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A 72-year-old woman with a prominent asymmetric goiter presents to her physician complaining of recent onset of hoarseness and neck pain. Received for intraoperative consultation is a “midline neck mass probably thyroid” measuring 6.0 cm x 4.0 cm x 5.0 cm with attached skeletal muscle. Noted on the cut surface was a fleshy tan mass with indistinct borders, firmly attached to muscle and containing zones of necrosis.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2008, Case 8, and is undifferentiated (anaplastic) carcinoma of thyroid.
Criteria for Diagnosis and Comments:
This malignant neoplasm, with predominately spindled cells, is an undifferentiated (anaplastic) carcinoma of thyroid (UCT). The sections contain a tumor composed of sheets of intersecting fascicles of pleomorphic spindled and epithelioid cells which efface any evidence of thyroid parenchyma. Areas of coagulative necrosis, nuclear atypia and readily identifiable mitotic figures are noted. The cellular growth pattern and anatomic location are hints to the diagnosis; however, the differential diagnosis includes a number of entities listed in the above master list.
Approximately 2 - 5% of all thyroid carcinomas are undifferentiated carcinoma. This neoplasm is more prevalent in areas where goiter is endemic. The vast majority of patients are elderly with a mean age of 70 years. Unlike other thyroid gland neoplasms there is only a slight female predilection (male: female rate 1:1.1 to 1.2). Most patients present with a rapidly growing neck mass or a sudden enlargement of a long standing goiter. The onset of enlargement is often associated with concomitant hoarseness, vocal cord paralysis, dysphagia and pain. These tumors on occasion have been reported to produce granulocyte-stimulating factor resulting in leukocytosis. Due to the rapid and widely invasive nature of this neoplasm, at the time of presentation about half of the patients are inoperable and have regional lymph node or distant metastasis. Despite aggressive multimodality therapy most patients survive less than 1 year; mean survival is 4 - 6 months.
Although the histologic features of UCT are variable, pleomorphic, epithelioid, spindle and giant cells are quite commonly seen. Some tumors may be composed entirely of one cell type. Spindle cell type in particular mimics a variety of sarcomas. A variety of morphologic subtypes of UCT have been described: angiomatoid, osteoclastic, rhabdoid, lymphoepithelioma-like, paucicellular variant, carcinosarcoma, adenosquamous and squamous cell carcinoma. Coagulative necrosis is usually extensive and mitotic figures are easily identified. Frequently, UCT contains an intense neutrophilic inflammatory component with aggregates of neutrophils as well as areas of notable vascular proliferation. A noteworthy characteristic feature of UCT is the propensity for vascular permeation with tumor obliteration of the vascular lumina. In thoroughly sampled tumors it has been reported that residual areas of differentiated thyroid carcinoma were found in 50 - 90% of the UCTs. This observation along with reported findings of progressive increase in p53 staining from convention carcinoma to UCT (differentiated thyroid carcinoma papillary/follicular 10 - 15% vs. UCT 70%) suggests that UCT may arise via “dedifferentiation” of differentiated thyroid carcinoma.
Cytokeratin (40 - 100%) and epithelial membrane antigen (50%) are the most common positive “epithelial” markers in UCT although often only focally or in individual cells. Vimentin is positive in 50 - 100% of the tumors. Thyroglobulin and thyroid transcription factor (TTF-1) are usually negative except in residual differentiated carcinoma. Calcitonin, HMB-45, neuroendocrine markers and lymphoid markers are negative. Some tumors may show focal staining with factor VIII related antigens.
The differential diagnosis includes a variety of entities including the following: Angiosarcoma as a primary tumor of thyroid exists; however, there is some histologic and immunohistochemical staining overlap with UCT. The prognosis of the two entities is similar. Angiosarcomas of the thyroid are usually epithelioid and contain binucleate cells but rarely contain multinucleated giant cells. The diagnosis of angiosarcoma should only be applied when unequivocal evidence of endothelial differentiation is demonstrated (positive for CD 31, CD34 and factor VIII related antigens) however some angiosarcomas occasionally are cytokeratin positive.
Lymphoma usually shows less cellular cohesion and can readily be distinguished by immunohistochemistry and flow cytometric analysis.
Papillary carcinomas of thyroid have the conventional nuclear features of papillary carcinoma, stain positive for TTF-1 and thyroglobulin. These tumors lack the pleomorphic nuclei and pleomorphic cytoplasmic shapes and abundant mitotic figures seen in UCT.
Riedel thyroiditis is a densely sclerotic inflammatory process which causes the thyroid gland to become adherent to adjacent structures. However atypical mitoses, ghosted vessels with spindle cells and the presence of marked cellular pleomorphism are not present. A small biopsy could prove the task problematic, if not impossible, in distinguishing these two entities.