Carcinogenesis in the prostate is a complex and heterogeneous disease process exhibiting a wide spectrum of light microscopic morphological features and biological behavior.1,2
In contrast to tumors of many other organs, multifocal prostate cancer is the rule rather than the exception.3,26
Small cell carcinoma in particular is a unique variant with behavior distinct from that of typical prostatic adenocarcinoma. Its light microscopic appearance is indistinguishable from small cell carcinoma of other organs, such as the lung; however, its histogenesis remains poorly understood.2,27–29
To gain insight into its development and also to evaluate the diagnostic utility of molecular testing in this setting, we studied rearrangement of the ERG
genes at the 21q22 locus by FISH in a series of 30 cases of prostatic small cell carcinoma.
The histogenesis of prostatic small cell carcinoma has been long debated. Cells with neuroendocrine differentiation are demonstrable in many or all prostatic carcinomas, as well as in normal prostatic glands, although their relationship to the tumor cells in small cell carcinoma has been incompletely elucidated.2,27,28
Some authors have postulated an origin of the tumor directly from stem cells, based on the frequent absence of immunohistochemical staining with organ-specific markers of differentiation, such as prostate-specific antigen, coupled with the exceedingly high proliferation rate, greater than that of dedifferentiated adenocarcinoma.29,30
In addition, the relationship between poorly differentiated adenocarcinoma with ‘small cell’ morphology and true neuroendocrine small cell carcinoma has been debated.30
Although it is true that many cases are negative for prostate-specific markers, a significant subset of cases show positivity for prostate-specific antigen (17–19%), prostein (P501S, 28%), or prostate-specific membrane antigen (25%).10,11
This finding, combined with the coexistence of an acinar adenocarcinoma component in another distinct subset of cases27
and identical TP53 mutations in both components,31
suggests that small cell carcinoma may originate from dedifferentiation of conventional adenocarcinoma.
To more thoroughly evaluate this question, we compared TMPRSS2
fusion status in cases of concurrent prostatic acinar adenocarcinoma and small cell carcinoma. We found that prostatic small cell carcinoma showed ERG
rearrangement with comparable frequency to prostate cancer in general16,32,33
(47%). We found identical abnormalities in adenocarcinoma and small cell carcinoma for 85% of cases; however, a small subset of cases showed discordance of FISH abnormalities in the two components. In one case (case 17), both small cell and adenocarcinoma components showed gene fusion with 21q22 gain; however, only the adenocarcinoma component showed deletion of 5′ ERG
. In the second case, (case 16) gene fusion was detected only in the acinar adenocarcinoma component, associated with 21q22 gain. Along these lines, Barry et al
found that the majority of cases of multifocal prostate cancer showed homogeneity of TMPRSS2
fusion status within a single tumor focus, while comparing separate tumor foci yielded differences in the molecular abnormalities. Other authors have noted similar findings.34,35
Our results support the hypothesis that in most cases, acinar adenocarcinoma and small cell carcinoma arise from a common clonal origin through dedifferentiation. The presence of occasional discordance in the two tumor components is in keeping with the tendency of the prostate gland to harbor multiple spatially separate and clonally distinct tumor foci.3
As such, the two morphologically distinct elements may have arisen separately from their own precursor lesions.
In 20% of cases with rearrangement, we found gene fusion to be associated with deletion of 5′ ERG
, a somewhat lower rate than has been reported in other studies including cases of prostatic small cell carcinoma.22,24
However, this finding has been examined in only a relatively small number of cases thus far. This discrepancy may be attributable to a variety of factors, such as varying patient population and methodology/threshold setting, as well as sample size. Using the FISH method, a significant spectrum of probe sets has been utilized, complicating accurate comparison.23,36,37
Further investigation in this area may reveal differing mechanisms of gene fusion that occur preferentially in small cell carcinoma as compared with typical acinar adenocarcinoma.
Other avenues of utility for FISH studies include the differentiation of metastatic small cell carcinoma originating from an unknown primary site. In some cases, definitively establishing an origin of small cell carcinoma from the prostate gland may be very challenging. As noted above, usual immunohistochemical markers of prostatic differentiation may be negative in prostatic small cell carcinoma.10,11
Further compounding this problem, thyroid transcription factor-1 is positive in a significant number of prostatic small cell carcinomas,10,11
limiting the utility of the marker in distinguishing them from pulmonary small cell carcinomas. In such circumstances, our findings support the use of FISH for TMPRSS2
gene fusion as a specific marker of prostatic origin.
Furthermore, urinary bladder small cell carcinoma may also represent a source of diagnostic difficulty. Tumors originating in the prostate can be difficult to discern pathologically from those originating in the bladder and involving the prostate, and vice versa, especially if a component of differentiated urothelial or prostatic carcinoma is absent. As some authors have noted differences in behavior between tumors of the two primary sites,38
this distinction may be in some cases clinically or prognostically useful. We found absence of TMPRSS2–ERG
fusion in all of the 25 studied cases of urinary bladder small cell carcinoma, supporting the utility of FISH in resolving this differential diagnosis.
In 17% of cases, we noted copy number gain at the 21q22 locus, comprising 20% of cases with rearrangement in either component. The significance of this finding is not completely understood. Some authors have noted copy number gain associated with 5′ ERG
deletion to correlate with more aggressive disease;39,40
however, others have noted that copy number gains are associated with generalized chromosomal instability and a non-diploid status at other chromosomal loci.41
Therefore, the unfavorable behavior of these tumors may be a function of non-diploid/aneuploid status. In support of the latter hypothesis, two of our cases of small cell carcinoma showed copy number increase without other ERG
rearrangement, in addition to the three other cases (five total) in our study that showed copy number gain, one with 5′ ERG
deletion. If indeed the combination of 5′ ERG
deletion and copy number gain is associated with more aggressive behavior in prostate cancer, our results suggest that the transformation to small cell carcinoma need not necessarily progress through this pathway. Copy number increase alone or in combination with other ERG
abnormalities may be an indicator of increased chromosomal instability and may represent one of the pathways to development of an aggressive tumor.
In summary, prostatic small cell carcinoma is an interesting and aggressive neoplasm associated with a poor prognosis. Its histogenesis has long been debated. Our findings are in keeping with the hypothesis that prostatic small cell carcinoma arises from dedifferentiation of typical acinar adenocarcinoma, although a small subset of cases show variation between tumor components in their genetic abnormalities, perhaps due to the multifocal carcinogenesis typical of prostate cancer. Differentiation of prostatic from urinary bladder small cell carcinoma in some cases may be achieved based on the presence of TMPRSS2–ERG gene fusion, although not all prostate cancers are positive for this abnormality. Similarly, determination of prostatic origin in metastatic small cell carcinoma may be achieved in many cases using this method.