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Prevalence of subclinical lung cancer detected at autopsy: a systematic review

Prevalence of subclinical lung cancer detected at autopsy: a systematic review Background Lung cancer screening in high-risk populations with low-dose computed tomography is supported by international associations and recommendations. Overdiagnosis is considered a risk of screening with associated harms. The aim of this paper is to determine the prevalence of subclinical lung cancer diagnosed post-mortem to better understand the reservoir of subclinical lung cancer. Methods We searched EMBASE, PubMed, and MEDLINE databases from inception until March 2022 with no language restrictions. We considered all studies with ≥100 autopsies in adults. Two reviewers independently assessed eligibility of studies, extracted data, and assessed risk of bias of included studies. We performed a meta-analysis using a random-effects model for prevalence of subclinical lung cancer diagnosed post-mortem with sensitivity and subgroup analyses. Results A total of 13 studies with 16 730 autopsies were included. Pooled prevalence was 0.4% (95% CI 0.20 to 0.82%, 2 2 I = 84%, tau = 1.19, low certainty evidence,16 730 autopsies). We performed a sensitivity analysis excluding studies which did not specify exclusion of children in their cohort, with a pooled prevalence of subclinical lung cancer of 2 2 0.87% (95% CI 0.48 to 1.57%, I = 71%, tau = 0.38, 6998 autopsies, 8 studies). Conclusions This is the first published systematic review to evaluate the prevalence of post-mortem subclinical lung cancer. Compared to autopsy systematic reviews in breast, prostate and thyroid cancers, the pooled prevalence is lower in lung cancer for subclinical cancer. This result should be interpreted with caution due to the included studies risk of bias and heterogeneity, with further high-quality studies required in target screening populations. Keywords Lung cancer, Subclinical, Latent, Screening, Overdiagnosis, Autopsy *Correspondence: Department of Anatomical Pathology, The Royal Melbourne Hospital, Asha Bonney Melbourne, Australia Asha.Bonney@mh.org.au Thoracic Medicine Program, The Prince Charles Hospital, Chermside, Department of Respiratory and Sleep Medicine, The Royal Melbourne Australia Hospital, 300 Grattan Street, Parkville, VIC, Australia UQ Thoracic Research Centre, School of Medicine, The University of Department of Medicine, The University of Melbourne, Melbourne, Queensland, Brisbane, Australia Australia Department of Respiratory Medicine, Northern Hospital, Epping, Division of Surveillance and Policy Evaluation, National Cancer Center Australia Institute for Cancer Control, Tokyo, Japan Statistical Consulting Centre, School of Mathematics and Statistics, The Cardiac Surgery Department, Austin Hospital, Heidelberg, Australia University of Melbourne, Melbourne, Australia © The Author(s) 2023. 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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Bonney et al. BMC Cancer (2023) 23:794 Page 2 of 11 Background median VDT of 229 days and lepidic adenocarcinomas Lung cancer is the second most diagnosed cancer in the having a median VDT of 647 days in one study [9]. world and remains the leading cause of cancer-related Systematic reviews of cancers diagnosed at autopsy death, responsible for almost 1.8  million deaths globally have already contributed immensely to understand- in 2020 [1]. This is despite lung cancer incidence rates ing the risk of overdiagnosis and reservoir of subclinical declining in males in Australia, Canada, Denmark, Ger- cancer in prostate, breast, and thyroid cancers [10–12]. many, Netherlands, New Zealand and United States of In prostate cancer, there was an increased prevalence of America (USA), although concerningly lung cancer inci- subclinical prostate cancer with increasing age, with the dence rates in younger women (30 to 49 years old) are estimated mean adjusted prevalence of prostate cancer trending upwards [2, 3]. diagnosed at autopsy in men aged > 79 years old of 59% A recent systematic review of randomised controlled (95% CI 48–71%) [11]. In breast cancer, the estimated trials (RCTs) using low-dose computed tomography mean prevalence diagnosed at autopsy was 20% (includ- (LDCT) for lung cancer screening in high-risk popula- ing precursor lesions) [10]. For thyroid cancer diagnosed tions (current or former smokers) concluded a reduction at autopsy, the pooled prevalence was 11% (95% CI 6 to in lung cancer-related mortality of 21% compared with 16%) [12]. The significant risk of overdiagnosis in prostate control groups (no screening or chest radiograph screen- and thyroid cancer has contributed to recommendations ing), (relative risk (RR) 0.79, 95% confidence interval (CI) against routine screening in asymptomatic individuals 0.72 to 0.87) [4]. Additionally, there was also a reduc- [13, 14]. Whilst breast cancer screening is recommended tion in all-cause mortality of 5% (RR 0.95, 95% CI 0.91 routinely in many countries, overdiagnosis is a recog- to 0.99) [4]. Multiple international guidelines now rec- nised risk and consideration when counselling women ommend screening for lung cancer in high-risk smoking [15]. populations with LDCT, with South Korea implementing There has been no previously published systematic a national screening program [5] and the USA funding review of the prevalence of subclinical lung cancer diag- screening in individuals meeting criteria (current or for- nosed at autopsy. However, in one Swedish autopsy study mer smokers with ≥20 pack-year history, quit ≤15 years of 7020 adults with a mean age of 55 years for men and ago, and aged between 50 and 80 years old) [6]. 58 years for women, only 5 had a post-mortem diagno- Whilst there are limited data on the harms of LDCT sis of subclinical lung cancer (0.07% prevalence) [16]. screening, one significant consideration is the risk of This review is not only useful in the discussion around overdiagnosis. Overdiagnosis refers to detection and lung cancer screening, but also to explore potential asso- diagnosis of lung cancer that would never have caused ciations between demographics and subgroups regarding the patient harm or death [7]. In lung cancer, there possible predictors for subclinical lung cancer. remains some uncertainty about the extent of overdiag- This review aims to describe the prevalence (or res - nosis, with the meta-analysis of lung cancer screening ervoir) of subclinical lung cancer detected at autopsy in in high-risk groups with LDCT RCTs reporting an esti- adults. mated range of 0 to 36% of lung cancers being overdiag- nosed at 10 or more years [4]. This estimate was graded Methods low certainty evidence due to the quality of the studies The systematic review was registered with the Inter - and heterogeneity. Overdiagnosis of lung cancer can national Prospective Register of Systematic Reviews cause harm by resulting in unnecessary investigations (PROSPERO registration: CRD42020140747) and report- and treatment (most commonly surgery in early-stage ing has been guided by the Preferred Reporting Items for disease), along with associated complications and cost. Systematic Reviews and Meta-analyses (PRISMA) check- There are many different histological subtypes of lung list [17]. cancer as defined by the World Health Organization (WHO) [8]. Of note, in the systematic review of LDCT Criteria for considering studies for this review lung cancer screening RCTs in high risk populations, We considered all studies with more than 100 autopsies the longer-term results (≥ 7 years post-randomisation), in adults (aged 18 or over) who were not known to have demonstrated probably no difference in the prevalence of lung cancer ante-mortem. We included studies which small cell lung cancer (SCLC) and squamous cell carci- specified information about whether lung cancer caused noma between the groups who received LDCT screening or contributed to death or was subclinical. and those who did not [4]. Conversely, adenocarcinoma was more prevalent in the LDCT screening group com- Search methods for identification of studies pared to the control group. This is potentially related to We searched EMBASE, PubMed, and MEDLINE data- the more variable volume doubling time (VDT) of ade- bases from inception until March 2022 using the follow- nocarcinomas, with the micropapillary subtype having ing search strategy. Bonney et al. BMC Cancer (2023) 23:794 Page 3 of 11 1. exp Lung Neoplasms/. author (RM) was consulted if required to reach consen- 2. (lung* adj3 (neoplasm* or neoplasia* or cancer* sus. We considered the following domains. or carcinoma* or adenocarcinoma* or tumour* • Selection bias -patient selection: we scored ‘low risk’ or tumor* or malignan* or pre-malignan* or when consecutive autopsy cases were included and premalignan*)).tw. there was avoidance of inappropriate exclusions, 3. Autopsy/. ‘high risk’ when non-consecutive autopsy cases were 4. (autops* or post-mortem* or post mortem*).tw. enrolled and/or there were inappropriate exclusions, 5. (#1 or #2) AND (#3 or#4). and ‘unclear risk’ when there was insufficient 6. limit 5 to humans. information to make this judgement. At least two review authors (AB, MN, KS, KT) indepen- • Detection bias- autopsy procedure: we scored dently screened all titles and abstracts retrieved by elec- ‘low risk’ when autopsies were standardised, lung tronic searches using Covidence [18]. At least two review examination methods were described, and there authors (AB, MN, KT) then obtained the full texts for all was adequate correlation with medical history, ‘high relevant studies and independently checked eligibility of risk’ when there was non-standardised approach each study against review eligibility criteria. We resolved to autopsy or inadequate correlation with medical discordant evaluations by discussion to reach consensus, history, and ‘unclear risk’ when there was insufficient and when necessary, involved a third review author (RM). information to make this judgement. We report the search results and study selection process • Detection bias- clinical criteria: we scored ‘low risk’ using a PRISMA flow diagram [ 17]. when studies described adequate detail on methods The review authors (AB, RM) developed a data extrac - used to classify lung cancer as incidental as opposed tion form of which parts were adapted from the Check- to clinically significant, ‘high risk’ when there was list for Prevalence Studies [19]. Two review authors (AB no differentiation between subclinical and clinically and KT) independently extracted relevant data and per- significant, and ‘unclear risk’ when there was formed a cross-check. If required, a third review author insufficient information to make this judgement. (RM) was consulted to reach consensus. We were not • Incomplete outcome data: we scored ‘low risk’ when blinded to publication details. When there were multiple all autopsy cases were included in results, ‘high risk’ publications related to the same study, we chose the pub- when not all cases where included, ‘unclear risk’ lication with the primary outcome as the study identifier. when there was