Abstract The evolution to metastatic disease is a major determinant of cancer mortality. Cancer evolution involves a complex interplay between intrinsic genetics and transcriptional alterations and the microenvironment. To define mechanisms underpinning metastatic heterogeneity in late-stage disease, we focus on metastatic castration-resistant prostate cancer and employed single-cell multi-omics and whole-genome sequencing to deeply profile 34 metastatic lesions obtained from 9 patients through rapid autopsy. We find evolutionary convergence of intra-tumour heterogeneity, characterised by recurrent tumour populations acting as critical functional components of the tumour ecosystem, irrespective of clonal and microenvironmental backgrounds. We find little evidence of the microenvironment driving transcriptional heterogeneity, but there are signatures of co-adaptation between the microenvironment and tumour cells. In contrast, clonal evolution primarily foster widespread transcriptional changes that did not result in de novo functional states. Intra-patient functional convergence of tumour ecosystems across metastases indicates system-level selection pressures that drive the heterogeneity landscape of metastatic castration-resistant prostate cancer. Our findings reveal functional evolutionary convergence of metastatic disease into distinct intra-tumour subpopulations, identifying critical determinants for therapeutic targeting.

Patients with pancreatic neuroendocrine tumours (PNETs) often have similar baseline clinical characteristics, including grade and molecular imaging phenotype, yet have highly variable responses to peptide receptor radionuclide therapy (PRRT). To identify genomic alterations and mutational patterns associated with PRRT treatment response and acquired somatic changes following PRRT exposure, whole genome or exome sequencing was applied to 40 PNET samples from 32 patients, including eight paired pre- or post-PRRT samples. The genomic profile of tumours reflected the known mutational landscape of PNET with MEN1 (34%), ATRX/DAXX (47%) alterations and a recurrent pattern of aneuploidy (38%) detected. A recurrent PSIP1::TBL1X fusion of unknown function was also identified in four tumours. The disease control rate following PRRT using RECIST1.1 and molecular imaging criteria was 88% (28/32). No mutational features were found to be statistically associated with progression-free survival. There was no significant increase in tumour mutational burden in the post-PRRT tumours, nor recurrent emergent mutational changes in cancer driver genes to explain progression to higher-grade disease, when observed. However, a small indel signature (ID8) previously associated with DNA damage repair by non-homologous end joining (NHEJ) was higher in PRRT-exposed compared with PRRT-naive samples (23.8 vs 4.8%, respectively; P < 0.001). Thus, comprehensive DNA analysis of pancreatic NETs did not identify biomarkers predictive of PRRT response nor evidence for high-level PRRT-induced genomic instability or hypermutation, yet mutation signature analysis supports NHEJ as being important for DNA repair and survival of neuroendocrine cells following exposure to beta-particle radiation.

