Papillary thyroid carcinoma presenting as a solitary soft tissue arm metastasis in an elderly hyperthyroid patient. Case report and review of the literature

A case of papillary thyroid carcinoma (PTC) presenting as a solitary metastasis in the right arm muscle is described in an elderly hyperthyroid male patient. A 2-cm nodule in the right bycipites muscle was found to be a papillary carcinoma of thyroid origin and a primary, 3.5-cm tumor was subsequently found in the left lobe of a hyperfunctioning gland due to toxic goiter. Both tumors were well differentiated PTC, follicular variant. No high grade features, nor extrathyroidal spread, nor regional lymph node metastases were found, but histology evidenced intrathyroidal vascular invasion. After radical surgery and radioiodine therapy, the patient is currently disease-free 4 years after diagnosis. This is the third reported case of PTC manifesting as a single soft tissue metastasis and the first associated with hyperthyroidism. Hematogenous spread of differentiated PTC is rare, although less unusual in PTC follicular variant. Histological vascular invasion, hypervascularity and increased blood flow in the hyperfunctioning thyroid gland might have facilitated the dissemination of malignant tumor cells through the bloodstream. Literature data indicate that PTC in elderly patients is increasing and is often clinically aggressive. Radical surgical and radiometabolic treatments are required also in this age group to improve clinical outcome.This work was partially supported by grants from the Italian Ministry of Education and University (ex 60% to MP).     

Pathologic study and clinical significance of Hürthle cell papillary thyroid carcinoma.

Hürthle cell papillary thyroid carcinoma is a variant of papillary thyroid carcinoma (PTC). Its pathologic and clinical significance has not been well documented. The authors studied the relative incidence of Hürthle cell PTC and the relationship of Hürthle cell PTC to other variants of thyroid carcinoma. Three hundred eighty consecutive cases of thyroid carcinoma were reviewed to identify cases with focal or extensive areas of Hürthle cell PTC, classic PTC, Hürthle cell carcinoma (ie, non-Hürthle cell PTC), and follicular carcinoma. In addition, the status of lymphoid infiltrate in the tumor, stromal invasion with desmoplastic reaction, vascular invasion, and distant and lymph node metastasis were noted by microscopic examination, review of clinical charts, or both. A total of 24 (HCs) and 42 PTCs with Hürthle cells were identified. The latter category was divided into pure Hürthle cell PTC or extensive Hürthle cell (HPTC) (28 cases) and PTC or Hürthle cell carcinoma with focal areas of Hürthle cell PTC (14 cases). The Hürthle cell PTC/Hürthle cell carcinoma ratio was lower than that of PTC/follicular carcinoma (39:289) (P = 0.001). Follicular or solid structures were present in all HPTCs. HPTCs were associated with frequent stromal intrathyroid and extrathyroid invasion, but they tended to have a lower rate of lymph node metastasis (8/28) compared with classic PTC with stromal invasion (108:200) (P = 0.12) and a lower rate of distant metastasis (2:28) compared with Hürthle cell carcinoma (15:24) (P = 0.02) or follicular carcinoma (13:39) (P = 0.04). Warthin-like Hürthle cell PTC (10 cases) was associated with extrathyroid invasion in five cases. In Hürthle cell PTC associated with tall cell variant (10 cases), areas of gradual transition between Hürthle cell PTC and tall cell variant were identified. The latter variant showed the highest rate of extrathyroid stromal and vascular invasion with distant metastasis and patient death compared with all Hürthle cell PTCs and classic PTCs. In conclusion, Hürthle cell PTC is frequently associated with tall cell variant. It has a higher potential for extrathyroid invasion than classic PTC and has vascular invasion and distant metastasis characteristics intermediate between those of classic PTC and Hürthle cell carcinoma with or follicular carcinoma. Hürthle cell PTC tends to show a greater likelihood of extrathyroid invasion when associated with Warthin-like features and tall cell variant PTC, and higher vascular invasion and distant metastasis when associated with tall cell variant.     

Primary thyroid spindle cell tumors: spindle cell variant of papillary thyroid carcinoma?

