A cfDNA methylation-based tissue-of-origin classifier for cancers of unknown primary.

Cancers of Unknown Primary (CUP) remains a diagnostic and therapeutic challenge due to biological heterogeneity and poor responses to standard chemotherapy. Predicting tissue-of-origin (TOO) molecularly could help refine this diagnosis, with tissue acquisition barriers mitigated via liquid biopsies. However, TOO liquid biopsies are unexplored in CUP cohorts. Here we describe CUPiD, a machine learning classifier for accurate TOO predictions across 29 tumour classes using circulating cell-free DNA (cfDNA) methylation patterns. We tested CUPiD on 143 cfDNA samples from patients with 13 cancer types alongside 27 non-cancer controls, with overall sensitivity of 84.6% and TOO accuracy of 96.8%. In an additional cohort of 41 patients with CUP CUPiD predictions were made in 32/41 (78.0%) cases, with 88.5% of the predictions clinically consistent with a subsequent or suspected primary tumour diagnosis, when available (23/26 patients). Combining CUPiD with cfDNA mutation data demonstrated potential diagnosis re-classification and/or treatment change in this hard-to-treat cancer group.

Head and neck cancer of unknown primary: unveiling primary tumor sites through machine learning on DNA methylation profiles.

BACKGROUND: The unknown tissue of origin in head and neck cancer of unknown primary (hnCUP) leads to invasive diagnostic procedures and unspecific and potentially inefficient treatment options for patients. The most common histologic subtype, squamous cell carcinoma, can stem from various tumor primary sites, including the oral cavity, oropharynx, larynx, head and neck skin, lungs, and esophagus. DNA methylation profiles are highly tissue-specific and have been successfully used to classify tissue origin. We therefore developed a support vector machine (SVM) classifier trained with publicly available DNA methylation profiles of commonly cervically metastasizing squamous cell carcinomas (n = 1103) in order to identify the primary tissue of origin of our own cohort of squamous cell hnCUP patient's samples (n = 28). Methylation analysis was performed with Infinium MethylationEPIC v1.0 BeadChip by Illumina. RESULTS: The SVM algorithm achieved the highest overall accuracy of tested classifiers, with 87%. Squamous cell hnCUP samples on DNA methylation level resembled squamous cell carcinomas commonly metastasizing into cervical lymph nodes. The most frequently predicted cancer localization was the oral cavity in 11 cases (39%), followed by the oropharynx and larynx (both 7, 25%), skin (2, 7%), and esophagus (1, 4%). These frequencies concord with the expected distribution of lymph node metastases in epidemiological studies. CONCLUSIONS: On DNA methylation level, hnCUP is comparable to primary tumor tissue cancer types that commonly metastasize to cervical lymph nodes. Our SVM-based classifier can accurately predict these cancers' tissues of origin and could significantly reduce the invasiveness of hnCUP diagnostics and enable a more precise therapy after clinical validation.

Cancer-related thrombotic microangiopathy and disseminated intravascular coagulation in a patient with bone marrow carcinomatosis of unknown primary origin: A case report.

BACKGROUND: Cancer-related thrombotic microangiopathy (CR-TMA) is a rare type of Coombs-negative hemolytic anemia, which is caused by malignancy and has a poor prognosis. CASE: A 76-year-old female was referred to our hospital due to Coombs-negative hemolytic anemia, which was causing fatigue and dyspnea on exertion, accompanied by schistocytosis. A bone marrow examination demonstrated bone marrow carcinomatosis, and the tumor cells were morphologically suspected to be signet-ring cell carcinoma cells. As we failed to find the primary tumor site before the patient died, she was diagnosed with CR-TMA due to bone marrow carcinomatosis of unknown primary origin. Thrombotic thrombocytopenic purpura (TTP) was rapidly ruled out based on her PLASMIC score. In addition, immunohistochemical staining of a clot section of the bone marrow and tumor marker data were useful for narrowing down the likely primary tumor site. CONCLUSION: Although CR-TMA is an extremely rare phenomenon, clinicians who suspect CR-TMA should quickly rule out TTP and decide whether to provide appropriate chemotherapy or plan for palliative care.

Retrospective analysis of clinical characteristics and outcomes of patients with carcinoma of unknown primary from three tertiary centers in Australia.

