Low-Grade Serous Ovarian Cancer: What Experts Agree On in

Table of Contents

• Key Points
• Background: Why This Disease Needs Its Own Playbook
• Study Methods: How the Expert Panel Worked
• Pathology: Defining the Disease and Its Borderline Forms
• What Happens With Serous Borderline Tumors and Implants
• Rare Cases: Low-Grade and High-Grade Cancer Together
• Translational Research: What Happens Inside the Tumor
• MEK Inhibitors: Which Patients Respond Best
• Endocrine Therapy: Hormone Treatment and Its Biomarkers
• Epidemiology: How Common Is This Disease
• Risk Factors and the BRCA Question
• Genetic Testing: What Every Patient Should Know
• Tumor Testing: Looking Inside the Cancer Itself
• Prognostic Factors: What Predicts Outcomes
• Imaging: How the Disease Is Tracked
• Limitations: What the Consensus Could Not Answer
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• Low-grade serous carcinoma is a rare ovarian cancer distinct from high-grade serous carcinoma.
• Expert pathologist review is important because borderline tumors and low-grade serous carcinoma can be confused.
• Serous borderline tumors with non-invasive implants: chemotherapy is not recommended; extended follow-up is needed.
• All patients with ovarian cancer should undergo germline genetic testing, though LGSC is rarely BRCA-associated.
• Residual disease after surgery and age 35 or younger predict worse outcomes in LGSC.

Background: Why This Disease Needs Its Own Playbook

Low-grade serous carcinoma (LGSC) of the ovary or peritoneum (the tissue lining the abdominal cavity) is a relatively rare type of epithelial ovarian cancer. Epithelial ovarian cancer is the most common form of ovarian cancer, starting in the cells on the surface of the ovary. LGSC represents less than 10% of epithelial ovarian cancers.

Compared with high-grade serous carcinoma (HGSC), LGSC carries a longer survival outlook. But the trade-off is harsh in another way. The disease is often diagnosed in younger women. Many of them endure years of ineffective treatments and suffer poor quality of life.

LGSC is molecularly distinct from other ovarian cancers. That means the genetic machinery driving the disease is fundamentally different. Because of this, a unique approach to clinical management is required to maximize survival. Standard ovarian cancer approaches built for HGSC simply do not translate well.

The pathogenesis (the biological process that creates the disease) and its management remain incompletely understood. However, recent advances in molecular characterization have identified new targeted therapies with real activity in LGSC. These offer the promise of improved outcomes.

In 2019, a panel of experts convened at a state-of-the-science conference to address the unique needs of LGSC. That meeting produced a published consensus paper. Since then, research has progressed. In October 2022, experts gathered again, this time in New York, USA, for a one-day workshop. This article explains what they concluded and what it means for patients.

Study Methods: How the Expert Panel Worked

In October 2022, investigators with expertise in the basic, translational, and clinical science of LGSC gathered in New York for a one-day workshop. Basic science looks at laboratory mechanisms. Translational research bridges lab discoveries and patient care. Clinical science studies treatments in people.

A steering committee developed a series of questions before the workshop. The categories included pathology (the study of how the disease looks under a microscope), translational research, epidemiology (how the disease spreads through populations) and risk, clinical management, clinical trials, and future research directions.

At the workshop, a qualified investigator presented the current evidence relating to each question. The entire group then discussed the findings. Experts developed consensus statements based on each question and the ensuing discussion. The panel also assembled a patient perspective from a social media-based survey, ensuring patient voices were part of the conversation.

Pathology: Defining the Disease and Its Borderline Forms

In 2020, the World Health Organization (WHO) defined LGSC as "an invasive serous neoplasm with low-grade malignant features." An invasive neoplasm is a tumor that has broken through the tissue where it started. Serous refers to the type of cell involved, one that produces a watery, serum-like fluid. Low-grade malignant features mean the cells look less aggressive under a microscope than high-grade cancer cells.

The WHO also defined ovarian serous borderline tumor (SBT) as "a non-invasive, low-grade, proliferative serous epithelial neoplasm." Borderline tumors sit between benign (non-cancerous) growths and fully invasive cancers. They have a low potential for malignancy but are not entirely harmless.

The WHO added an important clarification about implants. Implants are deposits of cells that spread to the peritoneum, the tissue lining the abdomen. The WHO stated that "Implants of serous borderline are, by definition, non-invasive; if there is invasion, a diagnosis of low-grade serous carcinoma should be made." In other words, if the implant is actively invading tissue, the disease has crossed the line into cancer.

