The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.

Diagnosing a pulmonary neuroendocrine neoplasm (NEN) may be difficult, challenging clinical decision making. In this review, the following key clinical and pathologic issues and informative molecular markers are being discussed: (1) What is the preferred outcome parameter for curatively resected low-grade NENs (carcinoid), for example, overall survival or recurrence-free interval? (2) Does the WHO classification combined with a Ki-67 proliferation index and molecular markers, such as OTP and CD44, offer improved prognostication in low-grade NENs? (3) What is the value of a typical versus atypical carcinoid diagnosis on a biopsy specimen in local and metastatic disease? Diagnosis is difficult in biopsy specimens and recent observations of an increased mitotic rate in metastatic carcinoid from typical to atypical and high-grade NEN can further complicate diagnosis. (4) What is the (ir)relevance of morphologically separating large cell neuroendocrine carcinoma (LCNEC) SCLC and the value of molecular markers (RB1 gene and pRb protein or transcription factors NEUROD1, ASCL1, POU2F3, or YAP1 [NAPY]) to predict systemic treatment outcome? (5) Are additional diagnostic criteria required to accurately separate LCNEC from NSCLC in biopsy specimens? Neuroendocrine morphology can be absent owing to limited sample size leading to missed LCNEC diagnoses. Evaluation of genomic studies on LCNEC and marker studies have identified that a combination of napsin A and neuroendocrine markers could be helpful. Hence, to improve clinical practice, we should consider to adjust our NEN classification incorporating prognostic and predictive markers applicable on biopsy specimens to inform a treatment outcome-driven classification.

Generally, patients with stage I-IIIa (TNM) pulmonary carcinoid disease have a favourable prognosis after curative resection. Yet, distant recurrence of disease after curative surgery occurs in approximately 1–6% of patients with typical carcinoid and 14–29% in patients with atypical carcinoid disease, respectively. Known predictors of distant recurrence of disease are atypical carcinoid, lymphatic involvement, and incomplete resection status. However, none of them can be reliably used, alone or in combination, to exclude patients from long-term follow-up (advised 15 years). By genomic profiling, Orthopedia homeobox (OTP) has been identified as a promising prognostic marker for pulmonary carcinoid with a favourable prognosis and low risk of distant disease recurrence. Moreover, OTP is a highly specific marker for carcinoids of pulmonary origin and recent genome wide analysis has identified OTP as a crucial predictor of aggressive tumor behaviour. OTP in combination with CD44, a stem cell marker and cell-surface protein, enables the identification of patients with surgical resected carcinoid disease that could potentially be excluded from long-term follow-up. In future clinical practice OTP may enable clinicians to reduce the diagnostic burden and related distress and reduce costs of long-term radiological assessments in patients with a pulmonary carcinoid. This review addresses the current clinical value of OTP and the possible molecular mechanisms regulating OTP expression and function in pulmonary carcinoids.

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