EVALUATION OF CYSTIC LESIONS OF THE PANCREAS BASED ON CLINICOPATHOLOGIC PARA- METERS

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1 Acta Medica Mediterranea, 2015, 31: 383 EVALUATION OF CYSTIC LESIONS OF THE PANCREAS BASED ON CLINICOPATHOLOGIC PARA- METERS FATMA OZ ATALAY*, NESRIN UGRAS, BERNA AYTAC, OMER YERCI Department of Pathology, Uludag University School of Medicine, Bursa, Turkey ABSTRACT Aims: To identify demographic, histopathologic and immunohistochemical features of pancreatic cystic lesions, which could assist diagnosis of neoplastic ones. Materials and methods: Sixty-seven cystic lesions from pancreatic resections between 2001 and 2013 were studied. Patient demographics and cyst location and size were recorded. Forty-six specimens with adjacent non-lesional parenchyma were evaluated for pancreatic intraepithelial neoplasia (PanIN). Neoplastic cysts were immunohistochemically tested for ki67, p53, and progesterone receptor. Ten high-power fields were examined to determine ki67 proliferative index (PI; average percentage of nuclear staining) and p53 status (<1% stained nuclei indicating negative). Presence/absence of progesterone receptor (PR)-positive nuclei in pericystic stromal cells was recorded. Results: Eighteen (26.9%) of the 67 lesions were non-neoplastic and 49 (73.1%) were neoplastic. Serous cystadenomas (SCAs) were most common (n=23; 34.3%), and 59 (88%) of the patients were women. Mean ages for the mucinous cystic neoplasm (MCN) and SCA subgroups were 46.7 and 64.6 years, respectively, and these lesions tended to be in the pancreatic tail and head, respectively. ki67 PI was higher for non-invasive MCNs with high-grade dysplasia than low-grade dysplasia (20% vs. 4-6%, respectively). No neoplasms were p53-positive. Only MCNs were PR-positive. SCA was the lesion most frequently associated with PanIN. Conclusion: Age of patient and the location of cyst are distinctive features in neoplastic pancreatic cysts. Diameter of the cyst gives an idea about the malignancy potential of the lesions. In MCNs, considering the increased risk of multiple foci of varying degrees of dysplasia, ki67 proliferative index is useful as well as the adequate sampling of the cyst for the accurate diagnosis of these foci, particularly when the presence or degree of it cannot be adequately assessed in hematoxylin and eosin (HE)-stained sections. Key words: Pancreas, pancreatic cysts, mucinous cystic neoplasia, serous cystadenoma. Received June 18, 2014; Accepted October 02, 2014 Introduction Although cystic lesions of the pancreas are considered relatively rare, improved diagnostics have resulted in higher reported incidence. Cystic neoplasms comprise approximately 10% to 15% of primary cystic masses of the pancreas, and 1% to 15% of all pancreatic neoplasms (1-3). While non-neoplastic cystic lesions predominantly affect men with a wide age range, the vast majority of neoplastic cysts occur in middle-aged and elderly women (4). Patients with malignant tumors are 5 to 10 years older than the patients with benign ones (5). Clinical presentation of cystic neoplasms depends particularly on the size of the tumor. Small cysts are usually non-symptomatic, and emerge as an incidental finding at physical examination and in radiological imaging studies. Larger ones produce symptoms related to local mass effect such as abdominal pain, nausea, vomiting and weight loss (5). Published series of cystic lesions of the pancreas have aided the diagnosis and management of these relatively rare entities. It is essential to be able to discriminate pseudocysts and rare non-neoplastic cystic lesions from cystic neoplasms of the pancreas. It is also vital to be able to diagnose pancreatic cysts that feature high-grade dysplasia and malignant foci, particularly those within mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMNs). The objectives of this study were to identify demographic and histopathologic features of pan-

