Introduction
Mucinous cystic neoplasm (MCN) is an uncommon cystic tumor of pancreas, accounting for about 10% of pancreatic cystic lesions. It occurs almost exclusively in women (male-to-female ratio, 1:9–20), with age at diagnosis being 40 and 60 years. Most such tumors are located in the pancreatic body and tail (93%–95%).[1,2] Nearly half of the patients are symptomatic at diagnosis, with chief complaints including a palpable mass in the epigastric region and non-specific abdominal pain or distension.[3] Some patients may have other concomitant disorders such as acute pancreatitis, diabetes mellitus, chronic pancreatitis and pancreas divisum.[4] Imaging studies often show a medium to large well-defined cystic lesion with thick walls and intracystic septa; a mural nodule or solid component can be present. The tumor is not connected to the duct system.[5,6]
Pathologically, MCN is characterized by unilocular or multilocular cystic spaces and usually has a fibrous capsule, which occasionally contains focal calcifications. The cysts are lined by a single layer of columnar or cuboidal mucin-producing epithelial cells. The defining histologic feature is the distinctive ovarian-type stroma beneath the epithelium.[7] MCN of the pancreas is a known precursor lesion of pancreatic ductal adenocarcinoma (PDAC), with low-grade dysplasia or high-grade dysplasia. Malignancies arising from MCN, namely, MCN with associated invasive carcinoma (MCN-AIC) may rarely occur.[7] Surgical removal of the tumor is the only curative therapy and is recommended for all MCNs. The resected specimens need to be carefully examined, and entirely submitted for histology to avoid missing an invasive component in pathologic assessment. The prognosis of MCN is excellent for non-invasive tumors[8,9]; even patients with MCN-AIC have a much better overall survival as compared to those with conventional PDAC.[10]
In general, the factors associated with risk of malignancy in MCN include tumor size, presence of papillary projection or nodules, and elevated CA19-9 level.[3,8,10] However, pathologic features that are helpful in further predicting the clinical outcomes of MCN-AIC have not been well studied. Capsule invasion may be associated with a poor survival,[11–13] but findings from our most recent study suggest that pattern of invasion may have further prediction value.[14] Molecular changes similar to those found in PDAC had been identified in MCN, including KRAS, CDKN2A/p16, TP53, SMAD4 mutations, as well as others such as RNF43 and PIK3CA mutations.[15–17] But their potential value in prognosis is unknown. In this review, we attempt to provide an update to the current knowledge of prognostic histopathology parameters for MCN-AIC and advances in molecular genetics of this tumor.
Database search strategy
The authors performed a systematic search of the literature using the PubMed database. The search strategy focused on obtaining all literature that discussed MCN and MCN-AIC between 1970 and 2021. The following search terms were used to initially select the articles to be evaluated: pancrea∗ and (mucinous cystic or mucinous cystadeno∗). The authors firstly judged whether the title or abstract of the articles were relevant to the topics that discussed in this study. If so, the entire article would be screened comprehensively to assess for eligibility of inclusion. To look for other potentially useful studies, the authors also manually searched the bibliographies of the articles included in the screening process. Only English language and full-text articles were considered.
Definition
MCN is defined as a cystic-forming, mucin-producing neoplasm of pancreas that lacks communication with the pancreatic ductal system. Histologically, the cysts are lined by columnar or cuboidal mucin-producing epithelial cells, with a characteristic ovarian-type stroma beneath the epithelium.
Compagno and Oertel[18] first separated pancreatic MCNs from serous cystic neoplasms (SCN) in 1978. The presence of subepithelial dense cellular stroma “resembling that of the ovary” was described as one of the histological features for this tumor. It was concluded the tumor had potential of “overt or latent malignancy.” In 1996, the World Health Organization (WHO) international histological classification of tumors further classified mucin-producing cystic tumors into two individual entities, namely, mucinous cystic tumor (MCT) and intraductal papillary mucinous tumor (IPMT), with the latter lacking the ovarian-type stroma. In 2000, the WHO classification of tumors of the digestive system re-named the two entities as MCN and intraductal papillary mucinous neoplasm (IPMN), respectively. The WHO Classification of Tumors (5th edition) published in 2019 emphasized that the distinctive ovarian-type stroma is required for the diagnosis of MCN. Based on the degree of cytoarchitectural atypia of the epithelium, the tumor is further categorized as “MCN with low-grade dysplasia” or “MCN with high-grade dysplasia.”
