Path. Res. Pract. 188, 1098-1100 (1992)
Extra-adrenal Pheochromocytoma-Ganglioneuroma A Case Report N. YoshimP, T. Tanakal, A. Haral, Y. Bunai 1,2, K. Kato 1 and H. MorP Departments of 1Pathology and 2Legal Medicine, Gifu University School of Medicine, Gifu city 500, Japan
SUMMARY
A case of rare extra-adrenal tumor composed of pheochromocytoma-ganglioneuroma which developed in a 48-year-old Japanese male is reported. Histologically, the tumor contained equal proportion of two distinct patterns, pheochromocytoma and ganglioneuroma. Immunohistochemical examination revealed that pheochromocytoma cells were po~itive for Leu-7 and ganglion cells in ganglioneuroma were positive for vasoactive intestinal peptide (VIP), respectively. Neuron specific enolase (NSE) was positive in the neoplastic cells of both components, and S-l 00 protein was also positive in fibers around ganglion cells. Ultrastructural examination revealed that neurosecretory granules were present in the neoplastic cells.
Introduction Pheochromocytomas arise from the chromaffin cells of the sympathoadrenal system. Most pheochromocytomas are found in the adrenal glands and about 10 % are extra-adrenal. The most common site of occurrence of extra-adrenal pheochromocytoma is the organ of Zuckerkandl. On the other hand, on rare occasions, adrenal medullary tumors possess more than one cellular constituent. For example, it has been reported that both pheochromocytoma and ganglioneuroma occur together within a single adrenal tumor 5,6, 7, 10. However, to our knowledge, extra-adrenal tumors composed of pheochromocytoma and ganglioneuroma have not yet been reported. We report here an extra-adrenal tumor composed of pheochromocytoma and ganglioneuroma in a 48-year-old Japanese man. The results of immunohistochemical and ultrastructural examinations of this neoplasm are also described. 0344-0338/92/0188-1098$3.50/0
Report of a Case A 48-year-old man was admitted to Tohkai-Chuo Hospital with acute abdomen. An emergency operation for volvulus of the sigmoid colon was performed and the sigmoid colon was resected. A large left-sided retroperitoneal tumor was also found, but the tumor was not resected because there was no evidence of malignancy. His medical history was unremarkable except for a megacolon 3 years prior to admission. Blood pressure was 132/90 mm Hg and he had no symptom of intractable diarrhea, weight loss or weakness. Laboratory data revealed no abnormalities except increased white blood cell count (10900/mm 3 ) and elevated serum and urine "catecholamines: noradrenaline 0.62 ng/ml (normal range: 0.05-0.40), 191 mg/day (10-90); adrenaline 0.33 ng/ml «0.10), 126 mg/day «10); dopamine 5.7 ng/ml «0.20),9,000 mg/day (100-700). These data suggested that the tumor was a neoplasm producing catecholamine. © 1992 by Gustav Fischer Verlag, Stuttgart
Extra-adrenal Pheochromocytoma-Ganglioneuroma . 1099
The tumor was removed 1 month after the emergency operation under the diagnosis of pheochromocytoma. At operation, an elastic soft and movable tumor in the retroperitoneal space was away from the left kidney and adrenal gland. The feeding artery of the tumor was a branch of inferior mesenteric artery. Postoperatively, serum and urine catecholamines were returned within normal range. Pathological Findings Grossly, the tumor consisted of an ovoid, well-circumscribed encapsulated mass weighing 350 g and measuring 7 x 8 x 5 cm in size. On cut section, the tissue was yellowish-tan with hemorrhagic and cystic areas. After
Fig. 1
Fig. 2
fixation in 10 % formalin, paraffin sections were stained with hematoxylin & eosin, Masson-Fontana and Grimelius. Immunohistochemical staining for neuron specific enolase (NSE) (DAKOPATTS, Denmark), S-100 protein (S-100) (DAKOPATTS) glial fibrillary acidic protein (GFAP) (DAKOPATTS), Leu-7 (Becton Dickinson, USA) and vasoactive intestinal peptide (VIP) (Cambridge Research Laboratory, MA, U.S.A.) was performed using Universal DAKO PAP KIT (DAKOPATTS). For ultrastructural examination, a few pieces from a 10 % formalinfixed tumor were prepared. Microscopically, the tumor contained two distinct patterns. The first pattern comprised sheets or nests of round or polygonal cells with finely eosinophilic granular cytoplasm and a thin stroma with abundant blood vessels (Fig. 1). This pattern was considered to be a pheochromo-
1100· N. Yoshimietal.
