Clinical case
Forty-year-old G1P1 presented to her local emergency department with back pain. A CT scan showed a 14 cm right ovarian cyst, and CA-125 was elevated at 49 U/mL. She underwent a robotic-assisted laparoscopic right salpingo-oophorectomy, with surgical findings of adhesions in the posterior cul-de-sac ( Fig. 4.1 ). Final pathology was consistent with clear cell carcinoma of the ovary with evidence of endometriosis. She subsequently underwent completion staging with total abdominal hysterectomy, left salpingo-oophorectomy, pelvic and paraaortic lymph node dissection, omentectomy, and pelvic washings. Her final stage was FIGO stage IC3, and she was offered chemotherapy with carboplatin and paclitaxel. Is there benefit of adjuvant chemotherapy in stage I ovarian clear cell carcinoma?
Epidemiology
Incidence/mortality
In the United States, it is estimated that there will be 21,410 new diagnoses of ovarian cancer and 13,770 deaths from ovarian cancer. For these women with newly diagnosed ovarian cancer, estimated five-year survival for all stages and histologies is approximately 49%. The most recent average annual age-adjusted incidence of ovarian cancer for all Surveillance, Epidemiology, and End Results (SEER) areas is 10.9 per 100,000 women, and the average age-adjusted mortality rate is 6.7 per 100,000 women .
Ovarian clear cell carcinoma represents 5% to 10% of ovarian cancers in the United States; however, there are known geographical and racial differences in incidence. For example, there is a much higher incidence of ovarian clear cell carcinoma in Japan, Taiwan, and Korea, where ovarian clear cell carcinoma represents 15% to 25%, 19%, and 10% of ovarian cancers, respectively. In the United States, Asian/Pacific Islanders have the highest incidence rates of ovarian clear cell carcinoma (1.0 per 100,000 women), which is about twice that of women in other racial groups. Environmental and genetic factors likely play a role in development of ovarian clear cell carcinoma but reasons for variation of incidence among racial groups are unclear. Additionally, it is unknown why ovarian clear cell carcinoma is more likely to present in younger women with a median age of 55 years, compared to the more common high-grade serous counterpart, where the median age of presentation is 64 years.
Ovarian clear cell carcinoma is a rare ovarian malignancy; as a result, clinical trials are not powered to make conclusions for ovarian clear cell carcinoma despite known differences in response to treatment. Recommendations for surveillance and treatment of ovarian clear cell carcinoma are nonspecific and follow recommendations for the most common histology of ovarian cancer, high-grade serous. In this chapter we will highlight the known distinct features of ovarian clear cell carcinoma and treatment recommendations.
Etiology/risk factors
Similar to endometrioid ovarian carcinoma, ovarian clear cell carcinoma is often associated with or arises from endometriosis. Women with endometriosis have a significantly elevated age-adjusted incidence rate ratio for ovarian clear cell carcinoma (2.29, 95% CI, 1.24–4.20). A metaanalysis combining data from 13 ovarian cancer case–control studies found that self-reported endometriosis significantly increased the risk of ovarian clear cell carcinoma (OR 3.05, 95% CI, 2.4–3.8). On final pathology, endometriosis is identified in up to 51% of ovarian clear cell carcinoma cases. The association of endometriosis is further supported by the protective nature of tubal ligation against the development of ovarian clear cell carcinoma. The Ovarian Cancer Cohort Consortium found that tubal ligation and hysterectomy were associated with a significantly reduced risk of ovarian clear cell carcinoma (RR 0.35, 95% CI, 0.18–0.69; RR 0.57, 95% CI, 0.36–0.88, respectively). Theoretically, occlusion of the tubes or hysterectomy could prevent retrograde menstruation and subsequent development of endometriosis. However, the effect of endometriosis may confound these results. Most women undergo tubal ligation after childbearing is complete and women with endometriosis have higher rates of infertility. The group who did not undergo tubal ligation may have a disproportionate number of patients with endometriosis.
Endometriosis with cytologic atypia or complex hyperplasia (atypical endometriosis) is the most likely precursor to clear cell ovarian cancers. Studies have found that similar gene mutations are detected in ovarian clear cell carcinoma and adjacent atypical endometriosis. Chronic inflammation associated with endometriosis has also been identified as a potential risk factor for development of cancers, involving the intensive release of cytokines and infiltration of immune cells.
In addition to endometriosis, patients with germline mutations associated with BRCA1/2 or Lynch syndrome also have an increased risk of ovarian clear cell carcinoma. In a study of 1119 BRCA1/2 associated ovarian cancers, 2% were of clear cell histology. In Lynch syndrome, a Swedish/Danish cancer registry found that ovarian cancer subtypes differed from the sporadic population, with 35% endometrioid and 17% clear cell histology. Therefore, as in all epithelial ovarian cancers, women with ovarian clear cell carcinoma should be recommended to undergo genetic testing.
