Paraganglioma

Gangliocytic paraganglioma (GP) is a rare neoplasm described almost exclusively in the gastrointestinal tract, especially the periampullary region. However, several examples have been reported at various sites, including the stomach, jejunum, and appendix. Herein we report a case of GP involving the nasopharynx. To our knowledge, this is the first report of GP at this site. A 44-year-old woman presented with headaches and symptoms of fullness and pressure related to mass effect. An initial endoscopic biopsy was followed by surgical excision of the nasopharyngeal mass. The triphasic tumor fulfilled the morphologic and immunohistochemical criteria for GP. The histogenesis of GP is uncertain, and the current belief is that it arises from the embryonic ventral pancreas. This concept is based largely on the location of most cases, which is along the embryologic migration route of the ventral pancreas, as well as the expression of pancreatic polypeptide by the tumor. The nasopharyngeal location of our case clearly refutes the pancreatic origin of GP. We propose that the tumor probably arises from totipotential adult stem cells, which in the right microenvironment differentiate along nonnative cell lineages. (Arch Pathol Lab Med. 2001;125:1098-1100)

Gangliocytic paraganglioma (GP) is a rare and distinctive neoplasm of controversial histogenesis and biologic behavior.1 Although initially thought to arise exclusively in the periampullary region,1,2 it has recently been described in various sites, including the jejunum, appendix,3 and stomach.2 Gangliocytic paraganglioma is a triphasic tumor,1 consisting of epithelioid, spindle cell, and ganglion cell-like elements in varying proportions. The spindle cell component is often reminiscent of nerve sheath or Schwann cells. While some cases may exhibit a predominance of the spindle cell component and resemble a ganglioneuroma, others are largely epithelioid and resemble a paraganglioma or carcinoid tumor. Considering the close proximity of most GPs to native or ectopic pancreatic tissue, it has been suggested that the tumor is a hamartoma or choristoma developing in misplaced embryonic pancreatic tissue.2 However, metastasizing GPs have rarely been documented.4 To the best of our knowledge, we report the first case of a GP arising in the nasopharynx and therefore refute the putative pancreatic origin of this entity.

REPORT OF A CASE

A 44-year-old woman presented with daily headaches and photophobia; her symptoms were worse in the evening and incompletely controlled with various medications. She also complained of pressure and fullness in her throat and difficulty swallowing. Magnetic resonance imaging revealed an enhancing mass projecting posteriorly off the nasal septum and extending through the floor of the left sphenoid compartment near the midline. A follow-up computed tomographic scan indicated expansion of the posterior septum, with erosion of the clivus leading superiorly into the sphenoid sinus. There was no intracranial extension. Her past medical history was unremarkable except for hypertension. An endoscopic biopsy of the mass was interpreted as a GP, and a complete surgical excision of the mass followed.

PATHOLOGIC FINDINGS

The completely excised mass consisted of multiple fragments of gray-brown soft tissue measuring 2.0 x 1.5 x 0.5 cm in aggregate.

Microscopically, the tumor was composed of a haphazard admixture of 3 elements: mononuclear round to polygonal cells arranged in a nesting pattern with admixed multinucleated ganglion-like cells and fascicles of spindle cells, which were more prominent at the periphery of the tumor. There was focal cytologic atypia in both the mononuclear and multinucleated giant cells; however, no necrosis or mitotic figures were noted (Figure 1).

