Descriptive epidemiology of cancer of unknown primary site in Scotland, 1961–2010

BackgroundCancers of unknown primary site (CUP) pose problems for diagnosis, treatment, and accurate prediction of prognosis. However, there are limited published data describing the epidemiology of this disease entity. Our aim was to describe the epidemiology of CUP in Scotland.MethodsAnonymised data, covering the period 1961–2010, were extracted from the Scottish Cancer Registry database, based on the following ICD-10 diagnostic codes: C26.0, C26.8, C26.9, C39, and C76–C80. Age-standardised incidence rates were calculated by direct standardisation to the World Standard Population. Estimates of observed survival were calculated by the Kaplan–Meier method.ResultsBetween 1961 and 2010, there were 50,941 registrations of CUP, representing 3.9% of all registrations of invasive cancers. Age-standardised rates increased to a peak in the early to mid-1990s, followed by a steeper decrease in rates. During 2001–2010, age-standardised rates of CUP were higher in the most compared with the least deprived fifth of the population. Observed survival was marginally higher in patients diagnosed during 2001–2010 (median 5.6 weeks) compared with those diagnosed in the previous two decades. During the most recent decade, survival decreased with age at diagnosis, and was higher in patients with squamous cell carcinoma and with lymph node metastases.ConclusionPatterns of CUP in Scotland are largely consistent with those reported from the few other countries that have published data. However, in comparing studies, it is important to note that there is heterogeneity in terms of definition of CUP, as well as calendar period of diagnosis or death. Variation in the definition of CUP between different epidemiological studies suggests that there would be merit in seeking international agreement on guidelines for the registration of CUP as well as a standard grouping of diagnostic codes for analysis.     

A machine learning framework to trace tumor tissue-of-origin of 13 types of cancer based on DNA somatic mutation

Carcinoma of unknown primary (CUP), defined as metastatic cancers with unknown cancer origin, occurs in 3‐5 per 100 cancer patients in the United States. Heterogeneity and metastasis of cancer brings great difficulties to the follow-up diagnosis and treatment for CUP. To find the tissue-of-origin (TOO) of the CUP, multiple methods have been raised. However, the accuracies for computed tomography (CT) and positron emission tomography (PET) to identify TOO were 20%–27% and 24%–40% respectively, which were not enough for determining targeted therapies. In this study, we provide a machine learning framework to trace tumor tissue origin by using gene length-normalized somatic mutation sequencing data. Somatic mutation data was downloaded from the Data Portal (Release 28) of the International Cancer Genome Consortium (ICGC), and 4909 samples for 13 cancers was used to identify primary site of cancers. Optimal results were obtained based on a 600-gene set by using the random forest algorithm with 10-fold cross-validation, and the average accuracy and F1-score were 0.8822 and 0.8886 respectively across 13 types of cancer. In conclusion, we provide an effective computational framework to infer cancer tissue-of-origin by combining DNA sequencing and machine learning techniques, which is promising in assisting clinical diagnosis of cancers.     

An audit of cancer of unknown primary notifications: A cautionary tale for population health research using cancer registry data

Background: Cancer of unknown primary (CUP) is a common cancer yet little is known about the reliability of incidence data. Methods: We audited 574 CUP (C80.9) diagnoses (median age 81 years) registered by the New South Wales (NSW) Central Cancer Registry (2004–2007) in a cohort of Australian Government Department of Veterans’ Affairs clients. The registry did not clarify diagnoses with notifiers during this period due to interpretation of privacy legislation. For the audit, current registry practice was applied by seeking additional information from CUP notifiers and reclassifying diagnoses as necessary. In addition, clinicopathological characteristics were extracted from notifications. Fisher's exact test and Student's t-test were used to compare the demographic and clinicopathological characteristics of the CUP subgroups. Age/sex-standardised CUP incidence rates and 95% confidence intervals were calculated, standardised to the 2001 Australian population. Results: 172 (30.0%) cases were reclassified to a known primary site, mostly cutaneous, and nine (1.6%) were found to be non-malignant diagnoses. After the audit the age/sex-standardised CUP incidence rates decreased from 26.0 (95% CI 21.2–30.8) to 15.9 (95% CI 12.5–19.3) per 100,000 person-years. Of the 393 remaining CUP cases, 202 (51%) were registered on the basis of a clinical diagnosis (46 by death certificate only) and 191 (49%) by pathological diagnosis (79 by cytology alone). Compared to cases with a pathological diagnosis, cases with a clinical diagnosis were older (85.6 vs. 82.0 years, p < 0.001), and the reported number and location of metastases differed (p < 0.001); metastatic sites were more likely to be unspecified for clinical diagnoses (36.1% vs. 4.2%). Conclusions: Cancer registry processes can markedly influence CUP incidence. Future population-based CUP research should take this into account, and consider stratification by basis of diagnosis due to differences in patient and tumour characteristics.     