insufficient information to make this When data was missing or unsuitable for analysis, we judgement. (AB) contacted study authors to request further informa- • External validity-generalisability: we scored ‘low tion using email addresses from study reports or registers risk’ when the study participants were representative where available. of the population, ‘high risk’ when they were not We collected the following data. representative, and ‘unclear risk’ when there was • Source: citation, contact details. insufficient information to make this judgement. • Eligibility criteria and reasons for exclusion. • Other sources of bias: we scored ‘low risk’ when • Methods: study design, total duration of study, the study did not appear to have other sources of number of centres and locations, autopsy rate. bias, ‘high risk’ when there was at least one other • Characteristics of participants: number of important bias, for example, deviations to protocol, participants, demographics (age, sex, exposures, lung and ‘unclear risk’ when there was insufficient cancer risk factors, co-morbidities). information to make this judgement. • Autopsy: methodology. • Results: lung cancer diagnoses, histology, stage of Analysis lung cancer, cause of death. We performed meta-analyses of prevalence using a ran- • Miscellaneous: funding source, conflicts of interest. dom intercept logistic regression model in R version There were no validated tools for assessing the quality of 4.2.2 [22], using the packages ‘meta’ version 6.0 [23] and autopsy studies for prevalence of subclinical cancer. The ‘metafor’ version 3.8 [24]. The results of the meta-analy - authors (AB and RM) developed a risk of bias (RoB) tool ses were presented visually using forest plots. Statistical with components adapted from previous tools used in heterogeneity of prevalence between pooled studies was prevalence and diagnostic accuracy studies [20, 21]. Two evaluated using I statistic and between-study variance review authors (AB and KT) independently applied the with tau [25]. RoB tool to assess quality of included studies. We rated We performed subgroup analyses for the following; each domain of the tool as having ‘low’, ‘high’, or ‘unclear 1. Consecutive versus non-consecutive case selection. risk of bias for each study and supported the rating of 2. Setting – hospital or forensic versus population- each domain with a brief description. A third review based studies. Bonney et al. BMC Cancer (2023) 23:794 Page 4 of 11 3. Location – continent. Results 4. Age – median/mean study age of 40–59 years, 60–89 Results of the search years, and 90 or greater years. 5233 citations were identified during our database search, 5. Risk factors. of which 170 were selected for full text review. 4501 6. Histological types. records were excluded after review of the title and/or 7. Lung cancer stage. abstract as they were judged irrelevant. 13 studies (with a Sex was assessed using mixed-effects model meta-regres - total of 15 citations) with a total of 16 730 autopsies were sion analyses. included in this systematic review. 155 studies did not We performed two sensitivity analyses (1) including meet inclusion criteria and were excluded, and reasons high quality studies only, i.e. excluding studies which are detailed in Fig. 1. potentially included people under the age of 18 years old, and (2) including those with low risk of bias autopsy Included studies procedures. Of the 13 studies, 6 were conducted in North America Publication bias was assessed using the Luis Furuya- [26–31], 5 in Europe [16, 32–36], and 2 in Asia [37–39] Kanamori asymmetry index (LFK index) and the Doi (Table 1). plot. Fig. 1 Study selection flow diagram Bonney et al. BMC Cancer (2023) 23:794 Page 5 of 11 Table 1 Characteristics of 13 included studies Study and Country Median year Study Num- Consecutive Median age at Fe- Sources of funding Year of when au- Population ber of Death, range(years) male and Conflicts of Publication topsies were Autopsies (%) Interest (COI) performed Examined Berezowska Switzerland 2017 Hospital 189 Yes 69, 26–104 63 No external funding. 2021(32) (50) No COI declared. Burrows USA 1973 Hospital 252 NS NS (inclusion of NS NS 1975(26) adults only) Gezelius. Sweden 1982 Forensic 7020 Yes Median age not NS NS 1988(16) specified. Mean age for men 55 years +/- 20 years SD. Mean age for women 58 years +/- 21 years SD Hudak 2022 Hungary 1994** Stroke 534 Yes Median age not 251 National Research, (33, 34) specified. Mean age (47) Development and 70.4 +/- 12.6 years Innovation Fund, SD (adults only GINOP-2.3.2-15- included)** 2016-00048 (Stay Alive), ELKH-DE Cerebrovascular and Neurodegenerative Research Group. No COI declared. Imaida 1997 Japan 1988 Hospital 871 NS Estimated median 510 Grant in aid for can- (37) 82, 48 to 100+ (59) cer research from the Ministry of Health and Welfare, Japan. Grant from the Society of Promo- tion of Toxicologic Pathology. COI NS. Ishii 1979 Japan 1966 NS 1366 NS Estimated median 432 NS (38, 39) 67, 65+ (35) Murphy 1977 USA 1977* Forensic 1300 Yes NS NS NS (27) Rosenblatt USA 1966 Hospital 466 NS NS NS NS 1973 (28) Sclare Scotland 1979* (based Hospital 143 No NS, 90–100 years old 91 NS 1991(35) on 24-year pe- (64) riod and date published) Sens 2009 USA 2009 (date Majority of 412 NS NS. Mean age 62 155 NS (29) published)* cases forensic years for unsuspect- (38) ed cancers. Stanta 1997 Italy 1967 (based General, older 267 No NS, 95–106 214 NS (36) on 20-year population (80) time frame and publica- tion 1997)* Suen 1974 USA 1965 Hospital 3535 Yes Estimated median 1693 NS (30) 70, 66–107 (48) Torbenson USA 1989 Transplant 375 Yes NS. Mean age 46, SD 158 NS 2001 (31) 11 years (42) *Estimated based on stated timeframe or year of publication if not otherwise stated ** Confirmed with authors NS = not specified Bonney et al. BMC Cancer (2023) 23:794 Page 6 of 11 Ishii 1979 [38, 39] was the earliest study to commence included people 65 years and older. Sclare 1991 [35] in 1955, with three other studies having an end date restricted subjects to those aged 90 to 100 years old before 1979 [26, 28, 30]. Four studies ended between and Stanta 1997 [36] included only those aged 99 years 1980 and 1999 [16, 31, 33, 37]. The most recent study to and older in the analysis. Murphy 1977 [27] comprised conclude was Berezowska 2021 [32] in 2017. Four studies of autopsies completed by the author exclusively. Three did not specify the specific decade autopsies were con - studies had specific co-morbid cohorts [ 28, 31, 33]. ducted (Sclare 1991 [35], Sens 2009 [29], Murphy 1977 Hudak 2022 [33] included participants who had a stroke [27], Stanta 1997 [36], although Stanta 1997 [36]reported and died. Rosenblatt 1973 [28] included only those who a 20-year period for autopsies, Sens 2009 [29]reported a had a malignant disease listed as the cause of death. Tor- 5-year period of autopsies, and Sclare 1991 [35] reported benson 2001 [31] included patients who had died within a 24-year period for autopsies. 100 days of a solid organ transplant. Four studies did not Five studies (Berezowksa 2021 [32], Gezelius 1988 [16], adequately specify age inclusions to determine children Burrows 1975 [26], Sens [29], Imaida 1997 [37] included were excluded with certainty [16, 27–29]. Ten studies did all autopsies performed during the study period at their not have any specified exclusion criteria [ 16, 26–28, 30, institution. Berezowska 2021 [32] included all adults 18 32, 33, 35, 36, 39]. Imaida 1997 [37] specified cases with years and older. Burrows 1975 [26] also included adults incomplete autopsy records were excluded and Torben- only. Two studies, Ishii 1979 [39] and Suen 1974 [30], son 2001 [31] specified cases with incomplete autopsies were excluded. Sens 2009 [29] excluded cases of intra- uterine foetal demise, skeletal remains, and externally referred neuropathology cases. Autopsy procedure and thoroughness of examination for included studies are detailed in table S1 (supplemen- tary materials). Of the 13 studies, five studies (Gezelius 1988, Imaida 1997, Ishii 1979, Sclare 1991 and Santa 1997) had pri- mary objectives focused on malignancy. Four studies (Rosenblatt 1973, Sens 2009, Suen 1974, and Torbenson 2001) had a primary objective focused on subclinical or clinically unsuspected cancer. Three studies (Berezowska 2021, Burrows 1975, and Hudak 2022) primarily focused on diagnostic accuracy and the value of autopsy. One study (Ishii 1979) had no specified objective other than to present autopsy findings in general. Excluded studies We excluded 155 studies. 107 for wrong outcomes, 29 had the wrong patient population, 9 studies were the wrong study design, 8 studies were abstracts only and provided insufficient information to evaluate eligibility for inclusion, and 2 studies were duplicates. Risk of bias We performed risk of bias assessment for all included studies and summarised the results in Fig.  2. Justifica - tions for grading are detailed in table S2 (supplementary materials). Outcomes Prevalence of lung cancer in the included studies is sum- marised in Table 2. Given the small number of lung can- cers diagnosed antemortem or post-mortem cause of death, the total autopsy denominator was not adjusted to calculate prevalence of subclinical lung cancer as Fig. 2 Risk of bias summary Bonney et al. BMC Cancer (2023) 23:794 Page 7 of 11 Table 2 Lung cancer prevalence Total # of Autopsies # Subclinical lung cancers # Lung cancers diagnosed # Lung cancers Examined diagnosed post-mortem (%) post-mortem and COD diagnosed antemortem Gezelius. 