Cancer Of Unknown Primary Cases Research Articles

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

ObjectivesHead 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. MethodsThe 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. Results81,053 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. ConclusionIn 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.

Early Improved Functional Outcomes in Head and Neck Cancer Patients with Primary Tumor Detection.

We characterize functional outcomes in head and neck cancer of unknown primary (CUP) based on primary site identification. In this retrospective study, CUP cases were categorized as known primaries (KP) if a tumor was localized after diagnostic workup or persisting unknown primaries (UP). Age, sex, HPV status, diagnostic methods, and treatments regimens were collected. Pretreatment and short-term posttreatment (3-6 months after completion of treatment) weights, PHQ-9, Eating Assessment Tool (EAT-10), and Voice Handicap Index (VHI-10) scores were compared between UP and KP. Among 67 CUP patients, 35 (52.2%) had identified primaries (91.4% oropharyngeal and 8.6% nasopharyngeal). KP patients were younger (58 vs. 64, p = 0.04) and more likely to be HPV-positive (88.6% vs. 50%, p = 0.002). Overall detection rates were 16.7% for PET/CT, 34.7% for direct laryngoscopy, and 46.6% for transoral robotic oropharyngectomy. Diagnostic workup was not significantly different between groups. Patients with KP received smaller intermediate radiation dose volumes (436.5 vs. 278.9 cc, p = 0.03) and lower doses to the cricopharyngeal muscle (41.6 vs. 24.6 Gy, p = 0.03).Pretreatment weights, PHQ-9, EAT-10, and VHI-10 scores did not differ between groups. However, posttreatment, UP had greater relative weight loss (-14.1% vs. -7.6%, p = 0.032), higher EAT-10 scores (12.5 vs. 3, p = 0.004), and higher PHQ-9 scores (6 vs. 1.4, p = 0.017). Specifically, UP reported more stressful swallowing, difficulty swallowing solids and pills, and swallowing affecting public eating. KP patients experienced less weight loss, depression, and reduced swallowing dysfunction, highlighting an early functional benefit of primary tumor identification likely driven by reduced radiation treatment volumes. 4 Laryngoscope, 134:701-707, 2024.

Multimodal machine learning analysis of more than 220,000 tumor profiles to diagnose molecular and morphological subtypes of cancer.

3078 Background: The diagnosis of a malignancy is typically informed by clinical presentation and tumor tissue features including cell morphology, immunohistochemistry, and molecular markers. Additionally, multi-omic approaches (Abraham 2021 Transl Oncol) and deep learning models using digital pathology (da Silva 2021 J Pathol) have augmented expert pathologists and led to improved diagnoses but are often not employed together on the same patient. The opportunity exists for a truly multimodal, multi-omic machine learning classifier that comprehensively assesses all aspects of a tumor from the molecular underpinnings to the morphological and histological phenotypic presentation to provide the most accurate diagnosis while at the same time providing predictive biomarker data from the same specimen. Methods: Whole transcriptome data from 220,246 tumor profiles, large panel and whole exome data from over 170,000 tumor profiles, and digital pathology features from over 50,000 tumors were used to construct a multi lineage classifier. The classifier was trained on 256 Oncotree classifications corresponding to established WHO diagnoses where a tumor of each class has been observed at least 30 times in our dataset. The dataset was split 50% for training and the other 50% for testing, UMAP was employed for dimensionality reduction, and ensemble models were used for making the final calls. The performance of the classifier was evaluated by comparing with traditional pathologist-directed diagnostic workup. Results: Tumor lineage classifiers predicted the correct classifications where the primary site was known with accuracies ranging between 97% and 100% when using the 32 highest level Oncotree categories corresponding to human tissues. Accuracy on the most granular Oncotree categories varied with many between 90 and 95%. When applied to Cancer of Unknown Primary (CUP) cases (n = 3589), an unequivocal Oncotree classification could be obtained over 90% of the time. Conclusions: Combining multi-omic and digital pathology information into a multimodal artificial intelligence platform can provide comprehensive information to pathologists to aid in diagnosis. This tool can be used to meet an unmet clinical need to define the lineage of CUP cases, which when coupled with biomarker data, will provide an opportunity to examine whether this information can be used to improve the outcomes of patient with CUP.

Temporal Changes in Cholangiocarcinoma Incidence and Mortality in the United States from 2001 to 2017.

