The literature on the clinicopathologic characteristics of tumoral intraepithelial neoplasms (neoplastic polyps) of the gallbladder (GB) is fairly limited, due in part to the variability in definition and terminology. Most reported adenomas (pyloric gland type and others) were microscopic and thus regarded as clinically inconsequential, whereas papillary in situ carcinomas have been largely considered a type of invasive adenocarcinoma under the heading of “papillary adenocarcinomas.” In this study, 123 GB cases that have a well-defined exophytic preinvasive neoplasm measuring ≥1 cm were analyzed. The patients were predominantly female (F/M=2:1) with a mean age of 61 y and a median tumor size of 2.2 cm. Half of the patients presented with pain, and in the other half the neoplasm was detected incidentally. Other neoplasms, most being gastrointestinal tract malignancies, were present in 22% of cases. Gallstones were identified in only 20% of cases. Radiologically, almost half were diagnosed as “cancer,” roughly half with polypoid tumor, and in 10% the lesion was missed. Pathologic findings: (1) The predominant configuration was papillary in 43%, tubulopapillary in 31%, tubular in 26%. (2) Each case was assigned a final lineage type on the basis of the predominant pattern (>75% of the lesion) on morphology, and supported with specific immunohistochemical cell lineage markers. The predominant cell lineage could be identified as biliary in 50% (66% of which were MUC1+), gastric foveolar in 16% (all were MUC5AC+), gastric pyloric in 20% (92% MUC6+), intestinal in 8% (100% CK20+; 75% CDX2+; 50%, MUC2+), and oncocytic in 6% (17% HepPar+ and 17% MUC6+); however, 90% of cases had some amount of secondary or unclassifiable pattern and hybrid immunophenotypes. (3) Of the cases that would have qualified as “pyloric gland adenoma,” 21/24 (88%) had at least focal high-grade dysplasia and 18% had associated invasive carcinoma. Conversely, 8 of 47 “papillary adenocarcinoma”-type cases displayed some foci of low-grade dysplasia, and 15/47 (32%) had no identifiable invasion. (4) Overall, 55% of the cases had an associated invasive carcinoma (pancreatobiliary type, 58; others, 10). Factors associated significantly with invasion were the extent of high-grade dysplasia, cell type (biliary or foveolar), and papilla formation. Among systematically analyzed invasive carcinomas, tumoral intraepithelial neoplasia was detected in 6.4% (39/606). (5) The 3-year actuarial survival was 90% for cases without invasion and 60% for those associated with invasion. In contrast, those associated with invasion had a far better clinical outcome compared with pancreatobiliary-type GB carcinomas (3-yr survival, 27%), and this survival advantage persisted even with stage-matched comparison. Death occurred in long-term follow-up even in a few noninvasive cases (4/55; median 73.5 mo) emphasizing the importance of long-term follow-up. In conclusion, tumoral preinvasive neoplasms (≥1 cm) in the GB are analogous to their pancreatic and biliary counterparts (biliary intraductal papillary neoplasms, pancreatic intraductal papillary mucinous neoplasms, and intraductal tubulopapillary neoplasms). They show variable cellular lineages, a spectrum of dysplasia, and a mixture of papillary or tubular growth patterns, often with significant overlap, warranting their classification under 1 unified parallel category, intracholecystic papillary-tubular neoplasm. Intracholecystic papillary-tubular neoplasms are relatively indolent neoplasia with significantly better prognosis compared with pancreatobiliary-type GB carcinomas. In contrast, even seemingly innocuous examples such as those referred to as “pyloric gland adenomas” can progress to carcinoma and be associated with invasion and fatal outcome.
Departments of *Pathology
††Piedmont Hospital, Emory University School of Medicine
§§Department of Epidemiology, Emory University School of Public Health, Atlanta, GA
#Memorial Sloan-Kettering Cancer Center, New York, NY
**The Karmanos Cancer Institute and Wayne State University, Detroit, MI
∥∥Department of Public Health, College of Education, Health & Human Sciences, The University of Tennessee of Knoxville, TN
†Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
‡Department of Pathology, Frontera University School of Medicine, Temuco, Chile
§Department of Pathology, Istanbul Education and Research Hospital, Istanbul, Turkey
∥First Department of Pathology, Showa University School of Medicine, Tokyo, Japan
¶Department of Pathology, Rize University, School of Medicine, Rize, Turkey
V.A. and K-T.J. contributed equally.
Presented in part at the annual meeting of the United States and Canadian Academy of Pathology in Washington, DC, March 2010, and San Antonio, TX, March 2011.
Conflicts of Interest and Source of Funding: Supported in part by Fondecyt Grant #1090171, Chile, and in part by the Georgia Cancer Coalition Distinguished Cancer Clinicians and Scientists Program, GA. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.
Correspondence: Volkan Adsay, MD, Department of Pathology and Laboratory Medicine, Emory University Hospital, 1364 Clifton Road NE, Atlanta, GA 30322 (e-mail: firstname.lastname@example.org).