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Hindawi Case Reports in Oncological Medicine Volume 2021, Article ID 8856167, 6 pages https://doi.org/10.1155/2021/8856167 Case Report Metastatic Malignant Paraganglioma Presenting as a Neck Mass Treated with Radiolabeled Somatostatin Analog 1 2 2 3 Waqas Jehangir , Alexander Karabachev, Jackie Tsao, Christopher J. Anker, 4 5 1 Sree Susmitha Garapati, Janusz K. Kikut, and Hibba Tul Rehman University of Vermont Medical Center, Hematology and Medical Oncology, 89 Beaumont Ave. Burlington, VT 05405-0068, USA University of Vermont College of Medicine, Larner College of Medicine, 89 Beaumont Ave. Burlington, VT 05405-0068, USA University of Vermont Medical Center, Radiation Oncology, 89 Beaumont Ave. Burlington, VT 05405-0068, USA University of Vermont Medical Center, Endocrinology Diabetes & Metabolism, 89 Beaumont Ave. Burlington, VT 05405-0068, USA University of Vermont Medical Center, Radiology, 89 Beaumont Ave. Burlington, VT 05405-0068, USA Correspondence should be addressed to Waqas Jehangir; firstname.lastname@example.org Received 9 May 2020; Revised 1 March 2021; Accepted 4 May 2021; Published 8 June 2021 Academic Editor: Raﬀaele Palmirotta Copyright © 2021 Waqas Jehangir et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Paragangliomas are rare neuroendocrine tumors that arise from chromaﬃn-containing tissue. Surgical resection and/or radiation are used for locoregional disease, and reduction of tumor burden with systemic therapy is reserved for metastatic disease. Iobenguane I-131, somatostatin analog (octreotide), and Sunitinib are noncytotoxic options for treatment, while cyclophosphamide, vincristine, and dacarbazine (CVD) and temozolomide are often used as initial chemotherapy options as studies have shown that they oﬀer some tumor response. However, there are no randomized clinical trials demonstrating prolonged survival with the use of chemotherapeutics in metastatic cases. Investigation of alternative therapies that provide survival beneﬁt is thus necessary. We present a case of a 69-year-old female with metastatic malignant paraganglioma presenting as a left parapharyngeal neck mass, which metastasized after surgery, requiring radiation therapy for bony metastasis who was treated with a radioisotope somatostatin analog for disease progression. 1. Introduction mediastinum and may cause pain, hoarseness, and dysphagia secondary to a mass eﬀect on surrounding structures . Para- Paragangliomas and pheochromocytomas are rare neuroen- sympathetic paragangliomas are often benign but locally invasive. Surgical resection remains the standard therapy as docrine tumors that arise from chromaﬃn-containing tissue. The combined prevalence of these tumors lies roughly paragangliomas tend to respond poorly to chemotherapy between 1 : 6500 and 1 : 2500 with an annual incidence of and radiation . 500-1600 cases per year in the United States . Sympathetic Though typically benign, parasympathetic paraganglio- paragangliomas arise from chromaﬃn cells along the sympa- mas can become malignant and metastasize. Because spread thetic chain in the chest, abdomen, and pelvis, and pheochro- is rare, there is currently no standard treatment for metastatic mocytomas arise from similar cells in the adrenal glands. malignant paragangliomas. Cyclophosphamide, vincristine, These two types of tumors are known to synthesize and and dacarbazine (CVD) are often used as initial chemother- release catecholamines, which can cause severe hypertension, apy as studies have shown that they oﬀer some tumor palpitations, stroke, and possibly death. By contrast, parasym- response . However, there are no randomized clinical pathetic paragangliomas are typically nonfunctional and do trials demonstrating prolonged survival with the use of che- not produce symptoms associated with catecholamine hyper- motherapeutics in metastatic cases . Investigation of alter- secretion. They instead are usually space-occupying lesions native therapies that provide survival beneﬁt is thus derived from parasympathetic nerves in the head, neck, or necessary. We present the case of a 69-year-old female with 2 Case Reports in Oncological Medicine metastatic malignant paraganglioma who was treated with a somatostatin analog for widespread disease refractory to sur- gery, radiation, and targeted therapy. 2. Case Presentation A 69-year-old female with no smoking history or family his- tory of paragangliomas or other neuroendocrine tumors ini- tially noted discomfort in her left neck in 2007 which was 46.08 m thought to be related to a cervical disk pathology; however, 31.73 m by March 2010, her symptoms had persisted and then she had laryngitis for about 5 weeks. She was seen by her doctor who could not hear her left carotid, and she was also noted to have a grayish appearance. A left tonsillar lesion was noted, which was felt to be secondary to medial disposition of the tonsil from some extrinsic compression. A mass was noted at the left angle of the jaw in level 2. She was prescribed anti- biotics; however, they did not improve her symptoms and vascular surgery was consulted. A CT angiogram of the neck was performed in 2010. Contiguous axial CT images were Figure 1: CT neck showing encasement and marked narrowing of obtained of the neck using 80 mL of Isovue-370 IV contrast the left cervical internal carotid artery. followed by 60 mL of normal saline infused at 6 mL/seconds. A 4:6×3:2×5:5cm heterogenous attenuation, hypervascular