Sections of formalin-fixed, paraffin-embedded tissue were stained for various antibodies by the immunoperoxidase method. All immunohistochemical stains were performed on a TechMate 1000 automated immunostainer (Biotek Solutions, Inc, Santa Barbara, Calif). The antibodies and their sources and dilutions are described in the Table. The results of the immunohistochemical stains are summarized in the Table. There was diffuse positive reactivity for chromogranin and synaptophysin (Figure 2), while vasoactive intestinal peptide reactivity was focal. The mononuclear neoplastic cells were positive for chromogranin and synaptophysin, whereas the ganglion-like cells were negative for these markers. Focal staining for cytokeratin (AE1/AE3) was demonstrated in the mononuclear cells. The fascicles of spindle cells were positive for 5100 protein (Figure 3). Scattered S100positive sustentacular cells were seen at the periphery of the cell nests. Immunoreactivity for pancreatic polypeptide and somatostatin stains was negative

COMMENT

Gangliocytic paragangliomas are not exclusive to the periampullary region, as was once thought. In addition to the classic periampullary location, GPs have been reported in the pylorus,2 jejunum, and appendix.3 One case was associated with a duodenal diverticulum. Some GPs have been associated with neurofibromatosis.5 Most cases range from 1 to 3 cm, although a 10-cm example has been reported.6 Although the majority of GPs behave in a benign fashion, rare examples of malignant GPs have been documented.4 The metastases usually contain the endocrine component of the tumor. We recently encountered a case of GP of the periampullary region that metastasized to 3 regional lymph nodes. The histologic appearance varies from case to case, even in different regions of the same tumor.7 Three cell types--epithelioid, ganglion-like, and spindle-are present in varying proportions in a haphazard distribution. Some cases exhibit a predominance of the spindle cell component, resembling a ganglioneuroma, while others have largely epithelioid elements, resembling a paraganglioma or carcinoid tumor. Occasionally, the enlarged nuclei of the ganglion-like cells, as in our case, may suggest a carcinoma.

The cell of origin of GP has been a matter of controversy. The tumor consists of both neuroectodermally derived elements (Schwann-like spindle cells, neurons, and ganglion cells) and an endodermally derived component (neuroendocrine cells).7 The focal keratin reactivity in the epithelioid cells favors a relationship to carcinoid tumors; however, the absence of cytokeratin in many epithelioid areas and the presence of S100-positive spindle cells, analogous to sustentacular cells, support a relationship to a paraganglioma.5 Perrone et all postulated that the tumor is derived from Van Campenhout endodermal-neuroectodermal complexes in the ventral primordium of the pancreas. These complexes are embryologic structures found in the pancreas of humans as well as some animals. They are composed of islet cells and branches of sympathetic nerves, including ganglion cells.7 In the cases reported to date, the consistent localization of the GP along the route traveled by the ventral pancreatic primordium as it rotates around the duodenum, coupled with its reactivity for pancreatic polypeptide, was the basis for the postulated pancreatic origin of this lesion.1 Additionally, immunohistochemical reactivity for a wide array of endocrine products has been variously described in GPs,l for example, pancreatic polypeptide, calcitonin, cholecystokinin, somatostatin, gastrin, leu-enkephalin, met-enkephalin, serotonin, substance P, and vasoactive intestinal peptide. However, there are several pitfalls to this histogenetic theory. Kermarec et al8 noted that if the pancreatic origin were to be true, then at least a few cases should have arisen in the pancreas proper, a site where a GP has yet to be described. Also, the pancreatic theory fails to explain the origin of the 2 neuroectodermal elements (ie, Schwann-like spindle cell and the ganglion cell) as an intrinsic part of GP.

Immunoreactivity for pancreatic polypeptide in the majority of GPs is a feature considered supportive of their pancreatic origin; however, immunoreactivity of pancreatic polypeptide is not specific for pancreatic endocrine phenotype. Immunoreactivity for pancreatic polypeptide has been demonstrated in a host of both neoplastic and nonneoplastic conditions of the pancreas, as well as in extrapancreatic tissues. In addition to carcinoids of the lung, rectum, common bile duct, and appendix, immunohistochemical staining for pancreatic polypeptide has been described in some cortical neurons of the brain,9 in epidermal Merkel cells of psoriatic skin lesions,10 and in specialized epithelium such as Barrett esophagus.11 Eeden et al3 recently described a GP of the appendix in which the presence of ectopic pancreatic tissue was ruled out. Our case of nasopharyngeal GP provides additional evidence arguing against the pancreatic origin of GE