BackgroundPrevious studies report increasing cholangiocarcinoma (CCA) incidence up to 2015. This contemporary retrospective analysis of CCA incidence and mortality in the US from 2001-2017 assessed whether CCA incidence continued to increase beyond 2015.Patients and MethodsPatients (≥18 years) with CCA were identified in the National Cancer Institute Surveillance, Epidemiology, and End Results 18 cancer registry (International Classification of Disease for Oncology [ICD-O]-3 codes: intrahepatic [iCCA], C221; extrahepatic [eCCA], C240, C241, C249). Cancer of unknown primary (CUP) cases were identified (ICD-O-3: C809; 8140/2, 8140/3, 8141/3, 8143/3, 8147/3) because of potential misclassification as iCCA.ResultsForty-thousand-and-thirty CCA cases (iCCA, n=13,174; eCCA, n=26,821; iCCA and eCCA, n=35) and 32,980 CUP cases were analyzed. From 2001-2017, CCA, iCCA, and eCCA incidence (per 100 000 person-years) increased 43.8% (3.08 to 4.43), 148.8% (0.80 to 1.99), and 7.5% (2.28 to 2.45), respectively. In contrast, CUP incidence decreased 54.4% (4.65 to 2.12). CCA incidence increased with age, with greatest increase among younger patients (18-44 years, 81.0%). Median overall survival from diagnosis was 8, 6, 9, and 2 months for CCA, iCCA, eCCA, and CUP. From 2001-2016, annual mortality rate declined for iCCA (57.1% to 41.2%) and generally remained stable for eCCA (40.9% to 37.0%) and for CUP (64.3% to 68.6%).ConclusionsCCA incidence continued to increase from 2001-2017, with greater increase in iCCA versus eCCA, whereas CUP incidence decreased. The divergent CUP versus iCCA incidence trends, with overall greater absolute change in iCCA incidence, provide evidence for a true increase in iCCA incidence that may not be wholly attributable to CUP reclassification.

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

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. 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). 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. 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.

Adherence to the World Cancer Research Fund and the American Institute for Cancer Research lifestyle recommendations for cancer prevention and Cancer of Unknown Primary risk

The World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR) updated their cancer prevention recommendations in 2018. Adherence to these recommendations has been associated with lower cancer risk and mortality. However, adherence in relation to Cancer of Unknown Primary (CUP) risk has not been studied. This study investigates whether adherence to the WCRF/AICR recommendations is associated with CUP risk. Data from the prospective Netherlands Cohort Study on diet and cancer was used to measure adherence to the recommendations in relation to CUP risk. The cohort includes 120852 participants (aged 55-69 years), who completed a self-administered questionnaire on cancer risk factors at baseline. Adherence was investigated with respect to body fatness, physical activity, plant foods, meat consumption and alcohol. Incident CUP cases were identified through record linkage to the Netherlands Cancer Registry and Dutch Pathology Registry. A follow-up of 20.3 years, resulted in 856 incident CUP cases and 3911 subcohort members with complete information available for case-cohort analyses. Multivariable adjusted hazard ratios were estimated using proportional hazards models and were adjusted for age at baseline, sex, cigarette smoking (status, frequency, and duration) and total energy intake. Highest adherence appeared to be associated with decreased CUP risk in the age-sex adjusted model (HR: 0.76, 95% CI: 0.62-0.92). After additional adjustment for cigarette smoking (status, frequency, and duration), the association attenuated and was no longer statistically significant. No multiplicative interactions were observed between sex nor smoking status and overall adherence in relation to CUP. Within this cohort, highest adherence to the WCRF/AICR recommendations is not statistically significantly associated with decreased CUP risk after multivariable adjustment.

P59.08 Identifying the Origin of Lung-Specific Cancer of Unknown Primary Based on Comprehensive Genomic Profiling Optimized With DNA Methylation

Precise diagnosis of the tissue origin for metastatic carcinoma is essential to decide the treatment scheme and improve outcome. The purpose of this study is to predict the primary site for lung-specific cancer of unknown primary (CUP) through genomic and DNA methylation profiles. Comprehensive genomic profiling (CGP) was performed to determine the genomic status within individual paired samples, and targeted bisulfite sequencing was exploited to interrogate their methylation status. Model training subjects were consisted of lung cancer and another type of cancer to compute the prediction signature weights for each DMR feature. A total of 300 patients with multi-site malignancies including lung and other organ lesions were screened retrospectively. Excluding individuals clearly diagnosed with imaging modalities and IHC staining, 40 patients needed further differential diagnosis. Among them, 26 cases were identified with novel molecular events like EGFR or ALK alterations; the remaining 14 lung-specific CUPs were located with another type of caners in stomach (n=5), intestine (n=5) and cervix (n=4). Of the 14 CUP cases, mutation spectrum analyses could distinguish metastatic disease from multiple primary tumors, while it was hard to determine the origin of metastatic cancers. However, methylation profiles not only predicted the consistent results with mutation spectrum, but also identified the origin of tumors through our train classification models (AUC>0.98), which can be confirmed with patients’ clinical efficacy who received treatments guided by prediction signature. Collectively, compared with genomic profiles, DNA methylation demonstrated better tumor traceability to determine the primary site of CUPs. The signature based on within-sample CGP testing optimized with DNA methylation could exactly identify the origin of lung-specific CUPs.

