Case 1 -

Pancreatic Mucinous Cystadenoma Dr. Benoît Terris Service d'Anatomie Pathologique Hôpital Cochin, Paris, France

Case History: A 22-year-old female with no significant past medical history was admitted for further evaluation of anemia. She had no evidence of gastrointestinal bleeding such as hematemesis. On admission, she was slightly pale and an abdominal mass was palpable. Laboratory examination confirmed the anemia (haemoglobin 7.4g/dl, hematocrit 25;2% and MCV 85 fl). Upper gastrointestinal endoscopy revealed nodular esophageal and gastric varices with red spots suggesting stigmata of bleeding. On abdominal CT, the tail of the pancreas revealed a 10cm unilocular cystic lesion with irregular walls and septations. Mild splenomegaly, obstruction of splenic vein and gastrooesophageal varices were also observed. A clinical diagnosis of pancreatic cystadenocarcinoma was proposed. The patient underwent a distal pancreatectomy. Macroscopically, the tail of pancreas was occupied by a 10cm cyst showing numerous septa and filled with serosanguineous fluid. The inner lining of the cystic space did not show nodular masses. The selected slide is of the cyst wall. Case 1 - Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Microscopic examination of the wall of this cyst revels two main features permitting the diagnosis : Whereas large areas of extensive denudation are present, this cyst is lined focally by a single layer of regular columnar cells. By definition, the presence of an epithelial lining defines a true cystic pancreatic lesion. The epithelial lining is better preserved in small cysts included in the wall than in the principal cyst. The columnar cells show basally orientated regular nuclei and abundant eosinophilic cytoplasm with small amount of mucosecretion at the apical pole of cells. This mucosecretion is better appreciated on Alcian Blue or PAS staining. There is no significant cytological or architectural atypia. Moreover this cyst did not communicate with the main pancreatic duct. The epithelial lining is characteristically surrounded by a distinctive cellular stroma composed of spindled-shaped cells resembling to an ovarian stroma. Although this stroma becomes partially or even completely hyalinized in some areas, it is well observed particularly around the small cystic lesions included in the wall. This stroma shows frequently evidence of luteinization consisting of epithelioid cells with eosinophilic cytoplasm. The pathologic diagnosis proposed is a pancreatic mucinous cystadenoma. This patient's portal hypertension can be explained by the compression and obstruction of the splenic vein by this benign cystic pancreatic lesion [1]. Such case underlines that pre-operative diagnosis between large compressing benign mucinous cystadenoma of the pancreas and advanced cystadenocarcinoma can be difficult [2]. Surgery must be considered whenever possible to provide curative treatment. Cystic Pancreatic Lesions Cystic neoplasms of the pancreas are rare accounting for less than 10% of pancreatic neoplasms. However, due to recent improvements in pancreatic imaging, an increasing number of cystic lesions are identified both in asymptomatic and symptomatic patients. Diagnostic assessment and therapeutic indications in patients with cystic lesions of the pancreas are often difficult. Cystic neoplasms encompass a spectrum of tumors from neoplasms with indolent biological behaviour, to neoplasms with a potential of more aggressive behaviour (premalignant), to frankly malignant neoplasms. Most often, they can be cured by surgical resection in contrast to ductal adenocarcinomas [3]. Different classifications of cystic pancreatic neoplasms exist. Based on the presence or absence of an epithelial or non epithelial cystic lining [4], we can distinguish: Cysts with no lining corresponding to pseudocysts. These unilocular cysts are the most common and are often pancreatitis associated [5]. Cysts with a true lining: Among them, serous cystadenomas, mucinous cystadenomas and intraductal papillary mucinous neoplasms (IPMNs) represent the majority of these lesions in daily practice. Rare acinar cystadenomas, lymphoeepithelial or retentional cysts and lymphangiomas can be encountered. Cysts secondary to degenerative or necrotic changes in neoplasms: This group comprises solid-pseudopapillary neoplasms, endocrine neoplasia, rare ductal adenocarcinomas and mesenchymal tumors and pancreatic metastasis [6]. Mucinous Cystic Neoplasms Mucinous cystic neoplasms represent the most frequent cystic neoplasms occurring in pancreas. The WHO subclassification of mucin-producing neoplasms of the pancreas includes two main categories : mucinous cystic neoplasms (MCNs) and IPMNs [7]. These two entities share numerous histopathological features but differ respectively by the presence of a communication with the pancreatic ductal system for IPMNs and a dense