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Background
Clear cell adenocarcinoma (CCA) of the ovary is a strongly chemoresistant tumor in contrast to most of the ovarian surface epithelial carcinomas.
OUTLINE
DISEASE ASSOCIATIONS CHARACTERIZATION Pelvic endometriosis Frequent accompaniment in 20-70% of cases
CHARACTERIZATION RADIOLOGIC
MR imaging of clear cell carcinoma of the ovary.Matsuoka Y, Ohtomo K, Araki T, Kojima K, Yoshikawa W, Fuwa S.
Department of Radiology, Toshiba General Hospital, 6-3-22, Higashi Ooi, Shinagawa-ku, Tokyo 140-8522, Japan
Eur Radiol 2001;11(6):946-51 Abstract quote Magnetic resonance imaging findings are reported for 12 pathologically proven lesions of clear cell carcinoma (CCC) of the ovary in 11 women (mean age 50 years). T1- and T2-weighted MR images were obtained in all patients, and gadolinium-enhanced MR images were obtained in 9.
The mean diameter of the tumors was 13 cm. Seven patients presented with stage-I tumors. All 12 lesions consisted of cystic masses with solid protrusions occurring in 10 and solid masses in 2. The cysts were unilocular in 9 lesions and multilocular in 1. In four lesions, the cysts displayed with high intensity on T1-weighted images. Round solid protrusions were identified in 8 lesions. In 5 lesions, the number of protrusions was only a few. The solid portions of 5 masses had slightly high-intensity regions on T1-weighted images. The number of patients with ascites was three. Magnetic resonance imaging of CCC usually shows a unilocular large cyst with solid protrusions, which are often round and few in number.
Such MR imaging findings suggest malignant tumor but are not specific.
CLINICAL VARIANTS CHARACTERIZATION
Clinical characteristics of clear cell carcinoma of the ovary.Behbakht K, Randall TC, Benjamin I, Morgan MA, King S, Rubin SC.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology,The University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, 19104, USA.
Gynecol Oncol 1998 Aug;70(2):255-8 Abstract quote OBJECTIVE: The aim of this study is to evaluate the clinical characteristics of clear cell carcinoma of the ovary.
METHODS: Between 1986 and 1996, 45 patients with clear cell carcinoma of the ovary were identified by scanning the medical records department and the tumor registry at our institution.
RESULTS: Median age was 55 years (range 31-80 years). Tumors were 60% (27/45) stage I, 11% (5/45) stage II, 20% (9/45) stage III, and 9% (4/45) stage IV. All patients presented with a pelvic mass ranging in size from 2 x 3 to 20 x 30 cm and all except 1 had optimal cytoreduction. All patients received postoperative platinum-based chemotherapy, 47% (21/45) in combination with paclitaxel. One stage Ia patient refused therapy. Of the 6 stage III/IV patients with measurable residual tumor, 67% (4/6) partially responded to first line chemotherapy by CT scan or second look laparotomy. Recurrences occurred in 37% (10/27) stage I patients, including 18% (2/11) stage Ia, 33% (1/3) stage Ib, and 54% (7/13) stage Ic. Time to recurrence was 16 and 38 months for the two stage Ia patients and 35 months (median, range 18-56 months) for the stage Ic patients. Survival after recurrence was significantly related to disease-free interval after primary chemotherapy. With a median follow-up of 40 months (range 4-145 months), 93% (25/27) of stage I patients are alive, 20% (5/25) with disease, while 46% (6/13) of stage III/IV patients are alive. Median survival for the stage III/IV patients was 22 months (range 4-70 months).
CONCLUSIONS: Clear cell tumors of ovary frequently present at early stages. However, these tumors have a propensity for recurrence even after primary chemotherapy in early stage tumors.
SPECIAL STAINS/
IMMUNOPEROXIDASECHARACTERIZATION Special stains Immunoperoxidase
The Use of Cytokeratin 7 and EMA in Differentiating Ovarian Yolk Sac Tumors From Endometrioid and Clear Cell Carcinomas.
Ramalingam P, Malpica A, Silva EG, Gershenson DM, Liu JL, Deavers MT.
