Thyroid-like Follicular Carcinoma of the Kidney: The Follicles Are out There in the Kidney-Now What?

Metastatic thyroid follicular carcinoma presenting as pathological left clavicle fracture: An unusual skeletal metastasis at the time of diagnosis

Concurrent skull and liver metastases from follicular thyroid carcinoma is a very rare event. We herein present the case of a 72-year-old woman who initially presented with a swelling in the right supraorbital region that proved to be metastasis from a well-differentiated follicular thyroid carcinoma of clear-cell type. The metastatic workup disclosed a huge liver metastasis and an additional metastasis in the left iliac fossa. The treatment of this patient included a total thyroidectomy, an excision of the skull lesion, and the administration of radioiodine therapy, as well as thyroid-stimulating hormone (TSH) suppression therapy. However, the course of her disease was relentless. Although well-differentiated thyroid carcinoma tends to show an excellent course, the presence of metastatic disease leads to a very dismal prognosis.

To study the roles of matrix metalloproteinases-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), vascular endothelial growth factor (VEGF) and transforming growth factor β-1 (TGFβ-1) in differentiation, invasiveness and metastatic potential of papillary carcinoma and follicular carcinoma of thyroid. Eighty-five cases of papillary thyroid carcinoma and 59 cases of follicular thyroid carcinoma were enrolled into the study. Immunohistochemistry using EnVision method was carried out for assessment of the expression of MMP-9, TIMP-1, VEGF and TGFβ-1 in the tumor tissue. MMP-9, TIMP-1, VEGF and TGFβ-1 were expressed in the cytoplasm of tumor cells. The positivity rates of MMP-9, TIMP-1, VEGF and TGFβ-1 in papillary thyroid carcinoma (83.5%, 81.2%, 90.6% and 75.3%, respectively) were similar to or lower than those in follicular thyroid carcinoma (93.2%, 86.4%, 89.9% and 78.0%, respectively). The expression rates in papillary thyroid carcinoma with lymph node metastasis were also higher than those in tumors without lymph node metastasis. The expression rates of MMP-9, VEGF and TGFβ-1 in poorly-differentiated follicular thyroid carcinoma were higher than those in well-differentiated follicular thyroid carcinoma. The expression of TIMP-1 however showed a negative correlation with the tumor cell differentiation. In general, the expression of VEGF and MMP-9 was higher than that of TIMP-1 and TGFβ-1 in papillary thyroid carcinoma and follicular thyroid carcinoma. Immunohistochemical detection of MMP-9, TIMP-1, VEGF and TGFβ-1 expression may carry clinical significance in evaluating the degree of differentiation, invasiveness, metastatic potential and prognosis of papillary thyroid carcinoma and follicular thyroid carcinoma.

NDRG1 protein overexpression in malignant thyroid neoplasms

There is limited clinical information of Chinese patients with occult well-differentiated thyroid cancer (OTC). The purposes of this study were to elucidate the clinical presentations and results of treatment in the patients with OTC in Taiwan. The data of 568 patients with pathologically verified papillary and follicular thyroid carcinomas who received primary treatment in Chang Gung Memorial Hospital were retrospectively reviewed. Seventy-four of 568 patients with well-differentiated thyroid carcinoma were OTC; those included 71 papillary thyroid carcinomas and three follicular carcinomas. Among the 74 OTC patients, five cases (6.8%) presented with distant metastases, but 41 cases (10.1%) were found with distant metastases in 416 nonoccult thyroid cancer (NOTC) (p = 0.509). In the five OTC with distant metastases, there were three papillary carcinomas and two follicular carcinomas. Only one case (1.4%) died of distant metastasis of the occult papillary thyroid carcinoma versus 20 cases out of the total 568 (4.1%) well-differentiated thyroid carcinomas. After statistical analysis, there were no differences between the survival rates of OTC and NOTC patients. In the present study, 1 month postoperative serum thyroglobulin level could be used as prognostic factor in both OTC and NOTC patients. Only 54.17% of OTC patients were diagnosed as thyroid cancer by thyroid ultrasonography with the fine needle aspiration cytology. In conclusion, most OTC had relatively benign clinical courses, but distant metastases may result in mortality still observed. Therefore, OTC should be treated as NOTC, since relatively high rate of distant metastases were found in the patients with OTC.

The prognosis of the follicular variant of papillary thyroid carcinoma (FVPTC) falls between that of classical papillary thyroid carcinoma (cPTC) and follicular thyroid carcinoma (FTC) (1). FVPTC has lower mortality and less frequent distant metastases than FTC, but higher mortality and more frequent distant metastases than cPTC. FVPTC has fewer lymph node metastases and less frequent infiltrative disease and extrathyroidal extension than cPTC, but more than FTC. But is it a hybrid disease or a mixture of diseases? The pathological appearance of a follicular-patterned tumor with the nuclear features of cPTC suggests that FVPTC is a hybrid. However, the heterogeneous nature of the disease and the mutational profile of FVPTC strongly suggest that it is a mixture of diseases (2). It is the intersection of classical descriptive pathology and modern molecular biology that permits an understanding of this group of diseases.

