CASE PRESENTATION

A 45-year-old patient sought gynecological consultation in January 2018 due to persistent severe pelvic pain since August 2017. She had no relevant medical or surgical history. Her family history was significant for two paternal aunts and two cousins diagnosed with breast and ovarian cancer. In the physical exam, there was only tenderness on superficial palpation, without abdominal distension. Initial vaginal ultrasound imaging revealed an 8.2 cm left ovarian tumor with minimal free fluid. Subsequent CT scan showed the lesion, characterized by a predominantly cystic structure with solid components. Serum tumor markers were notable for an elevated carcinoembryonic antigen (CEA, 78 U/mL) and cancer antigen 125 (CA125, 2399 U/mL).

In April 2018, a primary cytoreduction was performed, including total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, and omentectomy. Unfortunately, an intra-operative tumor rupture occurred. The final pathology confirmed stage IC low-grade serous ovarian cancer. One month after the surgery, CA125 levels dropped to 62 U/mL. Additionally, the post-surgical CT scan revealed no signs of disease. The patient underwent four cycles of carboplatin and paclitaxel from May to August 2018. The treatment was well-tolerated, and CA125 levels normalized following the second cycle. Given her family history, the patient was referred to a genetic counselor, where a pathogenic BRCA2 mutation was identified.

DR GRISHAM: Given the findings on her pathology and the fact that she has a BRCA2 mutation, would this patient have been a candidate for PARP inhibitor?

For stage IC epithelial ovarian cancer, I generally do not recommend PARP (poly (ADP-ribose) polymerase) inhibitor (PARPi) maintenance following completion of first line chemotherapy. Patients with stage I disease were excluded from the phase III studies which showed the substantial benefit that PARPi maintenance adds when used as primary maintenance for advanced stage patients with a BRCA mutation.1–4 Furthermore, since the incidence of germline BRCA mutations in patients with low-grade serous ovarian cancer approaches that found in the general population, it is unclear if BRCA is a true driver of the disease in this patient or an unrelated finding. For patients with stage IC low-grade serous ovarian cancer I would generally follow with observation alone following completion of adjuvant therapy, as was done in this case.

In February 2020, due to a slow and progressive elevation of CA125, a positron emission tomography- CT (PET/CT) scan was requested revealing several abdominal hypermetabolic lesions. These were located in the pelvic region, specifically in front of the left psoas, anterior and lateral to the right sacrum, para-aortic, and parallel to the sigmoid, suggesting a possible relapse. The tumor board at her reference center proposed a secondary cytoreduction. However, during the laparoscopy in March 2020, unresectable disease was observed, including a 5 cm para-aortic mass, a 4–5 cm mass involving the sigmoid colon, left lateral aspect of the bladder, and distal ileum. Multiple peritoneal implants were found in the remaining abdominal cavity, including the hepatic surface and diaphragmatic domes; the Peritoneal Cancer Index was 25.

In April 2020, treatment with carboplatin and paclitaxel was initiated. Following the third cycle, a desensitization protocol was implemented due to a platinum allergy. Following the first cycle, CA125 levels notably decreased but stayed above the normal range. After the fourth cycle, the CT scan indicated findings consistent with stable disease, leading the tumor board at her reference center to exclude the possibility of a cytoreduction. In September 2020, after six cycles of this regimen, the patient sought a second opinion in Cancer Center Clínica Universidad de Navarra due to symptomatic recurrent disease with signs of partial bowel obstruction, despite chemotherapy. A review of the pathology and a PET/CT were requested.

DR ISCAR: Could you describe the findings of the pathology review?

The sample received for review corresponded to a peritoneal biopsy taken during the March 2020 laparoscopy. The neoplasia showed an epithelial lineage proliferation arranged in micropapillary and pseudoglandular patterns. Epithelial cells displayed mild to moderate atypia, with a low mitotic index <12 mitotic figures/10 high power field, and distinctive concentric calcifications (psammoma bodies) were identified (Figure 1A).

