BRAF T1799A mutation occurring in a case of malignant struma ovarii

Struma ovarii is an extremely rare tumor that occasionally undergoes malignant transformation. Because struma ovarii is composed of thyroid tissue, it is conceivable that the pathogenetic events involved in thyroid follicular transformation may take place also in struma ovarii. The authors describe a case of a classical variant of papillary thyroid carcinoma arising in a struma ovarii of a 22-year-old female. The tumor was heterozygous for BRAF T1799A mutation. No ret/ PTC-1 or ret/PTC-3 rearrangements were detected. This finding would suggest that malignant struma ovarii is similar histologically and genetically to primary papillary thyroid carcinoma.     

Molecular genetic study comparing follicular variant versus classic papillary thyroid carcinomas: association of N-ras mutation in codon 61 with follicular variant

Although the follicular variant of papillary thyroid carcinoma (FVPTC) has been classified as a papillary cancer based on nuclear features, its follicular growth pattern and potential for hematogenous spread are more characteristic of follicular carcinoma. To gain insight into the biologic nature of FVPTC, we compared genetic alterations characteristic of papillary and follicular thyroid carcinomas in 24 FVPTCs and 26 classic PTC (CPTCs). In FVPTCs, we observed ras mutation in 6 of 24 cases (25%), BRAF mutation in 1 of 13 cases (7.6%), and ret rearrangement in 5 of 12 cases (41.7%). In CPTCs, we found ras mutation in no case, BRAF mutation in 3 of 10 cases (30%), and ret rearrangement in 5 of 11 cases (45%). One FVPTC exhibited simultaneous ras mutation and ret/PTC1 rearrangement, and one CPTC harbored simultaneous BRAF mutation and ret/PTC3 rearrangement. Based on these findings, we concluded that ras mutation correlates with follicular differentiation of thyroid tumors whereas ret activation is associated with papillary nuclei but not with papillary architecture. ret activation is not exclusive of ras or BRAF mutation, whereas ras and BRAF mutations are mutually exclusive. The implications of these results for follicular and papillary carcinogenesis are discussed.     

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.     

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.     

Immunohistochemical diagnosis of papillary thyroid carcinoma.

In thyroid, the diagnosis of papillary carcinoma (PC) is based on nuclear features; however, identification of these features is inconsistent and controversial. Proposed markers of PC include HBME-1, specific cytokeratins (CK) such as CK19, and ret, the latter reflecting a ret/PTC rearrangement. We applied immunohistochemical stains to determine the diagnostic accuracy of these three markers. Formalin-fixed, paraffin-embedded tissue from 232 surgically resected thyroid nodules included 40 hyperplastic nodules (NH), 35 follicular adenomas (FA), 138 papillary carcinomas (PC; 54 classical papillary tumors and 84 follicular variant papillary carcinomas [FVPC]), 4 follicular carcinomas (FC), 6 insular carcinomas (IC), 7 Hürthle cell carcinomas (HCC), and 2 anaplastic carcinomas (AC). HBME-1 and ret were negative in all NH and FA; some of these exhibited focal CK19 reactivity in areas of degeneration. Half of the FC and AC exhibited HBME-1 staining but no positivity for CK19 or ret. In PC, 20% of cases stained for all three markers. Classical PC had the highest positivity with staining for HBME-1 in 70%, CK19 in 80%, and ret in 78%. FVPC were positive for HBME-1 in 45%, for CK19 in 57%, and for ret in 63%; only 7 FVPC were negative for all three markers. The six IC exhibited 67% staining for HBME-1 and 50% positivity for CK19 and ret. The seven HCC had 29% positivity for HBME-1 and CK19, and 57% positivity for ret. This panel of three immunohistochemical markers provides a useful means of diagnosing PC. Focal CK19 staining may be found in benign lesions, but diffuse positivity is characteristic of PC. HBME-1 positivity indicates malignancy but not papillary differentiation. Only rarely are all three markers negative in PC; this panel therefore provides an objective and reproducible tool for the analysis of difficult thyroid nodules.     

Unilateral malignant struma ovarii in a case of bilateral ovarian teratoma with raised CA-125 level: a rare case with treatment dilemmas

Struma ovarii are specialized form of mature ovarian teratoma comprised predominantly of thyroid tissue (>50%). Most of the struma ovarii are benign; rarely can they undergo malignant transformation. Elevated CA-125 levels with benign struma ovarii have been seen in only 5 cases in literature. The association of malignant struma ovarii and high CA-125 levels with pseudo-Meig syndrome has been reported in only 2 cases in English literature. We describe a case of a 46-year-old multigravida who presented with an abdominal mass and raised CA-125 levels. Radiological investigations revealed bilateral cystic adnexal masses with ossified elements on left side suggesting a teratoma. Intraoperative frozen section and final pathology revealed bilateral teratoma with follicular variant of papillary thyroid carcinoma arising in the left ovary. To the best of our knowledge, this is the first case of malignant struma ovarii in combination with bilateral teratoma. The dilemmas related to preoperative diagnoses with elevated CA-125 levels, mimicking an epithelial ovarian neoplasm; intraoperative frozen section consultation; management and follow-up issues in this rare malignancy are discussed.     

