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.     

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.     

Distinction between papillary thyroid hyperplasia and papillary thyroid carcinoma by immunohistochemical staining for cytokeratin 19, galectin-3, and HBME-1

The histopathology of papillary thyroid hyperplasia and papillary thyroid carcinoma is similar enough to cause a diagnostic dilemma in a few cases. Both lesions may have papillary fronds with fibrovascular cores, nuclear crowding, and nuclear anisocytosis. Formalin-fixed paraffin-embedded tissues from 30 randomly selected patients with papillary thyroid hyperplasia and an equal number from patients with papillary thyroid carcinoma were analyzed for expression of cytokeratin 19 (CK19), galectin-3, and HBME-1. Cases of papillary thyroid carcinoma had moderate to strong CK19, galectin-3, and HBME-1 reactivity although both CK19 and galectin-3 showed positive staining in a significant number of nonneoplastic thyroid cases. HBME-1 was uncommon in the nonneoplastic cases. These results indicate that HBME-1 may be useful in helping to distinguish papillary thyroid carcinoma from hyperplasia in diagnostically difficult cases.     

能谱CT测定甲状腺组织碘含量的临床研究

目的利用宝石cT能谱成像技术（GSI）测量甲状腺乳头状癌与结节性甲状腺肿患者非瘤区甲状腺组织内碘含量,并与正常甲状腺内碘含量比较,探索甲状腺碘含量与甲状腺疾病的关系。方法收集北京大学深圳医院2011年8月—2013年7月接受甲状腺能谱CT检查并经手术病理证实的甲状腺病变患者36例,其中甲状腺乳头状癌18例、结节性甲状腺肿18例。正常甲状腺对照组15例,为怀疑颈部或颈椎疾病进行能谱CT扫描,无甲状腺功能及结构异常。使用GE公司宝石CT（GEDiscoveryCT750HI）CT）GSI模式扫描,图像采集后用GSIViewer浏览器处理,在碘基图中对结节性甲状腺肿与甲状腺乳头状癌病变外正常甲状腺组织及正常对照组甲状腺组织进行测量,采用Wilcoxon秩和检验及t检验进行统计学分析并探究其碘含量的分布特点。结果甲状腺乳头状癌中非瘤区腺体组织与正常甲状腺、结节性甲状腺肿中非瘤区腺体组织与正常甲状腺碘含量两两比较,差异均有统计学意义（P〈0．05）,甲状腺乳头状癌中非瘤区腺体组织与结节性甲状腺肿中非瘤区腺体组织的碘含量比较,差异无统计学意义（P〉0．05）,甲状腺乳头状癌中非瘤区腺体组织与结节性甲状腺肿中非瘤区腺体组织甲状腺碘含量呈“U”型分布。结论cT能谱成像技术作为一种新的方法,能够无创性地检测人体甲状腺碘含量,此技术将有助于进一步揭示甲状腺碘含量与甲状腺疾病关系。     

NPC2 expression in thyroid tumors and its possible diagnostic utility

Histopathologic diagnosis of thyroid lesions is sometimes difficult and may require the assistance of immunohistochemistry. Currently-used immunohistochemical biomarkers share the weakness of staining both papillary thyroid carcinoma and other non-papillary thyroid lesions. We examined NPC2 as an immunohistochemical marker in various thyroid lesions to determine the subcellular localization of the immunohistochemistry signal and evaluated the value of NPC2 as a diagnostic marker of papillary thyroid carcinoma. NPC2 immunostaining was performed on various thyroid tumors and tumor-like lesions. The immunostaining revealed significantly different patterns for papillary carcinomas and the other lesions. Papillary carcinomas exhibited moderate to strong granular cytoplasmic staining, often with basal membranous accentuation. In contrast, the other lesions showed mostly weak cytoplasmic staining, often with apical membranous accentuation. The subcellular localization of NPC2 provided insight into contrasting histopathologic morphology and reversed cellular polarity between the papillary patterns of papillary carcinomas and the follicular patterns of non-papillary carcinoma lesions. The diagnostic characteristics of NPC2 immunohistochemistry for non-follicular papillary carcinomas versus non-papillary carcinoma lesions were a sensitivity of 97.3%, specificity of 96.9%, positive predictive value of 94.7%, and negative predictive value of 98.4%. Significant differences were present between the two staining patterns in papillary carcinoma relative to mean age, nodal metastasis, and follicular and non-follicular variants (P = 0.02, P = 0.03, and P = 0.000, respectively). In conclusion, our evaluation of the subcellular localization of NPC2 using immunohistochemistry demonstrated possible value of NPC2 as a biomarker and provided insight into the morphologic characteristics of papillary carcinoma.     