cytoma. The second pattern displayed fully differentiated ganglion-like cells scattered in a fibrous stroma (Fig. 2). Ganglion-like cells had abundant eosinophilic cytoplasm and eccentric round nuclei with a large nucleoleus, and some had yellowish-tan granules, suggesting melanin pigments. This pattern suggested a ganglioneuroma. Transition between both patterns was rather abrupt and the border was relatively clear with fibrous tissue. No mitoses were noted in both components. The tumor cells in both areas had argyrophilic and argentaffin granules in their cytoplasm as shown by the Grimelius and MassonFontana stains. Immunohistochemically, N5E reacted in both tumor cells. Positive cells for VIP were observed in the ganglion-like cells and Leu-7 was positive in pheochromocytoma cell. The strong positiveness for 5-100 was shown in the stroma around ganglion-like cells. GFAP was negative in this tumor. Ultrastructurally, tumor cells possessed numerous granules in their cytoplasm. The granules were divided into two types such as round or elongated granules (100-300 nm in size) showing medium density, and dense core granules (150-400 nm in size) eccentrically placed in a vacuole. It is suggested that the former were adrenaline granules and the latter noradrenaline granules. However, myelin structures indicating 5chwann cells were not observed in the examined samples. Discussion A mixed neoplasm consisting of pheochromocytoma and ganglioneuroma within a single tumor is rare S,6,7, 10. All reported cases occurred in the adrenal gland. In the present case, the findings of reoperation suggested that the tumor be developed in the organ of Zuckerkandl. It is well known that pheochromocytoma is one of the tumors representing various histological figures 8 • For example pheochromocytomas partially differentiate into neuroblastoma elements 4 and contain ganglion cells 2 • However, both pheochromocytoma and ganglioneuroma cells were considered to originate from neural crest l . Therefore, a mixed tumor as shown in the present case is derived from the stem cells of neural crest. In fact, both components of this tumor had argyrophilic and argentaffin granules. Immunohistochemical staining also showed that
neoplastic cells in both components were positive for N5E. In spite of the high levels of serum and urine catecholamines, hypertension was not observed. Moreover, other specific symptoms such as water diarrhea were not observed during the course. On the other hand, positive reaction for VIP in the neoplastic cells was present3,9. Therefore, catecholamine and VIP produced by the tumor had not enough biological activities to cause such symptoms. References 1 Bolande RP (1974) The neurocristopathies: A unifying concept of disease arising in neural crest maldevelopment. Human Pathol 5: 409 2 Dawson DW, Tapp E (1969) A compound tumour of the adrenal medulla. J Pathol 97: 231-233 3 Fausa 0, Fretheim B, Elgjo K, Semb LS, Gjone E (1973) Intractable watery diarrhea, hypokalaemia, and achlorhydria associated with non-pancreatic retroperitoneal neurogenous tumour containing vasoactive intestinal peptide (V.I.P.). Scand J Gastroent 8: 713 4 Fernando PB, Cooray GH, Thanabalasundram RS (1951) Adrenal pheochromocytoma with neuroblastomatous elements. Report of a case with autopsy. AMA Arch Path 52: 182-186 5 Kragel PJ, Johnston CA (1985) Pheochromocytoma-ganglioneuroma of the adrenal. Arch Pathol Lab Med 109: 470-472 6 Layfield LJ, Glasgow BJ, De Puis MH, Bhuta S (1987) Aspiration cytology and immunohistochemistry of a pheochromocytoma-ganglioneuroma of the adrenal gland. Acta Cytol31 : 33-39 7 Min KW, Clemens A, Bell J, Dick H (1988) Malignant peripheral nerve sheath tumor and pheochromocytoma: A composite tumor of the adrenal. Arch Pathol Lab Med 112: 266 8 Page DL, DeLellis RA, Hough AJ (1986) Tumors of the adrenal. Washington, DC, Armed Forces Institute of Pathology, p183 9 SackelSG, MansonJE, Harawi SJ, BurakoffR (1985) Watery diarrhea syndrome due to an adrenal pheochromocytoma secreting vasoactive intestinal polypeptide. Digestive Diseases and Sciences 30: 1201 10 Trump DL, Livingston IN, Baylin SB (1977) Watery diarrhea syndrome in an adult with ganglioneuroma-pheochromocytoma: Identification of vasoactive intestinal peptide, calcitonin, and catecholamines and assessment of· their biological activity. Cancer 40: 1526-1532
Received January 18, 1989· Accepted in revised form November 4, 1991
Key words: Pheochromocytoma-ganglioneuroma - Extra-adrenal retroperitoneal tumor - Organ of Zuckerkandl Naoki Yoshimi, M.D., Department of Pathology, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu city 500, Japan
Extra-adrenal Pheochromocytoma-Ganglioneuroma A Case Report N. YoshimP, T. Tanakal, A. Haral, Y. Bunai 1,2, K. Kato 1 and H. MorP Departments of 1Pathology and 2Legal Medicine, Gifu University School of Medicine, Gifu city 500, Japan
SUMMARY
A case of rare extra-adrenal tumor composed of pheochromocytoma-ganglioneuroma which developed in a 48-year-old Japanese male is reported. Histologically, the tumor contained equal proportion of two distinct patterns, pheochromocytoma and ganglioneuroma. Immunohistochemical examination revealed that pheochromocytoma cells were po~itive for Leu-7 and ganglion cells in ganglioneuroma were positive for vasoactive intestinal peptide (VIP), respectively. Neuron specific enolase (NSE) was positive in the neoplastic cells of both components, and S-l 00 protein was also positive in fibers around ganglion cells. Ultrastructural examination revealed that neurosecretory granules were present in the neoplastic cells.