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Figure 1

Pathology review. (A) Peritoneal biopsy arranged in micropapillary and pseudoglandular patterns with mild to moderate atypia (H&E stain, ×20 magnification). (B) WT1 expression was positive. (C) ER expression was positive. (D) P53 expression was WT. ER, estrogen receptor; H&E, hematoxylin and eosin; WT, wild-type.

The immunohistochemical analysis showed widespread positivity for PAX8 and WT1, 95% estrogen receptor (ER) expression, p53 wild-type (WT), and negative progesterone receptor (PR) (Figure 1B–D). The Ki67-assessed proliferative index ranged from 10–20%. Our final pathology report confirmed gynecological-origin low-grade serous carcinoma infiltration in the peritoneal biopsy.

DR SANCHO: What led to the selection of PET/CT for staging purposes?

Previous studies in patients with low-grade serous ovarian cancer have revealed that, despite a notable reduction in CA125, radiographic imaging often indicates minimal or no response. This phenomenon is believed to stem from the histological presence of desmoplasia, calcification, and fibrosis, as identified by our pathologists.5 Consequently, multimodality imaging, combining PET and CT, facilitates a comprehensive evaluation encompassing functional and structural aspects. [¹⁸F]Fluorodeoxyglucose (¹⁸F-FDG) PET/CT is a potentially impactful tool in the clinical management of approximately 30% of patients with low-grade serous ovarian cancer.5 The metabolic activity of lesions can assist in distinguishing active from treated tumors, providing crucial information in evaluating treatment response or recurrence.6 Moreover, ¹⁸F-FDG PET/CT has demonstrated superior staging performance compared with CT and MRI in detecting lymph node metastasis.7 Parameters such as maximum standard uptake value (SUVmax), total lesion glycolysis, and metabolic tumor volume derived from PET/CT offer valuable prognostic information and aid in assessing treatment response.8

Contemplating the future, impending challenges involve assimilating a new hybrid imaging modality, PET/MRI, into routine clinical practice. While already implemented in some centers, this advanced tool remains a subject of ongoing research and development. Additionally, the introduction of novel PET tracers for tumor assessment has shown promise, with some exhibiting encouraging results as potential alternatives to ¹⁸F-FDG7 8

DR SANCHO: Could you please provide details regarding the imaging findings?

In the maximum intensity projection (MIP) image (Figure 2A), the ¹⁸F-FDG PET highlights numerous pathological deposits distributed throughout the abdominopelvic cavity, each marked by colored arrows. Further visualizations from the multimodality fused ¹⁸F-FDG PET/CT images (Figure 2B3 and C1–C6) offer clearer insights into partially calcified peritoneal implants, corresponding to the aforementioned deposits observed in the MIP image.

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Figure 2

¹⁸F-FDG (2-deoxy-2-[fluorine-18] fluoro-d-glucose) PET (positron emission tomography)/CT images. The ¹⁸F-FDG PET maximum intensity projection (MIP) image (A) displays multiple pathological deposits of ¹⁸F-FDG throughout the abdominopelvic cavity (colored arrows) corresponding to partially calcified peritoneal implants that are more distinctly evident in the multimodality fused ¹⁸F-FDG PET/CT images (B3, C1–C6). Axial sections of the ¹⁸F-FDG PET (B1), non-contrast CT (B2), and fused ¹⁸F-FDG PET/CT image (B3) of the pelvic region reveal partially calcified hypermetabolic implants (blue arrow in the MIP image), encompassing the terminal ileum and contacting the rectum, leading to retrograde dilation of the small bowel loops. Multimodality fused ¹⁸F-FDG PET/CT images (B3, C1–C6) demonstrate partially calcified hypermetabolic peritoneal implants located in the visceral pelvic peritoneum (B3, blue arrow), hepatic round ligament (C1, red arrow), splenic flexure of the colon (C2, green arrow), omentum (C3, yellow arrow), peritoneum immediately anterior to the left common iliac artery and ipsilateral ureter (C4, purple arrow), and right paracolic gutter (C5 and C6, orange arrow).

