Intraductal carcinoma of the prostate (IDC-P) is an excellent marker of clinically aggressive disease. Since its original description, numerous studies have confirmed that intraductal carcinoma is almost invariably associated with high grade invasive carcinoma in radical prostatectomy specimens (1
). Even when identified on biopsy as an isolated lesion without invasive tumor, because of its frequent association with unsampled concurrent high grade tumor (8
), it has been recommended that men with intraductal carcinoma should undergo definitive treatment. Finally, two recent studies demonstrate that identification of intraductal carcinoma in needle biopsies containing invasive tumor also predicts for worse clinico-pathologic outcomes, even after accounting for the Gleason grade and extent of the invasive component (10
Importantly, intraductal carcinoma exists along a morphologic spectrum. At one end, intraductal carcinoma shows significant morphologic overlap with cribriform high grade invasive adenocarcinoma, and since the advent of basal cell immunostains, it has been increasingly appreciated that as many as 30% of cribriform carcinomas have an intraductal component (12
). At the other end of the spectrum, however, intraductal carcinoma lesions can be more difficult to recognize and many have significant morphologic overlap with isolated high grade prostatic intraepithelial neoplasia (PIN), a lesion that is not by itself an indication for treatment or even clinical follow-up in most cases (3
). Because the diagnoses of intraductal carcinoma and high grade PIN have such different implications for patient care and prognosis, intraductal carcinoma is currently identified on needle biopsy using a strict set of morphologic criteria designed to avoid its over-diagnosis (8
). Since these criteria were intentionally created to be specific for intraductal carcinoma, they likely lack sensitivity and may result in the under-diagnosis of clinically significant intraductal tumors. Recently, we and others have identified a substantial group of intraductal cribriform proliferative lesions that do not formally qualify as intraductal carcinoma using current morphologic criteria, but are more concerning in terms of extent of involvement and/or cytologic atypia than typical high grade PIN (7
). We have called these intraductal cribriform proliferations, where the differential diagnosis is between high grade PIN and intraductal carcinoma (TLL and JIE, unpublished data). Management of these lesions remains uncertain.
Given the importance of distinguishing intraductal carcinoma from high grade PIN and the uncertainties associated with the current morphologic classification system, an ancillary test based on molecular alterations present in intraductal carcinoma and not high grade PIN would help identify these intraductal proliferative lesions with more accuracy. Importantly, current data suggests that intraductal carcinoma may be separable from high grade PIN at the molecular level. While pathologists have long debated whether intraductal carcinoma represents a de novo
intraductal lesion or late colonization of benign ducts by high grade invasive tumor (1
), the frequent association of intraductal carcinoma with concurrent and often physically adjacent invasive tumor suggests the latter etiology is most common (9
). Indeed, in the only molecular studies of intraductal carcinoma to date, it had a markedly higher rate of loss of heterozygosity (LOH) and ERG
gene rearrangement than high grade PIN (6
), and a rate even higher than that seen in invasive carcinoma in some cases. Given that isolated high grade PIN is the presumptive precursor lesion to many invasive carcinomas, these data suggest that intraductal carcinoma is molecularly more similar to invasive high grade carcinoma and may be distinguished from high grade PIN using appropriate molecular-based tools.
In order to develop an immunohistochemical (IHC) test to distinguish intraductal carcinoma and high grade PIN, we took advantage of the fact that ERG
gene rearrangements and deletions involving the PTEN
locus are common molecular changes identified in invasive prostatic carcinoma and these changes occur much more infrequently in high grade PIN (16
gene rearrangements occur in 40–60% of surgically treated invasive prostatic adenocarcinoma and have been identified in less than 20% of cases of high grade PIN (23
loss occurs in 30–70% of tumors, and is also quite rare in high grade PIN (25
). Because both genetic changes can be sensitively detected with previously validated immunohistochemistry assays (35
), we sought to determine whether we could develop an easily applied immunohistochemical test for PTEN and ERG that might help to distinguish intraductal carcinoma from high grade PIN.