Multiple paragangliomas: a case report

Pavlov et al. BMC Medical Genomics 2020, 13(Suppl 8):125 https://doi.org/10.1186/s12920-020-00789-8 CASE REPORT Open Access Multiple paragangliomas: a case report Vladislav S. Pavlov1†, Dmitry V. Kalinin2†, Elena N. Lukyanova1, Alexander L. Golovyuk2, Maria S. Fedorova1, Elena A. Pudova1, Maria V. Savvateeva1, Anastasiya V. Lipatova1, Zulfiya G. Guvatova1, Andrey D. Kaprin3, Marina V. Kiseleva3, Tatiana B. Demidova4, Sergey A. Simanovsky4, Nataliya V. Melnikova1, Alexey A. Dmitriev1, George S. Krasnov1, Anastasiya V. Snezhkina1* and Anna V. Kudryavtseva1 From 11th International Young Scientists School “Systems Biology and Bioinformatics” – SBB-2019 Novosibirsk, Russia. 24-28 June 2019 Abstract Background: Carotid and vagal paragangliomas (CPGLs and VPGLs) are rare neoplasms that arise from the paraganglia located at the bifurcation of carotid arteries and vagal trunk, respectively. Both tumors can occur jointly as multiple paragangliomas accounting for approximately 10 to 20% of all head and neck paragangliomas. However, molecular and genetic mechanisms underlying the pathogenesis of multiple paragangliomas remain elusive. Case presentation: We report a case of multiple paragangliomas in a patient, manifesting as bilateral CPGL and unilateral VPGL. Tumors were revealed via computed tomography and ultrasound study and were resected in two subsequent surgeries. Both CPGLs and VPGL were subjected to immunostaining for succinate dehydrogenase (SDH) subunits and exome analysis. A likely pathogenic germline variant in the SDHD gene was indicated, while likely pathogenic somatic variants differed among the tumors. Conclusions: The identified germline variant in the SDHD gene seems to be a driver in the development of multiple paragangliomas. However, different spectra of somatic variants identified in each tumor indicate individual molecular mechanisms underlying their pathogenesis. Keywords: Multiple paragangliomas, Carotid and vagal paragangliomas, SDHx, Germline and somatic mutations, High-throughput exome sequencing, Immunohistochemistry, Case report Background Paragangliomas of the head and neck (HNPGLs) are rare neuroendocrine tumors [1]. There are several common paraganglioma localizations corresponding to the locations of paraganglia from which they are formed. Carotid paragangliomas (CPGLs) are most common, followed by middle ear paragangliomas, vagal (VPGL), and laryngeal paragangliomas [2]. These tumors are highly hereditary * Correspondence: † Vladislav S. Pavlov and Dmitry V. Kalinin contributed equally to this work. 1 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova str, Moscow 119991, Russia Full list of author information is available at the end of the article and associated with the germline mutations in known susceptibility genes, including SDHx, SDHAF2, TMEM127, MAX, and others [3]. Mutations in these genes predispose to different forms of paragangliomas (early, syndromic, multiple, and malignant). HNPGLs commonly develop as single unilateral tumors, with only 1% of sporadic cases being multiple [4]. However, the number of multiple HNPGLs greatly increases in familial tumors. As multiple paragangliomas are rare, every case is important to study for a better understanding of genetics and molecular mechanisms causing their initiation and progression. © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Pavlov et al. BMC Medical Genomics 2020, 13(Suppl 8):125 Case presentation The case below describes multiple paragangliomas diagnosed in a Russian woman, presenting as two CPGLs at both sides of the neck and one VPGL. The aim of the study was to investigate the molecular mechanisms underlying the development of multiple paragangliomas by examining clinical and pathological characteristics along with the genetic variations of the three tumors. A 50-year-old female was diagnosed with extravascular compression of the carotid arteries and CPGLs on both sides of the neck. Clinical symptoms include arterial hypertension and painless rounded masses. Computed tomography (CT) and ultrasound (US) study revealed the presence of tumors in the areas of the carotid bifurcation, solid neoplasia 32 × 25 mm on the left side of the neck and two-nodal tumor 46 × 24 mm on the right side of the neck, respectively. These neck masses were heterogeneous in structure and predominantly hypoechoic and hypervascular. The CT study with contrast also revealed the presence of hypointense, highly vascularized masses at the right and left carotid bifurcations (Fig. 1). The patient was subjected to surgery for the left tumor resection. At the time of surgery, the lower pole of the hypervascularized tumor was located below the outer carotid artery (OCA) bifurcation, spreading along the carotid arteries in the proximal direction and wrapping around the posterior, anterior, and lateral surfaces. Bifurcation of carotid arteries was involved in the tumor mass. The upper pole of the tumor was associated with the vagus nerve. The tumor (25 × 2 × 17 mm) was completely removed and subjected to pathological evaluation. The patient was discharged with a planned re-hospitalization to Page 2 of 6 remove the tumor on the right. Histological examination of the resected tumor confirmed carotid paraganglioma (Fig. 2). Hematoxylin-eosin (H&E) staining showed a Zellballen structure that is typical for paragangliomas. Chief tumor cells exhibited positive staining for chromogranin A, synaptophysin, and CD56 antibodies indicating a neuroendocrine tumor. S100 protein was expressed in sustentacular cells. Tumor cells were negative for cytokeratin AE1/AE3. A surgery on the right side of the neck was performed after a year. As per the US study reports, VPGL and enlarged lymph node were primarily detected. During the surgery, lymph node (15 × 5 mm) above the carotid artery bifurcation was removed and further subjected to histological examination for metastases. (...truncated)