Ampullary Carcinoma (AMPCA)

Overview

Ampullary carcinoma arises at the ampulla of Vater, where the common bile duct and pancreatic duct join the duodenum. In the OncoTree hierarchy it sits under the Ampulla of Vater tissue node (parent: AMPULLA_OF_VATER). Clinically it is grouped with distal bile-duct (extrahepatic) cholangiocarcinoma and duodenal adenocarcinoma as the three periampullary cancers, all resected by pancreatoduodenectomy (Whipple procedure). Histologically, two IHC subtypes are recognised — pancreatobiliary (CK7+/CK20-) and intestinal (CK7-/CK20+) — but molecular profiling shows these subtypes do not cleanly segregate the driver mutation landscape.

Cohorts in the corpus

  • ampca_bcm_2016 — 98 ampullary adenocarcinomas from the Australian Pancreatic Cancer Genome Initiative (APGI), Baylor College of Medicine, MD Anderson, and TU Dresden, all from patients who underwent curative-intent pancreatoduodenectomy; whole-exome sequencing + SNP-array CNAs + RNA-seq (28/98 subset); reference genome GRCh37 PMID:26804919.

Recurrent alterations

  • WNT pathway mutated in 49% of AMPCA tumors (significantly lower than 72% in DUOAC and higher than 30% in CAC; ChiSq p < 0.05); intestinal-subtype AMPCA is 67% WNT-altered vs. 30% in pancreatobiliary tumors PMID:26804919.
  • ELF3 inactivating frameshift/nonsense mutations in 10.6% of periampullary tumors overall; predominantly AMPCA-enriched; mutation rate ~3× higher than in any other cancer in cBioPortal at the time; ELF3 loss-of-function co-occurs with WNT-pathway mutations in 71% of cases (Chi-square p = 0.02); proposed early driver (found in a duodenal adenoma with intraepithelial neoplasia) PMID:26804919.
  • SMAD4 — most commonly mutated TGF-β-pathway gene in AMPCA and EHCH (sites anatomically closest to the pancreas) PMID:26804919.
  • ARID1A, ARID2 — most frequent SWI/SNF chromatin-remodeling alterations; equally distributed across all three periampullary tumor types PMID:26804919.
  • KDM4C — statistically significant focal chromosome-9 deletion removing the promoter and 5′ end, reducing KDM4C expression and the upstream UHRF2; significant specifically in AMPCA PMID:26804919.
  • PMS2 — germline Lynch-syndrome gene mutated in ~50% of MSI-positive periampullary patients, disproportionately high vs. <5% in general Lynch-syndrome populations PMID:26804919.
  • MSI present in 12 patients overall (AMPCA 3%); all 6 MSI-AMPAC patients were alive 2–8 years post-diagnosis (p = 0.04); MSI confers dramatically elevated mutation rates (68/Mb in AMPAC MSI vs. 3.8/Mb MSS) PMID:26804919.
  • RTK/RAS/PI3K pathway activated in 84–94% across all periampullary sites (including KRAS, TP53, CDKN2A) PMID:26804919.

Subtypes

  • Pancreatobiliary subtype (IHC CK7+/CK20-): 51% of AMPCA in the APGI/BCM cohort; associated with pancreatobiliary morphology but IHC-based and molecular-based subtype assignment agreed only 53–77% of the time PMID:26804919.
  • Intestinal subtype (IHC CK7-/CK20+): 34% of AMPCA; enriched for WNT-pathway alterations (67% vs. 30% in pancreatobiliary); associated with better prognosis in some series.
  • MSI-high subset: 3% of AMPCA; dramatically elevated mutation burden; all 6 MSI patients in this cohort survived 2–8 years post-surgery PMID:26804919.

Therapeutic landscape

  • WNT pathway inhibitors: With ~49% of AMPCA WNT-mutated, the authors propose AMPCA, DA, and EHCH should be classified as a single “WNT+/–” entity for therapeutic stratification; small-molecule β-catenin inhibitors were in clinical trials at the time of publication PMID:26804919.
  • MSI as a prognostic biomarker: MSI strongly predicts favorable outcome; situates AMPCA alongside CRC in candidate MSI-directed immunotherapy contexts PMID:26804919.
  • PMS2 germline screening: May be disproportionately valuable in periampullary tumors vs. general Lynch-syndrome populations PMID:26804919.

Sources

  • PMID:26804919 — Gingras et al. (2016), whole-exome sequencing of 160 periampullary tumors.

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