BACKGROUND:MRI is recommended for men with clinical suspicion of significant prostate cancer. Those with high clinical risk but non-suspicious or equivocal MRI often undergo prostate biopsy, but have a low likelihood of clinically significant prostate cancer, and a high incidence of clinically insignificant prostate cancer. We aimed to investigate whether gallium-68 ([68Ga]Ga)-prostate-specific membrane antigen (PSMA)-11 PET-CT could reduce the number of people requiring prostate biopsy and limit biopsy to targeted cores, without compromising clinically significant prostate cancer diagnosis. METHODS:In this multicentre, non-inferiority, phase 3, randomised controlled trial, done at at seven Australian hospitals, we recruited biopsy-naive participants with clinical suspicion of significant prostate cancer, equivocal (Prostate Imaging-Reporting and Data System [PI-RADS] 3) or non-suspicious (PI-RADS 2) MRI but high clinical risk (eg, prostate-specific antigen [PSA] density of >0·1 ng/mL/mL, strong family history of prostate cancer, abnormal digital rectal examination, BRCA mutation, PSA >10 ng/mL, PSA doubling time <36 months, or PSA velocity >0·75 ng/mL per year), PSA of 20 ng/mL or less, and clinical T2 disease or less. Participants were randomly assigned (1:1) using a centralised web-based system to undergo [68Ga]Ga-PSMA-11 PET-CT (experimental group) or systematic transperineal prostate biopsy (control group), using block sizes of two or four and stratification by study site. There was no masking for participants or investigators. Participants with positive [68Ga]Ga-PSMA-11 PET-CT (PRIMARY score 3-5) underwent PSMA-PET-targeted transperineal prostate biopsies, whereas those with a negative result (PRIMARY score 1-2) avoided biopsy. The co-primary outcomes were the proportion of participants with clinically significant prostate cancer, defined as a Gleason score of 3 + 4 (≥10% pattern 4) or higher, and the proportion of participants in the [68Ga]Ga-PSMA-11 PET-CT group who avoided biopsy within 6 months of random assignment. A two-sided 95% Wald CI based on a binomial model was used to estimate the risk difference in the proportion of participants with clinically significant prostate cancer (non-inferiority margin 10%) and to estimate the proportion of participants in the experimental group who had avoided biopsy 6 months after random assignment (20% threshold), analysed based on intention to treat. This trial is registered with ClinicalTrials.gov, NCT05154162, and participant follow-up is ongoing. FINDINGS:Between March 2, 2022, and Aug 24, 2025, 660 eligible male participants were enrolled and had a median age of 61 years (IQR 56-66), a median PSA of 5·2 ng/mL (4·0-7·0), and a median PSA density of 0·13 ng/mL/mL (0·09-0·17). There were PI-RADS 2 in 335 (51%) participants and PI-RADS 3 in 325 (49%) participants. Ethnicity data were not collected. 329 (50%) were assigned to the control group with systematic transperineal prostate biopsy, and 331 (50%) were assigned to the experimental group with [68Ga]Ga-PSMA-11 PET-CT. The proportion of participants with clinically significant prostate cancer in the experimental group (39 [12%] of 331) was non-inferior to the control (51 [16%] of 329; difference -3·7% [95% CI -8·9 to 1·5%]; p=0·0093). Use of [68Ga]Ga-PSMA-11 PET-CT avoided biopsy in 163 (49%) of 331 participants (95% CI 44 to 55%; p <0·0001). After prostate biopsy, participants reported similar proportions of pain (33 [21%] in the experimental group vs 62 [21%] in the control group), haematuria (60 [38%] vs 126 [43%]), and haematospermia (77 [48%] vs 133 [45%]). INTERPRETATION:[68Ga]Ga-PSMA-11 PET-CT could have the potential to improve the diagnostic pathway of patients with a high clinical risk but non-suspicious or equivocal prostate MRI. Further research, including health-economic analyses and validation with other PSMA radiopharmaceuticals, are needed to confirm the clinical implementation and generalisability of this approach. FUNDING:Prostate Cancer Foundation, National Health and Medical Research Council, St Vincent's Curran Foundation, and Peter MacCallum Cancer Foundation.

Most primary retroperitoneal soft tissue tumors are malignant, with liposarcomas and leiomyosarcomas being the most common. However, other sarcomas and benign tumors can also occur in this location. Pathologic evaluation of retroperitoneal sarcomas (RPS) presents unique challenges. Sarcomas are a heterogeneous group with overlapping microscopic features, making accurate classification essential for prognosis and evolving targeted therapies. Core biopsies often capture only a small portion of the tumor, which may result in underestimation of key features such as differentiation, necrosis, and proliferation, leading to undergrading. Surgical management is complicated by the RPS's tendency to involve adjacent organs. Resections are often large and en bloc, and formalin fixation can obscure anatomic landmarks, making it difficult to identify and assess true surgical margins. In addition to the standard data elements required for cancer staging, specific pathologic features of RPS should be reported to aid in prognosis and treatment planning. This position paper/consensus statement was developed by members of the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) based on evidence and expert opinion. A detailed description of specimen handling, specimen sampling, and the inclusion of the key diagnostic elements required for an accurate pathology report are provided. The aim of this manuscript is to offer a comprehensive critical reappraisal of the role of pathologic evaluation of surgical specimens in RPS surgery, as well as to propose a standard pathology report to harmonize reporting and facilitate future data collection and interpretation for future research development.

