Gallbladder Paraganglioma Associated with SDHD Mutation: a Potential Pitfall on ¹⁸F-FDOPA PET Imaging

Abstract

A 36-year-old male patient initially presented with hypertension, tinnitus, bilateral carotid masses, a right jugular foramen, and a periaortic arch mass with an elevated plasma dopamine level but an otherwise normal biochemical profile. On surveillance MRI 4 years after initial presentation, he was found to have a 2.2-cm T2 hyperintense lesion with arterial enhancement adjacent to the gallbladder, which demonstrated avidity on ⁶⁸Ga-DOTATATE PET/CT and retrospectively on ¹⁸F-FDOPA PET/CT but was non-avid on ¹⁸F-FDG PET/CT. Biochemical work-up including plasma catecholamines, metanephrines, and chromogranin A levels were found to be within normal limits. This lesion was surgically resected and was confirmed to be a paraganglioma (PGL) originating from the gallbladder wall on histopathology. Pheochromocytoma (PHEO) and PGL are rare tumors of the autonomic nervous system. Succinate dehydrogenase subunit D (SDHD) pathogenic variants of the succinate dehydrogenase complex are usually involved in parasympathetic, extra-adrenal, multifocal head, and neck PGLs. We report an unusual location of PGL in the gallbladder associated with SDHD mutation which could present as a potential pitfall on ¹⁸F-FDOPA PET/CT as its normal excretion occurs through biliary system and gallbladder. This case highlights the superiority of ⁶⁸Ga-DOTATATE in comparison to ¹⁸F-FDOPA and ¹⁸F-FDG in the detection of SDHD-related parasympathetic PGL.

ClinicalTrials.gov Identifier: NCT00004847.

Introduction

Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare tumors of the autonomic nervous system. Around 35–40% of PHEO/PGLs are related to germline mutations in one of the susceptibility genes [1, 2]. The succinate dehydrogenase subunits (SDHx) proteins are part of the SDH complex and mutations in these gene-encoding subunits result in several familial PHEO/PGL syndromes. Succinate dehydrogenase subunit D (SDHD) pathogenic variants are usually associated with parasympathetic, extra-adrenal, and multifocal head and neck PGLs [1]. We report a rare case of SDHD-related PGL involving the gallbladder wall, a rare site not to be overlooked in these patients.

Case Report

A 36-year-old Caucasian male was found to have an SDHD mutation after he presented with multifocal PGLs. His initial presentation included mild hypertension, tinnitus, bilateral carotid masses (measuring 2.5 cm and 2.3 cm), a right jugular foramen mass (2.3 cm), and a periaortic arch mass (1.7 cm). This was associated with an elevated plasma dopamine level of 435 (normal: 3–46) pg/ml but an otherwise normal biochemical profile. The bilateral carotid body tumors and mediastinal paraaortic lesion were surgically resected; however, the right glomus jugulare tumor was unresectable due to a significant risk of stroke and, hence, was stabilized with 5400 cGy of intensity-modulated radiation therapy. A few years later, surveillance magnetic resonance imaging (MRI) of the abdomen and pelvis showed a T2 hyperintense 2.2 cm lesion with arterial enhancement adjacent to the gallbladder (Fig. 1a). This lesion was intensely avid on ⁶⁸Ga-DOTA(0)-Tyr(3)-octreotate (⁶⁸Ga-DOTATATE) positron emission tomography-computed tomography (PET/CT) (SUV_max = 285) and retrospectively on ¹⁸F-fluorodopa (¹⁸F-FDOPA) PET/CT (SUV_max = 69) but lacked avidity on ⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT (Fig. 1b–d, respectively). Biochemical work-up including plasma catecholamines, metanephrines, and chromogranin A levels was within normal limits. He subsequently had an uneventful laparoscopic cholecystectomy. The surgical pathology confirmed a 2.1-cm PGL originating from the gallbladder wall near the fundus with negative tumor margins. Immunohistochemistry confirmed tumor cells were positive for synaptophysin, chromogranin, and S100 (Fig. 2).

Fig. 1.

Anatomic and functional PET imaging of gallbladder paraganglioma. In this figure, an enhancing lesion adjacent to the gallbladder is seen on fat-suppressed delayed post-contrast T1W image (arrow, a), which demonstrates uptake on ⁶⁸Ga-DOTATATE PET/CT (arrow, b) and retrospectively on ¹⁸F-FDOPA PET/CT (dotted arrow, c). However, this lesion lacked avidity on ¹⁸F-FDG PET/CT (d)

Fig. 2.

Histopathologic examination of gallbladder paraganglioma. In this figure, staining with hematoxylin and eosin (a, ×100) shows gallbladder mucosa, lined by a single layer of columnar epithelial cells with pale eosinophilic cytoplasm, abutting directly onto muscularis propria. Tumor cells involve the muscularis propria and the mucosa (arrowheads). (b, ×100), shows a nested arrangement of paraganglioma cells with fine fibrovascular septa. Neoplastic cells are monomorphic with round nuclei and inconspicuous nucleoli. Chromogranin immunostain (c, ×100) is positive in neoplastic cells. Synaptophysin immunostain (not shown) is also strongly positive. SDHB immunostain (d, ×200) shows reduced granular cytoplasmic marking of neoplastic cells compared to endothelial cells (arrowheads), indicating an SDH-complex functional aberration

Discussion

We describe a case of a parasympathetic PGL associated with SDHD mutation that arose from the gallbladder wall. The human gallbladder is innervated by branches of the sympathetic and parasympathetic fibers derived from the left vagus nerve and celiac plexus [3]. Thus, the occurrence of PGL in this location can be explained by migration of ganglionic cells from nearby plexuses. PGL in the gallbladder was first reported by Miller et al. and Wolff et al. in 1972 and 1973, respectively [4, 5].