Demographic,social and lifestyle risk factors for cancer registry-notified cancer of unknown primary site (CUP)

BackgroundLittle is known about the risk factors for cancer of unknown primary site (CUP). We examined the demographic, social and lifestyle risk factors for CUP in a prospective cohort of 266,724 people aged 45 years and over in New South Wales, Australia.MethodsBaseline questionnaire data were linked to cancer registration, hospitalisation, emergency department admission, and mortality data. We compared individuals with incident cancer registry-notified CUP (n = 327) to two sets of controls randomly selected (3:1) using incidence density sampling with replacement: (i) incident cancer registry-notified metastatic cancer of known primary site (n = 977) and (ii) general cohort population (n = 981). We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs).ResultsIn a fully adjusted model incorporating self-rated overall health and comorbidity, people diagnosed with CUP were more likely to be older (OR 1.05, 95% CI 1.04–1.07 per year) and more likely to have low educational attainment (OR 1.77, 95% CI 1.24–2.53) than those diagnosed with metastatic cancer of known primary. Similarly, compared to general cohort population controls, people diagnosed with CUP were older (OR 1.10, 95% CI 1.08–1.12 per year), of low educational attainment (OR 1.69, 95% CI 1.08–2.64), and current (OR 3.42, 95% CI 1.81–6.47) or former (OR 1.95, 95% CI 1.33–2.86) smokers.ConclusionThe consistent association with educational attainment suggests low health literacy may play a role in CUP diagnosis. These findings highlight the need to develop strategies to achieve earlier identification of diagnostically challenging malignancies in people with low health literacy.     

Cancers of unknown primary: Survival by histologic type,demographic features,and treatment in the U.S. Military Health System

BackgroundCancers of unknown primary (CUP), a group of heterogenous metastatic cancers lacking a known primary site, have poor prognosis. This study compared survival of CUP by histologic type, patient characteristics, and treatment in the U.S. Military Health System (MHS), which provides universal care to its members.MethodsPatients histologically diagnosed with CUP were identified from the U.S. Department of Defense (DoD)’s Automated Central Tumor Registry. Median survival with 95 % confidence intervals was calculated for demographic and treatment variables by histologic type. A multivariable accelerated failure time model estimated time ratios and 95 % confidence intervals.ResultsThe study included 3358 CUP patients. The most prevalent CUP in this study was well- and moderately-differentiated adenocarcinomas. Median survival varied by histologic type with squamous cell carcinoma having the longest at 25.1 months and poorly-differentiated carcinomas having the shortest at 3.0 months. For each histologic type, survival was generally similar by sex and active-duty status although women with well- and moderately-differentiated adenocarcinoma had longer survival than their male counterparts. Younger patients tended to have longer survival than those aged 65 years or older. Generally, there were no racial differences in survival except poorer survival for Black patients than White patients in the group of other histologic types. Patients with chemotherapy and radiation treatment generally had improved survival whereas patients with squamous cell carcinoma who received chemotherapy had shorter survival than those without.ConclusionSurvival generally did not differ between racial groups, which may be related to equal healthcare access despite racial background. Further studies are warranted to better understand how survival in the MHS compares with that in the general U.S. population.     

Amplification of a gene for metallothionein by tandem repeat in a strain of cadmium-resistant yeast cells

Abstract In a cadmium-resistant strain of Saccharomyces cerevisiae , cells are protected against cadmium toxicity by the production of large amounts of cadmium-binding metallothionein, as occurs similarly in a copper-resistant strain. The apoprotein of the metallothionein is encoded by the CUP1 gene on chromosome VIII. The CUP1 gene is present as 8–10 copies in the cadmium-resistant strain as a result of tandem repeat of a 2.0-kb fragment of DNA that includes CUP1 , while the wild-type strain contains only a single copy of CUP1 . In the cadmium-resistant strain, some evidence for elongation of chromosome VIII with variations in length (maximum to 200 kb) was obtained. However, the elongation was not due to the tandem repeats of the CUP1 -containing region.     

