The prognostic and biological significance of cellular heterogeneity in medullary thyroid carcinoma: a study of calcitonin, L-dopa decarboxylase, and histaminase.

We evaluated the cellular distribution of calcitonin (CT), L-dopa decarboxylase (DDC), and histaminase [diamine oxidase (DAO)] in 33 patients with medullary thyroid carcinoma (MTC). CT immunostaining was uniform (greater than 90% of the cells) and intense (4+) in lesions from 7 patients with C-cell hyperplasia and 6 with microscopic MTC: conversely, patchy CT staining (less than 40% of the cells) and diminished intensity (1+) were found in metastases from 8 patients who died of virulent disease. In 17 patients who underwent thyroidectomy for macroscopic cervical MTC with no evidence distant metastases, CT staining was intense (3-4+) and homogeneous (greater than 90%) in 11 subjects who were well 0.5-16 yr postoperatively. Six patients with similar clinical presentations had heterogeneous staining for CT in primary tumor (less than 40% of the cells; 1-2+ intensity); 5 died of disseminated MTC 0.5-5 yr postoperatively (P less than 0.001). Biochemical studies of distant metastases revealed an inverse relationship between the distribution of CT and that of both relationship between the distribution of CT and that of both DDC (r = 0.71; P less than 0.01) and DAO (r = 0.81; P less than 0.001). We conclude that cellular heterogeneity in MTC tissue is associated with a distinct biochemical pattern, and its presence, whether in a primary or metastatic lesion, indicates a virulent neoplasm associated with a grave prognosis.