Abstract LB088: Meat consumption and Cancer of Unknown Primary (CUP) risk: results from the Netherlands Cohort Study on diet and cancer

Abstract Meat consumption and Cancer of Unknown Primary (CUP) risk: results from the Netherlands Cohort Study on diet and cancer Purpose: Cancer of Unknown Primary (CUP) is a metastasized cancer for which the primary tumor origin remains unidentifiable during a patient's lifetime. CUP prognosis is highly unfavorable with a median survival of 1.7 months. Research into CUP etiology with respect to dietary factors is particularly scarce. This study investigates whether meat consumption is associated with CUP risk, and whether there is multiplicative interaction between sex or cigarette smoking status and the relationship of meat consumption and CUP risk. Methods: Data was utilized from the prospective Netherlands Cohort Study (NLCS) that includes 120,852 participants aged 55-69 years from 204 Dutch municipalities. All participants completed a self-administered questionnaire on diet and other cancer risk factors at baseline. Habitual meat consumption was measured with respect to red meat (overall), beef, pork, minced meat, liver, processed meat, poultry and fish. The food-frequency questionnaire had been validated against a 9-day diet record and was tested for reproducibility. Cancer follow-up was established through record linkage to the Netherlands Cancer Registry and the Dutch Pathology Registry. As a result, a total of 899 CUP cases and 4,111 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, and were adjusted for age, sex, alcohol consumption, cigarette smoking variables (status, frequency, duration), and total energy intake. Results: In general, we observed no association between red meat (overall) consumption and CUP risk (multivariable adjusted HR for Q4 vs. Q1: 1.04, 95% CI: 0.83-1.30, Ptrend = 0.31). An increased risk was observed between beef consumption and CUP, for which a statistically significant trend was found (HR for Q4 vs. Q1: 1.22, 95% CI: 0.99-1.52, Ptrend = 0.02). The effect of beef consumption on CUP risk appeared to be stronger in women (HR Q4 vs. Q1: 1.47, 95% CI: 1.04-2.07, Ptrend = 0.004). A statistically significant association was also observed between processed meat consumption and CUP risk (HR for Q4 vs. Q1: 1.40, 95% CI: 1.12-1.75, Ptrend = 0.006). Our sex-stratified analysis indicated that the effect of processed meat consumption on CUP risk was more pronounced in women (HR for Q4 vs. Q1: 1.53, 95% CI: 1.08-2.16, Ptrend = 0.001), than in men (HR Q4 vs. Q1: 1.33, 95% CI: 0.99-1.79, Ptrend = 0.15). In contrast, no associations were observed between poultry or fish consumption and CUP risk (HR for C4 vs. C1: 0.97, 95% CI: 0.79-1.21, Ptrend = 0.28 &amp; HR for Q4 vs. Q1: 1.25, 95% CI: 0.99-1.57, Ptrend = 0.29, respectively). We found no multiplicative interaction between cigarette smoking status and meat consumption and CUP risk. Conclusion: Beef and processed meat consumption appear to be associated with increased CUP risk in women. In men, there appeared to be a non-significant positive association between processed meat consumption and CUP risk. Citation Format: Karlijn Hermans, Piet Van den Brandt, Caroline Loef, Rob Jansen, Leo Schouten. Meat consumption and Cancer of Unknown Primary (CUP) risk: results from the Netherlands Cohort Study on diet and cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB088.

Meat consumption and cancer of unknown primary (CUP) risk: results from The Netherlands cohort study on diet and cancer

PurposeCancer 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.MethodsData 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.ResultsWe 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.ConclusionIn 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.

AI-based pathology predicts origins for cancers of unknown primary.