BACKGROUND: Carcinoma of unknown primary (CUP) remains an important tumor entity and a disproportionate cause of cancer mortality. Little is known about the contemporary clinical characteristics, treatment patterns, and outcomes of CUP patients based on updated international classification guidelines. We evaluated a contemporary CUP cohort to provide insight into current clinical practice and the impact of tissue of origin assignment, site-specific and empirical therapy in a real-world setting. METHODS: We conducted a retrospective cohort study of CUP patients, as defined by the updated European Society of Medical Oncology (ESMO) 2023 guidelines, across three tertiary referral centers in Australia between 2015 and 2022. We analyzed clinical characteristics, treatment patterns, and survival outcomes using the Kaplan-Meier method and Cox regression proportional hazard model between favorable and unfavorable risk groups. RESULTS: We identified a total of 123 CUP patients (n = 86 unfavorable, n = 37 favorable risk as per the 2023 ESMO guidelines). Sixty-four patients (52%) were assigned a tissue of origin by the treating clinician. Median progression free survival (PFS) was 6.8 (95% confidence interval (CI) 5.1-12.1) months and overall survival (OS) 10.2 (95% CI 6.0-18.5) months. Unfavorable risk (hazard ratio [HR] 2.9, p = 0.006), poor performance status (HR 2.8, p < 0.001), and non-squamous histology (HR 2.5, p < 0.05) were associated with poor survival outcome. A total of 70 patients (57%) proceeded to systemic therapy. In patients with non-squamous histology and unfavorable risk, site-specific therapy compared to empirical chemotherapy did not improve outcome (median OS 8.2 vs. 11.8 months, p = 0.7). CONCLUSIONS: In this real-world cohort, CUP presentations were heterogenous. Overall survival and rates of systemic treatment were poor. Poor performance status and unfavorable risk were associated with worse survival. For most patients, site-specific therapy did not improve survival outcome. Improved and timely access to diagnostic tests and therapeutics for this group of patients is urgently required.

[A Patient with Cancer of Unknown Primary Who Responded to Chemotherapy].

Cancer of unknown primary is a class of malignant tumors, histologically identified as metastatic lesions whose primary origin is unknown despite adequate investigations for the primary tumor. Although the prognosis of cancer of unknown primary is generally poor, here, we report our experience with a patient who responded to chemotherapy. The patient was a 78-year-old woman. She had a history of gastric cancer at the age of 76 years. In June of year X-1, she was diagnosed with gastric cancer(tub1>tub2, pT1bN0M0, pStage Ⅰa)and underwent distal gastrectomy. One year after surgery, computed tomography revealed right supraclavicular lymphadenopathy, for which cervical lymphadenectomy was performed. The pathological diagnosis was ductal carcinoma with comedo necrosis and poorly differentiated solid adenocarcinoma that were suggestive of metastases from breast cancer. However, a detailed examination of the mammary glands revealed no mass. Imaging studies led to a diagnosis of cancer of unknown primary. Therefore, chemotherapy, according to the treatment of pancreatic cancer, was planned based on immunostaining, tumor markers, etc. Chemotherapy response evaluation after completing 4 courses demonstrated a partial response; the patient responded to the chemotherapy. We considered that estimating primary lesions from histopathological images, tumor markers, etc., may help determine effective chemotherapy regimens.

[Case of a Patient with Cancer of Unknown Primary in the Poor Prognosis Group Who Had a Experienced a Beneficial Treatment Course].

A 47-year-old woman with general malaise and abdominal pain presented with multiple liver tumors and lymph node metastasis. She was diagnosed with small cell carcinoma on the basis of a lymph node biopsy; however, the primary lesion was not identified. Finally, we diagnosed her with cancer of unknown primary lesion and placed her in the poor prognosis group. Although her general condition was poor, she experienced a relatively good response to treatment for small cell carcinoma.

Biomarkers of systemic inflammation provide additional prognostic stratification in cancers of unknown primary.

