- Email: [email protected]
Duodenal gangliocytic paraganglioma: a radiological-pathological correlation
Annals of Diagnostic Pathology 9 (2005) 143 – 147
Duodenal gangliocytic paraganglioma: a radiological-pathological correlation Jose Antonio Plaza, MDa, Kenneth Vitellas, MDb, William L. Marsh Jr., MDa,* a
Department of Pathology, The Ohio State University Medical Center, Columbus, OH 43210, USA Department of Radiology, The Ohio State University Medical Center, Columbus, OH 43210, USA
b
Abstract
Duodenal gangliocytic paraganglioma is a rare tumor that characteristically occurs in the second portion of the duodenum and typically presents with gastrointestinal bleeding. Gangliocytic paragangliomas have a characteristic triphasic microscopic appearance with epithelioid cells, spindle cells, and ganglion cells, resulting in a complex histology with features of paraganglioma, carcinoid, and ganglioneuroma. Duodenal gangliocytic paragangliomas have an excellent prognosis after surgical resection but metastatic spread to regional lymph nodes and recurrence may rarely occur. We report a case of duodenal gangliocytic paraganglioma and discuss the radiological and pathological differential diagnosis of this rare entity. D 2005 Elsevier Inc. All rights reserved.
Index words:
Duodenal gangliocytic paraganglioma; Periampullary tumor
1. Introduction Gangliocytic paraganglioma is a rare neoplasm that characteristically occurs in the second portion of the duodenum, but also has been reported in the fourth portion of the duodenum, jejunum, stomach, appendix, and lung [1,2]. Similar tumors have been described in the cauda equina [3,4]. Generally, these tumors have a relatively benign clinical course, although rarely tumors may metastasize to lymph nodes or recur locally [5-7]. Approximately 130 gangliocytic paragangliomas have been reported, 6 with lymph node metastasis [8]. Distant metastasis and death have not been reported to our knowledge. In 1957, Dahl et al [9] reported a duodenal ganglioneuroma. In 1962, Taylor and Helwig [10] described unusual polypoid duodenal tumors naming them nonchromaffin paragangliomas. In 1971, Kepes and Zacharias [11] reviewed the literature, described 2 similar cases that presented in the second portion of the duodenum, and proposed the term gangliocytic paraganglioma. Subsequently, multiple similar cases of gangliocytic paraganglioma were reported as individual case reports or in small series [12-30]. * Corresponding author. Department of Pathology, The Ohio State University Medical Center, Columbus, OH 43210, USA. Tel.: +1 614 293 5450. E-mail address: [email protected] (W.L. Marsh). 1092-9134/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2005.02.004
Gangliocytic paragangliomas have a characteristic histology consisting of varying proportions of 3 cell types: epithelioid cells, ganglion cells, and spindle cells. The epithelioid cells have a neuroendocrine growth pattern that may resemble paraganglioma and/or carcinoid. The spindle cells and ganglion cells may have a ganglioneuromatous growth pattern. Morphologic overlay between epithelioid cells and ganglion cells may be seen. The histogenesis of gangliocytic paraganglioma has engendered multiple theories, but is still unknown [10,15-17]. The 2 main possibilities are (1) neoplasm with divergent triphasic differentiation and (2) hamartoma related to abnormal pancreatic development. We report a case of duodenal gangliocytic paraganglioma in a 53-year-old woman who presented to our institution with upper gastrointestinal bleeding. The pathological and radiological features and differential diagnosis of this tumor are described. 2. Case report A 53-year-old woman was transferred from an outside institution to The Ohio State University Medical Center because of recurrent upper gastrointestinal bleeding. Upon arrival she was evaluated and underwent an esophagogastroduodenoscopy with biopsy that revealed a 2-cm peri-
144
J.A. Plaza et al. / Annals of Diagnostic Pathology 9 (2005) 143 – 147
Fig. 1. Contrast-enhanced CT scan showing polypoid lesion (arrows) protruding into duodenal lumen.
ampullary mass felt to be benign by endoscopy. Microscopic sections of the biopsy revealed a low-grade proliferation of spindle and ganglion-like cells with a differential diagnosis of gastrointestinal stromal tumor, ganglioneuroma, or an inflammatory process. Subsequently she underwent radiological studies followed by local surgical resection of the ampulla.