From the Departments of *Pathology and daggerGynecologic Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Am J Surg Pathol. 2004 Nov;28(11):1499-1505. Abstract quote
Yolk sac tumors (YSTs) have a variety of morphologic patterns, some of which can resemble either endometrioid adenocarcinoma (EAC) or clear cell carcinoma (CCC). Immunohistochemical staining for alpha-fetoprotein (AFP) is usually only focal and thus is not always helpful in the diagnosis of YST, and pancytokeratin (CK) is expressed by all three tumors.
We studied a battery of immunohistochemical markers with specific attention to the utility of cytokeratin 7 (CK7) in differentiating YST from EAC and CCC. A total of 46 ovarian tumors were retrieved for this study: 16 YST, 19 EAC, and 11 CCC. The three groups were analyzed for the expression of CK7, AFP, Leu-M1 (CD15), EMA, and WT1 by immunohistochemistry. In addition, CK and c-kit (CD117) were studied in the YSTs. All of the YSTs tested (100%) were positive for CK. CK7 was considered negative in all 16 YST cases (100%), although a few tumor cells (1%-2%) stained in 4 cases. In contrast, 17 of 19 EACs and all 11 CCCs had diffuse 3+ to 4+ positivity for CK7; the two other EACs showed 2+ positivity for CK7 (40% and 30% of the tumors). AFP was positive in 12 of 15 YSTs (80%), but was generally focal with 1+ staining in 10 cases (67%); only 2 cases were 3+. All of the EACs and CCCs were negative for AFP. Leu-M1 was 1+ in 9 of 15 YSTs (60%), while the remaining 6 were considered negative. Leu-M1 was positive in 10 of 15 EACs tested (67%), but the staining was variable with 1 case 3+, 3 cases 2+, and 6 cases 1+. In the CCCs, 10 cases (91%) were 3+ to 4+, and 1 case was 1+. EMA was essentially negative in 15 of 15 YSTs (100%), with 3 completely negative and 12 showing very focal (<5%) staining. Eight of 12 EACs showed 4+ staining, 3 showed 3+ staining, and 1 showed 2+ staining. All of the 11 CCCs (100%) showed 4+ staining. WT1 was negative in all cases of YST and CCC; 16 of 18 EAC tested (89%) were negative for WT1, but 2 (11%) were 4+ positive. C-kit was negative in all YSTs.
In conclusion, it is important for pathologists to be aware that YSTs may mimic EACs and CCCs and that this distinction is important for the clinical management of patients with these tumors. AFP staining is focal in most YST, so an absence of staining does not exclude this diagnosis. CK7 and EMA are essentially negative in YST but are diffusely positive in CCC and EAC, making them useful markers for differentiating YSTs from both CCCs and EACs. Leu-M1 may also be helpful for distinguishing YSTs from CCCs.
The value of immunocytochemistry in distinguishing between clear cell carcinoma of the kidney and ovary.Nolan LP, Heatley MK.
Department of Histopathology, Royal Liverpool & Broadgreen, University Hospitals, 5th Floor Duncan Building, Prescott Street, Liverpool, L69 3BX, England.
Int J Gynecol Pathol 2001 Apr;20(2):155-9 Abstract quote Renal clear cell carcinoma rarely metastasizes to the ovary potentially mimicking a primary ovarian clear cell carcinoma. The immunocytochemical profiles of the two tumors were compared. Control groups of ovarian endometrioid and serous adenocarcinomas were also examined using the same antibody panel.
Paraffin sections were studied with the immunocytochemical technique using eight antibodies. Renal clear cell carcinomas were positive for vimentin (8/12 cases), CK5/6 (0/12), 34 beta E12 (1/12), Ber-Ep4 (5/12), CA125 (0/12), ER (1/12), and PGR (1/12). Ovarian clear cell carcinomas showed positivity with vimentin (1/10 cases), CK5/6 (2/10), 34 beta E12 (10/10), Ber-Ep4 (10/10), CA125 (8/10), ER (7/10), and PGR (6/10). Endometrioid adenocarcinomas were positive for vimentin (9/10 cases), CK5/6 (8/10), 34 beta E12 (10/10), Ber-Ep4 (9/10), CA125 (9/10), ER (9/10), and PGR (10/10). Eight serous adenocarcinomas were positive in all cases for all the antibodies except CK5/6 (7/8 cases) and 34 beta E12 (7/8 cases).
All the tumors reacted for epithelial membrane antigen. This immunohistochemical panel allows clear cell carcinomas of kidney and ovary to be distinguished.
