Association of cysteine-rich secretory protein 3 and beta-microseminoprotein with outcome after radical prostatectomy

Abstract

Purpose: It has been suggested that cysteine-rich secretory protein 3 (CRISP-3) and beta-microseminoprotein (MSP) are associated with outcome in prostate cancer. We investigated whether these markers are related to biochemical recurrence and whether addition of the markers improves prediction of recurring disease.

Experimental design: Tissue microarrays of radical prostatectomy specimens were analyzed for CRISP-3 and MSP by immunohistochemistry. Associations between marker positivity and postprostatectomy biochemical recurrence [prostate-specific antigen (PSA) >0.2 ng/mL with a confirmatory level] were evaluated by univariate and multivariable Cox proportional hazards regression. Multivariable analyses controlled for preoperative PSA and pathologic stage and grade.

Results: Among 945 patients, 224 had recurrence. Median follow-up for survivors was 6.0 years. Patients positive for CRISP-3 had smaller recurrence-free probabilities, whereas MSP-positive patients had larger recurrence-free probabilities. On univariate analysis, the hazard ratio for patients positive versus negative for CRISP-3 was 1.53 (P=0.010) and for MSP was 0.63 (P=0.004). On multivariable analysis, both CRISP-3 (P=0.007) and MSP (P=0.002) were associated with recurrence. The hazard ratio among CRISP-3-positive/MSP-negative patients compared with CRISP-3-negative/MSP-positive patients was 2.38. Adding CRISP-3 to a base model that included PSA and pathologic stage and grade did not enhance the prediction of recurrence, but adding MSP increased the concordance index minimally from 0.778 to 0.781.

Conclusion: We report evidence that CRISP-3 and MSP are independent predictors of recurrence after radical prostatectomy for localized prostate cancer. However, addition of the markers does not importantly improve the performance of existing predictive models. Further research should aim to elucidate the functions of CRISP-3 and MSP in prostate cancer cells.

Fig. 1

Immunohistochemical detection of CRISP-3 and MSP in tissue microarray cores of primary tumors and HGPIN from RP specimens. A, a Gleason grade 4 tumor with strong immunostaining for CRISP-3 in most prostate cancer cells. B, an adjacent section of the same tumor as in (A), with virtually no detectable MSP immunoreactivity. C, another example of a Gleason grade 4 tumor, with almost complete lack of immunoreactivity for CRISP-3. D, Gleason grade 4 tumor cells and benign epithelium with strong expression of MSP. E, an HGPIN lesion, showing CRISP-3– immunoreactive cells. F, MSP immunoreactive cells in HGPIN. Magnification, ×200.

Fig. 2

Results from semiquantitative scoring of tissue microarrays. A, distribution of CRISP-3 immunostaining intensity. B, percentage of tumor cells positive for CRISP-3. C, MSP immunostaining intensity. D, Percentage of MSP-positive tumor cells.

Fig. 3

Kaplan-Meier recurrence-free probability. A, patients stratified by CRISP-3 positivity, defined as ≥80% of tumor cells positive and immunostaining intensity ≥1.5. Solid line, CRISP-3 negative. Dashed line, CRISP-3 positive. B, patients stratified by MSP positivity, defined as ≥20% of tumor cells positive and immunostaining intensity ≥1.0. Solid line, MSP negative. Dashed line, MSP positive. C, patients stratified by the combination of CRISP-3 and MSP. Solid line, group 1, CRISP-3 negative, and MSP positive. Dashed line, group 2, both CRISP-3 and MSP negative or both CRISP-3 and MSP positive. Dotted line, group 3, CRISP-3 positive and MSP negative.