Gastrointestinal Stromal Tumor Metastatic to the Ovary Julie A. Irving, MD, FRCPC Department of Pathology, Vancouver General Hospital Vancouver , Canada

History: A 54 year old woman underwent surgical resection of a unilateral ovarian mass and a small bowel mass. Clinical information and detailed gross pathologic features were not available for review. Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Microscopic examination : The ovarian tumor consisted of sheets and broad trabeculae of moderately atypical epithelioid cells with eosinophilic cytoplasm. Cells with more spindled morphology comprised approximately 10% of the tumor. Nuclei were round to oval with small nucleoli and occasional intranuclear inclusions. Extracellular hyalinized plaques were focally identified. The small bowel tumor showed an intramural, circumscribed mass consisting of intersecting fascicles of pale eosinophilic spindle cells. The tumor abutted but did not invade the muscularis mucosae. Brightly eosinophilic skeinoid fibers were present. Small foci of tumor cell necrosis were seen. Mitotic figures were scarce in both the ovarian and small bowel tumors, numbering 1-2 mitotic figures per 50 high power fields. The ovarian and small bowel tumors were diffusely immunoreactive for c-kit and negative for desmin; CD34 positivity was seen only in the small bowel tumor. Additional immunohistochemistry was performed on the ovarian tumor, which showed positivity for vimentin and h-caldesmon; cytokeratin and S100 were negative. Diagnosis: Gastrointestinal stromal tumor metastatic to the ovary Discussion: The majority of tumors metastatic to the ovary are carcinomas. [1]Metastatic sarcomas are only rarely encountered and are most often endometrial stromal sarcomas. [2] Six cases of gastrointestinal stromal tumors (GIST) metastatic to one or both ovaries have been reported. [3, 4] The ovarian tumors were detected simultaneously, prior to, and in one case, 27 years after detection of the gastrointestinal primary. The initial manifestation, in each case leading to a strong suspicion of ovarian malignancy, included abdominal pain and identification of a pelvic or abdominal mass on physical examination; one patient presented with clitoral hypertrophy likely due to ovarian stromal luteinization. [3] A predominantly spindle or epithelioid ovarian neoplasm raises a number of different diagnostic considerations. Several features help distinguish GIST from smooth muscle neoplasms. Primary smooth muscle tumors of the ovary are rare and are usually unilateral. [5] Uterine leiomyosarcoma metastatic to the ovaries are characterized by a bulky uterine mass with morphologically similar ovarian tumors, often exhibiting prominent vascular invasion. [2] Leiomyosarcomas of extra-genital origin that on occasion metastasize to the ovary include bladder and the gastrointestinal tract, but only rare cases are reported. [2] Smooth muscle tumors tend to have elongate fascicles of cells with eosinophilic cytoplasm and "cigar-shaped" nuclei, in contrast to the short fascicles of pale eosinophilic cells with ovoid to spindle shaped nuclei commonly encountered in spindle cell GISTs. Furthermore, GISTs rarely exhibit the degree of pleomorphism or atypical mitotic figures seen in leiomyosarcoma. [5, 6] A c-kit and CD34 positive, desmin negative immunophenotype can help confirm the diagnosis of GIST. A panel of immunohistochemical markers is recommended, as uterine leiomyosarcomas may or may not show c-kit positivity, [7, 8, 9, 10, 11]a nd on occasion are desmin negative, but are rarely CD34 positive. [8] Conversely, desmin immunoreactivity in GIST is extremely rare. [12] GIST metastatic to the ovary and ovarian smooth muscle tumors may be positive for either or both h-caldesmon and smooth muscle actin, limiting their usefulness in this setting. [3, 5, 12] Low grade endometrial stromal sarcoma and the less frequently encountered primary endometrioid stromal sarcoma show a diffuse proliferation of small, endometrial stromal-type cells, with oval to spindle-shaped nuclei and scant cytoplasm, numerous small arterioles, and frequent vascular invasion. [13, 14] They characteristically show infiltrative tongues of tumor at their periphery, in contrast to the broad, pushing borders of GISTs; [13] this tongue-like growth is, however, often not conspicuous in the ovary. Primary endometrioid stromal sarcomas are usually unilateral and may show associated endometriosis. [14] Diagnosis of metastatic endometrial stromal sarcoma is of course facilitated by the finding of a similar tumor in the uterus. The occasional glandular and/or sex cord differentiation in endometrial stromal neoplasms is not a feature of GISTs. Endometrial stromal tumors are typically CD10-positive and negative for c-kit and CD34, [8] helpful findings if routine microscopy is not definitive. Whorling fascicles of spindle cells and nuclear palisading, present in one reported case of GIST metastatic to the ovary, can raise the possibility of a nerve sheath tumor. Malignant schwannoma of the ovary has rarely been reported. [15] As a proportion of GISTs may be positive for S100, [12] immunoreactivity for c-kit is a more reliable discriminating marker in this setting. Cellular fibromas and fibrosarcoma may also be in the differential diagnosis of a GIST metastatic to the ovary. These neoplasms, which are usually unilateral, otherwise share gross characteristics of metastatic GISTs. Microscopically, the cells of a cellular fibroma have scant cytoplasm with spindle to wavy nuclei and show mitotic activity usually in the range of 0-3 mitotic figures per 10 high power fields. [16, 17] Ovarian fibrosarcomas usually show diffuse moderate to severe nuclear atypia. A diagnosis of cellular fibroma or