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Publications by CUPP-NL members

Background/aim: Unknown primary tumour (UPT) is the term applied to metastatic cancer, the origin of which remains unidentified. Since cancer treatment is primarily based on the tumour site of origin, treatment of UPT patients is challenging. The number of reports on incidence, treatment and survival of UPT is limited. We hereby report data on patients (2000-2012) with UPT in the Netherlands.

Methods: The age-standardised rate (ASR) of 'other and unspecified' malignancies in the Netherlands was compared with other European countries. Patients diagnosed with UPT between 2000 and 2012 were selected from the Netherlands Cancer Registry (NCR) to calculate incidence rates. Patient characteristics, treatment and survival rates were assessed.

Results: The ASR of 'other and unspecified' malignancies in the Netherlands did not differ from the European average ASRs (2008-2012). A total of 29,784 patients with an unknown primary tumour were selected from the NCR (2000-2012). The incidence decreased from 14 per 100,000 person years (European standardised rate) in 2000 to 7.0 in 2012. The most common metastatic sites were liver, lymph nodes, bone and lung (42%, 22%, 16% and 14%, respectively), and approximately two-thirds of patients were diagnosed with metastases at a single site. One-third of the patients were treated; these were mainly younger patients. The overall median survival for all patients was 1.7 months. The median survival of untreated patients was 1.0 month and of treated patients 6.3 months.

Conclusion: The incidence of UPT between 2000 and 2012 is decreasing in the Netherlands, and one-third of these patients received treatment. Survival after diagnosis is limited to months rather than years.


Patients with carcinoma of unknown primary (CUP) present with metastatic disease without an identified primary tumour. The unknown site of origin makes the diagnostic work-up and treatment challenging. Since little information is available regarding diagnostic work-up and treatment in daily practice, we collected and analysed these in a patient cohort with regard to the recommendations of the national CUP guideline. Data of 161 patients diagnosed with CUP in 2014 or 2015 were extracted from the Netherlands Cancer Registry (NCR) and supplemented with diagnostic work-up information from patient files and analysed. Patients underwent an average of five imaging studies during the diagnostic phase (range 1-17). From the tests as recommended in the national guideline on CUP, a chest X-ray was most commonly performed (73%), whereas a PET-CT was done in one out of four patients (24%). Biopsies were taken in 86% of the study population, with Cytokeratin 7 being the most frequently tested histopathological marker (73%). Less than half of patients received therapy (42%). CUP patients undergo extensive diagnostic work-up. The performance status did not influence the extent of the diagnostic work-up in CUP patients, but it was an important factor for receiving treatment.


Purpose: Cancer of unknown primary (CUP) is a metastasised cancer for which no primary lesion could be identified during life. Research into CUP aetiology with respect to dietary factors is particularly scarce. This study investigates whether meat consumption is associated with CUP risk.

Methods: Data was utilised from the prospective Netherlands cohort study that includes 1,20,852 participants aged 55-69 years. All participants completed a self-administered questionnaire on diet and other cancer risk factors at baseline. Cancer follow-up was established through record linkage to the Netherlands Cancer Registry and the Dutch Pathology Registry. A total of 899 CUP cases and 4111 subcohort members with complete and consistent dietary data were available for case-cohort analyses after 20.3 years of follow-up. Multivariable adjusted hazard ratios (HRs) were calculated using proportional hazards models.

Results: We found a statistically significant positive association with beef and processed meat consumption and CUP risk in women (multivariable adjusted HR Q4 vs. Q1 1.47, 95% CI 1.04-2.07, Ptrend = 0.004 and Q4 vs. Q1 1.53, 95% CI 1.08-2.16, Ptrend = 0.001, respectively), and a non-significant positive association with processed meat consumption and CUP risk in men (multivariable adjusted HR Q4 vs. Q1 1.33, 95% CI 0.99-1.79, Ptrend = 0.15). No associations were observed between red meat (overall), poultry or fish consumption and CUP risk.

Conclusion: In this cohort, beef and processed meat consumption were positively associated with increased CUP risk in women, whereas a non-significant positive association was observed between processed meat consumption and CUP risk in men.


Cancer of unknown primary (CUP) is a metastasised malignancy with no identifiable primary tumour origin. Despite the frequent occurrence and bleak prognosis of CUP, research into its aetiology is scarce. Our study investigates alcohol consumption, tobacco smoking and CUP risk. We used data from the Netherlands Cohort Study, a cohort that includes 120 852 participants aged 55 to 69 years, who completed a self-administered questionnaire on cancer risk factors at baseline. Cancer follow-up was established through record linkage to the Netherlands Cancer Registry and Dutch Pathology Registry. After 20.3 years of follow-up, 963 CUP cases and 4288 subcohort members were available for case-cohort analyses. Multivariable-adjusted hazard ratios (HRs) were calculated using proportional hazard models. In general, CUP risk increased with higher levels of alcohol intake (Ptrend = .02). The association was more pronounced in participants who drank ≥30 g of ethanol per day (HR: 1.57, 95% confidence interval [CI]: 1.20-2.05) compared to abstainers. Current smokers were at an increased CUP risk (HR: 1.59, 95% CI: 1.29-1.97) compared to never smokers. We observed that the more the cigarettes or the longer a participant smoked, the higher the CUP risk was (Ptrend = .003 and Ptrend = .02, respectively). Interaction on additive scale was found for participants with the highest exposure categories of alcohol consumption and cigarette smoking frequency and CUP risk. Our findings demonstrate that alcohol consumption and cigarette smoking are associated with increased CUP risk. Lifestyle recommendations for cancer prevention regarding not drinking alcohol and avoiding exposure to smoking are therefore also valid for CUP.