Histopathologic and immunohistochemical characterization of a primary papillary thyroid carcinoma in the lateral cervical lymph node

Lymph nodes in the neck are known to occasionally contain benign epithelial inclusions and can be rare primary site of various tumors usually occurring in other organs. Papillary thyroid carcinoma in the lateral neck lymph node with co-existing ectopic thyroid inclusions has not been reported previously. A 41-year-old male patient, who had normal thyroid function and no history of neck irradiation, was seen with a slowly enlarging mass in the right lateral neck. At surgery the cervical mass was found to be separate from the thyroid proper without any attachments in between. Papillary thyroid carcinoma and co-existing thyroid inclusions were identified within the lateral cervical lymph node. Immunohistochemistry detected strong and diffuse cytoplasmic positivity with antibodies against CK19 and CK903 in papillary thyroid carcinoma. Benign thyroid follicles within the lymph node were only weakly and focally stained. Thorough examination confirmed no malignancy in the total thyroidectomy specimen. Furthermore, small foci of metastatic papillary carcinoma were identified in two ipsilateral lymph nodes from neck dissection specimen. These findings suggest development of primary papillary thyroid carcinoma from malignant transformation of benign intranodal thyroid inclusions.     

Heterotopic intrathymic thyroid tissue

Heterotopic intrathymic thyroid tissue is an extremely rare condition, but it is important to distinguish it from metastases of clinically undetected thyroid carcinoma because metastatic papillary thyroid carcinoma is often so well differentiated, simulating normal thyroid tissue. Described herein are histological findings of heterotopic intrathymic thyroid tissue that was incidentally identified in a woman with papillary thyroid carcinoma during histological examination of a radical neck dissection specimen. These findings emphasize that this rare incidence may occur and should be differentiated from metastatic papillary carcinoma. Histologically, the patient's intrathymic thyroid follicles were identical to the normal thyroid follicles, having flat cuboidal cells with uniformly small nuclei without nuclear grooves or inclusions. The follicular cells had a low Ki-67 labeling index close to zero, and immunonegativity for galectin-3, HBME-1, and RET oncoprotein, in contrast to the tumor cells in primary papillary thyroid carcinoma of the patient. To the authors' knowledge this is the first case report of intrathymic heterotopic thyroid tissue posing a diagnostic difficulty in a patient with papillary thyroid carcinoma.     

Hashimoto's thyroiditis shares features with early papillary thyroid carcinoma

Neoplastic transformation is a multistep process that results in a continuous spectrum from the normal (physiological) state to a fully established neoplasm. The gold standard for diagnosis of papillary thyroid carcinoma is conventional histology, the essential element being the characteristic nuclear features, regardless of whether papillary structures are present or not. However, other criteria are being used increasingly in the diagnosis of neoplasms, including immunohistochemical staining and molecular profile. The RET/PTC gene rearrangement is highly specific for papillary thyroid carcinoma and is associated with the characteristic nuclear features seen in papillary thyroid carcinoma. There is an overlap in the morphological features, immunohistochemical staining pattern, and most importantly, molecular profile between papillary thyroid carcinoma and Hashimoto's thyroiditis. Although considered a 'benign' condition, Hashimoto's thyroiditis almost always harbours a genetic rearrangement that is strongly associated with and is highly specific for papillary thyroid carcinoma. Submicroscopic foci of papillary thyroid carcinoma must be present in Hashimoto's thyroiditis, although the clinical behaviour is still benign. Further studies are required to predict which foci will progress to papillary thyroid carcinoma.     