The old term "non-invasive low-grade serous carcinoma" is no longer recommended. Previously, this phrase was used synonymously with micropapillary serous borderline tumor. Micropapillary refers to a specific finger-like microscopic pattern. A micropapillary serous borderline tumor is not to be treated as cancer, provided the tumor is well sampled to rule out any apparent invasion.

The diagnosis of "microinvasive low-grade serous carcinoma" applies when there is a focus of ovarian stromal invasion measuring less than 5 mm. The stroma is the supportive connective tissue of the ovary. This diagnosis should only be made after careful pathologic examination, preferably with additional sampling of the specimen, to exclude overtly (clearly) invasive LGSC.

Here is some reassuring news: in most studies, ovarian SBT with microinvasive LGSC (or microinvasion) is not associated with an increased risk of recurrence. Therefore, it should not be considered equivalent to overtly invasive LGSC, provided that extra-ovarian invasive implants are not present. Extra-ovarian means outside the ovary itself.

Consensus on Pathologic Definitions

The expert panel accepted the WHO 2020 definition of LGSC ("an invasive serous neoplasm with low-grade malignant features"). They agreed the term "non-invasive low-grade serous carcinoma" should not be used. Ovarian SBT with microinvasive LGSC or microinvasion does not carry a concerning prognosis. It should be managed as a borderline tumor, not as full cancer.

What Happens With Serous Borderline Tumors and Implants

One major unresolved question is whether ovarian SBT with invasive peritoneal implants and advanced-stage ovarian LGSC behave the same way. Peritoneal implants are deposits of tumor cells on the peritoneum. "Invasive" means the deposits are pushing into the tissue beneath them.

Most stage III/IV ovarian LGSC tumors recur after primary therapy. Stage III means the cancer has spread within the abdomen or to lymph nodes. Stage IV means it has spread to distant organs. In contrast, the risk of malignant recurrence (recurrence as full cancer) is at least 30% for advanced-stage ovarian SBT with invasive implants.

The actual recurrence risk varies across studies. This variability should be interpreted with caution, because diagnostic criteria for classifying implants have become more standardized over time. Older studies may have used different criteria than newer ones.

A major terminology change occurred in 2014. The WHO renamed invasive peritoneal implants as "metastatic low-grade serous carcinoma." This change generated controversy. The European Society of Gynecological Oncology (ESGO) retained the former term. According to ESGO, SBT with invasive implants should be considered separate from advanced LGSC. ESGO also recommended against adjuvant systemic therapy (chemotherapy given after surgery to prevent recurrence) for the primary treatment of SBT with extra-ovarian invasive or non-invasive implants.

The current expert panel agreed that the extent of invasive disease as a prognostic factor has not been well studied. This should be a focus of future research. For example, focal microscopic invasive implants associated with ovarian SBT likely do not behave the same as ovarian LGSC with widespread peritoneal carcinomatosis. Carcinomatosis means extensive spread across the peritoneal surfaces. Even though both conditions are grouped in the same diagnostic category, their behavior may be very different. It may be premature to consider invasive implants equivalent to metastatic LGSC. Further studies are needed to characterize which invasive implants are more likely to recur as LGSC.

Pathologist Interpretation Can Vary

Another layer of confusion is variable interpretation by pathologists. The morphologic criteria (what the tissue looks like under a microscope) for distinguishing invasive from non-invasive implants are well defined. However, some cases can be subjective. The panel recommends consultation with a pathologist experienced in evaluating these lesions for accurate diagnostic classification.

The medical literature has used various terms for low-grade serous neoplasms over the years. This has caused confusion among clinicians about appropriate treatment. Here is a summary of the terminology and treatment recommendations the panel endorsed:

• Serous borderline tumor (formerly called atypical proliferative serous tumor or serous tumor of low malignant potential): chemotherapy is not appropriate.
• Micropapillary serous borderline tumor (formerly called non-invasive low-grade serous carcinoma): chemotherapy is not appropriate.
• Serous borderline tumor with microinvasive LGSC: chemotherapy is not appropriate.
• Serous borderline tumor with non-invasive implant(s): chemotherapy is not appropriate.
• Serous borderline tumor with invasive implant(s) / metastatic LGSC: chemotherapy may be considered.
• Ovarian LGSC: chemotherapy may be considered.