The latter has a greater phenotypic similarity with serous and endometrioid adenocarcinomas than with renal clear cell carcinoma demonstrating yet again that these ovarian tumors share a common histogenetic origin.
CD10
CD10 Expression in Epithelial Tissues and Tumors of the Gynecologic Tract: A Useful Marker in the Diagnosis of Mesonephric, Trophoblastic, and Clear Cell Tumors.Ordi J, Romagosa C, Tavassoli FA, Nogales F, Palacin A, Condom E, Torne A, Cardesa A.
Am J Surg Pathol 2003 Feb;27(2):178-86 Abstract quote We tested 417 cases of formalin-fixed, paraffin-embedded normal or hyperplastic gynecologic tissues as well as neoplasms involving the gynecologic tract with a monoclonal antibody against CD10 (clone 56C6), with special emphasis on epithelial and epithelial-like structures and tumors. CD10 was always expressed in mesonephric remnants (mesonephric remnants of the uterine cervix, epoophoron, rete ovarii) and tumors (mesonephric adenocarcinoma of the uterine cervix, tumors of wolffian origin of the broad ligament and ovary). CD10 was also positive in the syncytiotrophoblast, cytotrophoblast, and intermediate trophoblast of normal gestations, partial and complete moles, choriocarcinoma, and placental site trophoblastic tumors. Finally, CD10 was positive in several metastatic neoplasms to the gynecologic tract (100% in metastatic renal clear cell and intestinal carcinomas and melanomas).
In contrast, CD10 was almost invariably negative in mullerian epithelia of the female genital tract and in their corresponding tumors, with the exception of focal expression found in squamous epithelia and tumors with squamous differentiation.
Thus, the expression of CD10 may be useful in the establishing the diagnosis of mesonephric and trophoblastic tumors and in the differential diagnosis between gynecologic clear cell carcinoma (always negative) and metastatic clear cell carcinoma of renal origin.
CD44
Clear cell carcinoma of the ovary: characterization of its CD44 isoform repertoire.Sancho-Torres I, Mesonero C, Miller Watelet JL, Gibbon D, Rodriguez-Rodriguez L.
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Rochester, New York, 14642, USA.
Gynecol Oncol 2000 Nov;79(2):187-95 Abstract quote OBJECTIVE: CD44 is a cell surface receptor implicated in tumor metastases. We have previously shown that there is a loss of CD44 splice control in clear cell carcinoma (CCCa) of the ovary. Our aim is to characterize the expression of CD44-3v, -5v, -7v, and -10v in clear cell ovarian tumors and to determine their prognostic value.
METHODS: Twenty-two cases of ovarian CCCa were studied for CD44-3v, -5v, -7v, and -10v expression by immunocytochemistry.
RESULTS: The primary tumors showed expression of CD44-3v, -5v, -7v, and -10v in 44, 55, 61, and 39% of the cases, respectively. We were able to compare the expression of CD44 in the primary tumor and metastatic sites from the same patient in 7 cases (metastatic sites n = 16). We observed decreased immunoreactivity of CD44-3v, -5v, -7v, and -10v in 67, 100, 93, and 92% of the sites, respectively. CD44-3v and -10v expression was absent in 100% of the nonaffected contralateral ovaries while -7v and -10v were expressed in 1/11 (9%) of them. When CD44-10v was not expressed in the primary tumor, only 18% of the women recurred or died of disease; in contrast, of the cases where it was present, 71% of the women recurred or died of disease (P = 0.049).
CONCLUSIONS: There is aberrant alternative mRNA splicing in the development of CCCa of the ovary when compared to the contralateral nonaffected ovary. The expression of CD44-10v correlates with survival. Larger series are needed to further understand the role of CD44 isoforms in ovarian cancer metastases.
ESTROGEN AND PROGESTERONE RECEPTORS Absence of Estrogen Receptor- Expression in Human Ovarian Clear Cell Adenocarcinoma Compared With Ovarian Serous, Endometrioid, and Mucinous Adenocarcinoma
Masaki Fujimura, etal.
Am J Surg Pathol 2001;25:667-672 Abstract quote
The mechanism that regulates growth in ovarian clear cell adenocarcinoma (CCA) is not well understood. A high incidence of concurrent endometriosis with CCA may indicate that estrogen is a growth promotor in CCA.