Introduction Pheochromocytomas arise from the chromaffin cells of the sympathoadrenal system. Most pheochromocytomas are found in the adrenal glands and about 10 % are extra-adrenal. The most common site of occurrence of extra-adrenal pheochromocytoma is the organ of Zuckerkandl. On the other hand, on rare occasions, adrenal medullary tumors possess more than one cellular constituent. For example, it has been reported that both pheochromocytoma and ganglioneuroma occur together within a single adrenal tumor 5,6, 7, 10. However, to our knowledge, extra-adrenal tumors composed of pheochromocytoma and ganglioneuroma have not yet been reported. We report here an extra-adrenal tumor composed of pheochromocytoma and ganglioneuroma in a 48-year-old Japanese man. The results of immunohistochemical and ultrastructural examinations of this neoplasm are also described. 0344-0338/92/0188-1098$3.50/0
Report of a Case A 48-year-old man was admitted to Tohkai-Chuo Hospital with acute abdomen. An emergency operation for volvulus of the sigmoid colon was performed and the sigmoid colon was resected. A large left-sided retroperitoneal tumor was also found, but the tumor was not resected because there was no evidence of malignancy. His medical history was unremarkable except for a megacolon 3 years prior to admission. Blood pressure was 132/90 mm Hg and he had no symptom of intractable diarrhea, weight loss or weakness. Laboratory data revealed no abnormalities except increased white blood cell count (10900/mm 3 ) and elevated serum and urine "catecholamines: noradrenaline 0.62 ng/ml (normal range: 0.05-0.40), 191 mg/day (10-90); adrenaline 0.33 ng/ml «0.10), 126 mg/day «10); dopamine 5.7 ng/ml «0.20),9,000 mg/day (100-700). These data suggested that the tumor was a neoplasm producing catecholamine. © 1992 by Gustav Fischer Verlag, Stuttgart
Extra-adrenal Pheochromocytoma-Ganglioneuroma . 1099
The tumor was removed 1 month after the emergency operation under the diagnosis of pheochromocytoma. At operation, an elastic soft and movable tumor in the retroperitoneal space was away from the left kidney and adrenal gland. The feeding artery of the tumor was a branch of inferior mesenteric artery. Postoperatively, serum and urine catecholamines were returned within normal range. Pathological Findings Grossly, the tumor consisted of an ovoid, well-circumscribed encapsulated mass weighing 350 g and measuring 7 x 8 x 5 cm in size. On cut section, the tissue was yellowish-tan with hemorrhagic and cystic areas. After
Fig. 1
Fig. 2
fixation in 10 % formalin, paraffin sections were stained with hematoxylin & eosin, Masson-Fontana and Grimelius. Immunohistochemical staining for neuron specific enolase (NSE) (DAKOPATTS, Denmark), S-100 protein (S-100) (DAKOPATTS) glial fibrillary acidic protein (GFAP) (DAKOPATTS), Leu-7 (Becton Dickinson, USA) and vasoactive intestinal peptide (VIP) (Cambridge Research Laboratory, MA, U.S.A.) was performed using Universal DAKO PAP KIT (DAKOPATTS). For ultrastructural examination, a few pieces from a 10 % formalinfixed tumor were prepared. Microscopically, the tumor contained two distinct patterns. The first pattern comprised sheets or nests of round or polygonal cells with finely eosinophilic granular cytoplasm and a thin stroma with abundant blood vessels (Fig. 1). This pattern was considered to be a pheochromo-
1100· N. Yoshimietal.
