Compared with high-grade serous carcinoma, low-grade serous carcinoma of the ovary or peritoneum is a less frequent epithelial ovarian cancer type that is poorly sensitive to chemotherapy and affects younger women, many of whom endure years of ineffective treatments and poor quality of life. The pathogenesis of this disease and its management remain incompletely understood. However, recent advances in the molecular characterization of the disease and identification of novel targeted therapies with activity in low-grade serous carcinoma offer the promise of improved outcomes. To update clinicians regarding recent scientific and clinical trial advancements and discuss unanswered questions related to low-grade serous carcinoma diagnosis and treatment, a panel of experts convened for a workshop in October 2022 to develop a consensus document addressing pathology, translational research, epidemiology and risk, clinical management, and ongoing research. In addition, the patient perspective was discussed. The recommendations developed by this expert panel-presented in this consensus document-will guide practitioners in all settings regarding the clinical management of women with low-grade serous carcinoma and discuss future opportunities to improve research and patient care.

To describe trends in neoadjuvant chemotherapy (NACT) use for low-grade serous ovarian carcinoma (LGSOC) and to quantify associations between NACT and extent of cytoreductive surgery.
We identified women treated for stage III or IV serous ovarian cancer in a Commission on Cancer accredited program between January 2004-December 2020. Regression models were developed to evaluate trends in NACT use for LGSOC, to identify factors associated with receipt of NACT, and to quantify associations between NACT and bowel or urinary resection at the time of surgery. Demographic and clinical factors were used for confounder control.
We observed 3350 patients who received treatment for LGSOC during the study period. The proportion of patients who received NACT increased from 9.5% in 2004 to 25.9% in 2020, corresponding to an annual percent change of 7.2% (95% CI 5.6-8.9). Increasing age (rate ratio (RR) 1.15; 95% CI 1.07-1.24), and stage IV disease (RR 2.66; 95% CI 2.31-3.07) were associated with a higher likelihood of receiving NACT. For patients with high-grade disease, NACT was associated with a decrease in likelihood of bowel or urinary surgery (35.3% versus 23.9%; RR 0.68, 95% CI 0.65-0.71). For LGSOC, NACT was associated with a higher likelihood of these procedures (26.6% versus 32.2%; RR 1.24, 95% CI 1.08-1.42).
NACT use among patients with LGSOC has increased from 2004 to 2020. While NACT was associated with a lower rate of gastrointestinal and urinary surgery among patients with high-grade disease, patients with LGSOC receiving NACT were more likely to undergo these procedures.

Low-grade serous ovarian carcinoma (LGSOC) is a distinct, rare, ovarian cancer type characterised by younger patient age and intrinsic chemoresistance. Understanding the molecular landscape is crucial for optimising targeted therapy.
Genomic data from whole exome sequencing of tumour tissue was analysed in a LGSOC cohort with detailed clinical annotation.
63 cases were analysed and three subgroups identified based on single nucleotide variants: canonical MAPK mutant (cMAPKm: 52%, KRAS/BRAF/NRAS), MAPK-associated gene mutation (MAPK-assoc: 27%) and MAPK wild-type (MAPKwt: 21%). NOTCH pathway disruption occurred across all subgroups. Tumour mutational burden (TMB), mutational signatures and recurrent copy number (CN) changes varied across the cohort with co-occurrence of chromosome 1p loss and 1q gain (CN Chr1pq) a recurrent feature. Low TMB and CN Chr1pq were associated with inferior disease-specific survival (HR 6.43; p < 0.001 and HR 3.29, p = 0.011 respectively). Stepwise genomic classification in relation to outcome resulted in four groups (TMB low; CN Chr1pq; MAPKwt/MAPKassoc; cMAPKm). 5 year disease-specific survival was 46%, 55%, 79% and 100% respectively for these groups. The two most favourable genomic subgroups were enriched for the SBS10b mutational signature, particularly the cMAPKm subgroup.
LGSOC comprises multiple genomic subgroups with distinct clinical and molecular features. Chr1pq CN arm disruption and TMB represent promising methods to identify individuals with poorer prognosis. Further investigation of the molecular basis for these observations is required. MAPKwt cases represent around a fifth of patients. NOTCH inhibitors represent a candidate therapeutic strategy worthy of exploration across these cases.

