Gangliocytic paraganglioma

Authors


Correspondence
Ritu Verma, MD, Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Barelli Road, Lucknow 226014 Uttar Pradesh, India. Email: dr_rituverma@rediffmail.com

ABSTRACT

Gangliocytic paraganglioma (GP) is a rare tumor, which occurs nearly exclusively in the second portion of the duodenum. Generally, this tumor has a benign clinical course, although rarely, it may recur or metastasize to regional lymph nodes. We present a case of duodenal GP treated first by local resection followed by pancreaticoduodenectomy. Frozen section examination of the first specimen was diagnosed as low grade mesenchymal tumor. Formalin fixed paraffin section histology revealed composite tumor composed of three characteristic histologic components: epithelioid, ganglion, and spindle cell. Immunohistochemistry tumor cells were positive for neuron specific enolase, synaptophysin, chromgranin, S100, and neurofilament protein. Cytokeratin and bcl-2 were focally positive. Single mitotic figure was noted. Ki67 labeling index was < 3–4%. In the subsequent pancreaticoduodenectomy specimen, there was no residual tumor in the periampullary area. We discuss the differential diagnosis and review the current published literature on GP.

INTRODUCTION

Gangliocytic paraganglioma (GP) is a rare, typically benign tumor that shows neuroectodermal (neurosustentacular or Schwannian and neuronal) and neuroendocrine differentiation. GP occurs nearly exclusively in the second portion of the duodenum, particularly in the periampullary region. The lesion was first described by Dahl et al.1 in 1957 and further characterized as a benign nonchromaffin paraganglioma by Taylor and Helwig2 in 1962. In 1971, Kepes and Zacharias3 coined the term “gangliocytic paraganglioma,” recognizing the features in common with both paraganglioma and ganglioneuroma. The name is derived from its unique histologic features of neuroendocrine tumor, paraganglioma, and ganglioneuroma. The lesion is composed of three types of cells: spindle cells, ganglion-like cells, and epithelioid cells. The more common presenting symptoms of these sessile or polypoid tumors are abdominal pain, gastrointestinal bleeding, and biliary obstruction; otherwise they are discovered incidentally.4,5 GP is generally considered benign and may be cured by local excision of the tumor mass. Long term survival is common with appropriate resection.6-10 We report a case of duodenal GP that was treated by local resection and diagnosed as low grade mesenchymal tumor on frozen section histology. The procedure was followed by pancreaticoduodenectomy.

CASE REPORT

A 36-year-old man presented to the surgical gastroenterology outpatient department with history of recurrent episodes of upper gastrointestinal bleed and melena. He denied having any associated abdominal pain, jaundice or diarrhea. His general physical examination was unremarkable except for pallor. There was no significant finding on abdominal examination. Upper gastrointestinal endoscopy revealed a fleshy polypoid growth in the medial wall of the second part of the duodenum close to the papilla (Fig. 1a). Repeated endoscopic biopsies failed to give a conclusive diagnosis. A computed tomography scan of the abdomen demonstrated the presence of a 2 × 2 cm soft tissue density located at the junction of the second and third parts of the duodenum (Fig. 1b). The patient was taken up for surgery and a duodenotomy and excision of the periampullary mass was done and sent for frozen section. The pathology department received a 2.0 × 2.0 cm polypoid lesion covered with flattened mucosa that showed small ulceration. Submucosally, a well-circumscribed, firm mass was identified. The cut surface was firm grayish white to tan brown. Microscopically the tumor was present in the submucosa and invaded the lamina propria and muscularis propria (Fig. 2a). The tumor was well circumscribed without capsule formation. On frozen section histology we diagnosed the tumor as mixed cell type low grade mesenchymal tumor composed of admixture of epithelioid and spindle shaped cells. We were unable to identify ganglion cells in frozen sections. The tumor was close to the resection margin. Hence a pancreaticoduodenectomy was done. On subsequent formalin fixed paraffin sections we identified that the tumor was composed of three cell types: epithelioid cells, admixed with spindle shaped sustentacular cells and scattered ganglion cells. The epithelial cells were arranged in nests and were often set in a vascular matrix (a Zellballen arrangement), which is typical of paraganglioma, and a ribbon-trabecular pattern, which is typical of a carcinoid tumor surrounded by fine fibrovascular channel (Fig. 2b). They displayed round nuclei with finely granular or stippled chromatin, small yet conspicuous nucleoli, and eosinophilic to amphophilic granular cytoplasm. The major part of the tumor was composed of spindle Schwann-like cells with streamy bundled or broad fascicles arrangement. These spindle cells were elongated and occasionally plump, with granular chromatin and moderate amounts of elongated, eosinophilic cytoplasm (Fig. 2c). Few cells were arranged haphazardly. Focally, the spindle cells surrounded the epithelioid nests. The ganglion cells were scattered individually or in small aggregates intermixed with the epithelioid and spindle components. They were large with prominent nuclei and nucleoli and had abundant eosinophilic cytoplasm (Fig. 2d). We also appreciated acellular eosinophilic material in between spindle cells. The material was faintly positive on periodic acid-Schiff stain and negative for Congo red and Masson trichrome stain. There was minimal cytomorphologic atypia. There were small numbers of lymphomononuclear cells. A single mitotic figure was appreciated in tumor cells. However, no lymphatic or vascular vessel invasion, or necrotic foci were detected. Immunohistochemical staining for neuron specific enolase (NSE), cytokeratin, synaptophysin, chromogranin, S100, neurofilament protein (NFP), bcl-2, smooth muscle actin (SMA), desmin, CD34, CD117 and Ki67 (MIB1) was performed. The immunohistochemical findings are summarized in Table 1. NSE was diffusely positive in the tumor (Fig. 3a). The synaptophysin was diffusely positive in epithelioid cells and ganglion-like cells in the tumor (Fig. 3b). The chromogranin stain was focally positive in the epithelioid cells of the tumor (Fig. 3c). The S100 stain was positive in the spindle cells (Fig. 3d). NFP stain was positive in epithelioid and ganglion cells (Fig. 4a). Bcl-2 was faintly positive in a few tumor cells (Fig. 4b). Cytokeratin was positive in focal epithelioid tumor cells (Fig. 4c). CD117, CD34, desmin, SMA were negative. Ki67 labeling index was < 3–4% (Fig. 4d). Subsequently we received pancreaticoduodenectomy specimen with no evidence of residual tumor. Five lymph nodes were also identified and all were free of tumor. The patient had an uneventful recovery following the surgery and was discharged.

