Intraductal Carcinoma of the Prostate

Intraductal Carcinoma of the Prostate Morphologic Features, Differential Diagnoses, Significance, and Reporting Practices The differential diagnosis for atypical cribriform lesions of the prostate has become increasingly complex and includes intraductal carcinoma of the prostate, high-grade prostatic intraepithelial neoplasia, and atypical intraductal proliferations. In this review, we summarize the morphologic and molecular features and significance of intraductal carcinoma of the prostate. We also summarize our institution s strategy for reporting and treatment recommendations for intraductal carcinoma of the prostate. (Arch Pathol Lab Med. 2015;139:1234 1241; doi: 10.5858/arpa.2015-0206-RA) Martin Magers, MD; Lakshmi Priya Kunju, MD; Angela Wu, MD of IDC-P with emphasis on practical, diagnostic, and clinical implications for the surgical pathologist. INTRADUCTAL CARCINOMA OF THE PROSTATE Morphology Intraductal carcinoma of the prostate (IDCP) was historically a term used variably to describe prostatic acinar adenocarcinoma, prostatic ductal adenocarcinoma, and urothelial carcinoma extension into prostatic ducts and acini. 4 Now, IDC-P is a term that refers specifically to prostatic adenocarcinoma extending into and proliferating within preexisting prostatic ducts, first detailed by Kovi et The differential diagnosis of atypical medium and large al 5 in 1985. In practical terms, IDC-P consists morphologically of a robust proliferation of prostatic adenocarcinoma glands on prostate core needle biopsy has become increasingly complex. In this situation, the differential diagnosis is quite broad, with a diverse spectrum of clinical cells within and expanding native, irregular, branched prostatic ducts with at least a partially intact basal cell implications. On one end of this spectrum, intraductal layer. 3 The architecture of IDC-P may be solid, dense carcinoma of the prostate (IDC-P) is often associated with late-stage, high-grade invasive prostatic adenocarcinoma cribriform, loose cribriform, micropapillary, or rarely, flat. The cells can be cuboidal or columnar and typically exhibit and requires either definitive therapy or immediate nucleomegaly and anisonucleosis. 3 Several similar diagnostic rebiopsy. 1 In contrast to IDC-P, high-grade prostatic criteria schemes for the morphologic diagnosis of intraepithelial neoplasia is considered a preneoplastic lesion, which does not require definitive therapy and, when isolated in an extended core biopsy, does not require rebiopsy. 2 The distinction between these entities, however, is not always straightforward, and there are cases that are more complex and atypical than classic high-grade prostatic intraepithelial neoplasia but that do not reach the threshold for a definitive diagnosis of IDC-P. These borderline lesions have been referred to as atypical intraductal proliferations. 3 IDC-P have been suggested. 6,7 In the setting of enlarged, atypical, medium/large glands with at least a partially intact basal cell layer, the major criteria for IDC-P include (1) solid or very dense cribriform architecture (defined as atypical cells spanning.50% 70% of the lumina of the glands), (2) marked nuclear atypia and pleomorphism with nucleomegaly (6 times normal), and (3) nonfocal comedonecrosis 7 ; the presence of any of these criteria is considered diagnostic for IDC-P (Figure 1, A through D). Additionally, invasive prostatic acinar adenocarcinoma, Minor criteria for IDC-P that are often present and helpful prostatic ductal adenocarcinoma, and urothelial carcinoma involving prostatic ducts mimic IDC-P morphologically. Here, we review the morphology and differential diagnosis but not diagnostic include (1) involvement of many glands (n. 6), (2) involved glands that are irregular or branching at right angles, (3) easily identifiable/frequent mitoses, and (4) 2 distinct cell populations (consisting of an outer perimeter of tall, pleomorphic, mitotically active cells and Accepted for publication June 1, 2015. central cuboidal, monomorphic, quiescent cells). 3,6 8 The From the Department of Pathology, University of Michigan Hospitals, Ann Arbor. diagnosis of IDC-P may occasionally be supplemented by The authors have no relevant financial interest in the products or immunohistochemistry (IHC). The most practical use of companies described in this article. IHC staining is to confirm the presence of at least a partial Presented in part at the New Frontiers in Pathology: An Update for basal cell layer. Additionally, in IDC-P with 2 morphologically distinct cell populations, the outer, pleomorphic Practicing Pathologists meeting; University of Michigan; September 4 6, 2014; Ann Arbor, Michigan. Reprints: Angela Wu, MD, Department of Pathology, University of cells stain poorly with prostate-specific antigen (PSA), Michigan Hospitals, 1500 E Medical Center Dr, 2G332 UH, Ann whereas the inner, monomorphic cells exhibit robust PSA Arbor, MI 48109 (e-mail: angelawu@med.umich.edu). staining. 9 1234 Arch Pathol Lab Med Vol 139, October 2015 Intraductal Carcinoma of the Prostate Magers et al

