Solid Pseudopapillary Epithelial Neoplasm (SPEN) of the Pancreas

Etiology

The etiology of SPENs remains unclear, but the hypothesis with the most convincing evidence thus far is that SPENs originate from the pluripotent cells of the genital ridges that adhere to the pancreas during early embryogenesis. Features in favor of this theory are the sex and age distribution, the absence of pancreatic markers, and the expression of sex hormone receptors. Some SPENs tend to regress after menopause, which also supports this hypothesis.[2] 

An overwhelming majority of SPENs carry mutations in CTNNB1, which is the gene encoding ß-catenin, thus resulting in its nuclear accumulation.[3] A rare association between SPEN and familial adenomatous polyposis has also been documented in existing literature. Inactivation of the adenomatous polyposis coli (APC) gene and subsequent activation of the Wnt/ß-catenin pathway likely explains this association.[4]

Epidemiology

SPENs account for 1% to 2% of exocrine pancreatic lesions and approximately 5% of cystic pancreatic lesions in adults.[2][5] In children, however, SPENs comprise between 6% and 17% of all pancreatic tumors.[2] Recent literature suggests a 7-fold increase in the incidence of these tumors in the past 2 decades. Although this data may reflect a rise in cases, some authors attribute this to the advancement of imaging and diagnostic techniques.[6] Clinicians should be aware that SPENs have a female preponderance with a reported ratio of 10:1. The age at detection ranges from 8 to 67 years old, with an average age of 28.5 years at diagnosis.[7] In men, however, diagnosis typically occurs at a mean age of 18.5 years.[8]

Histopathology

On gross examination, SPENs are characteristically large and encapsulated. They have a variegated appearance with foci of necrosis, hemorrhage, and cystic changes. The variable appearance of SPENs has been attributed to vascular ischemia.[9] Similarly, on microscopic examination, different parts of the neoplasm vary significantly in their cellular arrangements. The solid component consists of sheets or cords of homogenous cells interspersed with numerous blood vessels. There are typically innumerable areas of cystic degeneration, and the presence of pseudopapillary patterns and pseudorosettes are pathognomic of SPENs. This pseudopapillary pattern occurs due to tumor cells getting detached from blood vessels. The presence of cercariform cells is a consistent cytological feature of SPENs and is a crucial distinguishing feature from neuroendocrine pancreatic tumors.[2] Mitosis is uncommon.

An exophytic pattern, incomplete encapsulation, calcifications, parenchymal or neurovascular invasion, and metastases indicate malignant transformation.[10] In terms of immunohistochemistry, SPENs are typically positive for ß-catenin, the dot-like pattern of CD99, vimentin, neuron-specific enolase (NSE), alpha-1-antitrypsin, and alpha-1-antichymotrypsin. However, identifying the CTNNB1 molecular marker alone is often sufficient to make a diagnosis.[2][6] These tumors are not associated with the elevation of tumor markers such as cancer antigen 19-9 (CA 19-9) or carcinoembryonic antigen (CEA).[11]

History and Physical

SPENs typically have a long asymptomatic period before developing any signs or symptoms. Most often, due to the indolent nature of these tumors, they are incidentally diagnosed on physical examination or upon obtaining imaging studies for other medical reasons. When patients are symptomatic, their symptoms result from the SPEN compressing adjacent organs.

Symptoms, when present, are nonspecific and include abdominal pain or discomfort, diarrhea, or nausea. Rarely, jaundice or gastric outlet obstruction may develop depending on the location of the SPEN. To date, no endocrine functional imbalances have been associated with these tumors.[6] As previously mentioned, SPENs have low malignant potential. In cases of malignant transformation, the liver is the most common site of metastasis. Other metastasis sites include regional lymph nodes, the mesentery or omentum, and the peritoneum.[8]

Evaluation

Imaging Studies

Although SPENs may be incidentally detected on physical exam, clinical diagnosis is impossible due to various differentials. The tumor has a distinctive morphology on imaging and is usually seen in the body or tail of the pancreas. On computer tomography (CT) imaging, SPENs characteristically are thick-walled encapsulated structures with peripheral solid and central cystic components. An important differentiating feature from other pancreatic neoplasms is that SPENs enhance similarly to surrounding pancreatic parenchyma with contrast.[12] However, magnetic resonance imaging (MRI) is considered superior to CT in diagnosing SPENs. On MRI, SPENs appear heterogeneous with varying signal intensity on T1-weighted imaging and heterogeneous with high intensity on T2-weighted imaging.[5] The capsule appears as a thin hypointense rim. Angiographies may further help to delineate SPENs from surrounding tissues, which may be necessary in determining the resectability of the tumor. 

Pathology Studies

A preoperative pathological diagnosis is best obtained via endoscopic ultrasound-guided biopsy and remains the diagnostic gold standard.[13] Different regions of this heterogeneous tumor have been found to have varying pathological and immunohistochemical patterns; therefore, biopsies must be taken from several sites to ensure an accurate diagnosis.[14]

Treatment / Management

Surgical parenchyma-preserving enucleation is often curative and is the treatment of choice for these tumors. In some cases, however, the tumor is deemed unresectable due to invasion or encasement of surrounding arteries (eg, aorta, superior mesenteric artery, or celiac artery). Radiofrequency ablation, gamma-knife treatment, arterial embolization, radiotherapy, or chemotherapy should be considered in such situations.[15] Because approximately 75% of tumors contain estrogen and progesterone receptors, there may be a role for systemic tamoxifen when surgical resection is not an option.[16] However, no clinical studies have been conducted in this regard, and the evidence of the success of tamoxifen use is limited to case reports.(B3)

Differential Diagnosis

The clinical presentation at the time of diagnosis is variable and could resemble other pathologic entities; therefore, the definitive diagnosis relies on radiological findings and immunohistological assessments. Differential diagnoses that should be considered with SPENs include:

• Mucinous cystic neoplasms of the pancreas
• Islet cell tumors
• Neuroendocrine tumors with cystic features (eg, cystadenoma or cystadenocarcinoma)
• Serous microcystic adenoma
• Intraductal papillary mucinous neoplasm (IPMN) 

Medical Oncology

Unresectable, metastatic, and recurrent cases of SPEN may require radiation therapy, chemotherapy, or hormonal therapy. Studies on these treatment modalities are sparse, and further research is necessary to formulate management guidelines. Nevertheless, evidence suggests that SPENs are radiosensitive and showed favorable responses to systemic chemotherapy and hormonal therapy.[5] Specifically, chemotherapeutic regimens with floxuridine and oxaliplatin, etoposide and cisplatin, or S-1 have proven successful.[15]

Staging

At present, no specific pathological staging systems exist for SPENs. However, these tumors can be staged based on the American Joint Committee on Cancer (AJCC) TNM staging system for high-grade or malignant tumors.[17]

Prognosis

The overall prognosis of SPENs remains relatively favorable due to minimal aggressiveness. However, these tumors tend to be more aggressive when they occur in older males.[7] Approximately 10% to 15% of all SPENs show highly malignant behavior and metastasize. Though tumor size, lymphovascular invasion, and the Ki-67 index have been proposed as predictors of aggressiveness and relapse, evidence is scant, and further research is needed.[18] The overall 5-year survival rate is about 97%.[19]

Complications

Most complications are associated with compression of adjacent structures, resulting in jaundice and gastric outlet obstruction. In the postoperative period, complications include pancreatic fistulas, pancreatitis, steatorrhea, infections, bleeding, and biliary fistulas, ileus. Additionally, the development of diabetes mellitus is seen in <1% of patients.[20] Although rare, close follow-up is recommended for the development of recurrence or metastasis.