Pathology
Gross
The gross appearance of ovarian clear cell carcinoma is variable with cut surface being entirely solid, entirely cystic or solid and cystic. The entirely cystic tumors are grossly not distinguishable from other benign ovarian cysts.
Microscopic findings
Histologically ovarian clear cell carcinomas are heterogeneous with papillary ( Fig. 4.2 ), tubulocystic, and solid patterns. The papillae of ovarian clear cell carcinomas are lined by cells with clear cytoplasm that have characteristic hobnail appearance, lining a hyalinized fibrovascular core. The tubulocystic pattern ( Fig. 4.3 ) is composed of numerous dilated cysts with markedly flattened epithelium that may impart a “benign” appearance on low power examination. However, on high power review, the prominent cytologic atypia is usually apparent. In ovarian clear cell carcinoma, the nuclei are variably atypical and usually round without significant pleomorphism, though bizarre cells may be seen in a subset of cases. Prominent “cherry-red” nucleoli, though not specific, are typically seen in ovarian clear cell carcinomas. While majority of ovarian clear cell carcinomas have typical cytoplasmic clearing, in some cases the cells have eosinophilic cytoplasm, and can mimic endometrioid or serous carcinoma. The mitotic activity is usually low. Ovarian clear cell carcinoma has been shown to have significant interobserver variability, even among gynecologic pathology experts, as both endometrioid adenocarcinoma and high-grade serous carcinoma can have prominent clear cell changes.
Ancillary testing
The currently available immunohistochemical (IHC) stains used to establish a diagnosis of ovarian clear cell carcinoma, are unfortunately neither sensitive nor specific, limiting their utility. The tumors are positive for PAX-8, hepatocyte nuclear factor 1 beta (HNF-1B) ( Fig. 4.4 ), napsin A ( Fig. 4.5 ), and α-methylacyl-coenzyme A racemase (AMACR, p504S), while negative for WT-1. Estrogen and progesterone receptors (ER and PR) are typically negative in ovarian clear cell carcinomas; however, focal and or diffuse weak staining can be seen in a subset of tumors. HNF-1B, frequently used to confirm ovarian clear cell carcinoma is highly sensitive but not specific, as it can be expressed in both endometrioid and serous carcinomas. Conversely, AMACR and napsin-A are more specific for a diagnosis of ovarian clear cell carcinoma but their low sensitivity results in them not being helpful in many cases.
Differential diagnosis
The differential diagnosis of clear cell carcinoma is quite vast and encompasses epithelial, germ cell and sex cord tumors, as well as metastatic tumors with clear cytoplasm. As mentioned earlier both endometrioid carcinoma and serous carcinoma can mimic ovarian clear cell carcinoma. IHC stains can show overlapping expression among ovarian clear cell carcinomas, serous carcinoma and endometrioid carcinoma, making a definite diagnosis challenging in some cases. This is further compounded by the lack of sensitivity and specificity of the available immunomarkers used to confirm a diagnosis of clear cell carcinoma. In typical cases endometrioid carcinoma and serous carcinoma will have hormone receptor expression with absent staining for HNF-1B, and napsin-A. p53 staining has limited utility in distinguishing serous carcinoma from clear cell carcinoma in isolation, as the former can rarely show wild-type staining and the latter can show p53 overexpression. An important differential is yolk sac tumor (YST), which can have histologic features that are virtually indistinguishable from clear cell carcinoma. Young age of presentation, elevated serum alpha-fetoprotein (AFP) and presence of Schiller-Duval bodies would favor YST. YSTs are positive for SALL-4, and AFP while negative for CK7, while ovarian clear cell carcinomas will show the opposite staining pattern. The solid variant of clear cell carcinoma can mimic steroid cell tumor and metastatic renal cell carcinoma. Steroid cell tumors and ovarian clear cell carcinomas have completely different immunoprofiles that will facilitate the correct diagnosis. Metastatic clear cell renal cell carcinoma (RCC) can be more challenging due to overlapping immunomarker expression such as PAX-8, napsin-A, and HNF-1B. Presence of a renal mass and positivity for RCC-specific markers will help in making the correct diagnosis.
Molecular findings
In ovarian clear cell carcinoma, the most common molecular genetic alterations are somatic inactivating mutations of AT-rich interactive domain 1A (ARID1A) , activating mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha ( PIK3CA), and deletion of phosphatase and tensin homolog ( PTEN) . ARID1A mutations are present in approximately 50% of ovarian clear cell carcinomas, but there are also reports of its presence in the adjacent foci of atypical endometriosis. This finding suggests that ARID1A mutations represent an early molecular event in ovarian clear cell carcinomas, and that endometriosis may be a precursor lesion for these tumors.