1988(16) 7020 5 (0.07) 12 8 Suen 1974 (30) 3535 47 (1.33) 0* 182 Ishii 1979 (38, 39) 1366 5 (0.37) 0* 120 Murphy 1977 (27) 1300 1 (0.08) 0 2 Imaida 1997 (37) 871 23 (2.64) NS 50 Hudak 2022 (33, 34) 534 1 (0.19) 0 NS Rosenblatt 1973 (28) 466 0 (0) 0 27 Sens 2009 (29) 412 4 (0.97) 4 1* Torbenson 2001 (31) 375 2 (0.53) 0* 0* Stanta 1997 (36) 267 2 (0.75) 1 0 Burrows 1975(26) 252 2 (1.40) 0 NS Berezowska 2021(32) 189 5 (0.07) NS 16 Sclare 1991 (35) 143 47 (1.33) 0 2 NS = not specified, * indicates number calculated from paper corresponding data were often not available for sub- 1. Asia: Two studies [37, 39] were included in this groups and the authors judged the impact to be small. analysis. Pooled prevalence was 1.01% (95% CI 2 2 We pooled the prevalence of subclinical lung can- 0.25 to 4.04%, I = 94%, tau = 0.93, 2237 autopsies). cers diagnosed post-mortem for all 13 trials. The evi - 2. Europe: Five studies [16, 32, 33, 35, 36] were dence showed a pooled prevalence of 0.4% (95% CI 0.20 included in this analysis. Pooled prevalence was 2 2 2 2 to 0.82%, I = 84%, tau = 1.19; low certainty evidence, 16 0.27% (95% CI 0.09 to 0.84%, I = 76%, tau = 0.88, 730 autopsies, Fig.  3a). Heterogeneity amongst studies 8153 autopsies). was high, with Imaida 1997 [37] having a higher preva- 3. North America: Six studies [26–31] were included lence than the other included studies. Imaida 1997 [37] in this analysis. Pooled prevalence was 0.37% 2 2 was conducted in Japan and recruited from a hospital (95% CI 0.13 to 1.07%, I = 54%, tau = 0.98, 6340 population with a median age of 82 years and the primary autopsies). objective. We performed a sensitivity analysis excluding There was no statistically significant difference between studies which did not specify exclusion of children (< 18 subgroups. Test for subgroup differences: Chi = 2.09, years old) in their cohort [16, 27–29]. Nine studies were df = 2 (p = 0.35). included in the analysis, with a pooled prevalence of • By age: Ten studies provided information regarding subclinical lung cancer of 0.74% (95% CI 0.40 to 1.37%, age. Analysis provided in supplementary material 2 2 I = 71%, tau = 0.49, 7532 autopsies, Fig.  3b). Heteroge- (Figure S2 supplementary materials). neity amongst studies was high, however had decreased 1. For those with a median or mean age of 40 to 59 comparatively. years old [16, 31]: prevalence of subclinical lung When we performed another sensitivity analysis of cancer was 0.13% (95% CI 0.03 to 0.59%, I = 83%, studies with low risk of bias for autopsy procedure. Four tau = 0.47, 7385 autopsies). Gezelius 1988 [16] did studies were included [30, 32, 37, 39], with a pooled not clearly exclude children, when this study was prevalence of 1.02% (95% CI 0.45 to 2.20%, I = 85%, removed from the analysis, prevalence was 0.52% tau = 0.51, 5961 autopsies). (91% 0.06 to 1.91%, 1 study [31], 375 autopsies). We performed a meta-regression analysis (proportion 2. For those with a median or mean age of 60 to 89 male) using the 9 available studies [29–33, 35–37, 39] years old [29, 30, 32, 33, 37, 39]: prevalence of which showed no statistically significant association with subclinical lung cancer was 0.81% (95% CI 0.0.38 2 2 sex, with an odds ratio (OR) = 0.085 (95% CI: 0.003, 2.55; to 1.69%, I = 79%, tau = 0.57, 6907 autopsies p = 0.155). Sens 2009 [29] did not clearly exclude children, We performed the following subgroup analyses. when this study was removed from the analysis, • By location: All 13 studies were included in prevalence was 0.76% (95% CI 0.31 to 1.86%, 2 2 this analysis by continent. Analysis provided in I = 83%, tau = 0.0.78, 5 studies, 6495 autopsies). supplementary material (Figure S1 supplementary 3. For those with a median or mean age of ≥90 years materials). old [35, 36]: prevalence of subclinical lung cancer 2 2 was 0.98% (95% CI 0.37 to 2.57%, I = 0%, tau = 0, Bonney et al. BMC Cancer (2023) 23:794 Page 8 of 11 Fig. 3 (a) Pooled prevalence of subclinical lung cancer (all studies). (b) Pooled prevalence of subclinical lung cancer (studies which specified children were not included) 410 autopsies). All studies clearly specified they category to proceed. Only three studies reported stages did not include children. of subclinical lung cancers diagnosed post-mortem [26, There was no statistically significant difference between 27, 31]. Burrows 1975 [26] reported one case of stage 4 subgroups. Test for subgroup differences: Chi = 5.29, lung cancer. Murphy 1977 [27] and Torbenson 2001 [31] df = 2 (p = 0.07). reported 1 and 2 cases of stage 1 lung cancer respectively. Subgroup analyses by patient selection and setting, study There was inadequate information provided in the period presented in Table S3, Figure S3, Figure S4, and studies to perform analyses looking at risk factors includ- Figure S5 (supplementary materials). There were no sta - ing smoking status. tistically significant differences in subgroup analyses. The LFK index was 4.32, with significant asymmetry Pooled analyses for histology were performed separately (Doi plot presented in Figure S6 of the supplementary for cancer subtypes and were also summarised in Table materials). S3 (supplementary materials). We attempted analysis of studies by stage, however there was insufficient number of studies within each Bonney et al. BMC Cancer (2023) 23:794 Page 9 of 11 Discussion reviews in other types of cancer (breast, prostate, and Our systematic review of 13 studies of 16 730 autopsies thyroid), was significantly lower [ 10–12]. across seven countries and seven decades demonstrated The strengths of this review include its comprehen - a pooled prevalence of 0.4% for subclinical lung cancer sive search strategy, with no language barriers, and thor- diagnosed post-mortem. When sensitively analysis was ough evaluation of study methodology. However, there performed excluding studies which did not clearly pro- were some limitations. Firstly, this systematic review and vide age ranges, the pooled prevalence was 0.74%. The search focused on post-mortem diagnoses of lung can- LFK index did demonstrate asymmetry, suggestive of cer, and as such studies which evaluated for pre-cursor possible small study effects, with a larger prevalence esti - lesions only were excluded. Two autopsies series which mate and less precision potentially overestimating the have evaluated precursor adenocarcinoma lesions are prevalence. Sterner 1997 [44] and Yokose 2000 [45]. Sterner 1997 [44] To our knowledge this is the first systematic review was a review of 100 consecutive autopsies in the USA of the prevalence of subclinical lung cancer detected at and found two cases of atypical alveolar cell hyperplasia autopsies in adults. Strauss 1993 [40] conducted a brief in a general autopsy population. Yokose 2000 [45] was an narrative review of subclinical lung cancer diagnosed at autopsy series of 241 cases in Japan and found 16 people autopsy, however the autopsy cases were contaminated had evidence of atypical adenomatous hyperplasia. Sec- with clinically unsuspected lung cancer which was the ondly, it should be acknowledged that the background cause of death. There was one large autopsy study that rates of CT in each country during the autopsy period was excluded from this review as the cohort included was not readily available. None of the included studies children [41]. Karwinski 1990 [41] was Norwegian series had the primary aim focused on subclinical lung cancer of 21, 530 autopsies conducted in people aged 1 to 99 diagnosed at autopsy. In one excluded retrospective study years old. The age range for subclinical lung cancers was [46] which had the primary aim of detecting subclinical 40 to 93 years old and there were 14 cases diagnosed lung cancer at autopsy, 47 cases were found amongst 24. post-mortem (0.65% prevalence), similar to the findings 708 autopsies in a coronial population (0.34% prevalence, in this review. Our results are also reasonably consistent 95% CI 0.24 to 0.44%). This study was excluded as the with the meta-analysis of LDCT lung cancer screen- population included children, although the median age ing RCTs (in studies with at least 10 years of follow up) was 67 years old. which estimated 7 cases of lung cancer overdiagnosis for The evidence in this review is low certainty due to the every 1000 people screened (95% CI of 2 to 84 cases) [4]. risk of bias in included studies, possible publication bias It should be noted that the study population in the RCTs and small study effect, and the significant heterogene - were high-risk populations for lung cancer with smoking ity between studies. However, in the case of prevalence histories, as opposed to the general population. The larg - studies, heterogeneity may also provide confidence that est lung cancer screening with LDCT RCT, the National the outcome is relevant to a wider population and was Lung Screen Trial (NLST), reported at 11.3 year follow- present in other autopsy reviews [12]. Most studies were up a lung cancer incidence of 1701 cases in the LDCT published before the year 2000 and descriptions of the screening group (6.3% of their LDCT cohort) [42]. Risk of population and methodology were limited. Pooled prev- overdiagnosis is challenging to assess in the NLST given alence increased with decade of publication with those the comparison group received CXR. After 10 years of published earlier having a lower pooled prevalence. Most follow-up, the Dutch–Belgian lung-cancer screening trial study periods were before 1999, with only 601 autopsies (Nederlands–Leuvens Longkanker Screenings Onder- being conducted after the year 2000. As such, consider- zoek [NELSON]) reported a cumulative incidence of ation regarding background smoking rates, use of ciga- 344 lung cancers in their LDCT screening group, data rette filters, environmental exposures should be given. for male participants only provided (5.2% of their male There were concerns listed about the thoroughness of LDCT screening cohort) [43]. The cumulative incidence autopsies in some studies which may have underesti- of lung cancer amongst male participants in NESLON mated the prevalence of lung cancers, particularly in trial control group was 4.6%. With an extended follow- detecting subsolid or ground glass lesions. The sensitiv - up to 11 years post randomisation, the NELSON study ity analysis in this review including only those studies estimated an excess-incidence overdiagnosis rate of 8.9% with a low risk of bias for autopsy procedure had a higher (95% CI -18.2 to 32.4%) [43]. It is clear screening detects pooled prevalence of subclinical lung cancer, however both clinically relevant lung cancers and those which may confidence intervals were overlapping. A previous study not progress to cause symptoms or death. in the USA compared 28 patients with post-mortem The pooled prevalence described in this review rep - examinations who had had a CT within 2 months of resents the best available estimate of the reservoir of their death [47]. They found that 19 patients had nodules subclinical lung cancer to date and compared to similar 15  mm or less in diameter noted on CT and 9 patients Bonney et al. BMC Cancer (2023) 23:794 Page 10 of 11 PRISMA Preferred Reporting Items for Systematic Reviews and had no mention of nodules on autopsy. This may suggest Meta-analyses RCT Randomised controlled trial the limitations of autopsy and need for high quality stud- RoB Risk of bias ies, although it could also be the result of interval lesion SCLC Small cell lung cancer resolution. USA United States of America VDT Volume doubling time Only five studies reported histology of subclinical lung WHO World Health Organization cancers, with a pooled prevalence of 0.14%, 0.11%, 0.11%, 0.05% for NSCLC not otherwise specified, adenocarci - noma, squamous cell carcinoma (SCC), and bronchoal- Supplementary Information The online version contains supplementary material available at https://doi. veolar carcinoma (BAC) respectively. This was a small org/10.1186/s12885-023-11224-3. cohort, with only 1840 autopsies included. Interestingly, in LDCT screening RCTs, whilst at baseline screening Supplementary Material 1 SCC, adenocarcinoma and BAC are more common in the LDCT screening compared with the control groups, Acknowledgements at later time points, only adenocarcinoma and BAC We would like to thank Catherine Voutier, The Royal Melbourne Hospital, for her assistance designing the search strategies. We would like to thank study remain more prevalent in the LDCT cohort [4]. Whilst author Lilla Hudak for response to our queries. adenocarcinoma-spectrum lesions growth patterns are more associated with overdiagnoses [9], due to the risk Authors contributions Design of the protocol: AB, KS, RMSelection of studies: AB, KT, MN, KS, RMData of competing mortality in those with a history of tobacco