Diagnosis Of Follicular Thyroid Carcinoma Research Articles

Establishing the First Diagnosis of Follicular Thyroid Carcinoma From the Femoral Metastatic Site in an 84-Year-Old Woman

Follicular thyroid carcinoma (FTC) commonly presents as a solitary thyroid nodule, which is diagnosed by thorough examination of thyroidectomy/lobectomy specimen for capsular and vascular invasions. First diagnosis of FTC from femoral metastasis is very rare. Here, we report such a case in an 84-year-old woman who presented with increasing pain in her left thigh. A bone scan revealed multiple lesions in the bones including left femur. Four years ago, the patient suffered right humeral pathological fracture. The humeral lesion was positive for TTF-1 and was interpreted as “metastatic non-small cell carcinoma consistent with lung primary”. However, subsequent bronchial washing and lung biopsy were negative for malignancy. Biopsy of left femoral lesion showed solid nests of cells with round to oval nuclei and abundant eosionophilic/granular cytoplasm. The nuclei of tumor cells contain one or more nucleoli and granular/vesicular chromatin. No typical nuclear morphology of papillary thyroid carcinoma (PTC) was noted. The tumor cells are positive for thyroglobulin and TTF-1, consistent with metastatic tumor from thyroid primary. Immunostains of HBME-1 and CK19 only mark scattered tumor cells, which do not support the differential diagnosis of metastatic PTC. CD56 and CK7 stains are both positive. Upon further communication, patient's remote history of “thyroid follicular adenoma”, status post right lobectomy was obtained. The femoral lesion was negative for BRAF mutation. In conclusion, based on the overall morphological and immunohistochemical features as well as patient’s history, the final diagnosis of metastatic FTC was made. We would like to raise the awareness that metastatic FTC should be included in the differential diagnoses for tumors metastasized to bone to avoid misdiagnosis.

Expression of Matrix Metalloproteinase-2, but not Caspase-3, Facilitates Distinction between Benign and Malignant Thyroid Follicular Neoplasms

Definite diagnosis of follicular thyroid carcinoma (FTC) is based on the presence of capsular or vascular invasion. To date, no reliable and practical method has been introduced to discriminate this malignant neoplasm from follicular thyroid adenoma (FTA) in fine needle aspiration biopsy material. Matrix metalloproteinase-2 (MMP-2), by degrading extracellular matrix, and caspase-3, by induction of apoptosis, have been shown to play important roles in carcinogenesis and aggressive behavior in many tumor types. The aim of this study was to examine expression of MMP-2 and caspase-3 in thyroid follicular neoplasms and to determine their usefulness for differential diagnosis. Sixty FTAs and 41 FTCs were analysed immunohistochemically for MMP-2 and caspase-3. MMP-2 was positive in 4 FTCs (9.8%), but in none of FTAs, with statistical significance (p=0.025). Caspase-3 was positive in 30 (50%) of FTAs and in 27 (65.9%) of FTCs. Our results show MMP-2 expression only in FTCs and suggest that this protein may be a useful marker to confirm diagnosis of FTC versus FTA with 100% specificity and 100% predictive value of a positive test. We failed to show any differential diagnostic value for caspase-3 in thyroid follicular neoplasms.