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 initial presentation of follicular thyroid carcinoma is rarely related to metastatic lesions. Presented here is the case of a 70-year-old woman with the initial presentation of a 13-cm chest wall mass identified as a metastatic follicular thyroid carcinoma. The chest wall lesion had features of a poorly differentiated carcinoma with areas of necrosis, an insular growth pattern focally and increased mitotic activity. A small follicular carcinoma was subsequently identified. The primary tumor was a 1-cm well-differentiated follicular carcinoma with capsular and vascular invasion. This represents a rare presentation of a follicular thyroid carcinoma with initial recognition of a large, dedifferentiated metastatic lesion from a small primary carcinoma. Dedifferentiation and metastasis in the context of microcarcinoma is an exceptionally rare event and suggests other mechanisms may be involved in disease spread other than simply increased cell proliferation.

Follicular Thyroid Tumors with the PAX8-PPARγ1 Rearrangement Display Characteristic Genetic Alterations

Follicular thyroid carcinoma is known to metastasize to distant places even before the primary follicular thyroid carcinoma is clinically obvious. One such unusual and distant metastasis of follicular thyroid carcinoma is its subcutaneous location. The present case report is an unusual one. A 50-year-old man with a history of trauma on the scalp developed non resolving hematoma. The swelling was soft with greenish discolouration to the skin over it. The swelling was soft with greenish discolouration to the skin over it. The Fine Needle Aspiration Cytology (FNAC) of the swelling revealed the classic cytomorphology of metastatic follicular thyroid carcinoma. The clinical examination of thyroid was normal at this juncture cytodiagnosis. The USG of the thyroid showed a deeply placed nodule of higher Thyroid Imaging Reporting & Data System (TIRAD). The FNAC from this nodule was also performed. The diagnosis of follicular neoplasm favoring follicular thyroid carcinoma was offered. The patient underwent thyroidectomy. The histological examination of tumor tissue was consistent with the diagnosis of thyroid follicular carcinoma. This case offers a unique insight into the non-resolving hematoma harboring the metastatic lesion of follicular thyroid carcinoma in the patient with the silent primary in the thyroid.

Cutaneous metastasis of follicular carcinoma of the thyroid is very rare, and when it occurs, can exhibit a variety of histologic appearances. The 4 cases presented here were identified from the surgical pathology files of the James Homer Wright Laboratories of Pathology at the Massachusetts General Hospital (MGH). The cases consisted of 4 patients, 3 men and 1 woman, aged 52 to 75 years, with cutaneous metastasis of follicular thyroid carcinoma. The tumors include a conventional follicular carcinoma, a follicular carcinoma with anaplastic transformation following initial metastasis, the first reported cutaneous metastases of a follicular carcinoma with oncocytic features (Hürthle cell carcinoma), and a follicular carcinoma with a prominent insular carcinoma component. All 4 tumors were widely invasive within the thyroid gland. Sites of dermal metastases included a post-thyroidectomy scar, scalp, and sacral skin. Three metastases retained the morphologic and immunocytochemical features of the primary thyroid tumors. However, in one case there was high-grade transformation to anaplastic carcinoma following treatment of a sacral metastasis with accompanying loss of the characteristic immunophenotype of follicular thyroid carcinoma. Awareness of the varied morphologies of metastatic follicular thyroid carcinoma to the skin may prompt immunohistochemical analysis and the request for a complete clinical history, ultimately preventing misdiagnosis.

Well-differentiated follicular thyroid carcinomas (FTCs) usually act indolently, while aggressively acting tumors are difficult to detect early enough. Estrogen receptors (ERs) have prognostic significance in many cancers. Thyroid diseases, including neoplasms, are associated with the female sex. The prognostic significance of ERs in FTCs has not been reported previously. We studied the role of ERα and ERβ in 83 cases of follicular thyroid adenoma (FTA) and 43 FTC cases, including seven cases of poorly differentiated FTC, obtained from the Department of Surgery, Helsinki University Central Hospital between 1990 and 2009. Patient follow-up was conducted until March 2011. Expression of ERα, ERβ, and MIB-1/Ki-67 was investigated by immunohistochemistry and correlated with clinicopathological characteristics, including survival. Two major observations were apparent. First, ERβ expression was significantly higher in FTA than in FTC, and it was a stronger differential diagnostic marker than MIB-1/Ki-67. Second, low ERβ expression correlated with poor survival in FTC. All cancer-specific deaths due to FTC were among low ERβ-score patients. ERβ is a differential marker for malignancy and could thus be used as a preoperative tool. FTC patients with a low ERβ score need more thorough follow-up and may benefit from more aggressive treatment.