mass appearing to arise from the left retrostyloid parapharyn- geal space was most consistent with a paraganglioma, likely globus vagale. Encasement and marked narrowing of the left cervical internal carotid artery were noted (Figure 1). MRI was performed which further demonstrated a large left cervical mass causing markedly diminished signal in the cervical left internal carotid artery likely representing dimin- ished ﬂow due to compression by the mass. Prior to surgery, she was put on alpha and beta blockade. She underwent 17.36 mm embolization as well as excision of the tumor by a combina- 20.09 mm tion of transcervical and transoral approaches with lip and mandibular split. Her tumor was encroaching the left jugular foramen with a persistent tumor evident extending up to the jugular foramen at the termination of the procedure, despite intentional sacriﬁce of the cranial nerves 9, 10, and 12, given their relationship to the tumor. There was a small portion of the residual tumor that could not be resected at the superior portion of the jugular foramen. The pathology showed an extra-adrenal pheochromocytoma (paraganglioma) from the left carotid space, superior to the carotid bifurcation. Immunohistochemical staining was positive for chromogra- nin, synaptophysin, and S-100 and was faint for glial ﬁbril- Figure 2: MRI of the neck with and without contrast showing a lary acidic protein (GFAP). It measured 4:3×3:8×2:5cm mass lesion centered within the left jugular foramen, appearing positive lymphovascular invasion, the mitotic rate is 1/10 mildly increased in size. The size was 20 mm in maximal high-power ﬁeld, and necrosis was present, likely due to dimension as opposed to 17 mm compared to previous imaging 6 embolization. The margins were positive. She was on surveil- months prior. lance after surgery. Since her surgery, sequential MRI scans of the brain showed a slowly progressive recurrence. Surgery was not rec- opposed to 17 mm compared to previous imaging 6 months ommended due to potential morbidity. In 2015, she under- prior (Figure 2). A CT scan of the chest showed scattered went stereotactic radiosurgery at a dose of 15 Gy to the left noncalciﬁed pulmonary nodules. The largest was noted to paraganglioma. In 2016, MRI of the neck with and without be in the right middle lobe, demonstrating no discernible contrast revealed a mass lesion centered within the left jugu- growth based on the volumetric analysis compared to previ- lar foramen, appearing mildly increased in size with an ous imaging. Her PET/CT revealed FDG uptake in the right unchanged mild mass eﬀect upon the adjacent left cerebellar middle lobe pulmonary nodule. She was also found to have hemisphere. The size was 20 mm in maximal dimension as FDG uptake within bony lesions involving T3, T7, L3, and Case Reports in Oncological Medicine 3 SS I I Figure 3: MRI of the thoracic and lumbar spine showing multiple osseous lesions. the T1 transverse process consistent with metastasis. FDG uptake was noted within the biopsy-proven left jugular fora- men paraganglioma. She underwent CT-guided FNA of a 6 mm right middle lobe lesion which revealed neoplastic, low-grade tumor, favoring a neuroectodermal tumor, and after discussion in MDC, it was concluded that her paragan- glioma disease was likely metastatic to the lung and spine. She underwent stereotactic ablative radiation therapy to the T7 and T3 paraganglioma metastasis to the spine to a dose of 1600 cGy. In 2017, she had a T4 vertebral body biopsy and kypho- plasty for her back pain secondary to metastasis. In the fall of 2017, she was found to have a compression fracture and underwent T3 vertebroplasty with improvement in pain. Her MRI of the thoracic and lumbar spine showed multiple osseous lesions (Figure 3). It also showed metastatic disease including the stable lung nodule which was biopsied and mild degenerative disc disease. In January 2018, CT of the chest abdomen pelvis showed stable disease (T3 and T7). CT of the neck showed stable disease in the left jugular fora- men. In the spring of 2018, she was diagnosed with a T8 com- pression fracture and underwent T8 vertebroplasty. She was Figure 4: PET/CT GA-68 dotatate scan showing multiple scattered started on monthly denosumab. In the fall of 2018, CT chest metastatic lesions to the spine with subtle increase in size and showed stable lung nodules and CT abdomen pelvis showed conspicuity of a few sacral and lumbar lesions. mixed sclerotic and lytic lesions at L1 and L3 with increased compression of the left side of the superior endplate of L3 since the prior CT. MRI showed that the metastatic lesions is expected to delete the last 37 amino acids of the SDHC pro- in the L-spine were slightly larger without any new lesions. tein. This variant has been reported in several individuals with Soft tissue mass in the left jugular foramen appears to be paragangliomas [7–10]. stable without any cervical lymphadenopathy; however, Her case was discussed with local and national experts, there was a concern of C3 metastatic lesion and metastatic and it was recommended to get a gallium 68 dotatate PET lesions in the thoracic spine that also increased in size. She scan (as MIBG is not helpful after the lesions have been radi- was referred for genetic testing, and the results came back ated). She underwent a PET/CT GA-68 dotatate scan in the spring of 2019 which revealed multiple scattered metastatic positive for a mutation in SDH-C, c.397C>T (p.Arg133∗), which is