CASE REPORT

Int J Clin Oncol (2009) 14:473–477 © The Japan Society of Clinical Oncology 2009DOI 10.1007/s10147-008-0872-1

T. Noda · H. Nagano (*) · A. Miyamoto · H. Wada · M. Murakami · S. Kobayashi · S. Marubashi · Y.Takeda · K. Dono · M. MondenDepartment of Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka 565-0871, JapanTel. +81-6-6879-3251; Fax +81-6-6879-3259e-mail: hnagano@surg2.med.osaka-u.ac.jp

K. UmeshitaDepartment of Health Sciences, Graduate School of Medicine, Osaka University, Osaka, Japan

K. WakasaDepartment of Pathology, Osaka City University Hospital, Osaka, Japan

Takehiro Noda · Hiroaki Nagano · Atsushi Miyamoto Hiroshi Wada · Masahiro Murakami · Shogo Kobayashi Shigeru Marubashi · Yutaka Takeda · Keizo Dono Koji Umeshita · Kenichi Wakasa · Morito Monden

Successful outcome after resection of liver metastasis arising from an extraadrenal retroperitoneal paraganglioma that appeared 9 years after surgical excision of the primary lesion

adrenal locations include the head and neck area, medias-tinum, retroperitoneum, gallbladder, extrahepatic bile ducts, urinary bladder, and spinal region. The behavior of extraadrenal retroperitoneal paragangliomas is known to be more malignant than the behavior of those found else-where.1 Malignant paragangliomas exhibit hematogenous spread, and some patients show distant metastases at presentation, with the most common sites being bone, liver, and lungs.2 Once distant metastases occur, the median survival is reported to be 16–34 months.3,4 As for the treatment of paragangliomas, surgical resection is the only effective treatment modality for primary and secondary tumors.3,5,6

Here, we present a case of a liver metastatic tumor origi-nating from extraadrenal retroperitoneal paraganglioma; the metastatic tumor was diagnosed 9 years after resection of the primary lesion, and was successfully treated by surgi-cal resection.

Case report

A 54-year-old man underwent surgical resection of a retro-peritoneal tumor at Osaka University Hospital in 1995. Pre-operative abdominal computed tomography (CT) showed a large and hypervascular tumor in the left upper abdominal cavity (Fig. 1a). The tumor size was 12 cm in diameter and its blood supply originated from the splenic and celiac arteries. The operation was performed safely and no hyper-tensive crisis was experienced perioperatively. Histopatho-logically, the mass was entirely covered with a fi brous capsule (Fig. 1b), and its architectural pattern resembled “zellballen”. The size of the tumor cells varied and the nuclei of the tumor cells were round or oval; some tumor cells had large nuclei or multiple nuclei (Fig. 1c). The cyto-plasm was clear. Immunohistochemical examination showed positive reaction for chromogranin A. Based on the above fi ndings, the tumor was considered to be an extraadrenal retroperitoneal paraganglioma without malignant changes (such as mitosis, infi ltration of the fi brous capsule, or

Received: February 7, 2008 / Accepted: December 23, 2008

Abstract A 54-year-old man underwent surgery for exci-sion of a retroperitoneal tumor that measured 12 cm in diameter, and histopathological examination revealed the tumor was an extraadrenal retroperitoneal paraganglioma. He presented 9 years later with epigastric discomfort. Abdominal ultrasound showed a solitary liver tumor. The diagnosis, based on radiological workup, was metastatic paraganglioma. The tumor was surgically resected and the histological fi ndings resembled those of the primary tumor. The patient has been followed up for 3 years and remains recurrence-free. Surgical resection is an effective treatment approach for primary and secondary paragangliomas, but the resectability of liver metastatic lesions is usually low, although complete resection with a wide surgical margin was possible in this patient. This case suggests that a good prognosis after the resection of hepatic metastasis depends not only on the curative resection of the metastatic lesion but also on the tumor characteristics, such as slow growth or low aggressiveness.

Key words Extraadrenal paraganglioma · Liver metastasis · Retroperitoneum · Operation

Introduction

Extraadrenal paragangliomas are unusual neoplasms that have been described in many anatomic sites. The extra-

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vascular invasion). The patient’s clinical course was un-eventful for 9 years after the surgery.