Focusing on the axial sections of ¹⁸F-FDG PET (B1), non-contrast CT (Figure 2B2), and the fused ¹⁸F-FDG PET/CT image (Figure 2B3) centered on the pelvic region, the blue arrow in the MIP image identifies partially calcified hypermetabolic implants around the terminal ileum, impacting the rectum and resulting in retrograde dilation of the small bowel loops. In the CT images, dilation of the distal small bowel loops and increased intestinal content in the colon were observed, without clear caliber changes or free fluid indicative of intestinal obstruction. The subsequent multimodality fused ¹⁸F-FDG PET/CT images (Figure 2B3 and C1–C6) elucidate distinct locations of these partially calcified hypermetabolic peritoneal implants.

DR CHIVA: What would be the recommendation for the patient at this point?

In patients diagnosed with low-grade serous ovarian cancer, secondary cytoreduction has shown benefits in terms of progression-free survival and a tendency towards improved overall survival before systemic therapy, although from retrospective data.9 10 Complete gross resection remains the primary goal of this approach. Retrospective analyses have indicated that patients with residual gross disease following the secondary cytoreduction tend to experience shorter progression-free survival. For instance, Crane et al observed a median progression-free survival of 60 months in patients with complete gross resection versus 11 months in those with residual disease (p=0.0008). Median overall survival times were 168 months and 89 months, respectively (p=0.10).9

Patients presenting with more extensive relapse of low-grade serous ovarian cancer should be evaluated by a gynecologic oncologist and not automatically excluded from considering secondary cytoreduction. Furthermore, in carefully selected cases, tertiary surgeries and beyond may continue to provide clinical benefit. Nonetheless, a significant challenge lies in the lack of well-defined criteria for selecting appropriate candidates.

In our tumor board, on reviewing the extent of disease and the patient’s recurring episodes of obstruction following laparoscopy at another hospital, the consensus was that she might benefit from secondary cytoreduction. Furthermore, the potential presence of concurrent abdominal adhesions could not be dismissed.

DR CHIVA: What were the challenges of this secondary cytoreduction?

The abdominal and retroperitoneal examination revealed dilation in the small intestine and severe adhesions extending from the terminal ileum to the pelvis, causing a noticeable change in size prior to reaching the large intestine. Disease sites were found in remnants of the hepatic ligament, omentum, mesentery over the left common iliac artery, and peritoneum around the splenic flexure of the colon. Moreover, a tumor plaque was identified in the Douglas pouch, trapping the terminal ileum and rectum, with internal cystic areas and small implants in the omental bursa’s peritoneum.

During the surgical procedure, adhesions in the intestines and liver were released, and implants and affected areas in various abdominal regions were removed. Anastomoses (ileocolic and colorectal) were performed to restore continuity in the gastrointestinal tract. During surgery, we intentionally avoided creating a protective stoma. Normally reserved for high-risk cases or if leakage is detected during colorectal anastomosis, we opted not to do so in this instance on the patient’s request. Our current leakage rate without a stoma is 2.7%. The surgery lasted for 6 hours, and a small amount of residual disease (implants <2 mm) was left in some areas of the serosa of the bowel.

DR ISCAR: Can you describe the results of the final pathology of the surgical specimens?

The pathology samples received after the secondary cytoreduction revealed infiltration by low-grade serous ovarian cancer in the terminal ileum, right paracolic gutter, appendix, omentum, right colon mesentery, splenic flexure of the colon, right pelvic peritoneum, root of the mesentery, duodenum, iliac primordial, left ovarian vessels, recto-sigmoid, round ligament, and sigmoid colon. A larger 3 cm focus was observed in the terminal ileum wall (Figure 3A,B). Additionally, a 0.4 mm nodal metastasis was detected in one of the 10 isolated lymph nodes. Sinusoidal infiltration of isolated tumor cells was noted in two of the lymph nodes. Immunohistochemical analyses indicated positivity for WT1 and PAX8, with 99% ER expression. Conversely, PR and napsin immunostaining were negative. P53 was WT and Ki67 was 12% (Figure 3C–E).

