Keywords

Clinical Features

Mucinous cystic neoplasm (MCN) is an uncommon tumor of the pancreas that is characterized by the presence of subepithelial ovarian-type stroma. Although most of these tumors are benign, they are considered to be premalignant as they can develop dysplasia and invasive carcinoma. The prevalence of invasive carcinoma has been reported to range from 3.9% to 34.4% in these lesions [1].

They occur almost exclusively in women in the fifth to sixth decades of life; the mean age being 48 years. Though patients may present with symptoms including abdominal pain, recurrent pancreatitis , abdominal mass, or weight loss, an increasing number of MCNs are asymptomatic, being incidentally detected on imaging [2].

Pathogenesis

The expression of the estrogen receptor (ER) and progesterone receptor (PR) and steroidogenic enzymes by the ovarian-type stroma in MCNs suggests a role of female sex steroids in their pathogenesis [3, 4]. Also, these tumors are mostly seen in women and are histologically similar to tumors arising in the liver and biliary tract and in the retroperitoneum. One possibility is that MCNs may originate from the ovarian primordium. This is supported by their similar morphology and immunophenotype and the presence of luteinized cells.

Another hypothesis is that they are derived from ectopic ovarian-type stroma in the distal pancreas which by producing hormones and growth factors may cause endodermally derived epithelium to proliferate and form cystic neoplasms. However, such mechanisms do not explain the occasional occurrence of MCNs in men [3].

Imaging Findings

Majority (>95%) of MCNs are located in the body or tail of the pancreas [5]. On imaging, they usually appear as macrocystic lesions that may have a solid component. Unlike side-branch intraductal papillary mucinous neoplasms (IPMNs), there is usually no communication with the pancreatic duct.

MCNs, especially if small in size, may be indistinguishable from pseudocysts, serous cystadenomas, and IPMNs on imaging. Lesion shape on computed tomography (CT) scan has been reported to be a helpful discriminating feature between oligocystic serous adenomas, MCNs, and IPMNs. Serous cystadenomas tend to have a multicystic or lobulated contour with or without septation, while MCNs have a smooth contour with or without septation, and IPMNs either have a pleomorphic or a clubbed fingerlike cystic shape [6]. In a study of 33 patients with unilocular pancreatic cystic lesions, Cohen-Scali reported that location in the pancreatic head, lobulated contour, and lack of wall enhancement were specific for serous cystadenomas in comparison to MCNs [7]. Endoscopic ultrasound (EUS) can help visualize septations, thick cyst walls, and mural nodules better than CT and/or magnetic resonance imaging (MRI) (Fig. 8.1). Also, it can allow the aspiration of the cyst contents and biopsy of the cyst wall for a tissue diagnosis [8].

Fig. 8.1
figure 1

Endoscopic ultrasound of mucinous cystic neoplasm (MCN) shows a septated cyst in the body of the pancreas with calcifications in the wall. Histologic follow-up revealed a MCN with low-grade dysplasia

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The predictors of malignancy in MCNs on imaging have been variably reported. A retrospective study of 52 patients by Procacci and colleagues showed that the presence of septal or wall calcifications, septations, and a thick wall on CT scan was associated with malignancy in 95% of cases [9]. In a study of 90 MCNS, Park et al. found that the presence of mural nodules on CT scan was a significant predictor of malignancy [2]. A study of 32 resected MCNs with preoperative MDCT or MRI showed that MCN size (>8.5 cm) and volume were the only features that correlated with high-grade dysplasia/carcinoma. A cyst size of >8.5 cm was associated with 60% sensitivity and 97% specificity for the presence of high-grade dysplasia/carcinoma [10].

Pathologic Features

Gross Findings

MCNS are usually solitary, large, multilocular or unilocular cysts with a thick fibrotic capsule and a mean diameter of 6.5 cm [1].The cysts contain abundant mucus and cloudy brown fluid. Solid areas may be seen in the cysts that should be sampled extensively for histologic examination. Typically, there is no communication with the pancreatic duct system.