On histopathologic examination, the tumor was composed of round to polygonal nests with a finely granular cytoplasm with delicate fibrous septa containing prominent capillaries (Fig. 2) and was positive for chromogranin A, synaptophysin, and S100 on sustentacular cells [3, 4].

A genetic etiology for PGL in the gallbladder has only twice been reported and associated with a RET gene mutation [6, 7]. To the best of our knowledge, gallbladder PGL associated with an SDHx mutation has not been reported in the past [3–9]. SDHx genes encode the four subunits of SDH complex [1, 2]. The latter not only catalyzes the oxidation of succinate into fumarate in the tricarboxylic acid cycle but also transfers electrons to the ubiquinone pool in the respiratory chain [1]. Defects in SDH lead to activation of the hypoxia pathway and thus, cause tumor development. SDHD is one of the two anchorage proteins in SDH and is commonly affected by pathogenic mutations. The germline heterozygous mutations in SDHD, together with the loss of heterozygosity, cause highly penetrant multifocal tumor development with a characteristic paternal transmission [1].

Functional imaging is the backbone of PHEO/PGL diagnosis [2]. The patient’s genetic mutation has an important effect on the PET tracer utilization. The various functional imaging radiopharmaceuticals target different mechanisms of tumorigenesis in PHEO/PGLs. Somatostatin receptors (SSTR) are expressed in PHEO/PGLs especially SSTR2 subtype [10] and ⁶⁸Ga-DOTATATE demonstrates higher affinity for SSTR2 [11]. ¹⁸F-FDOPA targets the cell via the large amino acid transporter system which is found in PHEO/PGLs [12], whereas ¹⁸F-FDG is a nonspecific radiopharmaceutical that enters the cell via glucose transporters [13] and its increased uptake in SDHx-related PHEO/PGLs occurs due to altered glucose metabolism that is related to genotype-specific tumor biology [14, 15]. In a recently published meta-analysis by Han et al. in PHEO/PGL of unknown genetic status, ⁶⁸Ga-DOTA-SSTR PET demonstrated a superior detection rate compared to ¹⁸F-FDOPA and ¹⁸F-FDG [16]. Further, ⁶⁸Ga-DOTATATE PET/CT is known to demonstrate superior detection in SDHB-related metastatic PHEO/PGL compared to ¹⁸F-FDOPA and ¹⁸F-FDG [2] and similarly in SDHD-related PHEO/PGL when compared to ¹⁸F-FDOPA [17]. In this patient, ⁶⁸Ga-DOTATATE PET/CT (Fig. 1b) was able to detect the gallbladder PGL whereas on ¹⁸F-FDG PET/CT (Fig. 1d), it was not detected. On ¹⁸F-FDOPA PET/CT (Fig. 1c), this lesion was detected only retrospectively after gaining knowledge of the lesion on ⁶⁸Ga-DOTATATE PET/CT (Fig. 1b) due to the observed physiologic uptake of ¹⁸F-FDOPA in the gallbladder attributed to the normal excretion of ¹⁸F-FDOPA through the biliary system and gallbladder and, hence, can be a potential pitfall on ¹⁸F-FDOPA PET/CT imaging [18, 19]. Therefore, correlative anatomic imaging should be performed in order to avoid overlooking any gallbladder PGLs on ¹⁸F-FDOPA PET/CT, as was the case described above.

Conclusion

Based on the 2017 WHO Classification of Endocrine Tumors, primary PGLs can be found in any tissue except bone and lymph nodes. Here, we present a very unusual location of possible SDHD-related primary PGL in the gallbladder wall associated with SDHD mutation which could present as a potential pitfall on ¹⁸F-FDOPA PET/CT. Moreover, this case shows the superiority of ⁶⁸Ga-DOTATATE in comparison to ¹⁸F-FDOPA and ¹⁸F-FDG in the detection of SDHD-related parasympathetic PGL. Therefore, careful surveillance imaging including functional imaging using ⁶⁸Ga-DOTATATE is necessary for the follow-up of any patient with hereditary PGL, including those associated with SDHD mutations.

Funding Information

This study was funded by the National Institutes of Health (grant number: Z1AHD008735) awarded to Karel Pacak.

Conflict of Interest

Zahraa Abdul Sater, Abhishek Jha, Adel Mandl, Sheila K. Mangelen, Jorge A. Carrasquillo, Alexander Ling, Melissa K. Gonzales, Osorio Lopes Abath Neto, Markku Miettinen, Karen T. Adams, Pavel Nockel, Mustapha El Lakis, and Karel Pacak declare that they have no conflict of interest.

Disclosure

This work was supported, in part, by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development and was supported, in part, by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute.

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.

Informed Consent

Informed consent was obtained from the individual participant included in the study.