Intracholecystic tubular non-mucinous neoplasm (ICTN) of the gallbladder: a clinicopathologically distinct, invasion-resistant entity

Virchows Arch. 2021 Mar;478(3):435-447. doi: 10.1007/s00428-020-02877-7. Epub 2020 Jul 20.


Preinvasive tumor-forming gallbladder neoplasms that are composed of small, non-mucinous tubules with complex architecture remain a poorly characterized group. Here, we evaluated the clinicopathological characteristics of this entity. Twenty-eight examples were analyzed. Tumors were invariably pedunculated polyps with thin stalks, often presented as loosely attached intraluminal nodules, with cauliflower architecture (akin to cholesterol polyps) comprised of compact, back-to-back acinar-like, small tubular units with minimal/no cytoplasm showing variable complexity, creating a picture distinct from the other tubular type dysplasia in the gallbladder. Their limited stroma showed distinctive amorphous amyloid-like hyalinization (39%). While some had round nuclei with single prominent nucleoli, others exhibited slightly more elongated nuclei with washed out chromatin reminiscent of papillary thyroid carcinoma. Squamoid/meningothelial-like morules (71%) and subtle neuroendocrine cell clusters (39%) were frequent. The level of cytoarchitectural atypia qualified as high-grade dysplasia (HGD) in all cases, but none were invasive. The background mucosa showed no dysplasia, but cholesterolosis. The majority (n = 8/12) showed diffuse MUC6 expression and lacked MUC5AC expression. Based on these observations, 635 gallbladder carcinomas were re-analyzed for residual/adjacent lesions with entity-defining characteristics disclosed here, and none could be identified. Preinvasive tubular non-mucinous neoplasm of the gallbladder, which we propose to classify as intracholecystic tubular non-mucinous neoplasm, is a clinicopathologically discrete entity, which tends to occur in uninjured gallbladders and in association with cholesterol polyps. By being tubular, non-mucinous and MUC6-positive, it is akin to intraductal tubulopapillary neoplasms of pancreatobiliary tract, but it is also different in many other aspects. Although their cytoarchitectural complexity warrants an HGD/carcinoma classification, they do not show invasion and their distinct characteristics warrant their separate classification.

Keywords: Adenoma; Gallbladder; Preinvasive neoplasm; Pyloric; Tubular Papillary.

Publication types

  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / analysis
  • Databases, Factual
  • Female
  • Gallbladder Neoplasms / chemistry
  • Gallbladder Neoplasms / classification
  • Gallbladder Neoplasms / pathology*
  • Humans
  • Male
  • Middle Aged
  • Mucin 5AC / analysis
  • Mucin-6 / analysis
  • Neoplasm Invasiveness
  • Polyps / chemistry
  • Polyps / classification
  • Polyps / pathology*
  • Tumor Burden


  • Biomarkers, Tumor
  • MUC5AC protein, human
  • MUC6 protein, human
  • Mucin 5AC
  • Mucin-6