Dear editor,

Ovarian paragangliomas are rare tumours and are usually incidental. Most of the cases are associated with dermoid cyst of ovary. However, functional paragangliomas¹ and paragangliomas leading to peritoneal carcinomatosis are also known in literature.² Due to the varied behaviour of these tumours, correlation with biochemical markers and long term follow up are advised.

In this study, we present a lady in her 60's with recent onset of postmenopausal bleeding. She completed her cervical smears till date and had two children by vaginal delivery. Her past medical history includes hypertension and is on Candesartan for the same. She also has type 2 diabetes and is diet controlled. She is a non-smoker and consumes alcohol very occasionally. No family history of breast, uterine, ovarian or bowel cancer is present. She attained menarche at the age of 11 and took oral contraceptive (OCP) for 20 years for her post-menopausal symptoms. Examination of both breasts showed no discrete lump. She attended the outdoor patient department for post-menopausal bleeding.

Pelvic ultrasound scan showed endometrial thickening with fibroids with ovaries obscured by bowel gas. Rest of the examination was normal. At this stage, hysteroscopy and endometrial polypectomy was done and the specimen was sent to histopathology. Endometrial sampling revealed polyp with atypical glandular hyperplasia.

The patient then underwent MRI scan without contrast to look for malignancy, which revealed uterine adenomyosis with anterior submucosal and subserosal fibroids. No definite uterine malignancy or soft tissue mass lesion was identified. The right ovary measured 37 mm ​× ​18 mm and the left ovary measured 20 mm ​× ​12mm. The right ovary was slightly bulky and was thought to be composed of a solid lesion. However, differential diagnosis included ovarian atrophy or a small ovarian fibroma. No ovarian cyst or endometrioma was identified bilaterally.

Due to the biopsy findings of atypical endometrial hyperplasia in a post-menopausal background and following discussion at the multi-disciplinary meeting (MDM), the patient underwent total laparoscopic hysterectomy with bilateral salpingo-oophorectomy. The specimen was sent to the histopathology department of Queen's hospital, Barking, Havering and Redbridge NHS (BHR) trust.

Macroscopic examination of the specimen showed uterine fibroids and firm white areas in ovaries. Histologically, there was adenomyosis and pseudo-decidualised stroma in the uterus. The ovaries, on the other hand, revealed a well defined lesion measuring 15mm on right side and 9mm on left side. The lesion was composed of sheets of slightly pleomorphic cells arranged in nests (Zellballen pattern) surrounded by sustentacular cells and occasional dense fibrous septa (Fig. 1). Immunohistochemistry was done which showed tumour cells to be positive for neuroendocrine markers such as chromogranin A, synaptophysin (Fig. 2), CD56 (Fig. 3) and neuron specific enolase (NSE). The sustentacular cells were positive for S100 protein (Fig. 4). Tumour cells were also positive for GATA3 and negative for inhibin. Overall, the features were consistent with a “Paraganglioma of ovary” in a background of adenomyosis and uterine fibroids.

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Fig. 4

Sustentacular staining by S100(× 10)

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Fig. 3

Membranous staining by CD56 (× 10).

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Fig. 2

Tumour cells staining by synaptophysin (× 10).

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Fig. 1

Tumour cells arranged as Zellballen pattern (× 20)

Paraganglioma are non-epithelial, neural-crest derived neuroendocrine neoplasms arising from adrenal medulla in which case they are called pheochromocytoma and in extra-adrenal paraganglia, these are known as paraganglioma. These are composed of para-neuronal peptide hormone secreting neuroendocrine cells. Paragangliomas are broadly categorised as ‘parasympathetic’ arising from head and neck and ‘sympathetic’ arising from retroperitoneum, thorax and pelvis.

These tumours have highest degree of heritability amongst all human neoplasms and 40% have germline mutation such as VHL, SDH, NF1, to name a few.³ No family history was present in our present case. Clinical features depend on the tumour size and secretory phenotype. Functional paragangliomas secrete epinephrine, nor-epinephrine and dopamine. These hormones lead to paroxysmal tachycardia, hypertension and pallor. Majority of extra-adrenal pheochromocytomas are located in the uterus, retroperitoneum, lumbar spine, bladder, ocular orbit, heart and mediastinum.^4–8

Ovarian paragangliomas are very rare tumours. Possible theories of histogenesis of primary ovarian paraganglioma include an origin from extra-adrenal paraganglia in the region of the ovary or unidirectional differentiation within a teratoma.⁹ Out of the reported cases of ovarian paraganglioma in literature, most of the cases of were associated with mature cystic teratoma which were incidental and non-functional.^9–12 Only one case was functional and the patient showed catecholamine excess related symptoms.¹ Another case showed metastatic behaviour with peritoneal carcinomatosis.²

Ovarian paragangliomas show strong positivity for synaptophysin, variable staining for chromogranin and S100 staining of sustentacular cells.^9,11,12 They are usually negative for cytokeratins³ and sex cord stromal markers such as inhibin and calretinin, however exceptions are noted.^9,13 In the cases reported by Mc Cluggage et al.,⁹ inhibin and calretinin positivity did raise the possibility of sex cord stromal tumours but these were strongly positive for neuroendocrine markers as well.

It is also known that Inhibin alpha positivity could raise the possibility of germline mutations in paragangliomas and concomitant presence of such tumours at other sites.³ But, due to rarity of ovarian paragangliomas, familial association and presence of tumours at other sites cannot be drawn. However, in one case reported by Schudlt M et al.,¹³ ovarian paraganglioma was seen in the background of endometrial carcinoma. But, since the tumour was non-functional in that case, an association with endometrial carcinoma is unlikely. More research should be done to determine the malignant and metastatic behaviour of these tumours.

In our case as well, the tumour was purely incidental and not associated with any tumour. The patient had a history of hypertension but whether it was related to the tumour is not known as no pre-operative biochemical data was available. This was also the case with previously reported cases,^9,11,12 where the tumour was incidental and no pre-operative biochemical data was available. However, in our case, since the patient made excellent recovery following surgery and since the surgery was uneventful, it is believed that the tumour was non-functional and hypertension was unrelated to the tumour.

Non-functional paragangliomas are difficult to diagnose radiologically mainly due to the absence of feeding vessel and due to its resemblance to ovarian fibroma or atrophy, as in our case. Usually these are incidental and are found on specimens removed for other reasons. Baseline Catecholamine should always be checked, if available. These tumours can have metastatic potential in spite of their benign histology, therefore, long term follow up is always advised.