Intraductal and Papillary Variants of Acinar Cell Carcinomas A New Addition to the Challenging Differential Diagnosis of Intraductal Neoplasms Olca Basturk, MD,* Giuseppe Zamboni, MD,w David S. Klimstra, MD,z Paola Capelli, MD,w Aleodor Andea, MD,* Nabil S. Kamel, MD,* and N. Volkan Adsay, MD* Abstract: The recognition and differential diagnosis of pancrea- tic intraductal neoplasms (IN) have gained importance in the past few years, as the incidence of these tumors (especially intraductal papillary mucinous neoplasms-IPMNs) have risen to >10% of pancreatic resections, and their significance as precursors of invasive cancer is better appreciated. Acinar cell carcinomas (ACCs) are typically solid tumors; however, we have recently encountered 7 ACCs with either intraductal growth and/or a papillary/papillocystic pattern that could be mistaken for IN. The clinicopathologic features of these cases were studied. Four patients were male and 3 female, with a mean age of 59 and mean tumor size of 4.9 cm (as compared with 10 cm in conventional ACCs). Only 1 patient had metastasis at the time of diagnosis (as opposed to 50% in usual ACCs). In 5 cases, the tumors had nodular growth of sheet-forming acinar cells, some of which were within ducts, as evidenced by the polypoid nature of the process, partial ductal lining, and presence of small tributary ducts in the walls. In 3 cases, the tumor had papillary and/or papillocystic growth, at least focally. All cases had cystic areas. No mucin was identified. All expressed trypsin. Markers of ductal differentiation were either absent or focal. A minor endocrine component was present in 3. The main histologic findings that distinguished these tumors from IPMNs were the more sheetlike nature of the nodules (rather than villous or arborizing papillae), cuboidal cells, overall basophilia of the cytoplasm, prominent nucleoli, apical granules, intraluminal crystals or pale, acidophilic secretions (enzymatic condensa- tions), and lack of mucin. In conclusion, some ACCs show intraductal growth or exhibit papillary patterns, which can mimic IN, especially IPMNs. In such cases, attention to morphologic details described above, and immunohistochem- istry are helpful. The clinical significance of this variant is difficult to determine; however, it appears that the tumors are relatively small and metastasis at presentation is less common than typically seen in ACCs (1/7 vs. 50%). Key Words: acinar cell carcinoma, pancreas, papillary, papillo- cystic, intraductal (Am J Surg Pathol 2007;31:363–370) R ecently, there have been significant advances in the classification of pancreatic neoplasia, including the recognition and better characterization of intraductal neoplasms. In addition to the microscopic dysplastic changes commonly associated with ductal adenocarcino- ma, now referred to as pancreatic intraepithelial neopla- sia, 17–19 there is also a group of mass-forming intraductal neoplasia, namely, intraductal papillary mucinous neo- plasms (IPMNs), characterized by intraductal neoplastic mucinous cells that often form papillary nodules and lead to cystic dilatation of the ducts. 1,2,4,12,19,32,36,40 Papilla formation in the pancreas is not limited to intraductal neoplasia. Mucinous cystic neoplasms, a tumor that is typically seen in females of perimenopausal age group, and characterized by thick-walled multilocular cysts lined by ovarianlike stroma, may also exhibit ‘‘intracystic’’ papillary nodules. 5,34,41,44,45,47 In general, both IPMNs and mucinous cystic neoplasms are indolent neoplasia, with a protracted clinical course, even in the cases associated with invasive carcinoma. Acinar cell carcinomas (ACCs) are rare and fairly aggressive tumors, although not as dismal prognostically as invasive ductal adenocarcinomas. Metastases, usually to liver, are identified in 50% of patients at the time of diagnosis. The follow-up information in the literature, which is somewhat limited; 1, 3, and 5-year survival rates are estimated as 57%, 26%, and 6%, respectively. 23 ACCs are typically solid, cellular, stroma-poor tumors characterized by sheets of relatively uniform cells. 15,23 This sheetlike arrangement may be punctuated by acinar structures in some cases 23,43 and some may have a distinct endocrine component. 24,43 Occasionally, cystic change has been documented, and these tumors are Copyright r 2007 by Lippincott Williams & Wilkins From the *Department of Pathology, Wayne State University and Karmanos Cancer Institute, Detroit, MI; wDepartment of Pathology, Verona University, Italy; and zDepartment of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY. Supported in part by National Cancer Institute Specialized Program in Research Excellence (SPORE), P50-CA62924. Reprints: N. Volkan Adsay, MD, Department of Pathology, Harper University Hospital, Detroit, MI 48201 (e-mail: adsayv@med. wayne.edu). ORIGINAL ARTICLE Am J Surg Pathol  Volume 31, Number 3, March 2007 363