associated with autosomal dominant hereditary lesions to the spine with subtle increase in size and conspicu- paraganglioma-pheochromocytoma syndromes, gastrointes- ity of a few sacral and lumbar lesions (Figure 4). She was tinal stromal tumors, and renal cell carcinoma . This started on lutetium 177 dotatate (Lu 177), a radiolabeled sequence results in a premature translational stop signal in somatostatin analog, in April 2019 and received a half dose in the ﬁrst cycle due to concerns around catecholamine the penultimate exon of the SDHC mRNA at codon 133 which 4 Case Reports in Oncological Medicine storm. She had borderline elevated 24-hour urine meta- nephrine and mildly elevated norepinephrine and dopamine level on plasma catecholamine fractionation and was treated with alpha and beta blockade prior to Lu-177 treatment. Other labs performed prior to treatment include a basic met- abolic panel which was all within normal limits, liver func- tion tests which were within normal limits, a complete blood count with a hemoglobin of 10.2 gm/dl, normal platelet count of 368 K/cmm, and normal white blood cell count of 4.82 K/cmm. Her folate was elevated at 24 ng/ml. She toler- ated the ﬁrst cycle and received the full second dose in June 2019. A follow-up PET/CT GA-68 dotatate scan in Decem- ber 2019 showed a modest response to therapy with no new lesions identiﬁed while previously these lesions had been pro- gressively getting worse (Figure 5). During the most recent oncology follow-up visit in February 2020, the patient reports some continued fatigue that is beginning to improve. 3. Discussion Paragangliomas have varied clinical presentations depend- ing on tumor location and size, catecholamine secretory function, and extent of spread . Biochemical testing is Figure 5: PET/CT GA-68 dotatate scan showing a modest response encouraged even for patients who do not exhibit symptoms to therapy with no new lesions identiﬁed. associated with catecholamine hypersecretion. Catechol- amines are metabolized into metanephrines (normetanephr- ine, metanephrine) in chromaﬃn cells. In tumors, this The combination of CVD as an initial chemotherapy reg- process occurs independently of catecholamine release. imen was shown to improve symptoms for patients as well as Diagnosis involves 24 h urine collection to assess for the have a high response rate with a median survival of 39 presence of fractionated metanephrine and catecholamines. months after initiating treatment . However, a study in Several studies have demonstrated that measurement of uri- 2008 by Huang et al. evaluated eighteen patients 22 years nary metanephrines allows for greater diagnostic sensitivity after treatment with CVD for malignant paraganglioma. than measurement of serum metanephrines . Histological They reported that the overall survival of patients who had studies are then performed for deﬁnitive diagnosis . a positive response to CVD did not diﬀer from patients A diagnosis of malignant paraganglioma requires the pres- whose disease remained stable or even progressed after treat- ence of metastasis . Patients with metastatic involvement ment. An improvement in symptoms was noted when tumor have an estimated 5-year survival of <50% . Malignant dis- shrinkage occurred concluding that CVD may be an option ease is diﬃcult to treat because metastatic paragangliomas are to manage symptoms in patients and also for patients where often refractory to chemotherapy and radiation and recur- tumor shrinkage may make surgical resection an option [4, 5]. rence is common. A lifelong follow-up is strongly encouraged. Currently, no chemotherapy regimen has been shown to pro- Iobenguane I-131, somatostatin analogs (e.g., octreotide), and long survival for metastatic paraganglioma. Sunitinib are targeted options for treatment, while cyclo- Radionuclide therapy may be an option for symptom pal- phosphamide, vincristine, and dacarbazine (CVD) and tem- liation and tumor regression or stabilization. The eﬀective- ozolomide are often used as initial chemotherapy options as ness of this treatment is largely dependent on whether the studies have shown that they oﬀer some tumor response tumor takes up MIBG or somatostatin analogs that the [13–18]. Patients with rapid disease progression are usually beta-emitting isotopes are coupled to. This is evaluated using treated with chemotherapy or temozolomide, while patients Iobenguane I-131 scintigraphy for MIBG or PET imaging with slow to moderate disease progression are treated with using gallium-68-labeled somatostatin analogs [20, 21]. Our radiolabeled therapies. CVD is the recommended option for patient had positive uptake with the PET/CT GA-68 dotatate rapidly progressive metastatic disease, and the speciﬁc regi- scan and was therefore started on lutetium 177 dotatate (Lu men includes a 21- to 28-day cycle of cyclophosphamide 177), a radiolabeled somatostatin analog. It is likely that the 2 2 750 mg/m and vincristine 1.4 mg/m on day 1 and dacarba- increased accuracy of the PET/CT GA-68 dotatate scan is zine 600 mg/m on day 1 and 2 . For the SDH-B mutant, due to the SDH-C deﬁcient status of the patient. In addition CVD is the initial treatment choice while metronomic tem- to paragangliomas, gastrointestinal stromal tumors, and ozolomide is recommended for patients that do not tolerate renal cell carcinoma, SDH mutations have been shown to be related to pituitary tumors [6–10, 22]. the alkylating agents. 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