Most primary retroperitoneal soft tissue tumors are malignant, with liposarcomas and leiomyosarcomas being the most common. However, other sarcomas and benign tumors can also occur in this location. Pathologic evaluation of retroperitoneal sarcomas (RPS) presents unique challenges. Sarcomas are a heterogeneous group with overlapping microscopic features, making accurate classification essential for prognosis and evolving targeted therapies. Core biopsies often capture only a small portion of the tumor, which may result in underestimation of key features such as differentiation, necrosis, and proliferation, leading to undergrading. Surgical management is complicated by the RPS's tendency to involve adjacent organs. Resections are often large and en bloc, and formalin fixation can obscure anatomic landmarks, making it difficult to identify and assess true surgical margins. In addition to the standard data elements required for cancer staging, specific pathologic features of RPS should be reported to aid in prognosis and treatment planning. This position paper/consensus statement was developed by members of the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) based on evidence and expert opinion. A detailed description of specimen handling, specimen sampling, and the inclusion of the key diagnostic elements required for an accurate pathology report are provided. The aim of this manuscript is to offer a comprehensive critical reappraisal of the role of pathologic evaluation of surgical specimens in RPS surgery, as well as to propose a standard pathology report to harmonize reporting and facilitate future data collection and interpretation for future research development.

Background: Despite advancements in treatment of advanced testicular germ cell tumors (GCT), metastatic teratoma remains a significant challenge due to its intrinsic chemo- and radioresistance. Claudin-6 (CLDN6), a tumor-specific antigen, has shown promise in targeted therapies for various solid tumors, including metastatic GCT in early phase trials. Testicular GCT frequently exhibit a unique cytogenetic hallmark, isochromosome 12p (i12p), which is associated with tumor development and progression, underscoring its significance in oncogenesis and diagnosis, and potential as a potential biomarker.Objectives: We aimed to understand the expression of CLDN6 during progression from germ cell neoplasia in situ (GCNIS) to primary GCT and postchemotherapy teratoma, and to investigate persistence of i12p in postchemotherapy teratoma.Design: An observational cohort study.Methods: Using matched pre- and postchemotherapy formalin-fixed paraffin-embedded tumor tissue from patients with primary GCT and postchemotherapy teratoma identified from a national GCT registry, iTestis, CLDN6 expression, and presence of i12p were evaluated.Results: Twenty-two patients were eligible. The majority were diagnosed with mixed primary GCT (20/22, 91%) with teratoma the sole histologic component in 86% of postchemotherapy samples (19/22). CLDN6 expression was consistently observed in GCNIS (16/16, 100%) and primary nonteratoma GCT (20/20, 100%) though significantly lower in primary teratoma components (4/10, 40%) and metastatic teratomas (5/22, 23%). The mean proportion of CLDN6-positive cells was higher in primary nonteratoma components (87.5%) compared to primary (6.5%) and postchemotherapy teratoma (4.6%). i12p was also common in primary GCT (18/22, 82%), including pure teratoma (2/2, 100%), though concordance between i12p in primary orchidectomy and metastatic samples was lower (13/18, 72%).Conclusion: Our results demonstrate early overexpression of CLDN6 in GCNIS and high expression in nonteratoma components in primary GCTs, but limited expression in primary and posttreatment teratomas. CLDN6-targeted therapies may not be effective for teratoma. In contrast, i12p was prevalent across all stages of GCT progression, suggesting its potential as a biomarker for identifying viable GCT.

AIMS:This study aimed to evaluate temporal trends in treatment patterns for localized soft tissue sarcomas (STSs) and identify factors associated with relapse-free survival (RFS) and overall survival (OS). METHODS:A retrospective cohort study was conducted using the Australian Comprehensive Cancer Outcomes and Research Database (ACCORD) and electronic health records from a high-volume sarcoma unit. Patients aged ≥18 years with grade 3, localized STS ≥5 cm diagnosed between 2013 and 2023 were included. The cohort was divided into two periods (2013-2017 and 2018-2023) to assess changes in treatment practices. Kaplan-Meier and Cox proportional hazards models evaluated RFS and OS. RESULTS:Among 202 patients, radiation use decreased in the late period (79% vs. 64%, p = 0.03), with a trend toward increased systemic therapy (8% vs. 16%, p = 0.13). Median RFS was 19 months (95% confidence interval [CI]: 14.9-26.0), with no significant difference between periods (hazard ratio [HR] 1.30, 95% CI: 0.93-1.82, p = 0.13). Median OS was 48 months (95% CI: 38.1-62.9), also showing no difference (HR 1.20, 95% CI: 0.80-1.78, p = 0.38). Radiotherapy improved RFS (HR 0.69, 95% CI: 0.49-0.98, p = 0.04) but not OS. Systemic therapy showed no RFS or OS benefit. Exploratory analyses identified age, tumor size, FDG-PET SUVmax, site, and Sarculator risk as prognostic factors. CONCLUSION:Treatment patterns evolved over time, reflecting emerging evidence, but no significant RFS or OS differences were observed. Further research is needed, including exploring prognostic factors like elevated baseline FDG-PET SUVmax.