Primary thyroid spindle cell tumors or spindle cell component in the thyroid tumors are very rare. The spindle tumor cells were positive for thyroid papillary carcinoma markers. So these tumors were diagnosed as spindle cell variant of papillary thyroid carcinoma (PTC). To further delineate clinico-pathological features of primary thyroid spindle cell tumors and discuss differential diagnosis, we reported a 67-year-old man with a mass in the right thyroid without clinical symptom. Microscopy revealed that an encapsulated tumor with lot criss spindle cells arranged in bundles. Nuclear grooves were easy to see and rare displayed pseudoinclusions. Immunohistochemical studied showed that the spindle cells were all strong positive for TTF-1, Pax-8, thyroglobulin. Rare follicular were seen in the periphery of the tumor near the thyroid tissue. The cells formed follicular but the spindle tumor cells were positive for pan-keratins. The pathological diagnosis was primary thyroid spindle cell tumors, suspected spindle cell variant of PTC. Primary thyroid spindle cell tumors were presence and without the unified name. The further reports and more discussion were need about these tumors.     

BRAF mutations are associated with some histological types of papillary thyroid carcinoma

Mutations in the BRAF gene have recently been detected in a wide range of neoplastic lesions with a particularly high prevalence in melanoma and papillary thyroid carcinoma (PTC). The hot-spot mutation BRAF(V599E) is frequently detected in PTC (36-69%), in contrast to its absence in other benign or malignant thyroid lesions. In order to unravel whether there is any association between the occurrence of the BRAF mutation and the histological pattern of PTC, in this study a previous series of 50 PTCs was extended to 134 cases, including ten cases of PTC-related entities-hyalinizing trabecular tumour (HTT) and mucoepidermoid carcinoma (MEC). Using PCR/SSCP and sequencing, the BRAF(V599E) mutation was detected in 45 of the 124 PTCs (36%). No mutations were detected in any case of HTT and MEC. BRAF(V599E) was present in 75% of Warthin-like PTCs and 53% of conventional PTCs, whereas no BRAF(V599E) mutations were detected in any of the 32 cases of the follicular variant of PTC. BRAF(V599E) was also detected in 6 of 11 cases of the oncocytic variant of PTC that displayed a papillary or mixed follicular-papillary growth pattern and in none of the four oncocytic PTCs with a follicular growth pattern. A distinct mutation in BRAF (codon K600E) was detected in three cases of the follicular variant of PTC. This study has confirmed the high prevalence of BRAF(V599E) in PTC and has shown that the mutation is almost exclusively seen in PTC with a papillary or mixed follicular-papillary growth pattern, regardless of the cytological features of the neoplastic cells. The results support the existence of an oncocytic variant of PTC that should be separated from the oncocytic variant of follicular carcinoma and suggest that the follicular variant of PTC may be genetically different from conventional PTC.     

Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of ras mutations

The follicular variant (FV) of papillary thyroid carcinoma is characterized by a follicular growth pattern and cytologic features of papillary carcinoma. ret/PTC rearrangements are common in classic papillary thyroid carcinoma (PTC) and PAX8-PPAR gamma and ras mutations in follicular thyroid carcinoma. Their prevalence in FV has not been established. We studied these genetic alterations and clinical-pathologic features in 30 FV cases and compared those with 46 non-FV papillary carcinomas. FV cases revealed 1 ret/PTC rearrangement (3%) and 13 ras mutations (43%). Non-FV cases harbored 13 ret/PTC (28%) (P = .006) and no ras mutations (P = .0002). No PAX8-PPAR gamma was found in either group. FV cases demonstrated a significantly higher prevalence of tumor encapsulation, angiovascular invasion, and poorly differentiated areas and a lower rate of lymph node metastases. These data indicate that the FV of papillary carcinoma has a distinct set of molecular alterations and is characterized by a high frequency of ras point mutations.     

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.     

分化型甲状腺癌中BRAF V600E突变分析

目的探讨分化型甲状腺癌中BRAF V600E突变与临床病理特征的关系。方法收集甲状腺乳头状癌(papillary thyroid carcinoma,PTC)80例(其中经典型67例、滤泡亚型8例、嗜酸细胞亚型3例、高细胞亚型2例)、滤泡癌5例,其中30例PTC取相应癌旁组织,全部送基因检测室检测BRAF V600E突变情况。结果 80例PTC中BRAF V600E突变率为65.0%,5例滤泡癌及30例癌旁组织中未发现BRAF V600E突变;BRAF V600E突变与患者年龄、肿瘤包膜侵犯、淋巴结转移及TNM分期有关。PTC亚型中,经典型和高细胞亚型的BRAF V600E突变率较高(70.1%、100.0%),滤泡亚型的突变率较低(33.3%)。结论PTC中BRAF V600E突变可能与患者年龄有一定相关性,还与包膜侵犯、淋巴结转移及TNM分期有关,经典型和高细胞亚型的BRAF V600E突变率较高,明显高于滤泡亚型。     

