What causes metastatic prostate cancer to appear despite undetectable PSA after prostatectomy?
Executive summary
Metastatic prostate cancer can, rarely but convincingly, manifest despite an undetectable PSA after prostatectomy because PSA is an imperfect surrogate: tiny amounts of residual prostatic tissue, microscopic metastases below assay sensitivity, histologic variants that don't secrete PSA, and laboratory or sampling artifacts can all conspire to hide disease from a blood test [1] [2] [3] [4]. Clinical series and case reports from tertiary centers document these exceptions and show they are uncommon but clinically important, prompting imaging, pathology review, and alternative biomarkers when clinical suspicion rises [5] [6] [7].
1. Surgery should make PSA undetectable — but biology and technique complicate that promise
After radical prostatectomy, clinicians expect the PSA to fall to an undetectable level within weeks because the organ that primarily makes PSA has been removed, and an undetectable PSA has very high negative predictive value for freedom from disease; nonetheless, detectable PSA or later metastasis can reflect either surgical leave-behind of benign prostatic islands or true microscopic metastatic deposits that existed before or at the time of surgery [8] [1] [2] [9].
2. Micrometastases below assay sensitivity: small tumor burden, big consequence
Microscopically disseminated cancer cells can exist at levels too low to produce a measurable rise in serum PSA; several series and case reports show patients with metastases whose PSA remained low or undetectable because tumor burden was minimal or concentrated in sites that released little PSA into circulation, creating a false sense of biochemical remission [6] [3] [10].
3. Tumor dedifferentiation and histologic variants that don’t make PSA
A major biological explanation is a phenotypic shift: aggressive or atypical variants—most notably small cell or neuroendocrine-like prostate carcinomas—may lose the glandular differentiation that drives PSA production, so tumors can progress rapidly while PSA levels stay low; MD Anderson and other reports found a disproportionate share of such variants among patients with metastatic disease and undetectable PSA [5] [7] [6].
4. Clonal evolution and marker loss: cancer changing its identity
Tumors can undergo clonal evolution under treatment pressure or naturally, selecting cell populations that no longer express PSA or express it poorly; case reviews and molecular observations suggest this clonal shift explains some metastatic recurrences with low PSA and is linked to more aggressive clinical courses in documented series [7] [6].
5. Technical and laboratory pitfalls: residual benign tissue, assay limits, and rare “hook” effects
Not every detectable PSA means metastasis and not every undetectable PSA guarantees cure—benign prostatic remnants embedded in the bladder or surgical bed can produce measurable PSA, while rare lab phenomena (for example, very high antigen concentrations causing a hook effect) or assays with different sensitivities can mislead clinicians, so technical factors must be considered alongside biology [2] [4].
6. Clinical implications: when to suspect metastatic disease despite low PSA
Because undetectable PSA after prostatectomy has high negative predictive value, routine imaging is often not performed; however, persistent symptoms, atypical imaging findings, or aggressive histology at diagnosis should lower the threshold for further evaluation including targeted imaging, biopsy, and consideration of non‑PSA biomarkers because published reports show clinical progression can precede or occur without PSA rise [6] [9] [11].
7. Balancing surveillance: PSA is necessary but not sufficient
The literature converges on a pragmatic message: PSA monitoring remains the most sensitive routine tool after prostatectomy, yet clinicians must remain alert to its blind spots—atypical histology, minimal-volume metastases, assay limitations, and surgical factors—and pursue additional diagnostic steps when clinical context demands, accepting that the evidence base is built on case series and registry analyses that underscore rarity but real risk [8] [6] [5] [7].