Gangliocytic paraganglioma (GP) is rare and has been regarded as benign in general with a good prognosis. We present a patient with duodenal GP showing a malignant and lethal clinical course. A 47-year-old male patient was found to have a duodenal tumor and enlarged regional lymph nodes. The patient initially underwent a pancreaticoduodenectomy to resect the tumor and involved lymph nodes completely. Histological and immunohistochemical analyses showed findings typical of GP. However, the distant metastatic lesions in the liver and pelvic cavity were rapidly observed after surgery. The patient underwent chemotherapy and radiotherapy, as well as a second surgery to partly remove the metastatic mass in the pelvic cavity. The histological examination revealed no significant difference in histological features between the primary duodenal tumor and the metastatic pelvic mass. However, the patient finally died of the tumor due to the recurrence of the residual pelvic lesion and increased liver mass. To our knowledge, this is the first report of lethal GP with multifocal metastases. Our case confirms that GP should be regarded as a malignant potential tumor with behavior code of “1”, rather than a benign tumor of “0”.

Gangliocytic paraganglioma (GP) is a rare tumor, which occurs nearly exclusively in the second portion of the duodenum and is characterized by its triphasic cellular differentiation, consisting of epithelioid neuroendocrine cells, spindle-shaped cells with Schwannian cell differentiation, and ganglion-like cells[1]. Since this tumor was first described by Dahl et al[2], there have been no more than 200 cases reported in the literature in the world to date. According to the World Health Organization (WHO) classification, this lesion has been regarded as benign, but a few cases with regional lymph node metastasis and even distant metastasis have been reported. To the best of our knowledge, so far only 18 cases of GP with regional lymph node metastases[3-20] and two with bone or liver metastasis[21,22] have been described. Surprisingly, almost all patients with GP, including those having lymph node or distant metastasis, gain a good outcome without recurrence. Moreover, there is no record of a patient dying of GP although only one patient received irradiation intervention because of aggressive behavior of the tumor[12]. Herein, we report a unique case of this clinical entity in a middle-aged male patient. In contrast to previous cases, our case presents prominent aggressive biological behavior with regional lymph node, liver and pelvic cavity metastases. The patient died of GP finally after radiotherapy and chemotherapy. This is the first presentation of a malignant clinical course and poor prognosis of GP. The literature on this rare tumor is reviewed and its clinicopathological characteristics are discussed.

GP has been known as a rare and benign neuroendocrine tumor. It was first described as “duodenal ganglioneuroma” in 1957 by Dahl et al[2]. In that case, only a very small marginal area of epithelioid cells was found, where the greatest portion of the lesion was a ganglioneuroma and the authors classified it as such[2]. In 1962, Taylor et al[23] described a group of unusual polypoid tumors in the duodenum which they called “benign nonchromaffin paragangliomas”, mostly because they found the nests of epithelioid cells to be indistinguishable from the “Zellballen” of carotid body tumors and other chemoreceptor structures. In 1971, Kepes and Zacharias[24] suggested the term of “gangliocytic paraganglioma” for those duodenal lesions, because these tumors had light and electron microscopic features seen in paragangliomas as well as ganglioneuromas, indicating a transitional or hybrid form of tumor between gangliocytomas and nonchromaffin paragangliomas. In 1989, WHO accepted GP as a new entity of benign tumors of “neurogenic tumors” because of its distinct morphological and clinical characteristics[25]. However, the 3^rd edition[26] and the latest edition (4^th edition)[1] of the WHO classification revised GP to “endocrine tumor” and “neurodendocrine neoplasm”, respectively, which further emphasized neuroendocrine differentiation of the tumor.

GPs have been regarded as benign in general, but a few cases showing lymph node metastasis are well known which required extensive surgical removal and adjuvant radiotherapy[7,12,13]. However, the penetrative growth pattern of the tumor and even lymph node metastasis are not indicative of aggressive behavior or malignancy. Unlike previously reported cases, our case was characterized clinically by multifocal distant metastases and a rapidly aggressive clinical course. The patient died of the disease after surgical resection, chemotherapy and radiotherapy. To our knowledge, this is the first case of lethal GP with a malignant clinical course, but without obvious histological atypia of all three elements of the tumor, and high mitotic figures or proliferative index. We have compared the histological difference between the primary tumor of the duodenum and the metastatic pelvic mass in the present case, and tried to establish the histological prognostic indicators of malignant GP. However, the cytological bland spindle cells along with mild atypia of epithelioid cells were observed in both masses. No necrosis or high mitotic activity was found in tumors, which was consistent with all of reported GPs, even those with lymph node or distant metastasis. Our findings indicate that histological evaluation has limited prognostic value in GPs. We postulated that some important factors are involved in the process of GP invasion and metastasis, which cannot bring obvious morphological changes but indeed induce aggressive biological behavior, and result in the discrepancy between malignant clinical course and pathological findings. Further molecular or cytogenetic analysis is needed to elucidate the related mechanisms.

