a common feature of FNMTC. The familial follicular cell-derived tumors or non-medullary thyroid carcinomas encompass a heterogeneous group of diseases, including diverse syndromic-associated tumors and non-syndromic tumors. Based on clinico-pathologic findings, FNMTC is divided into two groups. The first includes familial syndromes characterized by a predominance of non-thyroidal tumors, such as familial adenomatous polyposis (FAP), PTEN hamartoma tumor syndrome (PHTS), Carney complex type 1, and Werner syndrome. The second group includes familial syndromes characterized by a predominance of NMTC, such as pure familial (f) PTC with or without oxyphilia, fPTC with papillary renal cell carcinoma, and fPTC with multinodular goiter. Some characteristic morphologic findings should alert the pathologist of a possible familial cancer syndrome, which may lead to further molecular genetic evaluation. [ABSTRACT FROM AUTHOR]

Factors that should be considered when studying the effect of dietary iodine in the development of thyroid cancer include pathological criteria, diagnostic techniques, screening programs, radioactive fallout, and standard of medical care in the studied population. In most surveys, papillary carcinoma forms the largest group of thyroid malignancies, both before and after iodine prophylaxis where an increase in the papillary:follicular carcinoma ratio is also noted. Undifferentiated carcinomas decrease after salt prophylaxis. In Salta, Argentina, the increasing incidence of clinically significant papillary thyroid cancer and the decrease of undifferentiated carcinoma after iodine prophylaxis are probably due to better access to health centers and consequent earlier detection of differentiated precursor tumors. Autoimmune focal and diffuse or Hashimoto’s thyroiditis are linked to dietary iodine. Pathological studies made in different regions indicate that these types of thyroiditis occur more frequently in areas of iodine sufficiency than in areas of iodine deficiency, and increase after iodine prophylaxis both in non-goitrous and iodine-deficient areas like Salta, Argentina. An increase of lymphocytic thyroiditis could be linked to an increased incidence of primary thyroid lymphoma, and thyroiditis is more commonly associated with papillary carcinoma than with other types of thyroid follicular or C-cell derived carcinomas regardless of iodine intake. [ABSTRACT FROM AUTHOR]

The rearranged during transfection ( RET) proto-oncogene encodes a receptor tyrosine kinase that is implicated in the development of endocrine tumors of the thyroid and adrenal glands. In humans, activating RET mutations are found in the inherited cancer syndrome multiple endocrine neoplasia 2 and in sporadic medullary and papillary thyroid carcinomas. The specific type and location of RET mutations are strongly correlated with the disease phenotype and have both diagnostic and prognostic value. Recent advances in the molecular characterization of the RET receptor and its mutants have begun to define the mechanisms underlying the transforming ability of the different RET mutant forms. This information has revealed key functional features of these mutant proteins that distinguish the different clinically recognized mutations and provide clues as to the functional origins of the phenotypes associated with specific RET mutations. The elucidation of molecular mechanisms involved in RET-mediated transformation is a key step in the development of much needed therapeutics that target RET’s oncogenic properties. Recent advances have begun to provide a deeper understanding of the receptor’s function, and dysfunction, in human tumors that may guide this process. [ABSTRACT FROM AUTHOR]

There is increasing evidence involving prolactin (PRL) and its receptor (PRLR) in the development of different cancers. The aim of the present study was to investigate the expression of PRLR and PRL in human thyroid tissues. Using tissue microarray (TMA) by immunohistochemical staining, we examined the expression level of PRLR and PRL in 314 specimens from 71 thyroid cancer patients and 15 normal thyroid samples. Expression of the PRLR was observed in 93.3% of normal thyroid samples and in 76.1% of all thyroid cancers, while expression of PRL was observed in only 10% of medullary thyroid carcinomas and not at all in the other specimens, whether normal or neoplastic. Moreover, results suggested an overexpression of PRLR in 70% of medullary thyroid carcinomas, whereas 53.3% of poorly differentiated thyroid carcinomas showed a negative pattern of staining ( p=0.014 vs normal). Present data revealed, for the first time, a widespread expression of PRLR in normal and neoplastic human thyroid tissues as well as a scarce expression of PRL, observed only in a few medullary thyroid carcinomas. Whether the overexpression of PRLR observed in medullary thyroid carcinomas or the underexpression of PRLR observed in poorly differentiated thyroid carcinomas play a contributory role in the oncogenesis of these tumors remains to be determined. [ABSTRACT FROM AUTHOR]

Pheochromocytomas and paragangliomas are rare tumors derived from chromaffin cells. These tumors can arise in the context of hereditary cancer syndromes such as von Hippel-Lindau disease, multiple endocrine neoplasia type 2, and neurofibromatosis 1. Recent studies indicate that germ line mutations of genes encoding specific succinate dehydrogenase (SDH) subunits also predispose individuals to pheochromocytomas and paragangliomas. This review focuses on the genetics of these tumors and suggests a possible link between familial pheochromocytomas/paraganglioma genes and control of neuronal apoptosis during embryological development. [ABSTRACT FROM AUTHOR]

