by Jason Wasserman MD PhD FRCPC
April 16, 2026
Clear cell carcinoma of the ovary is a type of ovarian cancer named for the appearance of its cells under the microscope — many of the tumor cells have large amounts of a substance called glycogen inside them, which washes out during the preparation of the tissue slide and leaves the cell’s interior looking pale, clear, or glassy. This distinctive appearance is what gives the tumor its name.
Clear cell carcinoma accounts for about 10–12% of ovarian carcinomas in North America and is one of the most common ovarian cancer subtypes in East Asia, where it represents approximately 25–27% of cases. Most cases are diagnosed at an early stage.
This article will help you understand the findings in your pathology report — what each term means and why it matters for your care.
What are the symptoms?
Most patients develop symptoms related to a pelvic mass. These may include abdominal swelling or bloating, pelvic pressure or pain, or a feeling of fullness. Some tumors are discovered incidentally during imaging or surgery performed for another reason. Because clear cell carcinoma often arises within an ovarian cyst related to endometriosis, some patients have a pre-existing history of pelvic pain.
Clear cell carcinoma is the ovarian cancer type most commonly associated with two specific complications: paraneoplastic hypercalcemia (abnormally high calcium levels in the blood caused by substances released by the tumor) and venous thromboembolism (blood clots in the veins, including deep vein thrombosis or pulmonary embolism). These complications can occur before, during, or after treatment and are important for the medical team to monitor.
What causes clear cell carcinoma of the ovary?
Endometriosis — a condition in which tissue similar to the lining of the uterus grows outside the uterus — is by far the most important risk factor for clear cell carcinoma of the ovary. Endometriosis is found in 50–74% of cases, and most tumors arise within an endometriotic cyst (sometimes called a “chocolate cyst”). It is thought that the iron-rich, inflammatory environment inside an endometriotic cyst causes DNA damage in the cells lining it, which can eventually lead to cancer. While the vast majority of people with endometriosis will never develop ovarian cancer, those with endometriosis do have a meaningfully elevated risk compared to the general population.
Other risk factors include increasing age, with a mean age at diagnosis of approximately 56 years. Lynch syndrome — an inherited condition caused by mutations in DNA mismatch repair genes — is a recognized predisposition for clear cell carcinoma. Notably, BRCA1 and BRCA2 mutations, which are strongly associated with high-grade serous carcinoma, do not appear to significantly increase the risk of clear cell carcinoma. Factors that lower risk include oral contraceptive use, pregnancy, breastfeeding, tubal ligation, and hysterectomy.
At the genetic level, several changes accumulate in the tumor cells as clear cell carcinoma develops. Loss-of-function mutations in the ARID1A gene — which normally helps regulate how DNA is packaged and read — are found in approximately 40–50% of cases. Mutations in PIK3CA, a gene involved in cell growth signaling, are also common and often occur together with loss of ARID1A. TP53 mutations and mismatch repair deficiency are each uncommon (less than 10% and 0–6% of cases, respectively).
How is the diagnosis made?
The diagnosis is usually made after a tissue sample is examined under the microscope by a pathologist. The sample is most often obtained when the tumor is removed at surgery. If surgery is not performed first, a biopsy of an abdominal mass or fluid from the abdomen may provide the diagnosis. When surgery is performed, the pathologist examines all removed tissues — including the fallopian tubes, uterus, lymph nodes, omentum, and any peritoneal samples — to determine how far the tumor has spread.
Under the microscope, clear cell carcinoma of the ovary shows a characteristic combination of growth patterns and cell types. The tumor typically contains a mixture of three patterns: tubulocystic (small glands and cyst-like spaces), papillary (short, rounded finger-like projections with dense cores), and solid (sheets of cells). Most tumors contain more than one of these patterns at the same time. The tumor cells themselves have distinctive features: many have clear cytoplasm (the clear, glassy material filling the cell) packed with glycogen, while others have a hobnail shape, with the nucleus bulging outward into the space of the gland. Areas of dense, pink (eosinophilic) secretions inside the glands are common. Mitotic figures (dividing cells) are usually infrequent. A key feature that distinguishes clear cell carcinoma from other ovarian cancer types is that the nuclear atypia — while present — tends to be relatively uniform across the tumor rather than dramatically variable.
To confirm the diagnosis and distinguish clear cell carcinoma from other ovarian cancer types, the pathologist uses immunohistochemistry (IHC) — a technique that uses antibodies to detect specific proteins in tumor cells. Clear cell carcinomas typically stain positively for PAX8, napsin A, and HNF1β (a protein strongly expressed in clear cell carcinomas of both ovarian and endometrial origin). They are typically negative for WT1 and estrogen receptor (ER), which distinguishes them from high-grade serous carcinoma (which is WT1-positive and often ER-positive). Napsin A positivity and progesterone receptor (PR) negativity help distinguish clear cell carcinoma from endometrioid carcinoma (which is typically napsin A-negative and PR-positive).