Figure 1. A, Intraductal carcinoma of the prostate is often extensive and forms solid nests. B, Dense, cribriforming glands, in which the atypical cells span more than 50% to 70% of the lumen, are also common. C, The cells in intraductal carcinoma of the prostate are usually high grade (.6 times adjacent benign nuclei) and pleomorphic with frequent mitoses. Note the obvious intact basal cells around the periphery of the involved glands in panels B and C. D, Nonfocal comedonecrosis is also a major criterion for intraductal carcinoma of the prostate (hematoxylin-eosin, original magnifications 34 [A], 310 [B and D], and 340 [C]). Significance IDC-P is not commonly observed in prostate core biopsies; a recent, large prospective cohort 10 of more than 100 consecutive prostate biopsies reported an overall incidence of only 2.8%. The incidence of IDC-P with concomitant, invasive adenocarcinoma in a core needle biopsy is 10.6% to 22%. 10 12 Isolated IDC-P without invasive adenocarcinoma is extremely rare, occurring in 0.06% to 0.26% of core needle biopsies. 1,7,10 In addition, IDC-P is associated with aggressive prostatic adenocarcinoma and is also an adverse prognostic marker in both core needle biopsy and radical prostatectomy specimens. Numerous studies have shown that IDC-P correlates with higher Gleason scores, larger tumor volumes, greater risk of extraprostatic extensions, seminal vesicle invasions, and pelvic lymph node metastases at radical prostatectomies. 5,8,11,13 16 The presence of IDC-P on a core biopsy correlates with seminal vesicle invasion at a radical prostatectomy, even when stratified for Gleason score, and correlates strongly with biochemical failure. 11 A recent study by Van der Kwast et al 12 found that IDC-P in prostate biopsies independently predicted early biochemical relapse and metastatic failure following radiation treatment in patients with intermediate or high-risk prostate cancer. In addition, there is evidence that IDC-P on radical prostatectomy predicts for decreased progression-free survival and for postsurgical biochemical recurrence and remains a poor prognostic indicator when stratified for Gleason score. 17 Similarly, a study by O Brien et al 18 suggests that the predictive accuracy of current postradical prostatectomy nomograms to predict PSA recurrence after radical prostatectomy may be improved by the inclusion of several new pathologic variables, including IDC-P on prostate biopsy. In most cases, IDC-P represents late-stage progression, characterized by intraductal extension of high-stage, advanced prostatic adenocarcinoma. Molecular studies have bolstered this theory. 3 Most compelling is that cytoplasmic PTEN loss (61% 84% of IDC-P versus 0% of high-grade prostatic intraepithelial neoplasia [HGPIN]) is observed in most IDC-Ps. 19 Furthermore, loss of heterozygosity is more frequently observed in IDC-P (60%) than it is in Gleason pattern 3 prostate acinar adenocarcinoma (absent), Gleason pattern 4 prostatic acinar adenocarcinoma (29%), and Arch Pathol Lab Med Vol 139, October 2015 Intraductal Carcinoma of the Prostate Magers et al 1235

Table 1. Our Recommendations for Reporting Findings Reporting Criteria IHC Required? High-grade cancer (Gleason Report IDC-P if recognized No score 8 10) and IDC-P morphologically Gleason score 7 and IDC-P Report IDC-P with a comment Required if overall Gleason that IDC-P is often score is affected (ie, to associated with high-grade differentiate invasive invasive cancer carcinoma from IDC-P) Gleason score 6 and IDC-P Definitive IDC-P with no invasive carcinoma (isolated IDC-P) Atypical (borderline) intraductal proliferation with no invasive carcinoma Report IDC-P with a comment that IDC-P is often associated with high-grade invasive cancer and that the well-differentiated cancer may be a separate nodule Report IDC-P with a comment that IDC-P is often associated with high-grade invasive cancer Report atypical intraductal proliferation, cannot exclude IDC-P Abbreviations: IDC-P, intraductal carcinoma of the prostate; IHC, immunohistochemistry. Required if overall Gleason score is affected (ie, to differentiate invasive carcinoma from IDC-P) Required if invasive carcinoma needs to be excluded Required if invasive carcinoma needs to be excluded Recommendations for Therapy? Definitive therapy Recommend definitive therapy Recommend definitive therapy or immediate rebiopsy (within 3 mo) Recommend definitive therapy or immediate rebiopsy (within 3 mo) Recommend immediate biopsy (within 3 mo) HGPIN (rare), 13 and loss of heterozygosity of p53 or Rb genes is more frequent in IDC-P (60% and 81%, respectively) than HGPIN (30% and 53%, respectively). 