The Role of CD147 in the Invasiveness of Follicular Thyroid Carcinoma Cells

In patients without metastases, capsular and vascular invasion must be noted to make the diagnosis of follicular thyroid carcinoma (FTC). Some patients are initially diagnosed as follicular adenoma (FA) but develop metastases, indicating the original lesion was FTC. A diagnostic marker for FTCs that appear to be FAs by conventional histopathology is urgently needed. CD147 is a transmembrane glycoprotein that induces matrix metalloproteinases (MMPs) and participates in carcinoma invasion. The objective of this study was to determine whether CD147 is upregulated in FTC and if measures directed against it could reduce the invasive activity of FTC cells. The expression levels of CD147, MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9 in surgical specimens of normal thyroid (n=8), FA (n=20), and FTC (n=9) was determined using immunoblot and immunohistochemical techniques. CD147 protein expression levels of epithelial growth factor stimulated FTC-133 cell lines was measured by immunoblotting with and without cell signaling inhibitors such as wortmannin, PD98059, SP600125, and SB203580. This was also done after exposure to short-hairpin interference RNA directed against CD147. Immunoblot analysis of thyroid tissues revealed significant increases in signals for CD147, MMP-3, MMP-7, and MMP-9 in FTC compared with FA or normal tissue, or both. Immunohistochemical analysis revealed colocalization of determinants of CD147 with those of all of MMPs studied, mainly in follicular cells in normal and neoplastic cells in FA and FTC; their immunoreactivities were to some extent more intense in the FTC than FA or normals. In FTC-133 cells, immunoreactive signals for CD147 were upregulated by epidermal growth factor (EGF), and the EGF-driven increases in CD147 were prevented by inhibitors against phosphoinositol-3 kinase (PI3K), extracellular signal-regulated protein kinase (ERK), or c-Jun N-terminal kinase (JNK) but not p38. RNA interference targeted against CD147 reduced the invasive activity of FTC-133 cells and was associated with downregulation of MMP-2, MMP-3, MMP-7, and MMP-9. These results provide in vivo evidence for CD147 upregulation in FTC and in vitro evidence for EGF-stimulated CD147 induction via the PI3K, ERK, and JNK pathways. They suggest the involvement of CD147 in the invasiveness of FTC cells via regulation of MMPs.

A Follicular Thyroid Carcinoma Presenting as Single Bone Metastasis to Distal Femur with Pathologic Fracture: a Case Report

Follicular carcinomas are the second most common form of thyroid cancer. There are a few cases regarding initial presentation of a patient with distant metastasis leading to the diagnosis of follicular thyroid carcinoma. Most follicular thyroid carcinomas present as asymptomatic thyr oid nodules, but the first sign of the disease is occasionally lymph-node metastases or in rare cases lung or bone metastases. Thirteen percentage of patients had distant metastasis at presentation, and bone metastasis constituted the majority. Vertebrae, pelvis, ribs, and femur were common sites of bone metastasis. Thus, cas e of metastasis to the femur only from follicular thyroid carcinoma is very rare. We recently experienced a case of follicular thyroid carcinoma with metastasis to the femur who presented with bone pain and pathologic fracture. We present this case with a review of the literature.

BRAFK601E Mutation in a Patient with a Follicular Thyroid Carcinoma

BRAF mutations, the most common genetic alteration associated with papillary thyroid carcinoma (PTC), have never been associated with follicular thyroid carcinoma (FTC) except for one possible case, which, however, had some cellular features of the follicular variant of PTC. Here, we present a patient with a BRAF mutation within a FTC. A 78-year-old man presented with a nodular lesion 8 cm in size in the right thyroid lobe, coexisting with a goiter. Fine-needle aspiration samples were obtained for cytology, immunocytology, and molecular analysis. Immunoblot analysis on thyroid tissues was performed to evaluate the most important tumor activating pathways. Cytology was consistent with "follicular neoplasia" (negative for galectin-3 immunostaining); molecular analysis on the cytology sample detected a K601E mutation in the exon 15 of the BRAF gene. After total thyroidectomy with lymph-node dissection, the diagnosis of FTC was established by histopathological examination. The BRAF(K601E) mutation was confirmed in DNA obtained from different areas of the FTC. In addition, an activating mutation (E545A) in the PKI3CA oncogene was found in the FTC. As expected, immunoblot analysis showed activation of the PI3K/Akt pathway. This article describes what may be the first case of a classical FTC carrying a BRAF mutation. Unlike the most common BRAF mutation seen in PTC carcinoma (BRAF(V600E)), this patient's mutation was a BRAF(K601E) mutation that previously has been associated with some cases of the follicular variant of PTC. The BRAF(K601E) mutation should be included in the spectrum of genetic alterations in FTC.

Larger tumor size predicts nodal involvement in patients with follicular thyroid carcinoma