Diagnosis and workup
Differential diagnosis
Diagnosis of ovarian clear cell carcinoma is difficult due to the diversity of clinical presentation, nonspecific symptoms and endometriosis-associated symptoms. In contrast to the more common high-grade serous ovarian cancer, patients with ovarian clear cell carcinoma often present with unilateral, sometimes large adnexal masses and more commonly present with earlier stage disease. The differential diagnosis for an adnexal mass is quite large, including but not limited to ectopic pregnancy, physiologic/ functional cysts, polycystic ovaries, serous/mucinous cystadenomas, germ cell tumors, sex cord stromal tumors, peritoneal inclusion cysts, fibroids, endometriosis, tubo-ovarian abscess, appendiceal/diverticular abscess, colon cancer, and/or metastasis from a different primary. The workup for an adnexal mass must keep this broad differential diagnosis in mind.
Signs and symptoms
Ovarian clear cell carcinoma typically presents as a pelvic mass, often large pelvic mass. In early-stage ovarian clear cell carcinoma, initial presentation is often an asymptomatic adnexal mass discovered incidentally during workup for another condition. Some may present with pelvic pain and pressure due to a growing, typically unilateral, adnexal tumor. Clinical presentation of patients with advanced ovarian cancer varies, and symptoms are often nonspecific, such as fatigue, loss of appetite, early satiety, nausea, and anorexia, and may overlap with symptoms of concurrent endometriosis. Symptoms in advanced-stage ovarian clear cell carcinoma may be due to ascites, pleural effusions and peritoneal carcinomatosis. Because symptoms overlap with more common disorders (e.g., endometriosis, menopause, constipation, irritable bowel syndrome) diagnosis may be delayed.
Ovarian clear cell carcinoma tumors range up to 30 cm in diameter, with a mean of 13 to 15 cm. As the mass grows, it may cause bulk symptoms. Urinary complaints are common including urinary urgency and frequency. As these tumors expand posteriorly, they can compress the colon, leading to constipation and pain. Pelvic and abdominal symptoms include bloating, and diffuse, dull, constant abdominal pain. Adnexal masses may also present with acute onset abdominal pain, which may be associated with rupture, torsion, or bowel obstruction.
Deep venous thrombosis (DVT) may develop due to the hypercoagulability associated with advanced cancer, or the tumor pressing on the pelvic veins. Of the epithelial ovarian cancers, ovarian clear cell carcinoma are most commonly associated with DVT which occur in up to 42% of cases. Ovarian clear cell carcinoma expresses high levels of tissue factor, a transmembrane protein that is associated with hypercoagulability. Complaints of lower extremity swelling/pain, shortness of breath, and pleuritic chest pain must be evaluated thoroughly due to elevated risk of DVT and pulmonary embolism. Hypercalcemia is observed at a higher frequency in ovarian clear cell carcinoma compared to other ovarian cancers due to production of parathyroid hormone-related protein.
There is no evidence that screening for symptoms aids in recognizing ovarian cancers at earlier stage or improves detection with use of CA-125 or ultrasound. Early referral to a gynecologic oncologist for patients with symptomatic, persistent or growing adnexal masses, ascites, or evidence of abdominal/ distant metastases is imperative.
Physical exam findings
Physical exam findings are similar for benign and malignant adnexal masses. It is nearly impossible to identify a malignant mass based on clinical exam alone. A comprehensive exam is essential, including evaluation of extremities, lungs, supraclavicular nodes, and breasts. Lower extremity edema, tenderness, or a palpable cord is suggestive of a DVT. Abdominal exam should include palpation and percussion. If the tumor produces a large amount of ascites, the abdominal cavity may be distended, causing increased abdominal circumference and marked discomfort. Ascites can also cause dyspnea, as the lower lungs are compressed by abdominal distension.
On pelvic exam, a bimanual and rectovaginal exam should be performed. Visually, a cystocele may indicate the presence of ascites. During pelvic exam, the clinician should note the size, borders, mobility, and location of the mass. Invasive cancers are typically large, fixed, and have irregular borders. Exam may also reveal involvement of the parametrium or nodularity of the rectovaginal septum, also known as a Blumer’s shelf.
Tumor markers
The most studied tumor marker associated with epithelial ovarian cancer is CA-125. Pretreatment CA-125 levels are elevated in the majority of patients with ovarian clear cell carcinoma, but levels do not predict clinical outcome. A retrospective case–control study of 375 patients with ovarian clear cell carcinoma, found that pretreatment CA-125 levels were not associated with relapse-free survival (RFS) or overall survival. Pretreatment CA-125 is normal in 30% of early-stage and 13% of advanced-stage ovarian clear cell carcinoma. The majority of ovarian clear cell carcinomas are diagnosed at early stage so elevated CA-125 levels are not a reliable marker of malignancy in these patients ( Table 4.1 ).
