—  SHORT COURSE #41  —

Pathology of the Thyroid Gland

Case 6 - Poorly Differentiated Carcinoma of Thyroid

Zubair W. Baloch and Virginia A. LiVolsi


Clinical History
A 47-year-old woman presented with a 7 cm neck mass with associated cervical lymphadenopathy. After FNA diagnosis of "malignant neoplasm", thyroidectomy was performed. Grossly, the tumor was poorly circumscribed, appeared to extend beyond the thyroid itself and showed foci of necrosis.


Case 6 - Figure 1 - Insular Carcinoma of Thyroid
Case 6 - Figure 2 - Insular Carcinoma of Thyroid


Case 6 - Figure 3 - Insular Carcinoma of Thyroid
Case 6 - Figure 4 - Insular Carcinoma of Thyroid

Diagnosis: Poorly Differentiated Carcinoma of thyroid

Discussion: Reviews of large numbers of thyroid carcinomas have often included examples of carcinomas that are recognizable as originating from follicular epithelium (often with evidence of coexistent papillary or follicular carcinoma), but with some notable differences: moderate to high rates of mitotic activity, composed of solid masses or trabeculae of relatively uniform epithelial cells, tiny follicles present in varying numbers, regions of acute necrosis, and more aggressive than the usual well-differentiated carcinomas. Included among these lesions are insular carcinoma; columnar cell, tall cell, and trabecular types of papillary cancer; and "poorly differentiated" carcinoma of Sakamoto. These tumors generally lack the usual histologic features and exceptional aggressiveness of anaplastic carcinomas, but they are neither typical follicular nor papillary carcinomas.

In the seminar case, the diagnosis of malignancy is fairly obvious. Necrosis, easily found mitoses and vascular invasion were seen. In some areas, an insular pattern was noted. Focally spindled cells and growth as sheets are apparent. FNA showed atypical epithelial cells in a background of necrotic debris.

Some pathologists consider insular carcinoma merely a moderately to poorly differentiated follicular carcinoma. The current author believes it should be separated as specific entity. These are tumors of adults and are often large with areas of necrosis. Histologically the tumor is composed of islands and nests of small cells within a richly vascularized stroma. Necrosis, high mitotic rate and lymphovascular invasion are common.

Many examples show better-differentiated areas including papillary carcinoma or its follicular variant. If insular carcinoma occurs as a recurrence of another thyroid tumor, the latter is usually papillary. Rare examples of papillary cancer metastases of a primary intrathyroidal insular tumor are recorded. Hence, these associations with papillary cancer and the ability for regional nodal metastasis should place insular cancer in a category different from true follicular carcinoma. Clinically these tumors are aggressive with regional and distant (hematogenous) metastasis in over 50% of cases and a 5-year mortality rate of about 50-60% .

A recent study from France showed that in thyroid tumor patients who develop distant metastases showed that in addition to large size of the primary, extrathyroidal extension and vascular invasion, an insular pattern was found at least in part of the tumor in 54% (compared to 6% showing insular component in patients without distant metastases).

The role of oncogenes in thyroid carcinogenesis is an evolving field of research. Well-differentiated thyroid cancers are rarely positive with immunostaining for p 53, whereas many anaplastic carcinomas show positivity (40%-60%). Correspondingly, bcl-2 (related to the mechanism of apoptosis) oncogene is often expressed in well- differentiated cancers and rarely in undifferentiated lesions. Tumors in the poorly differentiated group (tall cell or columnar cell papillary cancer, and insular carcinoma) show intermediate patterns of expression of p 53 (about 25% of cases) and of bcl-2.

Evaluation for proliferative indices in thyroid neoplasms (immunostaining for PCNA or Ki67 antigen) have shown, as expected, low proliferation rates for well-differentiated tumors and high rates in poorly differentiated or undifferentiated lesions. The value of these tests is not evident in the clinical evaluation of affected patients.

The poorly differentiated cancers are thyroglobulin positive although this may be focal. These lesions have led some to question the need for a grading system for differentiated or partially differentiated thyroid cancers. We have found this to be helpful and even to have some predictive prognostic value. Pleomorphism, necrosis, mitoses and vascular invasion appear to be important findings and we believe these should be mentioned in a pathology report on a resected thyroid cancer if they are present.

Fewer than 10% of thyroid carcinomas may be classified as anaplastic or undifferentiated. They are most common in regions of the world where iodine is deficient .

Both spindle cell and giant-cell tumors are aggressive neoplasms that usually occur in elderly people, more often women. The patient may relate a history of a thyroid nodule that, after many years of stability, suddenly begins to grow rapidly. Some patients are known to have had low-grade thyroid carcinoma; some have low-grade thyroid carcinoma discovered at the time of diagnosis of the anaplastic tumor; and some have no history of thyroid disease.

Careful pathologic examination of thyroids that contain anaplastic carcinomas has demonstrated a high (50%-70%) incidence of remnants of well-differentiated follicular or papillary carcinoma or sometimes an adenoma or adenomatoid nodules confirming the clinical impression that anaplastic carcinomas arise out of tumors of low-grade neoplasm.

Gross examination demonstrates a hard, pale, infiltrative mass that may contain soft foci of necrosis and hemorrhage. These tumors invade the cervical soft tissues and involve the regional lymph nodes, often by direct extension. Microscopic examination reveals varied histologic patterns, many mitotic figures, and regions of acute necrosis.

Anaplastic carcinomas are usually pleomorphic and are composed of medium-sized to large cells with a vaguely epithelial appearance. There may be squamous cell differentiation (or a tendency toward this pattern). Others appear sarcomatous, especially resembling malignant fibrous histiocytoma, fibrosarcoma, and angiosarcoma.

Ultrastructural studies have demonstrated the presence of structures resembling tiny follicles and junctions between the cells, supporting an epithelial phenotype. Immunohistochemical evidence of thyroglobulin has been found in a few anaplastic carcinomas; it is likely that in most of these cases, the thyroglobulin staining represents diffusion of thyroglobulin cells from destroyed thyroid follicles; 50% to 100% of these tumors contain keratin.

Most anaplastic carcinomas are diagnosed with minimally invasive techniques (FNA). The treatment options are poor. Aggressive combinations of treatment eg: radical surgery, radiotherapy and chemotherapy are reserved for the rare young individual with this tumor.

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