Primary cutaneous neoplasms that lack definitive histologic and immunophenotypic evidence of differentiation are a heterogeneous group of tumors with diverse prognoses and management options. These include undifferentiated and dedifferentiated melanoma (UM/DM), atypical fibroxanthoma (AFX), pleomorphic dermal sarcoma (PDS), and sarcomatoid squamous cell carcinoma. Diagnosis requires careful correlation between the clinicopathologic and molecular features, and the finding of a MAPK pathway variant commonly associated with melanoma may support the diagnosis of melanoma over other tumors in this group. To examine the frequency of typical melanoma-associated MAPK pathway-related variants ( BRAF, NRAS, KIT, GNAQ, GNA11 ) among a cohort of primary cutaneous sarcomatoid neoplasms, we conducted a retrospective analysis of 37 cases of immunohistologically unclassifiable primary cutaneous neoplasms, submitted for targeted NGS analysis. All cases lacked a history of a prior relevant tumor, were negative for melanocytic markers (S100, SOX10, HMB45, and Melan-A), or showed <5% staining with 1 or 2 of these markers. Other lineage markers were negative. We identified typical melanoma driver variants in 7 cases (7/37, 19%), including NRAS (5/37, 14%), KIT (1/37, 3%), and GNAQ (1/37, 3%). There were no significant differences in age, sex, tumor site, or mitotic rate between patients with and without a melanoma driver variant. Melanoma cases were thicker (16.3 vs. 9.25 mm, P =0.041) and more likely to show epithelioid cell phenotype ( P =0.008). In our cohort, nearly 20% of patients with immunohistologically unclassifiable cutaneous tumors could be reclassified as having primary UM/DM after molecular testing, thereby opening alternative management pathways.

Accurate detection of oncogenic gene fusions is important for histological diagnosis of a subset of tumours. Some fusions are also the target of precision therapies. We describe our validation and early diagnostic results for the detection of fusions using the commercially available Illumina TruSight RNA Fusion Panel (TRFP) and the Arriba fusion detection algorithm. Retrospective validation showed that this assay demonstrated high accuracy (94% positive predictive agreement) for a wide variety of fusions. Prospective diagnostic data comprised a cohort of 131 clinical samples (102 mesenchymal tumours, 29 epithelial tumours), of which 80 were excisional specimens and 51 were small specimens, predominantly core biopsies. The test failure rate was 10.7%. We detected 64 (54.7%) clinically-actionable fusions in passed samples, including 12 (10.3%) that either changed or were critical for the diagnosis and 14 (12.0%) that were potentially therapeutically targetable. Most samples (89.7%) fulfilled criteria for partial reimbursement by the Australian Government Medical Benefits Scheme. In addition to describing the utility of an RNA-based fusion assay in cancer diagnostics, it is hoped that this study will provide practical advice for other laboratories considering introducing such a test.

