Familial Non-Medullary Thyroid Carcinoma: An Update

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.     

Hereditary and familial thyroid tumours

The worldwide incidence of thyroid malignancies has been increasing rapidly. Sensitive imaging modalities and early detection of thyroid lesions have made thyroid cancers the most rapidly increasing cancers in the USA in 2017 (SEER Cancer Facts, 2017). Clinical awareness of potential risk factors, such as inherited thyroid cancers, has allowed earlier recognition of more vulnerable population clusters. Hereditary thyroid neoplasms arising from calcitonin‐producing C cells are known as familial medullary thyroid carcinomas (FMTCs), and include well‐documented syndromes such as multiple endocrine neoplasia IIA or IIB, and pure familial medullary thyroid carcinoma syndrome. Familial thyroid cancers arising from follicular cells are referred to as familial non‐medullary thyroid carcinoma (FNMTC), or familial follicular cell‐derived carcinoma. Clinicopathological correlations have resulted in the further subclassification of FNMTCs into two groups. Among the first group are found syndromes characterised by a predominance of non‐thyroidal tumours, including familial adenomatous polyposis, Cowden syndrome, Werner syndrome, Carney complex, and Pendred syndrome. The second group encompasses a spectrum of familial syndromes characterised by a predominance of non‐medullary thyroid tumours, such as pure familial papillary thyroid carcinoma with or without oxyphilia, familial papillary thyroid carcinoma with papillary renal cell carcinoma, and familial papillary carcinoma with multinodular goitre. Most familial thyroid cancers have been described as being more aggressive than sporadic thyroid cancers, with a predisposition for lymph node metastasis, extrathyroidal invasion, and a younger age of onset. The distinct thyroid pathology in some of these syndromes should alert the pathologist to a possible familial cancer syndrome.     

Familial Follicular Cell Tumors: Classification and Morphological Characteristics

Familial follicular cell-derived well-differentiated thyroid cancer, papillary (PTC), and follicular thyroid carcinomas (FTC), accounts for 95% of thyroid malignancies. The majority of are sporadic, and at least 5% of these patients will have familial disease. Familial thyroid syndromes are classified into familial medullary thyroid carcinoma (FMTC), derived from calcitonin-producing C cells, and familial follicular cell tumors or non-medullary thyroid carcinoma (FNMTC), derived from follicular cells. Twenty-five percent of patients with medullary thyroid cancer (MTC) have a familial form; however, this accounts for only 1% of all patients with thyroid cancer. The familial follicular cell-derived lesions or familial non-medullary thyroid cancer can be divided into two clinical-pathological groups. The first group includes familial syndromes characterized by a predominance of non-thyroidal tumors, such as familial adenomatous polyposis (FAP), PTEN-hamartoma tumor syndrome (Cowden disease; PHTS), Carney complex, Werner syndrome, and Pendred syndrome. The second group includes familial syndromes characterized by predominance of papillary thyroid carcinoma (PTC), such as pure fPTC, fPTC associated with papillary renal cell carcinoma, and fPTC with multinodular goiter. Most of the progress in the genetics of familial thyroid cancer has been in patients with MTC. This is usually a component of multiple endocrine neoplasias 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. The mutations in patients with isolated NMFTC have not been as well defined as in MTC. In many cases, patients have a known familial syndrome that has defined risk for thyroid cancer. The clinician must be knowledgeable in recognizing the possibility of an underlying familial syndrome when a patient presents with thyroid cancer. Some characteristic thyroid morphologic findings should alert the pathologist of a possible familial cancer syndrome, which may lead to further molecular genetics evaluation.     

