Metastatic neuroendocrine lesions in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH): a narrative review and case series.

Objective: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare entity characterised by the proliferation of neuroendocrine cells in the respiratory epithelium. DIPNECH is a pre-neoplastic condition that can progress to localised or metastatic neuroendocrine tumours (NETs). The understanding of DIPNECH remains limited, and although the European Neuroendocrine Society has recommendations for its management, there are currently no established guidelines. Method: This study involves a case series of three patients with DIPNECH progressing to metastasis, as well as a narrative review of previous cases screened from Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), Cochrane Central Register of Controlled Trials (CENTRAL) and SCOPUS databases. Results: In 40 documented cases of DIPNECH progression to metastasis, metastatic spread was more frequently observed in the thoracic lymph nodes, with a disproportionately high incidence of atypical carcinoid features on histological examination. Conclusion: Patients with DIPNECH are a heterogeneous group, and based on current data, it is difficult to confidently predict which are more likely to experience metastases. We provide recommendations for surveillance for a range of possible outcomes, including if there is DIPNECH without metastases, if there are no metastases but particularly large lesions and when metastases are present. Patients with DIPNECH-associated atypical neuroendocrine tumours, TNM stage > IIA, R1 resection margins and/or involvement of the visceral pleura ought to be monitored most closely. There are currently insufficient data to make meaningful recommendations regarding treatment options to prevent metastases. Learning points: There are more published cases of metastases developing in the context of DIPNECH, suggesting that this is not an indolent condition in all cases.Thoracic lymph nodes tend to be the source of metastases, with a disproportionately high incidence of cases having atypical carcinoid features on histological examination.Patients with DIPNECH are a heterogeneous group, and based on current data, it is difficult to confidently predict which are more likely to experience metastases. Patients with DIPNECH and one or more of the following features: atypical neuroendocrine tumours, TNM stage > IIA, R1 resection margins and/or involvement of the visceral pleura, ought to be monitored as per ENETS and ESMO guidelines for atypical bronchial NETs. DIPNECH with typical bronchial NET should be followed as per ENETS and ESMO guidelines for typical bronchial NETs. Surveillance for nodules with no confirmed histology of DIPNECH should be followed as per the British Thoracic Society Guidelines.For patients with histologically proved DIPNECH but without visible lung neuroendocrine tumours, CT thorax surveillance scans for 1-2 years appear appropriate. If dominant lesions are >8 mm, due to increased chances of these sized lesions being malignant, it would be reasonable to undertake a baseline SSTR-PET (somatostatin receptor positron emission tomography) to confirm if any lesions are avid. If negative, the subsequent surveillance should be CT thorax, as long as there is no evidence of metastatic disease.If the baseline SSTR-PET scan demonstrates avidity and there is no discordant disease (i.e. all lesions identified on SSTR-PET are also visualised on CT), then CT surveillance alone is considered sufficient. However, small lesions <8 mm may be well below the spatial resolution of SSTR-PET and, therefore, should not be regarded as discordant disease. A repeat SSTR-PET scan is indicated only if there is evidence of lesion size progression or the emergence of new lesions on CT imaging.For patients with typical or atypical neuroendocrine tumours on a background of DIPNECH, as they appear to be more likely to metastasis, we advise following the recommendations made by the European Neuroendocrine Tumour Society for long-term follow-up post-excision.