IJC International Journal of Cancer
Smoking and body mass index as risk factors for subtypes of cancer of unknown primary €ran Hallmans5 and Akseli Hemminki6 Kari Hemminki1,2, Bowang Chen1, Olle Melander3, Jonas Manjer3,4, Go 1
Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, 69120, Germany €, Sweden Center for Primary Health Care Research, Lund University, Malmo 3 €, Sweden Department of Clinical Sciences, Clinical Research Center, Lund University, Malmo 4 €, Sweden Department of Plastic and Reconstructive Surgery, Skane University Hospital, Malmo 5 Department of Medical Biosciences/Pathology, University of Umea, Umea, Sweden 6 Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki 00290, Finland 2
Letter to the Editor
Dear Sir, Cancer of unknown primary site (CUP) accounts for 3–5% of all cancer but because it is a fatal disease it ranks high among causes of cancer deaths. It has been called “an orphan disease” because it is diagnosed through metastatic tissue and the primary tumor often remains undetected. Based on autopsy data, the most common primaries were lung (27%), pancreas (24%), liver/bile (8%) and kidney/adrenals (8%).1 CUP can be called “orphan disease” also because, as a metastatic disease, it is disregarded as a cancer entity when only primary cancers are considered. Thus, hardly anything is known about the underlying causes or risk factors. A recent European study published in this Journal showed that heavy smoking causes a risk of 3.66 for CUP patients of diverse and unspecified histologies; alcohol drinking and wide waist circumference were borderline risk factors.2 The pathophysiology of CUP has remained an enigma, exemplified by the question presented in a review on CUP: “unknown primary or unknown biology?”3 The inability to find a primary tumor may not merely depend on its small size but may involve newly described cell biological processes related to stem cell characteristics, microenvironment, immunoediting and senescence-apoptosis which may halt tumor growth and induce phenotypic changes.3–5 In essence, an increased understanding of the interplay of host and tumor during the protracted process of carcinogenesis has made CUP less of a conundrum and more as a learning opportunity, in a 21st century parallel to the cancer biology gains provided by unravelling of several hereditary cancer syndromes in the previous century. Our recent studies support these data and suggest that the lung is a more common primary tissue than what the earlier data show.6–8 In the present letter, we extend the study of Kaaks et al. addressing the question of tobacco smoking and body mass index (BMI) as risk factors of site-specific CUP, that is, by location of the diagnosed metastasis.2 We hypothesize that smoking would have an effect on sites where smoking risks are highest among primary cancers, that is, lung. Patients and cancer-free controls were recruited from three Swedish prospective biobanks, the Umea Medical Biobank with 203 CUP patients and 1015 controls and the Malmo Diet and Cancer Study and the Prevention Study, jointly with 272 CUP patients
C 2014 UICC Int. J. Cancer: 136, 246–247 (2015) V
and 1360 controls;9 the controls were frequency matched on sex and age at interview. In Umea, the mean age at sampling was 57 years and at diagnosis it was 66 years; in Malm€o, the respective ages were 51 and 71 years. Cancers were identified up to year 2012 through the regional Oncology Centers. Diagnoses were based on International Classification of Diseases (ICD) codes 7, 9 and 10, the latter two were particularly useful because they included the anatomic site where metastases were found. These included “unspecified CUP” (ICD-9 code 1990–1991, CUP often spread to multiple organs), “liver CUP” with liver metastasis, “lung CUP” with lung involvement (including thorax and lymph nodes and organs, brain and bone, for which lung cancer is usually given as the cause of death in CUP patients7,8), “abdominal CUP” with abdominal metastases (including ovary) and “other CUP” with other metastatic locations (any other specified site). Histology was adenocarcinoma in 82.1%, squamous cell carcinoma in 5.0% and melanoma in 8.8% of the cases: 4.1% had miscellaneous or missing histology. Logistic regression analysis was used in the analysis of data. Detailed data on BMI were available but the dichotomous cutoff was at 20 kg/m2, best discriminated the risk groups. The study was approved by the ethics committee at Umea University. Linkage with cancer data up to year 2012 identified 475 CUP patients on whom smoking data were available on 463 CUP patients and BMI data on 447 patients. Unspecified CUP was the largest disease subgroup (43.4% of all cases), followed by lung (16.2%), abdomen (14.5%), liver (13.8%) and other CUP (12.1%). Smoking was a risk factor for all CUP cases taken together with an OR of 1.82 but the effect was particularly strong on lung CUP with an OR of 4.90 (Table 1). The commonest subgroup of unspecified CUP was also influenced by smoking (OR 1.89) as was liver CUP (OR 2.03). In univariable analysis (not shown), it was observed that the only BMI class that affected CUP was
