A 45-year-old man presented with 3 months of progressive left upper quadrant abdominal pain and a sensation of abdominal fullness. Complete blood count and comprehensive metabolic blood panel were normal. A CT scan showed a large solid pancreatic mass in the tail of the pancreas. Endoscopic ultrasound (EUS) was performed at 7.5MHz with Doppler. EUS revealed a hypoechoic, heterogeneous, 7×6 cm solid mass lesion in the pancreatic tail with scattered hyperechogenic foci consistent with some peripheral calcifications. (Figure 1). EUS guided core biopsy was performed with a 22 gauge needle. The pathology report revealed loosely clustered to discohesive monomorphic cells with eccentric nuclei and fine chromatin. There were hyalinized stromal fragments lined by monomorphic, bland-appearing, polygonal cells that appeared to be falling off the underlying stromal core. Immunohistochemical stains were used to aid in the evaluation of the pathology specimen. The cells of interest (associated with the hyalinized stromal core) are positive for B-catenin (nuclear), showed patchy positive staining for CD56. Tissue samples were mostly negative for Cam 5.2 and synaptophysin. The histology and immunohistochemistry together were supportive of a diagnosis of a solid pseudopapillary tumor (SPT). (Figures 2-5) The patient was referred to surgery and underwent a distal pancreatectomy and splenectomy. This confirmed the diagnosis of SPT. All resected lymph nodes were free of disease. He has done well thereafter.
Incidence and Demographics
SPT of the pancreas is a rare tumor that was first described by Virginia Frantz in 1959.1 SPT has previously been called many other names including solid and papillary epithelial neoplasm, papillary cystic neoplasm, solid and cystic papillary epithelial neoplasm, solid and cystic acinar cell tumor, low grade papillary neoplasm, Hamoudi tumor, and Frantz tumor.2 In 2010, the World Health Organization designated the name of this tumor as solid pseudopapillary tumor.2 SPT is a rare neoplasm, accounting for 1-2% of all exocrine pancreatic neoplasms and 0.17-2.7% of nonneuroendocrine tumors of the pancreas.3,4,5 Since 2000, there has been a seven fold increase in SPT, which has largely been attributed to more frequent and improved imaging tests as well as increased clinical awareness of this entity.3 SPT has a marked female predominance, affecting females around ten times more often than males.3,4,5,6 More than ninety percent of reported cases of SPT affect females in their second decade with a mean age of diagnosis around 22.5 years.5 Men are generally found to be diagnosed at a later age than women.14 The tumor has been found to have a higher prevalence in Asian and Black populations.
Symptoms
SPTs are often asymptomatic and are often incidentally noted.4,5 In patients who are symptomatic, the most common symptom is abdominal pain or mass with a reported incidence of 63% of symptomatic cases.5 Other less common symptoms include nausea, vomiting, fever, weight loss, jaundice, and early satiety. Acute abdomen can occur in the setting of tumor rupture.7 SPTs are not typically associated with exocrine or endocrine pancreatic insufficiency.3
Tumor Characteristics
SPTs can occur in any part of the pancreas; however, the most common site of the tumor in adults is the pancreatic tail, followed by the pancreatic head, then the body.3,5 SPTs are often large in size with a mean size of 7.5cm at time of diagnosis.5 There is significant variability in appearance of the tumor due to varying degrees of cystic degeneration within the tumor. There are often solid, cystic, and pseudopapillary components within the tumor.5 Smaller tumors tend to be more solid but less well circumscribed while larger tumors tend to have more cystic degeneration, hemorrhage, and necrosis with a pseudocapsule and variegated cut surface.5 Cyst formation tends to be more centrally located while solid components are usually found on the periphery.3 SPTs appear well circumscribed, but do not have a fibrous capsule and microscopically neoplastic cells infiltrate surrounding pancreatic parenchyma entrapping acinar cells and islets.8 Primary SPT can occur outside of the pancreas when there is presence of ectopic pancreatic tissue, but is extremely rare.3 The most common sites that this occurs include the ovary, mesocolon, and omentum.
