Kylie L Gorringe

A 5‐marker immunohistochemical panel of CK17 , MEP1A , PAX8 , SMAD4 , and CDX2 to distinguish ovarian mucinous carcinoma from metastatic pancreatic ductal adenocarcinoma

Aims Metastatic pancreatic adenocarcinoma (PDAC), albeit uncommon, may involve the ovary, and distinction from primary ovarian mucinous tumours (OMT) poses a diagnostic challenge. Our aim was to develop an ancillary immunohistochemical (IHC) panel to aid in diagnosis and to validate the morphological features of metastatic PDAC. Methods and results Six IHC markers (CDX2, CK17, MEP1A, MUC2, PAX8, SMAD4) selected based on a literature review were stained on tissue microarrays containing 256 PDAC, 102 mucinous ovarian carcinomas (MC) and 58 mucinous borderline ovarian tumours (MBOT). Detailed morphological features were reviewed in 16 ovarian metastases from PDAC, 25 MC, and 9 MBOT. We confirmed that tumours with a size less than 13 cm, bilaterality, ovarian surface involvement, low‐power nodularity, infiltrative invasion, pseudomyxoma ovarii despite cystadenoma or borderline areas, and moderate nuclear atypia should raise suspicion for metastatic PDAC and prompt evaluation with the recommended IHC panel. A 5‐marker panel consisting of CK17, MEP1A, PAX8, SMAD4, and CDX2 had an overall accuracy of 91.8% (95% CI 88.8%–94.3%) using recursive partitioning, with the highest weight resting on CK17. CK17 was expressed in 80.9% of PDAC compared to 18.6% of MC and 1.7% of MBOT, respectively. Conclusions This is the first ancillary IHC panel to distinguish between PDAC and OMT with high accuracy. These results inform further studies on diagnostic workflows tailored to the complexity of metastatic presentations of tumours at the ovary.

Cellular origins of mucinous ovarian carcinoma

AbstractMucinous ovarian carcinoma (MOC) is a rare histotype of epithelial ovarian cancer. Its origins are obscure: while many mucinous tumours in the ovary are metastases from the gastrointestinal tract, MOC can occur as an ovarian primary; however, the cell of origin is not well established. In this review we summarise the pathological, epidemiological, and molecular evidence for the cellular origins of MOC. We propose a model for the origins of the various tumours of the ovary with mucinous differentiation. We distinguish Müllerian from gastrointestinal‐type mucinous differentiation. A small proportion of the latter arise from teratoma and a distinct terminology has been proposed. Other gastrointestinal mucinous tumours are associated with Brenner tumours and arise from their associated benign lesions, Walthard nests. The remaining mucinous tumours develop either through mucinous metaplasia in established Müllerian tumours or with even greater plasticity through gastrointestinal metaplasia of epithelial or mesothelial ovarian inclusions. This model remains to be validated and mechanistically understood and we discuss future research directions. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Mucinous ovarian carcinoma: A survey of practice in Australia and New Zealand

AbstractBackgroundMucinous ovarian carcinoma (MOC) is a rare ovarian cancer with limited evidence to support clinical care.AimsWe undertook a clinician survey to better understand current practice in treating MOC in Australia and New Zealand, and to determine any features associated with variation in care. In addition, we aimed to understand future research priorities.MethodsA RedCap survey was distributed to clinician members of the Australia New Zealand Gynaecological Oncology Group (ANZGOG). Questions included respondent demographics, three case studies and future research priorities. Clinicians were asked questions specific to their speciality.ResultsRespondents (n = 47) were commonly experienced gynae‐oncology specialists, most often surgical (38%) or medical (30%) oncologists. There was good consensus for surgical approaches for stage I disease; however, variation in practice was noted for advanced or recurrent MOC. Variation was also observed for medical oncologists; in early‐stage disease there was no clear consensus on whether to offer chemotherapy, or which regimen to recommend. For advanced and recurrent disease a wide range of chemotherapy options was considered, with a trend away from an ovarian‐type toward gastrointestinal (GI)‐type regimens in advanced MOC. This practice was reflected in future research priorities, with ‘Is a GI chemotherapy regimen better than an ovarian regimen?’ the most highly ranked option, followed by ‘Should stage 1C patients receive chemotherapy?’ConclusionsAlthough the number of respondents limited the analyses, it was clear that chemotherapy selection was a key point of divergence for medical oncologists. Future research is needed to establish well‐evidenced guidelines for clinical care of MOC.

