Physiologic versus neoplastic C-cell hyperplasia of the thyroid: separation of distinct histologic and biologic entities.

BACKGROUND: Although hyperplasia of C-cells has been described in association with various pathologic and physiologic conditions, criteria for its diagnosis are poorly defined. Both neoplastic and physiologic C-cell proliferations have been lumped together under the umbrella designation of C-cell hyperplasia (CCH), creating considerable confusion among clinicians and pathologists.

METHODS: in order to compare the morphologic and immunohistochemical characteristics of the two major types of CCH, we examined thyroid sections of 17 patients with familial forms of C-cell hyperplasia and/or neoplasia and tissue sections of 19 thyroid glands known to have reactive or physiologic CCH (at least 50 C-cells per one low power field, 100X). Hematoxylin and eosin (H & E) stained sections and immunohistochemical stains for calcitonin were assessed in each case.

RESULTS: Physiologic or reactive CCH was not recognized with certainty on H & E stains in any of the cases due to morphologic similarities between C-cells and adjacent follicular cells. Detection of this form of hyperplasia, which was predominantly diffuse, required calcitonin immunostains and quantitative analysis. Conversely, nodular and diffuse neoplastic CCH was easily identified with conventional H & E stains at the periphery of 11/12 (92%) familial medullary thyroid carcinomas (MTC). In the other five cases, neoplastic C-cell hyperplasia was the only pathologic finding on thyroidectomy performed for elevated serum calcitonin levels detected via provocative biochemical screening or identification of the mutated RET proto-oncogene by genetic analysis. The C-cells in this neoplastic form of CCH were large, mildly to moderately atypical, and confined within the basement membrane of thyroid follicles. Moreover, these cells were cytologically indistinguishable from those of invasive MTC cells.

CONCLUSIONS: Physiologic and neoplastic CCH are biologically and morphologically distinct entities. The former cannot be recognized with certainty with conventional stains and requires immunohistochemistry and quantitative analysis for diagnosis. The latter consists of mildly to moderately atypical C-cells that can be identified with H & E stained sections. Consequently, the number of C-cells is of no importance for the diagnosis of neoplastic CCH which is considered to be the precursor (medullary carcinoma in situ) of invasive medullary carcinoma.