Mucinous Cystic Pancreatic Neoplasms

Etiology

The etiology of MCPNs is unclear; an association with female reproductive hormones has been proposed. The preponderance of MCPNs in women, the presence of estrogen and progesterone receptors on the epithelial lining, and the classic histologic finding of columnar lining cells with dense ovarian-like stroma support this theory.[3] Several mutations have been associated with mucinous cystic neoplasms, especially in those that progress to invasive carcinoma. These include mutations in KRAS, CDKN2A, TP53, and SMAD4.[4][5]

Epidemiology

Mucinous cystic pancreatic neoplasms primarily affect middle-aged women, with a female-to-male ratio of 20:1 and a median age of diagnosis at 48 years. However, as most MCPNs are asymptomatic, the true incidence and prevalence of MCPNs are unknown. The increased use of high-quality cross-sectional imaging has led to a dramatic increase in the number of identified asymptomatic pancreatic cysts; a study in 2015 reported that up to 10% of all abdominal computed tomography (CT) scans revealed pancreatic cysts.[6] 

MCPNs are the second-most commonly identified pancreatic cystic lesion after intraductal papillary mucinous neoplasms.[7] Approximately 93% of MCPNs are located in the body or tail of the pancreas as a solitary lesion with a median size of 5 cm.[8] Malignant MCPNs tend to be larger than their benign counterparts. Most (72%) MCPNs are benign; borderline (10.5%), in situ carcinoma (5.5%), and invasive carcinoma (12%) are less common.[9] Invasive MCPNs tend to present in older patients roughly a decade later than their benign counterparts.

Pathophysiology

MCPNs typically develop in the body or tail of the pancreas and enlarge slowly over time. Unlike intraductal papillary mucinous neoplasms, MCPNs rarely communicate with the pancreatic duct. While the development and growth of MCPNs are possibly related to hormonal stimulation, what instigates and promotes their growth is unclear.

Typical of pancreatic body and tail lesions, MCPNs are often asymptomatic until they are quite large.[10] The presenting symptoms of MCPNs are often due to compression of surrounding structures such as the pancreatic duct, duodenum, or stomach. Occasionally, MCPNs can induce pancreatic ductal obstruction secondary to extrinsic compression and precipitate acute pancreatitis.[2] When located in the pancreatic head, MCPNs may cause obstructive jaundice.

Worrisome features indicating the malignant transformation of MCPNs include increased lesional size, mural nodules, thickening or irregularity of the cyst wall, or calcification. Dysplastic cells confined to the capsule have a much better outcome with surgery than those with extracapsular invasion.[10] 

Histopathology

Gross examination of MCPNs typically reveals encapsulated cysts with a fibrous capsule. While often multicystic with thin septae, MCPNs can be unilocular. Calcification within the cyst walls is common. When present, mural nodules and irregular capsular thickening are more commonly associated with malignancy. The cysts often contain varying amounts of viscous mucus and necrotic material.

Microscopic evaluation of an MCPN typically reveals lesions lined by tall mucin-producing columnar or cuboidal cells. The underlying dense stroma closely resembles typical ovarian tissue and is characterized by a highly vascular spindle cell matrix.[8] The World Health Organization (WHO) criteria deem the presence of ovarian stroma essential for diagnosing an MCPN. The lining epithelium may demonstrate varying degrees of atypia, ranging from low-grade dysplasia to invasive adenocarcinoma. Infiltration of dysplastic cells beyond the cyst epithelial lining is the hallmark of invasive adenocarcinoma.[11] 

The 2019 WHO classification stratifies cystic pancreatic lesions as MCPNs with low-grade dysplasia, MCPNs with high-grade dysplasia, and MCPNs with associated adenocarcinoma.[12] Terms such as mucinous cystadenoma and mucinous cystadenocarcinoma were used historically to describe benign and malignant MCPNs; these lesions are now grouped under the WHO classification.

History and Physical

Patients with MCPNs are often asymptomatic. Those patients presenting with symptoms most commonly have abdominal pain (62.2%). Less common presenting symptoms include weight loss, abdominal fullness, loss of appetite, and fatigue. Large MCPNs can compress surrounding organs and structures, leading to abdominal pain and a sensation of fullness. Occasionally, they can cause ductal obstruction and acute pancreatitis.

The physical examination of patients with MCPNs is often unrevealing. In the presence of a large MCPN, a fullness or vague upper abdominal mass may be palpable. As MCPNs are rarely located in the pancreatic head, jaundice is uncommon.[13]

Evaluation

The evaluation of a patient with a suspected MCPN should include a complete blood count, comprehensive metabolic panel, serum lipase, and a cancer antigen 19-9 (CA 19-9).

High-quality cross-sectional abdominal imaging is the backbone of diagnosis. Triple-phase pancreas-protocol CT with arterial, venous, and portal venous phases or magnetic resonance imaging (MRI) with contrast provides excellent visualization of the retroperitoneal space. Radiological findings suggestive of an MCPN include a single, multiloculated lesion in the pancreatic body or tail, often with areas of calcification and without communication with the pancreatic duct (85%).[14] An MRI is useful in distinguishing an MCPN from an intraductal papillary mucinous neoplasm by discerning cyst communication with the pancreatic duct.[15] Imaging findings that are suggestive of malignant transformation include dense calcifications, the presence of mural nodules, infiltration of the capsule, and lymphadenopathy.

