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.

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.

Factors associated with unknown primary status in head and neck squamous cell carcinoma.

OBJECTIVES: Head and neck cancer of unknown primary (CUP) poses significant therapeutic challenges. We compare CUP and oropharyngeal primary (OP) cases to identify factors associated with tumor detection. METHODS: The 2004-2019 National Cancer Database was queried to identify CUP and OP cases based on clinical and pathologic TNM staging. Clinical and demographic characteristics were compared by primary detection and HPV status with descriptive statistics. Multivariable logistic regression models to characterize OP detection were constructed. Among HPV-positive and negative patients, respectively, OP and CUP patients were matched by clinical nodal disease. Cox proportional-hazards models were constructed using matched cohorts to characterize survival. RESULTS: 81,053 CUP and OP cases were identified; 64.3 % were HPV-positive. OP detection increased over time in HPV-positive and negative disease. HPV-positive status had higher odds of OP detection (odds ratio (OR) = 1.77, p < 0.001), while females (OR = 0.95, p = 0.008), and black (OR = 0.82, p < 0.001) and Asian (OR = 0.7, p < 0.001) patients had lower odds compared to males and whites, respectively. In HPV-positive and negative disease, OP patients had higher 2 and 5-year survival rates than CUP (p < 0.001). Primary detection status conferred lower death risk in HPV-positive (hazard ratio (HR) = 0.85, p < 0.001) and negative disease (HR = 0.87, p < 0.001) when controlling for age, sex, race, comorbidities, insurance, treatment facility, and income. CONCLUSION: In the largest cohort of CUP to date, we report a survival benefit in primary tumor detection regardless of HPV status. Groups with higher persistent CUP rates, including non-white, female, HPV-negative, and low income patients, may benefit from increased diagnostic workup to improve detection and treatment.

Management of unknown primary head and neck cancer with radiation therapy in the era of human papillomavirus (HPV): No longer cutting down the tree to get an apple.

PURPOSE: Given the central role that radiation has in the management of head and neck squamous cell carcinoma of unknown primary origin, it is imperative to review how treatment paradigms have been refined and continue to evolve in the modern era. METHODS AND MATERIALS: This study was designed based on the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) statement. A literature search of peer-reviewed publications was undertaken to identify works pertaining to the use of radiation for squamous cell carcinoma of unknown primary origin presenting as cervical lymph node metastases. Articles published from January 2002 to January 2023 with full text available on PubMed and restricted to the English language and human subjects were included. The full bibliographies of identified articles were reviewed and irrelevant studies were removed. RESULTS: While such breakthroughs as intensity-modulated radiotherapy, positron emission tomography, biomarker testing with immune-histochemistry, and minimally invasive surgical techniques such as transoral robotic surgery have fundamentally changed the approach to this disease in recent decades, controversies still exist with respect to the manner in which radiation is delivered. Although the incidence of head and neck unknown primary cancer is relatively low, questions regarding the necessity of comprehensive radiation using the age-old standard method of targeting the bilateral necks and entire pharyngeal axis to encompass all putative sites of mucosal disease persist. CONCLUSIONS: Prospective evidence is lacking, and the available studies have been complicated by such factors as the relatively limited sample sizes, as well as the variability in work-up, treatment, inclusion criteria, and follow-up. Regardless, advances in science and technology have ushered in more precise approaches with a high degree of customization, particularly given the increased proportion of patients presenting with human papillomavirus-related disease.

Liver failure as the initial presentation in cancer of unknown primary: a case report.

BACKGROUND: Liver failure is severe hepatic cellular damage caused by multiple factors that leads to clinical manifestations. Hepatic infiltration by malignancy is rarely reported as a cause of liver failure. CASE PRESENTATION: A 51-year-old male patient was admitted to the Wuhan Union Hospital complaining of bloating and jaundice. He had been diagnosed with polymyositis ten prior and was taking oral glucocorticoids. Physical examination revealed seroperitoneum and icteric sclera; laboratory tests revealed liver dysfunction, a coagulopathy, and negative results for the common causes of liver failure. Moreover, an ascitic tap and bone marrow aspirate and trephine confirmed a metastatic, poorly differentiated adenocarcinoma. These findings indicate that malignant infiltration is the most likely cause of liver failure. Regrettably, the patient refused complete liver and lymph node biopsies and was discharged on day 31. CONCLUSION: Clinicians should consider the possibility of malignant infiltration when approaching a case of liver failure with prodromal symptoms or imaging abnormalities, especially in patients with autoimmune diseases, such as polymyositis.