Recurrence Risk With Non-Invasive Implants

For SBT with non-invasive implants, studies consistently show an increased risk of LGSC recurrence, though the exact number varies. That variation depends on the study. Researchers observed the highest risk of recurrence at a tertiary referral center in a study by Silva and colleagues: overall recurrence 44%, with malignant recurrence 34%. The median progression-free survival (the time until the disease worsens) was 7.1 years from initial diagnosis. Notably, 77% of recurrences occurred after 5 years.

A population-based study by Vang and colleagues used two Danish cancer registries. It showed that the risk of LGSC recurrence with non-invasive implants is increased (16%) but not as high as with invasive implants (32%). Differences in study populations, length of follow-up, and how each study defined a non-invasive implant likely explain the variability in risk estimates.

The key takeaway for patients: regardless of the exact percentage, these patients require extended clinical follow-up. Malignant recurrences can occur more than a decade after the initial diagnosis. The good news is that survival for patients with SBT and non-invasive implants has been reported as greater than 90% at 10 years.

Adjuvant chemotherapy is not recommended for these patients. Studies have reported a greater number of deaths from treatment complications than from the disease itself.

Consensus on Implants

The panel concluded that non-invasive implants appear to confer at least a 15-20% increased risk of subsequent LGSC. Patients with no residual disease after surgery do not require adjuvant therapy. However, they do require extended clinical follow-up, because recurrences may happen 5 years or more after diagnosis. That long window matters. A patient who is disease-free after 3 years is not out of the woods yet.

Rare Cases: Low-Grade and High-Grade Cancer Together

LGSC and HGSC are distinct pathologic entities with different spectra of underlying molecular genetic alterations. However, rare cases of SBT or LGSC coexisting with, or recurring as, HGSC or poorly differentiated carcinoma have been reported. Poorly differentiated means the cancer cells look very unlike normal cells and their tissue of origin is hard to identify.

Most of these reported cases were associated with a poor prognosis. However, the numbers are small. The data are insufficient for drawing conclusions about the clinical behavior of this rare group of patients and how they should be treated.

The panel recommended that such cases should be excluded from LGSC clinical trials. These mixed tumors are not representative of the biology of most LGSC tumors, and including them could skew trial results.

Consensus on Mixed Tumors

LGSC coexisting with, or associated with, subsequent HGSC is rare. If HGSC is a substantial component of the cancer, the cancer should be managed according to HGSC treatment protocols. Further studies are needed to understand the biology and clinical behavior of these mixed tumors.

Translational Research: What Happens Inside the Tumor

Current evidence indicates that LGSC arises either de novo (on its own, without a precursor) or after a diagnosis of SBT. The mechanisms of LGSC tumorigenesis (how the tumor develops) are not well defined, particularly for tumors that do not involve the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway is a chain of proteins inside cells that controls growth and division. In LGSC, this pathway is frequently stuck in the "on" position, driving uncontrolled growth.

MAPK pathway alterations are prominent in 50% of tumors. An alteration is a change in the genetic code of a gene. Besides the well-known KRAS and BRAF genes, other genetic alterations under investigation include:

• CDKN2A/2B deletion (a loss of tumor suppressor genes that normally restrain cell growth)
• NRAS alterations
• ERBB2 alterations
• PIK3CA alterations (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
• Chromosome 1p36 deletion
• NF1 (neurofibromin 1) alterations
• ERBB3 alterations (erbb2 receptor tyrosine kinase 3)

It is currently unknown which of these genes are truly driving the disease. That distinction matters, because a driver gene is a target for therapy. Passenger alterations are just along for the ride.

There is also an open question about where LGSC originates. Whether LGSC arises from fallopian tube epithelial progenitor cells (early cells that later specialize) remains controversial. Typically, HGSC is thought to start in the fallopian tubes. For LGSC, the picture is less clear. The presence of AGR3-positive ciliated cells in LGSC, and the observation that 60% of LGSC tumors are associated with ciliated serous borderline tumors, might suggest an alternative cell origin. Ciliated cells have tiny hair-like projections called cilia. These findings point away from the non-ciliated secretory fallopian tube epithelial cells thought to give rise to HGSC.

One practical implication: no evidence currently supports opportunistic salpingectomy (removing the fallopian tubes during another surgery, such as a hysterectomy) specifically for the prevention of LGSC. For HGSC, this procedure has gained traction as a prevention strategy. For LGSC, the science has not caught up.