20 Finally, the TMPRSS2:ERG gene fusion (the most common recurrent chromosomal alteration of prostatic adenocarcinoma and present in approximately 50% of prostatic adenocarcinoma), 19,21,22 is present in most cases of IDC-P (75%) and never in HGPIN, as assessed by a break-apart fluorescence in situ hybridization assay. 23 This finding has been confirmed by ERG protein IHC, which shows ERG positivity to be much greater in IDC-P than in HGPIN (30% 58% for IDC-P versus 0% 18% for HGPIN). 19,24,25 In addition to parsing out the significance of IDC-P, these molecular studies may have some practical significance; these emerging data suggest that IHC with PTEN (especially as it becomes more common) and to a lesser extent ERG may be helpful in distinguishing IDC-P from other cribriform lesions. Although most IDC-P is thought to be a late-stage phenomenon in high-grade, high-stage prostate cancer, there is some evidence that, at least in a small subset of patients, IDC-P may represent a precursor lesion that has progressed beyond HGPIN but before invasive carcinoma has developed. Such precursor IDC-Ps may represent an entity in the spectrum of the consecutive pathway from HGPIN to invasive cancer or possibly an entity in a separate de novo pathway. There have been rare reports of IDC-P either in the absence of invasive carcinoma or in the presence of only Gleason score 6 cancer found on prostatectomy, and these patients, overall, seem to have a good prognosis, albeit with somewhat limited follow-up. 7,26 Some have argued that IDC-P may have a more variable morphology and clinicopathologic significance than what was originally reported and that up to 10% of IDC-P may in fact represent precursor-type lesions. 27 Our Strategy for IDC-P on Core Biopsy Table 1 summarizes our reporting practices and recommendations for IHC and therapy for IDC-P diagnosed on prostate core biopsy. At our institution, we report the presence of IDC-P in all settings (ie, IDC-P admixed with invasive carcinoma or isolated IDC-P in the absence of concomitant invasive carcinoma). We include IDC-P in overall volume (percentage) of tumor involvement in a core with concomitant invasive carcinoma. We do not assign a Gleason grade to IDC-P at our institution. We include a comment addressing the significance of IDC-P, typically reading: Several of the biopsies show a combination of either invasive prostatic adenocarcinoma with separate foci of intraductal carcinoma of the prostate or pure intraductal carcinoma of the prostate. Intraductal carcinoma of the prostate is strongly associated with high-grade, high-stage prostatic adenocarcinoma and with a poorer prognosis. The template grades reflect the invasive carcinoma only. Our practice is concordant with guidelines discussed at the recent International Society of Urological Pathology consensus meeting on prostate cancer grading in November 2014 in Chicago, Illinois, attended by 67 experts in prostate cancer pathology from 16 different countries (including one of the authors, L.P.K.) and 18 clinical leaders in the field of prostate cancer. The specifics of reporting practices and the use of IHC depend on the grade and type of concomitant invasive carcinoma. At our institution, in the setting of IDC-P associated with unequivocal, high-grade invasive prostatic adenocarcinoma (Gleason score 8 10), we mention the presence of IDC-P if we recognize it morphologically. In this setting of high-grade invasive prostatic adenocarcinoma (which would typically require definitive therapy), we do not routinely perform tests for basal cell IHC markers for confirmation of IDC-P. Basal markers (p63 and CK903) or PIN4 cocktail IHC (combination of basal markers [CK903 and p63] and AMACR [a-methylacyl coenzyme A racemase]) is performed in the setting of IDC-P only if it potentially affects the Gleason score. Hence, if Gleason score 7 adenocarcinoma coexists with IDC-P, we may perform basal cell markers (mainly to differentiate IDC-P from invasive adenocarcinoma because the IDC-P foci are not assigned a Gleason score). We report these cases as Gleason score 3 þ 4or4þ 3 with intraductal carcinoma and strongly recommend definitive therapy. In our experience, these cases with IDC-P and Gleason score 7 cancer are often 1236 Arch Pathol Lab Med Vol 139, October 2015 Intraductal Carcinoma of the Prostate Magers et al