Descriptive epidemiology of cancer of unknown primary in South Korea, 1999–2017

BackgroundCancers of unknown primary (CUPs) are tumors found after metastasizing from unidentified primary sites; these tumors generally have unknown treatment strategies, expected treatment results, and prognosis. We assessed the epidemiological characteristics of CUPs in Korea.MethodsWe extracted records for 1999 through 2017 from the Korea Central Cancer Registry using the International Statistical Classification of Diseases and Related Health Problems (10th revision) codes for CUP as defined by the International Agency for Research on Cancer. Age-standardized rates and relative survival rates were calculated.ResultsThe CUPs constituted 2.1 % of the total number of cancer registrations in 1999, declining to 0.7 % in 2017. The incidence rate decreased for both sexes (5.35 to 2.20 for men, 3.15 to 1.77 for women). Patients aged 80 years and older had the highest incidence rate at 40.2, and 86.3 % of CUPs occurred in those 50 years of age or older. The cases of retroperitoneum and peritoneum sites increased over time. Cases diagnosed by microscopic methods and death certification only were 62.3 % and 7.9 %, respectively. The malignant neoplasm of the retroperitoneum and peritoneum and unknown primary site had the highest and lowest survival rates, respectively. The 5-year relative survival rate increased over time from 14.2 % (1999–2002) to 27.3 % (2013–2017).ConclusionsOur analysis of data from the Korea Central Cancer Registry found decreasing rates of CUP, although with consistent disparities by patient age and sex. Advancements in diagnostic technology may be decreasing the number of CUP diagnoses. Expanding the amount of information recorded in the registry may further improve diagnostic accuracy.     

Human Papillomavirus and Cystic Node Metastasis in Oropharyngeal Cancer and Cancer of Unknown Primary Origin

The clinical significance of human papillomavirus (HPV) in neck node metastasis from cancer of unknown primary (CUP) is not well established. We aimed to address the relationship of HPV status between node metastasis and the primary tumor, and also the relevance of HPV status regarding radiographically detected cystic node metastasis in head and neck squamous cell carcinoma (HNSCC) and CUP. HPV DNA was examined in 68 matched pairs of node metastasis and primary tumor, and in node metastasis from 27 CUPs. In surgically treated CUPs, p16 was examined immunohistochemically. When tonsillectomy proved occult tonsillar cancer in CUP, HPV DNA and p16 were also examined in the occult primary. Cystic node metastasis on contrast-enhanced computed tomography scans was correlated with the primary site and HPV status in another series of 255 HNSCCs and CUPs with known HPV status. Node metastasis was HPV-positive in 19/37 (51%) oropharyngeal SCCs (OPSCCs) and 10/27 (37%) CUPs, but not in non-OPSCCs. Fluid was collected from cystic node metastasis using fine needle aspiration in two OPSCCs and one CUP, and all fluid collections were HPV-positive. HPV status, including the presence of HPV DNA, genotype, and physical status, as well as the expression pattern of p16 were consistent between node metastasis and primary or occult primary tumor. Occult tonsillar cancer was found more frequently in p16-positive CUP than in p16-negative CUP (odds ratio (OR), 39.0; 95% confidence interval (CI), 1.4–377.8; P = 0.02). Radiographically, cystic node metastasis was specific to OPSCC and CUP, and was associated with HPV positivity relative to necrotic or solid node metastasis (OR, 6.2; 95% CI, 1.2–45.7; P = 0.03). In conclusion, HPV status remains unchanged after metastasis. The occult primary of HPV-positive CUP is most probably localized in the oropharynx. HPV status determined from fine needle aspirates facilitates the diagnosis of cystic node metastasis.     

Regulation of the yeast metallothionein gene

To study regulation of the yeast CUP1 gene, we have employed plasmids containing the CUP1 regulatory sequences fused to the Escherichia coli galK gene. A comparison of galK expression from low- and high-copy-number CUP1/galK fusion plasmids demonstrated that both basal and induced levels of galactokinase (GalK) increase proportionately with plasmid copy number. Host strains with an amplified, single or deleted CUP1 locus were compared to look for effects of chromosomal CUP1 gene dosage on expression from the episomal CUP1 promoter. Basal GalK levels are similar in CUP1R and cupls hosts, but can be induced to higher levels in the cup1s than the CUP1R host. In contrast, in a strain deleted for the chromosomal copy of CUP1, synthesis of GalK is constitutive but can be induced to yet higher levels by copper. A hybrid vector, placing the CUP1 coding sequence under the control of a constitutive promoter, was constructed. Introduction of this hybrid CUP1 gene into the deletion host containing the CUP1/galK plasmid restores regulation. Thus, metallothionein, in trans, can effect repression of the CUP1 promoter. The possible roles of metallothionein and free copper in CUP1 regulation are discussed.     

