Case 1 -

Ovarian Paraganglioma Dr. W. Glenn McCluggage Belfast

History F 68, 22cm solid yellow/brown ovarian tumour Case 1 - Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer 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 case reports [1, 2]. 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 positive. 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 [1, 2]. One of 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 positive [3]. 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 differential diagnoses [4, 5]. 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 [6]. 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 [7]. 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 [4, 5]. 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 [8]. 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. References 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.