Abstract
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.
Highlights
Pulmonary carcinoids (PC) are rare, well-differentiated neuroendocrine tumors accounting for1–2 per cent of all lung cancers [1]
In contrast to high-grade neuroendocrine lung carcinomas, such as large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC), carcinoids are characterized by a lower metastatic rate and a relatively favourable prognosis
A possible explanation for the Orthopedia homeobox (OTP)+/TTF1− cases might be the involvement of the NOTCH receptor 1 (NOTCH1)-hairy and enhancer of split-1 (HES1) signalling pathway which is reported as an inhibitor of ASCL1, POU3F2, and NE molecules (CHGA, CD56, SYP) [39]
Summary
Pulmonary carcinoids (PC) are rare, well-differentiated neuroendocrine tumors accounting for. In contrast to high-grade neuroendocrine lung carcinomas, such as large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC), carcinoids are characterized by a lower metastatic rate and a relatively favourable prognosis. The utility of this marker to differentiate TCs from ACs or to predict prognosis within individual carcinoid tumors is limited [13]. These diagnostic limitations indicate the need for alternative molecular markers to subdivide carcinoids into clinical relevant categories [4]. We comprehensively review current literature on OTP function, OTP expression in lung neuroendocrine neoplasms, and possible molecular pathways through which it might operate in both normal and pulmonary neuroendocrine tumor tissue
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