BACKGROUND: Biomarkers of systemic inflammation have been shown to predict outcomes in patients with cancer of unknown primary (CUP). We sought to validate these findings in patients with confirmed CUP (cCUP) and explore their role alongside existing clinicopathological prognostic categories. PATIENTS AND METHODS: CUP oncologist from across the United Kingdom were invited to include patients with cCUP referred to their local CUP multidisciplinary team. Patient demographics, clinical, pathological and outcome data were recorded and analysed. RESULTS: Data were available for 548 patients from four CUP services. 23% (n = 124) of patients met clinicopathological criteria for favourable-risk cCUP. On multivariate analysis c-reactive protein (CRP) (p < 0.001) and the Scottish Inflammatory Prognostic Score (SIPS: combining albumin and neutrophil count) (p < 0.001) were independently predictive of survival. CRP and SIPS effectively stratified survival in patients with both favourable-risk and poor-risk cCUP based on clinicopathological features. CONCLUSIONS: Biomarkers of systemic inflammation are reliable prognostic factors in patients with cCUP, regardless of clinicopathological subgroup. We recommend that CRP or SIPS are incorporated into routine clinical assessments of patients with cCUP as a tool to aid investigation and/or treatment decision-making across all groups. Established clinicopathological factors can then be used to inform management pathways and specific systemic anticancer therapy selection.

Utility of UV Signature Mutations in the Diagnostic Assessment of Metastatic Head and Neck Carcinomas of Unknown Primary.

BACKGROUND: Metastatic carcinoma of unknown primary origin to the head and neck lymph nodes (HNCUP) engenders unique diagnostic considerations. In many cases, the detection of a high-risk human papillomavirus (HR-HPV) unearths an occult oropharyngeal squamous cell carcinoma (SCC). In metastatic HR-HPV-independent carcinomas, other primary sites should be considered, including cutaneous malignancies that can mimic HR-HPV-associated SCC. In this context, ultraviolet (UV) signature mutations, defined as ≥ 60% C→T substitutions with ≥ 5% CC→TT substitutions at dipyrimidine sites, identified in tumors arising on sun exposed areas, are an attractive and underused tool in the setting of metastatic HNCUP. METHODS: A retrospective review of institutional records focused on cases of HR-HPV negative HNCUP was conducted. All cases were subjected to next generation sequencing analysis to assess UV signature mutations. RESULTS: We identified 14 HR-HPV negative metastatic HNCUP to either the cervical or parotid gland lymph nodes, of which, 11 (11/14, 79%) had UV signature mutations, including 4 (4/10, 40%) p16 positive cases. All UV signature mutation positive cases had at least one significant TP53 mutation and greater than 20 unique gene mutations. CONCLUSION: The management of metastatic cutaneous carcinomas significantly differs from other HNCUP especially metastatic HR-HPV-associated SCC; therefore, the observation of a high percentage of C→T with CC →TT substitutions should be routinely incorporated in next generation sequencing reports of HNCUP. UV mutational signatures testing is a robust diagnostic tool that can be utilized in daily clinical practice.

Advances in Cancer Research: Current and Future Diagnostic and Therapeutic Strategies.

Cancers of unknown primary (CUP) exhibit significant cellular heterogeneity and malignancy, which poses significant challenges for diagnosis and treatment. Recent years have seen deeper insights into the imaging, pathology, and genetic characteristics of CUP, driven by interdisciplinary collaboration and the evolution of diagnostic and therapeutic strategies. However, due to their insidious onset, lack of evidence-based medicine, and limited clinical understanding, diagnosing and treating CUP remain a significant challenge. To inspire more creative and fantastic research, herein, we report and highlight recent advances in the diagnosis and therapeutic strategies of CUP. Specifically, we discuss advanced diagnostic technologies, including 12-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography (18F-FDG PET/CT) or 68Ga-FAPI (fibroblast activation protein inhibitor) PET/CT, liquid biopsy, molecular diagnostics, self-assembling nanotechnology, and artificial intelligence (AI). In particular, the discussion will extend to the effective treatment techniques currently available, such as targeted therapies, immunotherapies, and bio-nanotechnology-based therapeutics. Finally, a novel perspective on the challenges and directions for future CUP diagnostic and therapeutic strategies is discussed.

Cancer of unknown primary and the «seed and soil¼ hypothesis.

The worldwide incidence rate of cancer of unknown primary (CUP) reaches 5% (Kang et al, 2021; Lee, Sanoff, 2020; Yang et al, 2022). CUP has an alarmingly high mortality rate, with 84% of patients succumbing within the first year following diagnosis (Registration and Service, 2018). Under normal circumstances, tumor cell metastasis follows the «seed and soil¼ hypothesis, displaying a tissue-specific pattern of cancer cell homing behavior based on the microenvironment composition of secondary organs. In this study, we questioned whether seed and soil concept applies to CUP, and whether the pattern of tumor and metastasis manifestations for cancer of known primary (CKP) can be used to inform diagnostic strategies for CUP. We compared data from metastatic and primary CUP foci to the metastasis patterns observed in CKP. Furthermore, we evaluated several techniques for identifying the tissue-of-origin (TOO) in CUP profiling, including DNA, RNA, and epigenetic TOO techniques.