2 384 Fatma Oz Atalay, Nesrin Ugras et Al creatic cystic lesions, as well as immunohistochemical features that assist the diagnosis of those that are neoplastic. We report findings from 12 years of experience with pancreatic cystic lesions at our center, and discuss the similarities and discordance between our data and those in the literature. Materials and methods Non-neoplastic cysts with no lining Pseudocyst Paraduodenal wall cyst Parasitic cysts Hydatic cyst Taenia solium cyst Neoplastic cysts with mucinous epithelium MCN MCN with low- or intermediate-grade dysplasia (l-mcn) MCN with high-grade dysplasia (h-mcn) MCN with an associated invasive carcinoma IPMN / IOPN From 2001 to 2013, 351 pancreatic resections were performed at our center, including Whipple procedures, total and distal pancreatectomies, and enucleations. Sixty-seven of these operations were for cystic lesions of the pancreas, and the clinical and pathological findings for these cases were retrospectively reviewed. The pancreatic cysts were classified as non-neoplastic or neoplastic (benign, premalignant, malignant) in accord with the World Health Organization s (WHO) 2010 pancreatic tumor classification (Table 1). Demographic and pathological features of each case were recorded, including patient s sex and age, and cyst location and size. Hematoxylin and eosin (HE)-stained sections of the neoplastic cysts were examined for presence of mucinousserous epithelium, ovarian-type stroma, epithelial dysplasia, and signs of malignancy. The neoplastic lesions were also analyzed for immunoexpression of ki67, p53, and progesterone receptor (PR). Specimens were formalin-fixed and embedded in paraffin, and 4-mm thick sections were cut and mounted on slides. After deparaffinization and appropriate antigen retrieval, the slides were stained with a panel of antibodies for ki67 (clone SP6, predilue, Neomarkers, Lab Vision, Freemont, CA, USA), p53 (monoclonal, clone DO-7, dilution 1:400; Dako, Denmark), and PR (clone SP2, dilution 1:400; Neomarkers, Lab Vision, Freemont, CA, USA). For each lesion, we evaluated the cyst epithelium in 10 high-power fields (HPF) to determine the ki67 proliferation index (the average percentage of nuclei positively stained for ki67). We also calculated the percentage of nuclei immunostained for p53 in 10 HPF, and recorded a cyst as p53-negative when <1% of nuclei were positive. We also recorded presence/absence of PR-positive nuclei in pericystic stromal cells. Presence and grade of pancreatic intraepithelial neoplasia (PanIN) was also evaluated for all cysts (n=46) that were resected with adjacent non-lesional parenchyma. Grade of PanIN (1a, 1b, 2, 3) was interpreted as defined by published consensus guidelines (6). Other infection-related cysts Necrotic tuberculous infection IPMN with low- or intermediate-grade dysplasia IPMN with high-grade dysplasia Post-inflammatory cystic fluid collection IPMN with an associated invasive carcinoma Inflammatory exudative collection with serous epithelium with mucinous epithelium Mucocele / retention cyst with squamous epithelium Lymphoepithelial cyst Benign (serous cystadenoma) Malignant (serous cystadenocarcinoma) with acinar epithelium Benign (acinar cell cystadenoma) with enterogenous epithelium Malignant (acinar cell cystadenocarcinoma) Enteric duplications other rare cystic lesions Congenital / developmental cysts Endometriotic cyst Cystic hamartoma Unclassified cysts with endothelium Cystic lymphangioma Cavernous hemangioma with squamous epithelium Dermoid cyst Epidermoid cyst within intrapancreatic accessory spleen cystic / necrotic degeneration in solid tumors SPT Ductal adenocarcinoma of pancreas Neuroendocrine tumors Intraductal tubular