cytoma. The second pattern displayed fully differentiated ganglion-like cells scattered in a fibrous stroma (Fig. 2). Ganglion-like cells had abundant eosinophilic cytoplasm and eccentric round nuclei with a large nucleoleus, and some had yellowish-tan granules, suggesting melanin pigments. This pattern suggested a ganglioneuroma. Transition between both patterns was rather abrupt and the border was relatively clear with fibrous tissue. No mitoses were noted in both components. The tumor cells in both areas had argyrophilic and argentaffin granules in their cytoplasm as shown by the Grimelius and MassonFontana stains. Immunohistochemically, N5E reacted in both tumor cells. Positive cells for VIP were observed in the ganglion-like cells and Leu-7 was positive in pheochromocytoma cell. The strong positiveness for 5-100 was shown in the stroma around ganglion-like cells. GFAP was negative in this tumor. Ultrastructurally, tumor cells possessed numerous granules in their cytoplasm. The granules were divided into two types such as round or elongated granules (100-300 nm in size) showing medium density, and dense core granules (150-400 nm in size) eccentrically placed in a vacuole. It is suggested that the former were adrenaline granules and the latter noradrenaline granules. However, myelin structures indicating 5chwann cells were not observed in the examined samples. Discussion A mixed neoplasm consisting of pheochromocytoma and ganglioneuroma within a single tumor is rare S,6,7, 10. All reported cases occurred in the adrenal gland. In the present case, the findings of reoperation suggested that the tumor be developed in the organ of Zuckerkandl. It is well known that pheochromocytoma is one of the tumors representing various histological figures 8 • For example pheochromocytomas partially differentiate into neuroblastoma elements 4 and contain ganglion cells 2 • However, both pheochromocytoma and ganglioneuroma cells were considered to originate from neural crest l . Therefore, a mixed tumor as shown in the present case is derived from the stem cells of neural crest. In fact, both components of this tumor had argyrophilic and argentaffin granules. Immunohistochemical staining also showed that
neoplastic cells in both components were positive for N5E. In spite of the high levels of serum and urine catecholamines, hypertension was not observed. Moreover, other specific symptoms such as water diarrhea were not observed during the course. On the other hand, positive reaction for VIP in the neoplastic cells was present3,9. Therefore, catecholamine and VIP produced by the tumor had not enough biological activities to cause such symptoms. References 1 Bolande RP (1974) The neurocristopathies: A unifying concept of disease arising in neural crest maldevelopment. Human Pathol 5: 409 2 Dawson DW, Tapp E (1969) A compound tumour of the adrenal medulla. J Pathol 97: 231-233 3 Fausa 0, Fretheim B, Elgjo K, Semb LS, Gjone E (1973) Intractable watery diarrhea, hypokalaemia, and achlorhydria associated with non-pancreatic retroperitoneal neurogenous tumour containing vasoactive intestinal peptide (V.I.P.). Scand J Gastroent 8: 713 4 Fernando PB, Cooray GH, Thanabalasundram RS (1951) Adrenal pheochromocytoma with neuroblastomatous elements. Report of a case with autopsy. AMA Arch Path 52: 182-186 5 Kragel PJ, Johnston CA (1985) Pheochromocytoma-ganglioneuroma of the adrenal. Arch Pathol Lab Med 109: 470-472 6 Layfield LJ, Glasgow BJ, De Puis MH, Bhuta S (1987) Aspiration cytology and immunohistochemistry of a pheochromocytoma-ganglioneuroma of the adrenal gland. Acta Cytol31 : 33-39 7 Min KW, Clemens A, Bell J, Dick H (1988) Malignant peripheral nerve sheath tumor and pheochromocytoma: A composite tumor of the adrenal. Arch Pathol Lab Med 112: 266 8 Page DL, DeLellis RA, Hough AJ (1986) Tumors of the adrenal. Washington, DC, Armed Forces Institute of Pathology, p183 9 SackelSG, MansonJE, Harawi SJ, BurakoffR (1985) Watery diarrhea syndrome due to an adrenal pheochromocytoma secreting vasoactive intestinal polypeptide. Digestive Diseases and Sciences 30: 1201 10 Trump DL, Livingston IN, Baylin SB (1977) Watery diarrhea syndrome in an adult with ganglioneuroma-pheochromocytoma: Identification of vasoactive intestinal peptide, calcitonin, and catecholamines and assessment of· their biological activity. Cancer 40: 1526-1532
Received January 18, 1989· Accepted in revised form November 4, 1991
Key words: Pheochromocytoma-ganglioneuroma - Extra-adrenal retroperitoneal tumor - Organ of Zuckerkandl Naoki Yoshimi, M.D., Department of Pathology, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu city 500, Japan
