Moderator: Dr. W. Glenn McCluggage
Dr. W. Glenn McCluggage
F 68, 22cm solid yellow/brown ovarian tumour
Diagnosis: Ovarian Paraganglioma
The diversity of patterns and cell types encountered in ovarian tumors is probably as great, if not
greater, than in any other organ of the body. Clues to diagnosis reside in the admixture of patterns
present and the associated cell types. Many ovarian neoplasms typically or occasionally have oxyphilic
cells and a number of others a nested pattern but oxyphilic tumors that also have a nested architecture
are rare. It is the purpose of this report to draw attention to the occurrence in the ovary of such a
tumor, the paraganglioma, the literature on which is, to the best of my knowledge, represented by two
A 68 year old woman with a one year history of hypertension presented with symptoms related to a 22 cm
diameter left ovarian mass.
The left ovary was largely replaced by a solid yellow/tan tumor with a central white area.
Histological examination showed a well circumscribed tumor largely composed of closely packed nests of
cells resulting in a "zellballen" appearance. In a few areas, microcystic spaces were formed due to
central degeneration of tumor cell nests and in other foci there was a diffuse pattern. Tumor cells had
round to ovoid nuclei with a speckled chromatin and occasional small nucleoli but without nuclear
grooves. There was little nuclear pleomorphism and tumor giant cells were not identified. A formal
mitotic count revealed 2 mitoses per 10 high power fields (HPF). Most of the tumor cells had abundant
granular eosinophilic cytoplasm but focally the cytoplasm was clear. There was a scant stroma between
the cell nests and this was highly vascular with many thin-walled capillary-like vessels. There was no
lymphovascular invasion. The central white area seen grossly corresponded to a large area of edema and
necrosis. Immunohistochemistry showed no staining with the cytokeratin marker AE1/3. There was diffuse
cytoplasmic reactivity with chromogranin and membranous positivity with CD56. S-100 stained a focal
population of slender spindle shaped cells at the periphery of the cell groups, in keeping with
sustentacular cells. There was diffuse cytoplasmic inhibin positivity. Calretinin was also focally
This report highlights the occurrence of a vanishingly rare primary ovarian neoplasm , namely a
paraganglioma, with, as far as I am aware, only two previously reported cases
those was in an adolescent female with hypertension and the other represented a gangliocytic
paraganglioma arising in a dermoid cyst. There was a history of hypertension in this case which is, of
course, characteristic of paraganglioma secondary to elaboration of adrenaline and noradrenaline.
The diagnosis was strongly suspected on the morphological appearances and supported by
immunohistochemistry. Tumor cells were diffusely positive with the neuroendocrine markers chromogranin
and CD56. Other neuroendocrine neoplasms described in the ovary include carcinoid tumor and small and
large cell neuroendocrine carcinoma, all of which may be primary or secondary. These neuroendocrine
neoplasms (other than paraganglioma) would be expected to be positive, at least focally, with
anti-cytokeratin antibodies. Paragangliomas are usually cytokeratin negative, as in the cases we
describe, although a small proportion , especially when arising in the cauda equina, are cytokeratin
Because of the extreme rarity of ovarian paraganglioma, the pathologist may understandably not
consider this diagnosis. The neoplasm had a brown, tan or yellow colour, a gross appearance which raises
the possibility of a sex cord-stromal neoplasm. The histological features were of a bland oxyphilic
tumour with a nested pattern. Although this cell type (oxyphilic) and cell pattern (nested) are rarely
found in combination in an ovarian neoplasm, when present individually they raise a number of
Neoplasms in the sex cord-stromal category, including steroid cell tumor and luteinized granulosa cell
tumor, are likely to enter into the differential. A nested pattern is rare, although occasionally
described, in steroid cell tumor and the nuclear features are against a granulosa cell tumor in that the
nuclei were not pale and did not contain grooves but rather had a speckled chromatin pattern,
characteristic of neuroendocrine cells. Sex cord-stromal neoplasms would not be expected to be positive
with neuroendocrine markers. Reactivity of the paraganglioma with inhibin illustrates a significant
diagnostic pitfall which could result in misdiagnosis as a sex cord-stromal neoplasm, since this group of
tumors are mostly inhibin positive and illustrates that a judiciously chosen panel of antibodies should
be used, to include markers which are expected to be positive and negative in each of the tumors under
consideration. Positive staining with inhibin has been described in extraovarian
paragangliomas . Calretinin, another marker which is commonly positive in ovarian sex
cord-stromal tumors but which is less specific for this category of neoplasms than inhibin,
was focally positive. Due to the nested growth pattern, malignant melanoma might enter into the
differential diagnosis and some melanomas in the ovary have an oxyphilic appearance .