neoplasm Other primary neoplasms Adenosquamous cell carcinoma Undifferentiated carcinoma with osteoclast-like giant cells Cystic pancreatoblastoma Cystic choriocarcinoma Mature cystic teratoma Cystic mesenchymal neoplasms (schwannoma, GIST, inflammatory myofibroblastic neoplasm, solitary fibrous tumor, paraganglioma) Metastatic tumors (ovarian neoplasms, renal cell carcinoma) Table 1: Categorization of cystic lesions of the pancreas in accord with the World Health Organization s 2010 pancreatic tumor classification. GIST: gastrointestinal stromal tumor; IPMN/IOPN: intraductal papillary mucinous neoplasia/intraductal oncocytic papillary neoplasm; MCN: mucinous cystic neoplasia; SPT: solitary pseudopapillary tumor

3 Evaluation of cystic lesions of the pancreas based on clinicopathologic parameters 385 Results n Percentage among neoplastic cysts Percentage among nonneoplastic cysts Percentage of total Neoplastic cysts SCA % 34.3% Multicystic 20 Macrocystic / oligocystic 3 MCN % 29.9% with low/intermediate-grade dysplasia with high-grade dysplasia with invasive carcinoma IPMN with invasive ductal carcinoma Solid pancreatic tumors with cystic degeneration SPT 2 Invasive ductal adenocarcinoma Cavernous hemangioma 2 4.1% 3% 3 6.1% 4.5% % 1.5% Non-neoplastic cysts Pseudocyst 9 50% 13.4% Retention cyst % 3% Hydatid cyst 1 5.6% 1.5% Congenital cyst 1 5.6% 1.5% Unclassified cysts % 7.4% Table 2: Distribution of the 67 cases according to diagnostic categories. IPMN: intraductal papillary mucinous neoplasia; MCN: mucinous cystic neoplasia; SCA: serous cystadenoma; SPT: solitary pseudopapillary tumor [low-grade mucinous cystic neoplasia (l- MCN)], 6 (30%) featured high-grade dysplasia [high-grade mucinous cystic neoplasia (h-mcn)], and 3 (15%) were malignant. Table 3 summarizes patient demographics, cyst size and location, and immunohistochemical findings for the neoplastic cysts. There were more females than males in this patient group (n=43 vs. n=6, respectively). Mean age was lower in the subgroup with MCN than in the subgroup with SCA (46.7 years vs years, respectively). Most of the MCNs (n=14) were located in the tail of the pancreas, whereas SCAs were more frequent in the head (n=12). The largest of the neoplastic cysts were malignant neoplasms (mean diameter 15 cm), followed by h- MCNs (mean diameter 10 cm). All but 3 SCAs (oligocystic lesions) were multicystic, whereas most MCNs were unilocular. All 6 h-mcns had ki67 proliferative index of 20%, whereas the values for the 11 l-mcns ranged from 4% to 6%. Figures 1, 2, and 3 show ki67 immunostaining in cases of h- MCN, l-mcn, and MCN with invasive carcinoma, respectively. None of the cystic neoplasms was p53-positive, and only the MCNs were PR-positive with variable intensity and distribution in the pericystic stroma. Table 2 shows the distribution of the 67 pancreatic cysts according to diagnosis. Of the 67 total lesions, 18 (26.9%) were non-neoplastic and 49 (73.1%) were neoplastic. The non-neoplastic cysts were 9 pseudocysts, 5 non-classified epithelial cystic lesions, 2 retention cyst, 1 congenital cyst, and 1 hydatid cyst. Of the 49 neoplastic cystic lesions, 24 were benign, 17 were premalignant, and 8 were malignant. Three of the malignant cases were solid pancreatic tumors with cystic degeneration (2 solid pseudopapillary tumor and 1 invasive ductal adenocarcinoma). The other 5 malignancies were 3 MCNs and 2 IPMNs, with accompanying invasive carcinomas. Twenty-three (46.9%) of the 49 neoplastic lesions were serous cystadenomas (SCAs). The next most common neoplasm was MCN (n=20), and 11 (55%) of these cysts featured low-grade dysplasia Figure 1: Ki67 immunostaining of a mucinous cystic neoplasm with high-grade dysplasia (x200). Figure 2: Ki67 immunostaining of a mucinous cystic neoplasm with low/intermediate-grade dysplasia (x100).