| Early-stage | Advanced-stage | ||
|---|---|---|---|
| Imaging | Pelvic ultrasound: detect and characterize adnexal mass | Papillary surface excrescences, areas of necrosis, internal solid elements | Suspicious adnexal mass and ascites, upper abdominal disease |
| CT scan: assess extent of disease, assist with surgical planning | |||
| Tumor markers | CA-125 | Elevated in 70% | Elevated in 87% |
| Diagnostic tests | Pathologic tissue diagnosis required:
| ||
For advanced-stage ovarian cancers, CA-125 values are highest for patients with serous histology with a median of 2000 U/mL; patients with clear cell histology have lower CA-125 values with a median of 154 U/mL (normal < 35 U/mL). CA-125 normalization after initiation of chemotherapy is correlated with overall survival and is likely a surrogate for inherent chemosensitivity. A retrospective review of seven previously reported GOG phase three trials in patients with stage III/IV ovarian clear cell carcinoma found that changes in CA-125 at the end of treatment compared to baseline can serve as an indicator of progression-free survival (PFS) and overall survival.
It should be noted that elevated CA-125 levels may be false positives. For example, other gynecologic conditions that cause peritoneal or pelvic inflammation can elevate CA-125 levels, including endometriosis. Meanwhile, conditions that lead to ascites, such as cirrhosis or heart failure may also elevate the CA-125. Overall, tumor markers can be useful in monitoring treatment and surveillance of ovarian clear cell carcinoma, but clinical history remains integral to diagnosis.
Imaging
Imaging findings associated with epithelial ovarian cancer include partially solid and cystic components to the mass, irregularity of borders, and fixed location. The three main imaging modalities used for ovarian clear cell carcinoma are ultrasound, CT scan, and MRI. Imaging findings particular to ovarian clear cell carcinoma include unilocular or large cysts with solid protrusions into the cavity. Due to association with endometriosis, large endometriomas with solid components are highly suspicious for ovarian clear cell carcinoma. On CT scan, ovarian clear cell carcinoma margins are typically smooth, solid protrusions are rounded and few in number with high-attenuated cystic or necrotic portions. On T1-weighted MRI images, signal intensity varies from low to very high. Imaging can help identify patients in whom aggressive initial surgical cytoreduction may not be the most beneficial primary treatment option, as they have a lower chance of optimal cytoreduction. Preoperative imaging can also identify disease in unresectable locations.
Diagnostic tests
The diagnosis of ovarian clear cell carcinoma requires pathologic tissue diagnosis. Patients with early-stage disease benefit from removal of the adnexal mass intact, although data are conflicting on whether intraoperative mass rupture truly worsens prognosis. Therefore, imaging-guided biopsy of the ovary should not be performed when the patient is a good candidate for surgical exploration. The goal of surgery is to confirm whether malignancy is present and if so, proceed with staging and cytoreduction. In patients who are unable to tolerate aggressive surgical cytoreduction or with extensive/unresectable disease, image guided biopsy, paracentesis, or thoracentesis may be used to establish a tissue diagnosis.
Staging system
Ovarian clear cell carcinoma is diagnosed at an earlier stage than serous carcinoma, with 57% to 81% of patients presenting at stage I, and 19% to 22% at stage II. Epithelial ovarian cancers are surgically and pathologically staged according to the 2017 eighth edition American Joint Committee on Cancer (AJCC) and the joint 2017 International Federation of Gynecology and Obstetrics (FIGO)/Tumor, Node, Metastasis (TNM) classification system ( Table 4.2 ). The standard staging procedure for epithelial ovarian cancer includes total extra-fascial hysterectomy and bilateral salpingo-oophorectomy (BSO) with pelvic and paraaortic lymph node dissection if there is no gross evidence of intraperitoneal disease. Pelvic washings are collected, and omentectomy is performed. Further cytoreduction is dependent on each individual clinical situation.
