Multiple organ resection for large paraganglioma − a case report

Summary

Paragangliomas represent a group of neuroendocrine tumours which occur in various localizations. Most of them produce catecholamines, and in advanced cases present with typical symptoms and signs such as palpitations, headache and hypertension. The only curative treatment is radical resection. About one-quarter of paragangliomas are malignant, defined by the presence of distant metastases. There are multiple treatment options for unresectable metastatic tumours. They include radionuclid therapy, chemotherapy, and radiotherapy, although none of them are curative. Cytoreductive surgery can also be considered, especially when the goal is to decrease symptoms related to advanced disease. We present a rare case of a large paraganglioma of the left retroperitoneum. Despite radical surgery, early recurrence of the disease was observed. 

Keywords:

paraganglioma – neuroendocrine tumours – multiple organ resection – surgery – oncology

Introduction

Paragangliomas are rare, mostly benign neuroendocrine tumors, characterized by a high morbidity rate due to catecholamine excess. The most common symptom is arterial hypertension, which may be associated with severe cardiovascular complications. Occurrence is generally sporadic, but approximately one-fourth of cases are related to the hereditary syndrome [1]. The incidence of these rare tumors is 0.8/100 000 patients per year [2]. They may occur at all ages, with the highest incidence between 40 and 50, with approximately equal sex distribution. Paragangliomas may arise from ganglias in various localizations. If a tumor arises in the adrenal medulla, it is called pheochromocytoma, which in practice represents an intra-adrenal sympathetic paraganglioma. These usually secrete metanephrines. However, several other extra-adrenal sites of involvement have been recognized. Such tumours are called extra-adrenal paragangliomas, which consist of two main subtypes - paraganglia distributed along sympathetic nerves in the retroperitoneum, thorax and pelvis, or paraganglia distributed along parasympathetic nerves in the head, neck and mediastinum. These secrete normetanephrines. Diagnostic work-up includes detection of catecholamines in plasma or in 24-hour urine test and imaging [3]. 

Case report

A healthy 59-year old male patient was diagnosed with a massive bilateral pulmonary embolism with cor pulmonale due to deep vein thrombosis in the left leg. He was treated with low molecular heparin first, then peroral anticoagulant (pradaxa). On CT scanning, a solid lobular formation in the left subphrenic space measuring 96×65×70 mm was identified (Fig. 1). Another accidental finding was polycythemia in blood tests. Tumour markers were negative. A PET/MRI was performed. There was a huge mass 100×70 mm in the left retroperitoneum above the kidney, with paraaortal lymphadenopathy. This finding was very suggestive of lymphoma. A biopsy from this mass was indicated. Histological examination proved that it was not lymphoma but more likely paraganglioma/pheochromocytoma. Genetic examination showed no mutation. During this period the patient developed paraneoplastic signs: hard-to-correct hypertension (treated with a combination of four antihypertensive drugs), sweating, and palpitations. His case was presented at the multidisciplinary board. Due to the severity of his symptoms, surgical treatment was indicated. Due to the large tumour mass, we had to perform an open distal splenopancreatectomy, a left colectomy with a colostomy, a left nephrectomy and an adrenalectomy en bloc to obtain macroscopic R0 resection (Fig. 2). The procedure took 280 minutes, with a blood loss of 1000 ml. The resected specimen can be seen in Fig. 3a-c. In the postoperative course there were several complications due to this extensive multi-visceral resection. A pancreatic fistula was treated by somatostatin. One particular specific complication was caused by upper gastrointestinal malfunction presented as repeated vomiting and no toleration of oral intake. Gastroscopy found esophagitis without any other cause of GI malfunction. Even though the patient was fitted with a nasogastric tube, there was a large amount of gastric juices present, so we decided to perform a surgical revision. During surgery, we found postoperative adhesions on the small bowel and the stomach adhering to the left retroperitoneum. Consequently, we were forced to construct an anterior gastroenteroanastomosis. Following this procedure, the patient finally started to tolerate oral intake. He was discharged with no other complications. Histological examination of specimens confirmed paraganglioma of the adrenal gland with satellite cells in the lymph nodes (Fig. 4 and Fig. 5a-d). Due to the lack of data concerning adjuvant therapy, we decided for close follow-up. Subsequent PET/MRI imaging revealed early recurrence of the disease and palliative chemotherapy with Cyclophosphamide, Vincristine and Dacarbasin was initiated (CVD). The next PET/MRI was planned after 3 cycles of CVD. Unfortunately, significant disease progression was observed. An octreoscan revealed somatostatin receptor positivity of the metastatic lesions and Lanreotide was indicated as a second line of palliative treatment. Despite this therapy, the disease progressed further and the therapy was not associated with a survival benefit. The length of survival was 14 months after surgery.