Genetics in the endocrine system: the impact of the TRK family

Rearrangements in NTRK are rare actionable oncologic drivers in thyroid carcinoma. Although they only represent a small subset of most thyroid carcinoma subtypes, their identification remains important due to the availability of targeted therapy. Trk inhibitors are currently FDA-approved for NTRK-rearranged cancers independent of primary site and represent a crucial additional therapeutic option for patients with advanced or aggressive thyroid cancer. In the thyroid, NTRK-rearranged cancers have been shown to involve all NTRK family members (NTRK1, NTRK2, and NTRK3) as well as a multitude of different partner genes. Due to their rarity and relatively diverse molecular classification, the clinical and histologic characterization of NTRK-rearranged thyroid carcinoma remains challenging and is not currently well-defined. Given the relatively good prognosis of most thyroid carcinomas, the practical identification of NTRK-rearranged thyroid carcinomas for targeted therapy is case-specific and only considered when current therapeutic options have been exhausted.     

Letter regarding the article: “Multiple HABP2 variants in familial papillary thyroid carcinoma: Contribution of a group of “thyroid-checked” controls” by Kern et al.

This Journal recently published a study (Kern et al., 2017) reporting the genetic analysis of the whole HABP2 gene in 11 independent kindreds with familial non medullary thyroid cancer (FNMTC). The Authors showed that a new variant (p.R122W) displayed a minor allele frequency (MAF) significantly higher in FNMTC patients than in controls (7.5 vs 0.73%, p = 0.016) and cosegregated with thyroid cancer in one kindred, thus suggesting the need for the evaluation of its possible pathogenicity in other series.We thus analyzed this new HABP2 p.R122W variant in our wide series of 32 unrelated FNMTC Italian kindreds. The variant was not found in any of the 72 affected and 12 not affected family members.In conclusion, the HABP2^R122W was not found in our wide series and it is thus unlikely to be causal to FNMTC. We therefore suggest that careful replication studies should be performed when assessing the possible association between FNMTC risk and any HABP2 variant.     

Molecular pathology of thyroid tumours of follicular cells: a review of genetic alterations and their clinicopathological relevance

Thyroid cancer is the most common endocrine malignancy. Knowledge of the molecular pathology of thyroid tumours originating from follicular cells has greatly advanced in the past several years. Common molecular alterations, such as BRAF p.V600E, RAS point mutations, and fusion oncogenes (RET–PTC being the prototypical example), have been, respectively, associated with conventional papillary carcinoma, follicular‐patterned tumours (follicular adenoma, follicular carcinoma, and the follicular variant of papillary carcinoma/non‐invasive follicular thyroid neoplasm with papillary‐like nuclear features), and with papillary carcinomas from young patients and arising after exposure to ionising radiation, respectively. The remarkable correlation between genotype and phenotype shows how specific, mutually exclusive molecular changes can promote tumour development and initiate a multistep tumorigenic process that is characterised by aberrant activation of mitogen‐activated protein kinase and phosphoinositide 3‐kinase–PTEN–AKT signalling. Molecular alterations are becoming useful biomarkers for diagnosis and risk stratification, and as potential treatment targets for aggressive forms of thyroid carcinoma. What follows is a review of the principal genetic alterations of thyroid tumours originating from follicular cells and of their clinicopathological relevance.     

B-RAF mutations in the etiopathogenesis, diagnosis, and prognosis of thyroid carcinomas

The very recent discovery of B-RAF point mutations as the most prevalent genetic alteration in papillary thyroid carcinoma has revolutionized the molecular knowledge of thyroid malignancies. In this review, we address the role played by such mutations in the etiopathogenesis, diagnosis, prognosis, and therapy selection of thyroid cancer, with an emphasis on papillary carcinoma.     

Synchronous primary triple carcinoma of thyroid and kidney accompanied by solitary fibrous tumor of the kidney: a unique case report

Thyroid cancers coexisted with kidney cancer in a patient is an unusual event. Here, we described a case of 35-year-old woman with synchronous occurrence of primary papillary carcinoma and follicular carcinoma of the thyroid, accompanied by renal cell carcinoma and solitary fibrous tumor of the kidney, which has not been reported in literature to our best knowledge. Its clinical and pathological features, as well as the possible pathogenic factors were discussed.     

