Low Grade Serous Ovarian Cancer: Emerging Therapies and Key Insights

Low-grade serous ovarian cancer (LGSOC) is a rare but persistent subtype of epithelial ovarian cancer, known for its slow growth and resistance to conventional chemotherapy. Unlike the more aggressive high-grade serous carcinoma, LGSOC often affects younger women and has distinct molecular characteristics that influence treatment decisions.

Recent advancements in targeted therapies and a deeper understanding of tumor biology are reshaping management strategies, particularly for recurrent disease.

Distinctive Pathology

LGSOC exhibits a unique histological and molecular profile. Characterized by well-differentiated tumor cells with minimal nuclear atypia, it maintains a relatively uniform architecture, often forming papillary structures with fibrovascular cores. Unlike high-grade serous carcinoma, which is driven by TP53 mutations, LGSOC is frequently associated with alterations in the MAPK signaling pathway, particularly KRAS and BRAF mutations. These genetic distinctions contribute to its indolent nature but also confer resistance to standard platinum-based chemotherapy, necessitating alternative therapeutic strategies.

Compared to high-grade serous carcinoma, LGSOC has lower mitotic activity and reduced genomic instability. This stability contributes to slower progression but also limits the effectiveness of DNA-damaging agents commonly used in ovarian cancer treatment. Additionally, LGSOC demonstrates a strong dependence on estrogen signaling, with many tumors expressing estrogen and progesterone receptors. This hormonal sensitivity has led to the exploration of endocrine therapies, such as aromatase inhibitors, as potential treatment options.

Histopathological evaluation often reveals psammoma bodies—concentric calcifications that help differentiate LGSOC from other ovarian tumors. Immunohistochemical staining further supports diagnosis, with LGSOC typically exhibiting strong WT1 and PAX8 expression, markers associated with serous differentiation.

Common Symptoms

LGSOC often presents with subtle, nonspecific symptoms that can be mistaken for benign gynecological or gastrointestinal conditions. Many individuals experience persistent abdominal bloating due to peritoneal fluid accumulation or tumor-related inflammation. This bloating is frequently accompanied by early satiety as the growing mass exerts pressure on surrounding organs.

Pelvic discomfort is another common manifestation, often described as a dull, persistent ache. This arises as the tumor expands and presses on pelvic structures, including the bladder and rectum. Some individuals report increased urinary urgency or frequency, while others experience bowel disturbances such as constipation. These symptoms are frequently misattributed to irritable bowel syndrome or dietary factors, delaying diagnosis.

Menstrual irregularities may also signal LGSOC, particularly in premenopausal individuals. Given that this cancer subtype often affects younger women, disruptions in the menstrual cycle, such as prolonged or heavier-than-usual bleeding, warrant further evaluation. Hormonal influences play a significant role in LGSOC pathology, and some individuals may experience exacerbation of preexisting gynecological conditions, including endometriosis or polycystic ovary syndrome.

Laboratory And Imaging Techniques

Accurate diagnosis of LGSOC relies on a combination of laboratory tests and imaging modalities. Blood-based biomarkers play a supporting role, with cancer antigen 125 (CA-125) being the most commonly measured serum marker. However, its specificity for LGSOC is limited, as benign conditions such as endometriosis and pelvic inflammatory disease can also cause elevated levels. Clinicians interpret CA-125 trends over time rather than relying on a single measurement.

Imaging studies provide a more detailed assessment of tumor burden and anatomical involvement. Transvaginal ultrasound is often the initial modality used when evaluating adnexal masses. LGSOC typically appears as a complex cystic or solid mass with papillary projections. Doppler imaging may reveal low to moderate vascularity, distinguishing it from more aggressive ovarian malignancies. However, ultrasound findings alone are insufficient for definitive diagnosis.

Computed tomography (CT) and magnetic resonance imaging (MRI) play a pivotal role in staging and treatment planning. CT scans assess peritoneal dissemination, lymph node involvement, and potential distant metastases. LGSOC often exhibits nodular peritoneal spread rather than the widespread omental caking seen in high-grade serous carcinoma. MRI provides superior soft tissue contrast, making it valuable for evaluating tumor infiltration into adjacent organs. Diffusion-weighted imaging (DWI) sequences enhance the detection of small peritoneal deposits, which may be missed on CT scans. These imaging findings guide surgical decision-making.