Low-grade serous ovarian cancer is a rare subtype of epithelial ovarian cancer clinically characterized by younger age at diagnosis, relative chemoresistance, and prolonged survival compared with its high-grade serous counterpart. It is molecularly characterized by estrogen and progesterone receptor positivity, aberrations in the MAPK (mitogen-activated protein kinase) pathway, and wild-type TP53 expression pattern. As research into low-grade serous ovarian cancer as a distinct entity has been able to accelerate independently, we have learned more about its unique pathogenesis, oncogenic drivers, and opportunities for novel therapeutics. In the primary setting, cytoreductive surgery in combination with platinum-based chemotherapy remain the standard of care. However, low-grade serous ovarian cancer has demonstrated relative chemoresistance in the primary and recurrent settings. Endocrine therapy is also commonly utilized in the maintenance and recurrent settings and is being evaluated in the adjuvant setting. Given the many similarities of low-grade serous ovarian cancer to luminal breast cancer, many recent studies have utilized similar therapeutic strategies including endocrine therapy combinations with CDK (cyclin-dependent kinase) 4/6 inhibitors. Additionally, recent trials have investigated combination therapies targeting the MAPK pathway, including MEK (mitogen-activated protein kinase kinase), BRAF (v-raf murine sarcoma viral oncogene homolog B1), FAK (focal adhesion kinase), and PI3K (phosphatidylinositol 3-kinase) inhibition. In this review, we will outline these novel therapeutic strategies for low-grade serous ovarian cancer.

Low-grade serous carcinoma (LGSOC) is a rare epithelial ovarian/peritoneal cancer characterized by younger age at diagnosis, relative chemoresistance, prolonged overall survival (OS), and mutations in the mitogen activated protein kinase (MAPK) pathway compared to high-grade serous carcinoma. We describe the genomic profile of LGSOC by next generation sequencing (NGS) and evaluated its potential relationship to clinical outcomes.
The study included 215 women with LGSOC with: 1) pathologically confirmed LGSOC, 2) availability of NGS data, and 3) adequate clinical data. Clinical subgroups were compared for progression-free survival (PFS) and OS. Multivariable Cox regression analysis was performed.
Median age at diagnosis was 46.6 years. The majority had a stage III ovarian primary. One or more mutations were identified in 140 (65.1%) cases; 75 (34.9%) had none. The most common mutations were KRAS (n = 71; 33.0%), NRAS (n = 24; 11.2%), and BRAF (n = 18; 8.4%). Patients with MAPK-mutated tumors (n = 113) (52.6%) had a significantly longer OS compared to those with tumors lacking MAPK pathway mutations (n = 102) (47.4%) [median OS, 147.8 months (95% CI,119.0-176.6) versus 89.5 months (95% CI, 61.4-117.7) (p = 0.01)], respectively. Median OS for patients with MAPK-mutated tumors was also significantly better than for patients whose tumors had no mutations (n = 75) [median OS, 147.8 months (95% CI, 119.0-176.6) versus 78.0 months (95% CI, 57.6-98.3)], respectively (p = 0.001). Median OS for patients with non-MAPK-mutated tumors (n = 27) was 125.1 months (95% CI, 83.9-166.3). In multivariable analysis, having a MAPK mutation was associated with improved OS.
Patients with MAPK-mutated tumors have a significantly improved OS compared to those without MAPK-mutated tumors.

Uterine papillary serous carcinoma (UPSC) is a variant of endometrial cancer that is aggressive and associated with poor outcomes. We sought to evaluate the cost effectiveness of carboplatin/paclitaxel alone versus carboplatin/paclitaxel with trastuzumab among patients with Her2/neu-positive advanced or recurrent UPSC.
We designed a Markov model in TreeAge Pro 2019 software to simulate management of a theoretical cohort of 4000 patients with Her2/neu-positive advanced or recurrent uterine papillary serous carcinoma (UPSC) followed for four years. In the carboplatin/paclitaxel with trastuzumab strategy, we included the cost of testing for Her2/neu status. We obtained all model inputs from the literature and a societal perspective was assumed. Outcomes included progression-free survival, progression, UPSC-specific mortality, cost, and quality-adjusted life years (QALYs). The intervention was considered cost effective if the incremental cost-effectiveness ratio (ICER) was below the willingness-to-pay threshold of $100,000 per QALY. Sensitivity analyses were used to determine the robustness of the results.
In our theoretical cohort of 4000 women, treatment with the addition of trastuzumab resulted in 637 fewer deaths and 627 fewer cases of progression compared with treatment with carboplatin/paclitaxel alone. Treatment with trastuzumab was associated with an additional cost of $144,335,895, but was associated with an increase of 2065 QALYs. The ICER was $69,903 per QALY, which was below our willingness-to-pay threshold. Sensitivity analysis demonstrated that this treatment strategy was cost-effective until the cost of 6 months of treatment surpassed $38,505 (baseline input: $27,562).
We found that the addition of trastuzumab to carboplatin/paclitaxel was a cost-effective treatment strategy for patients with advanced/recurrent Her2/neu-positive UPSC.