Figure 1.

(a) Upper gastrointestinal endoscopy revealing a fleshy polypoid mass protruding from the medial wall of the second part of the duodenum. (b) Contrast enhanced computed tomography revealing an enhancing mass filling the lumen in the second part of the duodenum (black arrow).

Figure 2.

(a) Submucosal location of the tumor. (b) Nests of epithelioid cells. (c) Spindle cells. (d) Dispersed ganglion cells between spindle cells (inset: ganglion cell) (hematoxylin and eosin; (a) ×100; (b) ×200; (c) ×200; (d) ×400).

Table 1.  Immunohistochemical expression of markers in gangliocytic paraganglioma
Immunohistochemical markerEpithelioid cellsSpindle cellsGanglion like cells
Neuron specific enolase+++
Synaptophysin++
S100++
Chromogranin+
Neurofilament protein++
Cytokeratin+
Bcl-2+
CD117
CD34
Figure 3.

(a) Immunohistochemistry of tumor showing cytoplasmic positivity for neuron specific enolase in epithelioid cells nests. (b) Immunohistochemistry of tumor showing synaptophysin positivity in epithelioid cells and ganglion cells (inset: ganglion cells immunopositivity). (c) Immunohistochemistry of tumor showing chromogranin positivity in epithelioid cells. (d) Immunohistochemistry of tumor showing S100 positivity (a–d, ×200).

Figure 4.

(a) Immunohistochemistry of tumor showing cytoplasmic positivity for neurofilment in epithelioid cells and ganglion cells. (b) Immunohistochemistry of tumor showing bcl-2 positivity in epithelioid cells. (c) Immunohistochemistry of tumor showing cytokeratin positivity in epithelioid cells. (d) Immunohistochemistry of tumor showing Ki67 positivity in tumor cell nuclei (a–d, ×200).

DISCUSSION

In the World Health Organization (WHO) classification of tumors of the digestive tract (2000), GP is independently classified as a type of epithelial tumor.4 GP is a rare tumor of the gastrointestinal tract that almost always occurs in the second part of the duodenum, often at the ampulla of Vater. It has also been reported in the third and fourth parts of the duodenum with rare cases reported in the jejunum, pylorus, esophagus, pancreas, and appendix.5 It is usually diagnosed in the fifth or sixth decade of life. The age at presentation ranges from the second decade to the ninth decade (mean, 53 years), and there is slight male predominance, with a male-female ratio of 1.6:1.6-11

A GP is characteristically detected as a submucosal tumor and assumes the form of circumscribed, pedunculated, or sessile lesions. There is a tendency toward mucosal erosion and ulceration and a secondary gastrointestinal hemorrhage which is the most common presenting symptom (45%).12-14 However, both the severity and chronicity of the bleeding can vary greatly; some patients have presented with mild bleeding of several years’ duration, whereas others have presented in hypovolemic shock, requiring blood transfusion.15 Abdominal pain occurs in one-third of patients; it may be epigastric with dyspeptic qualities or refer to the right upper quadrant, and often it is initially attributed to peptic ulcer disease. Obstructive jaundice is less common.6 Many patients are asymptomatic, and the tumor is discovered only as an incidental radiographic or post-mortem finding. Because these lesions are mostly submucosal in nature, endoscopic biopsy may not be diagnostic.7 On computed tomography (CT) and magnetic resonance imaging (MRI), these tumors are solid and homogeneous in appearance. Findings on ultrasonography include submucosal location of a hypoechoic or isoechoic lesion, exclusion of adenopathy and submucosal confinement. Size average is 2.9 cm (range, 0.5 to 10.0 cm).5-11