Once the cancer is confirmed, imaging — typically CT of the chest, abdomen, and pelvis — is performed to determine the extent of disease and guide staging and treatment planning.
Histologic grade
Clear cell carcinoma of the ovary is not assigned a histologic grade. Unlike endometrioid carcinoma, which is graded 1 through 3 based on the proportion of solid growth, clear cell carcinoma is considered high grade by its very nature — the combination of architectural patterns and cell features that defines this tumor type already reflects a high-grade cancer. Assigning an additional grade does not provide useful additional information, and pathologists do not routinely grade clear cell carcinomas. The most important prognostic factors are the stage at diagnosis and whether all visible tumor can be removed at surgery.
Tumor spread
The pathologist examines all tissue samples to determine whether the tumor has spread beyond the ovary. Clear cell carcinoma may spread to the peritoneum (the thin lining of the abdominal cavity), the omentum, lymph nodes, or other abdominal and pelvic organs. Unlike high-grade serous carcinoma, the majority of clear cell carcinomas are diagnosed when they are still confined to the ovary, which contributes to their generally more favorable prognosis compared to serous carcinoma overall. However, when clear cell carcinoma is diagnosed at an advanced stage, it is often more resistant to standard chemotherapy than other ovarian cancer types.
Ovarian capsule status
The outer covering of the ovary is called the capsule. The pathologist will note whether the capsule is intact or ruptured, and whether tumor is present on the outer surface. These findings affect the stage:
- Intact capsule, no surface tumor — Suggests the cancer is still contained within the ovary, associated with an earlier stage and better prognosis.
- Ruptured capsule or tumor on the surface — Even if no other spread is found, capsule rupture or surface involvement increases the stage.
- Intraoperative rupture — If the capsule ruptures during surgery rather than before, this is noted separately and also affects staging.
Lymphovascular invasion
Lymphovascular invasion means that tumor cells have been found inside small blood vessels or lymphatic channels within the tissue. This finding suggests that tumor cells may have had an opportunity to travel to lymph nodes or distant sites, and it can influence staging and treatment planning.
Lymph nodes
Lymph nodes are small, bean-shaped structures that help filter the body’s lymphatic fluid and support the immune system. In ovarian cancer surgery, lymph nodes from the pelvis and along the major abdominal blood vessels (para-aortic nodes) may be removed and examined. If tumor cells are found in the lymph nodes, the cancer is considered to have spread beyond the ovary and the stage increases.
The pathology report will describe:
- The total number of lymph nodes examined.
- The number of lymph nodes containing tumor cells.
- The size of the largest tumor deposit.
- The location of any involved nodes (pelvic vs. para-aortic).
Lymph node deposits are classified by size. Isolated tumor cells (measuring 0.2 mm or less) are recorded as pN0(i+) and are not counted as definitive metastases in all staging systems. Deposits between 0.2 mm and 10 mm are classified as pN1a (small metastases), and deposits larger than 10 mm are classified as pN1b (large metastases). These size distinctions affect the N stage.
Biomarker and molecular testing
Biomarker testing in clear cell carcinoma of the ovary examines specific proteins and genetic changes in tumor cells that help guide treatment decisions and identify inherited cancer risk. Clear cell carcinoma develops through a different set of genetic changes than the most common type of ovarian cancer — a cancer called high-grade serous carcinoma, which accounts for about 70% of ovarian cancers and arises through a defect in the cell’s ability to repair damaged DNA. Because that DNA repair defect drives high-grade serous carcinoma, certain tests — particularly BRCA gene mutation testing and a related test called HRD (homologous recombination deficiency) testing — are standard for that cancer type, and the targeted therapies those tests identify (called PARP inhibitors) work specifically against tumors with that repair defect. Clear cell carcinoma typically does not arise from the same repair defect, so BRCA and HRD testing are not routinely indicated, and PARP inhibitors are generally not applicable. The most clinically important biomarkers for clear cell carcinoma are ARID1A, MMR proteins, and PD-L1.
ARID1A
ARID1A is a gene that produces a protein involved in controlling how DNA is packaged and read inside cells — a process called chromatin remodeling. The ARID1A protein is part of a large cellular complex called SWI/SNF that helps regulate which genes are switched on or off in a given cell. When the ARID1A gene is mutated, this regulatory function is lost, and cells can begin to grow abnormally. Loss-of-function mutations in ARID1A are found in approximately 40–50% of ovarian clear cell carcinomas, making this one of the most common molecular alterations in this tumor type.