As one of the pre-malignant tumors of ductal adenocarcinoma, around 15% of MCN will progress to invasive carcinoma with the presence of neoplastic cells beyond the epithelial lining of the cyst to invade the stroma, which was previously referred as “mucinous cystadenocarcinoma.” In the 5th edition of the WHO classification, MCN with invasive carcinoma component is formally designated as MCN with associated invasive carcinoma (MCN-AIC).
Pathologic features
Grossly, MCN manifests as a unilocular or multilocular cystic tumor of varying sizes with the median dimension of the tumor ranging from 4.2 to 6 cm. Rarely tumors of a few millimeters or up to 35 cm had been documented.[7,19] The cyst is walled by a thick fibrous capsule with focal hyalinization or calcification, and it contains either thick mucus or a mixture of mucus and hemorrhagic necrotic material.[11] Papillary projections may be seen from the inner surface of the cyst, which may contain foci of high-grade dysplasia and even invasive carcinoma (Fig. 1).
;)
Figure 1: An example of MCN of the pancreas: a large, well-circumscribed unilocular cystic neoplasm is located in the pancreatic tail, with dense fibrous wall of 0.1 to 0.3 cm in thickness. Papillary excrescence can be seen on the inner surfaces. Unpublished data. MCN = mucinous cystic neoplasm.
Microscopically, the capsule of MCN consists of thick collagen bundles, which may appear prominently hyalinized in large tumors. The cysts are lined by tall columnar mucin-producing epithelial cells, resembling gastric or intestinal epithelial cells. There may be varying degrees of cytological atypia, based on which MCN is histologically graded. In the latest WHO classification a 2-tiered grading system is proposed: mild-to-moderate architectural and cytological atypia with no or occasional mitotic figures is categorized as MCN with low-grade dysplasia (formerly low-grade and intermediate-grade dysplasia) (Fig. 2A); severe architectural and cytological atypia with the formation of papillary projections, nuclear stratification and pleomorphism and frequent mitotic figures qualify a tumor to be MCN with high-grade dysplasia (Fig. 2B). Presence of an invasive component leads to the diagnosis of MCN-AIC (Fig. 2C).
Figure 2: Photomicrography of MCN of the pancreas. (A) MCN with low-grade dysplasia: the epithelium is composed of columnar, mucin-containing cells with sub-epithelial spindle-like ovarian type stroma (hematoxylineosin staining, 100×). (B) MCN with high-grade dysplasia: epithelial cells developed cribriform structure with enlarged, disordered, stratified nuclei (hematoxylineosin staining, 100×). (C) MCN-AIC: epithelial cells with severe dysplasia can be seen at the top, invasive component beyond the basement membrane and invading the stroma of capsule (hematoxylin eosin staining, 25×). Unpublished data. MCN = mucinous cystic neoplasm, MCN-AIC = MCN with associated invasive carcinoma.
The defining feature of MCN is the ovarian-type stroma beneath the epithelium that consists of spindle-shaped cells with round or elongated nuclei and sparse cytoplasm.[20] The presence of ovarian-type stroma and lack of communication with the main pancreatic duct are critical for distinguishing MCN from IPMN (Table 1).[13] The origin of ovarian type stroma (OTS) in MCN remains to be determined. It has been postulated that it may be derived from the endodermal immature stroma stimulated by female hormones or from primary yolk cells implanted in the pancreas during embryogenesis.[21]
Table 1 -
Distinction between MCN, IPMN, and SCN
|
MCN |
IPMN |
SCN |
| Location |
Body/tail |
Head/body |
Body/tail |
| Gross |
Solitary, uni/multi-locular cyst |
Cystic papillary mass |
Multi-cystic cluster of individual small cysts |
| Tumor size (median, cm) |
4.2 |
2.5 |
5 |
| Connection with pancreatic duct |
No |
Yes |
No |
| Structure |
Cystic, occasional papillary projection |
Papillary growth |
Honeycomb or spongy |
| Cellular features |
Columnar mucin-containing cells and non-mucinous flat/ cuboidal cells; ovarian-type stroma |
Gastric, intestinal and pancreatobiliary cells |
Glycogen-rich “serous” cells |
| IHC |
Ovarian-type stroma: PR, ER, α-inhibin |
Gastric type: MUC5AC intestinal type: CDX2, MUC2 pancreatobiliary type: MUC1, MUC6 |
α-Inhibin, MUC1, MUC6 |
| Genetic alterations |
KRAS, TP53, SMAD4, RNF43
|
KRAS, GNAS, TP53, SMAD4, RNF43
|
VHL
|
| Precursor lesion |
Yes |
Yes |
No |
IHC = immunohistochemistry, IPMN = intraductal papillary mucinous neoplasm, MCN = mucinous cystic neoplasm, SCN = serous cystic neoplasms.