Endoscopic ultrasound with cyst wall biopsy and cyst fluid cytology may be employed and is especially useful in cases where high-risk radiological features are seen; a preoperative diagnosis of malignant transformation guides the timing and type of surgical intervention. Current American Gastroenterological Association (AGA) guidelines for the management of cystic pancreatic neoplasms recommend an endoscopic ultrasound with fine needle aspiration and potential cyst wall biopsy for lesions with a minimum of 2 high-risk features, such as a mural nodule, lesional size greater than 3 cm, or a dilated pancreatic duct.[16] 

The cyst fluid analysis from an MCPN typically reveals elevated carcinoembryonic antigen (CEA) levels, a positive mucin stain, low glucose levels, and normal amylase levels.[17] Molecular analysis is used increasingly for more precise diagnostics. Specifically, KRAS mutations have a 97 to 100% specificity for detecting mucinous differentiation and can be helpful in equivocal cases.[18]

Treatment / Management

The size of the neoplasm dictates the management of MCPNs, the presence of high-risk features, presenting symptoms, and the patient's ability to tolerate surgical intervention.

Guidelines for the management of MCPNs differ among international associations. The AGA and the American College of Gastroenterology recommend surveillance in asymptomatic cysts < 3 cm without high-risk features such as mural nodules, pancreatic duct dilation, or elevated CA 19-9. AGA guidelines recommend an MRI 1 year from diagnosis and scans every 2 years for 5 years if no significant change occurs.[16] Follow-up or surveillance is not recommended in patients with cystic pancreatic neoplasms who are not surgical candidates.

In contrast, the 2017 International consensus recommends surgical resection for all MCPNs.[19] Retrospective data suggests that the malignancy rate for MCPNs less than 3 cm with a normal CA 19-9 is almost zero, making observation a reasonable strategy in these patients.[20] (B3)

For MCPNs with high-risk features or lesions that are symptomatic, surgical resection is the standard of care. The extent of surgery depends on the size and location of the tumor. For most lesions in the body or the tail of the pancreas, a distal pancreatectomy or a distal subtotal pancreatectomy is usually sufficient. Splenic preservation may be attempted in patients without features suggestive of invasive disease. A distal pancreatectomy with splenectomy and regional lymph node dissection is recommended for lesions with high-risk features. In the rare instances where the tumor arises in the pancreatic head, pancreaticoduodenectomy may be required.[21]

Differential Diagnosis

The differential diagnosis of cystic pancreatic neoplasms includes, but is not limited to the following:

• Intraductal papillary mucinous neoplasm
• Pancreatic pseudocyst
• Serous cystadenoma
• Pancreatic ductal adenocarcinoma
• Pancreatic neuroendocrine tumor

Staging

Preoperative staging imaging should be performed for patients with suspected MCPN-associated invasive cancer, including a CT scan of the chest, abdomen, and pelvis. An intraoperative diagnostic laparoscopy at the start of the surgical procedure may also be indicated in these patients to rule out metastatic disease. 

Prognosis

The final pathology dictates the prognosis for patients with MCPNs. Noninvasive MCPNs have an excellent prognosis with a 5-year overall survival rate of 100%. Interestingly, there is no reported difference in survival rates between noninvasive lesions with low-grade or high-grade dysplasia.[22] Invasive neoplasms have a significantly poorer prognosis, with a 5-year overall survival rate of 26%.[10] Advanced age, degree of tumor invasion, and multifocality have been identified as poor prognostic factors. 

Complications

Most complications of MCPNs are related to the procedures required for diagnosis and treatment. Interventional diagnostic studies such as endoscopic ultrasound have a relatively low complication rate, although serious complications such as gastric or duodenal perforation, acute pancreatitis, and hemorrhage may occur.[23] 

Distal pancreatectomy or subtotal pancreatectomy are the most common operative procedures performed in the treatment of MCPNs. Operative complications include pancreatic stump leak with fistula, hemorrhage, injury to surrounding organs, infections secondary to splenectomy, and more general complications associated with lengthy operations under general anesthesia, such as deep vein thrombosis.[24] 

Postoperative pancreatic leaks are relatively common and are diagnosed by elevated amylase levels in the pancreatic drain fluid. Persistent leaks are known as fistulas. Most reported fistulas are grade A, and management consists of continued drainage as most of these fistulas will heal without other intervention. Occasionally, a patient may require percutaneous drainage of a small fluid collection (grade B). Rarely patients will require intensive care for sepsis and multiple organ failure secondary to a persistent pancreatic leak (grade C); such patients require swift surgical intervention.

Postoperative impaired glucose tolerance and diabetes may occur, depending on the amount of pancreatic parenchyma removed. Infections secondary to surgical splenia can be mitigated by appropriate preoperative vaccination.