4 386 Fatma Oz Atalay, Nesrin Ugras et Al Age* (yrs) Females/Males Lesion diameter* (cm) Lesion location ki67 PI p53 Progesterone receptor SCA Multicystic 65 19/1 5.2 H, C < 1% Oligocystic 62 1/2 1.5 C < 1% MCN l-mcn 45 11/0 6.3 T > H-C 4-6% + h-mcn 49 6/0 10 T > H-C 20% + MCN with invasive carcinoma 48 3/ T 60% + IPMN with invasive carcinoma 64 1/ T 50% Solid tumors with cystic degeneration: SPT 28 2/ T 20% Invasive ductal adenocarcinoma 72 0/1 1.5 H, C 50% Cavernous hemangioma 73 0/1 4.5 T < 1% Table 3: Patient demographics, lesion size and location, and immunohistochemical characteristics for the neoplastic cysts. *Values were given in means. C: corpus of pancreas; F: female; H: head of pancreas; IPMN: intraductal papillary mucinous neoplasia; M: male; MCN: mucinous cystic neoplasia; l-mcn: MCN with low/intermediate-grade dysplasia; h-mcn: MCN with highgrade dysplasia; PI: proliferative index; SCA: serous cystadenoma; SPT: solitary pseudopapillary tumor; T: tail of pancreas; T > H- C: much more frequent in tail than in head or corpus Of the 46 cases evaluated for PanIN, 29 were neoplastic (14 SCAs and 10 MCNs, 2 IPMN, 3 solid tumors with cystic degeneration) and 17 were nonneoplastic. Five of the multicystic SCAs and 2 of the oligocystic SCAs were associated with PanIN foci, whereas none of the l-mcns examined was associated with such foci. None of the 5 h-mcns in the series was evaluated for PanIN as these specimens did not include non-tumoral tissue. An MCN with invasive carcinoma and an invasive ductal adenocarcinoma also featured PanIN1a and PanIN2, respectively. The only non-neoplastic case that featured PanIN was one retention cyst with contiguous PanIN1b. Discussion The numbers of cystic lesions of the pancreas that are diagnosed at different health centers vary substantially because some clinics perform more oncological pancreatic resections than others. According to the literature to date, cystic neoplasms of the pancreas are less frequent than solid neoplasms (1, 2, 4, 7, 8). Approximately 19% of the 351 pancreatic resections performed at our clinic in the past decade were for cystic lesions. Previous reports suggest that the majority of pancreatic cysts are pseudocysts (1, 4, 9, 10) ; however, the most common diagnosis among our 67 cases was SCA (34.3%), and only 9 of our lesions (13.4%) were pseudocysts. Serous and mucinous cystic neoplasms combined represented 64.2% of all the pancreatic cysts in our series. This is in accord with the report of Simeone (11), a brief review of the Society for Surgery of the Alimentary Tract State of the Art conference, which determines that 50% to 60% of all pancreatic cystic lesions were serous or mucinous neoplasms. The same author also reported that 30% of the pancreatic cysts were pseudocysts, whereas we observed only 13.4% of this lesion type in our series. One possible reason for this discrepancy is that our study only included cysts that were either partially or totally resected. At our institution, patients with a preliminary diagnosis of pancreatic pseudocyst undergo tru-cut biopsy, and if the histopatologic diagnosis is confirmed these patients do not undergo a procedure for the resection of the lesion. While MCNs (2, 12, 13) and IPMNs (14-16) are reported as the most common neoplastic cystic lesion in different series, we and some other researchers have observed the SCAs at most (4, 17). None of our cases were serous cystadenocarcinomas, which are extremely rare malignant tumors (7, 17, 18). Serous cystadenomas are benign cysts lined with a single layer of cuboidal, glycogen-rich epithelial cells. Two his-

5 Evaluation of cystic lesions of the pancreas based on clinicopathologic parameters 387 tological variants of SCAs have been defined based on lesion diameter and number of cysts that comprise the lesion (19) : i) a microcystic type with numerous tiny cysts around a central fibrous stellate core, and ii) a macrocystic (oligocystic) type that is a grouping of a few larger cysts. All but 3 of the 23 SCAs in our study were in women, and the mean age of the patients with SCAs was 65 years. These (1, 3, 14- findings were in concordance with other studies 16, 20) ; however, the diameters and locations of the SCAs in our series differed from those in several published reports (1, 15, 16, 20, 21). Some authors have documented SCAs evenly distributed throughout the pancreas (16, 21), while others have concluded that