Lymph node metastases are rare in patients with follicular thyroid carcinoma, with an average incidence of 5.5% of all cases reported in the literature. In the present study we focused on the search for risk factors predictive of lymph node involvement in patients with follicular thyroid carcinoma to plan the most appropriate management and follow-up. We carried out a cross-sectional study among patients with follicular thyroid carcinoma and lymph node metastasis at diagnosis and patients without lymph node involvement. From January 1998 to April 2008, 930 patients underwent thyroidectomy in our surgical department for a variety of thyroid disorders, 420 (45.2%) of them for a differentiated thyroid carcinoma. The medical records of 55 patients with histological diagnosis of follicular thyroid carcinoma were analyzed. Four patients (7.3%) had lymph node metastasis from follicular thyroid carcinoma at presentation in both the lateral and central neck compartments. Mean tumor size was significantly greater for follicular thyroid carcinomas with nodal metastasis (5.1 ± 1.4 cm) than for those without nodal involvement (3.0 ± 1.2 cm, P <0.010). Among factors supposed to influence the presence of nodal metastasis at diagnosis (age, gender, tumor size, multifocality, tumor poorly differentiated, tumor widely invasive, vascular invasion, thyroid capsular invasion, and extra thyroid invasion), tumor size larger than 4.0 cm was the only factor retained in the multivariate statistical model. Lymph node dissection must be planned only in the case of large follicular thyroid carcinomas. Since follicular carcinoma is usually diagnosed postoperatively, more attention should be paid to nodal involvement in the tumor re-staging during follow-up of those patients with tumors larger than 4.0 cm in diameter.

The fifteen percent issue in molecular-based diagnosis of follicular thyroid carcinoma

Pathology InternationalVolume 61, Issue 3 p. 165-166 The fifteen percent issue in molecular-based diagnosis of follicular thyroid carcinoma Toru Takano, Toru Takano Department of Laboratory Medicine, Osaka University Graduate School of Medicine D2, 2-2 Yamadaoka, Suita, Osaka 565-0871 JapanSearch for more papers by this author Toru Takano, Toru Takano Department of Laboratory Medicine, Osaka University Graduate School of Medicine D2, 2-2 Yamadaoka, Suita, Osaka 565-0871 JapanSearch for more papers by this author First published: 01 March 2011 https://doi.org/10.1111/j.1440-1827.2010.02622.xCitations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume61, Issue3March 2011Pages 165-166 RelatedInformation

Diminishing diagnosis of follicular thyroid carcinoma

Follicular carcinomas have been reported as 10% to 15% of thyroid malignancies. Refinements in the histologic criteria applied in the classification of follicular lesions have occurred. We aim to document the true incidence of follicular cancers in a cohort from a high-volume endocrine practice. Patient charts were reviewed and cancers were classified into major subtypes; papillary cancers were further classified by common variants. Proportions were compared to historic Surveillance, Epidemiology, and End Results (SEER) database proportions. Only 2.7% of patients had follicular carcinoma. The proportion of patients with follicular cancer was less than the reported rates of 10% to 15%, and less than the 6.7% extrapolated from SEER. The proportion of follicular cancers is less than traditionally reported. This change is due to an increased incidence of papillary cancers, and modifications of the histologic criteria used for classification of encapsulated follicular lesions. There are potential prognostic consequences, as follicular cancers have been perceived as more aggressive.

Molecular signatures of thyroid follicular neoplasia

The molecular pathways leading to thyroid follicular neoplasia are incompletely understood, and the diagnosis of follicular tumors is a clinical challenge. To provide leads to the pathogenesis and diagnosis of the tumors, we examined the global transcriptome signatures of follicular thyroid carcinoma (FC) and normofollicular adenoma (FA) as well as fetal/microFA (fetal adenoma). Carcinomas were strongly enriched in transcripts encoding proteins involved in DNA replication and mitosis corresponding to increased number of proliferating cells and depleted number of transcripts encoding factors involved in growth arrest and apoptosis. In the latter group, the combined loss of transcripts encoding the nuclear orphan receptors NR4A1 and NR4A3, which were recently shown to play a causal role in hematopoetic neoplasia, was noteworthy. The analysis of differentially expressed transcripts provided a mechanism for cancer progression, which is why we exploited the results in order to generate a molecular classifier that could identify 95% of all carcinomas. Validation employing public domain and cross-platform data demonstrated that the signature was robust and could diagnose follicular nodules originating from different geographical locations and platforms with similar accuracy. We came to the conclusion that down-regulation of factors involved in growth arrest and apoptosis may represent a decisive step in the pathogenesis of FC. Moreover, the described molecular pathways provide an accurate and robust genetic signature for the diagnosis of FA and FC.