Discussion

Paragangliomas are usually benign, but about 10% of cases can be malignant [4]. Extra-adrenal paragangliomas can spread aggressively and invade the surrounding structures, including bones. Lymph node infiltration and the development of distant metastases has also been described. However, in rare cases, even pheochromocytoma can develop potentially lethal behaviour due to extensive local infiltration into adjacent organs and blood vessels. The only reliable feature to this date, confirming pheochromocytoma as a malignant tumour, is the presence of metastases. Several other criteria and their combinations were considered, but no other single histologic feature is uniquely able to identify the tumour developing malignant behaviour [5]. These criteria included features applicable in other tumours such as capsular and vascular invasion, nuclear atypias and cellular pleomorphism, increased mitotic figures, necrosis and others. Scoring systems were also applied [6], but none is universally accepted at present. Therefore, proof of metastases remains the only certain marker of malignant behaviour in paragangliomas. Even though the anatomical distribution can vary, the histological features usually tend to be identical for these neoplasms with only slight differences. We usually find an organoid pattern typical of the normal paraganglion, which is composed of a “Zell-Ballen” architecture, but a trabecular or spindled morphology is also possible. There are two types of cells forming the tumour – main cells with pale eosinophilic cytoplasm and a slightly atypical nucleus and sustentacular cells, which are inconspicuous in standard H&E staining. Tumour nests tend to be apolar and separated with a prominent vascular network, which is often embedded in a hyalinized stroma. The main cells can be stained using the immunohistochemical markers synaptophysin and/or chromogranin-A and sustentacular cells are positive for S100 protein and GFAP. In treatment, it is important whether symptoms are due to the secretion of catecholamines. In the absence of catecholamine production, the symptomatology of re­troperitoneal tumours is non-specific and the diagnosis is therefore often random or late. Paragangliomas are most often formed from paraaortic nerve plexuses (71%), which was also a probable localization in our patient, although the origin may be difficult to determine accurately in such large tumors [7]. Gene mutations are found in approximately one-third of patients with paraganglioma and are important in determining the prognosis or any change in treatment. Since 2014, the guidelines of the Endocrinological Society in the USA have recommended genetic testing of all patients with paragangliomas as well as members of the family [8]. For localized pheochromocytomas and paragangliomas, radical resection is the preferred approach [9]. No data on the prognostic role of radical surgery and lymphadenectomy are available for malignant pheochromocytomas [10]. Adjuvant therapy is not recommended as there is a lack of evidence. Thus, surgical treatment remains the main treatment modality for both primary and recurrent paraganglioma. It is also recommended as a cytoreductive approach in patients with metastatic disease, especially in cases of hormonally active tumours [11]. Curative surgery requires an en bloc/compartmental resection, dissecting safely outside of the tumour at all time. The same applies to the cytoreductive surgery, if possible. Invading the tumour always leads to quicker tumour progression. However, neither approach ensures a cure as shown in our case.

Adequate preoperative preparation is important to prevent a severe hypertensive reaction during the procedure. Successful surgeries are reported even for very large lesions exceeding 20 cm in diameter [12]. Of course, bulky malignant variants of paragangliomas are difficult to treat with an R0 resection. However, surgery can be combined with other procedures to achieve local control of the disease. It is uncertain whether postoperative radiotherapy can reduce local recurrences after an R1 resection. In case of clinical manifestation of recurrence, radiotherapy offers the possibility of good local control stopping further growth. The effect of stereotactic radiotherapy on metastatic foci of paragangliomas is debatable [13]. In contrast, very good results using radiofrequency ablation have been published in cases of PGL metastatic lesions. In 86% of patients, the achievement of both local control and the disappearance of symptoms resulting from catecholamine production were reported [14]. The extent of the disease required multivisceral resection, including resection of the pancreas, which increases the risk of postoperative complications. In the analysis of the results of multivisceral resections for pancreatic tumors, Petrucciani published a meta-analysis reporting postoperative morbidity in 56%−69%, and postoperative mortality in up to 10% of cases [15]. Our patient also experienced serious postoperative complications, which also had a negative effect on his ability to undergo subsequent oncological treatment and possible invasive procedures for local control of metastatic liver disease. A wait-and- see strategy is possible for patients with advanced disease, particularly in asymptomatic patients with a low-volume tumour burden. Treatment of progressive or high-volume disease includes systemic therapy, nuclear medicine, and locoregional therapy, such as transarterial chemoembolisation. A cytoreductive R2 resection (with macroscopic residuum) may also improve the quality of life and survival by controlling catecholamine hypersecretion after reduction of the tumour burden [16]. Currently, only limited cytostatics are known which benefit patients with malignant pheochromocytoma and paraganglioma. Moreover, prospective randomized phase II and III trials are still not available. The most frequently studied chemotherapeutic regimens are based on a combination of cyclophosphamide, vincristine and dacarbazine (CVD) ± doxorubicin (CVDD or CDD) and they have shown a clinical benefit in terms of normalisation of blood pressure, decreased dosages of antihypertensive medication and tumour regression in 33% of patients. However, the largest published trial to date included just 52 patients [17]. Approximately 50% of patients had a positive uptake and therefore ¹²³I-MIBG (metaiodobenzylguanidine) should be considered in any first line of treatment. To add, an overall response rate was observed in 22−47% of patients [18]. PRRT (peptide receptor radionuclide therapy) is another possible treatment which can be useful in patients with advanced and progressive disease. This approach can improve overall survival and quality of life [19]. 

Conclusion

We present a rare case of a large paraganglioma of the left retroperitoneum. Radical surgical resection was performed. Unfortunately, there was an early recurrence of the disease 6 months after surgery. Despite palliative oncological therapy, no significant survival benefit was achieved and the patient succumbed to a fulminant progression of the disease.

Conflict of interests

The authors declare that they do not have a conflict of interest in connection with this paper and that the article has not been published in any other journal, except congress abstracts and clinical guidelines.

Lumir Kunovsky, M.D., Ph.D.

Department of Surgery, University Hospital Brno,

Faculty of Medicine, Masaryk University

Jihlavska 20

62500 Brno

e-mail: kunovsky.lumir@fnbrno.cz

ORCID: 0000-0003-2985-8759