Case 2 -
University of Pittsburgh School of Medicine
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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).
- Well-differentiated neuroendocrine neoplasm (carcinoid)
- Gastrointestinal stromal tumor (GIST)
- Gangliocytic paraganglioma
- Poorly-differentiated carcinoma
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
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. The patient in this case underwent a transduodenal excision of
the mass with negative margins and had no evidence of recurrence as of late 2009.
- Aung W, Gallagher HJ, Joyce WP, Hayes DB, Leader M. Gastrointestinal hemorrhage from a jejunal gangliocytic paraganglioma. J Clin Pathol, 1995; 48:84-85.
- Burke AP, Helwig EB. Gangliocytic paraganglioma. Am J Clin Pathol, 1989; 92:1-9.
- Castoldi L, De Rai P, Marini A, Ferrero S, De Luca V, Tiberio G. Neurofibromatosis-1 and ampullary gangliocytic paraganglioma causing biliary and pancreatic obstruction. Int J Gastrointest Cancer, 2001; 29:93-98.
- Chalal P, Prasad GA, Sanderson SO, Gostout CJ, Levy MJ, Baron TH. Endoscopic resection of nonadenomatous ampullary neoplasms. J Clin Gastroenterol, 2007; 41:661-666.
- Hashimoto S, Kawasaki S, Matsuzawa K, Harada H, Makuuchi M. Gangliocytic paraganglioma of the papilla of Vater with regional lymph node metastasis. Am J Gastroenterol, 1992; 87:1216-1218.
- Kepes JJ, Zacharias DDL. Gangliocytic paragangliomas of the duodenum. A report of two cases with light and electron microscopic examination. Cancer, 1971; 27:61-67.
- Kheir SM, Halpern NB. Paraganglioma of the duodenum in association with congential neurofibromatosis: possible relationship. Cancer, 1984; 53:2491-2496.
- Nagai T, Torishima R, Nakashima H, et al. Duodenal gangliocytic paraganglioma treated with endoscopic hemostasis and resection. J Gastroenterol, 2004; 39:277-283.
- Palau MA, Merino MJ, Quezado M. Corticotropin- producing pulmonary gangliocytic paraganglioma associated with Cushing's syndrome. Hum Pathol, 2006; 37:623-626.
- Perrone T, Sibley RK, Rosai J. duodenal gangliocytic paraganglioma: clinicopathologic and ultrastructural study and a hypothesis concerning its origin. Am J Surg Pathol, 1985; 9:31-41.
- Reed RJ, Caroca Jr PJ, Harkin JC. Gangliocytic paraganglioma. Am J Surg Pathol, 1977; 1:207-216.
- Sakhuja P, Malhotra V, Gondal R, Dutt N, Choudhary A. Periampullary gangliocytic paraganglioma. J Clin Gastroenterol, 2001; 33:154-156.
- Scheithauer BW, Nora FE, Lechago J, et al. Duodenal gangliocytic paraganglioma. Clinicopathologic and immunocytochemical study of 11 cases. Am J Clin Pathol, 1986; 86:559-565.
- Sundararajan V, Robinson-Smith TM, Lowy AM. Duodenal gangliocytic paraganglioma with lymph node metastasis: a case report and review of the literature. Arch Pathol Lab Med, 2003; 127:e139-141.
- Wong A, Miller AR, Metter J, Thomas Jr, CR. Locally advance duodenal gangliocytic paraganglioma treated with adjuvant radiation therapy: case report and review of the literature. World J Surg Oncol, 2005; 3:15-18.