bulky and frequently associated with extraprostatic extension at resection (L.P.K. and A.W., unpublished data, 2015). In the rare situation of IDC-P identified in association with Gleason score 6 cancer, basal marker IHC stains may be necessary to confirm the diagnosis of IDC-P. In all such cases reviewed by us to date, the focus of Gleason score 6 prostate carcinoma is noted in a separate core. We have not yet encountered a single case in which invasive prostate carcinoma with Gleason score 6 is admixed with IDC-P in the same core. Such rare cases are signed out with the comment: IDC-P is often associated with high-grade, high-stage invasive prostate adenocarcinoma; the welldifferentiated prostatic adenocarcinoma may represent a separate nodule. Rarely, IDC-P is diagnosed in the absence of invasive adenocarcinoma (isolated IDC-P); we report IDC-P in such cases with a similar comment to that stated in the paragraph above. Recommendations about proceeding to definitive therapy or to an immediate repeat biopsy in the unusual settings of isolated IDC-P and IDC-P associated with only Gleason score 6 cancer are also controversial. In a study by Robinson et al, 1 of 66 cases of IDC-P only on prostatic core biopsy, 21 underwent prostatectomy with slides available for review. All but 2 had Gleason score 7 prostatic adenocarcinoma or higher, and a little more than one-half had pt3 disease. Twelve percent developed disease progression after definitive treatment. In a recent abstract, 26 it was further shown that when IDC-P and Gleason score 6 cancer are present on a core biopsy, of those patients who underwent radical prostatectomy about one-half (6 of 13) had pt3a or pt3b and most (8 of 10 available for review) had invasive carcinoma Gleason score of 7 or higher. Based on these findings, some genitourinary experts would recommend definitive therapy for IDC-P only or for IDC-P associated only with Gleason 6 cancer 7 ; however, it is recognized by other experts that immediate repeat biopsy within 3 months may also be acceptable. Deciding whether to recommend definitive treatment versus immediate rebiopsy in a case of either isolated IDC-P or IDC-P associated with Gleason score 6 cancer may be determined on a case by case basis. Some of this may depend on the overall features of the IDC- P; if a high volume of cores are involved by obviously highgrade malignant cells forming solid nests or dense cribriforming glands (of the type of IDC-P that might have been diagnosed as Gleason score 8 10 cancer in the absence of stains), definitive treatment could be recommended. If, on the other hand, the IDC-P is extremely focal or has some, but not many, morphologic features of IDC-P, an immediate repeat biopsy within 3 months may be recommended. Our Strategy for IDC-P on Prostatectomy Because IDC-P does have some independent, adverse prognostic significance (ie, for progression-free and cancerspecific survival) even on radical prostatectomy, we mention the presence of IDC-P if it is recognized. 17 Our strategy for radical prostatectomy specimens is similar to our strategy on core needle biopsy. We typically do not perform basal marker/pin4 IHC to confirm IDC-P if IDC-P is associated with unequivocal, concomitant, invasive, high-grade prostatic adenocarcinoma. Basal marker/pin4 IHC is only performed if we feel that its presence may affect the Gleason score, and so, it would typically only be performed in select cases of concomitant Gleason score 6 or 7 cancer. To date, we have not seen a radical prostatectomy with IDC- P only or IDC-P associated with Gleason score 6 at our institution. As with our core needle biopsies, we typically do not grade the IDC-P but would include a comment that IDC-P has been found in some studies to be an independent, adverse prognostic indicator. DIFFERENTIAL DIAGNOSIS High-Grade Prostatic Intraepithelial Neoplasia The most difficult and clinically critical differential diagnosis is HGPIN (Figure 2, A). Although both IDC-P and HGPIN comprise cytologically atypical cells within prostatic ducts and acini, the architectural and cytologic atypia of IDC-P is more severe. The glands of HGPIN are typically smooth with rounded contours (versus irregular with branched contours in IDC-P), and the involved glands are typically similar in size to adjacent, benign glands. The cells lack marked nuclear atypia (only 2 3 times adjacent benign nuclei), are typically uniformly atypical (versus pleomorphic in IDC-P), and only rarely are associated with mitoses. Although both IDC-P and HGPIN may have flat, micropapillary or loose cribriforming architecture, solid nests and dense cribriforming are typically not seen in HGPIN. 