Hepatic mucinous cystic neoplasm (MCN), historically classified as ‘biliary cystadenoma’ or ‘biliary cystadenocarcinoma’, is a rare cystic liver tumor with an enigmatic pathogenesis. According to the 2019 World Health Organisation (WHO) classification of digestive system tumors, the diagnostic terms ‘bile duct adenoma’ and ‘biliary cystadenocarcinoma’ are no longer used. Instead, the term ‘hepatic mucinous cystic neoplasm’ is adopted, which is divided into three types: Mucinous cystic neoplasm with low-grade dysplasia, mucinous cystic neoplasm with high-grade dysplasia and invasive carcinoma associated with mucinous cystic neoplasm (1). Current hypotheses suggest that the origin of this tumor may involve aberrant remodeling of the embryonic ductal plate (2), or the trans-differentiation of primitive germ cells into ovarian-like stromal (OLS) cells within the periductal fetal mesenchyme, while OLS occur exclusively in females (3). MCN of the liver is rare, comprising <5% of all hepatic cystic neoplasms. Notably, this is predominantly diagnosed in females in the fourth or fifth decade of life (4). The profound disparity in incidence between biological sex, coupled with the absence of established diagnostic biomarkers, highlights the clinical challenge faced in the management of male patients with cystic liver lesions.

MCN is a rare cystic malignant tumor of the liver that produces mucus and exhibits slow growth, with the potential to progress to invasive carcinoma over several years. Prior to 2005, <200 cases of MCN had been documented. At present, there are ~250 known cases of MCN; however, publications are limited due to small sample sizes and uncertainty regarding associated risk factors (5). MCNs predominantly affect the female population, while cases in male patients are considered rare (6). In the largest study to date on pancreatic MCNs, 155 of 163 patients (95%) were female, between 16 and 82 years of age, which indicates that MCNs predominantly affect women (4). Over the past decade, sporadic cases of hepatic MCN have been documented in male patients (7,8). Although a few cases of invasive pancreatic MCN in male patients have been reported, to date, no well-documented cases of invasive hepatic MCN in males have been identified in the literature (9). MCN is often asymptomatic in the early stages of the disease; however, it may cause abdominal distension, pain, dyspepsia and nausea (5).

MCN often exhibits a ‘cyst within cyst’ structure, with contents primarily consisting of mucus and thickened cyst walls, which may or may not be accompanied by calcification. MCN typically presents as a solitary, large, well-demarcated multilocular cystic mass, with the minority of the affected area being unilocular (6-10%). It is more commonly located in the left lobe of the liver and does not communicate directly with the bile ducts (1). MRI often demonstrates that MCN is hypointense on T1-weighted images and hyperintense on T2-weighted images, although the intensity of the signal can vary depending on the composition of the cystic fluid and the amount of mucin present. Key features of MCN include cyst wall calcification, thickened and improved septa, dilation of the upstream bile duct and mural nodules (10). Notably, a mural nodule exceeding 1 cm in size may be indicative of malignant transformation (11). Since 2010, the WHO has separated the classification of intrahepatic cystic neoplasms into MCN and IPNB. The primary distinction between these two conditions is the presence of OLS and direct communication with the bile ducts (9). The precision of preoperative imaging in diagnosing hepatic cystic lesions can be as low as 30% (12), leading to complexities in distinguishing MCN from IPNB. This underscores the critical importance of pathological analysis in accurately diagnosing hepatic MCN.