Case report: Malignant struma ovarii

Struma ovarii are specialized teratomas consisting of thyroid tissue with various microscopic features, ranging from benign to malignant. We report a rare form of malignant struma ovarii, composed exclusively of a follicular variant of papillary thyroid carcinoma with capsular invasion, which occurred in a 65-yr-old woman.     

Real-time analysis of beta- and gamma-catenin mRNA expression in ret/PTC-1 activated and nonactivated thyroid tissues.

Our group has previously demonstrated an association between ret/PTC-1 activation and decreased E-cadherin mRNA levels in papillary thyroid carcinoma. We also observed similarities in the E-cadherin expression profiles of Hashimoto thyroiditis and ret/PTC-1-positive papillary thyroid carcinomas and have hypothesized that ret/PTC-1 activation might cause not only the structural and nuclear peculiarities of PTC but also an immune reaction to thyroid epithelium. The objective of this study was to examine the expression of E-cadherin's ligands, beta- and gamma-catenin, in various thyroid tissue types in the context of ret/PTC-1 positivity using laser capture microdissection and TaqMan (Applied Biosystems, Foster City, CA). One-Step RT-PCR. Beta-catenin mRNA levels were found to be consistently decreased in both papillary and anaplastic carcinomas when compared with a normal/follicular adenoma group. A significant difference in expression levels was observed between papillary and follicular thyroid carcinomas with the latter having elevated mRNA levels of beta-catenin. Gamma-catenin mRNA was decreased in anaplastic carcinomas compared with normal/follicular adenoma groups. A similar expression profile of gamma-catenin as beta-catenin was observed in papillary and follicular carcinomas with the latter once again having higher mRNA levels. These results therefore suggest that although beta- and gamma-catenin may play a role in the progression of thyroid cancer in general, they do not appear to be associated with ret/PTC-1-modulated pathways.     

Diagnostic usefulness of HBME1, galectin-3, CK19, and CITED1 and evaluation of their expression in encapsulated lesions with questionable features of papillary thyroid carcinoma

We evaluated HBME1, galectin-3 (GAL3), cytokeratin (CK)19, and a new anti-CITED1 antibody in 127 follicular adenoma (FA) and papillary thyroid carcinoma (PTC) cases. The findings were used to evaluate 11 diagnostically challenging encapsulated follicular lesions with questionable features of PTC (FL/QPTC). All 4 markers showed higher expression in PTC than FA. HBME1 was the most specific (96%), whereas CK19 was the most sensitive (96%). In addition, 100% specificity was seen with coexpression of HBME1/CK19. Negative expression of all 4 markers was 97% specific for FA. GAL3 and CITED1, less useful individually, could help in selective cases. FL/QPTC showed heterogeneous, often intermediate, staining patterns, implying that some FL/QPTCs may be biologically borderline lesions or represent a biologic spectrum of PTC. These antibodies can have a confirmatory role in distinguishing the follicular variant of PTC and FA. For FL/QPTC, these antibodies are helpful in some cases, their limitation perhaps suggesting the biologic ambiguity of these lesions.     

RAS Mutation-Positive Follicular Variant of Papillary Thyroid Carcinoma Arising in a Struma Ovarii

Struma ovarii is an ovarian mature teratoma composed exclusively or predominantly of thyroid tissue. Malignant transformation of struma ovarii is rare and poorly understood, although this process is thought to be similar to carcinogenesis in malignant tumors of differentiated thyroid tissue originating in the thyroid gland. Genetic alterations in the mitogen-activated protein kinase pathway, including mutations of BRAF, RAS, and RET genes, have been implicated in the development of differentiated thyroid carcinoma arising in the thyroid gland. We report here a case with RAS mutation detected in a malignant struma ovarii. The patient is a 38-year-old female who had a 2.4 cm ovarian cyst noted incidentally on a first trimester ultrasound. She proceeded to ovarian cystectomy post-delivery, with pathologic examination detecting a papillary thyroid carcinoma, follicular variant, arising in a cystic teratoma. The tumor was tested for BRAF, RAS, and RET/PTC mutations. HRAS codon 61 mutation was identified. This is the first report of RAS mutation detected in the follicular variant of papillary carcinoma arising in a struma ovarii. It provides evidence that tumors developing in this setting involve molecular mechanisms similar to those implicated in tumors developing in the thyroid gland.     

