Case 1 -

Rhabdoid Tumor of Thyroid Sylvia L. Asa University Health Network Toronto, ON, Canada

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Clinical History This 66-year-old woman presented with a neck nodule. She had a history of a long-standing goiter. She was euthyroid; the goiter had been painless and non-tender. She had noted a sudden and rapid increase in size of her right neck in the preceding few weeks and she complained of dysphagia, dyspnea and hoarseness. On examination she had an assymetrical large goiter with a fixed 6 cm right nodule. She underwent thyroidectomy. The right lobe measured 6 x 5 x 5 cm and weighed 60 grams. It was multinodular with obvious infiltrating tumor. The left lobe weighed 6 grams and measured 4 x 3 x 1 cm with multiple small nodules measuring up to 5 mm in diameter. Case 1 - Figure 1 - The thyroid contains an invasive solid tumor. Case 1 - Figure 2 - The tumor is composed of a solid growth of neoplastic cells with focal inflammation, predominantly around vascular channels. Case 1 - Figure 3 - The tumor cells are large and discohesive. Case 1 - Figure 4 - The tumor cells have abundant cytoplasm with cytoplasmic inclusions; nuclear pleomorphism is prominent. Case 1 - Figure 5 - Tumor cells have eccentric nuclei with prominent nucleoli and occasional binucleate cells are identified Histologic, Immunohistochemical and Molecular Findings Histological examination showed an invasive, highly cellular neoplasm, involving the entire right lobe, with focal geographic necrosis, areas of hemorrhage and extrathyroidal invasion into skeletal muscle. Microscopic foci of malignancy were detected in the left lobe. The tumor was predominantly composed of a solid growth of large discohesive neoplastic cells with abundant cytoplasm, cytoplasmic inclusions and eccentric nuclei with prominent nucleoli; this was a typical rhabdoid tumor. At the periphery, there were sclerotic areas where this lesion merged with irregular follicles lined by cells with atypical nuclei that had features of papillary carcinoma. By histology, it could not be determined if this represented reactive changes in surrounding thyroid tissue. Immunohistochemical staining showed immunoreactivity in rhabdoid cells for low molecular weight cytokeratins, vimentin, sarcomeric actin and myoglobin. Immunostains for desmin, smooth muscle actin and S100 protein were negative in tumor cells but stained normal components of surrounding tissues. The atypical cells at the periphery of the lesion were immunoreactive for thyroglobulin, cytokeratin 19 and TTF-1. Stains for p53 were negative throughout. Ki67 labeled more than 90% of tumor cells. For molecular studies, RNA was extracted from the neoplastic tissue, reversed transcribed into cDNA, then amplified, using primers specific for RET/PTC1 and RET/PTC3 fusion genes [1]. In all tumor samples examined, including blocks with atypical follicles and blocks of pure rhabdoid tumor, RET/PTC 3 fusion transcripts were detected, indicating the presence of a RET/PTC3 gene rearrangement in rhabdoid tumor cells. Clinical Course The patient rapidly developed local recurrence with massive mediastinal lymph node metastases. She received external beam radiotherapy to the neck and mediastinal area with a total dose of 60 Gray over one month, but the disease progressed and the patient died one month later. The apparent cause of death was a severe mediastinal syndrome with possible pulmonary thromboemboli. Autopsy was not performed. Diagnosis Rhabdoid Tumor of Thyroid Discussion Rhabdoid tumor is a very aggressive neoplasm first described by Beckwith et al in 1978 as a variant of renal Wilm's tumor in children [2] . Subsequently, rhab doid tumors have been described in different organs [3, 4, 5, 6, 7, 8, 9] ; they can occur at any age [4, 8] and always exhibit aggressive behavior with a tendency to develop early metastasis [4]. They have a poor prognosis due to lack of responsiveness to radio- and chemotherapy. Morphological findings in this tumor include the presence of large pleomorphic cells with abundant cytoplasm, typical eosinophilic inclusions and eccentric nuclei with distinct nucleoli. The immunohistochemical