The clinical presentation of renal cell carcinoma in the ovary is rare and may closely resemble that of other ovarian clear cell tumors. Metastatic renal cell carcinoma was diagnosed in a patient who presented with a right adnexal mass and no other significant past medical history. The gross appearance of the tumor suggested a primary ovarian neoplasm. However, microscopic and immunohistochemical analysis revealed involvement of both ovaries by a clear cell tumor with features of renal cell carcinoma. A renal mass was subsequently discovered. We discuss the clinical, histologic, and immunohistochemical features of this tumor and the features of other clear cell neoplasms in the differential diagnosis.
Clear cell tumors in the ovary may pose a diagnostic dilemma because of the variety of primary and metastatic clear cell tumors that may occur there. Although renal cell carcinoma often metastasizes to unusual sites, its presentation in the ovary is rare. There have been 11 described cases of renal cell carcinoma metastatic to the ovary, few of which presented in the ovary prior to the discovery of a renal mass.1–4 We encountered another such case of metastatic renal cell carcinoma that closely resembled other clear cell tumors of the ovary. The clinical, histologic, and immunohistochemical characteristics of this tumor are described here, and features that help to distinguish it from other clear cell ovarian tumors are discussed.
REPORT OF A CASE
A 48-year-old woman was evaluated by her gynecologist for irregular menses. She had no significant past medical history except for a cesarean section. Her family history was notable for a renal tumor in her mother and a uterine malignancy in her sister. Physical examination was unremarkable. A pelvic ultrasound showed a heterogeneous right adnexal mass with multiple cystic spaces. Serum levels of carcinoembryonic antigen and CA 125 were within normal limits. The patient was admitted for an exploratory laparotomy.
At the time of surgery, a 6.0-cm partially cystic right adnexal mass was noted. A frozen section was performed, and a stromal ovarian tumor was considered. The patient subsequently underwent a vaginal hysterectomy, bilateral salpingo-oophorectomy, and intra-abdominal staging. She tolerated the procedure well and was discharged 3 days postoperatively with a follow-up visit scheduled at the clinic 2 weeks later.
The final pathology report suggested the possibility of a metastatic renal cell carcinoma, and the patient was referred for further imaging. A renal ultrasound and computed tomography scan of the pelvis revealed a 6.0-cm exophytic left renal mass with irregular enhancement consistent with renal cell carcinoma. A total bone scan revealed increased activity within the skull, spine, and left iliac bone, suspicious for metastases. At this writing, the patient has undergone 3 cycles of chemotherapy for renal cell carcinoma but has not yet undergone a nephrectomy.
The right ovary was replaced by a 6.0-cm hemorrhagic and multiloculated cystic mass with focal golden-yellow solid areas. The left ovary was 3.0 cm and without any visible abnormality. The uterus and fallopian tubes were unremarkable.
Microscopic examination of sections from both ovaries revealed solid areas containing clear, polygonal tumor cells arranged in sheets or nests surrounded by delicate, thin-walled vascular septa. Nuclei were bland and without mitoses or pleomorphism. Many areas showed tubules lined by attenuated tumor cells and filled with serous fluid or blood (Figure 1). Desmoplasia was absent in the surrounding stroma. There was no evidence of lymphovascular invasion at the periphery of either ovary or of metastatic spread to uterus, fallopian tubes, bladder, pelvic sidewall, gutter, or external iliac lymph nodes.
The tumor cells displayed strong diffuse immunoreactivity for epithelial membrane antigen (EMA, monoclonal, 1:1500, Dako Corporation, Carpinteria, Calif) (Figure 2), renal cell antigen (RCC, monoclonal, 1:40, Novocastra/Vector, Burlingame, Calif) (Figure 3), and CD10 (monoclonal, 1:80, Novocastra) (Figure 4) localized to the cytoplasmic cell membranes. Immunohistochemistry for cytokeratin cocktail (monoclonal AE1/AE3, 1:200, Dako; monoclonal CAM 5.2, 1:1500, Becton Dickinson, San Jose, Calif; monoclonal 34βE12, 1:50, Dako), estrogen receptor (monoclonal, 1:25, Dako), CA 125 (monoclonal, 1:20, Dako), inhibin (monoclonal, 1:25, Serotec, Raleigh, NC), calretinin (polyclonal, 1:200, Zymed, South San Francisco, Calif), CD34 (monoclonal, 1:200, Becton Dickinson), and alpha-fetoprotein (polyclonal, 1:1500, Dako) yielded negative results.
