Importance: Patients with extrapulmonary neuroendocrine carcinomas (EPNECs) receive essentially the same treatment as those with small cell lung cancer (SCLC) despite differences in origin, clinical course, and survival. This SCLC-based approach is attributable to the rarity of EPNECs, which impedes the use of randomized clinical trials. However, neuroendocrine carcinomas are becoming more common because of the increasing use of systemic cancer therapy for adenocarcinomas. This treatment can transdifferentiate certain adenocarcinomas into neuroendocrine carcinomas. In addition, the treatment landscape for SCLC is slowly changing, potentially impacting the treatment paradigms for EPNECs.
Observations: New information on tumorigenesis of EPNECs from different origins, either as a primary malignant tumor or after neuroendocrine differentiation from adenocarcinomas, demonstrates their biological similarity. Activated molecular pathways that appear to underlie the development of EPNECs are potentially targetable, and some of these targets, such as poly(adenosine diphosphate-ribose) polymerase, Wee1, and Aurora A kinase, are currently under investigation. Immune checkpoint inhibitors (ICIs) already constituted a new treatment modality for patients with SCLC and produced some promising results in patients with EPNECs.
Conclusions and relevance: Although only moderately effective, the introduction of ICIs signifies the first new option in systemic treatment of SCLC in decades. To prove the value of ICIs and other new drugs for patients with EPNECs, these patients should be included in clinical trials independent of the primary tumor site. Furthermore, to optimize clinical decision-making for patients with EPNECs, experts from the neuroendocrine tumor board should collaborate with members from tumor site-specific boards, which will require patient referral to a center with EPNEC expertise.