Fig. 3. Gangliocytic paraganglioma involving submucosa and muscular wall of duodenum. Epithelioid areas are marked by * and spindle cell area by bxQ (scanning power).
specific enolase (NSE) (5G10, 1:50-1:100 dilution, Novocastra, Newcastle upon Tyne, UK), synaptophysin (mouse monoclonal, 1:50 dilution, DAKO), HHF-35 (monoclonal mouse, 1:75 dilution, DAKO), CD117 (rabbit polyclonal, 1:50 dilution, DAKO), and CD34 (monoclonal antibody, 1:300 dilution, DAKO). Appropriate positive controls were run concurrently for all the antibodies tested.
3. Materials and methods The tissues were fixed in neutral buffered formalin and embedded in paraffin for histological processing. Tissue sections were stained with hematoxylin and eosin for conventional histology. Representative paraffin-fixed tissue blocks were cut and processed for immunohistochemical studies. The antibodies tested included: cytokeratin AE1/ AE3 (1:50 dilution, DAKO, Carpinteria, Calif), S-100 protein (polyclonal, 1:3000 dilution, DAKO), chromogranin (monoclonal mouse, 1:200 dilution, DAKO), neuron-
Fig. 2. Axial gadolinium-enhanced MRI showing an enhancing ampullary mass (arrows).
4. Radiological findings A computed tomography (CT) scan of the abdomen showed soft tissue attenuation in the periampullary region that was enhanced after intravenous contrast, revealing a solid homogeneous 2.4-cm periampullary mass protruding into the duodenal lumen (Fig. 1). Magnetic resonance imaging (MRI) showed a 1.8-cm solid homogeneous mass protruding into the lumen from the medial wall of the duodenum; the lesion showed increased T2 and decreased
Fig. 4. Epithelioid components at right and upper left, spindle cell component at lower left (medium power).
J.A. Plaza et al. / Annals of Diagnostic Pathology 9 (2005) 143 – 147
Fig. 5. Epithelioid cells at right, spindle cells at left (high power).
T1 signal and was enhanced after the administration of gadolinium (Fig. 2). Both CT and MR studies indicated that the lesion was confined to the duodenum, and neither study showed evidence of pancreatic mass, bile duct or pancreatic obstruction, nor metastatic disease. 5. Pathological findings The specimen consisted of a 2.0 1.5 1.0-cm portion of partially ulcerated bowel with attached soft tissue. A nodular component was felt within the soft tissue. Sectioning revealed a 1.3 0.8 0.6-cm irregular, tan white nodule with a homogeneous cut surface. No areas of cystic degeneration or necrosis were noted. Microscopic sections showed an infiltrative unencapsulated submucosal neoplasm extending into the muscularis propria and the mucosa, with focal mucosal ulceration (Fig. 3). The neoplasm was composed of spindle cells, ganglion cells, and epithelioid cells arranged in a nested pattern, intermixed with normal-appearing smooth muscle
Fig. 6. Scattered ganglion-like cells are present (high power).
145
Fig. 7. Immunohistochemical stain with anti–pancreatic polypeptide is positive in epithelioid cells at lower left and negative in spindle cells at upper right.
(Figs. 4 and 5). The spindle cells displayed thin, wavy nuclei with indistinct cytoplasm. The epithelioid nested pattern resembled the bZellballenQ arrangement in neuroendocrine neoplasias (paraganglioma-like), showing cells with granular eosinophilic cytoplasm and uniform rounded nuclei with stippled chromatin and inconspicuous nucleoli. Ganglion cells were scattered throughout (Fig. 6). Mitotic activity and tumor necrosis were not observed. Immunohistochemical stains (Figs. 7 and 8) showed that the epithelioid cells were positive for pancreatic polypeptide, somatostatin, serotonin, chromogranin, synaptophysin, and monoclonal NSE. S-100 protein highlighted the sustentacular cells. The spindle cell areas were strongly positive for S-100 protein and CD34. Ganglion cells were positive for synaptophysin, NSE, and somatostatin. Immunostains for cytokeratin AE1/AE3, muscle actin (HHF-35), and CD117 were predominantly negative.
