Answer: Medullary carcinoma

Histology: The background thyroid exhibits changes of Hashimoto’s thyroiditis with chronic inflammation, germinal center formation, and nodularity. One of the nodules is characterized by hypercellullar growth. It is well circumscribed, but it lacks a capsule and it permeates adjacent follicles at its periphery. Architecturally, the growth is sheet-like, but there are many well developed micro-follicles. The cells have uniformly round nuclei with speckled chromatin and prominent nucleoli. They lack chromatic clearing, nuclear elongation, nuclear grooves and intranuclear inclusions. Immunohistochemical stains were performed. Immunostains are shown for thyroglobulin, TTF-1, calcitonin, CEA and chromogranin.

Discussion: Medullary thyroid carcinoma (MTC) is a primary thyroid tumor derived from C-cells of the dispersed neuroendocrine system. They generally cause an elevation of serum calcitonin levels, but elevated serum calcitonin is a non-specific finding and by itself is not diagnostic of an underlying MTC.

Histologically, MTCs classically exhibit nested growth, uniform cells with round to slightly spindled nuclei, and the presence of extracellular deposition of amyloid. Departure from this prototype can cause diagnostic confusion to the degree that MTC mimics other types of primary thyroid neoplasm: The presence of a true papillary architecture can cause confusion with papillary carcinoma; the presence of oncocytic change can cause confusion with Hurthle cell neoplasms; and the presence of follicular growth can cause confusion with follicular neoplasms, particularly in the absence of stromal amyloid deposition.

Immunohistochemistry can be helpful in confirming the diagnosis, but there are a few diagnostic pitfalls that must be avoided when interpreting the results of immunohistochemical analysis. First, thyroglobulin staining can reflect entrapped non-neoplastic thyroid follicles. This common phenomenon should always be considered before excluding the diagnosis of MTC based on positive staining in the follicles scattered throughout the tumor nodule. Second, MTCs are commonly TTF-1 positive. Accordingly, TTF-1 immunohistochemical staining plays no role in distinguishing tumors of follicular epithelial origin from tumors of C-cell origin. Third, not all MTCs retain calcitonin positivity. It is a good idea to look for other markers of MTC in addition to calcitonin: chromogranin is a more sensitive marker of neuroendocrine differentiation, and CEA is generally expressed in all MTCs, even those that lose calcitonin expression.

The presence of follicular structures in a MTC raises consideration of: 1) entrapped non-neoplastic thyroid follicles, 2) follicular variant of MTC, and 3) mixed follicular and MTC. The finding that these scattered follicles express thyroglobulin but not CEA would support the interpretation of entrapped thyroid follicles.