MEK Inhibitors: Which Patients Respond Best

MEK inhibitors are targeted drugs that block a specific protein in the MAPK pathway. In patients with LGSC, MAPK alteration status may be associated with a higher response to mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors. However, doctors also observe activity in patients without MAPK alterations. That nuance makes treatment decisions less straightforward.

Monk and colleagues studied binimetinib, a MEK inhibitor. They observed that, compared with KRAS wild-type (WT) tumors (tumors with normal, unchanged KRAS genes), KRAS alteration was statistically significantly associated with:

• A greater objective response rate to binimetinib (odds ratio [OR] 3.4; 95% confidence interval [CI] 1.53 to 7.66; unadjusted p=0.003)
• Prolonged progression-free survival (median 17.7 months for KRAS mutant tumors vs 10.8 months for KRAS WT tumors; p=0.006)

An odds ratio of 3.4 means patients with a KRAS alteration had about 3.4 times the odds of responding to the drug compared with patients without it. The 95% confidence interval means researchers are 95% certain the true value falls between 1.53 and 7.66. Because the entire interval sits above 1, the finding is statistically significant. A p-value of 0.003 means there is only a 0.3% chance this result happened by random luck.

Gershenson and colleagues studied trametinib, another MEK inhibitor. They observed that RAS or BRAF alteration was associated with a greater objective response rate than wild-type status (50% vs 8%). However, the test for interaction did not achieve statistical significance (p=0.11). In plain terms, researchers could not prove with confidence that the biomarker truly predicted response. Alteration status was also not a significant predictor of progression-free survival (p for interaction 0.72).

Because of these mixed signals, no clear consensus exists that MEK inhibitors should be limited to a single biomarker-defined population. The National Comprehensive Cancer Network (NCCN) guidelines reflect this uncertainty. They do not require biomarker positivity for MEK inhibitor use. In other words, a patient without a MAPK alteration can still receive a MEK inhibitor, and a patient with one might not respond as expected.

Consensus on MEK Biomarkers

The optimal predictive biomarker for sensitivity of LGSC to MEK inhibitors is unknown. There is no blood test or tumor test yet that can reliably tell a doctor which patient will benefit from these drugs.

Endocrine Therapy: Hormone Treatment and Its Biomarkers

Endocrine therapy uses hormones or hormone-blocking drugs to slow cancer growth. Because LGSC is often fueled by estrogen and progesterone, hormonal approaches matter. But whether hospitals routinely test for estrogen receptor (ER) or progesterone receptor (PR) positivity varies by institution.

Most patients with LGSC have ER-positive or PR-positive disease. That raises a practical question: if nearly everyone is positive, should resources be spent testing at all? The panel found this debatable. Yet the testing question is not purely academic.

Whether lack of ER or PR positivity should exclude patients from hormonal therapy in the primary maintenance setting is controversial. Maintenance therapy is treatment given after initial treatment to keep the cancer from returning.

Low-PR status (Allred score <2) has been associated with increased copy number changes compared with high-PR tumors. An Allred score is a standard way of scoring hormone receptor positivity, combining the proportion of positive cells with the intensity of staining. Copy number changes are gains or losses of large DNA segments, often a sign of genomic instability. High-ER and high-PR status have been associated with improved overall survival.

However, no study has reliably shown that immunohistochemistry levels correlate with response to endocrine therapy. Immunohistochemistry is the laboratory technique used to detect proteins like ER and PR on tissue slides. Identifying predictive biomarkers for endocrine therapy is challenging due to the inherently low response rates observed in clinical trials.

Here are the numbers that frame the challenge: a benefit of endocrine therapy is observed, with stable disease rates of 50-62%. Stable disease means the cancer does not grow or shrink; it just holds steady. In contrast, objective response rates (where tumors measurably shrink) range from 9% to 14% in the recurrent setting. So endocrine therapy is more likely to hold the disease steady than to shrink it.

Another consideration involves ESR1 alterations. ESR1 is the gene that encodes the estrogen receptor. Based on evidence from breast and endometrial cancers, development of ESR1 alterations would be expected to confer resistance to aromatase inhibitor therapy. Aromatase inhibitors are drugs that block the enzyme converting androgens into estrogen, thereby lowering estrogen levels.