| Primary tumor (T) | ||
|---|---|---|
| T category | FIGO stage | T criteria |
| TX | Primary tumor cannot be assessed | |
| T0 | No evidence of primary tumor | |
| T1 | I | Tumor limited to ovaries (one or both) or fallopian tube(s) |
| T1a | IA | Tumor limited to one ovary (capsule intact) or fallopian tube, no tumor on ovarian or fallopian tube surface; no malignant cells in ascites or peritoneal washings |
| T1b | IB | Tumor limited to both ovaries (capsules intact) or fallopian tubes; no tumor on ovarian or fallopian tube surface; no malignant cells in ascites or peritoneal washings |
| T1c | IC | Tumor limited to one or both ovaries or fallopian tubes, with any of the following: |
| T1c1 | IC1 |
|
| T1c2 | IC2 |
|
| T1c3 | IC3 |
|
| T2 | II | Tumor involves one or both ovaries or fallopian tubes with pelvic extension below pelvic brim or primary peritoneal cancer |
| T2a | IIA | Extension and/or implants on the uterus and/or fallopian tube(s) and/or ovaries |
| T2b | IIB | Extension to and/or implants on other pelvic tissues |
| T3 | III | Tumor involves one or both ovaries or fallopian tubes, or primary peritoneal cancer, with microscopically confirmed peritoneal metastasis outside the pelvis and/or metastasis to the retroperitoneal (pelvic and/or paraaortic) lymph nodes |
| T3a | IIIA2 | Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes |
| T3b | IIIB | Macroscopic peritoneal metastasis beyond pelvis 2 cm or less in greatest dimension with or without metastasis to the retroperitoneal lymph nodes |
| T3c | IIIC | Macroscopic peritoneal metastasis beyond the pelvis more than 2 cm in greatest dimension with or without metastasis to the retroperitoneal lymph nodes (includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ) |
| Regional lymph nodes (N) | ||
|---|---|---|
| N category | FIGO stage | N criteria |
| NX | Regional lymph nodes cannot be assessed | |
| N0 | No regional lymph node metastasis | |
| N0(i +) | Isolated tumor cells in regional lymph node(s) no greater than 0.2 mm | |
| N1 | IIIA1 | Positive retroperitoneal lymph nodes only (histologically confirmed) |
| N1a | IIIA1i | Metastasis up to and including 10 mm in greatest dimension |
| N1b | IIIA1ii | Metastasis more than 10 mm in greatest dimension |
| Distant metastasis (M) | ||
|---|---|---|
| M category | FIGO stage | M criteria |
| M0 | No distant metastasis | |
| M1 | IV | Distant metastasis, including pleural effusion with positive cytology; liver or splenic parenchymal metastasis; metastasis to extraabdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity); and transmural involvement of intestine |
| M1a | IVA | Pleural effusion with positive cytology |
| M1b | IVB | Liver or splenic parenchymal metastases; metastases to extraabdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity); transmural involvement of intestine |
For patients who underwent comprehensive staging for clinical stage I ovarian clear cell carcinoma (disease grossly confined to the ovary) the rate of lymph node metastasis is 4.8%. In cases with ovarian surface involvement, 37.5% had lymph node metastasis. This brings to question the yield of detecting nodal metastasis in ovarian clear cell carcinoma cases lacking ovarian surface involvement. Takano et al. found that peritoneal cytology (pelvic washings) status was an independent prognostic factor for PFS but not overall survival, and that completion of surgical staging procedures was not a prognostic factor. Eight percent of all stages of ovarian clear cell carcinomas are bilateral, only 4% of stage I cases are bilateral.
Prognostic factors
Ovarian clear cell carcinoma typically presents at an early-stage (stage I or II) and has a relatively good prognosis. Patients with stage I ovarian clear cell carcinoma have 5-year PFS of 85.3% compared to 86.4% for women with serous carcinoma, 92.7% for endometrioid, and 93.1% for mucinous disease. Patients with stage II disease have 5-year PFS of 60.3% compared to 66.4% for women with serous carcinoma, 81.9% for endometrioid, and 61.3% for mucinous histologies. In a review of 9531 patients participating in 12 prospective randomized Gynecologic Oncology Group (GOG) studies, PFS was significantly better in stage I and II ovarian clear cell carcinoma when compared with serous ovarian carcinoma (PFS HR 0.69, 95% CI, 0.50–0.96) but PFS and OS were significantly worse in advanced-stage ovarian clear cell carcinoma (OS HR 1.66, 95% CI, 1.43–1.91).
When diagnosed at an advanced stage, ovarian clear cell carcinoma has a worse prognosis than serous or endometrioid ovarian cancer. For patients with stage III ovarian clear cell carcinoma, 5-year OS is 31.5% compared to 35.0% for patients with serous carcinoma, 50.6% for women with endometrioid carcinoma, and 34.5% for those with mucinous histology. Meanwhile, 5-year OS is 17.5% for patients with stage IV ovarian clear cell carcinoma compared to 22.2% for patients with stage IV serous carcinoma, 34.6% for women with endometrioid carcinoma, and 17.5% for those with mucinous histology. In a study of oncologic outcomes in ovarian clear cell carcinoma, 68% and 94% of deaths occurred within 12 and 24 of recurrence, respectively. In comparison, 41% and 73% of deaths occurred within 12 and 24 months of serous ovarian cancer recurrence, respectively. Poorer oncologic outcomes for advanced-stage ovarian clear cell carcinoma have been confirmed in SEER database studies as well as meta-analyses.
The incidence of vascular thrombotic events, such as DVT and pulmonary embolism, is high in patients with ovarian clear cell carcinoma (27%–42%) and is considered an independent poor prognostic factor. Studies on prognosis in endometriosis-associated ovarian clear cell carcinoma are mixed, but overall suggest no difference in survival after controlling for variables such as stage of disease. It is unclear if MMRd, MSI, TMB, PDL-1 IHC, or hormone receptor status is associated with survival.