extraction and management: AB, KT, RMAssessment of risk of bias: AB, KT, exposure, there is the potential for all histological types RMDealing with missing data: ABData analysis: AB, CPManuscript preparation: in lung cancer may be overdiagnosed. AB, KT, MN, MC, KF, HM, KS, CP, DS, RM. Whilst there were no statistically significant differ - Funding ences between the subgroups, there were some trends Asha Bonney has a Postgraduate Scholarship from the Australian National observed. The pooled prevalence based on patient selec - Health and Medical Research Council. Kwun Fong has an Australian Medical Research Future Fund Fellowship. tion demonstrated a lower prevalence of subclinical lung cancers in studies which recruited consecutively, Data Availability compared to those which were non-consecutive. Stud- All data analysed during this review are included in this published article and its supplementary information files. ies from Asia (both studies were conducted in Japan) had the highest pooled prevalence compared to Europe and Declarations North America. With both Imaida 1997 and Ishii 1979 also having a low risk of bias for autopsy procedure. This Competing interests may reflect the importance of race as a risk factor for The authors declare no competing interests. lung cancer development, particularly low VDT adeno- Ethics approval and consent to participate carcinoma, which may contribute to higher risks of over- Not applicable. diagnosis in certain populations [48]. The prevalence also Consent for publication increased with age and is significant as most screening Not applicable. programs are targeting those aged 50 to 80 years old. In order to advance our understanding about the risk of Received: 10 April 2023 / Accepted: 25 July 2023 overdiagnosis with lung cancer screening and the natural history of lung cancer, more information is needed. Fur- ther research is required regarding the reservoir of pre- cursor lung lesions and high-quality, prospective studies assessing post-mortem diagnosis of subclinical lung can- References 1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et cer in adult populations, including those who would be al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and eligible for lung cancer screening. Mortality Worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. 2. Fidler-Benaoudia MM, Torre LA, Bray F, Ferlay J, Jemal A. Lung cancer inci- Conclusions dence in young women vs. young men: a systematic analysis in 40 countries. This review has found that the reservoir for subclinical Int J Cancer. 2020;147(3):811–9. lung cancer is relatively small in published autopsy series, 3. Registry VC. Lung cancer factsheet Australia: Cancer Council Victoria; 2021 [updated 10/05/2021. Available from: https://www.cancervic.org. suggesting a relatively low risk of overdiagnosis with au/research/vcr/fact-sheets-and-annual-reports/lung-cancer-factsheet. screening compared with breast, prostate and thyroid html#:~:text=Figure%203%20shows%20that%20since,0.3%25%20per%20 cancer. . year%20in%20females. 4. Bonney A, Malouf R, Marchal C, Manners D, Fong KM, Marshall HM, et al. List of abbreviations Impact of low-dose computed tomography (LDCT ) screening on lung LDCT L ow-dose computed tomography cancer-related mortality. Cochrane Database Syst Rev. 2022;8(8):Cd013829. LFK Luis Furuya-Kanamori asymmetry index Bonney et al. BMC Cancer (2023) 23:794 Page 11 of 11 5. Park J, Lee J, Kim Y. Public opinion on implementing the National Lung 27. Murphy GK. Cancer and the coroner. JAMA. 1977;237(8):786–8. Cancer Screening Program in Korea. Translational Lung Cancer Research. 28. Rosenblatt MB, Teng PK, Kerpe S. Diagnostic accuracy in cancer as deter- 2021;10(3):1355–67. mined by post mortem examination. Prog Clin Cancer. 1973;5:71–80. 6. Division of Cancer Prevention and Control CfDCaP. Who Should Be Screened 29. Sens MA, Zhou X, Weiland T, Cooley AM. Unexpected neoplasia in autopsies: for Lung Cancer? USA: U.S. Department of Health and Human Services 2022 potential implications for tissue and organ safety. Arch Pathol Lab Med. [updated 25/10/2022. Available from: https://www.cdc.gov/cancer/lung/ 2009;133(12):1923–31. basic_info/screening.htm#:~:text=The%20only%20recommended%20 30. Suen KC, Lau LL, Yermakov V. Cancer and old age. An autopsy study of 3,535 screening%20test,or%20history%20of%20that%20disease. patients over 65 years old. Cancer. 1974;33(4):1164–8. 7. Brodersen J, Voss T, Martiny F, Siersma V, Barratt A, Heleno B. Overdiagnosis of 31. Torbenson MS, Wang J, Nichols L, Jain AB, Fung JJ, Nalesnik MA. Occult lung cancer with low-dose computed tomography screening: meta-analysis nonhematopoietic malignancies present at autopsy in solid organ transplant of the randomised clinical trials. Breathe (Sheff ). 2020;16(1):200013. patients who died within 100 days. Transplantation. 2001;71(1):64–9. 8. Nicholson AG, Tsao MS, Beasley MB, Borczuk AC, Brambilla E, Cooper WA, et al. 32. Berezowska S, Schmid A, Losmanová T, Trippel M, Blank A, Banz Y et al. The 2021 WHO classification of lung tumors: impact of advances since 2015. J Frequency and significance of pathologic pulmonary findings in Postmor - Thorac Oncol. 2022;17(3):362–87. tem Examinations-A single Center experience before COVID-19. Diagnostics 9. Park S, Lee SM, Kim S, Lee J-G, Choi S, Do K-H, et al. Volume doubling Times of (Basel). 2021;11(5). Lung Adenocarcinomas: correlation with predominant histologic subtypes 33. Hudák L, Nagy AC, Molnár S, Méhes G, Nagy KE, Oláh L, et al. Discrepancies and prognosis. Radiology. 2020;295(3):703–12. between clinical and autopsy findings in patients who had an acute stroke. 10. Thomas ET, Del Mar C, Glasziou P, Wright G, Barratt A, Bell KJL. Prevalence of Stroke Vasc Neurol. 2022;7(3):215–21. incidental breast cancer and precursor lesions in autopsy studies: a system- 34. Hudak LNAC, Mehes G, Molnar S, Nagy K, Olah L, Csiba L. Is the autopsy atic review and meta-analysis. BMC Cancer. 2017;17(1):808. stillvaluable the brain and bodyautopsy results of 534 stroke patients. Int J 11. Bell KJ, Del Mar C, Wright G, Dickinson J, Glasziou P. Prevalence of inciden- Stroke. 2020;15(142). tal prostate cancer: a systematic review of autopsy studies. Int J Cancer. 35. Sclare G. Malignancy in Nonagenarians. Scot Med J. 1991;36(1):12–5. 2015;137(7):1749–57. 36. Stanta G, Campagner L, Cavallieri F, Giarelli L. Cancer of the oldest old. What 12. Furuya-Kanamori L, Bell KJL, Clark J, Glasziou P, Doi SAR. Prevalence of differ - we have learned from autopsy studies. Clin Geriatr Med. 1997;13(1):55–68. entiated thyroid Cancer in autopsy studies over six decades: a Meta-analysis. 37. Imaida K, Hasegawa R, Kato T, Futakuchi M, Takahashi S, Ogawa K, et al. Clini- J Clin Oncol. 2016;34(30):3672–9. copathological analysis on cancers of autopsy cases in a geriatric hospital. 13. Force UPST. Screening for thyroid Cancer: US Preventive Services Task Force Pathol Int. 1997;47(5):293–300. Recommendation Statement. JAMA. 2017;317(18):1882–7. 38. Ishii T, Hosoda Y, Maeda K. Cause of death in the extreme aged–a patho- 14. Mottet N, van den Bergh RCN, Briers E, Van den Broeck T, Cumberbatch MG, logic survey of 5106 elderly persons 80 years old and over. Age Ageing. De Santis M, et al. EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate 1980;9(2):81–9. Cancer-2020 update. Part 1: screening, diagnosis, and local treatment with 39. Ishii T, Maeda K, Nakamura K, Hosoda Y. Cancer in the aged: an autopsy study curative intent. Eur Urol. 2021;79(2):243–62. of 940 cancer patients. J Am Geriatr Soc. 1979;27(7):307–13. 15. Siu AL. Screening for breast Cancer: U.S. Preventive Services Task Force Rec- 40. Strauss GM, Gleason RE, Sugarbaker DJ. Screening for lung cancer re- ommendation Statement. Ann Intern Med. 2016;164(4):279–96. examined. A reinterpretation of the Mayo Lung Project randomized trial on 16. Gezelius C, Eriksson A. Neoplastic disease in a medicolegal autopsy material. lung cancer screening. Chest. 1993;103(4 Suppl):337s–41s. A retrospective study in northern Sweden. Z Rechtsmed. 1988;101(2):115–30. 41. Karwinski B, Svendsen E, Hartveit F. Clinically undiagnosed malignant 17. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. tumours found at autopsy. Apmis. 1990;98(6):496–500. The PRISMA 2020 statement: an updated guideline for reporting systematic 42. Lung Cancer Incidence. And Mortality with Extended follow-up in the reviews. BMJ. 2021;372:n71. National Lung Screening Trial. J Thorac Oncol. 2019;14(10):1732–42. 18. Innovation VH. Covidence systematic review software. 2021 ed. Melbourne, 43. de Koning HJ, van der Aalst CM, de Jong PA, Scholten ET, Nackaerts K, Heu- Australia. velmans MA, et al. Reduced lung-Cancer mortality with volume CT screening 19. Munn Z, Moola S, Lisy K, Riitano D, Tufanaru C. Methodological guidance in a Randomized Trial. N Engl J Med. 2020;382(6):503–13. for systematic reviews of observational epidemiological studies report- 44. Sterner DJ, Mori M, Roggli VL, Fraire AE. Prevalence of pulmonary atypical ing prevalence and cumulative incidence data. Int J Evid Based Healthc. alveolar cell hyperplasia in an autopsy population: a study of 100 cases. Mod 2015;13(3):147–53. Pathol. 1997;10(5):469–73. 20. Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, et al. 45. Yokose T, Ito Y, Ochiai A. High prevalence of atypical adenomatous hyperpla- QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy sia of the lung in autopsy specimens from elderly patients with malignant studies. Ann Intern Med. 2011;155(8):529–36. neoplasms. Lung Cancer. 2000;29(2):125–30. 21. Hoy D, Brooks P, Woolf A, Blyth F, March L, Bain C, et al. Assessing risk of bias 46. Manser RL, Dodd M, Byrnes G, Irving LB, Campbell DA. Incidental lung in prevalence studies: modification of an existing tool and evidence of inter - cancers identified at coronial autopsy: implications for overdiagnosis of lung rater agreement. J Clin Epidemiol. 2012;65(9):934–9. cancer by screening. Respir Med. 2005;99(4):501–7. 22. R Foundation for Statistical Computing. In: Foundation TR, editor. Vienna, 47. Dammas S, Patz EF Jr, Goodman PC. Identification of small lung nodules at Austria2022. autopsy: implications for lung cancer screening and overdiagnosis bias. Lung 23. Balduzzi S, Rücker G, Schwarzer G. How to perform a meta-analysis with R: a Cancer. 2001;33(1):11–6. practical tutorial. Evid Based Ment Health. 2019;22(4):153–60. 48. Gao W, Wen CP, Wu A, Welch HG. Association of Computed Tomographic 24. Viechtbauer W. Conducting Meta-analyses in R with the metafor Package. J Screening Promotion with Lung Cancer Overdiagnosis among Asian Women. Stat Softw. 2010;36(3):1–48. JAMA Intern Med. 2022;182(3):283–90. 25. Higgins JPTJ, Chandler J, Cumpston M, Li T, Page MJ, et al. editors. (s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.3 (updated February 2022 2022 [Available from: training.cochrane.org/ Publisher’s Note handbook. Springer Nature remains neutral with regard to jurisdictional claims in 26. Burrows S. The postmortem examination. Scientific necessity or folly? JAMA. published maps and institutional affiliations. 1975;233(5):441–3. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Cancer Springer Journals