Molecular pathobiology of thyroid neoplasms

Tumors of thyroid follicular cells provide a very interesting model to understand the development of human cancer. It is becoming apparent that distinct molecular events are associated with specific stages in a multistep tumorigenic process with good genotype/phenotype correlation. For instance, mutations of the gsp and thyroid-stimulating hormone receptor genes are associated with benign hyperfunctioning thyroid nodules and adenomas while alterations of other specific genes, such as oncogenic tyrosine kinase alterations (RET/PTC, TRK) in papillary carcinoma and the newly discovered PAX8/peroxisome proliferator-activated receptor γ rearrangement, are distinctive features of cancer. Although activating RAS mutations occur at all stages of thyroid tumorigenesis, evidence is accumulating that they may also play an important role in tumor progression, a role that is well documented for p53. Environmental factors (iodine deficiency, ionizing radiations) have been shown to play a crucial role in promoting the development of thyroid cancer, influencing both its genotypic and phenotypic features. It is possible that the follicular thyroid cell has unique ways to respond to DNA damage. Similarly to leukemia or sarcomas (and unlike most epithelial cancers), numerous specific rearrangements are being discovered in thyroid cancer suggesting preferential activation of DNA repair instead of cell death programs after environmentally induced genetic alterations.     

Metastatic bronchioloalveolar carcinoma presenting as a solitary thyroid nodule: report of a case with fine-needle aspiration cytopathology

Although cancers metastatic to the thyroid are frequently mentioned in autopsy studies, such a finding is quite rare in routine clinical practice. Metastatic non-small-cell carcinomas to the thyroid may present a diagnostic dilemma, particularly when they share morphological similarities with primary thyroid tumors. Herein, we report a case of metastatic bronchioloalveolar carcinoma that presented as an isolated left thyroid nodule in a 68-year-old woman. The aspirates were cellular and showed numerous papillary-like tissue fragments, elongated nuclei with prominent nuclear grooves, frequent mitoses, and psammoma bodies. The latter features raised the possibility of papillary thyroid carcinoma. However, also seen were three-dimensional tumor nests and acinar-forming fragments. Immunostains (positive for cytokeratin-7 and carcinoembryonic antigen and negative for cytokeratin-20 and thyroglobulin) confirmed the metastatic nature of the carcinoma. In a patient with known primary neoplasm, the differential diagnosis of a thyroid nodule should always include a metastatic lesion along with primary neoplasia.     

The Relationship of Lymphocytic Thyroiditis to the Development of Thyroid Carcinoma

There are many reported predisposing factors for thyroid papillary carcinoma, including genetic factors [1], previous irradiation [2,3], abnormal iodine intake [4–6] hyperthyroidism [7], pregnancy [8], and a dyshormonogenetic state [9]. However, whether there is a causative link between lymphocytic thyroiditis and thyroid papillary carcinoma remains controversial. Most reports indicating some association have suffered from methodologic problems. In particular, race, age, and sex differences in susceptibility to chronic lymphocytic thyroiditis and thyroid cancer have not been well-controlled in previous studies. We have therefore carefully evaluated previous studies and tried to determine if there is a definite relation between lymphocytic thyroiditis and thyroid papillary carcinoma histopathologically. This article was presented in part at the Endocrine Pathology Society Companion Meeting of the USCAP in Orlando, FL, March 1, 1997.     