these lesions tend to occur in either the corpus or tail of the pancreas (1, 15, 20), and that the macrocystic (oligocystic) variant occurs predominantly in the head region (15, 22, 23). In our series, all but 3 of the 23 SCAs were multicystic, and all 23 SCAs were located in either the head or the corpus. Although it has been reported that SCAs are relatively large tumors (1, 24), the SCAs in our series tended to be smaller than the MCNs (mean diameters 4.7 cm vs. 9.4 cm, respectively). This finding was unexpected, and may be partially explained by the fact that our patients cysts were detected incidentally during investigations of nonspecific gastrointestinal symptoms. In such situations, the SCAs would have been diagnosed before they were large enough to cause a mass effect. Another finding was that, compared to all other types of pancreatic cysts in our series that were evaluated for PanIN in the adjacent parenchyma, SCAs were more likely to have these foci. This is because SCAs tend to occur in older adults, in which PanINs, especially PanIN 1, are so frequent (25). The second most frequent cystic lesion of the pancreas in our series was MCN. Mucinous neoplasms of the pancreas are important because they are associated with higher risk of malignancy than serous ones. We analyzed cystic neoplasms with mucinous epithelium in 2 groups: MCNs and IPMNs. The former features mucin-producing epithelium and ovarian-type subepithelial stroma. In the WHO 2010 classification, all non-invasive MCNs are considered premalignant and are categorized as MCNs with low-, intermediate-, or highgrade dysplasia (5). Those with an invasive carcinoma component are designated separately as such. Thus, in this new classification system, the terms mucinous cystadenoma and mucinous cystadenocarcinoma are no longer used. Previous reports have noted (1, 12, that MCNs occur almost exclusively in women 26), and in our series only women had these cysts. The mean ages of our patients with l-mcns and h- MCNs were similar (45 and 49 years, respectively). Our patients with MCN were approximately 2 decades younger than those with SCA. Most of the MCNs in our series were located in the tail and corpus of the pancreas, and predilection for these sites has been previously reported (5, 12, 24, 26). The other grouping of cystic neoplasms with mucinous epithelium, IPMNs, account for approximately 5% to 15% of all pancreatic neoplasms (1). These lesions are composed of intraductal papillary proliferations lined with neoplastic mucinous epithelium (gastric, intestinal, pancreatobiliary and oncocytic-type) and, unlike MCNs, they communicate with the pancreatic ductal system. Our series included only 2 IPMNs. These masses are generally considered to occur more frequently in the head of the pancreas; however, some authors have observed that IPMNs with multifocal growth tend to be distributed uniformly throughout the pancreas (1, 12, 27-30). The 2 IPMNs in our series was mainly in the tail of the pancreas, and they featured invasive foci and involved the major pancreatic duct as well as accessory ducts. Both of them had the pancreatobiliary type of epithelium, the least common type, and featured foci of invasive tubular (conventional ductal) adenocarcinoma. These cases featured multiple risk factors for malignancy, including mixed-type IPMN, pancreatobiliary epithelium, >1 cm dilatation of the major pancreatic duct, and symptoms of weight loss and fatigue; however, there was no mural nodule, no accessory ducts were dilated >3 cm, and the patients were younger than 70 years. Serous cystic neoplasms are associated with minimal to no risk of malignancy, whereas MCNs reportedly have up to 30% increased risk of malignancy (5, 31). Considering that mucinous cysts may have multiple foci of varying degrees of dysplasia, it is important to sample multiple sites within these lesions (1, 5, 14, 32). Our findings suggest that determining ki67 proliferative index helps to ensure that dysplastic fields in these lesions are not missed. The h- MCNs in our study had higher proliferation index values than the l-mcns and SCAs. Thus, the ki67 proliferation index may assist accurate diagnosis of dysplasia when the presence or degree of dysplasia cannot be adequately assessed in HE-stained sections. Our search of the English literature revealed no previous detailed study that evaluated ki67 proliferative index in pancreatic cystic neoplasms. However, Zhao et al. demonstrated that the ratio of