Prevalence of subclinical lung cancer detected at autopsy: a systematic review

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Abstract

Background Lung cancer screening in high-risk populations with low-dose computed tomography is supported by international associations and recommendations. Overdiagnosis is considered a risk of screening with associated harms. The aim of this paper is to determine the prevalence of subclinical lung cancer diagnosed post-mortem to better understand the reservoir of subclinical lung cancer. Methods We searched EMBASE, PubMed, and MEDLINE databases from inception until March 2022 with no language restrictions. We considered all studies with ≥100 autopsies in adults. Two reviewers independently assessed eligibility of studies, extracted data, and assessed risk of bias of included studies. We performed a meta-analysis using a random-effects model for prevalence of subclinical lung cancer diagnosed post-mortem with sensitivity and subgroup analyses. Results A total of 13 studies with 16 730 autopsies were included. Pooled prevalence was 0.4% (95% CI 0.20 to 0.82%, 2 2 I = 84%, tau = 1.19, low certainty evidence,16 730 autopsies). We performed a sensitivity analysis excluding studies which did not specify exclusion of children in their cohort, with a pooled prevalence of subclinical lung cancer of 2 2 0.87% (95% CI 0.48 to 1.57%, I = 71%, tau = 0.38, 6998 autopsies, 8 studies). Conclusions This is the first published systematic review to evaluate the prevalence of post-mortem subclinical lung cancer. Compared to autopsy systematic reviews in breast, prostate and thyroid cancers, the pooled prevalence is lower in lung cancer for subclinical cancer. This result should be interpreted with caution due to the included studies risk of bias and heterogeneity, with further high-quality studies required in target screening populations. Keywords Lung cancer, Subclinical, Latent, Screening, Overdiagnosis, Autopsy *Correspondence: Department of Anatomical Pathology, The Royal Melbourne Hospital, Asha Bonney Melbourne, Australia Asha.Bonney@mh.org.au Thoracic Medicine Program, The Prince Charles Hospital, Chermside, Department of Respiratory and Sleep Medicine, The Royal Melbourne Australia Hospital, 300 Grattan Street, Parkville, VIC, Australia UQ Thoracic Research Centre, School of Medicine, The University of Department of Medicine, The University of Melbourne, Melbourne, Queensland, Brisbane, Australia Australia Department of Respiratory Medicine, Northern Hospital, Epping, Division of Surveillance and Policy Evaluation, National Cancer Center Australia Institute for Cancer Control, Tokyo, Japan Statistical Consulting Centre, School of Mathematics and Statistics, The Cardiac Surgery Department, Austin Hospital, Heidelberg, Australia University of Melbourne, Melbourne, Australia © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Bonney et al. BMC Cancer (2023) 23:794 Page 2 of 11 Background median VDT of 229 days and lepidic adenocarcinomas Lung cancer is the second most diagnosed cancer in the having a median VDT of 647 days in one study [9]. world and remains the leading cause of cancer-related Systematic reviews of cancers diagnosed at autopsy death, responsible for almost 1.8  million deaths globally have already contributed immensely to understand- in 2020 [1]. This is despite lung cancer incidence rates ing the risk of overdiagnosis and reservoir of subclinical declining in males in Australia, Canada, Denmark, Ger- cancer in prostate, breast, and thyroid cancers [10–12]. many, Netherlands, New Zealand and United States of In prostate cancer, there was an increased prevalence of America (USA), although concerningly lung cancer inci- subclinical prostate cancer with increasing age, with the dence rates in younger women (30 to 49 years old) are estimated mean adjusted prevalence of prostate cancer trending upwards [2, 3]. diagnosed at autopsy in men aged > 79 years old of 59% A recent systematic review of randomised controlled (95% CI 48–71%) [11]. In breast cancer, the estimated trials (RCTs) using low-dose computed tomography mean prevalence diagnosed at autopsy was 20% (includ- (LDCT) for lung cancer screening in high-risk popula- ing precursor lesions) [10]. For thyroid cancer diagnosed tions (current or former smokers) concluded a reduction at autopsy, the pooled prevalence was 11% (95% CI 6 to in lung cancer-related mortality of 21% compared with 16%) [12]. The significant risk of overdiagnosis in prostate control groups (no screening or chest radiograph screen- and thyroid cancer has contributed to recommendations ing), (relative risk (RR) 0.79, 95% confidence interval (CI) against routine screening in asymptomatic individuals 0.72 to 0.87) [4]. Additionally, there was also a reduc- [13, 14]. Whilst breast cancer screening is recommended tion in all-cause mortality of 5% (RR 0.95, 95% CI 0.91 routinely in many countries, overdiagnosis is a recog- to 0.99) [4]. Multiple international guidelines now rec- nised risk and consideration when counselling women ommend screening for lung cancer in high-risk smoking [15]. populations with LDCT, with South Korea implementing There has been no previously published systematic a national screening program [5] and the USA funding review of the prevalence of subclinical lung cancer diag- screening in individuals meeting criteria (current or for- nosed at autopsy. However, in one Swedish autopsy study mer smokers with ≥20 pack-year history, quit ≤15 years of 7020 adults with a mean age of 55 years for men and ago, and aged between 50 and 80 years old) [6]. 58 years for women, only 5 had a post-mortem diagno- Whilst there are limited data on the harms of LDCT sis of subclinical lung cancer (0.07% prevalence) [16]. screening, one significant consideration is the risk of This review is not only useful in the discussion around overdiagnosis. Overdiagnosis refers to detection and lung cancer screening, but also to explore potential asso- diagnosis of lung cancer that would never have caused ciations between demographics and subgroups regarding the patient harm or death [7]. In lung cancer, there possible predictors for subclinical lung cancer. remains some uncertainty about the extent of overdiag- This review aims to describe the prevalence (or res - nosis, with the meta-analysis of lung cancer screening ervoir) of subclinical lung cancer detected at autopsy in in high-risk groups with LDCT RCTs reporting an esti- adults. mated range of 0 to 36% of lung cancers being overdiag- nosed at 10 or more years [4]. This estimate was graded Methods low certainty evidence due to the quality of the studies The systematic review was registered with the Inter - and heterogeneity. Overdiagnosis of lung cancer can national Prospective Register of Systematic Reviews cause harm by resulting in unnecessary investigations (PROSPERO registration: CRD42020140747) and report- and treatment (most commonly surgery in early-stage ing has been guided by the Preferred Reporting Items for disease), along with associated complications and cost. Systematic Reviews and Meta-analyses (PRISMA) check- There are many different histological subtypes of lung list [17]. cancer as defined by the World Health Organization (WHO) [8]. Of note, in the systematic review of LDCT Criteria for considering studies for this review lung cancer screening RCTs in high risk populations, We considered all studies with more than 100 autopsies the longer-term results (≥ 7 years post-randomisation), in adults (aged 18 or over) who were not known to have demonstrated probably no difference in the prevalence of lung cancer ante-mortem. We included studies which small cell lung cancer (SCLC) and squamous cell carci- specified information about whether lung cancer caused noma between the groups who received LDCT screening or contributed to death or was subclinical. and those who did not [4]. Conversely, adenocarcinoma was more prevalent in the LDCT screening group com- Search methods for identification of studies pared to the control group. This is potentially related to We searched EMBASE, PubMed, and MEDLINE data- the more variable volume doubling time (VDT) of ade- bases from inception until March 2022 using the follow- nocarcinomas, with the micropapillary subtype having ing search strategy. Bonney et al. BMC Cancer (2023) 23:794 Page 3 of 11 1. exp Lung Neoplasms/. author (RM) was consulted if required to reach consen- 2. (lung* adj3 (neoplasm* or neoplasia* or cancer* sus. We considered the following domains. or carcinoma* or adenocarcinoma* or tumour* • Selection bias -patient selection: we scored ‘low risk’ or tumor* or malignan* or pre-malignan* or when consecutive autopsy cases were included and premalignan*)).tw. there was avoidance of inappropriate exclusions, 3. Autopsy/. ‘high risk’ when non-consecutive autopsy cases were 4. (autops* or post-mortem* or post mortem*).tw. enrolled and/or there were inappropriate exclusions, 5. (#1 or #2) AND (#3 or#4). and ‘unclear risk’ when there was insufficient 6. limit 5 to humans. information to make this judgement. At least two review authors (AB, MN, KS, KT) indepen- • Detection bias- autopsy procedure: we scored dently screened all titles and abstracts retrieved by elec- ‘low risk’ when autopsies were standardised, lung tronic searches using Covidence [18]. At least two review examination methods were described, and there authors (AB, MN, KT) then obtained the full texts for all was adequate correlation with medical history, ‘high relevant studies and independently checked eligibility of risk’ when there was non-standardised approach each study against review eligibility criteria. We resolved to autopsy or inadequate correlation with medical discordant evaluations by discussion to reach consensus, history, and ‘unclear risk’ when there was insufficient and when necessary, involved a third review author (RM). information to make this judgement. We report the search results and study selection process • Detection bias- clinical criteria: we scored ‘low risk’ using a PRISMA flow diagram [ 17]. when studies described adequate detail on methods The review authors (AB, RM) developed a data extrac - used to classify lung cancer as incidental as opposed tion form of which parts were adapted from the Check- to clinically significant, ‘high risk’ when there was list for Prevalence Studies [19]. Two review authors (AB no differentiation between subclinical and clinically and KT) independently extracted relevant data and per- significant, and ‘unclear risk’ when there was formed a cross-check. If required, a third review author insufficient information to make this judgement. (RM) was consulted to reach consensus. We were not • Incomplete outcome data: we scored ‘low risk’ when blinded to publication details. When there were multiple all autopsy cases were included in results, ‘high risk’ publications related to the same study, we chose the pub- when not all cases where included, ‘unclear risk’ lication with the primary outcome as the study identifier. when there was insufficient information to make this When data was missing or unsuitable for analysis, we judgement. (AB) contacted study authors