Recent studies have shown that stem cells maintained in adult organs, under certain conditions, are capable of differentiation along a variety of cell lines.12 Adult neural stem cells possess a wider differentiation repertoire than previously recognized. In irradiated adult mice, neural stem cells from the adult forebrain were shown to produce blood cells and repopulate the hematopoietic system.12 Marrow stem cells, when transplanted to the brain, have been shown to generate astrocytes.12 It is clear that, depending on their microenvironment, stem cell populations in adult organs are able to differentiate along many different cell lines. This suggests that adult stem cells can potentially differentiate along nonnative cell lineages. We believe that the origin of the GP is best explained on the basis of the totipotential nature of adult stem cells that are capable of exhibiting differentiation along diverse cellular lineages.

References

1. Perrone T, Sibley RK, Rosai J. Duodenal gangliocytic paraganglioma: an immunohistochemical and ultrastructural study and a hypothesis concerning its origin. Amj Surg Pathol. 1985;9:31-41.

2. Burke A, Helwig E. Gangliocytic paraganglioma. Am J Clin Pathol. 1989; 92:1-8.

3. Van Eeden S, Offerhaus GJA, Peterse HL, Dingemans KP, Blaauwgeers HG. Gangliocytic paraganglioma of the appendix. Histopathology. 2000;36:47-49.

4. Buchler M, Malfertheiner P, Baczako K, Krautzberger W, Berger HG. A metastatic endocrine-neurogenic tumor of the ampulla of Vater with multiple endocrine immunoreaction: malignant paraganglioma? Digestion. 1985;31:54-59.

5. Stephens M, Williams GT, Jasani B, Williams ED. Synchronous duodenal neuroendocrine tumors in Von Recklinghausen's disease: a case report of coexisting gangliocytic paraganglioma and somatostatin-rich glandular carcinoid. Histopathology. 1987;11:1331-1340.

6. Scheithauer BW, Nora FE, Lechago J. Duodenal gangliocytic paraganglioma: clinicopathologic and immunocytochemical study of 11 cases. Am J Clin Pathol. 1986;86:559-565.

7. Albores-Saavedra J, Henson DE, Klimstra D. Tumors of the Gallbladder, Extrahepatic Bile Ducts and Ampulla of Vater. Washington, DC: Armed Forces Institute of Pathology; 2000. Atlas of Tumor Pathology, 3rd series, fascicle 27.

8. Kermarec J, Duplay H, Lesbros F. Paragangliome gangliocytique du duodenum: une observation, avec etude ultra-structurale. Arch Anat Cytol Pathol. 1976;24:261-268.

9. Vincent SR, Johansson 0, Hokfelt T, et al. NADPH-diaphorase: a selective histochemical marker for striatal neurons containing both somatostatin and avian pancreatic polypeptide (APP)-like immunoreactivities. J Comp Neurol. 1983;217: 252-263.

10. Wollina U, Mahrle G. Epidermal Merkel cells in psoriatic lesions: immunohistochemical investigations on neuroendocrine antigen expression.J Dermatol Sci. 1992;3:145-150.

11. Feurle GE, Helmstaedter V, Buehring A, Bettendorf U, Eckardt VF. Distinct immunohistochemical findings in columnar epithelium of esophageal inlet patch and of Barrett's esophagus. Dig Dis Sci. 1990;35:86-92.

12. Clarke D, Johansson C, Wilbertz J, et al. Generalized potential of adult neural stem cells. Science. 2000;288:1660-1663.

Prasanna Sinkre, MD; Guy Lindberg, MD; Jorge Albores-Saavedra, MD

Accepted for publication February 1, 2001.

From the Division of Anatomic Pathology, University of Texas Southwestern Medical Center, Dallas.

Reprints: Jorge Albores-Saavedra, MD, Department of Pathology, University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9073 (e-mail: Albores.jorge@pathology. swmed.edu).

Copyright College of American Pathologists Aug 2001
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