ERG gene rearrangements are common in prostatic small cell carcinomas

Abstract

Small cell carcinoma of the prostate is a rare subtype with an aggressive clinical course. Despite the frequent occurrence of ERG gene rearrangements in acinar carcinoma, the incidence of these rearrangements in prostatic small cell carcinoma is unclear. In addition, molecular markers to distinguish prostatic small cell carcinomas from lung and bladder small cell carcinomas may be clinically useful. We examined the occurrence of ERG gene rearrangements by fluorescence in situ hybridization in prostatic, bladder and lung small cell carcinomas. We also examined the expression of ERG, androgen receptor (AR) and NKX3-1 by immunohistochemistry in prostatic cases. Overall, 45% (10/22) of prostatic small cell carcinoma cases harbored ERG rearrangements, whereas no cases of bladder or lung small cell carcinomas showed ERG rearrangement (0/12 and 0/13, respectively). Of prostatic small cell carcinoma cases, 80% (8/10) showed ERG deletion and 20% (2/10) showed ERG translocation. In 83% (5/6) of prostatic small cell carcinoma cases in which a concurrent conventional prostatic acinar carcinoma component was available for analysis, there was concordance for the presence/absence of ERG gene rearrangement between the different subtypes. ERG, AR and NKX3-1 protein expression was detected in a minority of prostatic small cell carcinoma cases (23, 27 and 18%, respectively), while these markers were positive in the majority of concurrent acinar carcinoma cases (66, 83 and 83%, respectively). The presence of ERG rearrangements in nearly half of the prostatic small cell carcinomas is a similar rate of rearrangement to that found in prostatic acinar carcinomas. Furthermore, the high concordance rate of ERG rearrangement between the small cell and acinar components in a given patient supports a common origin for these two subtypes of prostate cancer. Finally, the absence of ERG rearrangement in bladder or lung small cell carcinomas highlights the utility of detecting ERG rearrangement in small cell carcinomas of unknown primary for establishing prostatic origin.

Figure 1

Top left: High-power photomicrograph (×400 magnification) of a hematoxylin and eosin-stained section of small cell carcinoma case 19. Top right: Fluorescence in situ hybridization (FISH) (×1000 magnification) reveals no evidence of ERG rearrangement in this case. Bottom left: High-power photomicrograph (×400 magnification) of a hematoxylin and eosin-stained section of small cell carcinoma case 32. Bottom right: FISH (×1000 magnification) reveals ERG rearrangement through translocation with one juxtaposed red–green (yellow) signal in each nucleus and the second pair of red and green signals split apart and spatially separated in different regions of the nucleus.

Figure 2

Top left: High-power photomicrograph (×400 magnification) of a hematoxylin and eosin-stained section of small cell carcinoma component of case 29. Top right: Fluorescence in situ hybridization (FISH, ×1000 magnification) reveals ERG rearrangement through deletion in the small cell component, with one juxtaposed red–green (yellow) signal in each nucleus and the absence of the second green signal. Bottom left: High-power photomicrograph (×400 magnification) of a hematoxylin and eosin-stained section of the acinar carcinoma component of case 29. Bottom right: FISH (×1000 magnification) reveals ERG rearrangement through deletion in the acinar component as well.

Figure 3

Top row: Small cell carcinoma case 8 is strongly and diffusely positive for the androgen receptor (AR), NKX3-1 and ERG protein. Bottom row: In contrast, case 29 shows negativity for all three markers in the small cell component, whereas the adjacent acinar component (arrows) is positive for all three markers.