Synchronous occurrence of medullary and papillary carcinoma of the thyroid gland is very rare. We describe two cases of synchronous medullary and papillary carcinoma of the thyroid. In both cases, medullary carcinoma and papillary carcinoma were separate in the thyroid but mixed in some of the lymph node metastases. A review of the literature and our own cases revealed that composite medullary and papillary carcinoma metastases in the lymph nodes is a common feature of patients with synchronous medullary and papillary carcinoma of the thyroid gland. [ABSTRACT FROM AUTHOR]

We report the case of a 72 yr-old woman who underwent total thyroidectomy and resection of neck lymph nodes because of a firm nodule in the right lobe, which was consistent with medullary thyroid carcinoma (MTC) on cytological examination. Histology showed multifocal bilateral MTC; a 2 mm papillary thyroid carcinoma (PTC) was also detected in the right lobe, next to a focus of MTC; five cervical lymph nodes contained MTC. In one right perithyroidal lymph node, concurrent metastases of MTC and PTC were demonstated. DNA analysis showed a point mutation in exon 14 at codon 804 of the RET proto-oncogene locus, as frequently found in cases of familial MTC (FMTC). To our knowledge, this case represents the first documented case of concurrent lymph node metastases of MTC and PTC in a patient with RET proto-oncogene germline mutation. We report this unique case, discuss related thyroid malignancies, and suggest possible underlying pathogenetic mechanisms. [ABSTRACT FROM AUTHOR]

Medullary thyroid carcinoma (MTC) occurs as both a sporadic and an inherited disease. MTC is a consistent feature of multiple endocrine neoplasia (MEN) 2A, MEN 2B, and familial non-MEN MTC (FMTC). Plasma calcitonin is a sensitive and specific marker for the presence of MTC. Genetic testing can identify mutant gene carriers, and prophylactic total thyroidectomy should be carried out in patients with the mutant gene. The outcome of MTC is progressively worse in FMTC, MEN 2A, sporadic MTC, and MEN 2B, and MEN 2B has been found to have the worst prognosis. There is a significant genotype-phenotype correlation, which allows a more sensitive individualized approach to the timing and extent of prophylactic thyroidectomy. [ABSTRACT FROM AUTHOR]

Pheochromocytomas and paragangliomas arise from the adrenal glands and extraadrenal paraganglia, respectively. Malignant behavior of these tumors is uncommon and is, in part, dependent on their sites of origin, such as extraadrenal location. Morphologic criteria for malignancy of pheochromocytoma and paragangliomas have not been clearly defined. In this study, to clarify the histologic features that distinguish the benign from malignant pheochromocytomas and paragangliomas, we examined metastatic and nonmetastatic tumors using immunohistochemical techniques. A total of eight cases, five pheochromocytomas from the adrenal glands (four benign and one malignant tumor) and three paragangliomas with invasion or metastasis, were studied. The markers used in this study were chromogranin A, synaptophysin, NCAM (CD56), SNAP25, neuron-specific enolase, S-100 protein, and MIB-1. Our results suggest that MIB-1 immunostaining is a useful adjunct marker to predict malignant behavior in these tumors. [ABSTRACT FROM AUTHOR]

The simultaneous occurrence of two neoplasms of different cellular origin in one organ is a known but rare event. Such a situation occurs in the thyroid when medullary and follicular carcinoma with differentiation develops. Several cases of transitional tumors have been reported, but the simultaneous occurrence of a carcinoma with medullary and follicular differentiated carcinoma is rare. In all patients, tumors were suspected after local examination of the thyroid. We report on a patient in whom a papillary microcarcinoma was detected on the left side and a medullary carcinoma on the right side while the patient was undergoing surgery for secondary hyperparathyroidism. Both tumors were confirmed by immunohistology; regional lymph nodes were free of tumor. Although the simultaneous occurrence of papillary and medullary carcinoma may have been a simple coincidence, the patient’s history offers room for further speculation; he had chronic replicative hepatitis C and a 13-yr history of immunosuppression following renal transplantation. Therefore, a common oncogenic stimulus may have been involved. In the final analysis, the reason for both malignancies could not be clearly established. [ABSTRACT FROM AUTHOR]

Thyroid carcinoma accounts for less than 1% of all human malignancies and carries one of the highest overall familial relative risks as compared with cancers from other sites. This is particularly true for medullary carcinoma, as well as for carcinomas of follicular cell origin in general, where inheritance has been implicated in 2.5 to 6.3% of the cases. Familial nonmedullary thyroid tumors show a variety of genetic mechanisms implicated in thyroid tumorigenesis and occur in several tumor-prone traits (e.g., familial adenomatous polyposis [FAP] and Cowden’s disease [CD]) or as the only or dominant inherited manifestation. The latter group includes the most common familial papillary carcinoma, in which environmental factors such as radiation exposure may also play an important etiological role. Familial follicular cell tumors show a variety of morphological features ranging from benign thyroid nodulation to carcinoma, usually develop in young individuals, and tend to be multicentric—an indication for total thyroidectomy to avoid tumor recurrence and potential risk of malignant transformation. The pathologist may play an important role in the histological interpretation of familial nonmedullary thyroid tumors, which may lead to further clinicogenetical investigations of the affected patient and family screening. Familial follicular cell thyroid neoplasms show a complex molecular biological pathway of tumorigenesis when compared between themselves and with their sporadic counterparts. [ABSTRACT FROM AUTHOR]