Consensus on Endocrine Biomarkers

The optimal biomarker for sensitivity of LGSC to endocrine therapy is unknown. Perhaps the most striking statement from the panel: ER-positive disease does not correlate with efficacy of hormonal therapy. A tumor can be packed with estrogen receptors and still ignore hormone-blocking drugs.

Epidemiology: How Common Is This Disease

The panel classifies LGSC as a distinct rare disease. Under the Orphan Drug Act, the US Food and Drug Administration (FDA) defines a rare disease as one affecting fewer than 200,000 people in the USA. This definition matters practically: orphan drug status creates financial incentives for pharmaceutical companies to develop treatments for small patient populations.

Current prevalence estimates for LGSC (the total number of people living with the disease at a given time) are not available. However, it has been estimated that LGSC represents less than 10% of new epithelial ovarian cancer cases. Given that the prevalence of all ovarian cancer cases in the USA was estimated at 233,565 in 2019, even with an approximate doubling in life expectancy, the prevalence of LGSC would not be expected to exceed 200,000 cases in the USA.

LGSC is also pathologically distinct from HGSC in an important way: it lacks BRCA-associated etiology. BRCA genes (BRCA1 and BRCA2) normally repair damaged DNA. When they are mutated, DNA errors accumulate and cancer can develop. LGSC is not driven by this mechanism, which sets it apart from many HGSC cases.

Consensus on Classification

It is appropriate to classify LGSC as a distinct rare disease. This classification has implications for research funding, drug development, and patient advocacy.

Risk Factors and the BRCA Question

Limited evidence from a Danish population-based case-control study helps identify factors affecting the risk of SBT, the precursor lesion to many LGSC cases. A case-control study compares people with the condition to similar people without it. The findings suggest:

• Lower risk of SBT associated with: parity (having given birth), older age at first birth, and oral contraceptive use
• Greater risk of SBT associated with: infertility and hormone replacement therapy

Whether BRCA alteration is associated with LGSC is an important consideration for patients and their families. The worry is understandable: if LGSC ran in families through BRCA mutations, relatives would need genetic testing and heightened surveillance. The data say otherwise.

Meager rates of BRCA mutation have been observed in LGSC cohorts, generally ranging from 0% to 5%. One notable study by Vineyard and colleagues evaluated personal and family histories of patients with ovarian cancer to elucidate factors suggestive of hereditary breast and ovarian cancer (HBOC) syndrome. They found that women with LGSC had a significantly lower risk estimate of hereditary breast and ovarian cancer than patients with HGSC. In plain terms, LGSC does not raise the same red flags for inherited cancer risk that HGSC does.

A second study corroborated this finding. It employed a secondary pathologic review (a second expert look at the tissue) and found no BRCA germline mutations among 79 patients with LGSC treated at a comprehensive cancer center in a geographic region enriched with patients of Ashkenazi Jewish descent. Ashkenazi Jewish women carry higher rates of specific BRCA mutations, making this population a sensitive test of the BRCA-LGSC connection. Even in that enriched population, no mutations appeared.

Overall, LGSC is not considered to be BRCA-associated. Still, as discussed below, the panel recommends that all patients with epithelial ovarian cancer undergo germline testing anyway.

Consensus on Risk Factors

Most participants agreed that the current evidence does not suggest that LGSC is driven by BRCA mutation. The reassurance extends to family members: the inherited cancer risk profile for LGSC families looks different from that of HGSC families.

Genetic Testing: What Every Patient Should Know

Germline testing examines the DNA you inherited from your parents. It looks for mutations present in every cell of your body. Germline testing is recommended for all patients with newly diagnosed ovarian cancer in guidelines from the American Society of Clinical Oncology (ASCO) and the NCCN. The recommendation exists for practical reasons that go beyond LGSC itself.

Panelists outlined several reasons for routine testing:

• Histologic uncertainty: Sometimes pathologists cannot be 100% certain whether a tumor is LGSC or HGSC. A germline BRCA result can provide a clue, since BRCA mutations are common in HGSC and rare in LGSC.
• Change in diagnosis over time: A tumor initially classified one way can be reclassified later. Knowing the germline status provides a stable reference point.
• Risk for both patient and family: Missing a BRCA alteration has serious consequences. Relatives could undergo unnecessary surveillance, or worse, miss opportunities for prevention and early detection.
• Knowledge generation: Routine testing will help provide additional knowledge about the true incidence of germline alterations in this population and whether any germline alterations are associated with LGSC. The more data collected, the better the science.

