By: Dan Sperling, MD

When scientists talk about the natural history of a disease, they are referring to the course of the disease if left untreated. The natural course of an infectious illness caused by exposure to a bacterial or viral agent begins with an incubation period in which the patient is unaware of a problem. Then symptoms develop along with a period of unwellness that usually culminates in a return to health. In the case of a chronic disease like cancer, the period before symptoms appear is called the subclinical or latency period, after which most untreated cancerous tumors progress in size and aggressiveness until they spread (metastasize) to other locations in the body and result in death. The rate of progression can vary widely from one type of cancer to another.

For decades, efforts have been made to identify the natural history of prostate cancer (PCa). The notion that a man is more likely to die with PCa rather than from PCa was based in observations of slow growing or indolent disease in the majority of cases. According to Popiolek et al. (2013), “Most localized prostate cancers are believed to have an indolent course. Within 15 years of diagnosis, most deaths among men with prostate cancer (PCa) can be attributed to other competing causes.”[i] Many scientists and clinicians theorize that Gleason grade 3+3 does not even behave like cancer and may never progress. They refer to this as insignificant PCa and question whether treatment would ever be necessary. However, it has not been determined if any prostate cancer can safely remain untreated. A number of factors confound the ability to identify and articulate the expectable course of PCa:

  • Sampling error is a problem associated with needle biopsy because it can miss cancer up to 30% of the time, or produce tissue that does not contain the most aggressive cells. This gives an inaccurate portrait of an individual’s cancer.
  • Inexpensive broad screening (PSA blood test) is not specific for prostate cancer. Efforts to increase the sensitivity and specificity of PSA (e.g. free PSA) have made some improvements, and other more expensive biomarkers are in development or currently FDA approved for use.
  • Imaging such as multiparametric MRI (mpMRI) cannot provide pathological staging of cancer cells within tissue, but it can reveal suspicious lesions and give information on the size, shape and location at baseline scanning. Monitoring by mpMRI can reveal an increase in size and aggression.
  • At least five different PCa cell lines have recently been identified[ii], some more aggressive than others, with the likelihood of a variance in natural history from one to another.
  • Some differences in rates of incidence and mortality have been observed in different ethnic groups and nationalities, but it is hard to know if statistical bias contributes to observation error.

A 30-year Swedish study of 233 men diagnosed with early stage, low-risk PCa sheds light on the natural history of untreated indolent PCa. A mid-term publication (2004) reported on patient outcomes during the first 15-20 years.[iii] The researchers found that most cancers “…had an indolent course during the first 10 to 15 years. However, further follow-up from 15 (when 49 patients were still alive) to 20 years revealed a substantial decrease in cumulative progression-free survival (from 45.0% to 36.0%), survival without metastases (from 76.9% to 51.2%), and prostate cancer–specific survival (from 78.7% to 54.4%).” Further results on the same population were published eight years later.[iv]  After 32 years, only 3 of the original cohort (1%) were still alive. Records on all patients revealed that over time, 38 men (17%) had died of PCa. All men with high Gleason grade (grade 8-10) PCa (9 patients) had died within the first 10 years of follow-up, but only five of them from PCa. After 20 years of follow-up, those with “well-differentiated, nonpalpable tumors” who were still alive demonstrated more rapid decline in survival between years 20 and 25 (from 75.2% to 25% survival). The conclusion of both publications was that PCa may have a long period of remaining indolent, after which local, regional and distant spread may occur.

A new study out of New York University Medical Center examines the role of mpMRI in short-term monitoring of insignificant (indolent) PCa.[v] The study began with 330 men who were scanned using mpMRI, which resulted in identifying 533 cancer suspicious regions (CSR); each CSR was rated on a scale from 1 to 5 regarding levels of suspicion, with a value of 5 being most suspicious. Each patient then underwent an MRI-ultrasound fusion-guided targeted biopsy into the CSR, plus a computer generated 12-core random biopsy. From this population, the authors report on 34 patients with 51 CSRs whose initial targeted and random biopsies revealed insignificant PCa, and who were followed up one year later with repeat mpMRI and PSA testing. When the repeat mpMRI scans were compared with the original mpMRI, the team recorded 1-year changes in greatest linear measurement (GLM) of the CSR, the 5-point suspicion scale, and the PSA test.

Only two patients (3.9%) had an increase in CSR and suspicion score (ss), though neither had a PSA increase greater than or equal to 0.5 ng/mL. For the rest, there were either no changes, or there were decreases in GLM and suspicion score. The authors conclude, “Our study provides compelling evidence that few benign CSRs increase in ss and/or GLM within one year, independent of baseline ss.” The work of this team supports the theory that PCa found to be insignificant at initial diagnosis is likely to remain indolent for at least the first year.

With mpMRI as a detection resource, patients diagnosed with insignificant PCa can afford the peace of mind that results from periodic imaging to track the natural history of their own unique disease.

[i] Popiolek MRider JRAndrén O et al. Natural history of early, localized prostate cancer: a final report from three decades of follow-up. Eur Urol. 2013 Mar;63(3):428-35. doi: 10.1016/j.eururo.2012.10.002.


[iii] Johansson JE, Andrén O, Andersson SW et al. Natural history of early, localized prostate cancer. JAMA. 2004;291(22):2713-2719. doi:10.1001/jama.291.22.2713.

[iv] Popiolek MRider JRAndrén O et al. Natural history of early, localized prostate cancer: a final report from three decades of follow-up. Eur Urol. 2013 Mar;63(3):428-35. doi: 10.1016/j.eururo.2012.10.002.

[v] Bryk DJ, Llukani E, Huang WC, Lepor H. Natural History of Pathologically Benign Multi-parametric MRI Cancer Suspicious Regions Following MRI-Ultrasound Fusion-targeted Biopsy. J Urol. 2015 May 20. pii: S0022-5347(15)04072-0. doi: 10.1016/j.juro.2015.05.078. [Epub ahead of print]

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