Cancer of unknown primary (CUP) origin is anenigmatic group of diagnoses in which the primary anatomical site of tumour origin cannot be determined1,2. This poses a considerable challenge, as modern therapeutics are predominantlyspecific to the primary tumour3. Recent research has focused on using genomics and transcriptomics to identify the origin of a tumour4-9. However, genomic testing is not always performed and lacks clinical penetration in low-resource settings. Here, to overcome these challenges, we present a deep-learning-based algorithm-Tumour Origin Assessment via Deep Learning (TOAD)-that can provide a differential diagnosis for the origin of the primary tumour using routinely acquired histology slides. We used whole-slide images of tumours with known primary origins to train a model that simultaneously identifies the tumour as primary or metastatic and predicts its site of origin. On our held-out test set of tumours with known primary origins, the model achieved a top-1 accuracy of 0.83and a top-3 accuracy of 0.96, whereas on our external test set it achieved top-1 and top-3 accuracies of 0.80 and 0.93, respectively. We further curated a dataset of 317 cases of CUP for which a differential diagnosis was assigned. Our model predictions resulted in concordance for 61% of cases and a top-3 agreement of 82%. TOAD can be used as an assistive tool to assign a differential diagnosis to complicated cases of metastatic tumours and CUPs and could be used in conjunction with or in lieu of ancillary tests and extensive diagnostic work-ups to reduce the occurrence of CUP.

Machine learning analysis using 77,044 genomic and transcriptomic profiles to accurately predict tumor type

Cancer of Unknown Primary (CUP) occurs in 3–5% of patients when standard histological diagnostic tests are unable to determine the origin of metastatic cancer. Typically, a CUP diagnosis is treated empirically and has very poor outcomes, with median overall survival less than one year. Gene expression profiling alone has been used to identify the tissue of origin but struggles with low neoplastic percentage in metastatic sites which is where identification is often most needed. MI GPSai, a Genomic Prevalence Score, uses DNA sequencing and whole transcriptome data coupled with machine learning to aid in the diagnosis of cancer. The algorithm trained on genomic data from 34,352 cases and genomic and transcriptomic data from 23,137 cases and was validated on 19,555 cases. MI GPSai predicted the tumor type in the labeled data set with an accuracy of over 94% on 93% of cases while deliberating amongst 21 possible categories of cancer. When also considering the second highest prediction, the accuracy increases to 97%. Additionally, MI GPSai rendered a prediction for 71.7% of CUP cases. Pathologist evaluation of discrepancies between submitted diagnosis and MI GPSai predictions resulted in change of diagnosis in 41.3% of the time. MI GPSai provides clinically meaningful information in a large proportion of CUP cases and inclusion of MI GPSai in clinical routine could improve diagnostic fidelity. Moreover, all genomic markers essential for therapy selection are assessed in this assay, maximizing the clinical utility for patients within a single test.

Anthropometry, physical activity and cancer of unknown primary (CUP) risk: Results from the Netherlands cohort study

BackgroundCancer 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. MethodsData 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). ResultsWe 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. ConclusionOur findings indicate that neither anthropometry nor physical activity are associated with the development of CUP.

Alcohol consumption, cigarette smoking and cancer of unknown primary risk: Results from the Netherlands Cohort Study.

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 (P trend = .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 (P trend = .003 and P trend = .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.

Sentinel node theory helps tracking of primary lesions of cancers of unknown primary

BackgroundSentinel lymph node is the first stop of lymphatic spreading of cancer with known primary. The lymph node metastasis pattern of cancer of unknown primary (CUP) is unclear and has been presumed to follow the same pathway. To test this hypothesis, data of all 716 patients clinically diagnosed as CUP in our center were collected.MethodsDiagnoses of lymph node metastasis were established by 18F-FDG PET-CT and/or biopsy pathology. Three hundred and forty-seven cases meeting the criteria were divided into three groups: pathology-confirmed primary with invasive biopsy or surgery of the suspicious lesion (group A, n = 64), primary still unknown even with invasive biopsy or surgery of the suspicious lesion (group B, n = 204), and others with no suspicious lesion or lesions who had not been sampled due to medical or other reasons (group C, n = 79). We assessed the clinicopathological features between these groups, and the relationship between lymph node metastasis pattern and confirmed primary site.ResultsIn group A, the primary sites of 61 cases were compatible with sentinel node theory, resulting in a positive predictive value of 95%. No significant differences in age, sex, bone metastasis, or visceral metastasis observed between group A and group B, except that group A had a higher ratio of differentiated carcinoma (94% vs. 77%, P = 0.003).ConclusionTo our knowledge, this is the first evidence indicating that the majority of clinical CUP cases follow the sentinel node theory to spread in lymph nodes, which helps tracking the primary, especially for differentiated carcinoma.