mesenchymal ovarian-like stroma for MCNs. A major characteristic of these lesions is that they may demonstrate a wide histologic spectrum of epithelial atypia within a single neoplasm. Based on the degree of atypia and the the presence or absence of an invasive component, these cystic tumors are classified in benign (low-grade dysplasia, adenomatous), moderate dysplasia (borderline), high-grade dysplasia (carcinoma in situ) and invasive cancer. Both IPMNs and MCNs are known to progress from non-invasive low-grade dysplasia to invasive carcinoma. As the prognosis depends on the presence of an invasive component, surgical resection of mucinous cystic tumours should be entirely examined histologically, in order to avoid designating a poorly sampled invasive carcinoma as a non-invasive neoplasm [8]. The discrepancy among the series concerning the frequency of invasive and non invasive form of these tumors is probably due to differences in the pathological sampling. 1. Mucinous cystic neoplasms MCNs which are found almost exclusively in women tend to occur most commonly in the tail or body of the pancreas (90%). MCNs do not communicate with the pancreatic ductal system, are usually uni-locular, may be rarely muli-locular [9, 10]. The neoplastic cysts are usually filled with clear mucoid fluid. The wall of the cyst may be dense and fibrous with occasionally foci of calcification and be confused with a pseudocyst. Histologically, MCNs are lined by tall mucinous epithelial cells. Adequate sampling of MCN is important. A wide variation in epithelial cell shape may be seen, ranging from flattened or low cuboidal to tall columnar. The chance of finding dysplastic or invasive foci is greater in the thickened fibrotic walls and septae as well in intramural nodules projecting into the cyst lumen. An invasive component is present in less of one third of MCN. The invasive component corresponds usually to well or moderately differentiated adenocarcinomas. Mucinous (colloid) carcinomas frequently seen in IPMNs are rarely observed in MCNs. Characteristically, a dense stroma resembling ovarian stroma surrounds the epithelial cells. Although this stroma becomes partially or even completely hyalinized, extensive sampling here again will almost always show it. Because such stroma is now required in the current definition of MCNs, the proportion of MCNs relative to IPMNs is declining in most series. There are two hypotheses on the origin of a neoplasm in the pancreas with ovarian-type stroma. The first hypothesis is that these neoplasms arise from an ectopic ovarian stroma. This is supported by the close proximity of the left primordial gonad to the dorsal pancreas during the fifth week of gestation, possibly facilitating the transfer of cells. The second hypothesis neoplasms is that the stroma represents an equivalent of periductal fetal mesenchyme, the primitive mesenchyme seen around the pancreatic and hepatic ducts in the developing fetus [11]. This last hypothesis could similarly explain mucinous cystadenoma occurring in the hepatobiliary tract. Regardless of its origin, it is clear that female sex hormones might have had a role in the pathogenesis of this neoplasm. This stroma which is often admixed with luteal-type cells (40% of cases) is hormone sensitive expressing in more than 50% of cases progesterone receptors and alpha-inhibin [9]. Rare observations of an undifferentiated carcinoma with sometimes osteoclast giant cells or sarcomatous transformation have been reported [12]. Accurate prognosis of MCNs depends of the presence and the extent of an invasive component as non-invasive lesions follow a benign course after surgical resection. It is important to evaluate the depth of invasion as the prognosis appears worth for tumors showing a peritumoral invasion than those limited to the cyst wall [9]. The 5-year survival rate of patients with invasive mucinous cystadenocarcinomas is 30%. It remains better than patients with typical infiltrating ductal adenocarcinomas highlighting the importance to distinguish these two entities. 2. Intraductal papillary mucinous neoplasms IPMNs are the neoplasms most frequently misdiagnosed as MCNs. In several pancreatic referral centers, IPMNs are now more frequent than MCNs due to a better clinical and pathological diagnosis of the former and the requirement of an ovarian stroma for the diagnosis of the later [13] . A consensus definition of IPMN has been recently proposed as follows: "a grossly visible non-invasive, mucin-producing, predominantly papillary, or rarely flat, epithelial neoplasm arising from the main pancreatic duct or branch ducts, with varying degrees of duct dilatation. IPMN usually produce a lesion > 1 cm in diameter and include a variety of cell types with a spectrum of cytologic and architectural atypia" [14] . In contrast to MCN, IPMN occurs equally in men and women, usually in the seventh