profile of rhabdoid tumor cells may vary from case to the next: immunoreactivity for vimentin, myogenic markers, keratins, markers of smooth muscle lineage, neuron specific markers and S100 have been reported [3, 4, 5] . Ultrastructural findings in these cells include the presence of whorled cytoplasmic filaments [8, 10] . Tumors with rhabdoid features are considered to represent a final pathway of dedifferentiation of neoplasms derived from multiple cell types, including tumors of neuroectodermal, myogenic, histiocytic, melanocytic and epithelial origin [4, 5, 6] . Primary rhabdoid tumor of thyroid gland is a very rare neoplasm. To the best of our knowledge, six cases have been reported in the recent literature [11, 12, 13] . All seven cases including this one occurred in women whose ages ranged from 38 to 69 years (mean age 51.8 years). All had extrathyroidal extension of tumor at the time of diagnosis, and all had local and distant recurrence. The disease has been uniformly rapidly lethal. These features confirm thyroid rhabdoid tumor to be a highly aggressive neoplasm, with a mean survival similar to that of anaplastic thyroid carcinoma. Indeed, rhabdoid tumors and anaplastic carcinomas of thyroid exhibit similar clinical, morphological and immunohistochemical features. Both are rare thyroid tumors that occur in older patients, both invade extrathyroidal tissues and surrounding structures, both give rise to cervical adenopathy and distant metastases, and both have very high mortality with a mean survival of 6 months. Both tumors are wholly or partially composed of undifferentiated cells that may exhibit immunohistochemical or ultrastructural features of epithelial differentiation. Anaplastic carcinoma usually arises by dedifferentiation of a pre-existing differentiated carcinoma [14, 15] . Origin of rhabdoid tumor from thyroid follicular epithelium has also been suggested. In our case, rhabdoid cells showed immunohistochemical evidence of both epithelial and muscle differentiation but thyroglobulin and TTF-1 were negative; in other cases reported, thyroglobulin was detected in the rhabdoid component [13] . In all cases reported, there has been evidence of differentiated follicular or papillary neoplasia admixed with the rhabdoid component. One could argue that reactive changes in adjacent parenchyma can mimic malignancy [16] , and in our case, this possibility was raised. To address this, we carried out molecular studies using a marker that is specific for papillary carcinoma of thyroid, RET/PTC [17] . In our case, a RET/PTC3 rearrangement was detected in blocks of tissue containing both the atypical cells at the periphery of the dominant tumor and in blocks with rhabdoid tumor only. This finding confirms the presence of underlying papillary carcinoma and indicates a direct relationship of the rhabdoid tumor to this differentiated component. This finding provides firm evidence that rhabdoid tumor derives from a pre-existing differentiated papillary thyroid carcinoma. In conclusion, the clinicopathological features supported by new molecular findings suggest that rhabdoid tumor of thyroid should be considered a variant of anaplastic carcinoma. Acknowledgement The author thanks Dr. Maria Letizia Lai of Cagliari, Italy for contributing this case. References Sugg SL, Ezzat S, Rosen IB, Freeman J, Asa SL. Distinct multiple ret/PTC gene rearrangements in multifocal papillary thyroid neoplasia. J Clin Endocrinol Metab 1998;83:4116-22. Beckwith JB, Palmer NF. Histopathology and prognosis of Wilms tumors: results from the First National Wilms' Tumor Study. Cancer 1978;41:1937-48. Chetty R, Bhana B, Batitang S, Govender D. Lung carcinomas composed of rhabdoid cells. Eur J Surg Oncol 1997;23:432-4. Wick MR, Ritter JH, Dehner LP. Malignant rhabdoid tumors: a clinicopathologic review and conceptual discussion. Semin Diagn Pathol 1995;12:233-48. Fischer HP, Thomsen H, Altmannsberger M, Bertram U. Malignant rhabdoid tumour of the kidney expressing neurofilament proteins. Immunohistochemical findings and histogenetic aspects. Pathol Res Pract 1989;184:541-7. Borek BT, McKee PH, Freeman JA, et al. 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