Primary rhabdoid tumor of thyroid gland. Description of a rare entity with molecular study

To the Editor: The term malignant rhabdoid tumor (MRT) has been used to describe a heterogeneous group of neoplasms, having in common distinct so-called ‘rhabdoid’ cytologic features (large cells with abundant cytoplasm and eosinophilic globular inclusions that displace vesicular nuclei, central prominent nucleoli resulting in a plasmacytoid appearance).1,2 Malignant rhabdoid tumors have been described in different organs and occur at any age with poor prognosis. The discovery of a candidate tumor suppressor gene for MRT, hSNF5/INI1 (SMARCB1) on long arm of chromosome 22, has established this neoplasm as a distinct entity in renal and extrarenal sites.3 Malignant rhabdoid tumors may arise also in the thyroid gland but is very rare with only eight cases published to date.4–7 Also in these cases the morphologic hallmark was the presence of rhabdoid features with the characteristic cytoplasmic eosinophilic inclusions, ultrastructurally composed of whorls of intermediate filaments, that displaced the nuclei to the periphery. These rhabdoid inclusions should be distinguished from thyroglobulin inclusions that occur in follicular neoplasms and containing thyroglobulin.5 Unlike rhabdoid inclusions, they are periodic acid–Schiff, alcian blue positive and immunoreactive for thyroglobulin. Immunohistochemically, almost all of the rhabdoid cells are positive for vimentin and cytokeratins with variable expression of other markers as desmin, myoglobin, smooth muscle actin and sarcomeric actin; usually thyroglobulin and TTF-1 are negative.1,4–7 In the present report an additional case of primary RT of the thyroid with a molecular study for RET/PTC gene rearrangement and BRAF point mutation is described. A 61-year-old woman presented with dysphagia due to rapidly growing mass of the neck. An ultrasonography (US) scan of the neck showed an invasive tumor of the right lobe of thyroid gland. A needle aspirate of the mass revealed a non-cohesive population of large cells with abundant cytoplasm and eccentric nuclei, some with prominent nucleoli in an inflammatory background (Fig. 1a). A first diagnosis of undifferentiated carcinoma with rhabdoid features was made. Grossly the tumor involved the entire right lobe with irregular margins, solid greyish cut surface (Fig. 1b) and extra-thyroidal invasion. Histologically the thyroid mass was composed of a monomorphic population of non-cohesive large neoplastic cells with round vesicular eccentric nuclei, prominent central nucleolus and abundant cytoplasm with hyaline cytoplasmic inclusions (Fig. 1c). Atypical mitotic figures were present but not frequent (1–2 mitoses for 10 high power fields). Necrotic foci were prominent in some areas of mass. The tumor grew in a markedly aggressive manner, substituting and entrapping the follicular parenchyma of the thyroid and invading the neighboring cervical structure. After adequate sampling of the surgical specimen areas of differentiated carcinoma were found. Immunohistochemically, the neoplasm co-expressed vimentin and epithelial antigens (AE1/AE3, Cam 5.2, CK8, CK18), most of them showing a peculiar immunostaining pattern in relation to the globular inclusions (Fig. 2d). Immunostains for LCA, desmin, smooth muscle actin, S100 protein, TTF-1, myoglobin, calcitonin and thyroglobulin were negative. p53 protein labeled more than 80% of tumor cells (Fig. 2c)) and stain for Ki67 was 60–70% (Fig. 2b). In the literature the overexpression of p53 in the rhabdoid component of undifferentiated carcinoma have been considered as marker of poor prognosis and implicated in the tumor dedifferentiation.8 A final diagnosis of MRT of the thyroid gland (Stage pT4b) was made. After total thyroidectomy, the patient received external-beam radiotherapy to the neck (60 Gy total dose). The tumor recurred three months after surgery and metastasized to mediastinal lymph nodes and soft tissue of the neck. Systemic chemotherapy including ifosfamide, liposomal doxorubicin, Taxol and cisplatin was performed. The patient died 2 months later. Autopsy was not performed. (a) Grossly right lobe contained an invasive solid white mass (b) A needle aspirate of the mass revealed a non-cohesive population of large cells with abundant cytoplasm and eccentric nuclei, some with prominent nucleoli in an inflammatory background (Giemsa 20×). (c) Tumor was composed of non-cohesive large neoplastic cells with round eccentric nuclei, prominent central nucleolus and abundant cytoplasm with hyaline cytoplasmic inclusions. A residual atrophic follicleresulted entrapped in rhabdoid population (Hematoxylin-Eosin 40× ). (d) Rhabdoid tumor cells expressed Vimentin (Immunoperoxidase 20x). (a) p53 protein (Immunoperoxidase 20×) and (b) Ki67 expression in rhabdoid cells (Immunoperoxidase 20×). In our case a molecular analysis was assessed for the BRAF mutation and RET/PTC rearrangements that are the most common activating genetic alterations in the MAPK pathway in thyroid cancer. The BRAF mutation studied has been the V599E in exon 15 reported in approximately 45% of papillary thyroid carcinoma (PTC). For this analysis exons 11 and 15 of BRAF were separately amplified by methods previously reported.9 No BRAF point mutations were identified. For molecular studies, RET/PTC rearrangements were analyzed by RT-PCR using primers specific for RET/PTC1 and RET/PTC3 fusion genes how previously reported.9 In all tumor samples examined of pure rhabdoid tumor, RET/PTC1 and RET/PTC3 fusion transcripts were not found. To the best of our knowledge this is the second case of RT of the thyroid gland arising without a pre-existing differentiated (follicular or papillary) carcinoma and studied for RET/PTC gene rearrangement and BRAF point mutation. An analogous previous study of Lai et al. demonstrated the presence of RET/PTC3 rearrangement in blocks of pure rhabdoid tumor confirming a direct relationship of the rhabdoid tumor to this differentiated (papillary) component detected at histological level. The conclusion of this study is that RT represent a variant of ATC that may originate by dedifferentiation of a pre-existing differentiated carcinoma.6 In different series' of thyroid carcinoma comprising anaplastic carcinomas (ATC) assessed for RET/PTC rearrangement, RET activation of the differentiated tumors was detected only in a small group of ATC.10 These results indicate that the subset of RET/PTC-positive papillary carcinoma do not progress necessarily to less differentiated carcinoma or ATC. According to pathological and molecular data we conclude that MRT represent a distinctive type of undifferentiated thyroid carcinoma composed mainly of rhabdoid cells with overexpression of p53 protein. This rhabdoid phenotype recognizes a type of tumor with aggressive behavior, that has a tendency to develop rapidly metastases or recurrence and lack of responsiveness to radio- and chemotherapy. We think that this rhabdoid phenotype may arise in differentiated carcinoma through tumor progression, clonal evolution and emergence of a particularly aggressive element (nonrhabdoid tumor components should be always identified) or de novo from nonneoplastic cells (usually in absence of a nonrhabdoid component). Cytogenetic and molecular data can assist in the confirmation of both hypotheses.