Retrospective study on mixed neuroendocrine non-neuroendocrine neoplasms from five European centres

ARTICLE HIGHLIGHTS

Research background

Mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is characterised by the coexistence of two histologies and is a rare disease, most commonly originating in the digestive system. Evidence from the literature is limited and inconsistent.

Research motivation

Although rare, when encountered, MiNEN represents a therapeutic riddle for clinicians, as there is still uncertainty as to how patients with this diagnosis should be managed, in the absence of data from clinical trials. In addition, the actual incidence of MiNEN remains unknown. Therefore, data from large retrospective studies is warranted.

Research objectives

The present study was designed to provide insights on the epidemiology and prognosis of MiNEN from the gastro-entero-pancreatic tract (GEP), as well as on commonly applied therapeutic approaches, with the ultimate aim of providing some guidance for clinical practice.

Research methods

To this end, a large retrospective, multicentre collection of clinical-pathological and survival data, and treatment modalities from patients with a diagnosis of GEP-MiNEN was carried out. Original diagnostic samples were reviewed by pathologists with expertise in neuroendocrine neoplasms to ascertain compliance with the most recent diagnostic criteria for MiNEN (WHO classification 2017). Potential differences in survival outcomes between subgroups with distinct clinical-pathological characteristics were also investigated.

Research results

MiNEN is most commonly diagnosed in the colon-rectum and oesophagus/oesophago-gastric junction. The neuroendocrine component is almost always grade 3, and is most commonly the predominant histology in both the primary tumour and distant metastatic sites. The non-neuroendocrine component is of adenocarcinoma histology in most cases. Patients with potentially curable MiNEN usually receive curative surgery, in combination or not with pre- and/or post-operative chemotherapy and/or radiotherapy as per standard of care for pure adenocarcinomas form the same sites of origin. Patients with advanced MiNEN most commonly receive chemotherapy following protocols for pure neuroendocrine carcinomas or adenocarcinomas from the same sites of origin. The prognosis of MiNEN is poor; patients with initially curative MiNEN have a high likelihood of recurrence (around 2/3 of cases), with half of cases developing disease recurrence within the first 12 months from curative treatment. Patients with advanced stage MiNEN progress soon after the beginning of palliative treatment and have survival outcomes very close to those of pure GEP-NECs.

Research conclusions

The incidence of MiNEN is likely underestimated, as tissue biopsies may not be able to capture both the histologies; it is a predominantly metastatic disease, and metastatic sites are usually occupied by a single component (most frequently G3, neuroendocrine). A pathological review of the samples by pathologists with expertise in neuroendocrine neoplasms is strongly recommended. A second biopsy from metastatic sites is encouraged, whenever possible, especially on disease progression. Systemic treatments directed against one of the two components have limited efficacy. Novel drug development should exploit common biological vulnerabilities between the two components. Biological studies and liquid biopsies may aid in unveiling the molecular landscape of MiNEN, and informing drug development and clinical trial design.