Decreased Immunoreactivity of CD99 Is an Independent Predictor of Regional Lymph Node Metastases in Pulmonary Carcinoid Tumors

Abstract

Few data are available on the prevalence and clinicopathological meaning of CD99, the transmembrane product of the pseudoautosomal MIC2 gene, in pulmonary neuroendocrine tumors. We evaluated CD99 immunoreactivity in lung tissues, pulmonary neuroendocrine hyperplasias, and 136 consecutive pulmonary neuroendocrine tumors of diverse histological types. 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. 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 TC/AC patients.