Fig. 8. Immunohistochemical stain with anti–S-100 protein is positive in spindle cells and sustentacular cells, but negative in epithelioid cells.
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J.A. Plaza et al. / Annals of Diagnostic Pathology 9 (2005) 143 – 147
6. Discussion Reported patients with duodenal gangliocytic paragangliomas range from 15 to 84 years of age, with a slight male predominance. Patients usually present with gastrointestinal bleeding due to mucosal ulceration, as experienced in the current case; other complaints include epigastric pain, nausea, and vomiting. Biliary obstruction is rare but has been reported [24]. In some patients, duodenal gangliocytic paraganglioma is discovered incidentally. As in this case, most duodenal gangliocytic paragangliomas occur in the second portion of the duodenum with a predilection for the ampulla of Vater [16,18]. The tumor varies from 0.5 to 7 cm in size, is polypoid or sessile, and is covered by the duodenal mucosa with scattered mucosal ulcerations [16-19]. The radiological findings in this case illustrate the typical features of a periampullary neoplasm, including a soft tissue mass projecting into the lumen of the duodenum and absence of a pancreatic mass or distal common bile duct abnormalities. The radiological differential diagnosis of ampullary and duodenal tumors includes lesions such as adenoma, carcinoma, leiomyosarcoma, gastrointestinal stromal tumor, lymphoma, lipoma, hemangioma, cysts, and hamartomas [26,28]. Reported upper gastrointestinal tract series findings in duodenal gangliocytic paraganglioma include pedunculated or sessile lesions apparently arising in the submucosa and deforming the overlying mucosa. Computed tomography and magnetic resonance imaging characterize duodenal gangliocytic paragangliomas as solid homogeneous enhancing polypoid or sessile masses [12,14,26], similar to the findings in this case. Ultrasound studies have shown well-circumscribed lesions that are often homogeneous and hypoechoic [26]. Ultrasound has recently been used to help justify endoscopic resection of duodenal gangliocytic paragangliomas [8,29]. Radiological findings of a circumscribed solid homogenous enhancing lesion confined to the duodenum without biliary obstruction are not specific, but should raise the consideration of duodenal gangliocytic paraganglioma. Carcinomas are often hypovascular and associated with biliary obstruction. Leiomyosarcomas, hemangiomas, and hamartomas often show heterogeneous enhancement. Lipomas show fatty attenuation. Inflammatory fibroid polyps and lymphomas are rare in the duodenum but may show radiological features similar to gangliocytic paraganglioma [26,28]. Histologically, gangliocytic paragangliomas have a characteristic triphasic pattern with varying proportions of epithelioid cells, ganglion cells, and spindle cells; the overall pattern is complex with features of ganglioneuroma, paraganglioma, and carcinoid. The tumors lack necrosis or significant mitotic rate, and appear histologically benign [17]. Because duodenal gangliocytic paragangliomas are predominantly submucosal, initial endoscopic biopsies
may not be diagnostic and may potentially be misleading, as illustrated in this case [8,26]. If the endoscopic biopsy does not contain all 3 elements, spindle cell neoplasms, epithelial neoplasms, or ganglioneuroma may be favored, depending upon which elements appear in the biopsy. In non-ulcerated sessile tumors, the endoscopic biopsy may lack tumor and show only inflammatory or reactive changes. Immunohistochemically, the epithelioid cells are typically positive for NSE, pancreatic polypeptide, and somatostatin, but negative for S-100 protein; they are also frequently positive for chromogranin and synaptophysin, and sometimes positive for cytokeratins and a variety of endocrine polypeptides. The ganglion cells are positive for NSE, synaptophysin, and neurofilaments. The ganglion cells may show morphologic overlap with the epithelioid cells and may be positive for endocrine polypeptides. The spindle cells are strongly positive for S-100 protein, supporting neural origin. Sustentacular cells positive for S-100 protein may be present in some tumors [5,12,17,18,25]. The histological differential diagnosis of duodenal gangliocytic paraganglioma includes conventional paraganglioma, well-differentiated neuroendocrine carcinoma (carcinoid), ganglioneuroma, and spindle cell neoplasms (nerve sheath, smooth muscle, and gastrointestinal stromal tumors) [17,21-23]. The characteristic triphasic pattern and duodenal location are the most important diagnostic features and are usually sufficient to exclude the other entities. In some tumors, thorough sampling and immunohistochemical stains may be required to demonstrate the triphasic pattern. In the second part of the duodenum, pure ganglioneuromas and paragangliomas may represent part of a spectrum with gangliocytic paraganglioma. Well-differentiated neuroendocrine carcinoma is an important differential, but should lack ganglion cells and S-100 protein– positive spindle cell proliferation. Gangliocytic paragangliomas should be negative for smooth muscle markers except for the admixed normal smooth muscle elements. The presence of ganglion cells and absence of staining for CD117 should eliminate the possibility of gastrointestinal stromal tumor.