New techniques to identify the tissue of origin for cancer of unknown primary in the era of precision medicine: progress and challenges.

Despite a standardized diagnostic examination, cancer of unknown primary (CUP) is a rare metastatic malignancy with an unidentified tissue of origin (TOO). Patients diagnosed with CUP are typically treated with empiric chemotherapy, although their prognosis is worse than those with metastatic cancer of a known origin. TOO identification of CUP has been employed in precision medicine, and subsequent site-specific therapy is clinically helpful. For example, molecular profiling, including genomic profiling, gene expression profiling, epigenetics and proteins, has facilitated TOO identification. Moreover, machine learning has improved identification accuracy, and non-invasive methods, such as liquid biopsy and image omics, are gaining momentum. However, the heterogeneity in prediction accuracy, sample requirements and technical fundamentals among the various techniques is noteworthy. Accordingly, we systematically reviewed the development and limitations of novel TOO identification methods, compared their pros and cons and assessed their potential clinical usefulness. Our study may help patients shift from empirical to customized care and improve their prognoses.

Health Economic Consequences Associated With COVID-19-Related Delay in Melanoma Diagnosis in Europe.

Importance: The COVID-19 pandemic resulted in delayed access to medical care. Restrictions to health care specialists, staff shortages, and fear of SARS-CoV-2 infection led to interruptions in routine care, such as early melanoma detection; however, premature mortality and economic burden associated with this postponement have not been studied yet. Objective: To determine the premature mortality and economic costs associated with suspended melanoma screenings during COVID-19 pandemic lockdowns by estimating the total burden of delayed melanoma diagnoses for Europe. Design, Setting, and Participants: This multicenter economic evaluation used population-based data from patients aged at least 18 years with invasive primary cutaneous melanomas stages I to IV according to the American Joint Committee on Cancer (AJCC) seventh and eighth editions, including melanomas of unknown primary (T0). Data were collected from January 2017 to December 2021 in Switzerland and from January 2019 to December 2021 in Hungary. Data were used to develop an estimation of melanoma upstaging rates in AJCC stages, which was verified with peripandemic data. Years of life lost (YLL) were calculated and were, together with cost data, used for financial estimations. The total financial burden was assessed through direct and indirect treatment costs. Models were building using data from 50 072 patients aged 18 years and older with invasive primary cutaneous melanomas stages I to IV according to the AJCC seventh and eighth edition, including melanomas of unknown primary (T0) from 2 European tertiary centers. Data from European cancer registries included patient-based direct and indirect cost data, country-level economic indicators, melanoma incidence, and population rates per country. Data were analyzed from July 2021 to September 2022. Exposure: COVID-19 lockdown-related delay of melanoma detection and consecutive public health and economic burden. As lockdown restrictions varied by country, lockdown scenario was defined as elimination of routine medical examinations and severely restricted access to follow-up examinations for at least 4 weeks. Main Outcomes and Measures: Primary outcomes were the total burden of a delay in melanoma diagnosis during COVID-19 lockdown periods, measured using the direct (in US$) and indirect (calculated as YLL plus years lost due to disability [YLD] and disability-adjusted life-years [DALYs]) costs for Europe. Secondary outcomes included estimation of upstaging rate, estimated YLD, YLL, and DALY for each European country, absolute direct and indirect treatment costs per European country, proportion of the relative direct and indirect treatment costs for the countries, and European health expenditure. Results: There were an estimated 111 464 (range, 52 454-295 051) YLL due to pandemic-associated delay in melanoma diagnosis in Europe, and estimated total additional costs were $7.65 (range, $3.60 to $20.25) billion. Indirect treatment costs were the main cost driver, accounting for 94.5% of total costs. Estimates for YLD in Europe resulted in 15 360 years for the 17% upstaging model, ranging from 7228 years (8% upstaging model) to 40 660 years (45% upstaging model). Together, YLL and YLD constitute the overall disease burden, ranging from 59 682 DALYs (8% upstaging model) to 335 711 DALYs (45% upstaging model), with 126 824 DALYs for the real-world 17% scenario. Conclusions and Relevance: This economic analysis emphasizes the importance of continuing secondary skin cancer prevention measures during pandemics. Beyond the personal outcomes of a delayed melanoma diagnosis, the additional economic and public health consequences are underscored, emphasizing the need to include indirect economic costs in future decision-making processes. These estimates on DALYs and the associated financial losses complement previous studies highlighting the cost-effectiveness of screening for melanoma.