Renal cell carcinoma most frequently metastasizes to lung and bone but is well known for its propensity to metastasize to unusual sites, sometimes prior to the detection of a renal mass. Despite the abundance of reports describing metastatic tumors to the ovary, only 11 cases of metastatic clear cell carcinoma of renal origin have been reported. Few cases that have been reported in detail have a similar presentation and course to the one we describe here. Spencer et al2 described a 40-year-old woman who presented with irregular menses. At laparotomy, bilateral ovarian tumors were found and presumed to be of primary ovarian origin. However, a left renal tumor with histology identical to that of the ovarian tumors was discovered 7 months later. In 2 of 3 cases described by Young and Hart,4 the ovarian pathology was discovered before a renal mass was identified. Both cases were initially interpreted as primary clear cell carcinoma of the ovary. In 1 of these cases, the primary renal tumor was not discovered until 8 years later.
The clear cell carcinoma of renal origin may pose a diagnostic challenge to the pathologist, especially when there are metastases to sites at which other clear cell tumors have the potential to arise, such as thyroid, liver, and female genital tract. In the ovary, the differential diagnosis of clear cell neoplasms includes primary clear cell carcinoma, steroid cell tumor, and dysgerminoma. Metastatic clear cell carcinoma of renal origin may mimic these entities. However, careful gross and microscopic examination combined with immunohistochemical analyses can aid in the distinction of this metastatic lesion.
Primary clear cell carcinoma of the ovary occurs in women between 50 and 70 years of age. Bilateral involvement is unusual and is seen in only 2% to 4% of patients with stage I disease.3 The gross appearance of this tumor may be identical to that of metastatic renal cell carcinoma, with a predominantly cystic mass and focal solid areas. Like renal cell carcinoma, the cysts in the tubulocystic variant of clear cell carcinoma may contain hemorrhagic or dark brown fluid if the carcinoma is arising in an endometriotic cyst. The microscopic appearance of clear cell carcinoma is most often clear cells or hobnail cells lining cysts and tubules. The clear cells may line complex papillae variably containing periodic acid–Schiff–positive hyaline basement membrane material expanding the papillary cores. Clear cells may also be arranged in solid nests or masses, closely resembling the pattern of a clear cell carcinoma of renal origin. Imunohistochemically stained tumor cells of primary ovarian clear cell carcinomas express cytokeratin, EMA, and CA 125.
Steroid cell tumors account for 0.1% of ovarian tumors.3 Included among the steroid cell tumors are the stromal luteomas, Leydig cell tumors, and steroid cell tumors not otherwise specified. The unspecified steroid cell tumors most likely present a differential diagnosis for a clear cell carcinoma of renal origin and usually occur in peri- to postmenopausal women who typically present with androgenic or estrogenic symptoms. These tumors are rarely bilateral. Grossly, they are solid, well-circumscribed tumors of variable color with occasional hemorrhage and cystic degeneration. Microscopic examination reveals lipid-rich tumor cells with clear intracytoplasmic vacuoles arranged in solid sheets, thin cords, or columns. The stroma may be fibromatous or myxoid, with focal calcifications. Immunohistochemical staining is usually positive for inhibin5 and negative for EMA and keratin.
Dysgerminomas make up 1% of all ovarian malignancies and are the most common of malignant germ cell tumors. They occur in women 20 to 40 years of age and present clinically with symptoms related to an abdominal mass. Although usually unilateral, these tumors may be bilateral in up to 20% of cases.3 Gross inspection reveals a solid, fleshy, and lobulated mass with cystic degeneration and hemorrhage. Microscopically, the tumor cells are uniform, with clear cytoplasm and large round nuclei, and are arranged in a diffuse, trabecular, insular, or cordlike pattern. The fibrous stroma includes numerous mature lymphocytes. Dysgerminomas generally display immunoreactivity for placental alkaline phosphatase and do not typically stain for cytokeratin or EMA.
