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    Intracholecystic Papillary-Tubular Neoplasms (ICPN) of the Gallbladder (Neoplastic Polyps, Adenomas,

    and Papillary Neoplasms That Are  Z1.0 cm) Clinicopathologic and Immunohistochemical 

    Analysis of 123 Cases 

    Volkan Adsay, MD,*  Kee-Taek Jang, MD,w  Juan Carlos Roa, MD,z  Nevra Dursun, MD,y  Nobuyuki Ohike, MD,8 Pelin Bagci, MD,z  Olca Basturk, MD,# Sudeshna Bandyopadhyay, MD,**

    Jeanette D. Cheng, MD,ww  Juan M. Sarmiento, MD,zz  Oscar Tapia Escalona, MD,z 

    Michael Goodman, MD,yy  So Yeon Kong, MPH,yy  and Paul Terry, PhD, MPH 88

    Abstract: 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 pre-

    invasive neoplasm measuring   Z1 cm were analyzed. The pa-

    tients 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 gastro-

    intestinal 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 pol-

    ypoid 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 on-

    cocytic 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 adenocar-

    cinoma”-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 (pan-

    creatobiliary type, 58; others, 10). Factors associated signi-

    ficantly with invasion were the extent of high-grade dysplasia,

    cell type (biliary or foveolar), and papilla formation. Among systematically analyzed invasive carcinomas, tumoral intra-

    epithelial 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 as-

    sociated with invasion had a far better clinical outcome com-

    pared 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) em-

    phasizing the importance of long-term follow-up. In conclusion,

    tumoral preinvasive neoplasms (Z1 cm) in the GB are analo-

    gous to their pancreatic and biliary counterparts (biliary

    From the Departments of *Pathology; zzSurgery; wwPiedmont Hospital, Emory University School of Medicine;   yyDepartment of Epidemio- logy, 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; 88Department of Public Health, College of Education, Health & Human Sciences, The University of Tennessee of Knoxville, TN; wDepartment of Pathology, Samsung Medical Center, Sungkyunk- wan University School of Medicine, Seoul, Korea;  zDepartment of  Pathology, Frontera University School of Medicine, Temuco, Chile; yDepartment of Pathology, Istanbul Education and Research Hos- pital, Istanbul, Turkey;   8First Department of Pathology, Showa

    University School of Medicine, Tokyo, Japan; and  zDepartment 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 rela- tionships 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:  volkan.adsay@emory.edu).

    Copyright  r  2012 by Lippincott Williams & Wilkins

    ORIGINAL  ARTICLE

    Am J Surg Pathol    Volume 36, Number 9, September 2012 www.ajsp.com   | 1279

    mailto:volkan.adsay@emory.edu mailto:volkan.adsay@emory.edu

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    intraductal papillary neoplasms, pancreatic intraductal papillary

    mucinous neoplasms, and intraductal tubulopapillary neo-

    plasms). 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 prog-

    nosis compared with pancreatobiliary-type GB carcinomas. In

    contrast, even seemingly innocuous examples such as those re-

    ferred to as “pyloric gland adenomas” can progress to carci-

    noma and be associated with invasion and fatal outcome.

    Key Words:   gallbladder, adenoma, carcinoma, in situ, pre-

    invasive neoplasm, papillary, pyloric, tubular, intestinal,

    oncocytic, biliary

    (Am J Surg Pathol  2012;36:1279–1301)

    In the pancreatobiliary tract, tumors composed of pre-invasive neoplastic (dysplastic) cells that form clinically detectable (Z1.0 cm) masses are now classified under a unified category of intraductal papillary neoplasms (IPNs) in the bile ducts1 and as intraductal papillary mucinous neoplasms (IPMNs) or intraductal tubulopa- pillary neoplasms (ITPNs) in the pancreas2 (Fig. 1). It is now well established that these preinvasive neoplasms (what we term tumoral intraepithelial neoplasms) repre- sent an “adenoma-carcinoma” sequence,3–18 and that their clinicopathologic, immunophenotypic, and molec- ular characteristics as well as biological behavior are different from the nontumoral (flat)-type preinvasive ne-

    oplasms of the respective organs.5,8,10,14,15,19 At the same time, they are also distinct from the conventional invasive cancers of these sites for which they are often mistaken because of their mass-forming nature.2,10,20–34

    In the pancreas, in which such tumors are best characterized, the category of IPMN was created to en- compass a wide spectrum of lesions ranging from in- nocuous cysts lined by gastric foveolar epithelium without atypia (previously called “hyperplasia” by the Japanese Pathology Society) and those that resemble villous ad- enomas, associated with extensive invasive carcinoma of  the mucinous type [previously called “papillary mucinous carcinoma” by World Health Organization (WHO)],35 to

    those that have complex papillary architecture associated with invasive carcinoma of the pancreatobiliary type, which used to be called “papillary adenocarcinomas.”26–28 The rare pyloric gland adenoma type lesions36,37 are now also regarded as part of the IPMN category.2 More recently, nonmucinous examples of tumoral intraepithelial neoplasia that occur in the pancreas have also been characterized and have been recognized by the WHO as ITPNs.2,28,38–41

    Recognition of pancreatic IPMNs has led to the reappraisal of preinvasive lesions in the biliary tract.20,22,42 Many authors originally adopted the term “biliary IPMN,”43–49 a category that encompasses tubu- lar, papillary, and villous preinvasive neoplasms including

    papillomatosis.20,22,31,42–45,50–53 However, because mucin production is much less evident in these biliary examples, these are now unified under the heading of intraductal papillary neoplasm (IPN) in the 2010 WHO classification for both intrahepatic and extrahepatic lesions.1 Likewise, we recently showed that in the ampulla of Vater, there

    is occurrence of analogous tumoral intraepithelial neo- plasms with distinctive properties. Accordingly, we pro- posed the term intra-ampullary pa