to request further informa- • External validity-generalisability: we scored ‘low tion using email addresses from study reports or registers risk’ when the study participants were representative where available. of the population, ‘high risk’ when they were not We collected the following data. representative, and ‘unclear risk’ when there was • Source: citation, contact details. insufficient information to make this judgement. • Eligibility criteria and reasons for exclusion. • Other sources of bias: we scored ‘low risk’ when • Methods: study design, total duration of study, the study did not appear to have other sources of number of centres and locations, autopsy rate. bias, ‘high risk’ when there was at least one other • Characteristics of participants: number of important bias, for example, deviations to protocol, participants, demographics (age, sex, exposures, lung and ‘unclear risk’ when there was insufficient cancer risk factors, co-morbidities). information to make this judgement. • Autopsy: methodology. • Results: lung cancer diagnoses, histology, stage of Analysis lung cancer, cause of death. We performed meta-analyses of prevalence using a ran- • Miscellaneous: funding source, conflicts of interest. dom intercept logistic regression model in R version There were no validated tools for assessing the quality of 4.2.2 [22], using the packages ‘meta’ version 6.0 [23] and autopsy studies for prevalence of subclinical cancer. The ‘metafor’ version 3.8 [24]. The results of the meta-analy - authors (AB and RM) developed a risk of bias (RoB) tool ses were presented visually using forest plots. Statistical with components adapted from previous tools used in heterogeneity of prevalence between pooled studies was prevalence and diagnostic accuracy studies [20, 21]. Two evaluated using I statistic and between-study variance review authors (AB and KT) independently applied the with tau [25]. RoB tool to assess quality of included studies. We rated We performed subgroup analyses for the following; each domain of the tool as having ‘low’, ‘high’, or ‘unclear 1. Consecutive versus non-consecutive case selection. risk of bias for each study and supported the rating of 2. Setting – hospital or forensic versus population- each domain with a brief description. A third review based studies. Bonney et al. BMC Cancer (2023) 23:794 Page 4 of 11 3. Location – continent. Results 4. Age – median/mean study age of 40–59 years, 60–89 Results of the search years, and 90 or greater years. 5233 citations were identified during our database search, 5. Risk factors. of which 170 were selected for full text review. 4501 6. Histological types. records were excluded after review of the title and/or 7. Lung cancer stage. abstract as they were judged irrelevant. 13 studies (with a Sex was assessed using mixed-effects model meta-regres - total of 15 citations) with a total of 16 730 autopsies were sion analyses. included in this systematic review. 155 studies did not We performed two sensitivity analyses (1) including meet inclusion criteria and were excluded, and reasons high quality studies only, i.e. excluding studies which are detailed in Fig. 1. potentially included people under the age of 18 years old, and (2) including those with low risk of bias autopsy Included studies procedures. Of the 13 studies, 6 were conducted in North America Publication bias was assessed using the Luis Furuya- [26–31], 5 in Europe [16, 32–36], and 2 in Asia [37–39] Kanamori asymmetry index (LFK index) and the Doi (Table 1). plot. Fig. 1 Study selection flow diagram Bonney et al. BMC Cancer (2023) 23:794 Page 5 of 11 Table 1 Characteristics of 13 included studies Study and Country Median year Study Num- Consecutive Median age at Fe- Sources of funding Year of when au- Population ber of Death, range(years) male and Conflicts of Publication topsies were Autopsies (%) Interest (COI) performed Examined Berezowska Switzerland 2017 Hospital 189 Yes 69, 26–104 63 No external funding. 2021(32) (50) No COI declared. Burrows USA 1973 Hospital 252 NS NS (inclusion of NS NS 1975(26) adults only) Gezelius. Sweden 1982 Forensic 7020 Yes Median age not NS NS 1988(16) specified. Mean age for men 55 years +/- 20 years SD. Mean age for women 58 years +/- 21 years SD Hudak 2022 Hungary 1994** Stroke 534 Yes Median age not 251 National Research, (33, 34) specified. Mean age (47) Development and 70.4 +/- 12.6 years Innovation Fund, SD (adults only GINOP-2.3.2-15- included)** 2016-00048 (Stay Alive), ELKH-DE Cerebrovascular and Neurodegenerative Research Group. No COI declared. Imaida 1997 Japan 1988 Hospital 871 NS Estimated median 510 Grant in aid for can- (37) 82, 48 to 100+ (59) cer research from the Ministry of Health and Welfare, Japan. Grant from the Society of Promo- tion of Toxicologic Pathology. COI NS. Ishii 1979 Japan 1966 NS 1366 NS Estimated median 432 NS (38, 39) 67, 65+ (35) Murphy 1977 USA 1977* Forensic 1300 Yes NS NS NS (27) Rosenblatt USA 1966 Hospital 466 NS NS NS NS 1973 (28) Sclare Scotland 1979* (based Hospital 143 No NS, 90–100 years old 91 NS 1991(35) on 24-year pe- (64) riod and date published) Sens 2009 USA 2009 (date Majority of 412 NS NS. Mean age 62 155 NS (29) published)* cases forensic years for unsuspect- (38) ed cancers. Stanta 1997 Italy 1967 (based General, older 267 No NS, 95–106 214 NS (36) on 20-year population (80) time frame and publica- tion 1997)* Suen 1974 USA 1965 Hospital 3535 Yes Estimated median 1693 NS (30) 70, 66–107 (48) Torbenson USA 1989 Transplant 375 Yes NS. Mean age 46, SD 158 NS 2001 (31) 11 years (42) *Estimated based on stated timeframe or year of publication if not otherwise stated ** Confirmed with authors NS = not specified Bonney et al. BMC Cancer (2023) 23:794 Page 6 of 11 Ishii 1979 [38, 39] was the earliest study to commence included people 65 years and older. Sclare 1991 [35] in 1955, with three other studies having an end date restricted subjects to those aged 90 to 100 years old before 1979 [26, 28, 30]. Four studies ended between and Stanta 1997 [36] included only those aged 99 years 1980 and 1999 [16, 31, 33, 37]. The most recent study to and older in the analysis. Murphy 1977 [27] comprised conclude was Berezowska 2021 [32] in 2017. Four studies of autopsies completed by the author exclusively. Three did not specify the specific decade autopsies were con - studies had specific co-morbid cohorts [ 28, 31, 33]. ducted (Sclare 1991 [35], Sens 2009 [29], Murphy 1977 Hudak 2022 [33] included participants who had a stroke [27], Stanta 1997 [36], although Stanta 1997 [36]reported and died. Rosenblatt 1973 [28] included only those who a 20-year period for autopsies, Sens 2009 [29]reported a had a malignant disease listed as the cause of death. Tor- 5-year period of autopsies, and Sclare 1991 [35] reported benson 2001 [31] included patients who had died within a 24-year period for autopsies. 100 days of a solid organ transplant. Four studies did not Five studies (Berezowksa 2021 [32], Gezelius 1988 [16], adequately specify age inclusions to determine children Burrows 1975 [26], Sens [29], Imaida 1997 [37] included were excluded with certainty [16, 27–29]. Ten studies did all autopsies performed during the study period at their not have any specified exclusion criteria [ 16, 26–28, 30, institution. Berezowska 2021 [32] included all adults 18 32, 33, 35, 36, 39]. Imaida 1997 [37] specified cases with years and older. Burrows 1975 [26] also included adults incomplete autopsy records were excluded and Torben- only. Two studies, Ishii 1979 [39] and Suen 1974 [30], son 2001 [31] specified cases with incomplete autopsies were excluded. Sens 2009 [29] excluded cases of intra- uterine foetal demise, skeletal remains, and externally referred neuropathology cases. Autopsy procedure and thoroughness of examination for included studies are detailed in table S1 (supplemen- tary materials). Of the 13 studies, five studies (Gezelius 1988, Imaida 1997, Ishii 1979, Sclare 1991 and Santa 1997) had pri- mary objectives focused on malignancy. Four studies (Rosenblatt 1973, Sens 2009, Suen 1974, and Torbenson 2001) had a primary objective focused on subclinical or clinically unsuspected cancer. Three studies (Berezowska 2021, Burrows 1975, and Hudak 2022) primarily focused on diagnostic accuracy and the value of autopsy. One study (Ishii 1979) had no specified objective other than to present autopsy findings in general. Excluded studies We excluded 155 studies. 107 for wrong outcomes, 29 had the wrong patient population, 9 studies were the wrong study design, 8 studies were abstracts only and provided insufficient information to evaluate eligibility for inclusion, and 2 studies were duplicates. Risk of bias We performed risk of bias assessment for all included studies and summarised the results in Fig.  2. Justifica - tions for grading are detailed in table S2 (supplementary materials). Outcomes Prevalence of lung cancer in the included studies is sum- marised in Table 2. Given the small number of lung can- cers diagnosed antemortem or post-mortem cause of death, the total autopsy denominator was not adjusted to calculate prevalence of subclinical lung cancer as Fig. 2 Risk of bias summary Bonney et al. BMC Cancer (2023) 23:794 Page 7 of 11 Table 2 Lung cancer prevalence Total # of Autopsies # Subclinical lung cancers # Lung cancers diagnosed # Lung cancers Examined diagnosed post-mortem (%) post-mortem and COD diagnosed antemortem Gezelius. 1988(16) 7020 5 (0.07) 12 8 Suen 1974 (30) 3535 47 (1.33) 0* 182 Ishii 1979 (38, 39) 1366 5 (0.37) 0* 120 Murphy 1977 (27) 1300 1 (0.08) 0 2 Imaida 1997 (37) 871 23 (2.64) NS 50 Hudak 2022 (33, 34) 534 1 (0.19) 0 NS Rosenblatt 1973 (28) 466 0 (0) 0 27 Sens 2009 (29) 412 4 (0.97) 4 1* Torbenson 2001 (31) 375 2 (0.53) 0* 0* Stanta 1997 (36) 267 2 (0.75) 1 0 Burrows 1975(26) 252 2 (1.40) 0 NS Berezowska 2021(32) 189 5 (0.07) NS 16 Sclare 1991 (35) 143 47 (1.33) 0 2 NS = not specified, * indicates number calculated from paper corresponding data were often not available for sub- 1. Asia: Two studies [37, 39] were included in this groups and the authors judged the impact to be small. analysis. Pooled prevalence was 1.01% (95% CI 2 2 We pooled the prevalence of subclinical lung can- 0.25 to 4.04%, I = 94%, tau = 0.93, 2237 autopsies). cers diagnosed post-mortem for all 13 trials. The evi - 2. Europe: Five studies [16, 32, 33, 35, 36] were dence showed a pooled prevalence of 0.4% (95% CI 0.20 included in this analysis. Pooled prevalence was 2 2 2 2 to 0.82%, I = 84%, tau = 1.19; low certainty evidence, 16 0.27% (95% CI 0.09 to 0.84%, I = 76%, tau = 0.88, 730 autopsies, Fig.  3a). Heterogeneity amongst studies 8153 autopsies). was high, with Imaida 1997 [37] having a higher preva- 3. North America: Six studies [26–31] were included lence than the other included studies. Imaida 1997 [37] in this analysis. Pooled prevalence was 0.37% 2 2 was conducted in Japan and recruited from a hospital (95% CI 0.13 to 1.07%, I = 54%, tau = 0.98, 6340 population with a median age of 82 years and the primary autopsies). objective. We performed a sensitivity analysis excluding There was no statistically significant difference between studies which did not specify exclusion