RET Proto-Oncogene and Thyroid Cancer

TheRET proto-oncogene has not only conclusively been identified as responsible for the three subtypes of the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN-2) but also shown to be involved in the molecular evolution of sporadic medullary and papillary thyroid carcinoma as well as Hirschsprung’s disease. A variety of recent studies have elucidated the pathophysiological mechanisms leading to neoplastic disease and we now understand that dominant activating germline mutations lead to MEN-2A, MEN-2B, and familial MTC; somatic mutations to sporadic medullary thyroid carcinoma;RET rearrangements to papillary thyroid carcinoma; and inactivating alterations to Hirschsprung's disease. The clinical significance, however, ofRET alterations especially in sporadic thyroid tumors is still controversial and therapeutic concepts in MEN-2 gene carriers only start to emerge. This article is a short summary of the recent findings on the structure and physiology of theRET proto-oncogene and its role in familial and sporadic thyroid cancer. This article was presented in part at the Endocrine Pathology Society Companion Meeting of the USCAP in Orlando, FL, March 1, 1997.     

How to define follicular thyroid carcinoma?

The appropriate diagnosis of follicular thyroid carcinoma (FTC) still depends on its histological discrimination from follicular adenoma (including the distinction of benign from malignant oncocytic variants), papillary thyroid carcinoma (particularly from the follicular variants) and poorly differentiated thyroid carcinoma. The use of immunohistochemical markers contributed only marginally to better defining FTC. The introduction of the micro array technique, however, may offer the possibility of getting a better insight into the natural history, as well as predicting the clinical course, of a given thyroid nodule. This review attempts to recapitulate common standards in the diagnosis of FTC, to summarise current molecular data available to distinguish FTC from other benign and malignant tumours and, finally, to outline future perspectives to define FTC on its specific genetic features.     

A case of multiple endocrine neoplasia type 1 combined with papillary thyroid carcinoma

This is the first report of papillary thyroid carcinoma combined with multiple endocrine neoplasia type 1 (MEN1) in Korea. MEN1 is a hereditary disease comprising neoplastic disorders such as pituitary, parathyroid and pancreatic neuroendocrine tumor, such as gastrinoma. But papillary thyroid cancer was never regarded as its component before in Korea. Herein we present a 39-year-old woman who manifested typical features of MEN1 with a coincidental papillary thyroid carcinoma. Although the family history of MEN1 was definite, her genetic analysis of DNA had revealed no germline mutation in MEN1 gene locus. Unidentified culprit gene unable us further genetic study to find LOH (loss of heterogeneity) in 11q13, the possible explanation of papillary thyroid carcinoma as a new component of MEN1. As we have first experienced a case of MEN1 combined with papillary thyroid carcinoma in Korea, we report it with the review of literature.     

microRNA在甲状腺乳头状癌中作用机制的研究进展

microRNA(miRNA)是一类长约22个核苷酸的非编码单链RNA分子。miRNA通过结合mRNA 3'非编码区(3'-UTR)调节基因的表达,抑制蛋白质的翻译。甲状腺癌是常见的内分泌系统恶性肿瘤,甲状腺乳头状癌是甲状腺癌中最常见的类型,它的发病率逐年上升。近年来,大量研究表明miRNA在甲状腺乳头状癌中发挥重要的作用,对癌的发生、发展及预后评估等方面具有重要意义。     

Thyroid neoplasms of follicular cell derivation: A simplified approach

Thyroid tumors of follicular cell derivation are increasing in incidence. These lesions exhibit a spectrum of morphologic and behavioral features that provide the opportunity to understand malignant transformation and progression. Molecular data suggest that the thyroid undergoes a series of genetic alterations that account for the development of the various types of thyroid carcinoma. Our understanding of these tumors has progressed dramatically over the past 50 years and the classification has become complex and cumbersome. We provide a practical approach to clinical diagnosis and propose a simplified classification of these common neoplasms.     