Pathology of Thyroglossal Duct: an Institutional Experience

Thyroglossal duct (TGD) is a developmental anomaly in which a remnant of the thyroid anlage is left in the neck during its descent from the foramen cecum of tongue to final pretracheal position. A persistent duct can lead to thyroglossal duct cyst (TGDC). Histologically, TGDC contains an epithelial lining of squamous or pseudostratified ciliated columnar epithelium and ectopic thyroid gland tissue in the duct wall. TGD-associated malignancy is rare, and the majority is papillary thyroid carcinoma (PTC). A total of 242 patients with a diagnosis of TGD-associated lesions were identified in our institute. Two hundred and seventeen cases were diagnosed as TGDC. Sixty-eight of 217 (31.3 %) cases of TGDC had ectopic thyroid tissue in the cystic wall. Thirty-nine cases had preoperative fine needle aspiration (FNA). Of these cases, 37 of 39 (94.9 %) demonstrated macrophages and 19 (48.7 %) also showed cells of squamous and/or columnar epithelial lining. Only two cases showed rare thyroid follicular cells. Thyroid carcinoma was identified in 18 of 242 (7.4 %) cases. All cases were diagnosed as PTC including 12 cases of classic PTC (66.7 %), 3 cases of follicular variant (16.7 %), 2 cases of tall cell variant (11.1 %), and 1 case of classic PTC with focal tall cell features (5.6 %). Nine cases had TGD component (either epithelial lining cysts or ectopic thyroid tissue). Ten patients also underwent total thyroidectomy (67 %). Of these patients, four had no tumor and one had an incidental medullary carcinoma. Five of 10 (50 %) cases had incidental PTC with a size range of 0.1–0.3 cm. Five patients had follow-up by imaging studies; no suspicious or nodular lesions were found in the thyroid. In conclusion, we report an institutional case cohort of 242 patients with TGD-associated lesions, including 217 TGDC and 18 cases of PTC. Only seven cases fulfilled the diagnostic criteria of TGD-associated PTC, i.e., the presence of components of TGD and a normal thyroid. In the remaining 11 cases, we could not differentiate with certainty between pyramidal primary thyroid PTC/Delphian node metastasis or TGD-associated PTC.     

Synchronous papillary thyroid carcinoma and follicular thyroid carcinoma: case report and review of literature

Collision tumor is a term denoting two histologically distinct tumor types occuring at the same anatomic site, which is a rare clinical entity. In the thyroid gland, collision tumors are rare. Here we report a case of the synchronous occurrence of follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC). The current case report describes a 40-year-old woman with synchronous FTC and PTC. Pathologists and surgeons should be aware of collision tumors to avoid possible misdiagnosis.     

RASSF1A and NORE1A methylation and BRAFV600E mutations in thyroid tumors

We analyzed RASSF1A and NORE1A methylation and BRAF mutation in 89 thyroid tumors, 42 non-neoplastic thyroid tissues and three thyroid tumor cell lines using polymerase chain reaction (PCR), methylation-specific PCR, Western blotting and DNA sequencing in order to study thyroid tumor pathogenesis and progression. RASSF1A promoter methylation was present in all three thyroid cell lines and in 27/78 (35%) of benign and malignant thyroid tumors. We showed for the first time that there was generally good agreement between RASSF1A methylation status and RASSF1A protein expression. We also examined for the first time NORE1A promoter region methylation in thyroid cell lines and primary tumors and showed that two of three thyroid cell lines were methylated in the NORE1A promoter region, while all primary thyroid tumors analyzed (n=51) were unmethylated. BRAF mutation was present in 38% of papillary thyroid carcinomas (PTC), including 20% of PTC with a follicular variant pattern and 67% of the tall cell variant of PTC. Hyalinizing trabecular tumors (n=23), which had nuclear features similar to PTC, did not have BRAF mutations, indicating that the presence of BRAF mutations can help to separate these two tumor types. Phospho-MEK expression was increased in the NPA cell line, which had a BRAF mutation, supporting the importance of the BRAF pathway alterations in PTC pathogenesis. These results indicate that RASSF1A epigenetic changes are an early event in thyroid tumor pathogenesis and progression and that NORE1A methylation is uncommon in primary thyroid tumors. BRAF mutation occurs later in thyroid tumor progression and is restricted mainly to PTC and anaplastic thyroid carcinoma.     