PURPOSE:Malignant melanoma is a highly lethal malignancy typically characterized by the expression of melanin, which is an attractive diagnostic and therapeutic target in these cancers because it is expressed in few other tissues. Following preclinical evaluation of the melanin-targeting PET tracer, [18F]-6-fluoro-N-[2-(diethylamino)ethyl] pyridine-3-carboxamide ([18F]MEL050), we sought to evaluate this agent in patients with melanoma. METHOD:A phase I clinical trial was performed in ten patients with metastatic melanoma. Safety, dosimetry and diagnostic performance of intravenously administered][18F]MEL050 were evaluated. Based on results from this trial, we further assessed the prevalence and prognostic significance of loss of melanin expression in two historical patient cohorts for which there were matching histological and clinical outcome data. RESULTS:Across the trial cohort, no adverse safety signals resulted from [18F]MEL050 administration. The whole-body effective dose was 0.0163 mSV/MBq for an adult male and 0.0206 mSV/MBq for an adult female. The human biodistribution was favorable with low uptake in organs at high risk of metastatic spread, including the brain. Of metastatic sites identified as melanoma on [18F]FDG PET/CT, only 31/65 (48%) were positive on [18F]MEL050 PET. Four [18F]FDG+[18F]MEL050+ metastases were resected from three patients and found to be melanotic by histological examination, whereas five [18F]FDG+[18F]MEL050- metastases from two patients were amelanotic. In our historical cohorts, amelanosis was more common in metastatic than primary disease (45% versus 20%) and the presence of melanin within sentinel lymph node metastases was associated with worse disease-free (HR 2.3 95% CI 1.3 - 4.3, p = 0.002) and disease-specific survivals (HR 3.6, 95% CI 1.4 - 9.7,p = 0.009) in stage III disease, compared with amelanotic sentinel lymph node metastases. CONCLUSION:We propose caution in the use of melanin-targeted agents for melanoma diagnosis and therapy until their utility as prognostic or predictive imaging biomarkers, and the biological implications of loss of melanin deposition during melanoma progression, are better understood.

Retroperitoneal sarcomas (RPS) are rare tumours, primarily treated with surgical resection. However, recurrences are frequent. Combining clinical factors with CT-derived radiomic features could enhance treatment stratification and personalization. This study aims to assess whether radiomic features provide additional prognostic value beyond clinicopathological features in patients with high-risk RPS treated with preoperative radiotherapy. This retrospective study included patients aged 18 or older with non-recurrent and non-metastatic RPS treated with preoperative radiotherapy between 2008 and 2016. Hazard ratios (HR) were calculated using Cox proportional hazards regression to assess the impact of clinical and radiomic features on time to event outcomes. Predictive accuracy was assessed with c-statistics. Radiomic analysis was performed on the high-risk group (undifferentiated pleomorphic sarcoma, well-differentiated/de-differentiated liposarcoma or grade 2/3 leiomyosarcoma). Seventy-two patients were included, with a median follow-up of 3.7 years, the 5-year overall survival (OS) was 67%. Multivariable analysis showed older age (HR: 1.3 per 5-year increase, p = 0.04), grade 3 (HR: 180.3, p = 0.02), and larger tumours (HR: 4.0 per 10 cm increase, p = 0.02) predicted worse OS. In the higher-risk group, the c-statistic for the clinical model was 0.59 (time to distant metastasis (TDM)) and 0.56 (OS). Among 27 radiomic features, kurtosis improved OS prediction (c-statistic 0.69, p = 0.013), and Neighbourhood Gray-Tone Difference Matrix (NGTDM) busyness improved it to 0.73 (p = 0.036). Kurtosis also improved TDM prediction (c-statistic 0.72, p = 0.023). Radiomic features may complement clinicopathological factors in predicting overall survival and time to distant metastasis in high-risk retroperitoneal sarcoma. These exploratory findings warrant validation in larger, multi-institutional studies.

BACKGROUND:Soft tissue sarcomas (STSs) comprise a group of rare malignancies with anatomic- and histologic-specific patterns of local and distant recurrence. Due to their rarity and histology-specific tumour behaviour, their natural history and the efficacy of various interventions may be challenging to assess. The aim of this review is thus to provide a comprehensive overview of diagnostic and treatment options for localized extremity and retroperitoneal STSs. METHODS:A literature search was conducted to identify articles related to the diagnosis and management of localized extremity and retroperitoneal STSs. English-language articles published until June 2025 were identified using Medical Subject Heading terms on PubMed. Results were reported using a narrative approach. Topics highlighted in this review include diagnosis, institutional volumes, treatment options, and multimodal management of STSs based on location. RESULTS:Accurate diagnosis of STS relies on carefully planned preoperative biopsies and in selected cases is supplemented by advanced molecular diagnostic tools. Surgery remains the cornerstone of curative-intent treatment for localized STSs; however, resectability criteria for retroperitoneal STSs vary by institution. Institutional case volumes are prognostic of outcome, with 10-20 retroperitoneal sarcoma cases per year considered by experts to be indicative of high-volume sarcoma centres. The role of adjunctive therapies, including chemotherapy, radiation, and/or other locoregional treatments, is dictated by histological and molecular characteristics associated with local and distant recurrence rates. CONCLUSION:The management of localized STSs is multidisciplinary in nature, requiring consideration of tumour and patient characteristics, and treatment factors. The rarity of STSs and the variable biological behaviour of the various histologic subtypes have impacted research in this field. Ongoing international collaborations and innovative study designs are essential for advancing the understanding of tumour behaviour and in optimizing treatment approaches.