Biopsy-proven first dose of oxaliplatin-induced acute tubular necrosis leading to end-stage renal failure: a case report.

BACKGROUND: Oxaliplatin is an anticancer therapy for pancreatic, gastric, and colorectal cancers. It is also used in patients with carcinomas of unknown primary sites. Oxaliplatin is associated with less frequent renal dysfunction than other conventional platinum-based drugs such as cisplatin. Albeit, there have been several reports of acute kidney injury with frequent use. In all cases, renal dysfunction was temporary and did not require maintenance dialysis. There have been no previous reports of irreversible renal dysfunction after a single dose of oxaliplatin. CASE PRESENTATION: Previous reports of oxaliplatin-induced renal injury occurred after patients received multiples doses. In this study, a 75-year-old male with unknown primary cancer and underlying chronic kidney disease developed acute renal failure after receiving the first dose of oxaliplatin. Suspected of having drug-induced renal failure through an immunological mechanism, the patient was treated with steroids; however, treatment was ineffective. Renal biopsy ruled out interstitial nephritis and revealed acute tubular necrosis. Renal failure was irreversible, and the patient subsequently required maintenance hemodialysis. CONCLUSIONS: We provide the first report of pathology-confirmed acute tubular necrosis after the first dose of oxaliplatin which led to irreversible renal dysfunction and maintenance dialysis.

Platelet RNA sequencing for cancer screening in patients with unprovoked venous thromboembolism: a prospective cohort study.

BACKGROUND: Platelet RNA sequencing has been shown to accurately detect cancer in previous studies. OBJECTIVES: To compare the diagnostic accuracy of platelet RNA sequencing with standard-of-care limited cancer screening in patients with unprovoked venous thromboembolism (VTE). METHODS: Patients aged ≥40 years with unprovoked VTE were recruited at 13 centers and followed for 12 months for cancer. Participants underwent standard-of-care limited cancer screening, and platelet RNA sequencing analysis was performed centrally at study end for cases and selected controls. Sensitivity and specificity were calculated, using the predefined primary positivity threshold of 0.54 for platelet RNA sequencing aiming at 86% test sensitivity, and an additional predefined threshold of 0.89 aiming at 99% test specificity. RESULTS: A total of 476 participants were enrolled, of whom 25 (5.3%) were diagnosed with cancer during 12-month follow-up. For each cancer patient, 3 cancer-free patients were randomly selected for the analysis. The sensitivity of limited screening was 72% (95% CI, 52-86) at a specificity of 91% (95% CI, 82-95). The area under the receiver operator characteristic for platelet RNA sequencing was 0.54 (95% CI, 0.41-0.66). At the primary positivity threshold, all patients had a positive test, for a sensitivity estimated at 100% (95% CI, 87-99) and a specificity of 8% (95% CI, 3.7-16.4). At the secondary threshold, sensitivity was 68% (95% CI, 48-83; p value compared with limited screening 0.71) at a specificity of 36% (95% CI, 26-47). CONCLUSION: Platelet RNA sequencing had poor diagnostic accuracy for detecting occult cancer in patients with unprovoked VTE with the current algorithm.

A case of refractory pelvic squamous cell carcinoma of unknown primary that responded to nivolumab.