of children (< 18 subgroups. Test for subgroup differences: Chi = 2.09, years old) in their cohort [16, 27–29]. Nine studies were df = 2 (p = 0.35). included in the analysis, with a pooled prevalence of • By age: Ten studies provided information regarding subclinical lung cancer of 0.74% (95% CI 0.40 to 1.37%, age. Analysis provided in supplementary material 2 2 I = 71%, tau = 0.49, 7532 autopsies, Fig.  3b). Heteroge- (Figure S2 supplementary materials). neity amongst studies was high, however had decreased 1. For those with a median or mean age of 40 to 59 comparatively. years old [16, 31]: prevalence of subclinical lung When we performed another sensitivity analysis of cancer was 0.13% (95% CI 0.03 to 0.59%, I = 83%, studies with low risk of bias for autopsy procedure. Four tau = 0.47, 7385 autopsies). Gezelius 1988 [16] did studies were included [30, 32, 37, 39], with a pooled not clearly exclude children, when this study was prevalence of 1.02% (95% CI 0.45 to 2.20%, I = 85%, removed from the analysis, prevalence was 0.52% tau = 0.51, 5961 autopsies). (91% 0.06 to 1.91%, 1 study [31], 375 autopsies). We performed a meta-regression analysis (proportion 2. For those with a median or mean age of 60 to 89 male) using the 9 available studies [29–33, 35–37, 39] years old [29, 30, 32, 33, 37, 39]: prevalence of which showed no statistically significant association with subclinical lung cancer was 0.81% (95% CI 0.0.38 2 2 sex, with an odds ratio (OR) = 0.085 (95% CI: 0.003, 2.55; to 1.69%, I = 79%, tau = 0.57, 6907 autopsies p = 0.155). Sens 2009 [29] did not clearly exclude children, We performed the following subgroup analyses. when this study was removed from the analysis, • By location: All 13 studies were included in prevalence was 0.76% (95% CI 0.31 to 1.86%, 2 2 this analysis by continent. Analysis provided in I = 83%, tau = 0.0.78, 5 studies, 6495 autopsies). supplementary material (Figure S1 supplementary 3. For those with a median or mean age of ≥90 years materials). old [35, 36]: prevalence of subclinical lung cancer 2 2 was 0.98% (95% CI 0.37 to 2.57%, I = 0%, tau = 0, Bonney et al. BMC Cancer (2023) 23:794 Page 8 of 11 Fig. 3 (a) Pooled prevalence of subclinical lung cancer (all studies). (b) Pooled prevalence of subclinical lung cancer (studies which specified children were not included) 410 autopsies). All studies clearly specified they category to proceed. Only three studies reported stages did not include children. of subclinical lung cancers diagnosed post-mortem [26, There was no statistically significant difference between 27, 31]. Burrows 1975 [26] reported one case of stage 4 subgroups. Test for subgroup differences: Chi = 5.29, lung cancer. Murphy 1977 [27] and Torbenson 2001 [31] df = 2 (p = 0.07). reported 1 and 2 cases of stage 1 lung cancer respectively. Subgroup analyses by patient selection and setting, study There was inadequate information provided in the period presented in Table S3, Figure S3, Figure S4, and studies to perform analyses looking at risk factors includ- Figure S5 (supplementary materials). There were no sta - ing smoking status. tistically significant differences in subgroup analyses. The LFK index was 4.32, with significant asymmetry Pooled analyses for histology were performed separately (Doi plot presented in Figure S6 of the supplementary for cancer subtypes and were also summarised in Table materials). S3 (supplementary materials). We attempted analysis of studies by stage, however there was insufficient number of studies within each Bonney et al. BMC Cancer (2023) 23:794 Page 9 of 11 Discussion reviews in other types of cancer (breast, prostate, and Our systematic review of 13 studies of 16 730 autopsies thyroid), was significantly lower [ 10–12]. across seven countries and seven decades demonstrated The strengths of this review include its comprehen - a pooled prevalence of 0.4% for subclinical lung cancer sive search strategy, with no language barriers, and thor- diagnosed post-mortem. When sensitively analysis was ough evaluation of study methodology. However, there performed excluding studies which did not clearly pro- were some limitations. Firstly, this systematic review and vide age ranges, the pooled prevalence was 0.74%. The search focused on post-mortem diagnoses of lung can- LFK index did demonstrate asymmetry, suggestive of cer, and as such studies which evaluated for pre-cursor possible small study effects, with a larger prevalence esti - lesions only were excluded. Two autopsies series which mate and less precision potentially overestimating the have evaluated precursor adenocarcinoma lesions are prevalence. Sterner 1997 [44] and Yokose 2000 [45]. Sterner 1997 [44] To our knowledge this is the first systematic review was a review of 100 consecutive autopsies in the USA of the prevalence of subclinical lung cancer detected at and found two cases of atypical alveolar cell hyperplasia autopsies in adults. Strauss 1993 [40] conducted a brief in a general autopsy population. Yokose 2000 [45] was an narrative review of subclinical lung cancer diagnosed at autopsy series of 241 cases in Japan and found 16 people autopsy, however the autopsy cases were contaminated had evidence of atypical adenomatous hyperplasia. Sec- with clinically unsuspected lung cancer which was the ondly, it should be acknowledged that the background cause of death. There was one large autopsy study that rates of CT in each country during the autopsy period was excluded from this review as the cohort included was not readily available. None of the included studies children [41]. Karwinski 1990 [41] was Norwegian series had the primary aim focused on subclinical lung cancer of 21, 530 autopsies conducted in people aged 1 to 99 diagnosed at autopsy. In one excluded retrospective study years old. The age range for subclinical lung cancers was [46] which had the primary aim of detecting subclinical 40 to 93 years old and there were 14 cases diagnosed lung cancer at autopsy, 47 cases were found amongst 24. post-mortem (0.65% prevalence), similar to the findings 708 autopsies in a coronial population (0.34% prevalence, in this review. Our results are also reasonably consistent 95% CI 0.24 to 0.44%). This study was excluded as the with the meta-analysis of LDCT lung cancer screen- population included children, although the median age ing RCTs (in studies with at least 10 years of follow up) was 67 years old. which estimated 7 cases of lung cancer overdiagnosis for The evidence in this review is low certainty due to the every 1000 people screened (95% CI of 2 to 84 cases) [4]. risk of bias in included studies, possible publication bias It should be noted that the study population in the RCTs and small study effect, and the significant heterogene - were high-risk populations for lung cancer with smoking ity between studies. However, in the case of prevalence histories, as opposed to the general population. The larg - studies, heterogeneity may also provide confidence that est lung cancer screening with LDCT RCT, the National the outcome is relevant to a wider population and was Lung Screen Trial (NLST), reported at 11.3 year follow- present in other autopsy reviews [12]. Most studies were up a lung cancer incidence of 1701 cases in the LDCT published before the year 2000 and descriptions of the screening group (6.3% of their LDCT cohort) [42]. Risk of population and methodology were limited. Pooled prev- overdiagnosis is challenging to assess in the NLST given alence increased with decade of publication with those the comparison group received CXR. After 10 years of published earlier having a lower pooled prevalence. Most follow-up, the Dutch–Belgian lung-cancer screening trial study periods were before 1999, with only 601 autopsies (Nederlands–Leuvens Longkanker Screenings Onder- being conducted after the year 2000. As such, consider- zoek [NELSON]) reported a cumulative incidence of ation regarding background smoking rates, use of ciga- 344 lung cancers in their LDCT screening group, data rette filters, environmental exposures should be given. for male participants only provided (5.2% of their male There were concerns listed about the thoroughness of LDCT screening cohort) [43]. The cumulative incidence autopsies in some studies which may have underesti- of lung cancer amongst male participants in NESLON mated the prevalence of lung cancers, particularly in trial control group was 4.6%. With an extended follow- detecting subsolid or ground glass lesions. The sensitiv - up to 11 years post randomisation, the NELSON study ity analysis in this review including only those studies estimated an excess-incidence overdiagnosis rate of 8.9% with a low risk of bias for autopsy procedure had a higher (95% CI -18.2 to 32.4%) [43]. It is clear screening detects pooled prevalence of subclinical lung cancer, however both clinically relevant lung cancers and those which may confidence intervals were overlapping. A previous study not progress to cause symptoms or death. in the USA compared 28 patients with post-mortem The pooled prevalence described in this review rep - examinations who had had a CT within 2 months of resents the best available estimate of the reservoir of their death [47]. They found that 19 patients had nodules subclinical lung cancer to date and compared to similar 15  mm or less in diameter noted on CT and 9 patients Bonney et al. BMC Cancer (2023) 23:794 Page 10 of 11 PRISMA Preferred Reporting Items for Systematic Reviews and had no mention of nodules on autopsy. This may suggest Meta-analyses RCT Randomised controlled trial the limitations of autopsy and need for high quality stud- RoB Risk of bias ies, although it could also be the result of interval lesion SCLC Small cell lung cancer resolution. USA United States of America VDT Volume doubling time Only five studies reported histology of subclinical lung WHO World Health Organization cancers, with a pooled prevalence of 0.14%, 0.11%, 0.11%, 0.05% for NSCLC not otherwise specified, adenocarci - noma, squamous cell carcinoma (SCC), and bronchoal- Supplementary Information The online version contains supplementary material available at https://doi. veolar carcinoma (BAC) respectively. This was a small org/10.1186/s12885-023-11224-3. cohort, with only 1840 autopsies included. Interestingly, in LDCT screening RCTs, whilst at baseline screening Supplementary Material 1 SCC, adenocarcinoma and BAC are more common in the LDCT screening compared with the control groups, Acknowledgements at later time points, only adenocarcinoma and BAC We would like to thank Catherine Voutier, The Royal Melbourne Hospital, for her assistance designing the search strategies. We would like to thank study remain more prevalent in the LDCT cohort [4]. Whilst author Lilla Hudak for response to our queries. adenocarcinoma-spectrum lesions growth patterns are more associated with overdiagnoses [9], due to the risk Authors contributions Design of the protocol: AB, KS, RMSelection of studies: AB, KT, MN, KS, RMData of competing mortality in those with a history of tobacco extraction and management: AB, KT, RMAssessment of risk of bias: AB, KT, exposure, there is the potential for all histological types