HOXB13-Related Familial Prostate Cancers: A Clinical, Histologic, and Molecular Survey
Steven C Smith, Nallasivam Palanisamy, Anna Johnson, Kimberly Zuhlke, Javed Siddiqui, Arul M Chinnaiyan, Lakshmi P Kunju, Kathleen A Cooney, Scott A Tomlins. University of Michigan, Ann Arbor, MI
Background: Recent genetic epidemiologic studies identified a germline mutation in the homeobox transcription factor, HOXB13 (G84E substitution), that is associated with markedly increased risk of prostate cancer (CaP). Concurrently, recent molecular studies have characterized several molecular subclasses of CaP, including both a class defined by oncogenic fusion of androgen responsive genes to one of several ETS transcription factors (most frequently ERG, prevalence ∼50%) and a mutually exclusive class defined by outlier-expression of the protein SPINK1 (∼10%). No study has examined conventional CaP histologic features or ERG/SPINK1 status in HOXB13-related cases.
Design: Prostatectomy cases and related clinicopathologic and outcome data were reviewed and tabulated for confirmed HOXB13 G84E cases from 1994-2011. We selected sections sampling dominant nodules and all additional cancer foci, re-graded foci by 2005 ISUP Gleason scoring criteria (as appropriate), and assessed histology. Sections were immunostained for ERG (clone EPR 3864) and SPINK1 (clone H00006690-M01); the molecular status of each disease focus was assessed as ERG positive (uniform nuclear stain of cancer cells), and/or SPINK1 positive (strong cytoplasmic stain of at least 10% of a focus), or negative for both molecular class-defining biomarkers.
Results: Of 26 confirmed cases, material for 22 cases was available for analysis; this subset showed mean age 56.2y, serum PSA 9.5 ng/ml, and prostatectomy weight of 45.2g. Dominant nodules were Gleason 3+3 in 18%, 3+4 in 32%, 4+3 in 32%, and >7 in 18%, with cases showing an average of 6.4 foci (range 1-15). A single biochemical recurrence and death of disease was seen over an average of 40.2 months follow-up. Histologic review found a high prevalence of the pseudohyperplastic variant of prostate cancer, with 77% of cases showing at least one such focus. At least one focus per case showed pink crystalloids (82%) and pink luminal secretions (86%); although blue mucin was focally present in 23%, no case showed abundant blue mucin. Dominant nodules were ERG positive in 18%, SPINK1 positive in 23%, and negative in 59%; across all foci prevalence of ERG and SPINK1 were each 19% (negative foci 63%).
Conclusions: HOXB13-related CaPs show prominent multifocality and frequent pseudohyperplastic features. Prevalence of ERG and SPINK1-related molecular classes are decreased and increased, respectively, compared to results reported in unselected prostatectomy series. If confirmed in additional series, these findings suggest that HOXB13 mutations may predispose to distinct CaP morphology and molecular subtypes.
Category: Genitourinary (including renal tumors)
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 159, Monday Morning