Thyroid papillary carcinoma arising in ectopic thyroid tissue within a branchial cleft cyst

A case of papillary carcinoma arising in ectopic thyroid tissue within a branchial cleft cyst is described. A 46-year-old woman presented with a 2.0 x 2.0 cm mass in her left lateral neck. The excised mass showed a cystic lesion with a thyroid papillary carcinoma. Following a lateral cervical cystectomy, subsequent thyroid gland and lymph nodes dissections were performed. Pathological examination showed an adenomatous goiter and no primary carcinoma in the thyroid gland, as well as metastatic papillary carcinoma in the lymph nodes. Two cases of thyroid papillary carcinoma arising in ectopic thyroid tissue within a branchial cyst have been reported previously, but no lymph node metastases were recognized. The first case of papillary carcinoma arising in ectopic thyroid tissue within a branchial cleft cyst, and accompanied by lymph node metastasis is presented.     

Simultaneous papillary carcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma of the thyroid; a case report

Primary lymphoma of the thyroid is an uncommon malignancy, whereas papillary thyroid carcinoma is the most common thyroid malignancy. Both have an association with Hashimoto's thyroiditis. We discuss a case of an 83 year old male who presented with a large neck swelling, which subsequently proved to be a primary thyroid lymphoma (extra-nodal marginal zone) with concurrent papillary thyroid carcinoma. These tumours manifested on a background of Hashimoto's thyroiditis. To date there have only been 13 other cases of joint papillary thyroid carcinoma and thyroid lymphoma within the literature. Our case report adds to this by discussing diagnosis, histopathological features and pitfalls in early detection.     

Reduced HBME-1 immunoreactivity of papillary thyroid carcinoma and papillary thyroid carcinoma-related neoplastic lesions with Hürthle cell and/or apocrine-like changes

BACKGROUND: We have recently observed that Hürthle cell tumours and papillary thyroid carcinoma with tumour cells showing decapitation of luminal portion of the cytoplasm (apocrine-like changes) display negative or decreased immunoreactivity for HBME. The purpose of this study is to correlate papillary thyroid carcinoma with positive and negative immunoreactivity for HBME with the histopathological features. METHODS AND RESULTS: Two hundred and five thyroid neoplasms including carcinoma and adenomas were grouped into Hürthle cell tumours, tumours with or without some features of Hürthle cells, tumours with apocrine-like changes and adenomas with or without limited nuclear features of papillary thyroid carcinoma but not diagnostic for papillary thyroid carcinoma. All neoplasms were submitted for immunostaining with cytokeratin 19 (CK19) and HBME. Papillary thyroid carcinoma, follicular carcinoma and follicular adenoma that have areas of limited nuclear features but not diagnostic for papillary thyroid carcinoma showed stronger immunostaining for HBME than their respective counterparts with Hürthle cell changes. All Hürthle cell tumours showed negative to focal reactivity. This decrease of reactivity for HBME was proportional to the levels of Hürthle cell changes. In addition, focal to extensive apocrine-like changes were seen in most Hürthle cell neoplasms and rarely seen in non-Hürthle cell neoplasms. Apocrine-like changes abolished or decreased HBME immunoreactivity of papillary thyroid carcinoma and tumours with limited nuclear features. Immunostaining for cytokeratin AE3 was not affected by Hürthle cell or apocrine-like changes. CONCLUSIONS: All papillary thyroid carcinomas without Hürthle cell or apocrine-like differentiation are reactive for HBME. Hürthle cell tumours and tumours with Hürthle cell or apocrine-like changes show negative or focal reactivity for HBME. Except for this limitation, HBME is a sensitive marker for papillary thyroid carcinoma and tumours with limited nuclear features.     