Copper ions and the regulation ofSaccharomyces cerevisiae metallothionein genes under aerobic and anaerobic conditions

We have previously reported that theSaccharomyces cerevisiae CRS5 metallothionein gene is negatively regulated by oxygen. The mechanism of this repression was the focus of the current study. We observed that the aerobic repression ofCRS5 is rapid and occurs within minutes of exposing anaerobic cultures to air. Furthermore, theCUP1 metallothionein gene ofS. cerevisiae was found to be subject to a similar down-regulation of gene expression. We provide evidence that the aerobic repression of yeast metallothioneins involves copper ions and Ace1, the coppertrans-activator ofCUP1 andCRS5 gene expression. A functional Ace1 binding site was found to be necessary for the aerobic repression ofCRS5. Moreover, the aerobic down-regulation of the metallothioneins was abolished when cells were treated with elevated levels of copper. Our studies show that anaerobic cultures accumulate higher levels of copper than do aerobic cells and that this copper is rapidly lost when cells are exposed to air. In fact, the kinetics of this copper loss closely parallels the kinetics ofCUP1 andCRS5 gene repression. The yeast metallothionein genes, therefore, serve as excellent markers for variations in copper accumulation and homeostasis that occur in response to changes in the oxidative status of the cell.     

Health-related predictors of cancer registry-notified cancer of unknown primary site (CUP)

BackgroundThe relationship between comorbid disease and health service use and risk of cancer of unknown primary site (CUP) is uncertain.MethodsA prospective cohort of 266,724 people aged 45 years and over in New South Wales, Australia. Baseline questionnaire data were linked to cancer registration, health service records 4–27 months prior to diagnosis, and mortality data. We compared individuals with incident registry-notified CUP (n = 327; 90% C80) to two sets of randomly selected controls (3:1): (i) incident metastatic cancer of known primary site (n = 977) and (ii) general cohort population (n = 981). We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs).ResultsIn fully adjusted models incorporating sociodemographic and lifestyle factors, people with cancer registry-notified CUP were more likely to have fair compared with excellent self-rated overall health (OR 1.78, 95% CI 1.01–3.14) and less likely to self-report anxiety (OR 0.48, 95% CI 0.24−0.97) than those registered with metastatic cancer of known primary. Compared to general cohort population controls, people registered with CUP were more likely to have poor rather than excellent self-rated overall health (OR 6.22, 95% CI 1.35–28.6), less likely to self-report anxiety (OR 0.28, 95% CI 0.12−0.63), and more likely to have a history of diabetes (OR 1.89, 95% CI 1.15–3.10) or cancer (OR 1.62, 95% CI 1.03–2.57). Neither tertiary nor community-based health service use independently predicted CUP risk.ConclusionLow self-rated health may be a flag for undiagnosed cancer, and an investigation of its clinical utility in primary care appears warranted.     

Copper ions and the regulation ofSaccharomyces cerevisiae metallothionein genes under aerobic and anaerobic conditions

We have previously reported that theSaccharomyces cerevisiae CRS5 metallothionein gene is negatively regulated by oxygen. The mechanism of this repression was the focus of the current study. We observed that the aerobic repression ofCRS5 is rapid and occurs within minutes of exposing anaerobic cultures to air. Furthermore, theCUP1 metallothionein gene ofS. cerevisiae was found to be subject to a similar down-regulation of gene expression. We provide evidence that the aerobic repression of yeast metallothioneins involves copper ions and Ace1, the coppertrans-activator ofCUP1 andCRS5 gene expression. A functional Ace1 binding site was found to be necessary for the aerobic repression ofCRS5. Moreover, the aerobic down-regulation of the metallothioneins was abolished when cells were treated with elevated levels of copper. Our studies show that anaerobic cultures accumulate higher levels of copper than do aerobic cells and that this copper is rapidly lost when cells are exposed to air. In fact, the kinetics of this copper loss closely parallels the kinetics ofCUP1 andCRS5 gene repression. The yeast metallothionein genes, therefore, serve as excellent markers for variations in copper accumulation and homeostasis that occur in response to changes in the oxidative status of the cell.     

Place de la TEP au 18FDG dans la localisation de primitifs néoplasiques

Carcinomas of unknown primary site (CUP) and paraneoplastic syndromes have the common characteristic that an extensive conventional biological and imaging analysis fails in some instance to detect the primary tumour. FDG-PET becomes recognized to provide interesting information in the case of “head and neck” CUP as well as in the case of neurological paraneoplastic syndromes biologically well defined. When, either CUP or paraneoplastic syndromes, are less defined, FDG-PET will not provide as much information as in the previous situation, although it can help in the etiologic diagnosis (oncologic or not) in some cases.     