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BACKGROUND Omental calcifications of the peritoneum are typically small and asymptomatic. However, larger psammomatous bodies that cause symptoms such as abdominal pain and bloating are often associated with tumors such as primary serous papillary carcinoma, mesothelioma, or metastatic ovarian cancer. CASE REPORT We describe omental calcifications in a 68-year-old woman who had been asymptomatic for the last 10 years. The case details the histomorphologic features and immunohistochemical signature of a 4.0×3.5×1.0 cm mass consisting of mature adipose tissue that was surgically removed together with an 8.5×6.5×1.8 cm irregular intra-abdominal/mesenteric mass composed of yellow-red fatty tissue. Microscopic sections contained fat with variable clustered classic/psammomatous calcifications, some with a thin epithelioid periphery, in association with a very focal and subtle papillary surface epithelial/mesothelial proliferation. Tumor cell invasion was not observed during examination. Immunohistochemical staining showed that mesothelial cells in the mass were strongly positive for calretinin and focally positive for EMA, CK903, and vimentin. Strong nuclear positivity for PAX8 was also reported. Additional stains were added in response to this pattern, showing strong positivity for CK8, moderate positivity for BAP1, focal positivity for ER, minimal positivity for CD56, and negativity for CK5/6 and D2-40. Three possible explanations are suggested for the phenomenon observed in the pathology slides: reactive mesothelial hyperplasia, well-differentiated papillary mesothelioma, or serous papillary carcinoma of the peritoneum. CONCLUSIONS Findings suggest that these calcifications are a benign, reactive phenomenon, and that the abundance of psammoma bodies may be related to ongoing crops of papillary mesothelial hyperplasia or benign well-differentiated papillary mesothelioma.

Determine the utility of a clinical calculator to predict the benefit of chemotherapy in stage IA uterine papillary serous cancer (UPSC).
Data were collected from NCDB from years 2010-2014. Based on demographic and surgical characteristics, a clinical score was developed using the random survival forest machine learning algorithm.
Of 1,751 patients with stage IA UPSC, 1,012 (58%) received chemotherapy and 739 (42%) did not. Older age (HR 1.06), comorbidities (HR 1.31), larger tumor size (HR 1.27), lymphovascular invasion (HR 1.86), positive peritoneal cytology (HR 2.62), no pelvic lymph node dissection (HR 1.51), and no chemotherapy (HR 2.16) were associated with poorer prognosis. Compared to no chemotherapy, patients who underwent chemotherapy had a 5-year overall survival of 80% vs. 67%. To better delineate those who may derive more benefit from chemotherapy, we designed a clinical calculator capable of dividing patients into low, moderate, and high-risk groups with associated 5-year OS of 86%, 73%, and 53%, respectively. Using the calculator to assess the relative benefit of chemotherapy in each risk group, chemotherapy improved the 5-year OS in the high (42% to 64%; p < 0.001) and moderate risk group (66% to 79%; p < 0.001) but did not benefit the low risk group (84% to 87%; p = 0.29).
Our results suggest a clinical calculator is useful for counseling and personalizing chemotherapy for stage IA UPSC.

BACKGROUND: Peritoneal serous papillary carcinoma (PSPC) is a rare disease. It is clinically and histologically similar to progressive ovarian serous adenocarcinoma and involves normal-sized ovaries, making it challenging to diagnose. In this report, we describe a case of peritoneal serous papillary carcinoma that was difficult to identify and how we made a correct diagnosis in order to begin a timely course of treatment.
METHODS: A 63-year-old woman with chief complaints of dizziness and abdominal pain was examined, but showed no particular abnormality. Class III cytology of the endometrium was detected through magnetic resonance imaging and a laparotomy was performed on suspicion of endometrial cancer. The patient was finally diagnosed with peritoneal serous papillary carcinoma and was treated with surgical resection and the standard indicated course of chemotherapy.
CONCLUSIONS: The diagnosis and treatment of peritoneal serous papillary carcinoma may be delayed or may not be performed unless Class III findings are detected through uterine mucosal cytology before surgery. Surgeons should not hesitate to perform laparotomy when necessary to identify and appropriately treat patients, even if abnormalities are not detected in the preoperative examination.