After reading the summary, try answering the three related multiple-choice questions below.
A 77-year-old woman presented with stridor and a thyroid mass. At surgery, she had a large ill-defined tumor that involved the entire gland and extended into surrounding strap muscles. A debulking procedure was performed consisting of necrotic and hemorrhagic tumor that grossly replaced the entire gland.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2009, case 35, and is undifferentiated (anaplastic) thyroid carcinoma.
Criteria for Diagnosis and Comments:
Your slide contains predominantly sheets of anaplastic epithelioid and spindled cells associated with areas of necrosis and neutrophilic inflammation. Some slides demonstrate parathyroidal soft tissue invasion, while others contain pre-existing areas of papillary carcinoma. The findings are diagnostic of undifferentiated (anaplastic) thyroid carcinoma.
UTC accounts for <5% of malignant thyroid neoplasms but over 50% of all thyroid cancer deaths. It usually occurs in elderly patients, typically >60 years old, with a slight female predilection (1.5:1 ratio). It is the most feared tumor of the thyroid gland, being a highly aggressive, and almost always fatal malignancy characterized by rapidly progressive local disease and a grim 5 year survival of <15%, and a 6 month mean survival after diagnosis is established. It presents either as a new-onset neck mass in a patient with long standing goiter, or as a recurrence of a prior well-differentiated thyroid carcinoma. Presenting symptoms often include signs of compression such as hoarseness, dysphagia, pain, vocal cord paralysis or dyspnea due to rapid growth that extends beyond the thyroid, and is often accompanied by weight loss. A high frequency of direct invasion of surrounding structures is characteristic of UTC and can include involvement of strap muscles, trachea, larynx and esophagus, making complete surgical resection difficult and consequently half the cases are inoperable. Hence, this tumor almost always presents in T4 stage. Almost half the patients additionally present with disseminated disease, most often lung followed by bone and brain. Rare cases of longer survival are usually associated with smaller size (<5.0 cm) and complete surgical resection followed by chemotherapy and radiation.
UTC is multicentric and bilateral in 25% of cases. Regional lymph nodes are often involved. Grossly, this tumor is usually large with fleshy areas containing hemorrhage and/or necrosis, and typically invades surrounding soft tissues. Most cases represent dedifferentiation of a pre-existing carcinoma (usually papillary, occasionally follicular or Hürthle cell, rarely insular). The residual morphologic evidence of such, however, may not be found due to rapid growth and obliteration by the large undifferentiated component. Unfortunately, the exact mechanism of transformation is unknown and it is not currently possible to predict which differentiated thyroid carcinoma will undergo anaplastic transformation. In the current case, papillary carcinoma remnants were found, sometimes transitioning into UTC, and which were observable in some of the distributed slides.
Histologically, UTC consists of an admixture of spindled, polygonal (epithelioid or squamoid), and giant (pleomorphic or osteoclastic) cells in varying proportions. Cells may be arranged in a fascicular, solid or storiform pattern. When more purely epithelioid, it may have a squamoid sheet-like appearance without follicles, papillae, trabeculae, or nests. Geographic necrosis, marked cytologic atypia, prominent vascular invasion and atypical mitoses are the norm. An inflammatory neutrophilic infiltrate may be seen as well. The typical immunohistochemical profile includes positivity for both pancytokeratin (may be patchy) and p53; and negativity for CEA (except occasionally in squamoid areas), thyroglobulin (which may be present due to entrapped follicles or present in the pre-existing differentiated component), and TTF1. When predominantly spindled, there can be a close resemblance to soft tissue sarcoma. Several reported variants may occur and include the osteoclastoma-like variant, carcinosarcoma variant (which may contain metaplastic bone and/or cartilage), the paucicellular variant with dense fibrosis/hyalinization resembling Riedel’s thyroiditis (but still with invasive qualities and cytologic atypia); and the lymphoepithelioma-like variant resembling its nasal counterpart but unassociated with EBV infection. On occasion, rhabdoid morphology may be seen. In the older literature, a small cell variant was recognized but it now appears that these were either lymphoma, insular carcinoma or small cell variants of medullary carcinoma. Finally, while uncommon, anaplastic transformation can occur in a focus of metastatic differentiated thyroid carcinoma. Thorough sampling in this scenario is critical in establishing thyroid as the site of origin.
The differential diagnosis varies according to the histologic composition and proportion of spindled to epithelioid cells. This tumor is often confused with true spindled cell soft tissue sarcomas (such as rhabdomyosarcoma, leiomyosarcoma and angiosarcoma) in part because >90% of UTC’s are vimentin-positive while pancytokeratin staining may be sparse. These sarcomas can be excluded immunohistochemically. Rhabdomyosarcoma would be positive for desmin, myogenin and Myo-D1; leiomyosarcoma would demonstrate smooth muscle actin and desmin staining; and angiosarcoma, although occasionally keratin-positive, would additionally be decorated with factor VIII, CD31 and CD34. Moreover, primary thyroid sarcomas are exceedingly rare with most cases representing undifferentiated (anaplastic) thyroid carcinoma. Metastatic melanoma should stain for HMB45, MelanA, S100 and/or WT1. And positivity for CD45 and CD20 should confirm the diagnosis of large B-cell lymphoma. Metastatic sarcomatoid renal cell carcinoma could theoretically pose a difficult challenge but here imaging studies confirming a renal mass would be the most important test in excluding that unlikely possibility. Anaplastic/spindled medullary carcinoma may also enter the differential diagnosis l. It should, however, be positive for CEA (which, except occasionally in squamoid areas, is negative in UTC), TTF1, calcitonin and amyloid all of which are negative in UTC. Medullary carcinoma should also not exhibit the rapid and invasive growth nor the marked cytologic atypia, mitotic activity or necrosis of UTC. Finally, Reidel’s struma, fibromatosis (desmoid) and papillary carcinoma with fibromatosis-like stroma should all be easily separable from UTC based on the lack of bizarre atypia, atypical mitoses, hypercellularity and necrosis in these cases.