References [1] Dante S, Viale G, Dalla Palma P. Gangliocytic paraganglioma of the duodenum: case report. Tumori 1987;73:425 - 9. [2] Hironaka M, Fukayama M, Takayashiki N, et al. Pulmonary gangliocytic paraganglioma: case report and comparative immunohistochemical study of related neuroendocrine neoplasms. Am J Surg Pathol 2001;25:688 - 93. [3] Hayes E, Lippa C, Davidson R. Paragangliomas of the cauda equina. AJNR Am J Neuroradiol 1989;10(5 Suppl):S45 - 7. [4] Hamid QA, Bishop AE, Rode J, Dhillon AP, et al. Duodenal gangliocytic paragangliomas: a study of 10 cases with immunocytochemical neuroendocrine markers. Hum Pathol 1986;17:1151 - 7. [5] Inai K, Kobuke T, Yonehara S, et al. Duodenal gangliocytic paraganglioma with lymph node metastasis in a 17-year-old boy. Cancer 1989;63:2540 - 5.
J.A. Plaza et al. / Annals of Diagnostic Pathology 9 (2005) 143 – 147 [6] 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;127:139 - 41. [7] Dookhan D, Miettinen M, Finkel G, et al. Recurrent duodenal gangliocytic paraganglioma with lymph node metastases. Histopathology 1993;22:399 - 401. [8] Nakamura T, Ozawa T, Kitagawa M, et al. Endoscopic resection of gangliocytic paraganglioma of the minor duodenal papilla: case report and review. Gastrointest Endosc 2002;55:270 - 3. [9] Dahl EV, Waugh JM, Dahlin DC. Gastrointestinal ganglioneuromas: brief review with report of a duodenal ganglioneuroma. Am J Pathol 1957;33:953 - 7. [10] Taylor HB, Helwig EB. Benign nonchromaffin paragangliomas of the duodenum. Virchows Arch A Pathol Anat Histopathol 1962;335: 356 - 66. [11] Kepes JJ, Zacharias DL. Gangliocytic paragangliomas of the duodenum. A report of two cases with light and electron microscopic examination. Cancer 1971;27:61 - 7. [12] Girgis PA, Henthorne WA. Pathologic quiz case. Mass at the ampulla of Vater in a 43-year-old man. Gangliocytic paraganglioma. Arch Pathol Lab Med 2002;126:1239 - 40. [13] Hashimoto S, Kawasaki S, Matsuzawa K, et al. Gangliocytic paraganglioma of the papilla of Vater with regional lymph node metastasis. Am J Gastroenterol 1992;87:1216 - 8. [14] Barbareschi M, Frigo B, Aldovini D, et al. Duodenal gangliocytic paraganglioma. Report of a case and review of the literature. Virchows Arch A Pathol Anat Histopathol 1989;416:81 - 9. [15] Goldman RL. Ganglioneuroma of the duodenum. Relationship to nonchromaffin paraganglioma of the duodenum. Am J Surg 1968; 115:716 - 9. [16] Perrone T, Sibley RK, Rosai J. Duodenal gangliocytic paraganglioma. An immunohistochemical and ultrastructural study and a hypothesis concerning its origin. Am J Surg Pathol 1985;9:31 - 41. [17] Riddell RH, Petras RE, Williams GT, et al. Tumors of the intestines. Washington (DC)7 Armed Forces Institute of Pathology; 2003. p. 291 - 3.