People with malignancy of undefined primary origin (MUO) have a poor prognosis and may undergo a protracted diagnostic workup causing patient distress and high cancer related costs. Not having a primary diagnosis limits timely site-specific treatment and access to precision medicine. There is a need to improve the diagnostic process, and healthcare delivery and support for these patients. This trial aims to implement and evaluate an optimal model of care for people presenting with MUO to reduce time to diagnosis, improve patient experiences and reduce healthcare costs. This is a pragmatic stepped-wedge cluster randomised trial comparing a control phase of standard practice with an intervention phase. Patient inclusion criteria are: 1) age 18 years or older, 2) presenting with suspected metastatic malignancy without an obvious primary site on imaging, 3) clinically appropriate to undergo diagnostic work-up and 4) able to provide written or verbal consent. The intervention is a new model of care comprising four key components: standardised diagnostic workup, dedicated cancer care coordinators, virtual multidisciplinary meetings and a website resource for patients, carers and clinicians. The primary endpoint is the time to completion of minimum diagnostic workup. Secondary outcomes are whether the type of tumour is diagnosed, clinical trial participation, referral to palliative care, patient-reported physical, social and mental health, patient-reported understanding and uncertainty. Implementation outcomes include acceptability, feasibility, fidelity and adoption and health care use and costs. Intervention implementation will be supported using clinical leadership, education and reinforcement. Patients who consent to having their data collected will receive the model of care active at the site at the time of recruitment. Patients will complete a patient-reported outcomes questionnaire four months after study enrolment. A health economic analysis will be included. Across 15 hospitals, a total sample size of 240 is planned. There is a lack of intervention research for people presenting with MUO. The stepped-wedge design seeks to mitigate the potential challenge of enrolling people with a poor prognosis and high symptom burden in trials. This research will generate important evidence with scalability for future research at trial completion. ACTRN12622001504707

BACKGROUND:Retroperitoneal sarcomas (RPS) comprise a heterogenous group of rare mesenchymal tumours. A complete macroscopic en bloc resection of the tumour with involved adjacent structures is the only curative treatment modality. There remain no consensus criteria regarding the definition of a resectable versus unresectable RPS. This study examined the rate, rationale and outcomes for resectable and unresectable RPS from a single large tertiary referral centre. METHODS:All patients with primary non-metastatic RPS referred between January 2017 and March 2023 were identified. Patient and tumour details as well as survival analyses were compared between resectable and unresectable cohorts, and factors for unresectability were analysed. RESULTS:A total of 104 patients were considered for the analysis, of which 91 (87.5%) were resectable and 13 (12.5%) unresectable. Gender, age, tumour size and side were similar in both cohorts. Unresectability was determined on pre-operative imaging in seven patients (53.8%) and intra-operatively in six (46.2%) patients. The most common technical cause for unresectability was the involvement of superior mesenteric vessels (38.5%). At a median follow-up of 18 months, 84.6% of the unresectable cohort and 8.8% of the resectable cohort had died. CONCLUSION:Approximately 12% of patients with primary RPS were unresectable at presentation, and in most cases, unresectability can be determined pre-operatively. Defining resectable and unresectable disease may improve the prognostication and management for patients with primary RPS.