To determine estrogen as a growth promotor, the authors investigated the presence or absence of estrogen receptor- (ER-), ER-, progesterone receptor, and dioxin receptor (i.e., aromatic hydrocarbon receptor) in clinically resected ovarian CCA, serous adenocarcinoma (SAC), endometrioid adenocarcinoma (EAC), and mucinous adenocarcinoma (MAC) specimens using an immunohistochemical method. Expression of ER- and ER- messenger ribonucleic acid was examined by reverse transcription–polymerase chain reaction in three established CCA cell lines: KK, RMG-1, and HAC-II.
None of the surgically resected CCA and CCA cell lines showed positive staining for ER-. Conversely, 97.2% of SACs, 100% of EACs, and 70% of MACs showed positive nuclear staining for ER- (p <0.001). Conversely, positive ER- staining for CCA (39.3%) was similar to that of SAC (41.7%) and MAC (30.0%). EAC (75%) showed a higher expression of ER- (p <0.02). Progesterone receptor was detected in only 10.7% of CCA, compared with SAC and EAC (SAC, 86.1%; EAC, 91.7%; p <0.01). Aromatic hydrocarbon receptor was detected in all histologic types at an incidence of approximately 50% to 60%.
Messenger ribonucleic acid of ER- and ER- was not detected in the three CCA cell lines. These findings indicate biologic characteristics that distinguish CCA from other types of ovarian epithelial cancer.
HUMAN KIDNEY INJURY MOLECULE-1 (hKIM-1)
*Department of Laboratory Medicine, Geisinger Medical Center, 100 N. Academy Avenue, Danville, PA 17822 daggerDepartment of Pathology, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 double daggerShanghai Institute of Cardiovascular Disease, Shanghai Zhongshan Hospital, Fudan University, Shanghai, P. R. of China section signDepartment of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 parallelDepartment of Pathology and Immunology, Washington University in St Louis, St Louis, MO 63110-1093 paragraph signDepartment of Pathology, The Methodist Hospital, Affiliated with Weil Medical College of Cornell University, Houston, TX 77030 musical sharpVan Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, MI 49503
Human kidney injury molecule-1 (hKIM-1), a type I transmembrane glycoprotein expressed in injured renal proximal tubules, was also found in renal cell carcinoma (RCC).
The current study attempts to evaluate the diagnostic utility of hKIM-1 in a large series of 480 neoplasms including defined subtypes of renal cell tumors, metastatic RCCs, and nonrenal tumors. Tissue microarray (TMA) sections containing 179 renal cell tumors (73 clear cell RCC, 30 papillary RCC, 16 chromophobe RCC, 15 oncocytoma, and 45 metastatic RCC) were included in this study. In addition, 80 cases of renal cell neoplasm and 221 nonrenal tumors in routine tissue sections were also included. Both TMA and routine sections were incubated with anti-hKIM-1 monoclonal antibody using an EnVision-HRP kit.
The results demonstrated that a membranous/cytoplasmic staining pattern for hKIM-1 was observed in 54 of 73 (74%) clear cell RCCs and 28 of 30 (93%) papillary RCCs on TMA sections. Zero of 54 chromophobe RCCs and 4 of 41 (9.75%) oncocytomas were positive for hKIM-1 when combining TMA and routine sections. Similar staining results were observed in 35 of 45 (78%) metastatic RCCs. Data from cDNA microarray expression and Western blot demonstrated similar findings. Fifteen of 16 cases (93.8%) of clear cell carcinoma of the ovary demonstrated positive reactivity for hKIM-1.
These data indicate that hKIM-1: (1) is a relatively sensitive and specific marker for papillary, clear cell, and metastatic RCCs, (2) can be used to distinguish clear cell from chromophobe RCC, and (3) may serve as a diagnostic marker for clear cell carcinoma of the ovary.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES GASTROINTESTINAL TUMORS METASTATIC
Metastatic intestinal carcinomas simulating primary ovarian clear cell carcinoma and secretory endometrioid carcinoma: a clinicopathologic and immunohistochemical study of five cases.Young RH, Hart WR.
Department of Pathology, Harvard Medical School and the James Homer Wright Pathology Laboratories of the Massachusetts General Hospital, Boston 02114, USA.