Pituitary Metastases from Follicular Thyroid Carcinoma

Metastatic carcinomas to the pituitary gland are uncommon, occurring in only 1% of the pituitary masses. They often originate from breast or lung carcinomas and may resemble a nonfunctioning pituitary adenoma both clinically and radiologically. Here we describe a patient with pituitary metastasis from follicular thyroid carcinoma and discuss the unique features of these lesions. A 45-year-old woman was admitted to the emergency rescue room of our hospital with a 2-month history of progressive headache and blurred vision. Evaluation revealed right eye amaurosis, with a mild abducens and oculomotor palsy. Pituitary magnetic resonance imaging showed a mass that was hypo-intense in T1-weighted and hyper-intense in T2-weighted-images, located from the sphenoid sinus up to chiasmatic cisterns, raising and deflecting the optic chiasm, down to hypopharynx region, and distorting the cavernous sinuses. No evidence of anterior or posterior hypopituitarism was recorded. The immediate trans-sphenoidal surgery was uncomplicated with partial improvement of the visual fields and headache. Histopathology revealed a metastasis with well-differentiated follicular thyroid architecture. Total thyroidectomy and lymph node dissection was performed with a final histopathological diagnosis of follicular thyroid carcinoma. Subsequently, her headache became more severe. 131-I ablation treatments were performed 15 days and 12 months after thyroidectomy with decrease in headache and a decline in serum thyroglobulin levels. Pituitary metastases from thyroid carcinoma are very uncommon. As this patient illustrates, they tend to produce symptoms relating to space-occupying expansion in the parasellar region rather than to those due to destruction of the pituitary gland. Although rare, pituitary metastases caused by thyroid malignancy should be considered in patients with expanding parasellar lesions if they have thyroid cancer or uncharacterized thyroid diseases. They are unlikely to be amenable to complete resection and should be considered for 131-I treatment, perhaps avoiding the need for extensive neurological surgery.

A PCR-based expression signature of malignancy in follicular thyroid tumors

The diagnosis of follicular thyroid carcinoma (FTC) in the absence of metastasis can only be established postoperatively. Moreover, high-risk FTCs are often not identifiable at the time of diagnosis. In this study, we aimed to identify transcriptional markers of malignancy and high-risk disease in follicular thyroid tumors. The expression levels of 26 potential markers of malignancy were determined in a panel of 75 follicular thyroid tumors by a TaqMan quantitative RT-PCR approach. Logistic regression analysis (LRA) was used for gene selection and generation of diagnostic and prognostic algorithms. An algorithm based on the expression levels of five genes (TERT, TFF3, PPARgamma, CITED1, and EGR2) could effectively predict high-risk disease with a specificity of 98.5%. The metastatic potential could be predicted in all four cases with apparently benign or minimally invasive (MI) disease at the time of diagnosis, but poor long-term outcome. In addition, a second model was produced by implementing two genes (TERT and TFF3), which was able to distinguish adenomas from de facto carcinomas. When this model was tested in an independent series of atypical adenomas (AFTA) and MI-FTCs, 16 out of 17 AFTAs were classified as 'benign', while MI-FTCs with vascular invasion (sometimes referred to as 'moderately invasive') and/or large tumor size tended to classify in the 'malignant' group. The reported models can be the foundation for the development of reliable preoperative diagnostic and prognostic tests that can guide the therapeutic approach of follicular thyroid neoplasms with indeterminate cytology.

Cytoarchitectural and kinetic features in the histological evaluation of follicular thyroid neoplasms

The diagnosis of follicular thyroid carcinomas is mainly based on capsular and vascular invasion. The aim of this study was to determine the diagnostic relevance of nuclear features, inflammation and stromal changes. Anisokaryosis, chromatin pattern, nucleolus, nuclear pleomorphism, nuclear/cytoplasmic ratio, necrosis, stromal changes and tumour interstitial lymphocytes (TIL) were analysed in adenomatous hyperplastic nodules (39), adenomas (43) and carcinomas (28 minimally invasive, 48 widely invasive and 27 anaplastic). Ki67 immunostaining, in situ end labelling (ISEL) for apoptosis and the Ki67/ISEL index were analysed by topographical compartments. Variables were compared by histological diagnosis using Fisher's exact test, analysis of variance and Student's t-tests and considered significant if P < 0.05. TIL were absent in 96% of neoplasms and 54% of adenomatous hyperplastic nodules. Conspicuous nucleoli, increased nuclear-cytoplasmic ratio and coexistent apoptosis-myxoid changes distinguished minimally invasive carcinomas from adenomas. The most specific variables of high-grade carcinoma were vasculonecrotic patterns, nuclear hyperchromatism and pleomorphism. A kinetic advantage predominated in the internal compartments of benign lesions and in the peripheral compartments of malignant lesions. Follicular carcinomas show up-regulation of proliferation markers and the distinctive topographical kinetic profiles provide a basis for the distinction between benign and malignant and an explanation for the circumscription and encapsulation of benign lesions.