Melanoma does not stain with neuroendocrine markers and S-100 was negative, except for a focal population
of sustentacular cells. Other markers such as melan-A, HMB45 and micropthalmia transcription factor may
assist in confirming a diagnosis of malignant melanoma. Some carcinomas in the ovary have an oxyphilic
appearance, including oxyphilic variants of endometrioid and clear cell carcinoma and hepatoid carcinoma,
either primary or secondary. In general, carcinomas would be expected to exhibit more pleomorphism and
be more mitotically active than paraganglioma. The various oxyphilic carcinomas would be positive with
anti-cytokeratins and negative with neuroendocrine markers. Other tumors in the ovary which may have an
oxyphilic cell type or a nested pattern and which may potentially enter into the differential diagnosis
include metastatic breast carcinoma, epithelioid smooth muscle tumor, hepatoid variant of yolk sac tumor
and oxyphilic struma ovarii
Metastatic breast carcinoma would be cytokeratin positive
while if the latter three neoplasms are seriously considered in the differential diagnosis they can be
easily excluded by an absence of staining with smooth muscle markers, aFP and thyroglobulin
respectively. None of these tumors would be positive with neuroendocrine markers.
The histogenesis of ovarian paraganglioma is unknown and in the recent World Health Organisation
Classification of Tumors of the Breast and Female Genital Organs, paraganglioma is categorised along with
other miscellaneous tumors and tumor-like conditions . One theoretical possibility is
unidirectional differentiation within a teratoma and, as mentioned, a gangliocytic paraganglioma arising
in a dermoid cyst has been described. However, in the case I describe, other elements were not
identified and I consider this possibility unlikely. Paragangliomas arise from the adrenal gland and the
extra-adrenal paraganglia which have a roughly symmetric distribution on either side of the midline,
extending from the base of the skull to the pelvic floor. It is not inconceivable that a primary ovarian
paraganglioma could arise from extra-adrenal paraganglia adjacent to the ovary and invade into the ovary,
although the gross findings suggested a mass centered in the ovarian parenchyma. As far as I am aware,
paraganglia have not been specifically described in the ovary. Clearly with ovarian paraganglioma, long
term follow-up is advised due to the extreme rarity of this neoplasm at this site and the fact that late
recurrence and, or, metastasis may occur with paraganglioma arising elsewhere.
- Fawcett FJ, Kimbell NK. Phaeochromocytoma of the ovary. J Obset Gynecol Br Commonw; 1971; 78: 458-9.
- Mahdavi A, Silberberg B, Malviya VK, et al. Gangliocytic paraganglioma arising from mature cystic teratoma of the ovary. Gynecol Oncol. 2003; 90:482-5.
- Chetty R, Pillay P, Jaichand V. Cytokeratin expression in adrenal phaeochromocytomas and extra-adrenal paragangliomas. J Clin Pathol. 1998; 51: 477-8.
- Young RH, Scully RE. Differential diagnosis of ovarian tumors based primarily on their patterns and cell types. Semin Diagn Pathol. 2001;18:161-235.
- McCluggage WG, Young RH. Immunohistochemistry as a diagnostic aid in ovarian neoplasia. Semin Diagn Pathol 2005;22;3-32
- Zhang PJ, Genega EM, Tomaszewski JE, et al. The role of calretinin, inhibin, melan-A, BCL-2, and C-kit in differentiating adrenal cortical and medullary tumors: an immunohistochemical study. Mod Pathol. 2003;16:591-7.
- Young RH, Scully RE. Malignant melanoma metastatic to the ovary. A clinicopathologic analysis of 20 cases. Am J Surg Pathol. 1991; 15: 849-60.
- Tavassoli FA, Devilee P, eds. World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of the Breast and Female Genital Organs. IARC Press. Lyon , 2003.