The risk of MCN harboring invasive carcinoma is ranged from 9.9% to 34% in various series.[1,3,19] Invasion is typically seen in the OTS-depleted areas with lower progesterone receptor expression.[8] The presence of solid component or mural nodule, larger tumor size, and duct dilation have been reported to be independent factors predictive of malignant transformation in MCNs, with tumor size to have the highest odds ratio.[4,5,10] Invasive components mostly resemble those of tubular adenocarcinoma, such as PDAC.[11,22] Other histological variants of invasive carcinoma have also been reported, including undifferentiated carcinomas with osteoclast-like giant cells and adenosquamous carcinomas[23]. Invasive carcinoma arising from MCN can be focal and minimal, and thus a thorough examination and extensive sampling of the submitted specimen for histology is necessary.
Immunohistochemically, the epithelial cells of MCN stain positive for epithelial membrane antigen (EMA) and pan-cytokeratins including cytokeratin (CK) 7, CK8, CK18 and CK19; the ovarian-type stroma cells express progesterone receptor and estrogen receptor (Fig. 3) but may also be positivity for steroidogenic factor (SF-1), vimentin, calretinin, α-inhibin and sometimes beta-human chorionic gonadotropin (β-hCG).[24,25]
Figure 3: Photomicrography of MCN showing two distinct components: an epithelial lining composed of tall mucin-producing cells and a subepithelial ovarian-type stroma (hematoxylineosin staining, 100×) (A). Immunohistochemical stains revealing the ovarian-type stromal cells to express progesterone receptor (B) and estrogen receptor (C). Unpublished data. MCN = mucinous cystic neoplasm.
Clinical management
Over the years, several guidelines have been introduced for the management of MCN, which are helpful in the initial evaluation, treatment and surveillance. According to the latest European evidence-based guideline,[26] it is recommended to follow-up rather than resecting MCN with a size of less than 4 cm examined by MRI, EUS or a combination of both, in the absence of risk features such as a suspicious mural nodule or symptoms. However, the consensus guidelines of the International Association of Pancreatology suggest that all MCNs should be surgically resected and examined carefully for an invasive component, whereas flat MCN of less than 4 cm long are less likely to be malignant and may thus be treated by laparoscopic or organ-preserving pancreatectomy.[27] Lifelong surveillance should be offered to surgically fit asymptomatic patients that are presumed to have MCN without risk factors.[28] In addition, a systematic analysis had found that MCNs without invasive carcinoma have no risk of recurrence after resection and do not require surveillance, but an MCN-AIC has a 25% risk of recurrence, which should be followed up in the same way as PDAC after partial pancreatectomy.[1,10]
Prognosis
The prognosis of MCN without invasive carcinoma is excellent, with a 5-year survival of 96% to 100% after surgical resection.[8,29] There is no difference in survival between MCN with low-grade dysplasia and MCN with high-grade dysplasia.[9] MCN-AIC had a poor survival with risk of recurrence or metastasis, although still better than PDACs.
Previous studies had suggested that the degree of invasion is a histological prognostic parameter of MCN-AIC, although the definition of different degrees varied (Table 2).[11–13,30]
Table 2 -
The survival rates of patients with different invasion patterns in malignant
mucinous cystic neoplasm surgically resected case series
| Study |
Degrees of invasion |
N
|
5-year survival rate (%) |
| Zamboni et al[11] |
Carcinoma in situ |
|
6 |
100 |
|
Invasive carcinoma |
(1) Intratumoral (only ovarian-type stroma is involved) |
3 |
100 |
|
|
(2) Confined to the tumor wall |
5 |
About 38 |
|
|
(3) Peritumoral (the surrounding pancreatic and extrapancreatic tissues were involved) |
8 |
About 17 |
| Crippa et al[13] |
Carcinoma in situ |
|
9 |
100 |
|
Invasive carcinoma |
(1) Intracapsular (confined to the tumor wall) |
13 |
57 (“Intracapsular” has a much better prognosis than “Extracapsular”) |
|
|
(2) Extracapsular (the surrounding pancreatic and extrapancreatic tissues were involved) |
6 |
|
| Yamao et al[30] |
Carcinoma in situ |
|
21 |
94.7 |
|
Minimally invasive carcinoma (a small amount of invasion of 5 mm or less in depth was visible beyond the cyst wall into the adjacent pancreatic parenchyma) |
4 |
100 |
|
|
Invasive carcinoma |
|
2 |
0 |
| Lewis et al[12] |
Minimally invasive carcinoma (confined to the ovarian-type stroma) |
(1) Unifocal (confined to one focus) |
10 |
100 |
|
|
(2) Multifocal (consisting of multiple, discontinuous foci of invasion) |
6 |
75 |
