Answer

Answer: Chronic cholecystitis with reactive proliferation of Luscka ducts.

Discussion:
Sections revealed acute/chronic cholecystitis with thickened wall and extensively denuded mucosa (Figure 1). There was also a florid glandular/ductular proliferation lined with bland-to-mildly atypical biliary-type epithelium within the perimuscular soft tissue (Figures 2- 4). These ductules were mostly uniform in size and were not connected to the lumen. Differential diagnoses included invasive adenocarcinoma despite the bland cytology as invasive adenocarcinoma of the gallbladder may reveal extremely bland cytology. However, based on the location of the lesion (within subserosa), and lack of mucosal dysplasia, a benign process, i.e., reactive/hyperplastic changes of Luschka ducts (also termed subvesical bile ducts^[1]) was also considered. 

As reported by Singhi et al^[2], reactive proliferation of Luschka ducts is characterized with lobular aggregates of small ductules lined by bland epithelium, associated with centrally located, larger ductules surrounded by concentric fibrosis. On the other hand, irregular growth pattern, full thickness involvement, loss of concentric fibrosis, epithelial atypia with significant nuclear variation (4:1), and vascular/perineural invasion strongly suggest malignancy.

Upon reviewing the microscopic findings in this case, the architecture/arrangement of those atypical glands was somewhat irregular (Figure 3). However, there were some foci with classic lobular architecture (Figure 2: right lower corner) and ducts with concentric fibrosis (Figure 2: inset). More importantly, the lesion was within the perimuscular soft tissue, there was no connection between the mucosal surface and the ducts and there was no dysplasia within the mucosal surface (Figure 1). Also, the lining epithelial cells were predominantly bland (Figures 3: inset & 4). Although mild cytologic atypia with mitosis (Figure 4, Arrow) was seen in some areas, there was no significant nuclear variation (Figures 3 & 4). No lymph-vascular or perineural invasion was identified, either.

The case was shared with several experts, who did not find overt features of malignancy and specifically stated that, in the absence of other malignant features, mitotic activity alone would not argue against a benign diagnosis (i.e. Chronic cholecystitis with reactive proliferation of Luschka ducts).  

Adenomyomatous hyperplasia is usually a grossly visible lesion characterized by a mural collection of cysts forming a small mass or a band of trabeculated thickening of the gallbladder wall, most often in the fundic region. “Adenomyomatosis” refers to the more diffuse form of this condition. Microscopic findings include cystically dilated and branched glands (Figure 5, thin arrows) surrounded by tunica muscularis (thick arrows). It should be noted that some glandular elements in benign adenomyomatous nodules may impinge on the nerves, mimicking perineurial invasion ^[3] .

Intracholecystic papillary neoplasm (ICPN) is a grossly visible (typically >1 cm) preinvasive epithelial neoplasms arising in the mucosa and projecting into the lumen of the gallbladder^[4]. Grossly it is characterized by granular, friable excrescences or by a distinct polypoid/exophytic mass. Microscopically, it demonstrates papillary (Figure 6) and/or tubular configuration, different cell lineages (biliary, gastric, intestinal or oncocytic) and a spectrum of dysplastic change, which can be graded as low- or high-grade based on architectural and cytologic complexity. Adsay et al reported that about 50% of ICPNs are associated with invasive adenocarcinoma, particularly the ones with predominantly biliary morphology or extensive high-grade dysplasia. However, even when only ICPNs with an associated invasive carcinoma are considered, the overall outcome of ICPNs is incomparably better than that of conventional gallbladder adenocarcinomas ^[4].

In conclusion, Luschka ducts are small bile ducts occasionally found at the gallbladder fossa and/or along the serosal surface. Rarely, prominent ductal proliferation with mild cytologic atypia might be seen and distinguishing this benign/reactive process from invasive adenocarcinoma could be difficult. Adequate sampling and meticulous microscopic examination may be required.

References:

1. Schnelldorfer T, Sarr MG, Adams DB. What is the duct of Luschka?–A systematic review. J Gastrointest Surg. 2012 Mar;16(3):656-62.

2. Singhi AD, Adsay NV, Swierczynski SL, Torbenson M, Anders RA, Hruban RH, Argani P. Hyperplastic Luschka ducts: a mimic of adenocarcinoma in the gallbladder fossa. Am J Surg Pathol. 2011 Jun;35(6):883-90

3. Albores-Saavedra J, Keenportz B, Bejarano PA, Alexander AA, Henson DE. Adenomyomatous hyperplasia of the gallbladder with perineural invasion: revisited. Am J Surg Pathol. 2007 Oct;31(10):1598-604.

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.

[line]

Case contributed by:

Cherif Ibrahim, MD, FRCPC
Department of Laboratory Medicine
Queensway Carton Hospital
Ottawa, ON, Canada
E-mail: cibrahim@qch.on.ca

Goo Lee, MD, PhD
Department of Pathology
University of Alabama at Birmingham
Birmingham, AL, USA
E-mail: glee@uabmc.edu