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[18] 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 - 65. [19] Reed RJ, Daroca Jr PJ, Harkin JC. Gangliocytic paraganglioma. Am J Surg Pathol 1977;1:207 - 16. [20] Beltrami CA, Montironi R, Cinti S. Gangliocytic paraganglioma of the duodenum: case report. Tumori 1980;66:637 - 41. [21] Furihata M, Sonobe H, Iwata J, et al. Immunohistochemical characterization of a case of duodenal gangliocytic paraganglioma. Pathol Int 1996;46:610 - 3. [22] Guarda LA, Ordonez NG, del Junco G, et al. Gangliocytic paraganglioma of the duodenum: an immunocytochemical study. Am J Gastroenterol 1983;78:794 - 8. [23] Perrone T. Duodenal gangliocytic paraganglioma and carcinoid. Am J Surg Pathol 1986;10:147 - 9. [24] Castoldi L, DeRai P, Marini A, et al. Neurofibromatosis-1 and ampullary gangliocytic paraganglioma causing biliary and pancreatic obstruction. Int J Pancreatol 2001;29:93 - 8. [25] Altavilla G, Chiarelli S, Fassina A. Duodenal periampullary gangliocytic paraganglioma: report of two cases with immunohistochemical and ultrastructural study. Ultrastruct Pathol 2001; 25:137 - 45. [26] Buetow P, Levine M, Buck J, et al. Duodenal ganglicytic paraganglioma: CT, MR imaging and US findings. Radiology 1997;204: 745 - 7. [27] Kotsis T, Voros D, Paphiti A, et al. Duodenal gangliocytic paraganglioma as a radiological moving defect. Dig Surg 2000; L17:636 - 40. [28] Kehagias D, Moulopoulos L, Pafiti A, et al. Quiz case of the month. Eur Radiol 1999;9:1465 - 6. [29] Hengstler P, Binek J, Menenberger C. Endoscopic resection of a juxtapapillary gangliocytic paraganglioma. Endoscopy 2003;35: 633 - 4. [30] Evans J, Wilson P, Barber P, et al. Duodenal gangliocytic paraganglioma presenting as an ampullary tumor. Int J Pancreatol 1996; 20:131 - 4.
Duodenal gangliocytic paraganglioma: a radiological-pathological correlation Jose Antonio Plaza, MDa, Kenneth Vitellas, MDb, William L. Marsh Jr., MDa,* a
Department of Pathology, The Ohio State University Medical Center, Columbus, OH 43210, USA Department of Radiology, The Ohio State University Medical Center, Columbus, OH 43210, USA
b
Abstract
Duodenal gangliocytic paraganglioma is a rare tumor that characteristically occurs in the second portion of the duodenum and typically presents with gastrointestinal bleeding. Gangliocytic paragangliomas have a characteristic triphasic microscopic appearance with epithelioid cells, spindle cells, and ganglion cells, resulting in a complex histology with features of paraganglioma, carcinoid, and ganglioneuroma. Duodenal gangliocytic paragangliomas have an excellent prognosis after surgical resection but metastatic spread to regional lymph nodes and recurrence may rarely occur. We report a case of duodenal gangliocytic paraganglioma and discuss the radiological and pathological differential diagnosis of this rare entity. D 2005 Elsevier Inc. All rights reserved.