BACKGROUND:Perivascular epithelioid cell tumors (PEComa) are a rare family of mesenchymal tumors that include several subtypes. There are very limited data describing the natural history of patients with extra-visceral retroperitoneal PEComas of the retroperitoneum. The aim of this study is to describe the clinical features, treatment patterns, outcomes, and diagnostic challenges of primary extra-visceral retroperitoneal or abdominopelvic PEComa over the past decade. PATIENTS AND METHODS:This is a retrospective analysis of all extra-visceral, non-renal, retroperitoneal, or abdominopelvic PEComas treated at participating centers over the past 10 years. RESULTS:A total of 77 patients from 13 centers were included. The median age at diagnosis was 56 years (range 18-81 years); 73% were female. The median size was 9 cm. The tumor was classified as a PEComa not otherwise specified (NOS) in 55 (71%), sclerosing PEComa in 11 (15%), and angiomyolipoma (AML) in 11 (15%). Treatment intent was curative in 59 (77%) patients. Adjuvant radiation was given in five (8%) patients, and (neo)adjuvant systemic therapy was given to six (10%). Of those who did not undergo curative intent treatment, four (22%) patients had metastatic disease and three (17%) had primary unresectable disease. With a median follow-up of 26 months (2.3-147 months), 24 (40%) of the 59 patients having curative treatment had recurred. Recurrence rates differed by subtype, with 20 (37%) of the PEComa NOS group, 3 (27%) of the sclerosing PEComa group, and 1 (9%) of the AML group developing recurrence. The estimated 5-year OS of the whole cohort was 63% and 75% for the curative intent group. CONCLUSIONS:Retroperitoneal and abdominopelvic PEComas show distinct behaviors by subtype. PEComa NOS had the highest recurrence and mortality, sclerosing PEComa showed intermediate risk, and AML was indolent. Histological classification is essential for prognosis and management.

e20567 Background: Advances in cancer diagnostics including genomic testing has improved our ability to determine the likely tissue of origin (TOO) in CUP. We aimed to describe the clinical and molecular phenotype of CUPs with a lung cancer profile enrolled in SUPER and SUPER-NEXT, a prospective national cohort study with clinical information and molecular data of provisional CUP pts. Methods: Cases were identified with a lung cancer profile based on genomic test results including a dominant tobacco smoking signature, typical lung cancer driver mutations and algorithmic TOO prediction using a Nanostring RNA gene-expression test or whole genome and transcriptome sequencing. Clinical and histopathological characteristics were reviewed to see how often this was consistent with a lung cancer diagnosis. Results: Within the cohort we identified 76/449 (17%) CUP pts with a lung cancer profile who received ≥1 molecular test. Median age was 61 (range:29-82) with 58% male. Key features are in Table 1. 65/76(86%) of pts received systemic therapy, of whom 41 received immune checkpoint inhibitor (ICI) +/- chemotherapy. mOS was 12.9months and was more favourable in pts who received ICI treatment compared to those who didn’t (16.7 vs 9.8 months, p-value 0.02). Conclusions: CUP pts with a lung cancer profile often have typical symptoms and disease sites but most are TTF-1 negative. Detection of a dominant smoking signature and/or lung mutational profile aided in a diagnosis. SMARCA4 (BRG1) mutations occurred in 45% of pts, suggesting BRG1 IHC may be a useful test in the absence of mutation data. Clinicians should be aware of this poor prognostic group with atypical histopathology that may be labelled as CUP but benefit from ICI. Count(%) Smoker – Current/Past 66/76(87) Presentation Pain Lump Dyspnoea Incidental 23/76(30) 11/76(14) 9/76(12) 20/76(26) Site of disease Nodal Lung Bone Liver Adrenal 52/76(68) 44/76(58) 31/76(41) 13/76(17) 6/76(8) Metastatic at diagnosis 71/76(93) Immunohistochemistry (IHC) TTF1+ve CK7+/CK20- PDL>1% 17/69(25) 48/68(71) 22/36(61) TOO assay - Lung 37/53(70) Genomic alterations reported SMARCA4 STK11 KEAP1 KRAS CDKN2A MET EGFR 33/73(45) 24/73(33) 21/73(29) 16/73(22) 7/73(10) 4/73(5) 3/73(4) Dominant smoking signature reported 52/59(88) TMB High (>10 mt/MB) 38/71(54)