Am J Surg Pathol 1998 Jul;22(7):805-15 Abstract quote Five cases of ovarian metastases of intestinal adenocarcinomas that suggested the diagnosis of clear cell adenocarcinoma or the secretory variant of endometrioid carcinoma of the ovary are reported. Patient age ranged from 27 to 71 years at the time of diagnosis of the ovarian neoplasms. In four, the ovarian and intestinal tumors were discovered synchronously, and, in the fifth, the ovarian metastasis occurred 1 year after the intestinal primary was diagnosed.
The ovarian tumors were unilateral in three patients and bilateral in two. They were up to 18 cm (mean, 12 cm) in maximum dimension and were characterized on microscopic evaluation by glands and cysts lined by cells whose most striking feature was abundant clear cytoplasm. In two cases, striking subnuclear or supranuclear vacuoles were present. An important clue to the diagnosis of metastatic intestinal adenocarcinoma was the presence in all cases of "dirty necrosis." The metastatic nature of the ovarian tumors was supported by the immunohistochemical findings. All tumors stained were strongly positive for carcinoembryonic antigen and cytokeratin 20 and failed to stain for CA125, whereas staining for HAM56 and cytokeratin 7 was absent or only focally positive in one case each. Three intestinal primary tumors involved the small bowel.
Microscopic evaluation of the intestinal tumors in three cases and metastases in a fourth, in which the intestinal primary was not resected, showed the features of the uncommon clear cell variant of intestinal adenocarcinoma; the fifth was predominantly a conventional intestinal adenocarcinoma with only a focal clear cell component.
Although intestinal adenocarcinomas metastatic in the ovary typically simulate endometrioid adenocarcinoma of the usual type or mucinous adenocarcinoma, they may mimic either primary clear cell adenocarcinoma or the secretory variant of endometrioid adenocarcinoma, particularly when the primary tumor is, even focally, the clear cell variant of intestinal adenocarcinoma.
RENAL CELL CARCINOMA METASTASTIC
Renal cell carcinoma metastatic to the ovary: a report of three cases emphasizing possible confusion with ovarian clear cell adenocarcinoma.Young RH, Hart WR.
Department of Pathology, Harvard Medical School, James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Boston 02114.
Int J Gynecol Pathol 1992;11(2):96-104 Abstract quote The clinical and pathological features of three personally observed and six previously reported cases of renal cell carcinoma metastatic to the ovary are reviewed. The patients' ages ranged from 39 to 64 (average, 52) years.
In five patients the ovarian tumor was discovered first. In four of these patients renal tumors were detected during the initial clinical studies or in the early postoperative period, but in the fifth the renal primary tumor was not detected until 8 years later. The ovarian tumor in two cases was initially misdiagnosed as a primary ovarian clear cell carcinoma. In the remaining four patients the ovarian metastasis was detected 5 months, 12 months, 19 months, and 11 years after a renal tumor had been removed. In two patients the initial clinical manifestations were due to a metastasis of the renal tumor, to the thyroid gland in one and to the vagina in the other.
The renal tumors in these nine patients typically were well-differentiated renal cell adenocarcinomas of clear cell type. The ovarian tumors measured from 7 to 18 (average, 12.5) cm in greatest dimension; two of them were bilateral. Grossly they were usually solid or solid and cystic; one was a unilocular cyst with a predominantly smooth lining and a 2.5-cm solid nodule in one area. The solid component of the tumors was typically either uniformly yellow or had focal yellow areas with hemorrhagic foci.
Microscopic examination showed a relatively uniform picture in most cases: solid or alveolar nests of epithelial cells with abundant clear cytoplasm or tubules lined by clear cells and containing intraluminal eosinophilic material and extravasated blood.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS PROLIFERATION RATE
Low proliferation activity may be associated with chemoresistance in clear cell carcinoma of the ovary.Itamochi H, Kigawa J, Sugiyama T, Kikuchi Y, Suzuki M, Terakawa N.
Department of Obstetrics and Gynecology, Tottori University, Yonago, Japan.
Obstet Gynecol 2002 Aug;100(2):281-7 Abstract quote OBJECTIVE: To estimate whether and how the biologic behavior of clear cell carcinoma contributes to the chemoresistance mechanism.
