Differential Diagnosis

Based on the histological features, the differential diagnosis includes ectopic parathyroid tumors, gastrointestinal stromal tumors, granular cell tumors, nerve sheath tumors, meningiomas, rhabdomyomas, melanoma, sarcoma, metastatic carcinoma, and adrenal cortical adenomas.

On immunohistochemical staining, the mass from this case is positive for synaptophysin and GATA3, while the mass is negative for AE1/AE3, SALL4, SDHB, and OCT3/4.

Ectopic parathyroid tumors can stain positive for neuroendocrine markers and GATA3, however, they will also be positive for pankeratin and PTH. Granular cell tumors, meningiomas, melanomas, rhabdomyomas, and sarcomas will be negative for neuroendocrine markers. Adrenal cortical adenomas will stain negative for GATA3. Finally, while gastrointestinal stromal tumors (GISTs) can stain negative for SDHB, they will also have positive staining for CD117, DOG1, and h-caldesmon. Metastatic carcinomas are difficult to differentiate from paragangliomas, however metastatic lesions will usually be positive for other markers dependent on their primary origin.

Discussion

Paragangliomas are a form of neuroendocrine cell tumors that arise from extra-adrenal autonomic paraganglia.

They are closely related to pheochromocytomas, however, pheochromocytomas are specifically paragangliomas of only the adrenal medulla. Therefore, pheochromocytomas are not found outside of the adrenal gland.

Sympathetic paragangliomas usually secrete catecholamines and can be found in the sympathetic paravertebral ganglia of the thorax, abdomen, and pelvis.

Parasympathetic paragangliomas are nonfunctional and can be found along the glossopharyngeal and vagal nerves in the neck and at the base of the skull.

Male to female ratio is equal among patients with hereditary paragangliomas. Females have an increased likelihood of sporadic tumors.

The vast majority of paragangliomas are benign, though malignant variants are possible. Specific criteria for malignant paragangliomas (as compared to benign variants) have yet to be defined.

A majority of paragangliomas are sporadic, however, approximately 30-50% of cases are associated with an inherited syndrome. Inherited syndromes that increase the risk of paragangliomas include:

• Hereditary SDHx paraganglioma syndromes (PGL1, PGL4, PGL3, PGL2, PGL5)
• MEN2 (A and B)
• Neurofibromatosis type 1
• von Hippel-Lindau

Patients with an inherited syndrome are more likely to have paragangliomas in other locations within their body and require full-body imaging. Patients with confirmed paragangliomas should undergo genetic testing, and, if the patients possess an inherited mutation, the patient’s family should also undergo genetic testing.

• The patient in this case had a SDHB mutation (PGL4 syndrome). This variant is associated with renal cell carcinoma, thus explaining his diagnosis of renal clear cell carcinoma of his L kidney. He was found to have only the one paraganglioma at this time, but he will need to undergo whole-body MRI scans every 2 years. His mother was found to be positive for the SDHB mutation as well.

Genetic syndromes and special histopathologic features:

• MEN2: unilateral or bilateral adrenal medullary hyperplasia
• SDHx related syndromes: granular eosinophilic cytoplasm
• von Hippel-Lindau syndrome: prominent stromal edema, clear cytoplasm and lipid degeneration

Immunohistochemical positive staining:

• INSM1 (diffuse nuclear)
• Chromogranin A
• Synaptophysin
• CD56
• S100 (may be diffusely positive)
• GATA3 (diffuse nuclear)
• Tyrosine hydroxylase (diffuse and strong in sympathetic paragangliomas, weak or focal in parasympathetic tumors)
• Dopamine beta hydroxylase and phenylethanolamine N methyltransferase in epinephrine-producing tumors
• For germline mutations:
• SDHB or SDHA expression loss: germline SDHx mutations
• Carbonic anhydrase IX (CAIX) expression: in 80% of VHL mutations
• Inhibin alpha: any hypoxic pathway disease (SDHx, VHL)
• Immunohistochemical negative staining:
• AE1/AE3
• CAM5.2
• CEAs