Continuing Education Activity

Solid pseudopapillary epithelial neoplasms (SPEN) of the pancreas are rare pancreatic tumors described by the WHO as low-grade malignant tumors. They tend to affect young women in the second or third decade of life and rarely affect children or men. Due to their indolent nature, SPENs are most frequently discovered incidentally on physical examination or imaging for other reasons. An alternating solid and pseudopapillary architecture is characteristic of these tumors, which makes prompt radiological detection possible. Though SPENs are considered to have a relatively favorable prognosis, they have garnered attention in recent years due to an apparent increase in incidence. Current literature has also demonstrated a risk of metastasis or recurrence following surgical resection, emphasizing the need for close follow-up post-operatively. This activity for healthcare professionals aims to enhance learners' competence in selecting appropriate diagnostic tests, appropriately managing solid pseudopapillary epithelial neoplasms of the pancreas, and fostering effective interprofessional teamwork to improve outcomes.

Objectives:

• Identify characteristic radiological findings of SPEN.

• Differentiate SPEN from other pancreatic tumors based on histopathology.

• Apply appropriate evidence-based treatment options in the management of unresectable SPEN.

• Implement effective collaboration and communication among interprofessional team members to improve outcomes in SPEN.

Introduction

Solid pseudopapillary epithelial neoplasms (SPEN) of the pancreas are rare pancreatic tumors first described by Dr. Virginia Kneeland Frantz in 1959. These neoplasms were previously known by various names, including solid and cystic tumors of the pancreas, Frantz tumors, solid and papillary epithelial neoplasms, Hamoudi tumors, and papillary-cystic tumors. Though SPENs were considered benign for a significant amount of time, these tumors have now been reclassified as low-grade malignant tumors with low metastasis rates and high survival rates.[1] They typically occur in young women, though these neoplasms can occasionally be seen in males and in pediatric and older populations. In adults, they occur more frequently in the body or tail of the pancreas, while in children, they are most often seen in the pancreatic head.[2]

Patients are usually asymptomatic for prolonged periods, and by the time symptoms have developed, tumors have typically grown to considerably larger sizes. Less frequently, SPENs may invade adjacent structures or metastasize to distant organs. An accurate and prompt diagnosis is paramount in minimizing complication rates and improving patient outcomes.

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.

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.

Deterrence and Patient Education

Solid pseudopapillary tumors of the pancreas are rare malignancies curable with surgical resection. Currently, no screening recommendations to identify these tumors earlier have been adopted. However, symptoms such as abdominal pain, nausea, or vomiting should prompt medical attention for further evaluation.

Pearls and Other Issues

Key facts to keep in mind regarding solid pseudopapillary epithelial neoplasms of the pancreas:

• SPEN are uncommon and often indolent pancreatic tumors.
• SPENs are commonly present in young women, suggestive of the possible role of hormonal factors.
• Diagnosis of these tumors is by diagnostic imaging and biopsy.
• The definitive treatment is surgery, often curative in most cases and associated with excellent long-term prognosis.
• These neoplasms should be considered in the differential diagnosis of cystic pancreatic tumors, specifically in a young woman.
• Despite the indolent nature of SPENs, most patients require surgical resection.
• Surgery can be curative regardless of the tumor's size or location, and local recurrence or metastasis after complete resection is rare. 
• In unresectable or metastatic cases, systemic therapies are often necessary, though formal treatment guidelines are lacking.

Enhancing Healthcare Team Outcomes

Properly managing solid pseudopapillary pancreatic neoplasms requires an interprofessional team approach and evidence-based strategies. In light of the prolonged asymptomatic period, detection often depends on a clinician's assessment skills and the ability to detect the mass on physical examination. Patient education and communication, as well as interprofessional communication, is imperative to ensure patient-centered care. 

Coordination between an interprofessional team, including histopathologists, radiologists, oncologists, and surgeons, can provide a holistic and integrated approach to achieve the best possible clinical outcomes. Clinicians must identify complications, interpret radiological findings, recognize characteristic histopathological features, and ensure prompt diagnosis. A collaborative effort is also essential in determining an individualized therapeutic approach, depending on each patient's presentation. Effective coordination in the treatment and follow-up period is critical to monitor for complications and maximize patient safety.