胃髓样癌的临床病理特征和分子遗传学改变

目的　探讨胃髓样癌的临床病理和分子遗传学特征。方法　 17例胃髓样癌和 6 4例非髓样癌 (低级别癌 19例 ,高级别癌 4 5例 )进行临床病理、免疫组织化学染色和微卫星不稳定性的比较研究。结果　胃髓样癌病理学以瘤细胞实体样排列和纤维少、富于淋巴细胞的间质为特征。与非髓样癌比较 ,还有以下特征 :(1)胃髓样癌、低级别癌平均生存时间好于高级别癌 ,差别有统计学意义 (P =0 0 0 4 )。 (2 )胃髓样癌 2 9 4 % (5 / 17例 )、非髓样癌 9 4 % (6 / 6 4例 )未累及浆膜 ,髓样癌较不易累犯浆膜 (P <0 0 5 ) ;髓样癌、非髓样癌各 70 5 % (12 / 17例 )和 2 0 8% (11/ 6 4例 )为推进性生长 ,髓样癌推进性生长较常见 (P =0 )。(3)胃髓样癌上皮内淋巴细胞中位数为 2 380 / 10HPF ,较非髓样癌 (14 7/ 10HPF)明显 (P =0 ) ;35 2 % (6 / 17例 )髓样癌、3 1%(2 / 17例 )非髓样癌瘤周淋巴细胞阳性 ,髓样癌瘤周淋巴细胞阳性较常见 (P =0 0 0 1) ;70 6 % (12 / 17例 )髓样癌Crohn样反应阳性 ,较非髓样癌 32 8% (2 1/ 6 4例 )常见 (P <0 0 5 )。 (4 )与低级别癌比较 ,胃髓样癌和高级别癌上皮钙粘素低表达更常见 (P<0 0 5 )。 (5 ) 4 1 2 % (7/ 17例 )胃髓样癌复制误差阳性 ,比非髓样癌的 2 5 % (1/ 6 4例 )更常见     

Clinicopathological and Molecular Histochemical Review of Skull Base Metastasis from Differentiated Thyroid Carcinoma

Skull base metastasis from differentiated thyroid carcinoma including follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC) is a rare clinical entity. Eighteen FTC cases and 10 PTC cases showing skull base metastasis have been reported. The most common symptom of skull base metastasis from FTC and PTC is cranial nerve dysfunction. Bone destruction and local invasion to the surrounding soft tissues are common on radiological imaging. Skull base metastases can be the initial clinical presentation of FTC and PTC in the presence of silent primary sites. The possibility of skull base metastasis from FTC and PTC should be considered in patients with the clinical symptoms of cranial nerve dysfunction and radiological findings of bone destruction. A variety of genetic alterations in thyroid tumors have been identified to have a fundamental role in their tumorigenesis. Molecular histochemical studies are useful for elucidating the histopathological features of thyroid carcinoma. Recent molecular findings may provide novel molecular-based treatment strategies for thyroid carcinoma.     

Sonographic detection of thyroid cancer in breast cancer patients

The purpose of our study was to analyze the incidence of incidental thyroid cancers which were detected by simultaneous sonographic examination of breast and thyroid glands. Between January 2001 and March 2004, 518 patients were diagnosed with breast cancer after modified radical mastectomy (n=369) or breast conserving surgery (n=149). We screened thyroid glands when we examined breast for diagnosis and follow-up after surgery. If we found the sonographic finding of suspicious for malignancy in thyroid, we immediately performed ultrasound-guided fine needle aspiration biopsy (FNAB). Forty-two cases showed suspicious sonographic findings and of those, 18 cases (42.9%) were determined to have suspicious malignant cytology by ultrasound guided FNAB. Among 518 breast cancers, total 13 cases (2.5%) were diagnosed with papillary carcinoma after thyroidectomy. The mean longest diameter of the thyroid masses was 9.9 mm (range 1-30 mm). Six cases (6/13, 46.2%) were diagnosed as simultaneous breast and thyroid cancers, and the rest of the thyroid cancers were detected after 6 to 33 months (mean 16.5 months) after surgery. In conclusion, the patients with breast cancer had a high incidence (2.5%) of thyroid cancer. Sonographic screening is useful for the early detection of thyroid cancer.