Index words:
Duodenal gangliocytic paraganglioma; Periampullary tumor
1. Introduction Gangliocytic paraganglioma is a rare neoplasm that characteristically occurs in the second portion of the duodenum, but also has been reported in the fourth portion of the duodenum, jejunum, stomach, appendix, and lung [1,2]. Similar tumors have been described in the cauda equina [3,4]. Generally, these tumors have a relatively benign clinical course, although rarely tumors may metastasize to lymph nodes or recur locally [5-7]. Approximately 130 gangliocytic paragangliomas have been reported, 6 with lymph node metastasis [8]. Distant metastasis and death have not been reported to our knowledge. In 1957, Dahl et al [9] reported a duodenal ganglioneuroma. In 1962, Taylor and Helwig [10] described unusual polypoid duodenal tumors naming them nonchromaffin paragangliomas. In 1971, Kepes and Zacharias [11] reviewed the literature, described 2 similar cases that presented in the second portion of the duodenum, and proposed the term gangliocytic paraganglioma. Subsequently, multiple similar cases of gangliocytic paraganglioma were reported as individual case reports or in small series [12-30]. * Corresponding author. Department of Pathology, The Ohio State University Medical Center, Columbus, OH 43210, USA. Tel.: +1 614 293 5450. E-mail address: [email protected] (W.L. Marsh). 1092-9134/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2005.02.004
Gangliocytic paragangliomas have a characteristic histology consisting of varying proportions of 3 cell types: epithelioid cells, ganglion cells, and spindle cells. The epithelioid cells have a neuroendocrine growth pattern that may resemble paraganglioma and/or carcinoid. The spindle cells and ganglion cells may have a ganglioneuromatous growth pattern. Morphologic overlay between epithelioid cells and ganglion cells may be seen. The histogenesis of gangliocytic paraganglioma has engendered multiple theories, but is still unknown [10,15-17]. The 2 main possibilities are (1) neoplasm with divergent triphasic differentiation and (2) hamartoma related to abnormal pancreatic development. We report a case of duodenal gangliocytic paraganglioma in a 53-year-old woman who presented to our institution with upper gastrointestinal bleeding. The pathological and radiological features and differential diagnosis of this tumor are described. 2. Case report A 53-year-old woman was transferred from an outside institution to The Ohio State University Medical Center because of recurrent upper gastrointestinal bleeding. Upon arrival she was evaluated and underwent an esophagogastroduodenoscopy with biopsy that revealed a 2-cm peri-
144
J.A. Plaza et al. / Annals of Diagnostic Pathology 9 (2005) 143 – 147
Fig. 1. Contrast-enhanced CT scan showing polypoid lesion (arrows) protruding into duodenal lumen.
ampullary mass felt to be benign by endoscopy. Microscopic sections of the biopsy revealed a low-grade proliferation of spindle and ganglion-like cells with a differential diagnosis of gastrointestinal stromal tumor, ganglioneuroma, or an inflammatory process. Subsequently she underwent radiological studies followed by local surgical resection of the ampulla.
Fig. 3. Gangliocytic paraganglioma involving submucosa and muscular wall of duodenum. Epithelioid areas are marked by * and spindle cell area by bxQ (scanning power).
specific enolase (NSE) (5G10, 1:50-1:100 dilution, Novocastra, Newcastle upon Tyne, UK), synaptophysin (mouse monoclonal, 1:50 dilution, DAKO), HHF-35 (monoclonal mouse, 1:75 dilution, DAKO), CD117 (rabbit polyclonal, 1:50 dilution, DAKO), and CD34 (monoclonal antibody, 1:300 dilution, DAKO). Appropriate positive controls were run concurrently for all the antibodies tested.
3. Materials and methods The tissues were fixed in neutral buffered formalin and embedded in paraffin for histological processing. Tissue sections were stained with hematoxylin and eosin for conventional histology. Representative paraffin-fixed tissue blocks were cut and processed for immunohistochemical studies. The antibodies tested included: cytokeratin AE1/ AE3 (1:50 dilution, DAKO, Carpinteria, Calif), S-100 protein (polyclonal, 1:3000 dilution, DAKO), chromogranin (monoclonal mouse, 1:200 dilution, DAKO), neuron-
Fig. 2. Axial gadolinium-enhanced MRI showing an enhancing ampullary mass (arrows).
4. Radiological findings A computed tomography (CT) scan of the abdomen showed soft tissue attenuation in the periampullary region that was enhanced after intravenous contrast, revealing a solid homogeneous 2.4-cm periampullary mass protruding into the duodenal lumen (Fig. 1). Magnetic resonance imaging (MRI) showed a 1.8-cm solid homogeneous mass protruding into the lumen from the medial wall of the duodenum; the lesion showed increased T2 and decreased
Fig. 4. Epithelioid components at right and upper left, spindle cell component at lower left (medium power).
