Diagnosis

Atypical Carcinoid Tumor with Melanocytic Differentiation

Discussion

Pulmonary carcinoid tumors are well-differentiated neuroendocrine neoplasms that account for around 1%-2% of primary lung malignancies.1,2 They are classified as typical or atypical carcinoids based on mitotic activity and necrosis.1,2 Typical carcinoids demonstrate fewer than 2 mitoses per 2 mm² and no necrosis, whereas atypical carcinoids demonstrate 2-10 mitoses per 2 mm² and/or necrosis.1,2 Atypical carcinoids have a higher risk of lymph node metastasis and recurrence than typical carcinoids.3

Histologically, pulmonary carcinoids typically demonstrate nests, trabeculae, cords, or organoid architecture composed of relatively uniform cells with finely granular (“salt-and-pepper”) chromatin. Neuroendocrine differentiation is supported by expression of chromogranin, synaptophysin, and INSM1.1,2 In our case, the tumor demonstrated neuroendocrine morphology and diffuse expression of these markers, while the mitotic rate of 5 per 2 mm² supported classification as an atypical carcinoid.

The striking feature of this case was the presence of melanin pigment and melanocytic marker expression within the tumor cells. Pigmented pulmonary carcinoids are exceptionally rare. Cebelin first described a melanocytic bronchial carcinoid in 1980, followed by several reports of pigmented pulmonary carcinoids demonstrating melanin production and divergent differentiation.4,5 A peripheral carcinoid with focal melanin production and a melanocytic bronchopulmonary carcinoid associated with multiple endocrine neoplasia type 1 have also been reported.6,7 Goel and Addis subsequently described a pigmented atypical carcinoid of the lung.8

The differential diagnosis includes metastatic melanoma, pigmented paraganglioma, malignant melanotic nerve sheath tumor, and melanotic PEComa.9-12 Metastatic melanoma is particularly important because of the presence of melanin and SOX10 and Melan-A expression. However, diffuse pancytokeratin and neuroendocrine marker expression strongly supported a pulmonary neuroendocrine neoplasm rather than melanoma. The presence of classic neuroendocrine morphology, including organoid architecture and pseudorosette formation, further supported the diagnosis. SOX10 is also not entirely specific for melanocytic differentiation and may be expressed in other neoplasms.13

An important distinction in this case is between sustentacular staining and true melanocytic differentiation. S100 and SOX10 highlighted sustentacular cells, while a subset of the neoplastic cells themselves expressed SOX10 and Melan-A. This distinction is important because sustentacular cells may be encountered in pulmonary carcinoids and paragangliomas and should not be interpreted as evidence of melanocytic differentiation within the tumor.

Pigment in pulmonary neuroendocrine tumors may represent melanin, neuromelanin, or lipofuscin.5,14 Therefore, pigment characterization and correlation with the immunophenotype are important in diagnostically challenging cases. In the present tumor, the combination of Masson-Fontana-positive pigment, negative Perls staining, and focal melanocytic marker expression within neoplastic cells supports true melanocytic differentiation within an atypical carcinoid.

Interestingly, melanocytic marker expression was more extensive in the metastatic lymph nodes than in the primary tumor, suggesting possible intratumoral heterogeneity, with preferential expansion of a subpopulation showing melanocytic differentiation; however, the mechanism cannot be established from a single case. Despite a relatively low Ki-67 index of around 5%, the tumor demonstrated 5 mitoses per 2 mm² and metastases to 7 of 14 regional lymph nodes. Mitotic activity and nodal status are important prognostic factors in pulmonary atypical carcinoids.15,16 This case therefore illustrates that a relatively low Ki-67 index does not preclude substantial regional metastatic disease in an atypical carcinoid.

This case highlights an unusual immunophenotypic pitfall in pulmonary carcinoid tumors. Recognition of neuroendocrine morphology and use of a broad immunohistochemical panel are essential when evaluating a pigmented pulmonary neoplasm, as melanocytic marker expression alone should not lead to a diagnosis of metastatic melanoma. In particular, diffuse pancytokeratin and neuroendocrine marker expression should prompt consideration of a neuroendocrine neoplasm even when melanocytic markers are expressed by a subset of tumor cells.

Resources

1. WHO Classification of Tumours Editorial Board. Thoracic Tumours. 5th ed. Lyon, France: International Agency for Research on Cancer; 2021.
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12. de la Fouchardiere A, Papke DJ, Pissaloux D, et al. Melanotic PEComa: a rare but distinctive subtype analyzed in a series of 7 cases. Am J Surg Pathol. 2024;48(1):71-81.
13. Miettinen M, McCue PA, Sarlomo-Rikala M, et al. Sox10—a marker for not only schwannian and melanocytic neoplasms but also myoepithelial cell tumors of soft tissue: a systematic analysis of 5134 tumors. Am J Surg Pathol. 2015;39(6):826-835.
14. Iihara K, Yamaguchi K, Fujioka Y, Uno S. Pigmented neuroendocrine tumor of the lung, showing neuromelanin. Pathol Int. 2002;52(11-12):734-739.
15. Soldath P, Bianchi D, Manfredini B, et al. Prognostic thresholds of mitotic count and Ki-67 labeling index for recurrence and survival in lung atypical carcinoids. Cancers (Basel). 2024;16(3):535.
16. García-Fontán EM, Cañizares-Carretero MÁ, Blanco-Ramos M, et al. Prognostic significance of histopathological factors in survival and recurrence of atypical carcinoid tumours. Interact Cardiovasc Thorac Surg. 2021;32(6):858-865.

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