Infiltrative pattern of invasion is independently associated with shorter survival and desmoplastic stroma markers FAP and THBS2 in mucinous ovarian carcinoma

AimsMucinous ovarian carcinoma (MOC) is a rare ovarian cancer histotype with generally good prognosis when diagnosed at an early stage. However, MOC with the infiltrative pattern of invasion has a worse prognosis, although to date studies have not been large enough to control for covariables. Data on reproducibility of classifying the invasion pattern are limited, as are molecular correlates for infiltrative invasion. We hypothesized that the invasion pattern would be associated with an aberrant tumour microenvironment.Methods and resultsFour subspecialty pathologists assessed interobserver reproducibility of the pattern of invasion in 134 MOC. Immunohistochemistry on fibroblast activation protein (FAP) and THBS2 was performed on 98 cases. Association with survival was tested using Cox regression. The average interobserver agreement for the infiltrative pattern was moderate (kappa 0.60, agreement 86.3%). After reproducibility review, 24/134 MOC (18%) were determined to have the infiltrative pattern and this was associated with a higher risk of death, independent of FIGO stage, grade, and patient age in a time‐dependent manner (hazard ratio [HR] = 10.2, 95% confidence interval [CI] 3.0–34.5). High stromal expression of FAP and THBS2 was more common in infiltrative MOC (FAP: 60%, THBS2: 58%, both P < 0.001) and associated with survival (multivariate HR for FAP: 1.5 [95% CI 1.1–2.1] and THBS2: 1.91 [95% CI 1.1–3.2]).ConclusionsThe pattern of invasion should be included in reporting for MOC due to the strong prognostic implications. We highlight the histological features that should be considered to improve reproducibility. FAP and THBS2 are associated with infiltrative invasion in MOC.

Targeted therapy for mucinous ovarian carcinoma: evidence from clinical trials

Mucinous ovarian carcinoma is a rare subtype of epithelial ovarian cancer. Despite being a chemoresistant tumour type, surgical resection and chemotherapy are still the current standard for management. This narrative review aims to explore the current evidence for targeted therapies in mucinous ovarian carcinoma. A review of the literature was performed to identify clinical trials and case reports of targeted therapy in patients with mucinous ovarian carcinoma. The databases and registers (PubMed, MEDLINE, Embase, Europe PMC, Cochrane Central Register of Clinical Trials, clinicaltrials.gov) were searched for articles published between January 2009 to June 2021 using keywords specific for mucinous ovarian carcinoma and targeted therapy. Records were screened and assessed for eligibility based on inclusion and exclusion criteria. From 684 records, 21 studies met the criteria to be included in the review. A total of 11 different targeted therapies were identified, each demonstrating varying degrees of clinical evidence supporting further investigation in patients with mucinous ovarian carcinoma. Targeted therapies identified in this review that warrant further investigations are bevacizumab, trastuzumab, nintedanib, AZD1775, sunitinib, cediranib and pazopanib. Many of the therapeutic agents may be investigated further in combination with other targeted therapies or chemotherapy. More clinical trials focusing on targeted therapy specifically in patients with mucinous ovarian cancer are required to inform clinical use. Multinational efforts are likely to be required to successfully conduct trials in this rare tumor type.

Primary mucinous ovarian neoplasms rarely show germ cell histogenesis

Molecular comparison of pure ovarian fibroma with serous benign ovarian tumours

Abstract Objective Ovarian fibromas and adenofibromas are rare ovarian tumours. They are benign tumours composed of spindle-like stromal cells (pure fibroma) or a mixture of fibroblast and epithelial components (adenofibroma). We have previously shown that 40% of benign serous ovarian tumours are likely primary fibromas due to the neoplastic alterations being restricted to the stromal compartment of these tumours. We further explore this finding by comparing benign serous tumours to pure fibromas. Results Performing copy number aberration (CNA) analysis on the stromal component of 45 benign serous tumours and 8 pure fibromas, we have again shown that trisomy of chromosome 12 is the most common aberration in ovarian fibromas. CNAs were more frequent in the pure fibromas than the benign serous tumours (88% vs 33%), however pure fibromas more frequently harboured more than one CNA event compared with benign serous tumours. As these extra CNA events observed in the pure fibromas were unique to this subset our data indicates a unique tumour evolution. Gene expression analysis on the two cohorts was unable to show gene expression changes that differed based on tumour subtype. Exome analysis did not reveal any recurrently mutated genes.

Therapeutic options for mucinous ovarian carcinoma

Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.

Options for the Treatment of Mucinous Ovarian Carcinoma

Complete surgical resection is the gold-standard treatment for all mucinous ovarian carcinoma (MOC) cases. Advanced-stage disease is often additionally treated with adjuvant platinum-based chemotherapy; however, these were developed largely against the more common high-grade serous ovarian carcinoma and have low efficacy in treating MOC. More effective therapeutics are needed to treat late-stage and platinum-resistant tumors; however, traditional drug development and clinical trial paradigms are a major challenge for such a rare disease. New approaches to support evidence-based treatment decisions are required, such as registry trials. Recently, a number of targeted therapies have emerged as viable treatment options in other cancer types, and for some of these, the actionable tumor mutations are also seen in MOC. Thus, a promising alternative approach to provide benefit to current MOC patients involves DNA sequencing to identify a tumor's unique mutational profile and allow matching to available targeted agents. Such a pipeline can involve special approval to administer a drug already approved for clinical use in other cancer types to a given MOC patient, or their inclusion in existing ongoing clinical trials, such as basket trials encompassing patients with tumors from a range of anatomical sites. Implementation of such personalized medicine can be boosted using improved pre-clinical models, where through a clinical research collaboration a patient's own tumor cells can be used to a test a range of putative therapies prior to administration in the clinic, enabling selection of the available pharmaceutical/s that give any given patient the best possible chance of cancer remission.