METHODS: Forty-one patients with clear cell carcinoma and 90 patients with serous adenocarcinoma, who had measurable disease after initial surgery, were examined. All patients underwent cytoreductive surgery followed by platinum-based chemotherapy. P-glycoprotein, multidrug resistance-associated protein, and Ki-67 expression were determined by immunohistochemical staining.
RESULTS: The 5-year survival rate for patients with clear cell carcinoma was significantly poorer, compared with serous adenocarcinoma (20.0% versus 31.9%). Response rate to chemotherapy was 14.6% for clear cell carcinoma and 72.2% for serous adenocarcinoma. The expression of P-glycoprotein and multidrug resistance-associated protein did not differ between responders and nonresponders in both tumor types. The Ki-67 labeling index (LI) in clear cell carcinoma was significantly lower than serous adenocarcinoma (18.4% versus 38.8%). The LI for responders was significantly higher than that for nonresponders in both tumor types. In clear cell carcinoma, the mean value of LI was 15.3% for nonresponders, but that for responders was 30.2%, which was similar to that for serous adenocarcinoma. When the cutoff value of LI was set at 18.4% (mean value), the 5-year survival rate for high LI (over 18.4%) patients was significantly greater than that for low LI patients (46.3% versus 9.2%). Multivariable analysis revealed that LI and residual tumor size were the independent prognostic factors.
CONCLUSION: Lower proliferation of tumor may be a behavior of clear cell carcinoma of the ovary that contributes to its resistance to chemotherapy.
Mechanisms of cisplatin resistance in clear cell carcinoma of the ovary.Itamochi H, Kigawa J, Akeshima R, Sato S, Kamazawa S, Takahashi M, Kanamori Y, Suzuki M, Ohwada M, Terakawa N.
Department of Obstetrics and Gynecology, Tottori University, Yonago, Japan.
Oncology 2002;62(4):349-53 Abstract quote Resistance of clear cell carcinoma (CCC) of the ovary to platinum-based chemotherapy is associated with a poor prognosis. However, the mechanism underlying the resistance of CCC to platinum has not yet been understood.
We conducted the present study to clarify the mechanism of cisplatin (CDDP) resistance in CCC cells. Eleven CCC and 5 serous adenocarcinoma (SAC) cell lines were used in this study. The IC(50) to CDDP ranged from 1.3 to 18.0 microM for CCC cells and from 2.2 to 13.0 microM for SAC cells. There was no correlation between multidrug resistance-associated protein expression and the sensitivity to CDDP in CCC cells. In contrast, the doubling time for CCC cells was significantly longer than that for SAC cells (61.4 vs. 29.8 h). A significant reverse correlation between the S-phase fraction and the response to CDDP was observed (r = 0.647, p < 0.05).
The present study suggests that the resistance of CCC to CDDP may be caused by low cell proliferation.
RECURRENCE
Recurrent ovarian clear cell carcinoma: complete remission after radiation in combination with hyperthermia; a case study and in vitro study.Suzuki M, Saga Y, Tsukagoshi S, Tamura N, Sato I.
Department of Obstetrics and Gynecology, Jichi Medical School, Tochigi, Japan.
Cancer Biother Radiopharm 2000 Dec;15(6):625-8 Abstract quote Since clear cell carcinoma of the ovary does not respond to conventional platinum-based chemotherapy, the prognosis of recurrent tumors is especially poor.
In a 51-year old female who underwent surgery for clear cell carcinoma of the ovary, a solitary metastatic carcinoma developed in the pelvic cavity seven months after the initial surgery. The patient underwent a whole pelvic irradiation at a total dose of 65 Gy combined with hyperthermia. Complete remission was achieved 46 months after treatment. A study using gynecologic carcinoma cell lines showed that the mean 50% growth inhibitory dose of radiation was 1.2 +/- 0.4 Gy in several clear cell carcinoma cell lines. The value did not significantly differ from those for serous carcinoma cell lines (2.3 +/- 1.2 Gy) and uterine cervical carcinoma cell lines (1.6 +/- 0.4 Gy).
Currently, no anticancer agents are effective for clear cell carcinoma. Radiotherapy combined with hyperthermia may be effective for localized tumors.