Molecular Profiles

LGSOC is defined by a distinct molecular landscape. Unlike high-grade serous carcinoma, which is driven primarily by TP53 mutations, LGSOC is frequently characterized by alterations in the MAPK signaling cascade, particularly in KRAS, BRAF, and NRAS genes. These mutations lead to constitutive activation of downstream signaling pathways, promoting uncontrolled cell proliferation and survival. KRAS mutations are the most common, present in approximately 30–40% of cases, followed by BRAF mutations. Targeting the MAPK pathway has emerged as a promising strategy for managing LGSOC.

Beyond MAPK pathway dysregulation, LGSOC exhibits relatively low genomic instability compared to its high-grade counterpart. Whole-exome sequencing studies have demonstrated a paucity of additional driver mutations, reinforcing the notion that LGSOC follows a distinct tumorigenic trajectory. While some tumors harbor copy number variations, these alterations are generally less extensive. This genomic stability contributes to the cancer’s slow-growing nature but also limits the effectiveness of DNA-damaging agents, such as platinum-based chemotherapy.

Treatment Modalities

Managing LGSOC requires a tailored approach due to its resistance to conventional chemotherapy. Surgery remains the primary treatment, with the goal of achieving maximal cytoreduction. Given that LGSOC often presents with widespread peritoneal involvement, complete tumor resection can be challenging but is associated with improved progression-free survival. Unlike high-grade serous carcinoma, where neoadjuvant chemotherapy is frequently employed, LGSOC patients typically undergo upfront surgery unless the disease burden necessitates initial systemic therapy. Patients who achieve no visible residual disease have the best prognosis.

For those with unresectable disease or postoperative residual tumors, systemic therapies are utilized to control progression. Hormonal treatments have gained prominence due to the estrogen receptor positivity observed in many LGSOC cases. Aromatase inhibitors such as letrozole and anastrozole are commonly prescribed to suppress estrogen-driven tumor growth. Clinical trials have demonstrated that these agents can prolong progression-free survival, particularly in patients with recurrent disease.

Targeted therapies have also emerged as a promising avenue, with MEK inhibitors like trametinib showing efficacy by disrupting MAPK pathway signaling. The FDA approval of trametinib for LGSOC underscores the shift toward molecularly guided treatment strategies. Ongoing research continues to explore combination approaches, integrating MEK inhibitors with hormonal agents or immunotherapies to enhance therapeutic responses.

Organ-Specific Metastases

While LGSOC tends to remain confined to the peritoneal cavity, metastatic spread can involve specific organs, influencing symptoms and treatment strategies. The omentum is frequently affected, serving as a common site for tumor deposits. These omental metastases can contribute to abdominal discomfort and bloating due to their impact on peritoneal fluid dynamics. Unlike more aggressive ovarian cancers, LGSOC metastases often exhibit a fibrotic response, leading to the formation of dense, adhesive nodules.

Beyond the peritoneum, the lungs represent a notable site of distant metastasis. Patients with pulmonary involvement may experience persistent cough, pleural effusions, or dyspnea due to tumor-associated fluid accumulation. Thoracentesis is sometimes required to alleviate respiratory symptoms, and targeted therapies are considered to manage disease progression. Less commonly, metastases can develop in the liver or lymph nodes. The indolent nature of LGSOC means that metastatic lesions often remain stable for extended periods, reinforcing the importance of long-term monitoring.

Recurrence Patterns

Despite its slower progression, LGSOC has a high recurrence rate, necessitating prolonged surveillance and adaptive treatment strategies. Unlike high-grade serous carcinoma, which tends to recur rapidly and aggressively, LGSOC recurrences often manifest years after initial treatment. The peritoneal cavity remains the most frequent site of relapse, with recurrent tumors typically appearing as nodular implants rather than diffuse carcinomatosis. These lesions can be asymptomatic for extended periods, underscoring the importance of routine imaging and biomarker monitoring.

Recurrent disease management relies heavily on hormonal and targeted therapies, as repeated cytoreductive surgery is only considered in select cases with isolated, resectable disease. The use of MEK inhibitors in recurrent LGSOC has demonstrated meaningful clinical benefit, particularly in patients harboring KRAS or BRAF mutations. Given the chronic nature of the disease, treatment decisions prioritize regimens that maintain disease control while minimizing toxicity, allowing patients to sustain long-term therapy without significant adverse effects.