Decreased immunoreactivity of CD99 is an independent predictor of regional lymph node metastases in pulmonary carcinoid tumors

Background: Few data are available on the prevalence and clinicopathological meaning of CD99, the transmembrane product of the pseudoautosomal MIC2 gene, in pulmonary neuroendocrine tumors. Methods: We evaluated CD99 immunoreactivity in lung tissues, pulmonary neuroendocrine hyperplasias, and 136 consecutive pulmonary neuroendocrine tumors of diverse histological types. Results: By immunohistochemistry, a membranous and/or cytoplasmic immunoreactivity was seen in 60 of 136 (44%) tumors, whereas both normal and hyperplastic neuroendocrine cells of the lung were consistently nonreactive. A steady decrease of the CD99 labeling index was observed from better to poorly differentiated tumors, with a prevalence of the membranous pattern in typical carcinoids (TCs), and of the cytoplasmic pattern in atypical carcinoids (ACs) and large cell neuroendocrine carcinoma/small cell lung carcinoma (P < 0.0001), independent of tumor stage. In TCs/ACs, increased levels of CD99 labeling index or the membranous pattern were associated with low proliferative fraction (P = 0.0011) and smaller tumor size (P = 0.0054) and with lack of regional lymph node metastases (P = 0.0078). Moreover, CD99 expression decreased according to the pN0-2 classes (P = 0.0016), with an inverse relationship between the number of positive lymph nodes, the labeling index (P = 0.013) and the nonmembranous pattern (P = 0.016). At multivariate analysis, both the decreased CD99 labeling index and the negative/cytoplasmic staining were independent risk indicators for lymph node metastases in the subset of TC/AC patients. No relevant relationships were found in large cell neuroendocrine carcinoma/small cell lung carcinoma. Conclusion: CD99 is especially present in low- to intermediate-grade neuroendocrine tumors of the lung, and loss of the marker correlates with the occurrence of nodal metastases in TOAC patients.