Incidence and survival for hepatic, pancreatic and biliary cancers in England between 1998 and 2007

Introduction: Hepatic, pancreatic and biliary (HPB) cancers are a group of diverse malignancies managed ideally in specialist centres. This study describes recent patterns in the incidence and survival of HPB cancers in England over a ten year period (1998–2007). Methods: Data on 99,379 English patients (50,656 males; 48,723 females) diagnosed with HPB cancers between 1998 and 2007 were extracted from the National Cancer Data Repository. Data were divided into six site-specific cancer groups; pancreas, ampulla of Vater, biliary tract, primary liver, gallbladder and duodenum. Age-standardised incidence rates (per 100,000 European standard population, (ASR(E))) were calculated for each of the six groups by year of diagnosis and by socioeconomic deprivation. Survival was estimated using the Kaplan–Meier method. Results: The largest group was pancreatic cancers (63%), followed by primary liver (14%) and biliary cancers (13%). ASR(E) were highest for pancreatic and primary liver cancers whereas cancers of the gallbladder, duodenum and ampulla of Vater had a very low incidence. Over time the incidence of all six groups remained relatively stable, although primary liver cancer increased slightly in males. Incidence rates were higher in males than in females in all groups except gallbladder cancer, and all six groups had a higher incidence in the more deprived quintiles. Overall survival was poor in each of the HPB cancer groups. Conclusions: HPB tumours are uncommon and are associated with poor long term survival reflecting the late stage at presentation. Incidence patterns suggest variable rates linked to socioeconomic deprivation and highlight a male predominance in all sites except the gallbladder. Identification of high risk populations should be emphasised in initiatives to raise awareness and facilitate earlier diagnosis.     

Human Papillomavirus in Head and Neck Squamous Cell Carcinoma of Unknown Primary Is a Common Event and a Strong Predictor of Survival

Background

The purpose of this study was to examine the prevalence of human papillomavirus (HPV) in patients with head and neck squamous cell carcinoma of unknown primary (CUP).

Methods

All patients diagnosed with and treated for CUP between January 1, 2000, and June 1, 2011, at two Danish medical centers were included. All patients received a thorough diagnostic work-up, including FDG-PET, before being diagnosed as CUP. We determined the HPV status in all patients using a combination of HPV DNA PCR and p16 stain. In addition, clinical information on the study patients was retrieved from clinical records.

Results

Of the identified 60 patients with CUP, 13 were shown to be positive for HPV DNA, amounting to 22% of the study population. In addition, we were able to show a clear disease-free and overall-survival benefit in the HPV-positive group, with a hazard ratio of 0.16 (95% CI: 0.038–0.67) for over-all survival. This survival benefit was also apparent when adjusted for advanced age in a multivariate Cox regression analysis.

Conclusion

A fairly large percentage of CUP cases are HPV-related, and because this is related to both the location and prognosis, we recommend HPV testing as part of the diagnostic work-up.     

Carcinoma of unknown primary in the head and neck: The evaluation of the effectiveness of 18F-FDG-PET/CT,own experience

AimThe aim of the present study was to estimate the clinical effectiveness of ¹⁸F-FDG-PET/CT in the detection of the primary tumor in patients with histologically proven squamous cell carcinoma cervical lymph nodes metastasis from an unknown primary.Background¹⁸F-fluorodeoxyglucose positron emission tomography combined with CT (¹⁸F-FDG-PET/CT) is believed to be very helpful in localization of primary tumor in CUP Syndrome patients.Material and method41 patients referred to Poznan Medical University Department of Head and Neck Surgery from January 2010 to December 2013 with CUP Syndrome were included in the study. All patients presented fine-needle biopsy proven squamous cell carcinoma metastasis of the upper-, or mid neck lymph nodes. The final results were obtained from the histopathologic reports of tissue samples from anatomical regions suspected for primary tumor, additional imaging exams as well as clinical follow-up data.ResultsThe ¹⁸F-FDG-PET/CT successfully detected primary tumor in 7 out of 41 patients (17%). In two more cases the primary tumor was indicated in the lung. 24 of 41 patients (58.5%) analyzed in our study remained without evidence of a primary tumor. In 4 cases (9.75%) we did not reveal any pathology within the localizations indicated by PET/CT on panendoscopy. In 4 cases we obtained histological confirmation of neoplasm on panendoscopy despite the negative results of PET/CT examinations.ConclusionWe may suppose a relatively high usefulness of ¹⁸F-FDG-PET/CT in the diagnosis process of CUP Syndrome patients. High NPV may indicate patients with no symptoms of primary tumor, which allows to avoid extensive resection or extra imaging.