Histology

MCNs are characterized by mucinous epithelium with varying degrees of dysplasia. The epithelium may be mostly bland with tall columnar to cuboidal cells with basally located nuclei in a flat or papillary architecture (Fig. 8.2). Although scattered goblet cells may be present, intestinal differentiation is not a usual feature of MCNs [11]. Some foci of the epithelium may be lined by a single layer of pancreatobiliary-type, non-mucinous cuboidal cells [12].

Fig. 8.2
figure 2

Mucinous cystic neoplasm (MCN) with low-grade dysplasia. The epithelium is composed of tall, columnar mucinous cells with basally located nuclei. It overlies a characteristic spindled ovarian-type stroma that is a prerequisite for the diagnosis of MCN (hematoxylin-eosin stain, 400×)

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The subepithelial ovarian-type stroma is essential for the diagnosis of MCN and should be present at least focally in the tumor. At times, the epithelium may be denuded; but the ovarian-type stroma may still be identifiable, providing an important clue to the diagnosis. The spindle cell stroma may also contain nests of epithelioid cells with features suggestive of luteinization. The stroma can also exhibit degenerative changes such as hyalinization, calcification, and cholesterol clefts.

As per the 2010 World Health Organization classification, the dysplasia in MCN is graded as low, intermediate, or high, based on the most severely dysplastic focus [13]. It is critical that the tumor is extensively, if not completely, sampled for histologic examination as high-grade dysplasia may be present only focally in the tumor. In low-grade dysplasia, the lining epithelium is cytologically bland with minimal architectural complexity. Intermediate-grade dysplasia is characterized by loss of nuclear polarity, moderate atypia, and mild architectural complexity. High-grade dysplasia is associated with marked cytologic atypia and mitotic figures with significant architectural complexity.

Invasive carcinomas arising in MCNs are usually of the tubular type, resembling conventional pancreatic ductal adenocarcinomas. Adenosquamous carcinoma and undifferentiated carcinoma (with or without osteoclast-like giant cells) may rarely occur in MCNs [3, 14].

Cytology

On FNA specimens, MCNs and IPMNs cannot be distinguished from one another based on cytologic features [15, 16].The subepithelial ovarian-type stroma that is considered a prerequisite for the diagnosis of MCNs cannot be visualized on cytologic samples.

The cytologic diagnosis for a neoplastic mucinous cyst is based on the presence of extracellular thick mucin and/or neoplastic mucinous epithelium that can show a range of atypias (Figs. 8.3 and 8.4). The aspirates of MCNs are usually paucicellular. In an analysis of 61 MCNs, Scourtas et al. reported lack of epithelial cells in 74% of cases. Extracellular mucin was seen in 39% of low-risk cysts and 33% of high-risk cysts. Necrosis or cellular debris were identified in 31% of low-risk cysts and 50% of high-risk cysts. The presence of mucin or necrosis/cellular debris was not found to be significantly associated with the degree of dysplasia on histology. Inflammation and/or histiocytes were more frequently seen in low-risk cysts in contrast to high-risk cysts [8].

Fig. 8.3
figure 3

Thick mucin on cytology is indicative of a neoplastic mucinous cyst by itself (ThinPrep, Papanicolaou stain, 200×)

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Fig. 8.4
figure 4

Low-grade atypia characterizes the majority of mucinous cystic neoplasms on cytology. The low-grade epithelium reveals abundant mucinous cytoplasm with a low nuclear-cytoplasmic ratio and finely distributed nuclear chromatin (ThinPrep, Papanicolaou stain, 400×)

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A purely cytologic approach is inferior to an integrated approach of cytology with ancillary testing in diagnosing a neoplastic mucinous cyst of the pancreas. Until recently, there had been no standardized guidelines for the cytopathologist to report pancreatico-biliary cytology. The Papanicolaou Society of Cytopathology (Pap Society) advocates a multidisciplinary approach for the diagnosis of pancreatic lesions and recommends the incorporation of all available relevant ancillary data to make a cytologic diagnosis. In addition, they support a two-tiered approach for grading cytologic atypia in mucinous cysts when features suspicious or unequivocal for malignancy are not seen: low-grade atypia (usually correlates with low-grade or intermediate-grade dysplasia on histology) and high-grade atypia (usually correlates with high-grade dysplasia or worse on follow-up) [15, 16].