Expression of X-linked inhibitor of apoptosis protein in neoplastic thyroid disorder

X-linked inhibitor of apoptosis protein (XIAP) is associated with tumor genesis, growth, progression and metastasis, and acts by blocking caspase-mediated apoptosis. In the present study, we sought to evaluate the expression patterns of XIAP in various neoplastic thyroid disorders and determine the association between XIAP expression and clinicopathologic factors. Expression of XIAP was evaluated with immunohistochemical staining using monoclonal anti-XIAP in 164 specimens of conventional papillary thyroid carcinoma (PTC) and 53 specimens of other malignant or benign thyroid tumors. XIAP positivity was observed in 128 (78%) of the 164 conventional PTC specimens. Positive rates of XIAP expression in follicular variant PTC, follicular, medullary, poorly differentiated, and anaplastic thyroid carcinoma specimens were 20%, 25%, 38%, 67%, and 38%, respectively. Six nodular hyperplasia specimens were negative and 1 of 7 follicular adenomas (8%) was positive for XIAP. Lateral neck lymph node metastases were more frequent in patients negative for XIAP expression (P = 0.01). Immunohistochemical staining for XIAP as a novel molecular marker may thus be helpful in the differential diagnosis of thyroid cancer. Moreover, high XIAP expression in conventional PTC is strongly associated with reduced risk of lateral neck lymph node metastasis.     

Concomitant papillary thyroid carcinoma and Hashimoto's thyroiditis

An association between papillary thyroid carcinoma (PTC) and Hashimoto's thyroiditis (HT) is well recognized. Both entities may often display overlapping morphologic features. The aim of this study was to evaluate the accuracy of fine needle aspiration (FNA) of concomitant PTC and HT. Twenty nine thyroid FNAs with a diagnosis of concomitant PTC and HT on follow-up surgical material were retrospectively reviewed (11% of all HT cases diagnosed in the same period of time). The cytologic specimens were evaluated for the presence of diagnostic features of PTC and HT. In 16 of 29 cases, the diagnosis of PTC was made or suggested; however, only in 3 cases were both entities recognized on the FNA material. The review of the remaining cases (13 cases) showed diagnostic features of PTC in 2 cases (interpretation errors), some features of PTC in 8 cases (insufficient diagnostic features), features of only HT in 2 cases, and 1 case was acellular (sampling errors). Originally, 10 cases with features of PTC were diagnosed as either follicular neoplasm or colloid nodule with or without HT. Histologically, 1 of 13 cases was a cystic variant and 7 of 13 cases were follicular variants of papillary carcinoma. It is important to be aware of the coexistence of PTC and HT. Deliberate search for evidences of PTC in every case of HT may be necessary to improve diagnostic accuracy of the FNA. However, the cytologic diagnosis of follicular variant of PTC coexisting with HT can be challenging. The sampling error may also cause false negative results.     

TROP‐2 expression in papillary thyroid carcinoma

TROP‐2 is a type I transmembrane glycoprotein which is over‐expressed in various malignancies, and is related to epithelial cell adhesion molecule (EpCAM), also called TROP‐1, gp40, and KSA. In this study, we evaluated TROP‐2 expression in papillary thyroid carcinoma (PTC) and compared it to other thyroid neoplastic and non‐neoplastic lesions. Immunohistochemical (IHC) evaluation for TROP‐2 was performed on 137 thyroid fine needle aspiration (FNA) cell blocks (CB) which included classic PTC (64), follicular variant PTC (FVPTC) (10), anaplastic thyroid carcinoma (AC) (2), medullary carcinoma (MC) (8), follicular neoplasms (FN) (8), Hurthle cell neoplasms (HCN) (9), follicular lesion of uncertain significance (FLUS) (12), and benign thyroid nodule (BTN) (24). IHC for TROP‐2 expression was also performed on 331 BTN and malignant tumor tissue sections in tissue microarray (TMA). Membranous staining in >5% of tumor cells was considered positive. TROP‐2 stained 61 of 64 PTC CB, 7 of 10 FVPTC CB, and 9 of 12 FLUS CB. All other cases were negative for TROP‐2. TROP‐2 showed a sensitivity of 95.31% and specificity of 89% for classic PTC in FNA CB. In TMA samples, TROP‐2 stained 54 of 60 classic PTC cases and hence showed a high sensitivity and specificity. All BTN in CB and TMA were negative. We conclude that TROP‐2 is a highly sensitive and specific IHC marker for identifying classic PTC. TROP‐2 may play an important role in diagnosing classic PTC, especially in equivocal cases. This study also identifies a strong role for TROP‐2 in separating PTC from BTN. Diagn. Cytopathol. 2016;44:26–31. © 2015 Wiley Periodicals, Inc.     