Head and Neck Cancer of Unknown Primary: A Multicenter Retrospective Cohort study in Northern Thailand, an Endemic Nasopharyngeal Cancer Area.

OBJECTIVE: This study aimed to evaluate the characteristics and oncological outcomes of head and neck carcinoma of unknown primary (HNCUP) patients in an endemic nasopharyngeal cancer (NPC) area. METHODS: One hundred and forty-four HNCUP patients curatively treated between January 1995 and December 2022 from 5 centers were retrospectively recruited onto the study to analyze the clinicopathological characteristics and oncological outcomes and compare them with historical data. A multivariate Cox proportional hazards model analysis was performed to evaluate factors affecting survival outcomes. A propensity-matched pair analysis of the patients with positive and negative EBV-encoded small RNA (EBER) staining was applied to compare the characteristics and outcomes between the two groups. RESULTS: The median follow-up time was 45 months. Most patients (88.2%) received total mucosal irradiation (TMI). Primary tumor emergence (PTE) was detected in 6 patients (4.2%) who did not have TMI. The 5-year overall survival (OS), disease-free survival, and locoregional recurrence-free survival were 51.3%, 64.9%, and 72.7%, respectively. Extranodal extension and N3 compared with the N1 stage were the significant independent predictors for OS (HR 2.90, 95% CI 1.12-7.51, p = 0.028 and HR 3.66, 95%CI 1.23-11.89, p = 0.031, respectively). The matched-pair analysis demonstrated comparable all survival outcomes between the EBER-positive and -negative groups. All patients in the matched pair analysis received TMI, and no PTE was detected. CONCLUSION: Our survival outcomes were comparable to previous studies with a low rate of PTE. The matched pair analysis of EBER-positive and -negative groups revealed similar oncological outcomes and no primary tumor emergence when total mucosal irradiation was administered.

Comprehensive biomarker diagnostics of unfavorable cancer of unknown primary to identify patients eligible for precision medical therapies.

PURPOSE: Current guidelines recommend combination chemotherapy for treatment of patients with unfavorable cancer of unknown primary (CUP). Biomarker-guided targeted therapies may offer additional benefit. Data on the feasibility and effectiveness of comprehensive genomic biomarker profiling of CUP in a standard clinical practice setting are limited. METHODS: This analysis included 156 patients with confirmed unfavorable CUP diagnosis according to ESMO guidelines, who were treated at the West German Cancer Center, Essen, Germany, from 2015 to 2021. Clinical parameters and outcome data were retrieved from the electronic hospital information system. Genomic biomarker analyses were performed in formalin-fixed paraffin-embedded tumor tissue whenever possible using the QIAseq Multimodal-Pancancer-Panel. RESULTS: Non-squamous histologies, high tumor burden, and age above 60 years associated with poor survival outcome. Tissue availability restricted comprehensive biomarker analyses to 50 patients (32%), reflecting a major limitation in the real-world setting. In those patients a total of 24 potentially actionable alterations were identified in 17 patients (34% of profiled patients, 11% of total population). The most prevalent biomarkers were high tumor mutational burden and BRCA-mutations. CONCLUSION: In a real-world setting precision medicine for patients with CUP is severely restricted by tissue availability, and a limited spectrum of actionable alterations. Progress for patients may require emphasizing the need for sufficient biopsies, and prospective exploration of blood-based biomarker profiling.

Tissue of origin prediction for cancer of unknown primary using a targeted methylation sequencing panel.