Smoking and body mass index as risk factors for subtypes of cancer of unknown primary €ran Hallmans5 and Akseli Hemminki6 Kari Hemminki1,2, Bowang Chen1, Olle Melander3, Jonas Manjer3,4, Go 1
Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, 69120, Germany €, Sweden Center for Primary Health Care Research, Lund University, Malmo 3 €, Sweden Department of Clinical Sciences, Clinical Research Center, Lund University, Malmo 4 €, Sweden Department of Plastic and Reconstructive Surgery, Skane University Hospital, Malmo 5 Department of Medical Biosciences/Pathology, University of Umea, Umea, Sweden 6 Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki 00290, Finland 2
Letter to the Editor
Dear Sir, Cancer of unknown primary site (CUP) accounts for 3–5% of all cancer but because it is a fatal disease it ranks high among causes of cancer deaths. It has been called “an orphan disease” because it is diagnosed through metastatic tissue and the primary tumor often remains undetected. Based on autopsy data, the most common primaries were lung (27%), pancreas (24%), liver/bile (8%) and kidney/adrenals (8%).1 CUP can be called “orphan disease” also because, as a metastatic disease, it is disregarded as a cancer entity when only primary cancers are considered. Thus, hardly anything is known about the underlying causes or risk factors. A recent European study published in this Journal showed that heavy smoking causes a risk of 3.66 for CUP patients of diverse and unspecified histologies; alcohol drinking and wide waist circumference were borderline risk factors.2 The pathophysiology of CUP has remained an enigma, exemplified by the question presented in a review on CUP: “unknown primary or unknown biology?”3 The inability to find a primary tumor may not merely depend on its small size but may involve newly described cell biological processes related to stem cell characteristics, microenvironment, immunoediting and senescence-apoptosis which may halt tumor growth and induce phenotypic changes.3–5 In essence, an increased understanding of the interplay of host and tumor during the protracted process of carcinogenesis has made CUP less of a conundrum and more as a learning opportunity, in a 21st century parallel to the cancer biology gains provided by unravelling of several hereditary cancer syndromes in the previous century. Our recent studies support these data and suggest that the lung is a more common primary tissue than what the earlier data show.6–8 In the present letter, we extend the study of Kaaks et al. addressing the question of tobacco smoking and body mass index (BMI) as risk factors of site-specific CUP, that is, by location of the diagnosed metastasis.2 We hypothesize that smoking would have an effect on sites where smoking risks are highest among primary cancers, that is, lung. Patients and cancer-free controls were recruited from three Swedish prospective biobanks, the Umea Medical Biobank with 203 CUP patients and 1015 controls and the Malmo Diet and Cancer Study and the Prevention Study, jointly with 272 CUP patients
C 2014 UICC Int. J. Cancer: 136, 246–247 (2015) V
and 1360 controls;9 the controls were frequency matched on sex and age at interview. In Umea, the mean age at sampling was 57 years and at diagnosis it was 66 years; in Malm€o, the respective ages were 51 and 71 years. Cancers were identified up to year 2012 through the regional Oncology Centers. Diagnoses were based on International Classification of Diseases (ICD) codes 7, 9 and 10, the latter two were particularly useful because they included the anatomic site where metastases were found. These included “unspecified CUP” (ICD-9 code 1990–1991, CUP often spread to multiple organs), “liver CUP” with liver metastasis, “lung CUP” with lung involvement (including thorax and lymph nodes and organs, brain and bone, for which lung cancer is usually given as the cause of death in CUP patients7,8), “abdominal CUP” with abdominal metastases (including ovary) and “other CUP” with other metastatic locations (any other specified site). Histology was adenocarcinoma in 82.1%, squamous cell carcinoma in 5.0% and melanoma in 8.8% of the cases: 4.1% had miscellaneous or missing histology. Logistic regression analysis was used in the analysis of data. Detailed data on BMI were available but the dichotomous cutoff was at 20 kg/m2, best discriminated the risk groups. The study was approved by the ethics committee at Umea University. Linkage with cancer data up to year 2012 identified 475 CUP patients on whom smoking data were available on 463 CUP patients and BMI data on 447 patients. Unspecified CUP was the largest disease subgroup (43.4% of all cases), followed by lung (16.2%), abdomen (14.5%), liver (13.8%) and other CUP (12.1%). Smoking was a risk factor for all CUP cases taken together with an OR of 1.82 but the effect was particularly strong on lung CUP with an OR of 4.90 (Table 1). The commonest subgroup of unspecified CUP was also influenced by smoking (OR 1.89) as was liver CUP (OR 2.03). In univariable analysis (not shown), it was observed that the only BMI class that affected CUP was
