Answer: C cell hyperplasia

Histology: The thyroid gland was of normal size and without nodule formation. Both lobes of the thyroid were blocked in their entirety for histologic examination. Sections corresponding to the middle thirds of both lobes show increased cellularity. In these areas, collars of cells surround and fill the follicles. The cells have uniformly round to oval nuclei with a finely stippled chromatin pattern. Although some of the expanded follicles coalesce, but there is no associated stromal fibrosis to suggest interstitial invasion.

Discussion: The recent identification of mutations in the RET proto-oncogene in patients with familial forms of medullary thyroid carcinoma (MTC) has now provided a means to identify patients who have or will develop a this carcinoma. The RET proto-oncogene is located on chromosome 10 and encodes for a transmembrane tyrosine kinase. Germline mutations of the Ret proto-oncogene can be detected in the vast majority of patients with familial forms of MTC. RET analysis is a sensitive, specific, and highly predictive means of identifying patients who have or will develop familial MTC. It is a 1 time test that is both safe and inexpensive. It effectively differentiates sporadic from familial forms of MTC in index cases. For asymptomatic family members who carry germline mutations of the RET proto-oncogene, the thyroid gland can be removed prophylactically before the tumor has had the opportunity to develop, grow and metastasize.

The presence of C cell hyperplasia is a common finding in prophylactically removed thyroids from young asymptomatic patients that carry a germline RET gene mutation. C cells normally are positioned in an intrafollicular position and are bounded by the follicular basal lamina (i.e. they do occur in the interstitium). In C cell hyperplasia, increased numbers of C cells surround the follicles and progressively obliterate the follicle spaces. Although there are subtle morphologic differences between the C cell and the follicular epithelial cell (the cytoplasm of the C cell is more abundant, amphophilic and stippled), an immunohistochemical stain for calcitonin is useful in discriminating between the two cell types.

Expansion of the C cell population by itself is not diagnostic of C cell hyperplasia. Isolated C cell nodules can be encountered adjacent to follicular and papillary carcinomas, and even in otherwise normal glands. Some would argue that a diagnosis of C cell hyperplasia requires the presence of high C cell density (i.e. >50 C cells per single low-power field) involving multifocal areas of both thyroid lobes.

The distinction between florid areas of C cell hyperplasia and an early MTC is critical but sometimes difficult. Expansion and coalescence of the C cell nodules can confound interpretation of early interstitial invasion. In these instances, it is important to look for a stromal reaction. C cells that extend beyond the follicular basal lamina to infiltrate the interstitium characteristically induce stromal fibrosis and, at times, amyloid deposition. In the absence of interstitial invasion, total thyroidectomy is curative and eliminates any future threat of MTC for patients who carry the germline RET gene mutation.