The Morphologic Spectrum of Gastric Type 1 Enterochromaffin-Like Cell Neuroendocrine Tumors

Although most well-differentiated gastric neuroendocrine tumors (gNETs) arise from enterochromaffin-like (ECL) cells in patients with autoimmune metaplastic atrophic gastritis (AMAG), the morphologic spectrum of these type 1 ECL-cell gNETs is not well defined. The extent of metaplastic progression in the background mucosa of AMAG patients with gNETs is likewise unclear. Here we report the histomorphology of 226 gNETs, including 214 type 1 gNETs (78 cases from 50 AMAG patients) pooled from a population with high AMAG prevalence. Most type 1 gNETs were ≤1.0 cm, of low grade, and multifocal, consistent with the results of previous reports. However, a high proportion (70/214, 33%) displayed unusual gNET morphologies not previously appreciated in AMAG patients. Unlike other type 1 gNETs with conventional neuroendocrine tumor morphologies, unconventional type 1 gNETs displayed cribriform networks of atrophic cells embedded within myxoid matrix (secretory-cribriform variant, 59%), sheets of deceptively bland discohesive cells resembling inflammatory infiltrates (lymphoplasmacytoid variant, 31%), or wreath-like arrangements of columnar cells wrapped around collagenous cores (pseudopapillary variant, 14%). Another unusual feature was that unconventional gNETs grew laterally within the mucosa (50/70, 71%) and were only rarely sampled from the submucosa (3/70, 4%). These features also differed from the conspicuous radial nodules (99/135, 73%) and frequent submucosal involvement (57/135, 42%) observed for conventional gNETs (P < .0001). Irrespective of morphology, type 1 gNETs were nearly always detected at first AMAG diagnosis (45/50, 90%) and tended to persist thereafter (34/43, 79%), despite similar clinical symptoms and laboratory values between AMAG patients with gNETs and those without. However, unlike AMAG patients without gNETs (n = 50), the background mucosa in patients with gNETs (n = 50) had already progressed to the morphologic equivalent of end-stage metaplasia (P < .0001). This included diffuse loss of parietal cells (92% vs 52%), complete intestinal metaplasia (82% vs 40%), and pancreatic metaplasia (56% vs 6%). Thus, type 1 ECL-cell gNETs are morphologically heterogeneous with a high prevalence of unconventional gNET morphologies. They tend to present silently at first AMAG diagnosis as multifocal lesions that persist within fields of mature metaplasia.