SURVIVAL 5-year survival rate of patients with stage I ovarian CCA ranged from 90% of patients to approximately 50% to 60% of patients, comparable with the other histologic types of surface epithelial ovarian carcinoma
5-year survival rate for stage II disease declines to only 17% to 29%, which is worse, probably because of the chemoresistance of CCA
Clear cell carcinoma of the ovary: poor prognosis compared to serous carcinoma.Tammela J, Geisler JP, Eskew PN Jr, Geisler HE.
Department of Obstetrics and Gynecology, St. Vincent Hospital and Health Care Center, Indianapolis, Indiana 46260, USA.
Eur J Gynaecol Oncol 1998;19(5):438-40 Abstract quote BACKGROUND: A review of literature comparing the survival of patients with clear cell carcinoma of the ovary to patients with serous carcinoma reveals divided opinions. No studies of statistical significance have demonstrated worse survival in a cohort of patients with clear cell carcinoma matched stage for stage with patients with serous carcinoma of the ovary. The purpose of this study was to compare survival in a cohort of clear cell carcinoma patients to a cohort of serous carcinoma patients matched for stage, age, treatment, and cytoreduction.
METHODS: All cases of clear cell carcinoma and serous carcinoma of the ovary operated on by the gynecology oncology service from January 1, 1981 to December 31, 1989 were evaluated for patient age, length of survival and level of primary cytoreduction, as well as FIGO stage and histology.
RESULTS: Twenty-two patients with clear cell carcinoma found in the years noted were compared to a cohort of 22 patients with serous carcinoma matched for stage (I, 18.2%; II, 9.1%; III, 63.6%; IV, 9.1%), age (clear cell carcinoma 58 years, serous carcinoma 60 years (p = 0.330)), and level of primary cytoreduction (optimal in 63.6% of both clear cell carcinoma and serous carcinoma cohorts and non-optimal in 36.4% of both groups). Survival in the clear cell carcinoma cohort (16 months) was worse than in the serous carcinoma cohort (36 months) (p = 0.045).
CONCLUSION: Patients with clear cell carcinoma have a significantly worse prognosis than patients with serous carcinoma when matched for age, stage, and level of primary cytoreduction.
TREATMENT Strongly chemoresistant to conventional therapies
Optimal treatment of CCA is believed to be complete resection of the tumor; however, a complete resection is difficult to achieve in patients with advanced disease
CHEMOTHERAPY
Sensitivity to anticancer agents and resistance mechanisms in clear cell carcinoma of the ovary.Itamochi H, Kigawa J, Sultana H, Iba T, Akeshima R, Kamazawa S, Kanamori Y, Terakawa N.
Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago 683-8504, Japan
Jpn J Cancer Res 2002 Jun;93(6):723-8 Abstract quote We conducted the present study to determine the chemoresistance mechanisms in clear cell carcinoma of the ovary (CCC). Five human CCC cell lines (HAC-2, RMG-I, RMG-II, KK, and KOC-7c) were used in this study.
The sensitivity of the cells to the anticancer agents was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and we assessed drug sensitivity by calculating assay area under the curve (AUC) for each agent.
The expression of multi-drug resistance genes (MDR-1, MRP-1, MRP-2) was detected by reverse transcription-polymerase chain reaction (RT-PCR). Glutathione (GSH) concentration was measured by an enzymatic assay. Topoisomerase (topo) I activity was assayed in terms of relaxation of supercoiled plasmid substrate DNA. The IC(50) to anticancer agents ranged widely. The assay AUC indicated that 3 of 5 cell lines (RMG-I, RMG-II, and KK) were sensitive to paclitaxel (PTX), 3 (HAC-2, RMG-I, and RMG-II) were sensitive to 7-ethyl-10-hydroxycamptothecin (SN-38), which is an active metabolite of camptothecin (CPT-11), and only one (HAC-2) was sensitive to cisplatin (CDDP). All cell lines were resistant to mitomycin-C (MMC) and etoposide (VP-16). The MRP-1 gene was detected in all cell lines. Only one cell line showed both MRP-2 and MDR-1 gene expression. Except for HAC-2 cells, expression of MRP genes was related to CDDP resistance, and MDR-1 gene expression was associated with PTX resistance. GSH concentrations increased after exposure to CDDP or MMC in all cell lines. There was a significant correlation between topo-I enzymatic activity and the response to SN-38.
The present study revealed several resistance mechanisms in CCC and the results suggested that PTX and CPT-11 might be effective agents to treat CCC.
