Carotid body tumor with neck metastasis due to germline SDHB variant: a case report and literature review

Abstract

Carotid body tumor involving the succinate dehydrogenase subunit B (SDHB) variant reportedly had a higher frequency of metastasis than other variants of succinate dehydrogenase. However, the correlation between genotype and phenotype among patients with carotid body tumor with SDHB gene variant remains unclear. Thus, we present a case of carotid body tumor with neck lymph metastasis caused by a novel SDHB variant, which resulted in long-term disease-free survival achieved after surgery. A 43-year-old man presented to our hospital with a 2-year history of a painless neck mass. Based on the radiographic findings, the patient was diagnosed with carotid body tumor with a possible Shamblin type III tumor. Another mass was detected and suspected to be a lymph node metastasis. The patient underwent resection of the tumor and lymph nodes. The common carotid artery, internal carotid artery, external carotid artery, internal jugular vein, vagal nerve, and hypoglossal nerve were resected with the tumor. Histopathological examination revealed a paraganglioma. The histological findings of the lymph nodes were similar to those of the carotid body tumor and were confirmed to be metastases of paraganglioma. To analyze the germline SDHx variant, a nonsense variant was detected in the SDHB gene at exon 2, c. 136C > T, p. Arg46*. During the follow-up 80 months after surgery, the patient exhibited no signs of recurrence, metastasis, or development of paragangliomas in other organs. This was the first case of carotid body tumor accompanied by neck metastasis caused by a germline nonsense SDHB variant at exon 2, c. 136C > T, p. Arg46*. Carotid body tumor with neck lymph metastasis caused by this nonsense variant could achieve long-term disease-free survival after surgery. Gene analysis, including SDHB variant, should be performed to predict the prognosis and future risk of metastasis. Genetic testing of SDHB may give a crucial information for the treatment and follow-up strategies of carotid body tumor.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13691-021-00522-x.

Introduction

A carotid body tumor (CBT) is a paraganglioma (PGL) from the carotid body accounting for approximately 60% of the head and neck PGLs [1]. The 4th edition of the World Health Organization criteria is used to classify malignant CBTs [1]. Most CBTs are slow-growing masses that do not invade or metastasize to surrounding organs. However, metastasis is observed in 4–6% of CBTs [1]. The treatment of malignant CBT is limited. The 5-year overall survival of patients with distant metastatic CBT is only 11% [1].

Various CBTs are hereditary diseases caused by genetic variants related to hereditary pheochromocytoma (PCC)/PGL. Most hereditary CBTs have genetic variants affecting the succinate dehydrogenase (SDH) subunits [1]. In regard to head and neck PGL, the majority with SDH germline mutation is SDHD and SDHC, followed by SDHAF2 and SDHB [1]. Among the genes encoding the SDH subunits (SDHx), SDHB variant was associated with the highest metastatic rate [1]. In contrast, multiple variants have been reported for SDHB gene. Recent studies have reported phenotypical differences such as the age of disease development among SDHB gene variants [2, 3]. However, the specific correlation between genotype and phenotype has not been fully elucidated.

We present a case of CBT with neck lymph metastasis caused by a novel SDHB variant as CBT, in which long-term disease-free survival was achieved after surgery.

Case report

A 43-year-old man with a 2-year history of a painless neck mass consulted our hospital. His medical and family histories were unremarkable for PGL. Physical examination revealed a non-tender, immobile, and hard left-sided neck mass. Left-sided vocal cord paralysis was observed on laryngoendoscope. Ultrasound imaging showed a hypoechoic mass with increased blood flow at the level of the carotid artery bifurcation. Computed tomography revealed a 4.8-cm contrast-enhancing mass, which encased the left common carotid artery (CCA) proximally and the internal carotid artery (ICA) and external carotid artery (ECA) distally (Fig. 1a). Another mass was detected and suspected to be lymph node metastasis (Fig. 1b). On magnetic resonance imaging, these tumors appeared hypo-intense on T1- and T2-weighted imaging and were enhanced by gadolinium. Flow voids were seen within the primary lesion (Fig. 1c). Carotid angiography revealed that the main feeders of the tumors were the external carotid and occipital arteries. The balloon occlusion test revealed adequate collateral flow from the opposite carotid artery, and no neurological symptoms were noted after the test. Based on these radiographic findings, the patient was diagnosed with CBT with a possible Shamblin type III tumor [4].

Fig. 1.