6 388 Fatma Oz Atalay, Nesrin Ugras et Al nuclear ki67 stained cells was >5% in all 9 of the mucinous cystic pancreatic tumors (8 benign and 1 borderline tumor) in their study (33). Although the authors did not report exact percentages of ki67 immunostaining, they did observe higher proportions of ki67-positive nuclei in mucinous cystic tumors than in non-neoplastic groups (chronic pancreatitis and normal pancreatic tissue). In addition to differences in ki67 immunopositivity, we also observed that h-mcns tended to be larger than l- MCNs (mean diameters 10 cm vs. 6.3 cm, respectively). Therefore, large tumor diameter in MCNs could be a clue to expect a high dysplasia focus in the cyst epithelium. The malignant cystic neoplasms of the pancreas in our series included IPMNs with invasive carcinoma, MCNs with invasive carcinoma, and solid pancreatic tumors with cystic degeneration (solid pseudopapillary tumor, invasive ductal adenocarcinoma). Most pancreatic cysts are benign cystic neoplasms, yet the 3 solid tumors in our series highlight the fact that cystic appearance of a pancreatic lesion may also signal degeneration of a solid malignancy. Three MCNs with invasive carcinomas featured marked invasive foci in the cyst wall and one of them was the largest lesion (diameter 25 cm) in our series. Not surprisingly, the ki67 proliferative index for the carcinoma foci of this lesion was high (60%) (Figure 3). Figure 3: Ki67 immunostaining of a mucinous cystic neoplasm with invasive carcinoma (x200). Conclusion In accord with other studies, we found that neoplastic cysts, such as SCAs and MCNs, were much more prevalent among our pancreatic resection specimens than pseudocysts. Our results suggest that patients with SCAs tend to be older with lesions located in the head and corpus portion of the pancreas, whereas individuals with MCNs tend to be younger with lesions located in the tail region. Further, our findings indicate that diameter of a pancreatic cyst tends to be an indicator of malignancy potential. We also conclude that ki67 proliferation index should be determined for any cystic neoplasm of the pancreas that has mucinous epithelium, particularly not to miss out high grade dysplasia. Studies with larger series are essential to prove that the ki67 proliferation index >5% points out l-mcn and >20% designates h-mcn. References 1) Adsay NV. Cystic lesions of the pancreas. Mod. Pathol. 2007; 20: ) Lahat G, Lubezky N, Haim MB, Nachmany I, Blachar A, Santo I, Nakache R, Klausner JM. Cystic tumors of the pancreas: high malignant potential. Isr Med Assoc J 2011; 13: ) Hutchins GF, Draganov PV. Cystic neoplasms of pancreas: a diagnostic challenge. World J Gastroenterol 2009; 15: ) Klimstra DS, Adsay NV. Tumors of the pancreas and ampulla vater. In: Odze RD, Goldblum JR, eds. Surgical pathology of the GI tract, liver, biliary tract, and pancreas. 2 nd Ed. Philadelphia: Saunders Elsevier 2009: ) Zamboni G, Fukushima N, Hruban RH. Mucinous cystic neoplasms of the pancreas. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. WHO classification of tumours of the digestive system. 4 th Ed. Lyon: IARC Press 2010: ) Hruban RH, Takaori K, Klimstra DS, Adsay NV, Albores-Saavedra J, Biankin AV, Biankin SA, Compton C, Fukushima N, Furukawa T, Goggins M, Kato Y,Klöppel G, Longnecker DS, Lüttges J, Maitra A, Offerhaus GJ, Shimizu M, Yonezawa S. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 2004; 28: ) Ceppa EP, De la Fuente SG, Reddy SK, Stinnett SS, Clary BM, Tyler DS, Pappas TN, White RR. Defining criteria for selective operative management of pancreatic cystic lesions: does size really matter? J Gastrointest Surg 2010; 14: ) Sakorafas GH, Sarr MG. Cystic neoplasms of the pancreas; what a clinician should know. Cancer Treat Rev 2005; 31: ) Sand J, Nordback I. The differentiation between pancreatic neoplastic cysts and pancreatic pseudocyst. Scand J Surg 2005; 94: ) Sachithanandan A, Diamond T. Cystic tumours of the pancreas--the importance of correct diagnosis and treatment. Ulster Med J 2000; 69: ) Simeone DM. SSAT/AGA/ASGE state of the art conference on cystic neoplasms of the pancreas. J Gastrointest Surg 2008; 12: ) Jeurnink SM, Vleggaar FP, Siersema PD. Overview of the clinical problem: facts and current issues of mucinous cystic neoplasms of the pancreas. Dig Liver Dis 2008; 40:

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