Treatment of primary disease
Surgery
Early-stage disease
Staging surgery is a fundamental aspect of ovarian clear cell carcinoma care, as it both prognosticates and guides treatment decisions in early-stage disease ( Fig. 4.6 ). In cases of presumed early-stage disease, surgery should also include a lymphadenectomy, as risk of lymph node metastases in ovarian clear cell carcinoma is 5% to 15%. While lymphadenectomy has not been associated with improved survival in advanced stages, it has been associated with significantly improved disease-specific survival in patients with pT1 or pT2 disease in several large, retrospective cohorts including the Multicenter Italian Trials in Ovarian Cancer (MITO 9) study.
In patients desiring fertility preservation with apparent early-stage disease, full peritoneal staging (including washings, inspection of the cavity, and biopsies if necessary) accompanied by unilateral salpingo-oophorectomy (USO), omentectomy, and lymph node dissection should be considered. While laparotomy is generally favored for advanced-stage disease, minimally invasive surgery may be considered in early-stage ovarian cancer. A systematic review comparing 1450 patients undergoing laparoscopy and 1615 undergoing laparotomy demonstrated no difference in survival outcomes between route of surgery. Patients undergoing laparoscopy had a significantly lower estimated blood loss, shorter length of stay, fewer postoperative complications, and shorter time to chemotherapy compared to patients who underwent an open approach. A subsequent National Cancer Database (NCDB) analysis of 1096 patients (including 195 patients with ovarian clear cell carcinoma) demonstrated no survival benefit to laparotomy compared with laparoscopic staging after propensity score matching. Given these data, it is reasonable to offer a minimally invasive approach to women with presumed early-stage disease, although it should be noted that this has been independently associated with an almost 20% relative increase in capsule rupture among all epithelial ovarian cancer patients.
In patients desiring fertility, preservation of the contralateral ovary and uterus may be considered in select cases after careful patient counseling as this is a deviation from the standard of care. Data informing the decision to offer fertility-sparing surgery are limited, but evidence thus far suggests that this approach is relatively safe. An NCDB Analysis of 33 women with stage IA and 24 women with stage IC ovarian clear cell carcinoma undergoing fertility preservation demonstrated no difference in survival between patients undergoing fertility sparing surgery versus those undergoing radical cytoreduction. A systematic review of 132 patients with stage IA-IC ovarian clear cell carcinoma undergoing fertility sparing surgery demonstrated a relapse rate of 15.2%, a median of 18 months from surgery. Of patients with available staging and recurrence data, 5 (12.5%) of 40 patients with IA disease recurred, 6 (21.4%) of 28 patients with stage IC1 recurred, and 5 (38.5%) of13 patients with IC2/3 disease recurred. Sites of relapse included local sites including retroperitoneal lymph nodes, the remaining ovary, the pelvis as well as distant sites including the lung, the brain, and perihepatic soft tissue.
Surgery for advanced stage ovarian clear cell carcinoma
In advanced-stage disease, surgery should include an exploratory laparotomy, pelvic washings, hysterectomy, BSO, omentectomy, and removal of all gross visible disease including upper abdominal tumor. As in all epithelial ovarian cancers, complete gross resection (CGR) confers maximum overall survival compared to optimal or suboptimal residual disease ( P < 0.001). In fact, the survival curves for optimal residual disease and suboptimal residual disease after cytoreductive surgery for ovarian clear cell carcinoma are relatively similar. Thus, all efforts should be made to remove all visible tumor at time of debulking surgery.
Because ovarian clear cell carcinoma thought to be less responsive to platinum-based chemotherapy regimens when compared to high-grade serous counterpart, there may be a risk that patients will have refractory disease and lose the opportunity to derive surgical benefit. In certain instances, however, such as in patients with stage IVB disease, extremely poor functional status, or thromboembolic disease, neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS) should be considered. Data are limited on the efficacy of NACT-IDS in ovarian clear cell carcinoma: the two largest randomized controlled trials comparing NACT-IDS to primary debulking surgery (EORTC-55971 and CHORUS) included only 10 (out of 670) and 17 (out of 550) ovarian clear cell carcinoma patients among the study populations, respectively.
Systemic treatment of ovarian clear cell carcinoma
Although ovarian clear cell carcinoma appears to be less chemosensitive than other epithelial ovarian histologic subtypes, treatment guidelines recommend an approach paralleling high-grade serous carcinoma. Current National Comprehensive Cancer Network (NCCN) guidelines recommend systemic therapy for all patients with stage IB, IC, and II–IV disease, while patients with stage IA cancer should be offered IV platinum-based chemotherapy versus observation ( Fig. 4.6 ). The European Society for Medical Oncology (ESMO) guidelines differ from NCCN guidelines in offering either adjuvant chemotherapy or observation in patients with completely staged IA, IB, or IC1 ovarian clear cell carcinoma.