Cancer of unknown primary (CUP) is a heterogeneous group of metastatic tumors with a usually unfavorable prognosis. A 33-year-old female was diagnosed with pelvic squamous cell carcinoma of unknown primary. The tumor was p16-positive, suggesting that it was human papillomavirus (HPV)-related. The tumor progressed for 4 months after concurrent chemoradiotherapy (initial treatment) and was refractory to paclitaxel plus carboplatin (second-line therapy). Liquid-based cancer genomic profiling identified five pathogenic variants, including Neurofibromin1 (NF1) (p.T1690Mfs*5); however, due to the lack of domestic clinical trials, the patient could not receive genome-based molecular-target therapies. Simultaneously, nivolumab was administered to the patient post its approval in Japan for CUP. The tumor responded to nivolumab, accompanied by decreased levels of tumor markers. NF1 mutations and HPV-related carcinogenesis may be associated with a favorable response to nivolumab treatment. It may therefore serve as a potential treatment against cancers of unknown primaries.

Occult colon cancer with liver abscess and pancreatitis as the first manifestations: A case report.

INTRODUCTION: Klebsiella pneumoniae-induced liver abscess (KP-PLA) is a common type of pyogenic liver abscess, severe acute pancreatitis (SAP) has high mortality, and poor prognosis in advanced colon cancer. There have been no report of SAP complicated with colon cancer after KP-PLA as so far. In this study, we reported a case of SAP secondary to KP-PLA with colon cancer for the first time, so as to provide reference for clinical diagnosis and treatment of these diseases. PATIENT CONCERNS AND DIAGNOSIS: A 64-year-old woman with a history of diabetes visited our hospital with abdominal pain for 5 + days. He was diagnosed with KP-PLA a month ago, which had not healed when he was admitted. He was diagnosed with SAP, and histological examination of colonic biopsy confirmed the diagnosis of moderately differentiated adenocarcinoma. INTERVENTIONS AND OUTCOMES: He was treated with intravenous antibiotics and underwent modified endoscopic mucosal resection under colonoscopy. We conducted a 2-month follow-up, and there was no recurrence of liver abscess and pancreatitis. CONCLUSION: Screening for intestinal tumors is necessary in patients with cryptogenic liver abscess, especially KP-PLA with diabetes.

18F-Fluorodeoxyglucose positron emission/computed tomography for occult cancer among patients with unprovoked venous thromboembolism: What do we know?

18F-Fluorodeoxyglucose Positron Emission/Computed Tomography (FDG PET/CT) is a non-invasive whole-body imaging modality that has the potential for replacing multiple cancer screening tests by one. Previous studies showed that FDG PET/CT has an excellent sensitivity and negative predictive value for occult cancer screening in patients with unprovoked venous thromboembolism (VTE). In this patient population, FDG PET/CT is a reproducible imaging procedure with a kappa value estimated at 0.75. Although false positive results may lead to unnecessary investigations, it seems from recent evidence that invasive procedures triggered by a positive scan often resulted in cancer diagnosis. Trials assessing use of FDG PET/CT for occult cancer screening in patients with VTE at high risk for occult cancer diagnosis are ongoing.

[Screening for cancer in case of venous thromboembolism: when and how?] / Quand et comment rechercher un cancer en cas de maladie thromboembolique veineuse ?

Screening for cancer in case of venous thromboembolism: when and how? Cancer associated thrombosis (cat) is an important challenge. When venous thromboembolism (vte) occurs without any identified risk factors, the risk of cat raises the question of a hidden cancer and the need for an extensive screening or not. Several series have shown a prevalence between 5% and 10% of cancer when non provoqued vte is diagnosed. Most of cancers occur during the following year of vte. If we consider diagnosing the cancer in early stage, we might improve the patient outcome and reduce cancer mortality. A simple screening, including clinical examina¬tion, personal and familial history of cancer, basic laboratory tests and recommended age and sex testing is mandatory. Other exams are considered as useless at present time. Whether a tep-scan, prescribed in patients older than 50, brings a clinical benefit, is still unresolved. Screening for cancer in case of venous thromboembolism: when and how? Cancer associated thrombosis (cat) is an important challenge. When venous thromboembolism (vte) occurs without any identified risk factors, the risk of cat raises the question of a hidden cancer and the need for an extensive screening or not. Several series have shown a prevalence between 5% and 10% of cancer when non provoqued vte is diagnosed. Most of cancers occur during the following year of vte. If we consider diagnosing the cancer in early stage, we might improve the patient outcome and reduce cancer mortality. A simple screening, including clinical examina¬tion, personal and familial history of cancer, basic laboratory tests and recommended age and sex testing is mandatory. Other exams are considered as useless at present time. Whether a tep-scan, prescribed in patients older than 50, brings a clinical benefit, is still unresolved.