Preoperative radiographic imaging. Computed tomography shows a 4.8 cm mass (a) with lymph node metastasis outside of the tumor (b). Gadolinium-enhanced magnetic resonance imaging of the neck reveals an enhanced mass, completely encasing the left internal and external carotid arteries (c). A flow void is observed within the tumor (arrow)

The patient underwent tumor resection under general anesthesia. The CCA, ICA, ECA, internal jugular vein, vagal nerve, and hypoglossal nerve were resected en bloc with the tumor because they were completely encased by it. The CCA, ICA, ECA, internal jugular vein, vagal nerve, and hypoglossal nerve were firmly affixed to the tumor and completely encased by the tumor, and it was impossible to peel them from the tumor. Therefore, these vessels and nerves were resected en bloc with the tumor. The frozen section diagnosis of the preoperatively identified lymph node was a metastatic tumor. Therefore, the lymph nodes surrounding the tumor were simultaneously resected. After the resection, the ICA was immediately reconstructed using the greater saphenous vein graft. The vein was end to end anastomosed CCA and ICA. We performed a tracheostomy to prevent airway disturbance due to pharyngeal edema. After the surgery, there were no signs of neurogenic complications, except for the symptoms caused by resecting the vagal and hypoglossal nerves. He underwent laryngoplasty to improve voice phonation 7 months after the initial surgery.

Histopathological examination revealed the tumor size to be 4.8 × 2.6 × 2.2 cm³. The proliferation of oval and polygonal cells with slight atypia was observed on microscopic examination (Figs. 2a, b). The tumor cells formed cell nests and were surrounded by trabecular sustentacular cells. The adventitia of the ECA was invaded by the tumor, and lympho-vascular infiltration was observed. Immunohistochemistry showed that the tumor cells were positive for chromogranin A and synaptophysin, and the Ki-67 index was 2–3% (Fig. 2c). The SDHB immunohistochemistry results were negative. The tumor was histopathologically diagnosed as PGL. The histological findings of the lymph nodes were similar to those of the CBT and were confirmed to be metastases of PGL.

Fig. 2.

Histopathologic examination of the surgical specimen. Hematoxylin–eosin staining reveals that the tumor cells form cell nests and are surrounded by trabecular sustentacular cells (a low-power view; b high-power view). The percentage of Ki-67-positive nuclei is approximately 2–3% (c)

To analyze the germline SDHx variant, genomic DNA was extracted from the peripheral blood of the patient using GenElute™ Blood Genomic DNA Kit (Sigma-Aldrich #NA2020, Germany), and the exon of SDHB was analyzed by Sanger sequence (Additional file 1 presents the primer set for the sequence). A nonsense variant was detected in SDHB gene at exon 2, c. 136C > T, p. Arg46* (Fig. 3). The variant was found to be pathogenic (PVS1, PM2, and PM6) according to the American College of Medical Genetics and Genomics standards and guidelines criteria [5]. Germline mutation analyses of the patient’s family were not performed, because the patient did not wish.

Fig. 3.

Result of Sanger sequence analysis of SDHB exon 2 in the germline genome DNA. A nonsense variant at exon 2, c. 136C > T, p. Arg46* is detected in the present case

The patient exhibited no evidences of recurrence, metastasis, or development of PGLs in other organs during follow-up 80 months after surgery.

Discussion

At least one-third of CBTs have genetic variants including SDHD, SDHB, SDHC, and SDHAF2 [1], which are associated with tumorigenesis. The rate of metastasis was 4–6% in the whole CBT. The majority of SDHx variants in patients with CBT is SDHD variant; however, the risk of metastasis in CBT with SDHD variant is low [6]. Meanwhile, CBT involving SDHB variant reportedly had a higher frequency of metastasis than other SDHx variants [1], 6]. In previous reports, metastasis occurred in 23–50% of SDHB variants, whereas 4% of SDHD variants, 3% of SDHC variants, and low risk of SDHAF2 variants [1]. The differences in the frequency of metastases have not been explained by molecular genetics. However, Barbolosi et al. speculated that PGL with SDHB variants exhibited a more complex pattern and greater genomic instability, compared with the other variants. More genetic events can be accumulated at primary tumor development, thereby acquiring metastasis-promoting genetic events at a higher frequency than that of the other variants [7].

To the best of our knowledge, this was the first report of CBT with neck metastasis caused by a germline nonsense SDHB variant at exon 2, c. 136C > T, p. Arg46*. This variant had reportedly caused PGL in other organs, including the para-adrenal gland [8], Zuckerkandl [9], mediastinum [10], abdominal cavity [11–13], thoracic cavity [14–16], and vagal nerve [17]. The previous PGL cases with this variant are summarized in Table 1 [8–19]. Based on the summarized data, the metastatic rate of this nonsense variant was 50% (7/14 cases), which was similar to that of the whole SDHB variant (30–60%) [2, 20]. The rate of multiple PGLs with this variant was 17% (2/12 cases), which was equivalent to SDHB variant of hereditary PGL syndrome (10–25%) [20]. In contrast, a previous study reported that SDHB-related PCC and PGL patients with Arg46* (n = 20) and Val140Phe (n = 25) variants developed the disease earlier than those with Ile127Ser (n = 33), IVS1 + 1G > T (n = 27), exon 1 deletion (n = 31), and Arg90* (n = 48) variants [2]. Since the sample size of this variant was small and the phenotype data were lacking in some reports, more data on the genotypes, including variants and their phenotypes, are required to clarify the clinical features of patients with each variant of SDHB gene.

