Intraocular Paraganglioma
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Disease Entity
Disease
Intraocular paragangliomas are an exceedingly rare type of neuroendocrine tumors that arise from the chromaffin cells of the autonomic nervous system. There are only a few case reports described in the literature1,2,4,5 and are difficult to diagnose due to their propensity to mimic other types of metastatic disease. Paragangliomas themselves, often grouped with pheochromocytomas and referred to as PPGLs, are so rare that they are estimated to occur in about 0.4 to 9.5 per 1 million individuals per year3. The two tumor types are histologically identical but separated by the location in which they occur. While pheochromocytomas are found in the adrenal medulla, PGLs are extra-adrenal and much less frequent (accounting for only 5-10% of pheochromocytomas)5,6. They are most often found in sympathetic paravertebral ganglia of the thorax, abdomen or pelvis or parasympathetic ganglia in the neck and base of skull3,6.
Etiology
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Risk Factors
While most arise sporadically, up to 24% are associated with germline mutations, notably in familial syndromes such as MEN2 and VHL3.The metastatic potential of these tumors is variable due to their marked clinical heterogeneity, but it has been noted that 10-15% are metastatic at initial diagnosis6
General Pathology
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Pathophysiology
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Primary Prevention
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Diagnosis
Histologically, most pheochromocytomas and paragangliomas show a classic zellballen pattern. This appears as a nest of uniform chromaffin cells surrounded by support cells and a vascular cuff. These chromaffin cells will often express immunohistochemical markers such as synaptophysin, chromogranin, and neural crest markers such as S100. Typically, epithelial cell markers will be absent3
History
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Physical Examination
Based solely on physical examination and imaging, intraocular paragangliomas are difficult to distinguish from other types of metastatic disease or choroidal tumors, such as amelanotic choroidal melanomas. On fundoscopic exam for the cases reported, the most common finding was a non-pigmented or partially pigmented choroidal tumor with either concommitant retinal detachment or disturbance of overlying retinal pigment epithelium
Signs
Symptoms
Though tumor presentation varies greatly by location, PGLs are classically associated with features of catecholamine excess such as hypertension, headache, diaphoresis and palpitations3,6. However, many extra-adrenal PGLs are asymptomatic, and are more likely to be found incidentally or as slow-growing, painless masses3
Symptoms are heterogenous, and intraocularly, the case reports described have noted both painful and painless vision loss of varying degrees, dependent on the location of the lesion and unilateral or bilateral eye involvement.
Clinical Diagnosis
A thorough review of the patient’s symptoms and family history is critical. Patients should be screened for any symptoms of catecholamine excess such as hypertension, palpitations, anxiety, and diaphoresis. Screening of family history for other neuroendocrine tumors or genetic syndromes that can predispose patients to neuroendocrine tumors such as VHL and MEN2 should be completed as well.
Diagnostic Procedures
Tissue biopsy is the gold standard for diagnosis, but can pose risks to the patient such as hemorrhage, extraocular seeding of tumor cells, retinal detachment, and hypotony.
Notably in all case reports described, thorough neuroendocrine oncology workup yielded additional tumor sites identified throughout the body. Additional imaging through PET or CT is often recommended to identify potential primary tumor sites
Laboratory Test
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Differential Diagnosis
Nonpigmented choroidal melanomas and intraocular paragangliomas can be difficult to distinguish as they can both clinically present as single-lobed masses with low internal reflectivity and subretinal fluid. Metastatic disease from extraocular origin should also be considered in the differential diagnosis, with biopsy as the only way to obtain a definitive diagnosis.
Management
Similar to other metastatic choroidal tumors, intraocular paragangliomas are believed to respond well to brachytherapy. However, it is noted that in two of the case reports that were unilateral at time of diagnosis, lesions later developed in the contralateral eye. Cases reviewed were managed primarily with resection4,5,1 or enucleation.
General Treatment
Identification of the primary tumor site is often the first step, as well as histologic confirmation and correlation with any other sites identified. Based on level of metastatic burden, radiotherapy and chemotherapy have both been used to control the tumor locally and systemically.
Medical Therapy
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Medical Follow-up
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Surgery
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Surgical Follow-up
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Complications
Overall vision loss, recurrence, and metastases are all possible complications. The potential for radiation retinopathy, cataracts, and glaucoma are also present if local control is chosen, similar to risks for other indications for ocular radiation7.
Prognosis
Like many other tumors, prognosis is dependent on multiple factors, most notably level of metastatic disease at diagnosis. In one case where the primary tumor was excised and the intraocular mass was slow growing and not causing significant visual burden, observation was elected1. In contrast, other cases have been reported with local recurrence managed with repeated irradiation5 or development of lesions in the contralateral eye, where the patient ultimately succumbed to generalized disease2. Overall, factors associated with poor prognosis are similar for other tumor types being large size, increased mitoses, and extensive necrosis2
Additional Resources
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References
1. Aaberg TM, Benjamin EP, Biscotti CV, Singh AD. Bilateral choroidal tumors consistent with metastatic malignant paraganglioma. Retin Cases Brief Rep. 2013 Fall;7(4):301-3. doi: 10.1097/ICB.0b013e31828ef023. PMID: 25383831.
2. Ginderdeuren RV, Missotten GS, van den Oord J. Choroidal paraganglioma with metastases to the fellow eye. Case Rep Ophthalmol. 2013 Jan;4(1):17-22. doi: 10.1159/000347169. Epub 2013 Feb 25. PMID: 23525329; PMCID: PMC3604866.
3. Guilmette J, Sadow PM. A Guide to Pheochromocytomas and Paragangliomas. Surg Pathol Clin. 2019 Dec;12(4):951-965. doi: 10.1016/j.path.2019.08.009. Epub 2019 Sep 28. PMID: 31672301; PMCID: PMC7403630.
4. Sandboe FD, Elgjo K, Eide N, Medin W, Scott H. An intraocular paraganglioma? Acta Ophthalmol (Copenh). 1994 Feb;72(1):138-41. doi: 10.1111/j.1755-3768.1994.tb02755.x. PMID: 8017189.
5. Schalenbourg A, Moulin A, Guillou L, Zografos L. Metastatic choroidal paraganglioma. Ophthalmology. 2011 Nov;118(11):2238-41. doi: 10.1016/j.ophtha.2011.04.017. Epub 2011 Sep 9. PMID: 21906814.
6. Tarling JA, Kumar R, Ward LJ, et al. Phaeochromocytoma and paraganglioma. Journal of Clinical Pathology 2024;77:507-516.
7. Nuzzi R, Trossarello M, Bartoncini S, Marolo P, Franco P, Mantovani C, Ricardi U. Ocular Complications After Radiation Therapy: An Observational Study. Clin Ophthalmol. 2020 Oct 9;14:3153-3166. doi: 10.2147/OPTH.S263291. PMID: 33116366; PMCID: PMC755528
