Case 2 -

Gangliocytic Paraganglioma Scott Owens University of Pittsburgh School of Medicine Pittsburgh, PA

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Clinical Summary: A 50 year-old man presented three days after an umbilical hernia repair with rapidly-progressive left axillary and lower anterior chest pain, accompanied by jaundice and dark urine. His amylase and bilirubin were elevated and he was presumptively diagnosed with biliary pancreatitis. A subsequent CT scan showed a large (8.8 cm) enhancing mass in the second portion of the duodenum, which an endoscopic ultrasound found to be a submucosal/intramural mass with cystic areas, located adjacent to the papilla of Vater. Clinically, it was felt most likely to be a gastrointestinal stromal tumor. The mass was locally excised approximately two months after the patient's initial presentation. Case 2 - Figure 1 Gross photograph of submucosal tumor with variegated surface and areas of hemorrhage. Case 2 - Figure 2 Low-power photomicrograph of tumor showing submucosal location and variable histology; areas of spindle cells are admixed with cells arranged in nests and cords. Case 2 - Figure 3 Medium-power view of epithelioid cells arranged in nests and cords, with overlying reactive duodenal mucosa. Case 2 - Figure 4 High-power view of nests of epithelioid cells. Case 2 - Figure 5 High-power view of intimately admixed spindle cells and large cells with round, vesicular nuclei and prominent nucleoli. Case 2 - Figure 6 High-power photomicrograph illustrating the three cells types comprising the tumor: spindle cells (upper right corner), epithelioid cells in nests and cords, and large cells with round nuclei and prominent nucleoli. Case 2 - Figure 7 High-power view of largest tumor cells, which have abundant cytoplasm, eccentric nuclei with prominent nucleoli, and basophilic substance at their periphery. Case 2 - Figure 8 Synaptophysin immunostain is positive in most of the tumor cells (bottom 1/3 of photomicrograph). Case 2 - Figure 9 CAM5.2 immunostain is positive in the epithelioid cell component. It also highlights the epithelium in the overlying mucosa. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The tumor consists of a nodular submucosal collection of cells with several different appearances. Close inspection reveals three cell types: first, there are epithelioid cells arranged in nests, cords and trabeculae. These cells have stippled chromatin and monotonous, round or oval nuclei, imparting a neuroendocrine appearance. There are also nondescript spindle cells with tapered ends and often undulating or "wavy" nuclei that have the appearance of nerve sheath or Schwannian cells. Last and most distinctive are large cells with eccentric nuclei, prominent nucleoli and (in some) Nissl substance in the peripheral cytoplasm. These cells have an appearance suggestive of ganglion cells. Immunohistochemical stains reveal the neuroendocrine-like cells to express CAM5.2 and many of the tumor cells to be positive for synaptophysin (Figures 8 and 9). Differential Diagnoses: Well-differentiated neuroendocrine neoplasm (carcinoid) Gastrointestinal stromal tumor (GIST) Gangliocytic paraganglioma Poorly-differentiated carcinoma Schwannoma Ganglioneuroma Final Diagnosis: Gangliocytic paraganglioma Case Discussion: Because of the similarity of each of the three cellular components of gangliocytic paraganglioma to the cells of other tumors, the most crucial element in diagnosis is the recognition of the "triphasic" nature of the tumor, with an intimate admixture of the three cell types. Cases with a predominant neuroendocrine cell-like component can be easily mistaken for carcinoid tumors or carcinomas, while those with a large spindle cell component arranged in intersecting fascicles may be misdiagnosed as GIST or nerve sheath tumor. Once the ganglion cell-like population is identified, the potential misdiagnosis is a ganglioneuroma. The clinical presentation can also be a useful clue to the diagnosis, as the vast majority of gangliocytic paragangliomas arise in the periampullary duodenum and may lead to gastric outlet obstruction, pain and/or hemorrhage. The current example was immediately adjacent to the papilla of Vater and presented with pain and obstructive symptoms that mimicked biliary pancreatitis. Once the three cell types have been recognized, immunohistochemistry can play a confirmatory role. Without the identification of the unique cell population, however, immunostains may only be confusing! There is some overlap in staining, but the bland spindle cells are typically positive for S100 and are negative for c-kit (CD117). They may also stain with neuron-specific enolase (NSE) and neurofilament protein. The epithelioid neuroendocrine-like cells may express a variety of antigens, including synaptophysin, chromogranin, NSE, somatostatin, and other endocrine markers. In about 50% of cases, they express cytokeratin, potentially contributing to a misdiagnosis as carcinoma. Finally, the ganglion-like cells are typically positive for NSE and neurofilament protein. Review of the Literature/Treatment Options: Gangliocytic paraganglioma is a very rare tumor that usually behaves benignly. Most tumors arise in middle-aged patients (5th or 6th decade) and involve the submucosa of the descending duodenum, often near the papilla/ampulla of Vater. They appear as 2-4 cm polypoid nodules and lack a discrete capsule, often infiltrating the overlying lamina propria and causing a mucosal ulcer. While most are localized and indolent, there have been a few reports of metastasis to regional lymph nodes. The clinical presentation depends on the exact location of the mass, and ranges from pyloric or biliary obstruction to occult fecal blood as described above. Some cases are discovered incidentally, and there is one report of a tumor producing a hormone (corticotropin). The differential diagnosis is perhaps the biggest challenge when gangliocytic paraganglioma is encountered. Other, more reliably aggressive entities such as GIST, certain sarcomas, and carcinoma must be excluded, since a misdiagnosis as one of these entities could potentially result in overly aggressive therapy. Recognition of the triphasic composition of the tumor is the best weapon in diagnosis, as inappropriate interpretation of ancillary studies such as immunohistochemistry may only push one further toward a misdiagnosis. Because of their location and clinical symptoms, many cases (including this one) are clinically suspected to be GISTs. In addition to recognition of the ganglion cell-like component, negativity with c-kit immunohistochemistry is very useful in excluding this diagnosis. The mode of development of gangliocytic paragangliomas is controversial, and several theories have been put forth, including a neural crest origin, a genesis in the pancreatic primordium, and a derivation from pluripotent cells in the intestinal crypts. While the tumor has a somewhat "hamartomatous" appearance, the reports of lymph node metastases suggest a neoplastic process. Several of the entities in the differential diagnosis have been associated with type I neurofibromatosis (NF1). While not as strong a connection, gangliocytic paraganglioma has also been reported in the setting of NF1. Thus, when these rare tumors are encountered it may be useful to mention this association in a diagnostic comment to make clinicians aware of the potential connection. The treatment of choice for gangliocytic paraganglioma is local excision. Smaller examples and/or those that present as a pedunculated polyp in the lumen may be removable endoscopically, but transduodenal approaches and pancreaticoduodenectomy (Whipple resection) may be utilized for larger tumors; the latter may be the treatment of choice if there is a priori evidence of metastatic disease in regional nodes. When incompletely excised, the tumors may recur, and there is at least one report of adjuvant radiotherapy being used for a tumor with regional lymph node metastases. Conclusion(s): Gangliocytic paraganglioma is a very rare neoplasm occurring predominantly in the duodenum. Recognition depends on careful examination to document the three cell types (epithelioid/neuroendocrine-like, spindled, and ganglion cell-like) that characterize the tumor. Its behavior is almost always benign, although rare reports of lymph node metastasis exist. It may also be associated with type I neurofibromatosis. 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