J.A. Plaza et al. / Annals of Diagnostic Pathology 9 (2005) 143 – 147
Fig. 5. Epithelioid cells at right, spindle cells at left (high power).
T1 signal and was enhanced after the administration of gadolinium (Fig. 2). Both CT and MR studies indicated that the lesion was confined to the duodenum, and neither study showed evidence of pancreatic mass, bile duct or pancreatic obstruction, nor metastatic disease. 5. Pathological findings The specimen consisted of a 2.0 1.5 1.0-cm portion of partially ulcerated bowel with attached soft tissue. A nodular component was felt within the soft tissue. Sectioning revealed a 1.3 0.8 0.6-cm irregular, tan white nodule with a homogeneous cut surface. No areas of cystic degeneration or necrosis were noted. Microscopic sections showed an infiltrative unencapsulated submucosal neoplasm extending into the muscularis propria and the mucosa, with focal mucosal ulceration (Fig. 3). The neoplasm was composed of spindle cells, ganglion cells, and epithelioid cells arranged in a nested pattern, intermixed with normal-appearing smooth muscle
Fig. 6. Scattered ganglion-like cells are present (high power).
145
Fig. 7. Immunohistochemical stain with anti–pancreatic polypeptide is positive in epithelioid cells at lower left and negative in spindle cells at upper right.
(Figs. 4 and 5). The spindle cells displayed thin, wavy nuclei with indistinct cytoplasm. The epithelioid nested pattern resembled the bZellballenQ arrangement in neuroendocrine neoplasias (paraganglioma-like), showing cells with granular eosinophilic cytoplasm and uniform rounded nuclei with stippled chromatin and inconspicuous nucleoli. Ganglion cells were scattered throughout (Fig. 6). Mitotic activity and tumor necrosis were not observed. Immunohistochemical stains (Figs. 7 and 8) showed that the epithelioid cells were positive for pancreatic polypeptide, somatostatin, serotonin, chromogranin, synaptophysin, and monoclonal NSE. S-100 protein highlighted the sustentacular cells. The spindle cell areas were strongly positive for S-100 protein and CD34. Ganglion cells were positive for synaptophysin, NSE, and somatostatin. Immunostains for cytokeratin AE1/AE3, muscle actin (HHF-35), and CD117 were predominantly negative.
Fig. 8. Immunohistochemical stain with anti–S-100 protein is positive in spindle cells and sustentacular cells, but negative in epithelioid cells.
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J.A. Plaza et al. / Annals of Diagnostic Pathology 9 (2005) 143 – 147
6. Discussion Reported patients with duodenal gangliocytic paragangliomas range from 15 to 84 years of age, with a slight male predominance. Patients usually present with gastrointestinal bleeding due to mucosal ulceration, as experienced in the current case; other complaints include epigastric pain, nausea, and vomiting. Biliary obstruction is rare but has been reported [24]. In some patients, duodenal gangliocytic paraganglioma is discovered incidentally. As in this case, most duodenal gangliocytic paragangliomas occur in the second portion of the duodenum with a predilection for the ampulla of Vater [16,18]. The tumor varies from 0.5 to 7 cm in size, is polypoid or sessile, and is covered by the duodenal mucosa with scattered mucosal ulcerations [16-19]. The radiological findings in this case illustrate the typical features of a periampullary neoplasm, including a soft tissue mass projecting into the lumen of the duodenum and absence of a pancreatic mass or distal common bile duct abnormalities. The radiological differential diagnosis of ampullary and duodenal tumors includes lesions such as adenoma, carcinoma, leiomyosarcoma, gastrointestinal stromal tumor, lymphoma, lipoma, hemangioma, cysts, and hamartomas [26,28]. Reported upper gastrointestinal tract series findings in duodenal gangliocytic paraganglioma include pedunculated or sessile lesions apparently arising in the submucosa and deforming the overlying mucosa. Computed tomography and magnetic resonance imaging characterize duodenal gangliocytic paragangliomas as solid homogeneous enhancing polypoid or sessile masses [12,14,26], similar to the findings in this case. Ultrasound studies have shown well-circumscribed lesions that are often