Background: Cancer of Unknown Primary (CUP) is a metastatic disease for which the primary tumour origin could not be identified during life. Few studies have investigated the risk factors associated with this disease. This study investigates anthropometry, physical activity and CUP risk.

Methods: Data is used from the Netherlands Cohort Study, which includes 120,852 participants aged 55-69 years. All cohort members completed a self-administered questionnaire on cancer risk factors at baseline in 1986. Cancer follow-up was established through record linkage to the Netherlands Cancer Registry and the Dutch Pathology Registry. After a follow-up of 20.3 years, 926 incident CUP cases and 4099 subcohort members were available for case-cohort analyses. Proportional hazards models were used to compute multivariable adjusted hazard ratios (HRs).

Results: We found no associations between height, body mass index (BMI) at baseline, BMI at age 20 years, change in BMI since age 20 years, clothing size (trouser/skirt size), or non-occupational physical activity and CUP risk.

Conclusion: Our findings indicate that neither anthropometry nor physical activity are associated with the development of CUP.



Guidelines intend to provide the medical professional with a set of recommendations on the best standards of care. For carcinoma of unknown primary, a heterogeneous group of metastatic malignancies for which the site of origin is not detected, several guidelines are internationally available. Because each guideline is developed by a different committee with their own point of view, these guidelines might advise differently regarding diagnostic and treatment strategies for patients with a malignancy of unknown origin. Via an internet search, using the terms “guideline(s)”, “CUP” and “carcinoma unknown primary”, four guidelines were identified: the NCCN guideline from the USA, the SEOM guideline from Spain, the NICE guideline from the United Kingdom and the European guideline (ESMO), based in Switzerland. These guidelines and our national guideline used in The Netherlands, were compared and an overview was made of the differences and consistencies of the advised diagnostic, treatment and follow-up strategies.

Of the five compared guidelines, only one guideline (NICE) mainly focuses on the logistics with regard to patient care while other guidelines focus more on the diagnostic strategies to identify the primary tumor site. The described diagnostics sometimes show overlap but frequently differ on the various recommended diagnostic tools to identify the site of tumor origin such as PET, CT, MRI, IHC markers, ultrasound and endo-, colo-, colposcopy. For the treatment of patients with CUP the guidelines often refer to the guideline of the suspected primary tumor site. Only one guideline (NICE) generally refers to a multidisciplinary team to discuss the best possible treatment for the patient.

Numerous differences between the CUP guidelines were observed. These differences in diagnostic strategies, and the different diagnostic tools used, result in divergent perceptions regarding the definition of the term “carcinoma unknown primary” and makes comparison of incidence rates, survival times and treatment strategies challenging. International collaboration regarding evidence based guideline development might be of benefit for medical professionals and their patients.


Objective: Cancer of Unknown Primary (CUP) refers to the presence of metastatic lesions, with no identifiable primary site during the patient's lifetime. Poor survival and lack of available treatment highlight the need to identify potential CUP risk factors. We investigated whether a family history of cancer is associated with increased CUP risk.

Methods: We performed a case cohort analysis using data from the Netherlands Cohort Study, which included a total of 963 CUP cases and 4,288 subcohort members. A Cox Proportional Hazards Regression was used to compare CUP risk in participants who reported to have a family member with cancer to those who did not, whilst adjusting for confounders.

Results: In general, we observed no increased CUP risk in those who reported a family history of cancer. CUP risk appeared slightly increased in those who reported cancer in a sibling (HR: 1.16, 95% CI: 0.97-1.38), especially in those with a sister with cancer compared with those without (HR: 1.23, 95% CI: 0.99-1.53), although these findings are not statistically significant.

Conclusion: Having a family history of cancer is not an independent risk factor of CUP.

CUP in the national media




Het aantal patiënten met gemetastaseerd carcinoom waarbij de primaire tumor onbekend is, is tussen 2000 en 2012 gehalveerd. De overleving van deze patiënten is echter nog steeds heel laag, zo bleek uit onderzoek van dr. Caroline Loef van het Integraal Kankercentrum Nederland.


Er moet een landelijk beleid komen met bij voorkeur een expertpanel voor patiënten bij wie de diagnose primaire tumor onbekend (PTO) wordt gesteld, vinden dr. Caroline Loef, onderzoeker bij IKNL, en dr. Yes van de Wouw, internist-oncoloog bij het VieCuri Medisch Centrum. Behandelaars weten nu niet goed wat ze met deze patiënten aan moeten en door de onbekendheid van het ziektebeeld blijven patiënten en hun naasten met veel onzekerheden zitten.



CUP in other media

Expert: Nicholas Pavlidis answering questions on Cancer of Unknown Primary (CUP) proposed by 'Missie Tumor Onbekend' (Mission Tumor Unknown).

Questions: 1-What do we know about CUP? 2-What do we know about the impact of genomic analysis in CUP diagnosis and treatment? 3-What standard diagnostic work-up is recommended to have completed, before a case can be called a CUP case? 4-Does speeding up the diagnostic process help patients’ outcome? 5-How doctors transfer the bad news about CUP diagnosis and outcome to the patients? Does support with palliative care helps CUP patients?