Chemotherapy
The optimal first-line treatment regimen for clear cell carcinoma is a carboplatin/paclitaxel doublet (paclitaxel 175 mg/m 2 IV followed by carboplatin AUC 5–6 IV day 1 q3 weeks), which can be dose-reduced if required by patient comorbidities such as kidney dysfunction or poor performance status. Special attention should be paid to dose-reduction of carboplatin based on renal function. It is estimated that the response rate of ovarian clear cell carcinoma to this platinum doublet is 22% to 79%.
Special considerations
Early-stage disease
The largest debate surrounding treatment in ovarian clear cell carcinoma is in early-stage disease, and data informing adjuvant treatment guidelines in this setting are limited by the relative rarity of this disease. The two largest randomized trials addressing this issue are the ICON1 trial, which included 36 ovarian clear cell carcinoma patients randomized to observation and 31 ovarian clear cell carcinoma patients randomized to adjuvant chemotherapy and ACTION trial, which included 26 ovarian clear cell carcinoma patients randomized to observation and 37 ovarian clear cell carcinoma patients randomized to adjuvant chemotherapy. Although these studies were not powered to offer an ovarian clear cell carcinoma-specific subgroup analysis, ICON1 performed a subgroup analysis of high-risk patients, including those with stage IB/IC grade 2/3 or any stage I grade 3 or clear cell histology. The greatest benefit of adjuvant chemotherapy was observed in this high-risk subgroup, with a PFS and OS HR of 0.48 (95% CI, 0.31–0.73) and 0.52 (95% CI, 0.33–0.81) at 10 years, respectively.
Large, retrospective cohort studies can also offer additional guidance on the association between adjuvant chemotherapy and survival in patients with early-stage ovarian clear cell carcinoma. A SEER database review of 1995 patients with stage I ovarian clear cell carcinoma found no OS survival benefit associated with adjuvant chemotherapy when analyzed by stage. For patients with stage IA/B disease, 5-year OS was 87% with chemotherapy versus 84% without chemotherapy ( P = 0.308). For patients with stage IC disease, 5-year OS was 83% with chemotherapy versus 80% without ( P = 0.620). Given the above findings, it is recommended that chemotherapy be offered to all patients with stage IC2 and above ovarian clear cell carcinoma.
Society guidelines differ with regards to patients with stages IA, IB, and IC1 disease. Although data are limited, it should be noted that patients upstaged to IC1 by intraoperative capsule rupture carry a similar prognosis to patients with stage IA disease. A retrospective study of 93 patients with stage IC1 ovarian clear cell carcinoma found no survival benefit to adjuvant chemotherapy in this subgroup. However, patients with preoperative capsule rupture (positive washings) demonstrate a less favorable prognosis: in one study, patients with IC disease and negative washings ( n = 74) had a 86% 5-year PFS while patients with IC disease and positive washings ( n = 33) had a 41% 5-year PFS.
In early-stage ovarian clear cell carcinoma, the number of cycles of adjuvant therapy is also a point of contention. GOG-157 compared 3 to 6 cycles of a carboplatin/paclitaxel doublet in early-stage epithelial ovarian carcinoma and found a nonsignificant decreased risk of recurrence with additional cycles (HR 0.76, 95% CI, 0.51–1.13). A subgroup analysis of GOG-157 explored survival differences in 3 versus 6 cycles of carboplatin/paclitaxel based on histologic subtype. Among 130 patients with ovarian clear cell carcinoma, there was no difference in PFS (HR 0.90, 95% CI, 0.43–1.91) among those receiving 3 versus 6 cycles of chemotherapy. A subsequent retrospective multiinstitutional study of 210 patients confirmed these findings, demonstrating no difference in PFS or OS in stage IA-II ovarian clear cell carcinoma patients receiving 3 versus 6 cycles of chemotherapy. Ultimately, the number of cycles of therapy to pursue should be tailored to individual patients, taking into consideration toxicities of adjuvant treatment.
Role of radiation
There are limited studies examining the role of primary radiation in early-stage ovarian clear cell carcinoma. The largest available study by Hoskins et al. reported on 241 patients with stage I and II ovarian clear cell carcinoma treated with 6 abdominopelvic radiation versus observation after 3 to 6 cycles of adjuvant carboplatin/paclitaxel. This study found no benefit associated with radiation for patients with stage IA–IC1 disease, while patients with IC2/3 disease undergoing abdominopelvic radiation had a 20% improvement in PFS at 5 years (RR 0.54, 95% CI, 0.33–0.95). A follow-up study compared 153 patients with stage IC2/3-II ovarian clear cell carcinoma treated with adjuvant chemotherapy versus chemoradiotherapy (chemoRT) (i.e., whole abdominal radiotherapy (WAR)/ pelvic nodal radiotherapy). Receipt of chemoRT ( n = 90) was associated with improvement in PFS and disease-specific survival compared to chemotherapy alone ( n = 63) (HR 0.57, 95% CI, 0.34–0.94; HR 0.46, 95% CI, 0.24–0.89, respectively). Several smaller studies have also demonstrated a survival advantage of adjuvant radiation. In a 2007 study comparing 16 patients with stage IC-III ovarian clear cell carcinoma treated with WAR to a historical cohort of 12 patients who underwent cyclophosphamide/adriamycin/cisplatin (CAP), authors noted a 5-year PFS of 81.2% versus 25.0% ( P = 0.006) and OS of 81.8% versus 33.3% in the WAR versus historical cohort ( P = 0.031). However, it should be noted that survival rates of the historical controls were lower than expected. Another prospective study that included 11 ovarian clear cell carcinoma patients showed improvement in patient outcomes after combining chemotherapy with WAR.