Morphologic predictors of papillary carcinoma on fine-needle aspiration of thyroid with ThinPrep preparations

Although the cytologic features of papillary carcinoma of the thyroid are well-known, none is entirely specific. We conducted this study to determine the minimal criteria necessary to achieve 100% specificity for the diagnosis of papillary carcinoma on fine-needle aspiration (FNA). Forty patients with histologically confirmed papillary carcinoma and 17 patients with other thyroid lesions who underwent preoperative FNA at Beth Israel Deaconess Medical Center during a 4-yr period were included in the study. All cytology slides were prepared with the ThinPrep processing technique. Various architectural and nuclear features were evaluated, with a score assigned to each feature, and correlated with the histologic diagnosis of papillary carcinoma. Intranuclear inclusions, papillary and/or sheet arrangements, nuclear grooves, powdery chromatin, nuclear molding, high cellularity, and small nucleoli were significantly associated with papillary carcinoma (P < 0.05). The requirement of any intranuclear inclusions and many nuclear grooves, or a minimum of sum of scores (of the above eight features) of 10, yields 100% specificity and approximately 70% sensitivity. Cases with fewer features can be reported as suspicious or indeterminate for papillary carcinoma. A quantitative/probabilistic approach in the reporting of thyroid FNA provides a practical guide for management of patients with thyroid nodules.     

Annexin-Ⅱ及VEGF-C在甲状腺乳头状癌中的表达及其意义

目的 观察Annexin-Ⅱ及VEGF-C在甲状腺乳头状癌中的表达及其临床意义.方法 使用免疫组化的方法检测44例甲状腺乳头状癌、16例甲状腺腺瘤、20例结节性甲状腺肿及10例正常甲状腺组织中Annexin-Ⅱ及VEGF-C的表达情况及与临床病理的关系.结果 Annexin-Ⅱ及VEGF-C在甲状腺乳头状癌中的阳性表达率明显高于甲状腺腺瘤、结节性甲状腺肿及正常甲状腺组织;Annexin-Ⅱ及VEGF-C的表达与肿瘤大小及淋巴结转移有关,差异有统计学意义.结论 Annexin-Ⅱ及VEGF-C的表达与甲状腺乳头状癌的发生有密切关系,且与甲状腺乳头状癌的发展及淋巴结转移有一定关系.     

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.     

血管内皮生长因子-C和血管内皮生长因子受体-3在侵袭性甲状腺乳头状癌中的表达及意义

目的 观察血管内皮生长因子(VEGF-C)和血管内皮生长因子受体(VEGFR3)在侵袭性甲状腺乳头状癌组织中的表达,探讨甲状腺乳头状癌细胞淋巴管转移机理.方法 用免疫组化方法检测VEGF-C和VEGFR3在人侵袭性甲状腺乳头状癌和非侵袭性甲状腺乳头状癌中的表达情况,并进行比较和分析.结果 在侵袭性和非侵袭性甲状腺乳头状癌中均可见到VEGF-C和VEGFR3阳性表达,但在侵袭性甲状腺乳头状癌组织VEGF-C (x2=4.738,P=0.030)和VEGFR3(x2=11.951,P=0.010)的表达率和表达强度均高于非侵袭性甲状腺乳头状癌.结论 VEGF-C和VEGFR3在侵袭性甲状腺乳头状癌细胞中高表达,并且可能与此肿瘤的侵袭性相关.     

