Pathology

Pathologists are agreed that there are peculiar difficulties in the classification and diagnosis of malignant tumors of the thyroid. The histologic changes required for diagnosis of carcinoma include absence of a true capsule, invasion of surrounding normal tissue, invasion of blood and lymph channels, loss of normal follicular architectural arrangements, and cellular abnormalities such as an increase in the ratio of nucleus to cytoplasm, enlarged vesicular nuclei, nuclear folding, increased mitoses, and hyperchromasia of the nucleus. Recently, aneuploidy of nuclear DNA content has been added to this list. Obviously the presence of distant metastases is the most certain criterion. Most students of the disease agree that the ordinary criteria of malignancy have little prognostic value in thyroid tumors, except perhaps in the wildly growing anaplastic tumors. However, it may be noted that pathologists at the Mayo Clinic believe a histologic typing by their criteria provides significant information on prognosis.

Examples of the histologic patterns of several of these tumors are given in Figure 18-9. The papillary adenocarcinoma typically shows tumor cells around a fibrovascular core and, not infrequently, areas of follicular differentiation. Papillary lesions tend to be infiltrative, and encapsulation is rare. Lymphocytic "reactions" are prominent. The cell nuclei have a ground-glass or "cat's eye" appearance and intracellular inclusions are common. Vascular invasion is rare. Psammoma bodies are often abundant. Multiple intraglandular foci are frequent, especially in children. Areas of lymphocyte infiltration, and even extensive lymphocytic thyroiditis, are common, especially in papillary tumors. Many tumors look much like follicular cancers, but have the characteristic nuclei of papillary cancers. These constitute the "follicular variant" of papillary cancer, and behave more or less as do other papillary cancers.

Follicular adenocarcinomas vary from those with a definite follicular pattern to those with solid sheets of cells. The lesions are more frequently encapsulated, but capsular and blood vessel invasions are typical. The nuclei are normo- or hyper- chromated, or may be quite vesicular. One variant, the so-called malignant adenoma, appears to be nearly benign and can be identified as malignant only by the demonstration of invasion of vessels or capsule, or because of the presence of distant metastases, which may also be composed of normal-appearing thyroid tissue. Hurthle cell carcinomas usually grow as solid sheets of large eosinophilic granular cells with much cytoplasm, and less often with a follicular pattern. An Hurthle cell appearance can also be observed in some papillary tumors.(Figure 18-9d)

Medullary tumors have an ominous histologic pattern, with solid masses of cells with large vesicular nuclei (200). There may be considerable associated fibrosis, and deposits of amyloid are a helpful diagnostic point. At the time of initial histologic examination the pathologist should recognize these tumors as entities distinct from the undifferentiated cancers, for the medullary carcinomas have a much better prognosis. Medullary thyroid carcinoma (MTC) is associated with amyloid deposition in the  Surrounding tissues. Recent studies demonstrated that full-length calcitonin is the sole constituent of amyloid in MTC. (Endocrinology. 2004 Dec;145(12):5465-70. Unraveling the amyloid associated with human medullary thyroid carcinoma. Khurana R, Agarwal A, Bajpai VK, Verma N, Sharma AK, Gupta RP, Madhusudan KP.)

In the undifferentiated group of small-cell tumors, giant- cell tumors, and carcinosarcomas, or in the miscellaneous group, the histologic pattern has little resemblance to the original thyroid structure. (Fig 18-9e, above)

The general experience of pathologists has been that, in the absence of irradiation, the substrate in which thyroid tumor forms is usually normal thyroid tissue or displays the changes of multinodular goiter or adenoma in approximately the proportion found in any sampling of the general population (201). There is a slightly increased frequency of association with benign adenomas and with Hashimoto's thyroiditis (202). Lymphomas are associated with Hashimoto's thyroiditis, and there is considerable evidence that lymphoma actually evolves from a gland with thyroiditis (203).

Multicentricity is a common feature of thyroid cancer, especially papillary cancer. Innumerable separate foci are sometimes found. Estimates of multicentricity range from 20 to 80% (204, 205). Whether this phenomenon represents truly multicentric sites of origin or intrathyroidal dissemination is not clear. This multifocality is thought to be one cause of recurrences in patients treated by subtotal rather than total thyroidectomy.

Both papillary and follicular tumors may appear as small (less than 1.5-cm) tumors surrounded by a densely fibrotic reaction. Although it is frequently said that these "occult" (because they may be found incidentally at operation) tumors are benign, the original report by Hazard (206) and subsequent studies show that cervical lymph node metastases occur (207).

Occasionally pathologic examination suggests conversion of differentiated papillary or follicular cancers into anaplastic forms or conversion of an adenoma into a carcinoma.

An interesting aspect of thyroid tumor pathology is the frequency of metastatic tumors to the thyroid -- 5% in the data of Silverberg and Vidone ¹⁴² for unselected autopsies and 24% for patients dying of metastatic malignant disease.