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Figure 3

Histopathological findings. (A) Segment of the small intestine infiltrated by low-grade serous carcinoma of gynecological origin (H&E stain, ×4 magnification). (B) Proliferation of epithelial cells arranged in a micropapillary pattern, with numerous identified psammoma bodies (H&E, ×10 magnification). (C) ER expression was positive. (D) P53 expression was WT. (E) Proliferation index Ki67 of 24% approximately. ER, estrogen receptor; H&E, hematoxylin and eosin; WT, wild-type.

DR SANCHEZ and DR CHIVA: Could you describe the discussion with the patient regarding further management at this time?

After the extensive secondary cytoreduction that reduced the residual disease to <1 cm, we explored diverse treatment options. We proposed comprehensive or limited next-generation sequencing (NGS)-based genetic testing for KRAS, HRAS, NRAS, BRAF, NF1, which the patient declined. This case was thoroughly discussed in our tumor board, prompting a re-evaluation of the patient’s images. Despite imaging studies indicating stable disease following six cycles of carboplatin and paclitaxel, a positive biochemical response was evident through serum CA125 levels.

Given the patient’s prior chemotherapy and secondary cytoreduction, we proposed endocrine therapy, potentially in combination with anti-angiogenic agents. We also deliberated on employing PARPi, acknowledging the limited evidence for its use in low-grade serous ovarian cancer with a germline BRCA mutation.

In November 2020, she initiated niraparib as per the RADAR criteria, beginning with a personalized daily dosage of 200 mg determined by body weight (cut-off 77 kg) and/or platelet count (cut-off 150 000/µL).11 Due to hematological toxicity (neutropenia), the dosage was adjusted to 100 mg daily as per safety guidelines. From the start, there was a consistent decline in CA125 levels, reaching and sustaining normal levels after 3 months of treatment. Thus far, the patient has tolerated the treatment without any signs of disease recurrence.

DR GRISHAM: What suggestions would you have for treatment and surveillance at completion of surgery?

This patient’s case underscores the importance of genetic testing for all patients with ovarian cancer regardless of histology. The knowledge of her germline BRCA mutation was helpful both for individualizing her treatment, and likely also aided in informing family members of their relative risk. I would recommend to continue to follow this patient with routine surveillance including blood work to monitor for potential hematologic and renal toxicity and CA125 every 6 weeks and radiographic imaging every 3–6 months.

We currently do not know what the optimal duration of maintenance PARPi therapy is in the recurrent maintenance setting. The NOVA study, which led to the initial US Food and Drug Administration approval of niraparib as a maintenance treatment for patients with recurrent ovarian cancer who have had a complete or partial response to platinum-based chemotherapy, allowed patients to remain on maintenance treatment until time of progression or intolerable toxicity.12 However, there has been recent concern about whether maintenance PARPi should be limited in duration similar to the front-line setting.

A subgroup analysis of the exceptional benefit subgroup of patients treated with rucaparib maintenance for recurrent ovarian cancer in the ARIEL3 study found that myelodysplastic syndrome or acute myeloid leukemia occurred in 15.2% (7/25) of patients with a germline or somatic BRCA mutation.13 Therefore, in my clinical practice I generally limit PARPi maintenance to 2–3 years and would consider stopping niraparib in this patient at completion of 3 years of maintenance if she shows no evidence of disease at that time. At completion of niraparib maintenance, I would discuss observation versus switch maintenance to endocrine therapy with the patient.

Although she previously declined, I would encourage this patient to again consider NGS testing for somatic tumor mutations as this may guide future lines of therapy and also provide prognostic information in patients with low-grade serous ovarian cancer.14 Interestingly, the combination of the PARPi olaparib with the mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib showed promising results in women with recurrent low-grade serous ovarian cancer in the phase 1b dose-expansion portion of the SOLAR study.15 This drug combination is currently being further explored in a biomarker selected population in the ComboMATCH Treatment Trial (NCT05554328).