Bilateral involvement of the ovaries by tumor should always raise the possibility of metastatic disease. Nearly 10% of bilateral ovarian tumors are metastatic, most commonly from the gastrointestinal tract and breast.3 Recognition of the metastatic nature of an ovarian tumor depends on an adequate clinical history, but a panel of immunohistochemical markers may play an important role if the primary lesion is unknown. The Table lists some primary and metastatic clear cell tumors in the ovary and the characteristic immunohistochemical staining profile of each.
In the present case, the diagnosis of metastatic renal cell carcinoma was based primarily on microscopic examination and immunohistochemical analysis. The multicystic, hemorrhagic macroscopic appearance of the right ovary suggested a unilateral malignancy and offered few distinguishing characteristics. Bilateral involvement of the ovaries by tumor was apparent only upon microscopic examination. The presence of a solid and tubular microscopic growth pattern composed of clear bland cells within a prominent vascular network was characteristic and raised the possibility of a renal primary tumor. An important microscopic feature not found in other clear cell tumors in the differential diagnosis was the presence of dilated tubules with intratubular eosinophilic fluid or blood. This useful finding has been described previously.4
A panel of immunohistochemical markers provided additional support for the diagnosis of metastatic renal cell carcinoma over other clear cell ovarian neoplasms. The renal cell marker RCC is a monoclonal antibody that recognizes the carbohydrate domain of a 200-kd glycoprotein (gp200) present along the brush border of the proximal tubule. The use of this antibody as a marker of proximal nephrogenic differentiation has resulted in positive immunostaining in 93% of primary and 84% of metastatic renal cell carcinomas.6,7 In our laboratory, we frequently incorporate the RCC antibody into a limited immunohistochemical panel when the differential diagnosis includes renal cell carcinoma. We recently investigated the potential use of RCC in the differential diagnosis between renal cell carcinoma, hepatocellular carcinoma, and adrenocortical tumors. Sixty-nine of the 87 renal cell carcinomas (79%) showed strong membranous staining for RCC. All 31 of the adrenocortical tumors were negative for RCC. Only 1 of the 57 hepatocellular carcinomas displayed a positive reaction for the antibody. We concluded that RCC is a useful addition to the immunohistochemical panel used in this limited differential diagnosis of tumors (unpublished observations). To our knowledge, the specificity of RCC as a single marker for distinguishing clear cell carcinomas of renal origin from other clear cell tumors has not been established.
CD10 is a monoclonal antibody that recognizes a cell surface zinc-dependent metalloproteinase that is expressed in many different cell types. The utility of CD10 in hematopoietic malignancies has been well established, but the recent development of an antibody that is reactive in paraffin-embedded materials has led to its use in the diagnoses of a number of mesenchymal and epithelial neoplasms. CD10 was used recently to reliably distinguish renal cell carcinomas of clear cell and papillary types.8 Similar to RCC, the reactivity of CD10 in other clear cell tumors has not been carefully examined to date.
CA 125 is a monoclonal antibody that recognizes a cell surface glycoprotein originally identified in mucinous epithelial ovarian tumors. This marker has been previously included in the immunohistochemical profile to distinguish between clear cell carcinoma of the kidney and ovary. Nolan and Heatley9 demonstrated that 8 of 10 ovarian clear cell carcinomas were positive with CA 125, whereas all 10 renal cell carcinomas were negative for this marker.
Renal cell carcinomas, particularly the clear cell types, demonstrate a weakly positive or negative staining pattern for cytokeratins.10 Cytokeratin 7, which is expressed by most adenocarcinomas including those of ovarian origin, is typically negative in carcinomas of renal origin.11 In contrast, EMA is a useful marker of epithelial differentiation for these tumors.
Although rare, the possibility of metastatic renal cell carcinoma should be considered in the differential diagnosis of clear cell tumors in the ovary. Careful attention should be paid to characteristic morphologic patterns and the immunohistochemical profile.
Corresponding author: Carmen Gomez-Fernandez, MD, Department of Pathology, University of Miami/Jackson Memorial Medical Center, Holtz Center, Room 2151, 1611 NW 12th Ave, Miami, FL 33136 (email@example.com)