Imaging
On both CT imaging and MR imaging, SPTs appear to be well circumscribed, encapsulated, and heterogeneous with hemorrhagic and cystic degeneration. MR imaging is more sensitive than CT imaging in evaluating intratumoral hemorrhage, cystic degeneration, and presence of capsule.14 Transabdominal ultrasound imaging often shows a heterogeneous solid and cystic mass with occasional calcifications.9 Findings of pancreatic duct dilation and vessel invasion are suggestive of more aggressive tumor.12 Other than surgery, the best diagnostic and imaging test is endoscopic ultrasound (EUS) with fine needle aspiration (FNA) or fine needle biopsy (FNB). On EUS examination, the mass will appear as a wellcircumscribed, hypoechogenic, heterogeneous tumor with solid and cystic components with calcifications.10 EUS has a reported sensitivity of 91-95% and specificity of 92-95% in the diagnosis of SPT3,11 Given concern for seeding of tumor cells to the peritoneum with laparoscopic biopsy, it is not recommended or routinely performed.
Pathology
On cytological examination, cells are typically bland, uniform, round to oval with eccentrically located nuclei, moderate cytoplasm, and finely dispersed chromatin.8,12 Metachromatic hyaline globules can be found in the cytoplasm.8 Clear myxoid material surrounds papillae.13 Large, cytoplasmic vacuoles can be helpful in differentiating SPTs from other pancreatic tumors.12 Clusters of foamy macrophages, multinucleated giant cells, cholesterol, and necrotic debris are occasionally seen. Histologically, the classic finding of a SPT is presence of pseudopapillary areas with fibrovascular stalks or rosette-like structures secondary to poor cohesion of the malignant cells. Immunohistochemically, most SPTs demonstrate intense nuclear localization of B-catenin and loss of membrane expression of E-cadherin with disruption of the activated Wnt pathway.8 SPTs are typically positive for vimentin, alpha-1-antitrypsin, alpha-1-antichymotrypsin, and neuron specific enolase. SPTs are typically negative for chromogranin A, epithelial membrane antigen, and cytokeratin.7 The presence of the CTNNB1 molecular marker in conjunction with the lack of KRAS, GNAS, RNF43 and LOH on chromosome 18 is helpful in making the diagnosis of SPT.7 Histiogenesis and the cell of origin of SPT have yet to be definitively identified. Given the female predominance of SPTs and the increased estrogen receptors associated with SPT, a proposed theory is that female sex hormones may play a role in tumorigenesis.3 In vitro studies have shown an increased proliferation of SPTs with estrogen.
Differential Diagnosis
The differential diagnosis of SPT is broad due to its variable appearance. The differential includes pancreatic neuroendocrine neoplasms, acinar cell cancer, mucinous or serous cystic neoplasms, and lymphoma. Pancreatic neuroendocrine neoplasms can often have similar histologic features as a SPT. The presence of pseudopapillae, hyaline globules, foamy histiocytes, and grooving of the nucleus are more consistent with the diagnosis of SPT. Alternatively, the appearance of speckled chromatin would favor a neuroendocrine tumor.12 Acinar cell carcinoma of the pancreas can be differentiated from SPTs by the presence of irregular nuclei with maintained cytoplasmic polarity and clusters of cohesive clusters of cells with acinar formation.12 SPT can be sometimes confused with serous cystadenoma on cross sectional imaging; however, serous cystadenomas are typically well circumscribed nodules with cystic spaces lined by cuboidal cells with clear, glycogen containing cytoplasm.12 EUS is often helpful in distinguishing SPT from serous cystadenoma, either by visualization alone or with the addition of FNA or FNB. Additionally, serous cystadenomas sometimes contain a central scar with a radiating pattern.