Telomerase activity in fine needle aspiration biopsy samples: Application to diagnosis of human thyroid carcinoma

Background The diagnosis of thyroid follicular carcinoma by fine needle aspiration biopsy is a well known problem in thyroid pathology. Methods We evaluated telomerase activity (TA) in 85 fine needle aspiration biopsy (FNAB) samples from patients with thyroid nodules. Surgery samples from patients with tumor or follicular adenomas were also analyzed. Results Twenty of the FNAB samples corresponded to carcinomas and were positive to telomerase assay (TA > 10 Units). Among them, 4 follicular carcinomas and 1 papillary carcinoma were labeled as indeterminate by FNAB cytological examination. Four percent false positive cases and no false negative cases for TA in FNABs were reported. FNAB samples from follicular adenomas were diagnosed as indeterminate by cytological examination, but they showed no detectable TA. Tumor tissues from patients with follicular or papillary thyroid carcinomas presented TA > 10 Units, whereas follicular adenoma tissues (benign nodules) showed no TA. Conclusion Our results showed a good correlation between TA in FNAB samples and tumor/nodule thyroid tissue. This suggested that use of TA as a biological marker of malignancy might be a useful tool in the diagnosis of follicular thyroid carcinomas or follicular thyroid adenomas using FNAB samples.

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.

Follicular Thyroid Carcinoma: From Diagnosis to Treatment

Unusual presentations with bone, lung or soft tissue metastases in initial diagnosis of follicular thyroid carcinoma have been reported occasionally. This implies how difficult it is to diagnosis this type of cancer at the pre-operative or intra-operative stage of treatment. Fine needle aspiration cytology has been shown to be an ineffective method for diagnosing vascular or capsule invasion of follicular thyroid cancer. Multiple frozen sections, usually 5 to 12 depending on the size of the tumor, can achieve a diagnostic accuracy of 98%. Clinical application of various gene expressions in thyroid follicular tumors by needle aspiration using in situ hybridization requires further investigation. Although radioactive iodide (131I) has been used as the standard treatment for follicular thyroid carcinoma with distant metastases, the effectiveness of 131I treatment for follicular thyroid carcinoma depends on the differentiation of cancer cells. The possibility of 131I for thyroid remnant ablation replacing a secondary operation for follicular thyroid carcinoma has been debated. Recent studies applied more expressions of sodium iodide symporters to attain the effect of 131I treatment and slow the proliferation of thyroid cancer cell which, in turn, slows the progression of follicular carcinoma. Consensus for the surgical procedures for the specific prognostic risks for follicular thyroid carcinoma is needed. Dedifferentiated, anti-angiogenic, or gene therapies for follicular thyroid cancer with distant metastases or anaplastic transformation comprise the principal directions in future research for this cancer.

HBME-1 and cyclin D1 as diagnostic markers for follicular thyroid carcinoma

Follicular carcinomas account for 15% of thyroid malignant tumors. The differential diagnosis between adenoma and minimally invasive follicular carcinoma is difficult and lacks reproducibility especially in frozen sections. As the diagnosis depends on finding foci of capsular invasion, multiple sections must be examined. Numerous immunohistochemical markers have been studied for determining malignancy. To assess the efficacy of HBME-1 and Cyclin-D1 as diagnostic markers for follicular thyroid carcinoma. We evaluated retrospectively 21 thyroidectomy specimens of 18 women and 3 men with diagnosis of adenoma or follicular carcinomas, both by hematoxylin and eosin stain and by immunohistochemistry using the avidin biotin method for the markers HBME-1 and Cyclin D1. The sensitivity and specificity of HBME-1 for the diagnosis of follicular thyroid carcinoma, were 88.9% and 100%, respectively whereas for Cyclin D1 the sensitivity and specificity were 22.2% and 100%, respectively. There were no false positive cases. HBME-1 has excellent sensitivity and specificity for the diagnosis of follicular carcinoma.