28,29 In addition, although very focal comedonecrosis may be seen in HGPIN, nonfocal comedonecrosis (seen in.1 gland) is not seen in HGPIN. Using the above-described criteria for the diagnosis of IDC-P, HGPIN is usually readily distinguished from IDC-P. However, IDC-P is occasionally low-grade with uniform nuclei and small, regularly contoured glands 3 ; in this scenario, the distinction between IDC-P and HGPIN is more problematic. Complicating the issue is that HGPIN and IDC-P share similar IHC phenotypes, including AMACR expression and patchy expression of basal cell markers. Per the molecular differences between IDC-P and HGPIN detailed above, IHC staining for PTEN may also be helpful (loss of expression in IDC-P, expression retained in HGPIN). 19 In very difficult cases, in which the lesion is focal or in which there are overlapping features between IDC-P and HGPIN, a diagnosis of atypical intraductal proliferation may be required (see below). Table 2 details the morphologic and immunohistochemical features that distinguish HGPIN from IDC-P. The incidence of HGPIN in the absence of invasive adenocarcinoma is 4% to 8%, 2 making it much more common than IDC-P. The clinical significance of HGPIN, however, is diminishing with the advent of extended core biopsies. The risk of invasive adenocarcinoma on repeat core needle biopsy following a diagnosis of isolated HGPIN in extended core biopsies is 19% to 25% (median, 23%), which is nearly the same as the risk of invasive adenocarcinoma following a benign diagnosis (median, 19%), and it is not necessarily mandatory to require repeat biopsy following a diagnosis of isolated HGPIN on an extended core biopsy. 2 Therefore, the distinction between HGPIN and IDC-P is critical. Atypical Intraductal Proliferation An atypical intraductal proliferation is defined as a lumenspanning lesion containing cytologically atypical cells that do not meet the threshold for a definitive diagnosis of IDC- P but that exceed the criteria for HGPIN (Figure 2, B). 3,30 Similar to an atypical small acinar proliferation diagnosis on a core biopsy, this is not viewed as a true entity, but rather as a borderline lesion in which neither HGPIN nor IDC-P can be definitively diagnosed. Morais et al 25 proposed the Arch Pathol Lab Med Vol 139, October 2015 Intraductal Carcinoma of the Prostate Magers et al 1237

Table 2. Morphologic Features of High-Grade Prostatic Intraepithelial Neoplasia (HGPIN) and Intraductal Carcinoma of the Prostate (IDC-P) Features HGPIN IDC-P Growth patterns Frequently micropapillary, tufted; rarely loose cribriform, flat Frequently solid, a dense cribriform a, both solid and dense cribriform, or rarely, flat, loose cribriform, micropapillary, tufted Glands involved, No. Usually a few glands Frequently.6 glands Gland size Usually similar to adjacent benign glands Often expanded, branching, irregular glands Nuclear size 2 3 times normal 6 times normal a Pleomorphism Uniformly atypical Marked pleomorphism/anaplasia Comedonecrosis Extremely rare (if present, only focal) Nonfocal comedonecrosis a Mitoses Rare Easily identifiable PSA, PIN-4 immunostains PSA þ, basal markers þ, and AMACR þ PSA þ, basal markers þ, and AMACR þ ERG immunostain Uncommon (0% 18%); typically ERG þ when adjacent to ERG þ cancer or when associated with subsequent biopsies with ERG þ cancer Frequently positive in IDC-P, with or without invasive cancer (30% 58%) PTEN immunostain No loss of PTEN Loss of PTEN in 61% 84% LOH Rare (9%) Frequent (60%) LOH on p53 and Rb gene Rare (19%) Frequent (52%) T2:ERG fusion FISH Fusion absent (0 of 18) in isolated HGPIN Fusion present in 75% Significance No definitive therapy; repeat biopsy only if multifocal Definitive therapy usually recommended Abbreviations: AMACR, a-methyl CoA racemase; FISH, fluorescence in situ hybridization; LOH, loss of heterozygosity; PSA, prostate-specific antigen. a Major criteria for IDC-P. following morphologic criteria for atypical intraductal proliferations: (1) loose cribriform architecture beyond what would normally be seen in HGPIN, but lacking significant pleomorphism or necrosis to qualify for IDC-P; (2) atypical nuclei with significant pleomorphism falling short of what is required for IDC-P (,6 times adjacent benign nuclei), or (3) dense cribriform or solid proliferation of atypical cells in incompletely represented, large ducts on the edge of biopsy specimens. Of 60 patients with atypical intraductal proliferations in their study, repeat biopsy was performed in 35 and prostatectomy in one case. They found that about onehalf of the patients were found to have either invasive adenocarcinoma (15 cases) or IDC-P (3 cases) on repeat biopsies; in those with invasive carcinoma, 47% (7 cases) were assigned a Gleason score of 7 or higher. This rate of carcinoma on subsequent biopsies similar to that in atypical small acinar proliferation (atypical small acinar proliferation, approximately 50%), whereas the rate of significant (Gleason score, 7) cancer (47%) is significantly greater. Therefore, the diagnosis of atypical intraductal proliferation warrants immediate repeat biopsy. 