ARID1A status is assessed by immunohistochemistry. A result of retained expression (normal) means the ARID1A protein is present. A result of loss of expression (abnormal) means the protein is absent, which reflects an underlying mutation in the gene. ARID1A loss is primarily a diagnostic and biological marker at this time — it helps confirm the diagnosis and characterizes the tumor’s molecular profile. Research into treatments targeting ARID1A-deficient tumors is active, and clinical trials may be relevant for patients with ARID1A-loss tumors. Ask your oncologist whether any trials are applicable to your situation.
Mismatch repair proteins (MMR)
Mismatch repair (MMR) proteins — MLH1, PMS2, MSH2, and MSH6 — work together to fix small copying errors that arise when cells divide and duplicate their DNA. When one or more of these proteins is absent, the tumor is described as mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H). MMR deficiency is uncommon in clear cell carcinoma of the ovary, occurring in approximately 0–6% of cases.
When present, dMMR has two important implications. First, dMMR/MSI-H tumors may be eligible for immunotherapy with pembrolizumab (Keytruda), which has pan-tumor approval for dMMR/MSI-H solid tumors that have progressed after prior treatment. Second, dMMR may indicate Lynch syndrome — an inherited condition caused by a germline mutation in one of the MMR genes that significantly raises the lifetime risk of ovarian, uterine, colorectal, and other cancers. When MMR deficiency is identified, referral to a genetic counselor is recommended, as the implications extend to blood relatives who may not yet know they are at risk.
Testing is performed by immunohistochemistry on tumor tissue. Results are reported as retained expression (normal) or loss of expression (abnormal) for each of the four MMR proteins. When MLH1 and PMS2 are both lost, additional testing for a BRAF V600E mutation or MLH1 promoter methylation helps distinguish sporadic loss from Lynch syndrome. Loss of MSH2 or MSH6, or unexplained MLH1/PMS2 loss, should prompt referral to a genetic counselor.
PD-L1
PD-L1 is a protein that some tumor cells use to evade the immune system. Testing is performed by immunohistochemistry and is typically reported as a Combined Positive Score (CPS), which counts PD-L1-positive tumor and immune cells relative to the total tumor cell count. In ovarian cancer, PD-L1 testing is most relevant in the setting of advanced or recurrent disease, where immunotherapy may be considered. Clear cell carcinoma has a relatively immune-active tumor microenvironment compared to other ovarian cancer types, which has made it a focus of immunotherapy research. Your oncologist will consider PD-L1 results alongside other clinical and molecular findings when discussing treatment options.
Folate receptor alpha (FOLR1)
Folate receptor alpha (FOLR1) is a protein found on the surface of some cancer cells that helps transport folate — a B vitamin — into the cell. Testing is performed by immunohistochemistry. A tumor is considered FOLR1-positive when at least 75% of viable tumor cells show moderate-to-strong staining on the cell membrane. Patients with FOLR1-positive ovarian cancer may be eligible for treatment with mirvetuximab soravtansine (Elahere), an antibody-drug conjugate approved for platinum-resistant ovarian cancer. FOLR1 expression rates in clear cell carcinoma are generally lower than in high-grade serous carcinoma, but testing is performed because it identifies the subset of patients who may benefit.
For more information about biomarker testing in ovarian cancer, see the Biomarkers and Molecular Testing section.
Pathologic stage (pTNM)
Staging describes how far the cancer has spread. For ovarian cancer, the pathologic stage is based on the AJCC TNM system, which closely corresponds to the FIGO staging system used by gynecologic oncologists. The stage is made up of three components: T (how far the tumor has grown locally), N (whether it has spread to lymph nodes), and M (whether it has spread to distant organs). M stage is determined by imaging and is not typically assigned in the pathology report unless distant spread was sampled at surgery.
Tumor stage (pT)
- pT1 (FIGO Stage I) — Tumor is limited to one or both ovaries or fallopian tubes.
- pT1a — Tumor in one ovary or fallopian tube only; capsule intact; no tumor cells in abdominal fluid.
- pT1b — Tumor involves both ovaries or fallopian tubes; capsules intact; no tumor cells in abdominal fluid.
- pT1c — Tumor limited to ovary/fallopian tube but with capsule rupture, tumor on the outer surface, or cancer cells in abdominal fluid or washings.
- pT2 (FIGO Stage II) — Tumor has spread beyond the ovaries or fallopian tubes into the pelvis.
- pT2a — Spread to the uterus, the other fallopian tube, or the other ovary.
- pT2b — Spread to other pelvic tissues such as the bladder or rectum.
- pT3 (FIGO Stage III) — Tumor has spread beyond the pelvis to the peritoneum or regional lymph nodes.
- pT3a — Microscopic spread to the peritoneum outside the pelvis, with or without regional lymph node involvement.
- pT3b — Visible tumor deposits up to 2 cm on the peritoneum outside the pelvis, with or without lymph node involvement.