The utility of aspiration cytology for the distinction of aggressive and non-aggressive papillary carcinoma of the thyroid

Preoperative identification of the aggressive variants of papillary thyroid carcinoma (PTC) by fine needle aspiration (FNAC) has been suggested and different systems for distinguishing them from classical variant of PTC have been employed, including a point-based cytology grading system as suggested by Damiani et al., that we currently use in our Institution. The aim of this paper is to verify if distinction of PTC in aggressive or nonaggressive variants impacts on surgical treatment. In 7 years, from 1998 to 2005, 13586 cases of FNAC of thyroid have been performed; among them 156 PTC. The cytological material of thirty complete thyroidectomies with histology proven papillary thyroid carcinoma were reviewed. 11/30 cases were correctly stratified into the appropriate low or high-grade category. The cytological grading system was discordant with the final histopathological diagnosis in 9/30 cases while in 10 cases the grade was not assessed. Eight cases were downgraded and therefore the low grade papillary carcinoma diagnosed at cytological level turned to be high grade at histology. When those cases were reviewed, the histology of seven cases diagnosed as tall cell variant of PTC failed to show a percentage of tumour cells higher than 50% and therefore it would be better to diagnose them as classical variant of PTC. One case was under-graded at FNAC. The case that was cytologically upgraded was a follicular variant of PTC in Hashimoto thyroiditis with a focus of tall cells. All patients underwent thyroidectomy or thyroidectomy plus lymphadenectomy and from our results the pre-operative diagnosis did not effect the surgical treatment. No patient died of the disease.     

The contribution of molecular pathology to the classification of thyroid tumors

Significant molecular advances have been undertaken for the past two decades in the field of thyroid follicular neoplasms, including a detailed genomic profile of papillary thyroid carcinoma (PTC) by The Cancer Genome Atlas (TCGA) project. These molecular discoveries led to a better understanding of the pathogenesis of thyroid neoplasms and resulted in reclassification of certain types of thyroid tumors. This review discusses how, 1) the molecular profiles of follicular-patterned lesions led to the reclassification of the follicular variant of PTC into non-invasive follicular thyroid neoplasm with papillary like nuclei, 2) the genotyping of Hürthle cell neoplasm provided the rationale to classify these tumors independently from follicular adenomas and carcinomas, and 3) BRAF and RAS molecular signatures have the potential of subclassifying PTC and poorly differentiated thyroid carcinoma into clinically relevant molecular subtypes.     

Fine‐needle aspiration of the diffuse sclerosing variant of papillary thyroid carcinoma masked by florid lymphocytic thyroiditis; A potential pitfall: A case report and review of the literature

The diffuse sclerosing variant of papillary thyroid carcinoma (DSV–PTC) is a rare tumor with aggressive behavior that requires aggressive treatment. Despite characteristic clinical and histological features that easily permit diagnosis, pre‐operative fine‐needle aspiration cytology (FNAC) diagnosis is often challenging and thus delays diagnosis. We describe the cytological features of a case of DSV–PTC diagnosed by FNAC in a 30‐year‐old woman presenting with an ill‐defined mass in her neck lasting for 2 months. Ultrasonograpy revealed a heterogeneous enlargement of both thyroid lobes suspicious for a lymphoproliferative syndrome. Flow cytometry showed a suspect B‐lymphocyte population. FNAC showed in five out of six slides an overwhelming presence of slightly atypical monomorphic small lymphocytes. The remaining slide showed syncytial tissue fragments of follicular cells with nuclear enlargement and pleomorphism, irregular nuclear membrane, grooves with scattered intranuclear inclusions, squamous metaplastic epithelium, and abundant psammoma bodies. A diagnosis of DSV–PTC was rendered and confirmed by total thyroidectomy and lymph node dissection. Our report supports the possibility of obtaining a preoperative diagnosis of DSV–PTC by FNAC. In the case of diffuse thyroid enlargement, adequate sampling of the thyroid and the presence of the combination of features described in our case permitted the diagnosis of this PTC variant. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.