In June 2004, the patient presented with epigastric dis-comfort. Abdominal ultrasound examination revealed a hepatic tumor. He was admitted to our hospital for further evaluation of the tumor. Physical examination was normal. Laboratory tests showed normal results for biochemical tests with negative viral markers. Serum catecholamine con-centrations were normal, although 24-h urine catecholamine was not examined. The level of neuron-specifi c enolase (NSE), a tumor marker, was slightly elevated, at 10.2 ng/ml. Abdominal CT showed a solitary and hypervascular tumor with central necrosis in segments 8 and 4 of the liver (Fig. 2a). Magnetic resonance imaging (MRI) showed low-intensity signal in T1 weighted images and high-intensity signal in T2 weighted images (Fig. 2b, c). Angiography showed that the tumor was supplied by branches from the right and left hepatic arteries. No other lesions were detected. 131I-Metaiodobenzylguanidine (MIBG) scintigra-phy showed positive uptake of MIBG in the tumor in seg-ments 8 and 4 (Fig. 2d). 18F-Fluorodeoxyglucose (FDG) positron emission tomography showed FDG uptake in the tumor, but no uptake in any other areas of the liver or other organs.

Based on these fi ndings, the diagnosis was a solitary hepatic metastatic tumor of extraadrenal retroperitoneal paraganglioma. Accordingly, the patient underwent tumor resection, with a suffi cient surgical margin. No hypertensive crisis developed before or during surgery. The hepatic mass was visible from the liver surface, and was encapsulated by a thin layer of the serosa. It measured 8.2 × 6.0 × 6.0 cm. The cross-section showed a mass consisting of peripherally solid areas together with pockets of cystic degeneration (Fig. 3a). The histological fi ndings were consistent with a

metastatic lesion from the extraadrenal paraganglioma resected 9 years earlier (Fig. 3b, c; H&E staining). Infi ltra-tion of the capsule was evident, and the nontumorous tissue was normal liver tissue. Immunohistochemical examination showed positive immunoreactivity for chromogranin A (Fig. 3d) and synaptophysin. The fi nal diagnosis was meta-static paraganglioma.

The postoperative course was uneventful. At the last follow-up examination, 3 years after the second surgery, the patient was asymptomatic and free from any sign of recurrence.

Discussion

Extraadrenal paragangliomas typically exhibit variable clin-ical features. The majority of these tumors are functional and actively produce catecholamines. The clinical signs and symptoms are most likely caused by excess catecholamine secretion, and such excess secretion has been reported in 36% to 65% of patients.3,7 Moreover, extraadrenal paragan-gliomas are associated with a high rate of malignancy, ranging from 14% to 50%.3,5 Malignant paragangliomas demonstrate both hematogenous and lymphatic spread, with the most common sites of distant metastases being bone, liver, and lungs. Sclafani et al.3 reported a series of 22 cases of extraadrenal paragangliomas. In their report, 11 of the 22 (50%) patients developed distant metastases. The most frequent sites of metastasis were bone (7/11), liver (3/11), and peritoneum (2/11). The median time to fi rst metastasis after excision of the primary tumor was 2 months, but the time to the fi rst metastasis in 2 patients was more than 7 years. Morikawa et al.8 reported a case of adrenal

Fig 1a–c. Abdominal computed tomography and histopathologi-cal fi ndings of the primary extraadrenal paraganglioma. a Abdominal computed tomogra-phy showed a large hypervascular tumor in the left upper abdomi-nal cavity. b, c Histopathologi-cally, the mass was entirely covered with a fi brous capsule and its architectural pattern resembled “zellballen.” Note the lack of malignant changes such as mitosis and infi ltration of the fi brous capsule. b H&E ×40; c H&E ×200

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Fig. 2a–d. Abdominal computed tomography, magnetic resonance imaging, and I-metaiodobenzyl-guanidine (131I-MIBG) scintigra-phy. a Abdominal computed tomography showed a solitary and hypervascular tumor with central necrosis in segments 8 and 4 of the liver (arrow). b, c Mag-netic resonance imaging showed that the tumor had low intensity on T1-weighted imaging and high intensity on T2-weighted imaging (arrows). d 131I-MIBG scintigra-phy showed positive uptake of MIBG in the tumor in segments 8 and 4 (arrow), and no uptake in any other organs

Fig. 3a–d. Surgical specimen and histological fi ndings. a The hepatic mass was encapsulated with a thin layer of serosa. It mea-sured 8.2 × 6.0 × 6.0 cm. The cross-section showed that the mass consisted of peripherally solid areas with pockets of cystic degeneration. b, c The histologi-cal fi ndings were consistent with those of the primary extraadrenal paraganglioma resected 9 years earlier. d Immunohistochemical examination showed positive immunoreactivity for chromo-granin A. b H&E ×40; c H&E ×200; d chromogranin staining, ×200

pheochromocytoma with hepatic metastasis 10 years after resection of the primary tumor. In our patient, distant metastasis was diagnosed 9 years after the surgery for the primary tumor, and the period to fi rst metastasis in this patient was long.