Single agent MEK inhibitors are now a standard of care treatment in many countries for those patients with recurrent low-grade serous ovarian cancer based on results of the GOG281 study, which showed a statistically significant difference in progression-free survival for those patients treated with the MEK inhibitor trametinib (median 13 months) versus those treated with physicians’ choice of chemotherapy or endocrine therapy (median 7.2 months; HR 0.48, 95% CI 0.36 to 0.64, p<0.0001).16 Recently, the novel MEK inhibitor combination of the MEK/RAF clamp avutometinib in combination with the focal adhesion kinase (FAK) inhibitor defactinib has shown promising results, with a response rate of 45% seen in heavily pretreated patients with recurrent low-grade serous ovarian cancer.17 This combination is currently being explored in a randomized phase III study of avutometinib and defactinib versus physicians’ choice of chemotherapy or endocrine therapy in women with recurrent low-grade serous ovarian cancer (NCT06072781).

CLOSING SUMMARY

While a significant number of women diagnosed with high-grade serous carcinoma have germline BRCA mutations, low-grade serous ovarian cancer shows a notably weaker association with hereditary breast and ovarian cancer syndrome. Although there have been reports of low-grade serous ovarian cancer cases with BRCA1 (3/70) and BRCA2 (1/70) mutations,18 19 studies consistently indicate low rates of BRCA mutations in low-grade serous ovarian cancer cases, ranging from 0–5%.18 20 21 A study of 79 low-grade serous ovarian cancer patients at a cancer center in an Ashkenazi Jewish enriched region, employed a secondary pathological review and found no BRCA germline mutations, establishing an absence of correlation between this carcinoma type and germline BRCA mutations.22

Low-grade serous ovarian cancer is less likely to show a family history with first- or second-degree relatives having ovarian cancer.20 However, our patient’s family history was remarkable and the mutation she carries, BRCA2:c.7673_7674del (p.Glu2558fs), is clearly pathogenic. Guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network recommend BRCA germline testing for all newly diagnosed ovarian cancer.6 23 However, the European Society for Medical Oncology guidelines suggest this testing primarily for high-grade ovarian cancer, be it germline and/or somatic.24 A recent consensus on low-grade serous ovarian cancer emphasized the significance of BRCA testing in light of uncertain diagnoses, potential diagnostic changes, and the impact of BRCA alterations on both patients and families. Routine testing could unveil the actual prevalence of germline alterations in this group and their potential association with low-grade serous carcinoma.12

The identification of a clearly pathogenic BRCA1/2 variant raises the possibility of a misdiagnosis of high-grade serous ovarian cancer, especially in cases harboring TP53 mutations,25 who are much more likely to respond to PARPi. In our patient’s case, the pathology review confirmed the diagnosis of low-grade serous ovarian cancer and the p53 immunohistochemical expression was wild type, as expected in this case. Clinically, patient selection for PARPi typically relies on the BRCA1/2 mutation status, which is present in up to 20% of high-grade serous ovarian cancer, but it is also associated with BRCA1 promoter hypermethylation and homologous recombination deficiency, assessed by evaluating genomic ‘scars'. Those serve as predictors identifying women who will most benefit from robust responses to PARPi therapy.26 Clinical trials assessing PARPi in ovarian cancer predominantly involved platinum-sensitive high-grade serous ovarian cancer patients, excluding low-grade serous ovarian cancer individuals from phase III studies.

The evidence for treating low-grade serous ovarian cancer with PARPi remains very limited. Some of the published cases included variants of uncertain significance and those of dubious clinical significance in BRCA2, suggesting a potentially limited benefit of PARPi.25 Another published case involved a patient with a pathogenic BRCA1 germline mutation with a diagnosis of low-grade serous ovarian cancer treated with PARPi at relapse, but the duration of treatment was not specified.19

In conclusion, this case represents one of the few successful maintenance treatments of low-grade serous ovarian cancers with PARP inhibitors in the literature, generating further debate on their potential use in similar cases.