- pT3c — Visible tumor deposits larger than 2 cm outside the pelvis, or spread to the outer surface (capsule) of the liver or spleen, with or without lymph node involvement.
Note: Spread inside the substance of the liver or spleen (rather than only on their surface) is classified as M1 (Stage IVB).
Nodal stage (pN)
- pN0 — No cancer cells found in regional lymph nodes.
- pN0(i+) — Only isolated tumor cells (0.2 mm or less) found in lymph nodes; not counted as definitive metastases in all staging systems.
- pN1 — Cancer cells present in regional lymph nodes.
- pN1a — Tumor deposits up to 10 mm.
- pN1b — Tumor deposits larger than 10 mm.
What is the prognosis?
The prognosis for clear cell carcinoma of the ovary depends primarily on stage at diagnosis. Because approximately 70–74% of cases are confined to the pelvis (stage I–II) at diagnosis — and the majority are stage I — the overall prognosis is more favorable than for high-grade serous carcinoma when all stages are considered together. However, advanced-stage clear cell carcinoma carries a worse prognosis than advanced-stage serous carcinoma, largely because it responds less well to standard platinum-based chemotherapy.
Cause-specific five-year survival rates reported in the literature are approximately:
- Stage IA/IB — 85–90%. Most patients with clear cell carcinoma are diagnosed at this stage.
- Stage IC/II — 65–75%.
- Stage III/IV — 20–30%. Advanced-stage clear cell carcinoma has a significantly worse prognosis than early-stage disease, and responds less reliably to chemotherapy than high-grade serous carcinoma at the same stage.
Beyond stage, the following features influence prognosis:
- Residual disease after surgery — Complete surgical cytoreduction (no visible tumor remaining) is associated with better outcomes across all stages.
- Capsule status — Capsule rupture before or during surgery increases the stage and is associated with a higher risk of recurrence.
- MMR status — dMMR/MSI-H tumors may benefit from immunotherapy in the recurrent setting.
- Venous thromboembolism risk — Blood clots are more common with clear cell carcinoma than other ovarian cancer types and require active management throughout treatment.
What happens after the diagnosis?
Treatment is planned by a multidisciplinary team that typically includes a gynecologic oncologist, medical oncologist, pathologist, and radiologist. The approach depends on the stage and individual clinical circumstances.
Surgery is the cornerstone of treatment and aims to remove as much tumor as possible. For most patients, this involves removal of the affected ovary and fallopian tube, the uterus, the omentum, and any visible peritoneal deposits (cytoreductive surgery). For younger patients with early-stage, unilateral disease who wish to preserve fertility, conservative surgery affecting only the involved ovary and tube may be discussed with the gynecologic oncologist.
After surgery, chemotherapy is typically recommended for all but the lowest-risk stage IA tumors. Standard first-line chemotherapy for clear cell carcinoma is carboplatin and paclitaxel — the same regimen used for high-grade serous carcinoma — although response rates are lower. Because clear cell carcinoma is relatively platinum-resistant compared to serous carcinoma, the benefit of chemotherapy is more limited, particularly in advanced disease. This has driven interest in alternative approaches, including immunotherapy and targeted therapies.
In patients with dMMR/MSI-H tumors, pembrolizumab may be considered in the recurrent or advanced setting. Given the relatively immune-active tumor microenvironment of clear cell carcinoma, immunotherapy trials are an active area of investigation, and clinical trial participation may be particularly valuable for patients with this diagnosis. Anticoagulation (blood thinners) is often required throughout treatment to manage the elevated venous thromboembolism risk associated with this tumor type.
All patients with ovarian clear cell carcinoma should be assessed for Lynch syndrome risk, particularly those whose tumors show MMR deficiency or who have a personal or family history suggestive of a hereditary cancer syndrome. Referral to a genetic counselor is recommended in these situations.
Follow-up after treatment typically involves regular clinical assessments, CA-125 monitoring, and imaging when signs of potential recurrence are present.
Questions to ask your doctor
- What stage is my ovarian cancer, and what does that mean for my treatment and prognosis?
- Has the tumor spread beyond the ovary to the lymph nodes, peritoneum, or other organs?
- Was the ovarian capsule intact, or did it rupture before or during surgery?
- Was ARID1A testing performed, and what was the result?
- Was mismatch repair testing performed, and were any of the MMR proteins lost?
- If MMR deficiency was found, do I need testing for Lynch syndrome, and should my family members be tested?
- Was FOLR1 testing performed, and does the result affect my treatment options?
- Given that clear cell carcinoma responds less well to platinum chemotherapy than other ovarian cancers, what treatment approach do you recommend?
- Am I at increased risk of blood clots, and what measures will be taken to prevent or treat them?
- Is there a clinical trial that might be appropriate for my situation, given the limited treatment options for recurrent clear cell carcinoma?
- What follow-up schedule do you recommend after I complete treatment?
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