Does Cancer of Unknown Primary (CUP) Truly Exist as a Distinct Cancer Entity?

Cancer of unknown primary (CUP) designates an enigmatic cancer entity with histologic confirmation of malignancy from a metastasis but no identifiable primary tumor in spite of a thorough diagnostic work-up. In this review, we discuss the validity of CUP as a distinct cancer entity as well as diagnostic pitfalls. As arguments against a distinct entity, the diagnosis of CUP is erroneous in some cases. Diagnostic pitfalls include incomplete diagnostics, uncertainty in classifying a lesion as either primary or metastasis and mistaking a relapse of an antecedent malignancy as CUP due to histologic and immunohistologic disparities. Given the high frequency of prior malignancies in CUP patients, relapse of an antecedent cancer should always be carefully excluded. Gene expression profiling-based classifier assays aim at aligning the molecular profile of CUP patients with established primary cancer patterns for highest congruency in order to identify the putative primary and treat accordingly. However, the spectrum of predicted putative primaries by molecular techniques is somewhat at odds with the primaries identified in autopsy series. Also, a first randomized clinical trial did not show superiority of primary-tailored therapy over unspecific platinum-based chemotherapy. CUP cases share an aggressive clinical course, atypical metastasis pattern, rapid progression of metastases, a generally poor response to chemotherapy and dismal outcome as distinct clinical features. Metastatic spread appears to take place in the early stages of tumor evolution, with CUP metastases subsequently undergoing genetic evolution toward a chromosomally highly complex and instable karyotype independent from the primary tumor. In clinical practice, the diagnosis of CUP is valid when no primary tumor is detectable. Treatment should ideally offer broad spectrum coverage across numerous malignancies and be well-established in CUP as is the case for carboplatin/paclitaxel and cisplatin / gemcitabine in particular, but it should also cover the most likely putative primary. The diligent diagnosis of CUP is warranted for clinical trials, making the eligibility process particularly laborious. In conclusion, we deem CUP a distinct cancer entity and the diagnosis accurate in most patient cases.

Management options for pulmonary nodules with cancer of unknown primary

Cancer of unknown primary (CUP) is defined as a cancer with a histological diagnosis suggestive of a metastasis and incompatible with that of the biopsy site. This means that metastatic cancer has been diagnosed but the primary site remains unknown. It represents 2–3% of all cancers and 10% of tumors with metastasis, with the location of the primary never found in 40–50% in spite of exhaustive investigations. This may be because the primary is very small and slow growing, making it outside the resolution of modern imaging techniques or because the body’s immune system has already destroyed the primary but not before haematological or lymphatic spread has occurred. Staging of CUP located in the lung of necessity does not follow the traditional TNM classification, with the TNM classification in this scenario being ambiguous and open to differing interpretations. This means that there may be diverging perspectives and viewpoints between surgeons, physicians and pathologists leading to different treatment pathways. It can result in the chance of potentially curative surgical resection of a lung lesion, if necessary by lobectomy, being missed in the belief that the lung mass in such CUP cases is by definition a metastasis. This perspective explores the diagnostic challenges of CUP, highlights the diverging opinions between different specialties in CUP and illustrates how knowledge of the different survival subsets that make up the diverse pathologies under CUP, together with informed surgical decision regarding tumour resectability should guide treatment choices. Patients with surgical resectable lung pathology fall into the 20% of CUP identified as having better prognosis; these carry a 15% 5-year survival and a median survival of 3 years, compared to the unfavorable subset that carries a dismal mean survival of 6 months. This suggests that surgery, when possible, remains a treatment of first choice.

Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis

Cancer of unknown primary ranks in the top ten cancer presentations and has an extremely poor prognosis. Identification of the primary tumour and development of a tailored site-specific therapy could improve the survival of these patients. We examined the feasability of using DNA methylation profiles to determine the occult original cancer in cases of cancer of unknown primary. We established a classifier of cancer type based on the microarray DNA methylation signatures (EPICUP) in a training set of 2790 tumour samples of known origin representing 38 tumour types and including 85 metastases. To validate the classifier, we used an independent set of 7691 known tumour samples from the same tumour types that included 534 metastases. We applied the developed diagnostic test to predict the tumour type of 216 well-characterised cases of cancer of unknown primary. We validated the accuracy of the predictions from the EPICUP assay using autopsy examination, follow-up for subsequent clinical detection of the primary sites months after the initial presentation, light microscopy, and comprehensive immunohistochemistry profiling. The tumour type classifier based on the DNA methylation profiles showed a 99·6% specificity (95% CI 99·5-99·7), 97·7% sensitivity (96·1-99·2), 88·6% positive predictive value (85·8-91·3), and 99·9% negative predictive value (99·9-100·0) in the validation set of 7691 tumours. DNA methylation profiling predicted a primary cancer of origin in 188 (87%) of 216 patients with cancer with unknown primary. Patients with EPICUP diagnoses who received a tumour type-specific therapy showed improved overall survival compared with that in patients who received empiric therapy (hazard ratio [HR] 3·24, p=0·0051 [95% CI 1·42-7·38]; log-rank p=0·0029). We show that the development of a DNA methylation based assay can significantly improve diagnoses of cancer of unknown primary and guide more precise therapies associated with better outcomes. Epigenetic profiling could be a useful approach to unmask the original primary tumour site of cancer of unknown primary cases and a step towards the improvement of the clinical management of these patients. European Research Council (ERC), Cellex Foundation, the Institute of Health Carlos III (ISCIII), Cancer Australia, Victorian Cancer Agency, Samuel Waxman Cancer Research Foundation, the Health and Science Departments of the Generalitat de Catalunya, and Ferrer.

Germline genetics of cancer of unknown primary (CUP) and its specific subtypes.

Cancer of unknown primary site (CUP) is a fatal cancer diagnosed through metastases at various organs. Little is known about germline genetics of CUP which appears worth of a search in view of reported familial associations in CUP. In the present study, samples from CUP patients were identified from 2 Swedish biobanks and a German clinical trial, totaling 578 CUP patients and 7628 regionally matched controls. Diagnostic data specified the organ where metastases were diagnosed. We carried out a genome-wide association study on CUP cases and controls. In the whole sample set, 6 loci reached an allelic p-value in the range of 10−7 and were supported by data from the three centers. Three associations were located next to non-coding RNA genes. rs2660852 flanked 5′UTR of LTA4H (leukotriene A4 hydrolase), rs477145 was intronic to TIAM1 (T-cell lymphoma invasion and metastases) and rs2835931 was intronic to KCNJ6 (potassium channel, inwardly rectifying subfamily J, member 6). In analysis of subgroups of CUP patients (smokers, non-smokers and CUP with liver metastases) genome-wide significant associations were noted. For patients with liver metastases associations on chromosome 6 and 11, the latter including a cluster of genes DHCR7 and NADSYN1, encoding key enzymes in cholesterol and NAD synthesis, and KRTAP5-7, encoding a keratin associated protein. This first GWAS on CUP provide preliminary evidence that germline genes relating to inflammation (LTA4H), metastatic promotion (TIAM1) in association with lipid metabolic disturbance (chromosome 11 cluster) may contribute to the risk of CUP.

Prognostic significance of WNT and hedgehog pathway activation markers in cancer of unknown primary.

Cancer of unknown primary (CUP) possesses distinct biology and peculiar natural history, in which the roles of the winged and hedgehog signalling pathways are unclear. We constructed tissue microarrays and studied the immunohistochemical (IHC) expression of β-catenin, smoothened (SMO) and the transcription factors TCF, LEF, GLI1 in 87 CUP cases for prognostic significance. A low rate of IHC expression of proteins was seen, the cut-off used being any expression in ≥1% of tumour cells. At univariate analysis, only nuclear IHC SMO expression displayed a statistically significant association with favourable outcome [median Overall survival (OS) of 19months in SMO-positive vs. 12months in SMO-negative cases, P=0·01]. An activated Wnt pathway, defined as IHC expression of any of nuclear β-catenin, TCF and LEF, was significantly associated with favourable progression free survival (median 9 vs. 5months, P=0·037) and OS (median 19 vs. 13months, P=0·04). This prognostic impact on OS was mainly driven by nuclear expression of TCF and/or LEF (P=0·03). No prognostic significance of the hedgehog pathway activation status, defined as IHC expression of SMO or nuclear GLI1, could be established. A favourable prognostic impact of the concurrent activation of both pathways was observed. A trend for association of activated Wnt with response to chemotherapy (responders 67% among activated Wnt cases vs. 35% among nonactivated Wnt cases, P=0·07) was observed in CUP adenocarcinomas. Activation of the Wnt pathway was a positive prognostic factor in a small CUP series, possibly via enhanced chemosensitivity. Independent validation is warranted.

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.