Although most of GPs exhibited good outcomes, our case suggested that it should not be considered as a benign tumor. Because of its potentially metastatic behavior, we prefer to label GP as a tumor with “uncertain malignant potential”, at least for those with evidence of lymph node and/or distant metastasis. The behavior code of the tumor is probably best to be regarded as “1 (unspecified, borderline or uncertain behavior)”, rather than as “0 (benign)”. We focused on the significant factors associated with the malignant behavior of the tumor in previously reported cases. To date, there have been no more than 200 cases of GP reported in the literature in the world, but only 20 bona fide cases reported as GP with regional lymph node metastasis or distant metastasis (Table 1). The primary tumors of GP were usually large (> 2 cm in diameter), relatively well-circumscribed, had an infiltrative growth margin and frequently extend into the muscularis propria. However, almost all patients showed good outcomes without recurrence. Indeed, only one patient required additional surgical intervention due to a residue of the tumor at her first endoscopic procedure[13], one patient has been reported as showing a recurrence due to a residue of a previous tumor at his initial surgical intervention[7], one patient received radiotherapy after surgical intervention[12], and two patients had distant liver and bone metastasis, respectively[21,22]. GP patients with metastasis have extremely good prognosis with long survival periods (6 mo to 11 years), and there was no record of a patient dying of GP to date except for our presenting case. Furthermore, despite of metastatic locations, the neoplastic elements of GP in metastatic foci were not observed to influence the prognosis of the patients, although epithelioid component sometimes exhibited as the sole element in metastatic foci[3,5,6]. Some researchers tried to establish the immunohistochemical prognostic indicators of GP using bcl-2, p53, and Ki-67, which were acceptable prognostic indicators in several kinds of neuroendocrine tumors. However, bcl-2 and p53 showed negative reactivity in all of reported cases[15,27], and Ki-67 labeling index value was extremely low either in primary tumors or in metastatic tumors. Therefore, the immunohistochemical evaluation using these markers may have limited prognostic value in GPs at present.

Patients with GP usually have favorable prognosis when they receive total resection, although a residual mass can recur after a long time[7]. At present, no chemotherapy was advised due to the rarity of distant metastases and the lack of response of this tumor to conventional systemic therapy. The present case was also not responsive to conventional chemotherapeutic regimens, such as cyclophosphamide and vincristine, which were associated with response rates of 50%-55% for malignant paraganglioma. A few cases had been described to apply radiotherapy for the lesions that had regional lymph node metastasis, but the efficacy of treatment was difficult to ascertain[12]. Recent reports suggested that radiotherapy might be effective in the management of locally advanced malignant paraganglioma when used in conjunction with radionuclide therapy (¹³¹I-MIBG), but they have not been used in GP treatment yet. Some authors suggested that the presence of lymph node and liver metastases should not result in over-treatment as such behavior was not necessarily fraught with a bad clinical outcome[22]. So far there have been no acceptable prognostic factors for malignant GPs. But complete resection of the tumor combined with adjuvant chemo- or radiotherapy is suggested to apply for GP patients with lymph node and/or distant metastasis to avoid the potentially rapid progression of the disease. Of course, more effective chemotherapeutic regimens and long-term careful follow-up are necessary for these patients.

In conclusion, we report a rare case of duodenal GP with regional lymph node and distant metastases occurring in an adult patient. In contrast to previously reported GPs with metastasis, our presenting case exhibits marked malignancy with a rapid aggressive clinical course. The patient finally died of GP after surgery, chemotherapy and radiation intervention, which has not been previously described. To our knowledge, this is the first case of lethal GP with multifocal metastases. Despite the lack of acceptable prognostic indicators for GPs at present, especially for those with regional lymph node and/or distant metastasis, our case indicates that GP is indeed a tumor with uncertain malignant potential. We suggest adjuvant therapies for the patients with metastasis after complete excision of the tumor, although the consensus on the adjuvant chemotherapy and/or radiotherapy for this tumor has not been reached yet.