Papillary Thyroid Carcinoma with Predominant Spindle Cell Component: Report of Two Rare Cases and Discussion on the Differential Diagnosis with Other Spindled Thyroid Neoplasm

Spindle cell transformation or metaplasia has been so far demonstrated in the context of both benign and malignant conditions. Spindle cell lesions of the thyroid gland of either primary or secondary origin to metastatic disease represent rare entities. We describe two patients with papillary thyroid carcinoma (PTC) showing spindle cell metaplasia, submitted to thyroidectomy due to euthyroid bilateral nodular thyroid disease. Cytological examination of fine-needle aspiration biopsy performed in the dominant nodules was consistent with follicular neoplasm in one case and with a hyperplastic/adenomatous nodule in the other patient. Histological examination disclosed unencapsulated follicular variant of PTC with spindle cell metaplasia in either cases. Both patients are doing well without clinical or laboratory evidence of PTC recurrence at 3- and 1-year follow-up, respectively. We present the clinical, pathological, and immunohistochemical aspects of these unusual cases and thoroughly discuss the differential diagnosis with other spindle cell lesions of the thyroid gland.     

The p75 neurotrophin receptor is widely expressed in conventional papillary thyroid carcinoma

Papillary thyroid carcinomas (PTCs) are associated with alterations in several proto-oncogenes related with nervous system development and function, such as TrkA and RET, which are commonly rearranged in these carcinomas. The other oncogenic event recently identified in PTC is the BRAF V600E mutation. Because the role of TrkA was not completely elucidated in thyroid cancer ethiopathogenesis, we decided to study the expression of active, phosphorylated TrkA and of its coreceptor p75 neurotrophin receptor (p75 NTR) in a series of 92 PTC (37 lesions of conventional PTC, 28 of follicular variant of PTC [FVPTC], and 27 of other variants of PTC) as well as in 21 samples of normal thyroid and nonneoplastic thyroid lesions used as a controls. We observed neoexpression of p75 NTR in PTC, particularly in conventional PTC and in other variants of PTC displaying a papillary growth pattern, rather than in FVPTC. No immunoexpression of p75 NTR was observed in normal thyroid nor in nonneoplastic thyroid lesions. The cellular localization of p75 NTR immunoexpression was also significantly associated with the growth pattern of PTC, being much more frequently detected in an apical localization in PTC with papillary architecture than in PTC with a follicular or solid growth pattern. This apical localization of p75 NTR was significantly associated with the presence of BRAF V600E. No significant differences were detected between normal thyroid, nonneoplastic lesions, and PTC (or any PTC variant) regarding expression/activation of TrkA, thus suggesting that by itself and in contrast to p75 NTR, TrkA is not altered during PTC development.     

The triage efficacy of fine needle aspiration biopsy for follicular variant of papillary thyroid carcinoma using the Bethesda reporting guidelines

Diagnosis of follicular variant of papillary thyroid carcinoma (FVPTC) by ultrasound-guided fine-needle aspiration (FNA) is challenging. In this retrospective review, we evaluated triage efficacy (i.e., potential for triggering surgical intervention) in 44 archived FNA biopsies of surgically confirmed FVPTC obtained between December 2006 and December 2008. We compared the original FNA diagnoses with reclassified diagnoses based on 2007 National Cancer Institute (NCI)/Bethesda recommendations, and reviewed FNA cytologic features. Original FNA diagnoses included colloid nodule (7%, 3/44), atypical follicular cells (5%, 2/44), follicular lesion (11%, 5/44), follicular neoplasm (16%, 7/44), suspicious for malignancy/PTC (27%, 12/44), and papillary thyroid carcinoma (34%, 15/44). Reclassified diagnoses included indeterminate (5%, 2/44), colloid nodule (7%, 3/44), atypical cells of undetermined significance [ACUS] (7%, 3/44), Hurthle cell neoplasm (2%, 1/44), follicular neoplasm (7%, 3/44), suspicious for malignancy/PTC (25%, 11/44), and PTC (48%, 21/44). Triage efficacy was 77% (34/44) for original diagnoses versus 82% (36/44) for reclassified FNA diagnoses. We frequently observed cytologic features of PTC, such as nuclear grooves and fine chromatin; conversely, intranuclear inclusions, though present in 77% cases, were scant. Our review findings suggest that lack of characteristic cytologic features of PTC,coexistence with other thyroid lesions, and small tumor size arethe major obstacles to FNA diagnosis of FVPTC. Reclassification of thyroid FNA diagnoses does not significantly improve triage efficacy. Furthermore, FNA diagnoses of follicular neoplasm and suspicious for malignancy are valuable in patients with FVPTC because they trigger triage toward surgical intervention.     