Quand et comment rechercher un cancer en cas de maladie thromboembolique veineuse ? L'association thrombose et cancer est connue depuis longtemps et pose des problèmes diagnostiques et thérapeutiques spécifiques. La maladie thromboembolique veineuse (mtev) peut précéder le cancer et servir de signe d'alerte. Plusieurs publications font état d'une prévalence comprise entre 5 et 10 % de cancer occulte en cas de mtev non provoquée. La plupart des cancers apparaissent dans l'année qui suit le diagnostic de mtev. Dépister un cancer au stade infraclinique, au moment du diagnostic de la thrombose, permettrait de diminuer le risque d'extension du cancer et d'améliorer le pronostic des patients. Une recherche de cancer, simple, incluant interrogatoire, examen clinique et bilan biologique minimal, sans examens complémentaires inutiles et adaptée aux facteurs de risque, doit donc être effectuée. La question est aujourd'hui de savoir si une stratégie plus extensive, comprenant un tep-scan, notamment chez les patients de plus de 50 ans, apporte un bénéfice clinique.

Subacute sensory neuronopathy associated with Merkel cell carcinoma with unknown primary: a case report with literature review.

Paraneoplastic neurologic syndromes (PNSs) are a wide spectrum of neurologic diseases characterized by different clinical features, associated with a neoplasia, and triggered by an immune-mediated process. In most cases, it is possible to detect specific neuronal antibodies and the Hu protein is one of the most frequently recognized intracellular antigens in patients with PNSs. Small-cell lung cancer is the most common cancer associated with PNSs, followed by urological, gynecological and hematological malignancies. Otherwise, extra-pulmonary small-cell carcinomas, including Merkel cell carcinoma (MCC), have been rarely described as related to PNSs. In this article we report, for the first time in the published literature, a case of anti-Hu antibody-related subacute sensory neuronopathy in association with MCC.

Type 2 diabetes mellitus and cancer of unknown primary risk: results from the Netherlands Cohort Study.

OBJECTIVE: Cancer of unknown primary (CUP) is a metastatic malignancy with an unidentifiable primary tumour origin. Previous studies suggest that type 2 diabetes mellitus (T2DM) and CUP risk are associated. This study examines the association in greater depth by investigating T2DM status, T2DM duration, T2DM age at diagnosis, and medication that was being used in relation to CUP. METHODS: Data were utilized from the Netherlands Cohort Study, a prospective cohort that includes 120 852 participants aged 55-69 years at baseline in 1986. All participants completed a self-administered questionnaire on cancer risk factors. CUP cases were identified through record linkage with the Netherlands Cancer Registry and Dutch Pathology Registry. After 20.3 years of follow-up, 963 incident CUP cases and 4288 subcohort members were available for case-cohort analyses. Proportional hazards models were employed to estimate multivariable-adjusted hazard ratios (HRs). RESULTS: Overall, we observed a nonsignificant positive association between T2DM status and CUP risk [HR, 1.35; 95% confidence interval (CI), 0.92-1.99], which increased in women after stratification for sex (HR, 1.55; 95% CI, 0.90-2.64). For participants who were aged less than 50 years at diagnosis of T2DM, a statistically significant positive association was found in relation to CUP (HR, 2.42; 95% CI, 1.26-4.65), compared with participants without T2DM. CONCLUSION: Our findings indicate that there is a nonsignificant positive association between T2DM and CUP risk and that the association became stronger in women in stratified analyses.

Real-world experience with limited screening for occult malignancy in patients presenting with spontaneous venous thromboembolism: a single-centre, retrospective cohort study.