Case report: Different metastatic components from anaplastic thyroid carcinoma in mediastinal and neck lymph nodes simultaneously diagnosed by FNA

Anaplastic thyroid carcinoma (ATC) is a rare but aggressive form of undifferentiated thyroid carcinoma which arises from previously well‐differentiated thyroid carcinomas, such as papillary carcinoma or follicular carcinoma. We report on an interesting case of ATC found in an enlarging neck mass with metastatic papillary carcinoma found in mediastinal lymph nodes sampled by endoscopic bronchial‐ultrasound guided‐ fine‐needle aspiration, due to the incidental finding of a lung mass by CT scan. Divergent morphologies on cytology preparations were resolved by immunohistochemistry, which aided in the identification of both sites of malignancy and the common thread between them. The eventual palliative resection demonstrated the various components including undifferentiated thyroid carcinoma, papillary carcinoma, and background lymphocytic thyroiditis. Diagn. Cytopathol. 2014;42:694–699. © 2013 Wiley Periodicals, Inc.     

Occult oncocytic papillary thyroid carcinoma with lymphoid stroma (Warthin-like tumor): report of a case with concomitant mutations of BRAF V600E and V600K

Warthin-Like tumor of the thyroid is a recently described rare variant of papillary thyroid cancer. The distinct histological feature of this variant is papillary architecture lining oncocytic epithelial cells with nuclear characteristics of papillary carcinoma, accompanied by prominent lymphocytic infiltration in the papillary stalks. Here, we present a case of occult Warthin-like papillary thyroid carcinoma, 0.5-cm in maximum dimension, underwent left thyroid lobectomy in a 65 years old Chinese woman. In this case, there was no extrathyroid extension, vascular invasion and lymphatic metastasis, as well as no complication of lymphocytic thyroiditis. Immunohistochemistry staining revealed that the tumor cells were positive for Leu-M1, HBME-1, 34βE12, and MIB-1 labeling index was low. RET/PTC expression was absent in tumor cells. Furthermore, activated point mutations of BRAF V600E and V600K were concurrently detected by DNA sequencing. Further studies are needed to elucidate the prevalence and role of BRAF^V600K mutation in papillary thyroid carcinoma, and long-term follow-up for the patient is needed to clarify the biological behavior of this variant with dual BRAF mutations.     

HLA-Ⅱ类抗原在甲状腺乳头状癌组织中的表达及意义

目的 检测人类白细胞分化抗原-Ⅱ(human leukocyte antigen-Ⅱ)HLA-Ⅱ类抗原在甲状腺乳头状癌组织中的表达,探讨其与甲状腺乳头状癌发病的关系,为进一步的预防及治疗奠定基础.方法 应用Western印迹和免疫组化SP法检测20例甲状腺乳头状癌组织及其癌旁正常甲状腺组织中HLA-Ⅱ类抗原的表达.结果 Western印迹和免疫组化结果均显示HLA-Ⅱ类抗原在甲状腺癌乳头状组织和正常甲状腺组织中都有表达,且Western印迹结果显示前者的表达高于后者,差异具有统计学意义(P<0.05).结论 HLA-Ⅱ类抗原可能在甲状腺乳头状癌免疫逃逸机制中发挥重要作用.     

Cytological features of warthin‐like papillary thyroid carcinoma: A case report with review of previous cytology cases

Warthin‐like papillary thyroid carcinoma (WLPTC) is a rare morphological variant of papillary thyroid carcinoma which mimics various benign and malignant lesions on thyroid aspiration cytology. As correct cytological diagnosis is the cornerstone for appropriate patient management, awareness of the salient cytomorphological characteristics of this tumor is essential. Here, we present cytological features of a case of WLPTC along with discussion of the common differential diagnoses and a brief review of the literature to ascertain the most consistent cytological findings of WLPTC. The present case also harboured BRAFV600E mutation which is the commonest molecular alteration seen in WLPTC.     

Fine‐needle aspiration biopsy of a papillary thyroid carcinoma involved by malignant plasma cell disease: A case report

We described the fine‐needle aspiration biopsy findings in a case of papillary thyroid carcinoma involved by a malignant plasma cell disease of the thyroid gland in a 54‐year‐old female. Although papillary thyroid carcinoma is the most common malignant tumor of the thyroid gland, involvement by plasma cell disease is exceptionally unusual. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.