Consensus on Germline Testing

All patients with LGSC should undergo germline testing, consistent with the testing recommendations for the overall population of patients with epithelial ovarian cancer.

Tumor Testing: Looking Inside the Cancer Itself

Somatic tumor testing examines the DNA within the tumor cells themselves. These mutations are acquired, not inherited. The NCCN guidelines recommend a tumor molecular analysis panel in the upfront setting for both LGSC and HGSC. "Upfront" means at the time of initial diagnosis, not later when the disease recurs.

The somatic tumor testing panel should test for a minimum set of genes: KRAS, HRAS, NRAS, BRAF, NF1, and BRCA. Testing for this panel serves multiple purposes. KRAS, NRAS, and BRAF mutations guide MEK inhibitor decisions. NF1 loss also activates the MAPK pathway. BRCA mutations in the tumor can guide PARP inhibitor treatment decisions, though their role in LGSC remains less established.

Some studies demonstrate changes in somatic tumor alterations in patients over time. A tumor that starts out KRAS wild-type can acquire a KRAS mutation later, or vice versa. However, these studies were limited by small patient numbers and single-institution designs. The panel noted specific situations where repeating somatic tumor testing is justified:

• Aberrant clinical behavior (the tumor is not behaving as expected for its type)
• Clinical trial eligibility (many trials require a fresh biopsy or current mutation status)
• Prolonged disease course (a decade-long disease may evolve genetically)
• Cases of mixed LGSC/HGSC, to identify which component is active and driving the current clinical situation

Consensus on Somatic Testing

A somatic tumor testing panel should be conducted at diagnosis in patients with LGSC, consistent with current NCCN guidelines. Repeat somatic tumor testing may be justified in certain cases, particularly those listed above.

Prognostic Factors: What Predicts Outcomes

Two factors consistently predict worse outcomes in newly diagnosed LGSC: residual disease at the end of primary therapy (cancer left behind after surgery) and age ≤35 years. Residual disease gives the cancer a foothold to regrow. Younger age predicting worse outcomes seems counterintuitive but has been observed repeatedly in LGSC research. Younger women may present with more aggressive tumor biology or different hormonal environments.

More recently, researchers have evaluated the prognostic implications of MAPK alterations. The results are intriguing:

• In the MILO/ENGOT-ov11 and GOG-0281/LOGS clinical trials, MAPK pathway alterations were associated with prolonged progression-free survival in the standard-of-care arms. However, these differences were not statistically significant.
• Gershenson and colleagues observed statistically significantly prolonged overall survival among patients with MAPK pathway alterations versus MAPK wild-type: median 148 months vs 78 months, respectively (p=0.001). That is a survival difference of roughly 12.3 years versus 6.5 years.
• Manning-Geist and colleagues found even more dramatic differences: median 339 months vs 125 months, respectively (p=0.02 in multivariate analysis). That is about 28 years versus 10.4 years.

A p-value of 0.001 means there is only a 0.1% probability the survival difference occurred by chance. A p-value of 0.02 in multivariate analysis means the effect held up even after accounting for other variables like age, stage, and residual disease.

Other potential prognostic factors that require further evaluation include:

• Obesity
• CA-125 levels (pretreatment or normalization of this blood marker)
• Lymph node ratio (the proportion of lymph nodes containing cancer)
• Lymphovascular space invasion (cancer cells invading blood or lymph vessels)
• Omental involvement (spread to the omentum, the fatty apron of tissue over the abdomen)
• mRNA expression of Ki67 and polo-like kinase-1 (Plk1), both markers of cell proliferation

Consensus on Prognostic Factors

Residual disease at the end of primary therapy and younger age are associated with poor prognosis in patients with LGSC. In general, MAPK alteration is associated with improved prognosis. This makes biological sense: tumors with MAPK mutations may be more indolent (slow-growing), while those without identifiable MAPK drivers may rely on other, more aggressive pathways.

Imaging: How the Disease Is Tracked

Whether a preferred imaging technique exists specifically for LGSC is unknown. Imaging techniques vary according to institution. The NCCN guidelines recommend computed tomography (CT), positron emission tomography (PET)-CT, PET head to thigh, or magnetic resonance imaging (MRI). Each technique has strengths and weaknesses, and none has proven superior for LGSC specifically.