Spontaneous venous thromboembolism (VTE) may represent the first manifestation of previously undiagnosed malignancy; however, contemporary international guidelines call for a limited approach to screening for malignancy in such patients. This retrospective cohort study of 328 patients presenting to the Auckland City Hospital Thrombosis Unit identified 17 patients who were subsequently diagnosed with some form of malignancy within 12 months of their presentation. Review of their history, physical examination and limited age and gender-appropriate cancer screening investigations as described by the National Institute for Clinical Excellence and International Society of Thrombosis and Haemostasis guidelines revealed that all 17 would have been safely diagnosed by the 'limited' screening approach endorsed by these guidelines, thus presenting a 'real-world' basis for clinicians to pursue 'limited' screening for malignancy in their everyday practice in patients with spontaneous VTE.

Cushing's syndrome due to adrenocorticotropic hormone-secreting metastatic neuroendocrine tumor of unknown primary origin: a case report and literature review.

BACKGROUND: In this article, we present a case of neuroendocrine neoplasm of unknown primary origin (UPO NEN), which is a rare cause of ectopic Cushing's syndrome (ECS) presenting numerous challenges, together with a literature review. CASE REPORT: A 43-year-old male patient presented with clinical features consistent with Cushing's syndrome (CS) and adrenocorticotropic hormone (ACTH)-dependent hypercortisolemia. Despite a suspicious lesion on pituitary MRI, the high-dose dexamethasone suppression test and bilateral inferior petrosal sinus sampling results were not compatible with Cushing's disease. Bilateral non-homogeneous opacities were observed in the thorax CT of the patient, who also had a history of COVID-19 infection, but no tumoral lesion was detected. When 68Ga-SSTR PET/CT and 18FDG-PET/CT were performed, multiple metastatic foci were detected in mediastinal and hilar lymph nodes and the axial skeleton. Paratracheal-subcarinal lymph nodes were excised mediastinoscopically, and the diagnosis of NEN was made. Histopathological findings indicated that the possible origin was an atypical pulmonary carcinoid with a low Ki-67 labeling index. After controlling hypercortisolemia, a regimen of somatostatin analogs and capecitabine plus temozolomide was decided upon as treatment by a multidisciplinary council. CONCLUSION: This is a challenging case of UPO NEN presenting with ECS and confounding factors, such as previous infection and incidental lesions, during the diagnosis process. The case in question highlighted the fact that atypical pulmonary carcinoid with a low proliferation index may cause visible metastases even when radiologically undetectable.

Occult breast cancer: Where are we at?

Occult breast cancer (OBC) is described as an axillary metastatic carcinoma without detection of a primary breast lesion and is uncommon. Significant advances in breast imaging have occurred since its description, decreasing its incidence. However current management is based upon old studies, with variable clinical, radiological and pathological definitions of OBC. We suggest standardised definitions of OBC to facilitate more homogenous data representation in the literature. This review also discusses the conflicting heterogeneous data and its influence in determining the current management guidelines. We discuss whether the current significant surgical recommendations are necessary and postulate whether they could be safely substituted with less invasive management.

Performance of 18F-fluorodesoxyglucose positron-emission tomography/computed tomography for cancer screening in patients with unprovoked venous thromboembolism: Results from an individual patient data meta-analysis.

INTRODUCTION: Venous thromboembolism (VTE) may be the first manifestation of cancer. We aimed at evaluating the performance of 18F-Fluorodesoxyglucose Positron-Emission Tomography/Computed Tomography (FDG PET/CT) for occult cancer screening in patients with unprovoked VTE. METHODS: This was a pre-specified analysis of a systematic review and individual patient data meta-analysis including prospective studies assessing cancer screening in patients with unprovoked VTE. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FDG PET/CT were calculated based on cancer diagnosis during a 1-year follow-up period. RESULTS: Four studies were identified as using FDG PET/CT as part of their extensive screening strategy. Out of the 332 patients who underwent FDG PET/CT, the scan was interpreted as positive in 67 (20.2%), as equivocal in 27 (8.1%), and as negative in 238 (71.7%). Seventeen (5.1%) patients were diagnosed with cancer at inclusion or during the 12-month follow up period. All cancers were diagnosed at initial screening. Pooled sensitivity, specificity, NPV, and PPV were 87.3% (95% CI, 55.3 to 97.4), 70.2% (95% CI, 48.2 to 85.6), 98.9% (95% CI, 94.3 to 99.7), and 17.9% (95% CI, 8.5 to 33.6), respectively. CONCLUSION: FDG PET/CT appears to have satisfactory accuracy indices for cancer diagnosis in patients with unprovoked VTE. In particular, it exhibits a very high negative predictive value and could be used to rule out the presence of an underlying occult malignancy in this setting.