homogeneous and hypoechoic [26]. Ultrasound has recently been used to help justify endoscopic resection of duodenal gangliocytic paragangliomas [8,29]. Radiological findings of a circumscribed solid homogenous enhancing lesion confined to the duodenum without biliary obstruction are not specific, but should raise the consideration of duodenal gangliocytic paraganglioma. Carcinomas are often hypovascular and associated with biliary obstruction. Leiomyosarcomas, hemangiomas, and hamartomas often show heterogeneous enhancement. Lipomas show fatty attenuation. Inflammatory fibroid polyps and lymphomas are rare in the duodenum but may show radiological features similar to gangliocytic paraganglioma [26,28]. Histologically, gangliocytic paragangliomas have a characteristic triphasic pattern with varying proportions of epithelioid cells, ganglion cells, and spindle cells; the overall pattern is complex with features of ganglioneuroma, paraganglioma, and carcinoid. The tumors lack necrosis or significant mitotic rate, and appear histologically benign [17]. Because duodenal gangliocytic paragangliomas are predominantly submucosal, initial endoscopic biopsies
may not be diagnostic and may potentially be misleading, as illustrated in this case [8,26]. If the endoscopic biopsy does not contain all 3 elements, spindle cell neoplasms, epithelial neoplasms, or ganglioneuroma may be favored, depending upon which elements appear in the biopsy. In non-ulcerated sessile tumors, the endoscopic biopsy may lack tumor and show only inflammatory or reactive changes. Immunohistochemically, the epithelioid cells are typically positive for NSE, pancreatic polypeptide, and somatostatin, but negative for S-100 protein; they are also frequently positive for chromogranin and synaptophysin, and sometimes positive for cytokeratins and a variety of endocrine polypeptides. The ganglion cells are positive for NSE, synaptophysin, and neurofilaments. The ganglion cells may show morphologic overlap with the epithelioid cells and may be positive for endocrine polypeptides. The spindle cells are strongly positive for S-100 protein, supporting neural origin. Sustentacular cells positive for S-100 protein may be present in some tumors [5,12,17,18,25]. The histological differential diagnosis of duodenal gangliocytic paraganglioma includes conventional paraganglioma, well-differentiated neuroendocrine carcinoma (carcinoid), ganglioneuroma, and spindle cell neoplasms (nerve sheath, smooth muscle, and gastrointestinal stromal tumors) [17,21-23]. The characteristic triphasic pattern and duodenal location are the most important diagnostic features and are usually sufficient to exclude the other entities. In some tumors, thorough sampling and immunohistochemical stains may be required to demonstrate the triphasic pattern. In the second part of the duodenum, pure ganglioneuromas and paragangliomas may represent part of a spectrum with gangliocytic paraganglioma. Well-differentiated neuroendocrine carcinoma is an important differential, but should lack ganglion cells and S-100 protein– positive spindle cell proliferation. Gangliocytic paragangliomas should be negative for smooth muscle markers except for the admixed normal smooth muscle elements. The presence of ganglion cells and absence of staining for CD117 should eliminate the possibility of gastrointestinal stromal tumor.
References [1] Dante S, Viale G, Dalla Palma P. Gangliocytic paraganglioma of the duodenum: case report. Tumori 1987;73:425 - 9. [2] Hironaka M, Fukayama M, Takayashiki N, et al. Pulmonary gangliocytic paraganglioma: case report and comparative immunohistochemical study of related neuroendocrine neoplasms. Am J Surg Pathol 2001;25:688 - 93. [3] Hayes E, Lippa C, Davidson R. Paragangliomas of the cauda equina. AJNR Am J Neuroradiol 1989;10(5 Suppl):S45 - 7. [4] Hamid QA, Bishop AE, Rode J, Dhillon AP, et al. Duodenal gangliocytic paragangliomas: a study of 10 cases with immunocytochemical neuroendocrine markers. Hum Pathol 1986;17:1151 - 7. [5] Inai K, Kobuke T, Yonehara S, et al. Duodenal gangliocytic paraganglioma with lymph node metastasis in a 17-year-old boy. Cancer 1989;63:2540 - 5.
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