Second Primary Cancers After Liver, Gallbladder and Bile Duct Cancers, and These Cancers as Second Primary Cancers

Abstract

Background Second primary cancers (SPCs) are important clinically as they may negatively influence patient survival and they may tell about therapeutic side effects and general causes of cancer. Population-based literature concerning SPCs after hepatobiliary cancers is limited and here we assess risks of SPCs after hepatocellular cancer (HCC), and cancers of the gallbladder, bile ducts and ampulla of Vater. In reverse order, we consider the risk of hepatobiliary cancers as SPCs after any cancer. Methods We used standardized incidence ratios (SIRs) to estimate bidirectional relative risks of subsequent cancers associated with hepatobiliary cancers. Cancer diagnoses were obtained from the Swedish Cancer Registry from years 1990 through 2015. Results We identified 9997 primary HCCs, 1365 gallbladder cancers and 4721 bile duct cancers. After HCC, risks of four SPCs were increased: gallbladder (SIR = 4.38; 95% confidence interval 1.87–8.67), thyroid (4.13; 1.30–9.70), kidney (2.92; 1.66–4.47) and squamous cell skin (1.55; 1.02–2.26) cancers. In reverse order, HCC as SPC, in addition to the above cancers, associations included upper aerodigestive tract, esophageal, small intestinal and bladder cancers and non-Hodgkin lymphoma. For gallbladder and bile duct cancers, associations were found with small intestinal and pancreatic cancers. Conclusion The results suggested that HCC is associated with two types of SPC, one related to shared environmental risk factors, such as alcohol, exemplified by upper aerodigestive tract and esophageal cancer, and the other related to immune dysfunction, exemplified by squamous cell skin cancer. SPCs associated with gallbladder and bile duct cancers suggest predisposition to mutations in the mismatch repair gene MLH1.

Risk of extracolonic second primary cancers following a primary colorectal cancer: a systematic review and meta-analysis

“…2 . In contrast, there was a decreased risk of second primary gall bladder cancer (pooled SIR = 0.75; 95% CI = 0.60–0.94; p = 0.01) from three studies [ 21 , 33 , 38 ]; Fig. 3 ).…”

“… . Stomach: 751 Pancreas: 137 Ovary: 34 1.37 (1.28–1.47) 1.21 (1.02–1.43) 1.83 (1.27–2.56) 7 Ye et al [ 35 ] Retrospective cohort study Australia; Tasmanian Cancer Registry Men and women with a diagnosis of cancer > 2 months; aged > 15 years 1980–2009; 6.9 years (mean) 51,802 28,242 (54.5%) 23,560 (45.5%) 66.2 (median) Lung: 121 Skin: 80 Prostate: 182 1.13 (0.80–1.58) 1.88 (1.38–2.55) 1.15 (0.90–1.48) 8 Zheng et al [ 37 ] Retrospective cohort study Sweden; Swedish Cancer Registry Men and women with a diagnosis of bladder or upper urinary tract cancer 1990–2015; average follow-up unknown 49,584 36,614 (74%) 12,970 (26.0%) 73 (median) Urinary bladder: 521 Kidney: 22 1.11 (1.02 –1.21) 1.32 (0.83–1.54) 8 Zheng et al [ 38 ] Retrospective cohort study Sweden; Swedish Cancer Registry Men and women with a diagnosis of hepatobiliary cancer 1990–2015; 36 months (median) 19,995 10,102 (64.9%) 9893 (49.5%) 72 (median) Gallbladder: 44 Bile duct: 61 0.85 (0.61–1.14) 1.20 (0.92–1.54) 8 *Newcastle–Ottawa Scale ratings ≥ 6 were considered high quality …”

“…1). Thirteen studies published between 1999 and 2021, including 7,716,750 patients (2.01 × 10 9 person-years) with CRC that reported extracolonic SPCs cancer incidence, were included in the metaanalysis according to our inclusion criteria [16,18,21,27,[30][31][32][33][34][35][36][37][38]. The median Newcastle-Ottawa rating for the studies included was 8 (interquartile range (IQR) (7)(8)).…”

Long‐term incidence and survival trends in cancer of the gallbladder and extrahepatic bile ducts in Denmark, Finland, Norway and Sweden with etiological implications related to Thorotrast

“…21 Age groups 0 to 89 were considered, and for age-standardization the International Cancer Survival Standard was used. 20 NORDCAN did not include survival data for persons aged over 89 years, probably because of low case numbers and deficits of cancer notifications. 22 The country-specific life tables were used to calculate the expected survival.…”

“…The database combines GBC with cancer of the extrahepatic bile ducts, which has been almost equally common as GBC for men but about 1/3 of female GBC. We call these cancers jointly “GBC” to mark the largest constituent 20 . Much of the global Thorotrast cancer epidemiological data was generated in the Nordic countries, with the exception of NO from where no studies have been published, suggesting that Thorotrast was not used 14,15 .…”