fibrosarcoma that is not definitive on routine microscopy can be facilitated by immunohistochemistry; they are usually negative for c-kit but may show focal positivity in a minor proportion of cells. [7] Skeinoid fibers are brightly eosinophilic structures frequently present in the stroma of small bowel GISTs. [18] These fibers usually form individually dispersed globules and plaques with irregular, hard edges and a dense staining quality. In contrast, the hyaline plaques frequently seen in ovarian thecomas, and occasionally in fibromas, are paler, with more fibrillary wavy collagen fibers that often coalesce into larger aggregates. Although skeinoid fibers are thought to be non-specific, in the context of a spindle cell neoplasm of the ovary, their presence should raise the index of suspicion for metastatic GIST. Other diagnostic considerations raised by a spindle cell neoplasm of the ovary include a sarcomatoid sex cord-stromal tumor. Adult granulosa cell tumors can rarely undergo sarcomatous transformation, but residual areas exhibiting typical morphology of a granulosa cell tumor are usually present. Bilaterality and extra-ovarian spread at presentation are exceptionally rare, and in the presence of either of these features a diagnosis of granulosa cell tumor should be made with caution. Inhibin or calretinin immunoreactivity may help confirm the diagnosis of a sex cord stromal tumor in problematic cases. A final tumor warranting consideration in the differential diagnosis of a spindle and epithelioid ovarian neoplasm is metastatic melanoma. [19, 20] Although S100 immunoreactivity can be seen in GIST [12], negativity for additional markers including HMB45 and Mart-1 are helpful in excluding melanoma. A panel of immunohistochemical markers is recommended in the distinction of GIST from metastatic melanoma, since the latter may also show c-kit immunoreactivity. In summary, a diagnosis of metastatic GIST should be considered with spindle or epithelioid ovarian neoplasms, particularly if bilateral and if there is any involvement of the gastrointestinal tract. The occurrence of primary bilateral ovarian sarcomas is exceptionally rare, and when encountered, additional clinical information should be obtained with awareness that history of a primary tumor in the small bowel or stomach may be remote. The differential may include many other primary and secondary tumors, but alertness to the diagnosis of GIST is crucial in leading to its inclusion in the differential formulation and investigation by appropriate immunohistochemistry. References Scully RE, Young RH, Clement PB. Tumors of the ovary, maldeveloped gonads, fallopian tube, and broad ligament. Atlas of Tumor Pathology, 3rd series (Rosai, J Ed.).Washington , D.C.: American Registry of Pathology, 1998. Young RH, Scully RE. Sarcomas metastatic to the ovary: a report of 21 cases. Int J Gynecol Pathol 1990;9:231-52. Irving JA, Lerwill MF, Young RH. Gastrointestinal tumors metastatic to the ovary. A report of five cases. Am J Surg Pathol 2005;29:920-926. Zighelboim I, Henao G, Kunda A, et al. Gastrointestinal stromal tumor presenting as a pelvic mass. Gynecol Oncol 2003;91:630-635. Lerwill MF, Sung R, Oliva E, et al. Smooth muscle tumors of the ovary: a clinicopathologic study of 54 cases emphasizing prognostic criteria, histologic variants and differential diagnosis. Am J Surg Pathol 2004;28(11):1436-1451. Miettinen M, El-Rifai W, Sobin LH, et al. Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review. Hum Pathol 2002;33(5):478-83. Klein WM, Kurman RJ. Lack of expression of c-kit protein (CD117) in mesenchymal tumors of the uterus and ovary. Int J Gynecol Pathol 2003;22:181-4. Oliva E, Young RH, Amin MB, et al. An immunohistochemical analysis of endometrial stromal and smooth muscle tumors of the uterus: a study of 54 cases emphasizing the importance of using a panel because of overlap in immunoreactivity for individual antibodies. Am J Surg Pathol 2002;26:403-12. Rushing RS, Shajahan S, Chendil D, et al. Uterine sarcomas express KIT protein but lack mutation(s) in exon 11 or 17 of c-KIT. Gynecol Oncol 2003;91:9-14. Wang L, Felix JC, Lee JL, et al. The proto-oncogene c-kit is expressed in leiomyosarcomas of the uterus. Gynecol Oncol 2003;90:402-6. Winter WE 3rd, Seidman JD, Krivak TC, et al. Clinicopathological analysis of c-kit expression in carcinosarcomas and leiomyosarcomas of the uterine corpus. Gynecol Oncol 2003;91:3-8. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol 2002;33:459-65. Oliva E, Clement PB, Young RH. Endometrial stromal tumors: an update on a group of tumors with a protean phenotype. Adv Anat Pathol 2000;7:257-81. Young RH, Prat J, Scully RE. Endometrioid stromal sarcomas of the ovary. A clinicopathologic analysis of 23 cases. Cancer 1984;53:1143-55. Stone GC, Bell DA, Fuller A, et al. Malignant schwannoma of the ovary. Report of a case. Cancer 1986;58:1575-82. Prat J, Scully RE. Cellular fibromas and fibrosarcomas of the ovary: a comparative clinicopathologic analysis of seventeen cases. Cancer 1981;47:2663-70. Irving JA, Alkushi A, Young RH, and Clement PB. Cellular fibromas of the ovary: a study of 75 cases including 40 mitotically active tumors emphasizing their distinction from fibrosarcoma. Am J Surg Pathol, in press. Min KW. Small intestinal stromal tumors with skeinoid fibers. Clinicopathological, immunohistochemical, and ultrastructural investigations. Am J Surg Pathol 1992;16:145-55. Gupta D, Deavers MT, Silva EG, et al. Malignant melanoma involving the ovary: a clinicopathologic and immunohistochemical study of 23 cases. Am J Surg Pathol 2004;28:771- 80. Young RH, Scully RE. Malignant melanoma metastatic to the ovary. A clinicopathologic analysis of 20 cases. Am J Surg Pathol 1991;15:849-60.