Prognosis
SPTs typically carry a good prognosis as they have low malignant potential. There is a low likelihood of metastases and vascular invasion. Only 10-15% of patients will develop metastases.15 The most common site of metastasis is the liver.5 Peritoneal metastases are less frequently seen and are thought to be a result of trauma or rupture of tumor.5 Lymph node metastases occur infrequently with less than 10 reported cases.5 There are even few reports of pulmonary metastases.11 Rarely does tumor locally invade into the vasculature, stomach, duodenum, or spleen.5 The overall prognosis of SPT even in the presence of metastases is excellent. The reported five-year survival rate is greater than 95% and is highest in patients with SPT limited to the pancreas.5 The reported mortality from this tumor is reported as less than 2%.15 Male patients and elderly patients tend to have a worse prognosis.3,4 Compared to female patients, males have a twofold higher incidence of metastases and a threefold higher incidence of death.
Treatment
Surgical resection of the tumor, with as much sparing of normal pancreatic tissue, is the treatment of choice for SPTs and is often curative.17 The type of surgery is dictated by the location and size of the tumor. Tumor invasion to the portal vein or superior mesenteric artery is not considered a contraindication for surgical resection, but may limit complete resection.14 Surgical procedures utilized include pancreatoduodenenectomy, distal pancreatectomy, middle pancreatectomy, duodenum-preserving pancreatic head resection, spleen preserving distal pancreatectomy and local resection.3 More invasive surgical techniques include synchronous portal-superior mesenteric vein or adjacent organ resection if there is evidence of local invasion.3 Due to increased risk of dissemination, higher recurrence rate, and development of pancreatic fistula, tumor enucleation is not recommended.3
Unfortunately, SPT can be unresectable if there is evidence of large vessel invasion. In patients with unresectable tumors due to size or location, neoadjuvant chemotherapy and radiation has been utilized to decrease the size to create conditions favorable for potential resection.3 Long-term survival is thought to be improved after resection of metastatic SPT. In patients with liver metastases, synchronous or metasynchronous surgical resection can be performed.3 Recent studies have shown that a one centimeter margin in hepatic metastasis resection is considered curative. In patients with diffuse hepatic metastases, which are not amenable to resection, liver transplantation (both orthotopic liver transplant and living donor transplant) has been performed in the past, as removal of liver metastases in addition to removal of primary SPT can potentially be curative.18 Diffuse growth pattern, extensive necrosis, high mitotic rate, and sarcomatoid areas within tumor have been associated with more aggressive tumor behavior.19 Patients with lymph node metastases, tumors larger than 8cm, cellular atypia, capsule invasion, lymphovascular invasion, perineural invasion, and peripancreatic fat tissue invasion were found to have worse outcomes following surgery.20 The reported incidence of tumor recurrence is around 1.9-6%.
The role of chemotherapy and radiation is unclear at this time. Described chemotherapy regimens have included 5-fluorouracil, doxorubicin, and streptozocin or interferon, cisplatin, and topotecan or gemcitabine-based chemotherapy. Long term follow up is suggested following surgical resection. Given the rarity of this tumor, there does not currently exist guidelines or a current consensus regarding the interval, length, or modality of follow up. Due to the low rate of recurrence of this tumor, no risk factors have been associated with recurrence. A proposed further therapy for SPT includes selective estrogen receptor modulators as in vitro studies have shown the influence of estrogen on tumor proliferation.
CONCLUSION
SPTs are rare pancreatic tumors but are increasingly being identified due to more frequent and better cross sectional abdominal imaging. They typically occur predominantly in a younger female population. Our patient was notable for his age and male sex. SPTs are usually asymptomatic and incidentally noted on imaging, but commonly associated symptoms include abdominal discomfort as experienced by our patient. Luckily, SPTs typically carry a good prognosis as they have low malignant potential with low likelihood of metastases to liver, peritoneum, lungs, and rarely lymph nodes. The reported five-year survival rate of SPT is greater than 95%. Treatment of SPTs includes surgical resection of the mass with as much preservation of the pancreas as possible and in some cases, neoadjuvant chemotherapy may be indicated.