Scourtas et al. reported the finding of high-grade atypia in 33% of high-risk MCNs with available cytology. Though the sensitivity of cytology was limited in the detection of high-risk cysts, its specificity was 100% and accuracy 95% [8].

Immunohistochemistry

The lining epithelium of MCNs is typically positive for MUC5AC and negative for MUC1. MUC2 expression is restricted to goblet cells that are dispersed within the epithelium [14]. The stromal cells are positive for estrogen and progesterone receptors; and the luteinized cells exhibit positivity for inhibin, tyrosine hydroxylase, and calretinin.

p53 positivity increases with the grade of dysplasia and can also be seen in the invasive component [3]. Loss of DPC4 protein expression is a frequent event in invasive MCNs in contrast to noninvasive ones [17].

Cyst Fluid Biochemistry

Amylase levels are variable in MCNs and may not be helpful in differentiating them from IPMNs [18].

See also Cyst Fluid Biochemistry section in Chap. 7.

Molecular Genetics

Whole-exome sequencing of MCNs has revealed 16 ± 7.6 nonsynonymous somatic mutations per tumor. Mutations have been identified in RNF43 (which codes for a protein with intrinsic E3 ubiquitin ligase activity), KRAS, TP53, SMAD4, and CDKN2A. KRAS mutation is an early event, while tumor suppressor gene mutations (TP53, SMAD4, and CDKN2A) occur in MCNs with high-grade dysplasia or associated invasive carcinomas [19, 20]. GNAS mutations are not found in MCNs, in contrast to IPMNs [21]. PIK3CA mutations have also been detected in MCNs with high-grade dysplasia and may contribute to tumor progression [22].

Management

As per the 2012 Fukuoka consensus guidelines, surgical resection is recommended for all surgically fit patients with MCNs. Surgical resection has been the traditional management for MCNs due to their potential for malignant transformation, their location in the distal pancreas, and the relatively young age of the patients. MCNs are usually located in the pancreatic body and tail and therefore require distal pancreatectomy. Furthermore, there is no definitive method to determine preoperatively whether the tumor is benign or malignant, and conservative management would require years of surveillance with high-resolution imaging that is associated with high costs [23].

Although surgical resection has been the treatment of choice, more conservative management options are being explored for the management of MCNs. A study of 90 patients with MCNs showed that regardless of histologic grade, long-term outcome was excellent in MCNs. In this study, only 10% of MCNs were malignant. The overall 5-year disease-free survival was 98.8% for all patients, 100% for MCNs with high-grade dysplasia, and 75% for those with invasive carcinoma. Based on the results of this study, MCNs which are smaller than 3 cm that lack mural nodules and elevated serum carbohydrate antigen 19-9 are very likely to be benign. Therefore, the authors suggested that MCNs that met the aforementioned criteria could be followed conservatively [2].

In a study of 168 MCNs, Crippa et al. identified a low risk of cancer in these tumors (11% invasive and 6% in situ) and thereby indicated that nonoperative management could potentially be allowed in MCNs that are asymptomatic, <4 cm in size, and without solid components [24].

As per the 2018 European evidence-based guidelines on pancreatic cystic neoplasms, MCNs ≥ 40 mm should undergo surgical resection. Resection is also recommended for MCNs which are symptomatic or have risk factors (i.e., mural nodule) irrespective of their size. MCNs measuring <40 mm without a mural nodule or symptoms may undergo surveillance with MRI, endoscopic ultrasound (EUS), or a combination of both [25].

Prognosis

The complete resection of a noninvasive MCN is curative, requiring no postoperative surveillance with a 5-year disease-specific survival rate of 100% [26, 27]. However, the 5-year disease-specific survival rate drops to 20% to 60% for patients with MCNs with advanced invasive carcinoma [24, 28, 29].

Minimally invasive carcinomas (<0.5 cm) as well as MCNs with invasion limited to ovarian-like stroma or intratumoral septa reportedly have a good prognosis [13, 30]. Another study showed that MCN with T1a (≤0.5 cm) and T1b (>0.5 cm and <1.0 cm) carcinomas had an excellent prognosis similar to MCNs with low-grade or high-grade dysplasia after complete tumor sampling for histologic examination. These studies suggest that for such tumors, close follow-up may be a better approach as compared to aggressive systemic therapy [31].