RATIONALE: Cancer of unknown primary (CUP) is a group of rare malignancies with poor prognosis and unidentifiable tissue-of-origin. Distinct DNA methylation patterns in different tissues and cancer types enable the identification of the tissue of origin in CUP patients, which could help risk assessment and guide site-directed therapy. METHODS: Using genome-wide DNA methylation profile datasets from The Cancer Genome Atlas (TCGA) and machine learning methods, we developed a 200-CpG methylation feature classifier for CUP tissue of origin prediction (MFCUP). MFCUP was further validated with public-available methylation array data of 2977 specimens and targeted methylation sequencing of 78 Formalin-fixed paraffin-embedded (FFPE) samples from a single center. RESULTS: MFCUP achieved an accuracy of 97.2% in a validation cohort (n = 5923) representing 25 cancer types. When applied to an Infinium 450 K array dataset (n = 1052) and an Infinium EPIC (850 K) array dataset (n = 1925), MFCUP achieved an overall accuracy of 93.4% and 84.8%, respectively. Based on MFCUP, we established a targeted bisulfite sequencing panel and validated it with FFPE sections from 78 patients of 20 cancer types. This methylation sequencing panel correctly identified tissue of origin in 88.5% (69/78) of samples. We also found that the methylation levels of specific CpGs can distinguish one cancer type from others, indicating their potential as biomarkers for cancer diagnosis and screening. CONCLUSION: Our methylation-based cancer classifier and targeted methylation sequencing panel can predict tissue of origin in diverse cancer types with high accuracy.

Bone metastatic cancer of unknown primary at initial presentation

Introduction Cancer of unknown primary (CUP) is a challenging malignancy. The purpose of this study was to investigate the clinical characteristics and prognosis of bone metastatic CUP using the population-based Surveillance, Epidemiology, and End Results (SEER) database. Methods From the SEER database, we identified 1908 patients with bone metastatic CUP at initial presentation between 2010 and 2018. Histology was subdivided following International Classification of Diseases for Oncology codes as Adenocarcinoma, Squamous cell, Neuroendocrine, or Carcinoma not otherwise specified (NOS). Cox proportional hazard modeling was applied using factors of age, sex, ethnicity, histological subtype, and therapeutic intervention. Results Among the 1908 patients, histology was Neuroendocrine in 240 patients, Squamous cell in 201 patients, Adenocarcinoma in 810 patients and NOS in 657 patients. In each subtype, patients tended to be predominantly male and white. Chemotherapy was introduced for 28% of patients and radiation for 34% in the entire cohort. Survival in patients with bone metastatic CUP was unfavorable, with a median survival of 2 months. Among the histological subtypes, Adenocarcinoma showed shorter survival than the other groups. In addition, treatment interventions such as chemotherapy and radiation therapy prolonged survival, particularly for Squamous cell, Adenocarcinoma and NOS, but not for Neuroendocrine. Discussion Bone metastatic CUP showed extremely poor prognosis, but treatment interventions such as chemotherapy and radiation generally offered survival benefits. Further randomized clinical research is needed to confirm the present results (AU)

Surgical resection of an intraluminal tumor in the azygos vein with an unknown primary site causing superior vena cava syndrome.

Intraluminal tumor in the azygos vein is a rare disease that can cause superior vena cava (SVC) syndrome. Radiotherapy and endovascular stenting with or without chemotherapy are reported to have a high clinical success rate for the management of SVC syndrome with malignancy, but a poor survival rate. Here, we report a 69-year-old man who presented with swelling of the face and upper extremities, who was diagnosed with SVC syndrome caused by an intraluminal tumor in the azygos vein. Enhanced chest computed tomography revealed an intraluminal mass with a filling defect from the azygos vein to the SVC, with no extravascular extension or dissemination of the primary tumor. Surgical resection of the mass en bloc with the azygos vein and SVC reconstruction was performed. A poorly differentiated carcinoma was diagnosed on postoperative pathological evaluation. Twelve months after resection, the patient was well with no signs of recurrent disease. This case highlights that surgical resection should be considered as a treatment of choice for the management of SVC syndrome caused by an intraluminal malignancy in the azygos vein.

Idiopathic membranous nephropathy and synchronous mononeuritis multiplex secondary to idiopathic small vessel vasculitis.

Membranous nephropathy has been associated with demyelinating polyneuropathies and antiglomerular membrane disease; however, an association with vasculitic neuropathy has not been described. This case describes a patient with biopsy-proven idiopathic membranous nephropathy and synchronous mononeuritis multiplex secondary to idiopathic small vessel vasculitis, who presented with lower limb microvascular ischaemia, peripheral neuropathy and active urinary sediment. Her extensive non-invasive screening for immunological disease and radiological investigations for occult malignancy were unremarkable. The patient received intravenous methylprednisolone and intravenous rituximab induction therapy resulting in complete remission of both the idiopathic membranous nephropathy and small vessel vasculitis at 7 months post treatment.