Similar to the findings from the literature, our latest study defined two patterns of invasion in MCN-AIC: (1) encapsulated, if the invasive component is confined to the ovarian-type stroma, cystic septa or capsule; (2) extracapsular, if invasion is extended into the surrounding pancreatic parenchyma or extra-pancreatic tissue (Fig. 4).[14] This study included 15 MCN-AICs, with 12 classified as “encapsulated” and 3 “extracapsular”. Survival analysis showed a 5-year survival rate of 100% for the former and 0% of the latter, demonstrating that encapsulated MCN-AICs had a favorable clinical outcome similar to that of non-invasive MCN, while extracapsular MCN-AICs were dismal in post-operative survival. Thus, pattern of invasion is a strong prognostic histological parameter in MCN-AIC. This finding is supported by evidence from other studies: T1a and T1b invasive carcinomas arising from ovarian-type stroma, septa and cystic capsule have a long-term disease-free survival.[9,31] In our study the role of lymph node invasion could not be addressed due to the sample limitations. But another large retrospective study indicated that lymph node positivity is the most important factor for decreased survival of MCN-AIC,[32] a phenomenon also observed in a case report.[33]
Figure 4: Diagram showing the two invasion patterns in MCN-AICs (Reprinted from Liang et al.
[14]). MCN-AIC =
mucinous cystic neoplasm with associated
invasive carcinoma.
Molecular abnormalities
Genetic alterations observed in PDACs have also been partly seen in MCNs: hotspot mutations in the oncogene KRAS are most common in MCN and can occur in low-grade dysplasia. The frequency increases with the grade of dysplasia.[17,34,35]CDKN2A, TP53 are altered in lesions with high-grade dysplasia or associated invasive carcinoma, but rarely in low-grade dysplasia.[35–38] Smad4 expression is normal in either low-grade dysplasia or high-grade dysplasia MCNs but is lost in most invasive carcinomas, indicating that SMAD4 plays a key role in malignant transformation of MCN.[39] Latest genomic sequencing has shown that mutations in SMAD4 and TGFBR2 are restricted to invasive carcinoma, further supporting that this pathway is a driver in the progression to invasive carcinoma.[15]RNF43 alterations are largely in non-invasive lesions but not in invasive carcinoma, as previously shown to play a role as driving the formation of mucin-producing pancreatic cysts.[15,16]PIK3CA gene mutations, which frequently occur in colorectal cancers, has been found to have a low prevalence in MCN.[15,17] Minor alteration of LOH of 3p25 (VHL locus) has also been reported.[40]
Sorio et al[41] established the first cell line of MCN, designated as MCC1, from the high-grade dysplastic cell component of a non-invasive MCN; mutational analysis of the cultivated cells confirmed the presence of KRAS, P16, P53 and MUC1 mutations. It is worth noting that GNAS mutations have not been found in MCN, in contrast to its roles in IPMN.[42] Hedgehog signaling is an important mediator of tumorigenesis of PDAC; sonic Hh (sHh) is expressed in both stromal cells and epithelial cells of MCN, suggesting an autocrine regulation of sHh in the development of MCN.[43] In addition, the Wnt signaling pathway is activated and promotes development of the ovarian-like stroma to contribute to formation of MCN.[44]
Limitations and conclusions
Pancreatic MCNs are mucin-producing cystic neoplasms occurring almost exclusively in women, predominantly located in the body and tail of pancreas, and do not communicate with the duct system. The tumor contains a distinctive subepithelial OTS. Malignancy is relatively low in frequency in MCN, with slow progression. Prognosis is excellent for non-invasive MCNs, for which surgical resection is curative. For MCNs-AIC, based on limited follow-up studies, pathologically different patterns of invasion may predict clinical outcome. Molecular genetic studies have revealed KRAS mutations to occur in the early stage of the tumorigenesis, while CDKN2A and TP53 appeared more frequently as dysplasia progresses. SMAD4 inactivation is a late event and is restricted to invasive carcinoma.
Acknowledgments
None.
Author contributions
SYX conceived and designed the study. WX and HL wrote and edited the manuscript. YG and SYX critically revised the manuscript. All authors approved the final version of the manuscript.
Financial support
None.
Conflicts of interest
The authors declare no conflicts of interest.
Editor note: SX is an Editorial Board member of Journal of Pancreatology. He was blinded from reviewing or making decisions on the manuscript. The article was subject to the journal's standard procedures, with peer review handled independently of this Editorial Board member and their research groups.
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