Exploratory study of effective chemotherapy to clear cell carcinoma of the ovary.Kita T, Kikuchi Y, Kudoh K, Takano M, Goto T, Hirata J, Tode T, Nagata I.
Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
Oncol Rep 2000 Mar-Apr;7(2):327-31 Abstract quote Although clear cell carcinoma of the ovary is considered to be a tumor with poor prognosis, the clinical characteristics has not been defined.
The aim of this study was to evaluate the response of clear cell carcinoma of the ovary to first and second-line chemotherapy and explore effective chemotherapy. Fifty-three patients with clear cell carcinoma of the ovary were enrolled between 1988 and 1997 at our department. Since taxol was not available in Japan at that time, cisplatin-based combination chemotherapy has been exclusively used as a standard first-line chemotherapy.
Retrospective analyses of clinical characteristics and the response to first or second-line chemotherapy were performed. Median age was 52 years (range 27-71 years). Tumors were 34% (18/53) stage I, 19% (5/53) stage II, 38% (20/53) stage III, and 9% (5/53) stage IV. All patients with I or II stage disease had optimal cytoreduction.
Out of 25 patients with III or IV stage disease 20% (5/25) had negative residual tumor, 36% (9/25) had <2 cm residual tumor, and 44% (11/25) had >/=2 cm residual tumor. All patients received postoperative platinum-based chemotherapy. Of 23 patients with measurable residual tumor 8.7% (2/23) completely and 13% (3/23) partially responded to first-line chemotherapy consisting of cisplatin, adriamycin and cyclophosphamide (CAP) or cisplatin and cyclophosphamide (CP) by CT scan or second look laparotomy. Presence of endometriosis was 55% (29/53) but was not a prognostic factor. Although overall response rate of ovarian clear cell carcinoma to first-line chemotherapy by CAP or CP was about 22%, EP or EJ consisting of etoposide and cisplatin or carboplatin used as a second-line chemotherapy showed 29% response rate, while CPT-P consisting of CPT-11 and cisplatin showed 40% response rate.
Clear cell carcinomas were frequently present at early stage, with association of endometriosis and with poor overall prognosis. Although patients with advanced ovarian clear cell carcinoma seemed to have better response to CPT-P than conventional platinum-based chemotherapy, further studies are required with larger number of patients to draw firm conclusions.
A phase II study of combined CPT-11 and mitomycin-C in platinum refractory clear cell and mucinous ovarian carcinoma.Shimizu Y, Umezawa S, Hasumi K.
Department of Gynecology, Cancer Institute Hospital, Tokyo, Japan.
Ann Acad Med Singapore 1998 Sep;27(5):650-6 Abstract quote This article reviews the preliminary but encouraging clinical data obtained from patients with platinum-refractory clear cell or mucinous carcinoma of the ovary who were treated with a chemotherapy regimen including irinotecan hydrochloride (CPT-11).
Twenty-five patients with platinum-refractory macroscopic disease of which histologic type was either clear cell or mucinous carcinoma were treated. CPT-11 was administered at a dose of 120 mg/m2 intravenously (i.v.) over 4 hours on days 1 and 15, and mitomycin-C (MMC) was given IV as a bolus at a dose of 7 mg/m2 on days 1 and 15. At least 2 cycles of this regimen, 4 weeks apart, were given to the 25 patients. After a median of 4 cycles (range 2 to 8), we observed objective responses in 13 patients (52%), with 5 complete responses (CRs; 20%) and 8 (32%) partial responses (PRs) (95% confidence interval, 32.4% to 71.6%, 4.3% to 35.7%, 13.7% to 50.3%, respectively).
The median overall survival time for all 25 patients was 15.3 months (range 3.5 to 38.0). Median overall survival time of the responders was 33.7 months versus 6.1 months of the non-responders (Log-rank, P = 0.0003). The median progression-free survival times for patients obtaining CR, PR, and CR+PR were 31.8 months (range 12.9 to 34.4), 10.5 months (range 5.6 to 18.2), and 12.9 months (range 5.6 to 34.4), respectively.
Toxic effects were acceptable and included manageable haematologic reactions, diarrhoea, nausea/vomiting, and alopecia.
Gynecol Oncol 1989;35:199–203.
Int J Gynecol Pathol 1989;8:85–96.
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