Our medical discoveries often follow advancement in biologic techniques. The use of karyotypic analysis, fluorescent in situ hybridization, candidate gene sequencing, microarray expression analysis, and whole-genome associations has helped determine the molecular defects causing thyroid cancer. These and future discovered defects will allow clear classifications, precise prognosis, and targeted therapy. Genetic events involved in the development of well-differentiated papillary thyroid carcinoma (PTC) include rearrangement of the tyrosine receptor kinase (RET and TRK) and activating mutations of the intracellular signaling effectors (rat sarcoma oncogene) (B-type Raf kinase) and RAS. Rearrangement of PAX8 (paired box gene 8)/PPARγ (gamma) (peroxisome proliferator–activated receptor) and RAS mutations are frequent in well-differentiated follicular thyroid carcinoma (FTC). These mutations occasionally have been identified in benign follicular adenoma (FA). Also, loss of phosphate and tensin homolog (PTEN) and activation of PI3K/AKT (phosphoinositide-3-kinase/serine/thyreonine-specific protein kinase) are involved in FTC pathogenesis. Progression of PTC and FTC to anaplastic thyroid carcinoma (ATC) is associated with mutation of protein 53 (p53), β-catenin (beta), as well as members of PI3K/AKT pathway. Recent reports suggest that additional molecular mechanisms such as epigenetic modification and microRNA deregulation are involved in the development of thyroid tumorigenesis. This review summarizes the molecular characterization of thyroid cancer and the molecular mechanisms involved in thyroid carcinogenesis.

Background: Thyroid neoplasm is the commonest endocrine neoplasm. More than 80% of thyroid malignancies are papillary thyroid carcinoma (PTC) followed by follicular carcinoma (FC). The diagnosis of papillary thyroid carcinoma is based on characteristic nuclear morphology of a thyroid neoplasm. In contrast, follicular variant of PTC may cause, if the nuclear features of PTC are insufficiently appreciated, severe problems in differentiating from follicular thyroid carcinoma. Several immunohistochemical (IHC) markers such as P63 and CD56 have been recommended to differentiate between this two thyroid malignancies with overlapping histomorphology. Objectives: Our aim was to identify the possible diagnostic role of P63 and CD56 immunoexpression that distinguish PTC, including the follicular variant from follicular thyroid carcinoma. Methods: This cross-sectional descriptive study was conducted in the Department of Pathology, Rajshahi Medical College from March 2020 to February 2022. A total of 44 cases, histologically confirmed as papillary and follicular thyroid carcinoma were included in the study. Immunohistochemistry was done for P63 and CD56 from selected paraffin blocks. Results: Histologically, 39 cases were diagnosed as papillary thyroid carcinoma (27 were classical PTC &amp; 12 were FVPTC) and the rest 5 were follicular thyroid carcinoma. In this study, mean age of the patients was 40.86 ± 6.57 years (SD) and male to female ratio was 1:2.4. P63 showed 74.4% positivity with papillary thyroid carcinoma. Positive immunoreactivity of P63 was highly significant in distinguishing papillary from follicular thyroid carcinoma (P=0.003). Combined P63 positive CD56 negative (P=0.048) and P63 negative CD56 negative immunoexpression (P=0.039) were statistically significant in differentiating papillary from follicular thyroid carcinoma. Conclusion: This study suggested that the use of P63 and CD56 may be helpful in the diagnosis of papillary and follicular thyroid carcinoma along with histopathological examination and their combination may also help in this purpose.

To assess the expression of epithelial-mesenchymal transition (EMT) regulators in follicular thyroid tumours. The expression of E-cadherin (E-CAD) and transcription factors TWIST, SLUG and SNAIL in follicular thyroid tumours was examined by immunohistochemistry in tissue samples, including 18 follicular adenomas (FA), 12 minimally invasive follicular thyroid carcinomas (MI-FTC), 16 widely invasive follicular thyroid carcinomas (WI-FTC), 10 poorly differentiated follicular thyroid carcinomas (PDTC) and six anaplastic thyroid carcinomas (ATC). Metastatic tumour tissues from six of these cases were also examined. The results showed an increasing expression trend of EMT regulators in a panel of follicular tumour cases with a spectrum of morphological subtypes from low- to high-risk malignancy. The expression of EMT regulators was higher in the WI-FTC, PDTC and ATC groups but focal and lower in the FA and MI-FTC groups. Different expression intensity of E-CAD and EMT regulators at the tumour centre part and the invasive front (IF) was observed. The loss of E-CAD and expression of EMT regulators was significantly correlated with distant metastasis and vascular invasion (VI) in the well-differentiated follicular carcinoma (WD-FTC), and six tumours of metastatic sites also showed variables positive for EMT regulators. The disease-free survival analysis showed an apparent relationship between the expression of EMT regulators and the tumour disease-free outcomes in WD-FTC. Our study supported the role of EMT in the development of follicular thyroid carcinoma and indicated that EMT regulatory proteins may play an important role in WD-FTC that are widely invasive and exhibit distant metastasis.