decade of life and most often is found in the head of the pancreas (75% of cases). Different classifications of IPMN exist: IPMN can be subdivided into main duct and branch duct types depending on the location of the lesion in the main pancreatic duct or the branch ducts, respectively [15] [16, 17]. In both locations, the involvement may be relatively continuous along the duct with diffuse dilatation or segmental ectasia with a local cystic appearance. Multifocal involvement characterized by skip lesions occur. Grossly they may be alterations in surrounding pancreatic parenchyma attributed to pancreatitis which is due to mucinous obstruction of the duct system. Any solid or firm areas should be sampled in order to rule out invasive adenocarcinoma. Like MCN, several grades according to the cytological and architectural atypia of the proliferating epithelium may be encountered [7] : Non-invasive IPMNs can be categorized into mild dysplasia (adenoma), moderate dysplasia (borderline), and marked dysplaia (carcinoma in situ). An associated invasive carcinoma is seen in 30% of the cases and it can show either a ductal (tubular) or a mucinous (colloid) phenotype. Invasion may be especially difficult to identify in some tumors. Presence of extra ductal acellular mucin pools are often observed and do not necessarily indicate an invasive form of IPMN. In such situations, presence of viable neoplastic cells within lake of mucus is needed to establish definitive tissue invasion. IPMN may also been sub-classified according to the differentiation of epithelial cells and the related expression of MUC antigens [18, 19, 20] : the intestinal phenotype composed of macropapillae, similar to those in colonic villous adenomas, producing large amount of mucus (MUC2+, MUC1-), the pancreatobiliary type showing micropapillae (MUC1+, MUC2-) and the gastric foveolar type with few or no cellular atypia (MUC1-, MUC2-, MUC5AC+). Interestingly, the type of invasion is correlated to phenotype of intraductal proliferation : a colloid invasive pattern for the intestinal phenotype and a conventional ductal invasive pattern for the pancreaticobiliary type [19, 20] . Rare related entities of IPMN have been described: the intraductal oncocytic papillary neoplasms [21] and the intraductal tubular adenoma or pyloric gland adenoma [22] . Clinical recognition of IPMN is difficult and be confused with chronic pancreatitis or other cystic lesions. Invasive component may not be distinguish by imaging studies. Currently, the only treatment of non-invasive IPMN is surgical resection. The extent of resection that is necessary is usually determined by histological examination of the margins on frozen sections. Like MCN, the prognosis of IMPN is highly correlated to the presence or absence of an invasive component. The type of invasion plays probably also a role with a better prognosis of the colloid pattern as compared to the conventional ductal form [23] . However, overall five year survival rate remains higher in patients with malignant invasive IPMN compared with those with pancreatic ductal adenocarcinoma. 3. Differential diagnosis : As we have seen, several clinical and pathological characteristics can be used to distinguish MCNs and IPMNs (table 1). They are easily differentiated from other non mucinous cystic tumors as serous cystadenomas. It may be more difficult to distinguish : MCN from pseudocyst when the epithelium of the MCN is totally denuded and the ovarian stroma largely hyalinized, and from retentional cysts. IPMN from pancreatic intraepithelial neoplasia (PanIN) due to the similarities of the tumoral epithelium in some cases. However, PanIns are incidental and microscopic findings. They do not form macroscopic and/or radiologic detectable mass and usually involved ducts <5mm in diameter [14]. Table 1: Clinical and pathological characteristics of Mucinous Cystic Neoplasms and Intraductal Papillary Mucinous Neoplasms. Mucinous cystadenoma neoplasms Intraductal papillary mucinous neoplasms Average age 50 65 Gender Female +++ (>95%) Male / Female : 60 / 40 Specific endoscopic finding None Mucin extrusion from ampulla Endoscopic and radiological findings Macrocystic lesions with small cysts inside the wall Mucin extrusion from ampulla Macrocystic and microcystic lesions Ductal dilatation Pancreatic location Tail : 90% Head : 70% Histological findings Ovarian stroma No ductal communication Epithelium showing frequently a pancreaticobiliary type Ductal communication Epithelium showing frequently an intestinal phenotype with abundant mucosecretion References Iwasaki T, Nagata Y, Watahiki H, Yamamoto H, Ogawa H. A rare case of serous cystadenoma of the pancreas presenting with left-sided portal hypertension. Surg Today 1996;26:442-5. Maire F, Hammel P, Terris B, Vilgrain V, O'Toole D, Levy P, Belghiti J, Ruszniewski P. 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