CD44 and OTP Are Strong Prognostic Markers for Pulmonary Carcinoids

Abstract

Purpose: Pulmonary carcinoids are well-differentiated neuroendocrine tumors showing usually a favorable prognosis. However, there is a risk for late recurrence and/or distant metastasis. Because histologic classification in typical and atypical carcinoids is difficult and its reliability to predict disease outcome varies, we evaluated three genes as potential prognostic markers, that is, orthopedia homeobox (OTP), CD44, and rearranged during transfection (RET).Experimental Design: These genes were analyzed in 56 frozen carcinoids by quantitative real-time PCR (qRT-PCR). RET was further studied by methylation and mutation analysis. Immunohistochemistry for CD44 and OTP protein expression was conducted on 292 carcinoids.Results: Low mRNA expression levels of CD44 (P ¼ 1.8e À5) and OTP (P ¼ 0.00054), and high levels of RET (P ¼ 0.025), were strongly associated with a low 20-year survival of carcinoid patients. High RET expression was not related to promoter hypomethylation or gene mutations. A direct link between gene expression and protein levels was confirmed for CD44 and OTP but not for RET. Within all carcinoids as well as atypical carcinoids, absence of CD44 protein was significantly associated with low 20-year survival (P ¼ 0.00014 and 0.00013, respectively). The absence of nuclear OTP followed by complete loss of expression was also significantly associated with unfavorable disease outcome in all carcinoids (P ¼ 5. 2 À6 ). Multivariate analyses revealed that age at diagnosis, histopathology, stage, and cytoplasmic OTP immunoreactivity were independent predictors of prognosis.Conclusions: Our study indicates that CD44 and OTP are strong indicators of poor outcome. We therefore argue for implementation of these markers in routine diagnostics in addition to histopathology to improve subclassification of pulmonary carcinoids into prognostically relevant categories.

Ki-67 labeling index of neuroendocrine tumors of the lung has a high level of correspondence between biopsy samples and surgical specimens when strict counting guidelines are applied

“…In metastatic lung NET, the importance of the Ki-67 LI on biopsy samples is not so much the diagnosis as such (which paradoxically matters less once high-grade NET has been excluded) but rather to guide subsequent therapy choice [33]. This molecular, morphological, and clinical heterogeneity of lung NET [20,39,[46][47][48][49][50] is similar to that of G3 GEP NET for which the Ki-67 LI is of equal diagnostic importance [26,[51][52][53][54][55][56]. Of note, LCNECs of the lung show a wide range of histological and molecular features, as some cases are morphologically close to SCCs [13, 14,16,47], while others are closer to conventional non-small cell carcinoma [47,[57][58][59]] and yet others to AC [3,8,47].…”

Original paper Morphological and immunohistochemical profile of pancreatic neuroendocrine neoplasms

“…In pulmonary carcinoids, low levels of CD44 mRNA and absence of the CD44 protein are associated with a low 20-year survival [84]. In a combined group of pulmonary and gastrointestinal neuroendocrine neoplasms originally described as carcinoids, the patients with lymph node or distant metastasis lacked CD44 in the tumours significantly more frequently [85].…”

What clinicians are asking pathologists when dealing with lung neuroendocrine neoplasms?

“…Accordingly, it is not surprising that common genetic traits may be shared by each of these two broad tumor categories, with TC/AC on the one hand and LCNEC/SCLC on the other hand exhibiting major differences in the somatic mutation rates and engagement of diverse gene pathways 8,12,[26][27][28][29][30][31][32][33] . A further inherent molecular heterogeneity, however, is found within each histological variant on the basis of several functional and genetic biomarkers, which may identify different patient subsets with different prognosis 31,[34][35][36][37] .…”