Histologically, MCN is a cystic epithelial tumor with a wall composed of three layers. The inner epithelial layer is typically columnar or cuboidal in shape (13). The middle layer consists of subepithelial OLS, which is diffusely present in ~50% of cases. This layer is composed of densely packed spindle-shaped cells with elongated nuclei and cytoplasm surrounded by collagen. Notably, the outermost layer is a fibrous capsule (5). In cases of malignant transformation, the histological appearance of these three layers changes. The epithelium forms large pseudostratified nuclei with hyperchromasia. The cells lose polarity and there are numerous mitotic figures in cases of high-grade dysplasia. Furthermore, polypoid or papillary projections are often observed (4). The intermediate layer of the stroma undergoes degeneration, exhibiting hemorrhage, calcification and necrosis. The external fibrous capsule may exhibit focal erosion that is indicative of invasive behavior. Regarding the origin of the OLS in the liver, certain researchers propose that the close proximity of the liver and gonads during embryonic development allows the migration of gonadal cells to the liver surface, leading to the formation of OLS (14). In addition, results of a previous study revealed that the peritoneal surface epithelium of the embryonic gonads was covered with bulging cells, as opposed to the typical flat epithelium; the examination of embryos suggested that during the embryonic stage, these bulging cells detach and migrate to the surfaces of nearby organs, such as the liver (15).

When MCN is a benign cystic lesion, the cyst epithelium exhibits characteristics of biliary-type epithelium, specifically CK7(+)/CK20(-)/mucin 2 (MUC2)(-)/MUC5AC(-)/MUC6(-). At this stage, the immunohistochemical characteristics of MCN are comparable with those of cysts. As the tumor progresses, the cystic epithelium exhibits gastrointestinal epithelial characteristics. Furthermore, when MCN is considered borderline or malignant, positivity rates for CK20, MUC2, MUC5AC and MUC6 are markedly increased (3). This aids in differentiating MCN from benign cysts; however, distinguishing MCN from IPNB remains challenging. IPNB also exhibits gastrointestinal epithelial characteristics, often exhibiting levels of positivity for CK20, MUC2, MUC5AC and MUC6. However, positivity for MUC1 is often only observed in the malignant phases of both tumors. ER, PR and α-inhibin are often positively expressed in the OLS of MCN; however, positive expression levels of these proteins are not observed in IPNB (16,17).

According to the results of the imaging analysis, the patient of the present study presented with a solid cystic liver tumor that invaded the hepatic portal area, accompanied by secondary dilation of the intrahepatic bile ducts in the left liver. However, the tumor exhibited no direct communication with the bile duct and no cystic dilation or nodular growth were observed within the bile duct. Furthermore, septal thickening, enhancement and wall nodules were observed in the mass, and this was accompanied by cyst wall calcification. Notably, the aforementioned radiological features are typical of MCN.

The diagnostic accuracy of preoperative imaging for hepatic cystic lesions may be as low as 30% (10); thus, further diagnostic confirmation is required using pathological analysis. Although the presence of OLS is considered key for differentiating MCN from IPNB, OLS is only present in female patients and is replaced by hyaline stroma in male patients (9). Although OLS was not observed in the present case, PR(+) and α-inhibin(+) are used to distinguish OLS from IPNB. Furthermore, the patient showed positivity for CDX2 and CK20, which is consistent with the gastrointestinal epithelial characteristics observed in MCN with an associated invasive carcinoma (3). The hallmark of IPNB is the growth of the intraductal atypical epithelial papillary and spread along the duct. Microscopic examination may reveal adjacent bile ducts with intraepithelial neoplasia or peribiliary glands within the cyst wall (17). As these factors were not observed in the present case, the diagnosis of MCN was confirmed.

Diagnostic imaging of hepatic MCN is considered to be associated with low levels of accuracy; thus, histological evaluation remains the primary method for definitive diagnosis. Immunohistochemical analysis is therefore required when there are complexities in identifying the stromal layer, mucin production is limited or the diagnosis remains inconclusive (1).

In conclusion, the diagnosis of MCN should not rely on biological sex. When evaluating patients with suspected cystic liver disease, the potential for MCN should be considered. A comprehensive assessment that integrates clinical characteristics, imaging findings and pathological features is required for accurate diagnoses in clinical practice. Furthermore, a multi-disciplinary approach involving effective communication between pathologists and clinicians is required for improved patient outcomes.