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.     

Immunohistochemical study of papillary thyroid carcinoma and possible papillary thyroid carcinoma-related benign thyroid nodules

Recent immunohistochemical studies have identified different antisera that have various degrees of sensitivity and specificity for papillary thyroid carcinoma (PTC). In this study, we performed immunostaining for CK, EMA, HBME, CD57 and CD15 in PTC, and benign thyroid nodular lesions to compare the sensitivity and the specificity of these antisera for PTC. In addition, we studied the patterns of immunostaining of these antisera in benign nodular thyroid lesions displaying a fine chromatin pattern, foci of cells with nuclear grooves, and optically clear nuclei. Fifty-five PTC (composed of 30 papillary variants and 25 follicular variants), 5 follicular carcinomas, 30 follicular adenomas, and 20 thyroid nodular lesions (5 papillary variants and 15 follicular variants) were submitted for immunostaining with CK, EMA, HBME, CD57, and CD15. CK and HBME showed the highest sensitivity and specificity for PTC when an arbitrary cutoff of more than 10% positive cells was considered as positive diagnostic immunostaining for these sera. The other antisera were less sensitive and less specific. One case of PTC showed negative HBME but positive CD15, whereas three papillary variants and two follicular variants of benign thyroid nodules revealed a positive diagnostic HBME immunostaining for PTC and negative CK immunostaining. Any combination of positive diagnostic immunostaining with CK+ HBME, CK+ CD57 or CK+ CD15 has a sensitivity of 95% and specificity of 90% for PTC. Thyroid nodules with a diffuse or focal fine chromatin pattern and focal areas with nuclear grooves or optically clear nuclei displayed immunoreactivity ranging from 0% to 50% of cells. Three of five follicular carcinomas showed negative reactivity for HBME, CD57, and CD15. A combination of immunostaining with CK, HBME and CD57 (or CD15) is a sensitive and specific test for PTC. This panel can be used to rule out thyroid nodules posing a diagnostic problem with PTC. Follicular adenoma and nodules of the thyroid, with a fine chromatin pattern and focal nuclear grooves or optically clear nuclei, displayed an intermediate range of reactivity between reactive thyroid tissue and PTC.     

Follicular patterned lesions of the thyroid gland: a practical algorithmic approach

Follicular patterned lesions of the thyroid are problematic and interpretation is often subjective. While thyroid experts are comfortable with their own criteria and thresholds, those encountering these lesions sporadically have a degree of uncertainty with a proportion of cases. The purpose of this review is to highlight the importance of proper diligent sampling of an encapsulated thyroid lesion (in totality in many cases), examination for capsular and vascular invasion, and finally the assessment of nuclear changes that are pathognomonic of papillary thyroid carcinoma (PTC). Based on these established criteria, an algorithmic approach is suggested using known, accepted terminology. The importance of unequivocal, clear-cut nuclear features of PTC as opposed to inconclusive features is stressed. If the nuclear features in an encapsulated, non-invasive follicular patterned lesion fall short of those encountered in classical PTC, but nonetheless are still worrying or concerning, the term 'uncertain malignant potential or behaviour, most likely benign' is suggested. Indubitable, classical PTC nuclei (whether diffuse or restricted to a single high-power field) are diagnostic of a PTC be it classical, non-invasive or invasive follicular variant PTC. Capsular and vascular invasion remain the only reliable predictors of outcome, as non-invasive, encapsulated follicular variant PTC, even with diffuse PTC nuclear change, behaves in an indolent fashion.     

Paraganglioma‐like medullary thyroid carcinoma: A case report and literature review

Medullary thyroid carcinoma (MTC) accounts for 3%‐5% of all thyroid malignancies. Most MTC can be diagnosed by their typical cytologic and histologic morphology and immunohistochemical features. However, some rare variants of MTC may pose diagnostic difficulties on both cytology and histology. Paraganglioma‐like MTC (PLMTC) is a rare, but widely recognized variant of MTC. PLMTC is known to share morphological and architectural similarities with paraganglioma, hyalinizing trabecular tumor, and carcinomas of thyroid follicular cell origin, such as follicular carcinoma and follicular variant of papillary thyroid carcinoma. The combination of clinicopathologic features and a battery of immunohistochemical markers is essential for making a correct diagnosis. Herein, we report one case of PLMTC with both cytologic and histologic features and review the clinicopathologic features of previously reported cases.