RMDealing with missing data: ABData analysis: AB, CPManuscript preparation: in lung cancer may be overdiagnosed. AB, KT, MN, MC, KF, HM, KS, CP, DS, RM. Whilst there were no statistically significant differ - Funding ences between the subgroups, there were some trends Asha Bonney has a Postgraduate Scholarship from the Australian National observed. The pooled prevalence based on patient selec - Health and Medical Research Council. Kwun Fong has an Australian Medical Research Future Fund Fellowship. tion demonstrated a lower prevalence of subclinical lung cancers in studies which recruited consecutively, Data Availability compared to those which were non-consecutive. Stud- All data analysed during this review are included in this published article and its supplementary information files. ies from Asia (both studies were conducted in Japan) had the highest pooled prevalence compared to Europe and Declarations North America. With both Imaida 1997 and Ishii 1979 also having a low risk of bias for autopsy procedure. This Competing interests may reflect the importance of race as a risk factor for The authors declare no competing interests. lung cancer development, particularly low VDT adeno- Ethics approval and consent to participate carcinoma, which may contribute to higher risks of over- Not applicable. diagnosis in certain populations [48]. The prevalence also Consent for publication increased with age and is significant as most screening Not applicable. programs are targeting those aged 50 to 80 years old. In order to advance our understanding about the risk of Received: 10 April 2023 / Accepted: 25 July 2023 overdiagnosis with lung cancer screening and the natural history of lung cancer, more information is needed. Fur- ther research is required regarding the reservoir of pre- cursor lung lesions and high-quality, prospective studies assessing post-mortem diagnosis of subclinical lung can- References 1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et cer in adult populations, including those who would be al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and eligible for lung cancer screening. Mortality Worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. 2. Fidler-Benaoudia MM, Torre LA, Bray F, Ferlay J, Jemal A. Lung cancer inci- Conclusions dence in young women vs. young men: a systematic analysis in 40 countries. This review has found that the reservoir for subclinical Int J Cancer. 2020;147(3):811–9. lung cancer is relatively small in published autopsy series, 3. Registry VC. Lung cancer factsheet Australia: Cancer Council Victoria; 2021 [updated 10/05/2021. Available from: https://www.cancervic.org. suggesting a relatively low risk of overdiagnosis with au/research/vcr/fact-sheets-and-annual-reports/lung-cancer-factsheet. screening compared with breast, prostate and thyroid html#:~:text=Figure%203%20shows%20that%20since,0.3%25%20per%20 cancer. . year%20in%20females. 4. Bonney A, Malouf R, Marchal C, Manners D, Fong KM, Marshall HM, et al. List of abbreviations Impact of low-dose computed tomography (LDCT ) screening on lung LDCT L ow-dose computed tomography cancer-related mortality. Cochrane Database Syst Rev. 2022;8(8):Cd013829. LFK Luis Furuya-Kanamori asymmetry index Bonney et al. BMC Cancer (2023) 23:794 Page 11 of 11 5. Park J, Lee J, Kim Y. Public opinion on implementing the National Lung 27. Murphy GK. Cancer and the coroner. JAMA. 1977;237(8):786–8. Cancer Screening Program in Korea. Translational Lung Cancer Research. 28. Rosenblatt MB, Teng PK, Kerpe S. Diagnostic accuracy in cancer as deter- 2021;10(3):1355–67. mined by post mortem examination. Prog Clin Cancer. 1973;5:71–80. 6. Division of Cancer Prevention and Control CfDCaP. Who Should Be Screened 29. Sens MA, Zhou X, Weiland T, Cooley AM. Unexpected neoplasia in autopsies: for Lung Cancer? USA: U.S. Department of Health and Human Services 2022 potential implications for tissue and organ safety. Arch Pathol Lab Med. [updated 25/10/2022. Available from: https://www.cdc.gov/cancer/lung/ 2009;133(12):1923–31. basic_info/screening.htm#:~:text=The%20only%20recommended%20 30. Suen KC, Lau LL, Yermakov V. Cancer and old age. An autopsy study of 3,535 screening%20test,or%20history%20of%20that%20disease. patients over 65 years old. Cancer. 1974;33(4):1164–8. 7. Brodersen J, Voss T, Martiny F, Siersma V, Barratt A, Heleno B. Overdiagnosis of 31. Torbenson MS, Wang J, Nichols L, Jain AB, Fung JJ, Nalesnik MA. Occult lung cancer with low-dose computed tomography screening: meta-analysis nonhematopoietic malignancies present at autopsy in solid organ transplant of the randomised clinical trials. Breathe (Sheff ). 2020;16(1):200013. patients who died within 100 days. Transplantation. 2001;71(1):64–9. 8. Nicholson AG, Tsao MS, Beasley MB, Borczuk AC, Brambilla E, Cooper WA, et al. 32. Berezowska S, Schmid A, Losmanová T, Trippel M, Blank A, Banz Y et al. The 2021 WHO classification of lung tumors: impact of advances since 2015. J Frequency and significance of pathologic pulmonary findings in Postmor - Thorac Oncol. 2022;17(3):362–87. tem Examinations-A single Center experience before COVID-19. Diagnostics 9. Park S, Lee SM, Kim S, Lee J-G, Choi S, Do K-H, et al. Volume doubling Times of (Basel). 2021;11(5). Lung Adenocarcinomas: correlation with predominant histologic subtypes 33. Hudák L, Nagy AC, Molnár S, Méhes G, Nagy KE, Oláh L, et al. Discrepancies and prognosis. Radiology. 2020;295(3):703–12. between clinical and autopsy findings in patients who had an acute stroke. 10. Thomas ET, Del Mar C, Glasziou P, Wright G, Barratt A, Bell KJL. Prevalence of Stroke Vasc Neurol. 2022;7(3):215–21. incidental breast cancer and precursor lesions in autopsy studies: a system- 34. Hudak LNAC, Mehes G, Molnar S, Nagy K, Olah L, Csiba L. Is the autopsy atic review and meta-analysis. BMC Cancer. 2017;17(1):808. stillvaluable the brain and bodyautopsy results of 534 stroke patients. Int J 11. Bell KJ, Del Mar C, Wright G, Dickinson J, Glasziou P. Prevalence of inciden- Stroke. 2020;15(142). tal prostate cancer: a systematic review of autopsy studies. Int J Cancer. 35. Sclare G. Malignancy in Nonagenarians. Scot Med J. 1991;36(1):12–5. 2015;137(7):1749–57. 36. Stanta G, Campagner L, Cavallieri F, Giarelli L. Cancer of the oldest old. What 12. Furuya-Kanamori L, Bell KJL, Clark J, Glasziou P, Doi SAR. Prevalence of differ - we have learned from autopsy studies. Clin Geriatr Med. 1997;13(1):55–68. entiated thyroid Cancer in autopsy studies over six decades: a Meta-analysis. 37. Imaida K, Hasegawa R, Kato T, Futakuchi M, Takahashi S, Ogawa K, et al. Clini- J Clin Oncol. 2016;34(30):3672–9. copathological analysis on cancers of autopsy cases in a geriatric hospital. 13. Force UPST. Screening for thyroid Cancer: US Preventive Services Task Force Pathol Int. 1997;47(5):293–300. Recommendation Statement. JAMA. 2017;317(18):1882–7. 38. Ishii T, Hosoda Y, Maeda K. Cause of death in the extreme aged–a patho- 14. Mottet N, van den Bergh RCN, Briers E, Van den Broeck T, Cumberbatch MG, logic survey of 5106 elderly persons 80 years old and over. Age Ageing. De Santis M, et al. EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate 1980;9(2):81–9. Cancer-2020 update. Part 1: screening, diagnosis, and local treatment with 39. Ishii T, Maeda K, Nakamura K, Hosoda Y. Cancer in the aged: an autopsy study curative intent. Eur Urol. 2021;79(2):243–62. of 940 cancer patients. J Am Geriatr Soc. 1979;27(7):307–13. 15. Siu AL. Screening for breast Cancer: U.S. Preventive Services Task Force Rec- 40. Strauss GM, Gleason RE, Sugarbaker DJ. Screening for lung cancer re- ommendation Statement. Ann Intern Med. 2016;164(4):279–96. examined. A reinterpretation of the Mayo Lung Project randomized trial on 16. Gezelius C, Eriksson A. Neoplastic disease in a medicolegal autopsy material. lung cancer screening. Chest. 1993;103(4 Suppl):337s–41s. A retrospective study in northern Sweden. Z Rechtsmed. 1988;101(2):115–30. 41. Karwinski B, Svendsen E, Hartveit F. Clinically undiagnosed malignant 17. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. tumours found at autopsy. Apmis. 1990;98(6):496–500. The PRISMA 2020 statement: an updated guideline for reporting systematic 42. Lung Cancer Incidence. And Mortality with Extended follow-up in the reviews. BMJ. 2021;372:n71. National Lung Screening Trial. J Thorac Oncol. 2019;14(10):1732–42. 18. Innovation VH. Covidence systematic review software. 2021 ed. Melbourne, 43. de Koning HJ, van der Aalst CM, de Jong PA, Scholten ET, Nackaerts K, Heu- Australia. velmans MA, et al. Reduced lung-Cancer mortality with volume CT screening 19. Munn Z, Moola S, Lisy K, Riitano D, Tufanaru C. Methodological guidance in a Randomized Trial. N Engl J Med. 2020;382(6):503–13. for systematic reviews of observational epidemiological studies report- 44. Sterner DJ, Mori M, Roggli VL, Fraire AE. Prevalence of pulmonary atypical ing prevalence and cumulative incidence data. Int J Evid Based Healthc. alveolar cell hyperplasia in an autopsy population: a study of 100 cases. Mod 2015;13(3):147–53. Pathol. 1997;10(5):469–73. 20. Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, et al. 45. Yokose T, Ito Y, Ochiai A. High prevalence of atypical adenomatous hyperpla- QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy sia of the lung in autopsy specimens from elderly patients with malignant studies. Ann Intern Med. 2011;155(8):529–36. neoplasms. Lung Cancer. 2000;29(2):125–30. 21. Hoy D, Brooks P, Woolf A, Blyth F, March L, Bain C, et al. Assessing risk of bias 46. Manser RL, Dodd M, Byrnes G, Irving LB, Campbell DA. Incidental lung in prevalence studies: modification of an existing tool and evidence of inter - cancers identified at coronial autopsy: implications for overdiagnosis of lung rater agreement. J Clin Epidemiol. 2012;65(9):934–9. cancer by screening. Respir Med. 2005;99(4):501–7. 22. R Foundation for Statistical Computing. In: Foundation TR, editor. Vienna, 47. Dammas S, Patz EF Jr, Goodman PC. Identification of small lung nodules at Austria2022. autopsy: implications for lung cancer screening and overdiagnosis bias. Lung 23. Balduzzi S, Rücker G, Schwarzer G. How to perform a meta-analysis with R: a Cancer. 2001;33(1):11–6. practical tutorial. Evid Based Ment Health. 2019;22(4):153–60. 48. Gao W, Wen CP, Wu A, Welch HG. Association of Computed Tomographic 24. Viechtbauer W. Conducting Meta-analyses in R with the metafor Package. J Screening Promotion with Lung Cancer Overdiagnosis among Asian Women. Stat Softw. 2010;36(3):1–48. JAMA Intern Med. 2022;182(3):283–90. 25. Higgins JPTJ, Chandler J, Cumpston M, Li T, Page MJ, et al. editors. (s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.3 (updated February 2022 2022 [Available from: training.cochrane.org/ Publisher’s Note handbook. Springer Nature remains neutral with regard to jurisdictional claims in 26. Burrows S. The postmortem examination. Scientific necessity or folly? JAMA. published maps and institutional affiliations. 1975;233(5):441–3.

Journal

BMC Cancer – Springer Journals

Published: Aug 24, 2023

Keywords: Lung cancer; Subclinical; Latent; Screening; Overdiagnosis; Autopsy

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