The clinical differential diagnosis of a GP includes gastrointestinal stromal tumor and adenocarcinoma of either the pancreatic head or the duodenum.12 Other mural or extrinsic masses that involve the duodenum, such as non-neoplastic tumor-like lesions such as heterotopic gastric hyperplasia and Brunner's gland hyperplasia, and neoplastic lesions such as adenoma, carcinoid tumors, leiomyoma, leiomyosarcoma, hemangioma, lipoma, hamartoma, inflammatory fibroid polyps, and lymphoma, should also be considered.12 This differentiation can be performed based on the lesion's location, degree of attenuation by abdominal CT, common bile duct dilatation, and enhancing pattern. However, accurate preoperative diagnosis is often difficult. Radiologically, gastrointestinalstromal tumors (GIST) and leiomyosarcoma are commonly associated with cystic areas of haemorrhage with or without necrosis. Hemanigiomas and hamartomas show heterogeneous pattern of soft tissue. Lipomas show similar echo texture as surrounding fat and various cysts show cystic morphology. Isolated lymphomas of duodenum are extremely rare.13,14

Gangliocytic paraganglioma is an unusual tumor in the sense that it exhibits composite features of ganglioneuroma, paraganglioma, and carcinoid tumor. Histopathologically, this tumor consists of three cell components with different types of differentiation. Briefly: (i) columnar or polymorphic epithelioid cells with a nested, honeycomb or ribbon-like arrangement; (ii) spindle cells with a cordlike arrangement that may be derived from the nerve; and (iii) scattered ganglion-like cells are observed. The ratio of these three cell components differs among patients. The lesion is usually not encapsulated and has an infiltrative pattern. To date, histologic features predicting malignant potential have not been defined, although the presence of nuclear pleomorphism, mitotic activity, and infiltrative margin, raises the concern for aggressive behavior.4 Histopathologically carcinoid tumor, paraganglioma, ganglioneuroma or spindle cell tumors (including nerve sheath tumors, smooth muscle tumors and GIST) enter as differential diagnosis.4 Our case was clinically, and on frozen section histology, misdiagnosed as low grade mesenchymal tumor. This may be due to extreme rarity of this lesion as compared with GIST.

The unusual cellular composition of GP has created a great deal of interest in illuminating the histogenesis of this tumor. Many theories have been offered to explain the histogenesis of GP, but so far, no clear explanation has been formed.15 These include hamartomatous proliferation of endodermally derived epithelial cells originating from the ventral primodium of the pancreas, hamartomatous proliferation of ectopic pancreatic tissue, celiac ganglion, Meissner's plexus, or the so-called sympathicoinsular complex, an organoid neuroectodermal-neuroendocrine structure found in small bowel, liver, and appendix of mammalian embryos.15 However, previous reports of extra-ampullary GPs, and multifocal GPs provides evidence that strongly counters the aforementioned view of histogenesis and posits origin of the tumor from a more omnipresent progenitor cell. Also the findings of the regional lymph node metastasis in reported cases suggest that duodenal GP is a true neoplasm. Another possible candidate is a migratory neural crest stem cell with potential for divergent (neuroendocrine and neuroectodermal) differentiation. This tumor is analogous to the composite pheochromocytoma of the adrenal gland and should probably be classified as such.

Immunohistochemically, the epithelioid cells stain positively with a wide variety of antigens, including chromogranin, NFP, synaptophysin, NSE, cytokeratin, pancreatic polypeptide and somatostatin.15 The finding of keratin immunoexpression in epithelioid cells of GPs tested supports neuroendocrine differentiation. The spindle cells almost always stain strongly positive with S100 protein, but can also stain with NSE, NFP, and vimentin.15 These findings might confirm the neural differentiation, particularly the Schwannian one. In addition, the cytological and immunohistochemical features of spindle cells are very similar to those of sustentacular cells observed in the adrenal medulla as well as in pheochromocytoma and paraganglioma. The ganglion cells are less numerous and dispersed singly or in small groups (two to three cells), constantly circumscribed by spindle cells. The ganglion cells frequently stain positively with NSE, synaptophysin and NFP.14-17

Gangliocytic paragangliomas generally behave in a benign fashion, although instances of recurrence and/or lymph node metastasis have been described. Careful assessment prior to local excision is necessary. The location or difficult access to the mass, and/or the inability to exclude other malignant tumors lead to pancreatoduodenectomy in many cases. Endoscopic removal of a GP is an alternative to surgical resection when there are no abnormal findings in the duodenal wall, regional lymphadenopathy, or bile duct, and pancreatic duct involvement has been excluded with imaging studies. If the lesion is large or if there is suspicion of lymphnode involvement, pancreaticoduodenectomy is the preferred surgical therapy.5 There are no data in the literature to guide clinicians on the use of adjuvant therapy despite the fact that approximately 5% of cases demonstrate malignant features.

In conclusion, diagnosis of duodenal GP is difficult not due to the morphology but, rather, to the rarity and complexity of the morphology. We emphasize that careful observation of three distinct elements in this composite tumor and appropriate immunohistochemistry would lead to proper diagnosis.

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