Table 1.

Previous reports of paraganglioma with variant in the SDHB gene at exon 2, c. 136C > T, p. Arg46*

Case	Author	Years	Age/Sex	Tumor location	Family history	Metastasis	Multiple PGL	Outcome	Functional tumor
1	Benn et al.	2003	7/M	Bladder	No	N/A	No	N/A	Yes
2	Benn et al.	2006	35/NA	abdominal and thoracic cavity	N/A	N/A	Yes	N/A	N/A
3	Bailey et al.	2006	32/F	Vagal nerve	Yes	No	No	Died at 7 years after the diagnosis	N/A
4	Brouwers et al.	2006	N/A	N/A	N/A	Yes	N/A	N/A	Yes
5	Brouwers et al.	2006	N/A	N/A	N/A	Yes	N/A	N/A	Yes
6	Srirangalingam et al.	2008	18/M	Abdominal cavity	Yes	No	No	NED	Yes
7	Srirangalingam et al.	2008	26/M	Abdominal cavity	Yes	liver	No	Died due to metastatic PGL at 1.8 years	Yes
8	Srirangalingam et al.	2008	39/F	Thoracic cavity	Yes	No	No	Awaiting excision	No
9	Timmers et al.	2008	10/M	Para adrenal gland	N/A	Abdominal LN, lung, bone, and mediastinum	N/A	N/A	Yes
10	Ghayee et al.	2009	36/F	Mediastinum, bladder	No	No	Yes	NED for 6 years	Yes
11	Ghayee et al.	2009	25/M	Mediastinum	N/A	Lung, superior, mediastinum, spine, sternum, scapula, and ischium	No	7-year follow	No
12	Burnichon et al.	2009	N/A	N/A	N/A	N/A	N/A	N/A	N/A
13	Lodish et al.	2010	9/M	Zuckerkandl	N/A	No	N/A	AWD	Yes
14	Lodish et al.	2010	15/M	Zuckerkandl	N/A	No	N/A	AWD	Yes
15	Pandit et al.	2016	13/M	N/A	No	N/A	No	N/A	N/A
16	Sriphrapradang et al.	2017	29/M	Thorax	N/A	N/A	No	N/A	No
17	Chew et al.	2017	17/NA	Retroperitoneal space	N/A	Yes	N/A	N/A	N/A
18	Chew et al.	2017	56/NA	Neck	N/A	No	No	N/A	N/A
19	Present case	2021	43/M	CBT	No	LN	No	NED for 80 months	No

AWD Alive with disease; CBT Carotid body tumor; F Female; LN Lymph node; M Male; N/A Not applicable; NED No evidence of disease; PGL Paraganglioma; SDHB Succinate dehydrogenase subunit B

Conducting gene analysis is recommended for patients with CBT, including those with SDHB variant to predict the prognosis. The prognosis of patients with CBT caused by SDHB variant was poorer than those of non-SDHB variants. Ellis et al. reported that the median disease-free survival of the SDHB variant group was 97 months, whereas that of the non-SDHB variant group was 293 months in a retrospective review of 34 patients with CBT [21]. The recurrence rate was 50% in the SDHB variant group and 22.7% in the non-SDHB variant group [21]. Recurrence or metastasis can develop in CBT at any period during the 200-month follow-up in patients with SDHB variant [21]. Therefore, long-term follow-up is required. In addition, patients with SDHB variants can develop heterogeneous paragangliomas in other organs. In a previous review, the tumor detection rate in asymptomatic SDHB carriers was 15.4%, and the age-related penetrance for asymptomatic carriers with SDHB variant was 22–26% at 60 years and 30–44% at 80 years of age [3]. Tufton et al. highlighted the importance of surveillance screening for SDHB carriers [3]. In the present case, the patient did not experience recurrence or develop other lesions 80 months after surgery, but he needs to continue to be monitored for a long time.

Differences in the prognosis and metastatic behavior were observed among patients with CBT with SDHB variant. Although the phenotype might be influenced by the different SDHB variants, further studies are warranted to elucidate these relationships.

In conclusion, we experienced a case of CBT accompanied by neck lymph metastasis caused by a novel SDHB variant and achieved long-term disease-free survival after surgery. Gene analysis, including SDHB variant, should be performed to predict the prognosis and future risk of metastasis. Genetic testing of SDHB can provide crucial information for the treatment and follow-up strategies of CBT.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

All authors contributed to the patient’s diagnosis and treatment. HO and KY contributed to gene analysis. TM prepared the draft of the paper. TM and HO were responsible for the writing of the paper. All authors read and approved the final manuscript.

Funding

None.

Data availability

Not applicable.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The case report was approved by the Institutional Review Board and Research Ethics Committee of Keio University School of Medicine (reference number 20190093).

Informed consent

Written informed consent for publication was obtained from the patient.