There is considerable variation in the literature in regard to the defi nition of malignancy in paragangliomas. Almost all authors have defi ned malignancy as limited to patients with metastatic lesions. Furthermore, patient outcome after

surgical treatment is as important as the defi nition of malig-nancy. Lack et al.9 reviewed 12 cases and reported that the presence of mitosis or vascular invasion might be associated with poor prognosis. O’Riordain et al.7 reported that tumor size of more than 5 cm was a strong predictor of persistent or recurrent disease and of mortality. The close relation between tumor size and outcome has also been reported in other series.10, 11 In the present patient, we examined the histopathology of the primary tumor retrospectively, but no

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histological fi ndings of malignancy, such as mitosis, infi ltra-tion of the fi brous capsule, or vascular invasion were found. But the size of the tumor was 12 cm, which is a predictor of recurrent disease, and long follow up will probably be needed for the detection of a new metastatic lesion. This case indicated that it is diffi cult to distinguish benign from malignant tumors based only on histological examinations of these tumors. We note that we should consider other clinicopathological factors, such as tumor size, to determine malignancy, as previously reported.7

Diagnostic biochemical tests cannot be applied to a non-functional paraganglioma. With regard to tumor localiza-tion, MIBG, CT, and MRI are complementary procedures commonly used in evaluating patients with paraganglio-mas.12,13 CT and MRI have high sensitivity and are the main imaging modalities used to provide anatomical informa-tion.14,15 However, they are less accurate for detecting extraadrenal or metastatic tumors.16 Furthermore, although MIBG scintigraphy has a high specifi city (95%–100%), its sensitivity is lower than that of CT and MRI, ranging from 80% to 100%.15,17 In our patient, abdominal CT showed a hypervascular tumor in the liver, and MIBG scin-tigraphy showed uptake in the liver tumor only. Based on the use of these three imaging modalities, we were able to diagnose the solitary liver tumor as a metastatic paraganglioma.

With regard to the treatment of paragangliomas, surgi-cal resection is the only effective approach for both the primary and secondary tumors.3,5,6 However, the resectabil-ity of hepatic metastasis is usually low, because metastatic disease is often diagnosed in a state of multiple lesions. Morikawa et al.8 reported a curatively resected hepatic metastasis of pheochromocytoma, but the follow-up period after the operation was only 2 months. Mornex et al.18 reported that hepatic metastasis of malignant pheochro-mocytoma was diagnosed in 4 (29%) out of 14 patients, but only 1 patient had undergone surgery. Complete resec-tion of metastatic lesions was so diffi cult that many patients received other therapeutic modalities, such as systemic chemo- or radiotherapy. Several protocols of combination chemotherapy including cyclophosphamide, vincristine, and dacarbazine (CVD) were reported to stabilize the disease and produce tumor regression, with a considerable response rate.19–22 Transcatheter arterial embolization was reported to be effective for hypervascular tumors.23 In the present patient, because the metastatic liver lesion was solitary and curative resection was possible, we considered surgical resection as suitable treatment for the metastatic lesion.

Several authors have evaluated the prognosis of patients who develop distant metastases of a paraganglioma. Schlumberger et al.4 reported that the median survival time from the diagnosis of metastatic malignant pheochromocy-toma was 16 months. Sclafani et al.3 reported that the median survival time was 34 months after identifi cation of a distant metastatic tumor. But a few patients have shown prolonged survival after the diagnosis of metastases. Recently Huang et al.24 reported a series of ten patients with malignant pheochromocytomas, and the survival after diag-

nosis of malignancy raged from 1.5 years to 20 years. Huang et al.24 reported a long-term survivor (more than 20 years) after the diagnosis of lung and bone metastasis. In the present patient, the disease-free period from the primary resection was relatively long (i.e., 9 years) and this long disease-free survival suggests the presence of such tumor characteristics as a slow growth pattern or low aggressi-veness. Our patient has survived for almost 3 years without recurrence after resection of the liver metastatic lesion. This case suggests that good prognosis depends not only on the curative resection of a metastatic lesion but also on tumor characteristics such as slow growth or low aggres-siveness. The follow-up time in the present patient is still almost 3 years and the patient will need a longer follow-up time.

In summary, the present patient has had a successful outcome after the resection of a liver metastasis from an extraadrenal retroperitoneal paraganglioma which was diagnosed 9 years after resection of the primary lesion. To determine the malignancy of a lesion, we should consider not only its histology but also other clincopathological factors such as the size of the lesion. Furthermore, this case suggests that a good prognosis after the resection of a hepatic metastasis depends not only on the curative resec-tion of the metastatic lesion but also on tumor characteris-tics such as slow growth or low aggressiveness.

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