Highlights
- Analysis of 1.48 million autopsies over 66 years in Japan reveals that 55.2% of cases included a cancer diagnosis.
- The prevalence of multiple primary cancers increased nearly eightfold, from 1.8% in 1974 to 14.4% in 2023.
- Latent cancers—malignancies undiagnosed during life—were detected in 7.4% of autopsies by 2023, up from 1.7% in 1986.
- Approximately 7.3% of these latent cancers already exhibited metastatic spread at the time of autopsy.
Introduction: Mapping the Submerged Iceberg of Malignancy
Conventional cancer statistics, primarily derived from clinical diagnoses and death certificates, represent only the tip of the epidemiological iceberg. For decades, clinicians and researchers have recognized a disconnect between the incidence of cancer observed in the clinic and the true prevalence of malignant neoplasms within the population. This ‘hidden burden’ includes latent cancers—tumors that remain asymptomatic and undiagnosed throughout a patient’s life, only to be discovered during postmortem examination.
Understanding the trends of these undiagnosed malignancies is critical for evaluating the efficacy of current screening programs, the accuracy of diagnostic technologies, and the potential for overdiagnosis. A landmark cohort study published in JAMA Network Open, spanning 66 years of autopsy data from Japan, provides an unprecedented longitudinal view of how the burden of cancer has shifted in one of the world’s fastest-aging societies.
Study Design: A 66-Year Pathological Record
This comprehensive cohort study utilized data from the Annual of the Pathological Autopsy Cases in Japan (APAC-J), a nationwide registry maintained by the Japanese Society of Pathology. The researchers analyzed 1,486,557 hospital-based autopsies recorded between 1958 and 2023. The study population had a mean age of 59.1 years and was 62.5% male.
The primary objectives were to evaluate the long-term trends in total, multiple, and latent cancers. Latent cancers were defined as malignant neoplasms that were not clinically suspected or diagnosed during the patient’s lifetime but were identified by pathologists during autopsy. The researchers also introduced the ‘enrichment ratio in autopsy,’ a novel metric comparing the prevalence of specific cancers in the autopsy registry with national mortality statistics to identify populations at high risk for undiagnosed disease.
The Evolution of Multiple Primary Cancers
One of the most striking findings of the study was the dramatic rise in multiple primary cancers. In 1974, only 1.8% of autopsy cases involving cancer featured more than one primary tumor. By 2023, this figure had surged to 14.4%. This trend likely reflects several factors, including increased longevity, which allows more time for independent oncogenic events to occur, and improved pathological techniques that allow for the differentiation of distinct primary sites versus metastatic spread.
For the modern oncologist, this rising incidence of multiple primaries complicates treatment paradigms. It necessitates more rigorous diagnostic workups to ensure that a second malignancy is not misidentified as a recurrence or metastasis of the first, as the therapeutic implications—ranging from surgical approach to systemic therapy selection—are vastly different.
Latent Cancers: The Hidden Burden Revealed
Since 1986, the registry has systematically tracked latent cancers. Out of 811,159 autopsies performed in this period, 36,133 latent cancers were identified in 34,174 individuals (4.2%). However, the detection rate has not remained static; it increased from 1.7% in 1986 to 7.4% in 2023.
This increase in latent cancer detection suggests a growing reservoir of undiagnosed disease in the population. While some of this increase may be attributed to more meticulous autopsy procedures, it also points to a biological reality: as the population ages, the prevalence of indolent or slow-growing malignancies increases. The study found that the ‘enrichment ratio’ was particularly elevated in two distinct groups: adolescents/young adults (aged 15–24) and the very elderly (aged 80 and older). In younger populations, this may reflect aggressive but rare malignancies that escape early detection, while in the elderly, it reflects the accumulation of chronic, age-related neoplasms.
Disproportionate Findings in Prostate and Thyroid Tissues
The discrepancy between clinical incidence and autopsy prevalence was most pronounced in prostate and thyroid cancers. For men aged 75 to 79, latent prostate cancer was identified in 4.5% of autopsies. When compared to clinical incidence data from 2017–2021, the autopsy prevalence was 6.9-fold higher.
The results for thyroid cancer were even more dramatic. In the 50-to-54 age group, latent thyroid cancer was found in 0.9% of men and 1.7% of women. These figures represent a 94.5-fold and 60.7-fold higher prevalence, respectively, than clinical incidence rates. These findings provide strong pathological evidence for the phenomenon of overdiagnosis, particularly in thyroid and prostate tissues, where many detected tumors may never have caused clinical symptoms or death had the patient lived longer.
Metastatic Potential in Latent Tumors
A critical question in the study of latent cancer is whether these ‘hidden’ tumors are truly indolent or if they represent missed opportunities for life-saving intervention. The researchers found that 7.3% (2,649 of 36,133) of latent cancers had already metastasized by the time of autopsy. This finding is sobering, as it indicates that a non-negligible portion of undiagnosed cancers possessed significant biological aggression.
The presence of metastasis in latent cases underscores the ongoing need for improved diagnostic sensitivity. While the overdiagnosis of indolent tumors is a valid concern, the ‘underdiagnosis’ of aggressive, metastatic-capable tumors remains a significant clinical challenge that contributes to cancer mortality.
Expert Commentary: Navigating the Overdiagnosis Dilemma
The Japanese autopsy data presents a dual challenge to modern medicine. On one hand, the massive discrepancy between clinical and pathological prevalence in thyroid and prostate cancers supports a more conservative approach to screening in certain low-risk populations to avoid the harms of overtreatment. On the other hand, the rise in latent cancers with metastatic potential suggests that our current diagnostic net is still failing to catch some lethal malignancies.
The study’s ‘enrichment ratio’ provides a sophisticated way to view this. By identifying specific age groups where the autopsy prevalence vastly exceeds clinical mortality (such as the 15-24 age bracket), researchers can pinpoint where diagnostic innovation is most urgently needed. Furthermore, the rising trend of multiple primary cancers suggests that survivors of one cancer require lifelong surveillance for entirely new malignancies, rather than just monitoring for recurrence.
Conclusion
This 66-year analysis of over 1.4 million autopsies clarifies the shifting landscape of cancer in Japan. It highlights a substantial and growing reservoir of undiagnosed cancer, a significant rise in multiple primary malignancies, and the persistent reality of metastatic disease that escapes clinical detection. These findings underscore the enduring value of the autopsy as a ‘gold standard’ for epidemiological truth. For the clinical community, the study serves as a call to refine screening strategies—striving for the ‘Goldilocks zone’ of oncology: detecting the lethal while sparing the indolent.
References
- Uozaki H, Kikuchi Y, Watanabe M, et al. Trends in the Hidden Burden of Cancer in an Autopsy-Based Study Over 66 Years in Japan. JAMA Netw Open. 2026;9(2):e2557812.
- Welch HG, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst. 2010;102(9):605-613.
- Japanese Society of Pathology. Annual of the Pathological Autopsy Cases in Japan. Tokyo, Japan.