Panelists agreed that clinicians should follow the NCCN guidelines to the extent possible. They concurred that the chest, abdomen, and pelvis should all be included in CT imaging. Missing the chest could mean missing lung metastases. A majority of panelists prefer CT as the primary imaging modality for tracking this disease.

Limitations: What the Consensus Could Not Answer

This consensus report, like any scientific document, has important limitations. The original text was cut short, but several limitations are explicit within the content provided:

• Rare disease, small studies: Many findings come from studies with small patient numbers and single-institution designs. The data on somatic tumor changes over time, for example, were limited by these factors.
• Variable definitions: The risk of recurrence with non-invasive implants varies widely across studies (16% to 44%). Differences in study populations, length of follow-up, and pathologic definitions of implants may explain this variability.
• Unvalidated biomarkers: No optimal predictive biomarker exists for MEK inhibitor sensitivity. The trametinib data showed a 50% vs 8% response difference that failed to reach statistical significance (p=0.11). The binimetinib data showed significance for KRAS, but not all patients without KRAS mutations lacked benefit.
• Hormone receptor testing uncertainty: ER positivity does not correlate with hormonal therapy efficacy. No study has reliably shown that immunohistochemistry levels predict endocrine therapy response.
• Rare mixed tumors: Cases of LGSC coexisting with HGSC are too few to draw conclusions about clinical behavior or optimal treatment.
• No imaging standard: Whether any imaging technique is superior for LGSC remains unknown.

The panel itself acknowledged key unanswered questions. The extent of invasive disease as a prognostic factor has not been well studied. The mechanisms of tumorigenesis in MAPK wild-type tumors are not well defined. Whether LGSC arises from fallopian tube progenitor cells remains controversial. And no evidence supports opportunistic salpingectomy for LGSC prevention. Each of these gaps represents a target for future research.

Recommendations for Patients

Based on this expert consensus, here is what patients with LGSC or SBT should understand and discuss with their care team:

1. Get the diagnosis confirmed by an expert pathologist. LGSC can be confused with SBT and other serous neoplasms. Terminology has changed over the years, and some cases are subjective. A pathologist experienced in these lesions provides the most accurate classification. Ask whether your slides have been reviewed by a gynecologic pathology specialist.
2. Understand what your diagnosis does and does not mean. If you have SBT with microinvasion or non-invasive implants, your prognosis is excellent (over 90% survival at 10 years), and chemotherapy is not recommended. Recurrences can happen late, so extended follow-up matters even years after diagnosis.
3. Undergo germline genetic testing. This is recommended for all patients with newly diagnosed ovarian cancer. Although LGSC is not considered BRCA-associated (BRCA mutation rates are only 0-5%), testing provides certainty for you and your family. It also contributes to scientific knowledge.
4. Request somatic tumor testing at diagnosis. The NCCN recommends testing for KRAS, HRAS, NRAS, BRAF, NF1, and BRCA. Results can guide treatment decisions, particularly around MEK inhibitors. Repeat testing may be appropriate if your disease behaves unexpectedly, if you are considering a clinical trial, or if your disease course has been very long.
5. Know that hormone therapy works differently than chemotherapy. Endocrine therapy produces stable disease in 50-62% of patients but objective shrinkage in only 9-14%. That does not mean it is a weak treatment; holding the disease steady is a legitimate and valuable goal in a chronic, indolent cancer like LGSC.
6. Understand the role of MAPK alterations in your prognosis. If your tumor has a MAPK pathway alteration, your overall survival may be significantly longer (median 148 vs 78 months in one study, and 339 vs 125 months in another). This information can help frame expectations.
7. Know that residual disease matters. Complete surgical resection at the time of primary therapy is associated with better outcomes. If you are facing initial surgery, discuss with your surgeon whether optimal debulking (removing all visible disease) is achievable and what that means for your plan.
8. If you are under 35, be aware of your risk profile. Younger age at diagnosis is associated with worse outcomes in LGSC. This does not mean your prognosis is dire, but it does mean your care team should be especially vigilant and proactive.
9. Follow NCCN imaging guidelines. CT, PET-CT, PET head to thigh, or MRI are all acceptable. CT should include the chest, abdomen, and pelvis.
10. Seek out clinical trials. LGSC is a rare disease with specific biology. The panel strongly supports ongoing research into MEK inhibitors, endocrine therapy combinations, and novel targeted agents. Ask your doctor about trial eligibility, including whether repeat biopsy or somatic testing is needed for enrollment.
11. If you have SBT, do not rush into aggressive treatment. For SBT with non-invasive implants, chemotherapy offers no survival benefit and can cause harm. Studies have reported more deaths from treatment complications than from the disease itself. The panel recommends extended clinical follow-up instead.
12. If your tumor shows both LGSC and HGSC components, expect HGSC-guided management. The panel's consensus is that if HGSC is substantial, the cancer should be managed as HGSC. Mixed tumors should not be treated in LGSC-specific trials.