Of note, one large retrospective study of 163 patients with stage I or II ovarian clear cell carcinoma failed to demonstrate a survival benefit associated with radiation therapy. This study reported that patients receiving radiation ( n = 44) had no survival advantage compared to patients who did not ( n = 119): 10-year PFS was 65% with radiation versus 59% without radiation, and 10-year OS was 70% in both groups. Similar to the Hoskins study, these authors investigated the benefit of radiation in a “high-risk” subgroup that included patients with stages IC2/3 or II disease versus “low-risk” patients with stage IA, IB, and IC1 disease. In the high-risk subgroup, 9 (45%) of 20 patients receiving radiation recurred, while 13 (33%) of 39 women in the nonradiation group recurred. Radiation was not associated with improved PFS (HR 1.07, 95% CI, 0.47–2.43) or OS (HR 0.81, 95% CI, 0.28–2.33). It is unclear if endometriosis-associated ovarian clear cell carcinoma responds different to radiation treatment than nonendometriosis associated ovarian clear cell carcinoma.
Endometriosis-associated ovarian clear cell carcinoma
Endometriosis is predicted to affect 3% to 10% of reproductive-aged women and confers an approximately 3 times increased risk of ovarian clear cell carcinoma. Estimates suggest that 0.5% to 1.0% of endometriosis cases are complicated by neoplasia. In most cases, endometriosis is observed adjacent to or in continuity with ovarian clear cell carcinoma, suggesting that malignant transformation occurs, particularly in cases of ovarian endometriosis. This hypothesis is further supported by the observed spectrum of atypia in endometriosis, which can be subtyped into benign ectopic endometrial glands and atypical endometriosis.
The genetic underpinnings of this malignant transformation have begun to be elucidated, with ARID1A mutations identified in approximately 53% of ovarian clear cell carcinoma. ARID1A encodes the BAF250a protein, which acts as an accessory subunit in the chromatin remodeling pathway. Other commonly observed mutations are seen in important oncogenes, such as KRAS and PI3K , that are part of the MAPK and PI3K pathways. Similarly, mutations in the tumor suppressor gene PTEN are observed in approximately 21% of ovarian clear cell carcinoma. While these observational studies are important, it should be noted that whole-exome sequencing has identified many of these mutations, including ARID1A, PIK3CA, KRAS , and PP2R1A , in benign infiltrating endometriotic lesions without concurrent cancer, suggesting that there are additional drivers necessary for malignant transformation.
There is debate surrounding whether endometriosis-associated ovarian clear cell carcinoma carries a poorer prognosis. This debate is further complicated by the difficulty in classifying tumors as arising in endometriosis, because ovarian clear cell carcinoma may overgrow and replace endometriosis in an unknown portion of cases. Further, the demonstration of histologic continuity between endometriosis and cancer may be limited by sampling bias. A large meta-analysis of ovarian cancer (all histologies) in women with endometriosis demonstrated improved survival in women with endometriosis; however, authors noted these patients were more likely to have stage I–II and grade 1 disease. Another meta-analysis specific to ovarian clear cell carcinoma demonstrated no difference in PFS or OS in 331 patients with endometriosis-associated ovarian clear cell carcinoma versus 412 patients with nonendometriosis associated ovarian clear cell carcinoma (HR 1.15, 95% CI, 0.80–1.67 and HR 0.86, 95% CI, 0.63–1.17, respectively). Single-site studies have also echoed these conclusions, finding no survival difference in patients with a diagnosis of endometriosis, while only a few smaller, single-site studies have associated improved survival with endometriosis. In several studies, the reported improvement in survival associated with endometriosis disappears after controlling for stage, suggesting that these smaller scale studies may be confounded by the lower stage of diagnosis in patients with endometriosis.
Surveillance for recurrence
Surveillance intervals
Although routine follow-up of epithelial ovarian cancer patients has not been shown to improve outcomes, both NCCN and ESMO advocate for routine follow-up while emphasizing cost-effectiveness ( Table 4.3 ).
