Pathological characteristics and genetic features of melanin-producing medullary thyroid carcinoma

Melanin-producing medullary thyroid carcinoma (MTC) is an extremely rare MTC subtype. This malignant tumor of the thyroid originates from the C cells of the thyroid and displays varied cytological features and growth patterns. Several MTC subtypes, such as papillary/pseudopapillary, eosinophil, spindle cell, follicular, clear cell, giant cell, squamous cell, hemangiosarcoma, and paraganglioma-like subtypes, have been reported in the literature [1], but only a few reports on melanin-producing MTC have been published. According to the 2008 WHO tumor classification, melanin in MTC can range from microscopic foci to massive production, whereas MTC that produces large amounts of melanin is extremely rare. In the present report, we presented a case of MTC producing massive amounts of melanin. Given that this casehave yet to be reported in the literature, the genetic features of this type of MTC were studied at the same time.

MTC presents a wide variety of morphological phenotypes, such as follicular, papilliferous, small cell, giant cell, clear cell, oncocytic, squamous cell, and melanotic carcinomas [2‐13]. Melanin-producing MTC was reported first by J. N. Marcus [2] and is an extremely rare clinically. This type of MTC is characterized by melanin in the cytoplasm of tumor or stromal cells and amyloid in the interstitial tissue. Melanin in melanin-producing MTC ranges from scant to massive [8]. To date, 14 cases of melanin-producing MTC (including this case) have been reported in the literature. Seven cases were males, and seven were females. The ages of patients with melanin-producing MTC ranged from 20 years to 72 years (50.4 ± 15.0 years), with a broad age distribution in adults.

Melanin-producing MTC is diagnosed mainly based on the morphological features and necessary biomarkers but should be differentially diagnosed from the metastatic or primary thyroid tumors. (1) Malignant melanoma of thyroid: malignant thyroid melanoma is the most common metastatic tumor in the thyroid [8, 9]. It is difficult to differentiate from melanin-producing MTC based solely on the morphology of the tumor cell. However, the patient with metastatic melanoma presented a medical history; the primary locus is found through detailed inquisition. Immunohistochemistry distinguishes the tumors, the tumor cells of melanin-producing MTC are positive for calcitonin, the most specific marker for C cells, and confirms the melanin-producing MTC instead of metastatic melanoma. (2) Undifferentiated carcinoma of thyroid: The tumor cells of undifferentiated thyroid carcinoma are positive for TTF-1, TG, CK19 and negative for calcitonin, whereas the tumor cells of melanin-producing MTC are positive for calcitonin and TTF-1 and negative for TG and CK19. (3) Melanotic paraganglioma of thyroid: The tumor cells of melanotic thyroid paraganglioma are positive for syn and negative for CgA, pan-cytokeratin, calcitonin, and TG, and stromal cells are positive for S-100 [14]. The structural morphological characteristics of the tumor cells are different between melanotic paraganglioma and melanin-producing MTC.

A panel of primary antibodies was used to diagnose the melanin-producing MTC, but results varied. Singh K showed that the tumor cells are positive for calcitonin, HMB-45, carcinoembryonic antigen (CEA), syn, chromogranin, vimentin, and epithelial membrane antigen and negative for TG, S-100, melan A, and TTF-1 [12]. Guiping Qin demonstrated that the tumor cells are positive for vimentin, CK, CgA, syn, CEA, calcitonin, HMB-45, and S-100 and negative for TG and TTF-1 [11]. The published literature reported that the tumor cells are positive for calcitonin (100%, 11/11), HMB-45 (90.1%, 10/11), CgA (54.5%, 6/11), CEA (36.4%, 4/11), S-100 (36.4%, 4/11), and CK (36.4%, 4/11). The tumor cells are negative for TG and TTF-1. In this case, the tumor cells were positive for the abovementioned antibodies, as well as melan A, cyclin D1, and CD56. The tumor cells were also positive for TTF-1, which is a biomarker for follicular epithelium carcinoma of the thyroid. The tumor cells in our case were positive for both TTF-1 and calcitonin. This paper was the first report of such finding. The reported samples did not mention the result of TTF-1 in 10 cases; one case was negative for TTF-1.

Kimura et al. [5] showed that tumors of melanin-producing MTC are derived from cells with melanocytic and C cell characteristics, that is, the cells that produce both melanin and calcitonin. A study showed malignant melanoma originating from melanin-producing MTC [15].

Congo red staining was performed to verify the presence of amyloid materials among the nests of tumor cells, and results revealed amyloid materials in the stroma.

Owing to the low incidence, the prognosis of melanin-producing MTC is unclear clear. In the 14 cases of melanin-producing MTC, three subjects died with metastasis at 13, 20, and 24 months after surgery, respectively [6, 12], indicating a death rate of 23.1% (3/13). Satisfactory follow up information was not obtained from four cases. No evidence of recurrence or metastasis was detected in five cases at 30, 12, 12, and 12 months and 11 years after the operation ([2, 7, 9], present case, [15]). Two cases at 12 and 24 months after the operation, respectively, exhibited metastasis [5, 11]. Melanin-producing MTC may be a low-malignant tumor based on the limited data. The biobehavior and prognosis of melanin-producing MTC need to be further studied, and more cases should be retrospectively analyzed. Kamaljeet Singh showed that a high mitotic count is associated with recurrence and poor prognosis [12]. In our case, the mitotic rate was approximately 3/10 HPF, and the patient was tumor-free at the 12-month follow up.