Frequently Asked Questions

I was just diagnosed with low-grade serous ovarian cancer. Should I ask for a second opinion on the pathology?

Yes. Low-grade serous carcinoma can be confused with borderline tumors and other serous neoplasms, and terminology has changed over the years. Some cases are subjective. The expert panel recommends consultation with a pathologist experienced in evaluating these lesions to ensure accurate classification, which guides whether chemotherapy is appropriate or not.

I have a serous borderline tumor with non-invasive implants. Do I need chemotherapy?

No. For serous borderline tumors with non-invasive implants, adjuvant chemotherapy is not recommended. Survival is greater than 90% at 10 years, and studies report more deaths from treatment complications than from the disease itself. However, extended clinical follow-up is needed because recurrences can happen 5 years or more after diagnosis.

Should I get genetic testing if I have low-grade serous ovarian cancer?

Yes. Germline testing is recommended for all patients with newly diagnosed ovarian cancer. Although low-grade serous carcinoma is not considered BRCA-associated, with mutation rates of 0-5%, testing provides certainty for you and your family, helps clarify any histologic uncertainty, and contributes to scientific knowledge about this rare disease.

What does somatic tumor testing look for in low-grade serous ovarian cancer?

At diagnosis, tumor testing should check at least KRAS, HRAS, NRAS, BRAF, NF1, and BRCA. Results can guide treatment decisions, particularly around MEK inhibitors. Repeat testing may be justified if the disease behaves unexpectedly, if you are considering a clinical trial, or if your disease course has been very long.

My tumor has a MAPK pathway alteration. Does that affect my prognosis?

Some studies show that MAPK pathway alterations are associated with longer overall survival. In one study, median survival was 148 months versus 78 months; in another, 339 months versus 125 months. However, these findings come from specific studies, and individual outcomes vary. Discuss what this means for your care with your oncology team.

How well does hormone therapy work for low-grade serous ovarian cancer?

Endocrine therapy holds the disease steady in 50-62% of patients and causes measurable tumor shrinkage in only 9-14% of patients in the recurrent setting. Stable disease is a valuable outcome for this chronic, slow-growing cancer. Notably, estrogen receptor positivity does not reliably predict whether hormone therapy will be effective.

If I am under 35, is my prognosis worse with low-grade serous ovarian cancer?

Younger age at diagnosis, specifically age 35 or younger, is associated with worse outcomes in low-grade serous carcinoma, according to expert consensus. This does not mean your prognosis is dire, but your care team should be especially vigilant and proactive about treatment and follow-up. Discuss your individual risk factors and treatment plan with your doctor.

Source Information

Original Article Title: Low-grade serous ovarian cancer- expert consensus report

DOI: 10.1136/ijgc-2023-004610

Authors: Rachel N Grisham, Brian M Slomovitz, Nicole Andrews, Susana Banerjee, Jubilee Brown, Mark S Carey, Herman Chui, Robert L Coleman, Amanda N Fader, Stephanie Gaillard, Charlie Gourley, Anil K Sood, Bradley J Monk, Kathleen N Moore, Isabelle Ray-Coquard, Ie-Ming Shih, Shannon N Westin, Kwong-Kwok Wong, David M Gershenson

Publication: International Journal of Gynecological Cancer, 2023; Volume 33, pages 1331-1344. Published Online First on 17 August 2023. DOI: 10.1136/ijgc-2023-004610

Note: This patient-friendly article is based on peer-reviewed research published by the International Gynecologic Cancer Society (IGCS) and the European Society of Gynaecological Oncology (ESGO). It was translated for educational purposes. The consensus report was presented at a one-day expert workshop held in New York, USA, in October 2022. This patient summary preserves the scientific content, data, and conclusions of the original publication while explaining medical terminology in plain language.