Case 1: Quarter 1, 2023

Case 1: Quarter 1, 2023

Clinical History

A female patient in her 60s with gallstones underwent cholecystectomy. Upon gross examination, a detached polyp (1.2 cm) was found within the gallbladder. Multiple gritty stones were also found. The gallbladder mucosa had a yellow, speckled surface, which is grossly consistent with cholesterolosis. No mass lesion is grossly identified.

Histologic/Cytologic Features 

The low-power view of the bisected polyp showed nodular/cauliflower-like architecture with no distinct stalk (Figure 1). The polyp was composed of compact small tubules, lined by atypical cuboidal, non-mucinous epithelium (Figures 2 and 3). Intervening stroma is limited with scattered inflammatory cells. Occasional squamoid morules were noted (Figure 4).

Figure 1: low-power view of the bisected polyp showed nodular/cauliflower-like architecture with no distinct stalk
Figure 2: Polyp was composed of compact small tubules, lined by atypical cuboidal, non-mucinous epithelium
Figure 3: Compact small tubules, lined by atypical cuboidal, non-mucinous epithelium ( High Power view)
Figure 4: Squamoid morules

An immunohistochemical stain for MUC6 was positive (Figure 5). Immunohistochemical stain for Beta-catenin showed strong nuclear and cytoplasmic staining in the tumor cells as well as in the squamoid morules (Figure 6). Background mucosa was extensively submitted for microscopic examination and showed cholesterolosis, but no dysplasia (Figure 7). 

Figure 5. MUC-6 Immunohistochemical stain
Figure 6. Beta-catenin Immunohistochemical stain
Figure 7. Background mucosa with cholesterolosis, but no dysplasia

Please select your diagnosis in the poll, then see the answer and the discussion in the links below.

What is your diagnosis?

View Results

Loading ... Loading ...

Click Here To See The Answer

Answer: Intracholecystic Tubular Non-mucinous Neoplasm (ICTN) with high-grade dysplasia.


Click Here To See The Discussion

Final diagnosis:  

Intracholecystic Tubular Non-mucinous Neoplasm (ICTN) with high-grade dysplasia.


Intracholecystic Tubular Non-mucinous Neoplasm (ICTN) is an unusual type of intracholecystic neoplasm of the gallbladder, recently described as having distinct histologic findings from those of ICPN [1]. Pehlivanoglu et al. [1] analyzed 28 cases of ICTN. Demographic data revealed female/male ratio of 0.9, mean age of 51 years, and mean tumor size of 1.6 cm. The tumors presented as mass-forming lesions comprised of tightly packed, back-to-back, small tubule/glands with areas of cribriform architecture. The tubules/glands were lined by cuboidal, non-mucinous epithelium with high nuclear:cytoplasmic ratio and eosinophilic cytoplasm.

Nuclei were overlapping, round or ovoid with occasional nucleoli and clearing of the chromatin, reminiscent of the nuclear features seen in papillary thyroid carcinoma (Figure 3). The levels of nuclear atypia and architectural changes qualified as high-grade dysplasia in all cases. Squamoid morules were frequently noted. Amorphous amyloid-like hyalinization was sometimes present in the stroma. Immunohistochemical findings [1] showed diffuse positivity of MUC6 (about 70% of cases), scattered positivity of CDX2 (50%), particularly within squamoid morules and labeling for MUC5AC (10%). β-catenin showed diffuse nuclear expression in the tumor cells as well as the morular cells in two (2) cases.

The background gallbladders were without chronic inflammation/injury. Cholesterolosis/cholesterol polyps were commonly seen. However, there was no dysplasia in the background gallbladders and no association with invasive carcinoma. The authors also reviewed >600 gallbladder carcinomas in association with the initial characterization of ICTN and found no residual or associated lesions with similar features to the described cases of ICTN.