Casting a Wider NET: An Unusual Cause of Acute Liver Failure in a Pregnant Patient.

We present a case patient in her second trimester of pregnancy who developed acute liver failure from metastatic neuroendocrine tumor (NET). Although she underwent prompt induction of a non-viable fetus due to initial concerns of hemolysis, elevated liver enzymes, and low platelet count syndrome, her liver function continued to deteriorate postpartum. She was subsequently transferred to our institution in order to undergo further evaluation that included a transjugular liver biopsy and subsequent diagnosis of high-grade NET. She was given salvage carboplatin-based chemotherapy, as she was not a liver transplant candidate. Unfortunately, the patient expired from cardiovascular collapse as a component of multiorgan failure.

Screening for Occult Cancer in Patients with Venous Thromboembolism: Past, Present, and Future.

A strong link between cancer and thrombosis has been well recognized. The occurrence of venous thromboembolism (VTE) can be the first clinical sign of an undiagnosed (i.e., occult) cancer. Cancer is more often diagnosed after unprovoked compared with provoked VTE events, with a reported risk in recent studies of around 5%. Extensive, imaging-based screening strategies to detect occult cancer after unprovoked VTE do not appear to have a clear clinical benefit compared with a more limited cancer screening. To identify patients with unprovoked VTE at high risk of occult cancer, risk factors have been explored and prediction models developed. Relevant risk factors for occult cancer include male sex, age, anemia, chronic lung disease, and thrombocytosis. Studies with preselection of patients based on risk assessment and evaluation of limited versus extensive screening strategies are currently ongoing. Also, novel and promising approaches for early detection of cancer in patients with unprovoked VTE by means of liquid biopsies, which include analysis of circulating tumor cells, cell-free tumor DNA, proteomics, or platelet mRNA sequencing, are currently under investigation. In this review, we provide an overview of the risk of cancer diagnosis after VTE, discuss the studies which investigated different screening strategies for occult cancer, summarize risk factors and risk scoring models for identification of patients at high risk of cancer diagnosis after VTE, and highlight ongoing research to optimize screening and identification of patients at risk of occult cancer, which will shape the future clinical practice.

HPV driven squamous cell head and neck cancer of unknown primary is likely to be HPV driven squamous cell oropharyngeal cancer.

OBJECTIVES: To compare risk factors and survival in people with oropharyngeal cancer (OPC) and cancer unknown primary (CUP). MATERIALS AND METHODS: We recruited 5511 people with head and neck cancer between 2011 and 2014. We collected data on age, gender, smoking, sexual behaviour, treatment intent, stage, co-morbidity, p16 protein overexpression and biological samples. We assessed human papillomavirus (HPV) status using serological response and p16 immunohistochemistry. We followed up participants to identify those who had died. We used Cox proportional hazards regression models to estimate survival and adjust for confounders. RESULTS: Of the 4843 people with squamous cell cancer 196 had CUP - a prevalence of 4.0% (95% CI 3.5% to 4.6%). Of those people with OPC and CUP 69% (1150/1668) and 60% (106/178) respectively had HPV driven tumours. People with HPV driven tumours were likely to be younger, male, non-smokers, with higher stage disease, a history of oral sex and less co-morbidity. People with HPV negative CUP and HPV driven CUP had the survival of people with a stage II/III HPV negative OPC and a stage I/II HPV driven OPC respectively. The adjusted hazard ratio for HPV driven OPC and CUP compared with HPV negative OPC and CUP was 0.46 (95% CI 0.35 to 0.59) and 0.34 (95% CI 0.14 to 0.82) respectively. CONCLUSION: HPV driven CUP is likely to be HPV driven OPC. Identifying effective methods of detecting occult OPC could improve CUP management and allow the detection of early lesions in high risk groups.