The pathogenesis of ICTN has not been fully elucidated but may be associated with alteration of Wnt/β-catenin pathway. Lesions with similar morphology have previously been considered as either a pyloric type of ICPN or as a type of PGA [3].  In summary, cases similar to the one presented here appear to have distinct features from ICPN, occurring in gallbladders with largely normal mucosa and without an associated invasive carcinoma. Further investigation with additional cases is needed to follow to fully establish these features, relationships to other biliary neoplasms and clinical behavior.

Differential diagnosis:

ICPN is a precancerous lesion of the gallbladder. Grossly it forms a distinct polypoid/exophytic intraluminal mass and microscopically shows papillary and/or tubular configuration with dysplasia, which can have four major morphological patterns, e.g., biliary, intestinal, gastric, oncocytic, or combination of these morphologically patterns [2, 4]. Regarding the molecular characteristics of ICPN, mutations in STK11 and CTNNB1 have been identified [3]. Surrounding mucosal epithelium may be associated with dysplasia as well.  About 50% of ICPNs are associated with invasive adenocarcinoma, but it has a better clinical outcome compared to conventional gallbladder adenocarcinomas.

PGA of the gallbladder is a polypoid neoplasm consisting of uniform, back-to-back mucinous glands with pyloric or Brunner gland features.  Positive β-catenin by IHC and mutation of CTNNB1 were identified in 60% of PGAs [2]. They also show diffuse and strong positivity of MUC6. 20% of PGAs contain squamoid morules. PGAs may also have variation in the amount of cytoplasmic mucin, with mucin-poor variants identified, although this is not the typical morphology [3]. Similar to ICTN, multifocality (field effect) is not a feature of PGAs [2]. Taken together, ICTNs are considered to have overlapping pathologic features with PGAs, but the recent characterization of ICTN suggests that they should be considered separate entity from mucinous PGAs [3].

BilIN is a microscopic, non-invasive, flat or (micro)papillary neoplastic lesion, usually not grossly visible.  KRAS mutations were identified in about 40% of cases as an early molecular event of carcinogenesis. It is often present in the mucosa adjacent to the carcinomas. BilIN is graded as low-grade and high-grade according to the degree of cytologic atypia and architectural changes. Low grade is of no clinical significance but high grade warrants extensive sampling to detect an occult invasive carcinoma [2].


  1. Pehlivanoglu B, Balci S, Basturk O, Bagci P, Erbarut Seven I, Memis B, Dursun N, Jang KT, Saka B, Ohike N, Tajiri T, Roa JC, Sarmiento JM, Reid MD, Adsay V. Intracholecystic tubular non-mucinous neoplasm (ICTN) of the gallbladder: a clinicopathologically distinct, invasion-resistant entity. Virchows Arch. 2021 Mar;478(3):435-447. 
  2. Basturk O, Aishima S, Esoposito I. World Health Organization Classification of Tumours. Intracholecystic papillary neoplasm. In: Digestive System Tumours. 2019, IARC, Lyon.
  3. Fukumura Y, Rong L, Maimaitiaili Y, Fujisawa T, Isayama H, Nakahodo J, Kikuyama M, Yao T. Precursor Lesions of Gallbladder Carcinoma: Disease Concept, Pathology, and Genetics. Diagnostics (Basel). 2022 Jan 28;12(2):341.
  4. Adsay V, Jang KT, Roa JC, Dursun N, Ohike N, Bagci P, Basturk O, Bandyopadhyay S, Cheng JD, Sarmiento JM, Escalona OT, Goodman M, Kong SY, Terry P. Intracholecystic papillary-tubular neoplasms (ICPN) of the gallbladder (neoplastic polyps, adenomas, and papillary neoplasms that are ≥1.0 cm): clinicopathologic and immunohistochemical analysis of 123 cases. Am J Surg Pathol. 2012 Sep;36(9):1279-301. 

Case contributed by:

Goo Lee, MD- University of Alabama at Birmingham.


Special thanks to Volkan Adsay, MD, Koc University Hospitals, Turkey, for his consultative expertise.

Conflict of Interest: No