25 In the same study, cytoplasmic loss of PTEN or ERG expression was frequent in atypical intraductal proliferation (52% and 27%, respectively), and of the 11 cases with PTEN loss, 7 (64%) had subsequent biopsies with either invasive prostatic adenocarcinoma or definitive IDC-P. This rate of subsequent carcinoma is significantly higher than that associated with atypical small acinar proliferation but only slightly higher than that seen in PTEN-intact, atypical intraductal proliferation (50%). At our institution, in cases of atypical intraductal proliferation on core needle biopsy, we diagnose such lesions as atypical intraductal proliferation, IDC-P cannot be ruled out with a comment recommending immediate repeat biopsy. 3 Invasive Prostate Acinar Adenocarcinoma Invasive acinar adenocarcinoma may closely mimic IDC-P when it has cribriform or solid architecture (Gleason pattern 4 or 5). The key difference between IDC-P and high-grade invasive acinar adenocarcinoma is a lack of any basal cells present in invasive acinar adenocarcinoma. Indeed, some cases sent in consultation to the authors institution have morphologically appeared so convincingly to be Gleason pattern 4 or 5 adenocarcinoma that no IHC stains would have normally been performed, but stains for basal cell markers were performed at the referring hospital and were at least focally positive, necessitating a diagnosis of IDC-P. Thus, IHC staining for basal cells distinguishes IDC-P from invasive acinar adenocarcinoma, but use of IHC is not always mandatory because of similar clinical management. Prostatic Ductal Adenocarcinoma Prostatic ductal adenocarcinoma, an aggressive form of prostate adenocarcinoma, accounts for 0.4% to 0.8% of prostate adenocarcinoma and is frequently admixed with high-grade prostatic acinar adenocarcinoma. 3,31,32 Prostatic ductal adenocarcinoma can arise both in large periurethral and peripheral prostatic ducts. 33 When it arises in large periurethral ducts, it can create an exophytic, papillary mass protruding into the urethral lumen and causing obstructive symptoms or hematuria. Morphologically, prostatic ductal adenocarcinoma is defined by the presence of tall, columnar cells (Figure 2, C). Secondary features that are helpful but not diagnostic include (1) the presence of papillary fronds with fibrovascular cores, or (2) cribriform architecture with back-to-back, large glands with intraglandular bridging and slitlike lumina ( endometrioid pattern) 2 ; when the cribriforming architecture is prominent and the glands appear relatively round, prostatic ductal adenocarcinoma may mimic IDC-P. In contrast to prostatic ductal adenocarcinoma, the micropapillary architecture of IDC-P usually lacks true fibrovascular cores (versus true fibrovascular cores in prostatic ductal adenocarcinoma) and the cribriform pattern displays punched out lumens lined by cuboidal cells (versus pseudostratified, columnar cells in prostatic ductal adenocarcinoma). In contrast to IDC-P, results from IHC staining for basal cell markers are usually negative in prostatic ductal adenocarcinoma; when basal cells are present underlying 1238 Arch Pathol Lab Med Vol 139, October 2015 Intraductal Carcinoma of the Prostate Magers et al

Figure 2. The major differential diagnoses for intraductal carcinoma of the prostate (IDC-P) are pictured. A, High-grade prostatic intraepithelial neoplasia (HGPIN) typically involves a few glands, and although atypical, it lacks the marked architectural and cytologic atypia of IDC-P (nuclei only 2 3 times the adjacent benign nuclei). B, Atypical intraductal proliferation is not a distinct entity but is composed of glands that demonstrate atypia beyond what is seen in classic HGPIN but that fall short of a definitive diagnosis of IDC-P; here, note the loose cribriform architecture with atypical cells that are beyond those seen in classic HGPIN but which fall short of those typically seen in IDC-P. C, Prostatic duct adenocarcinoma is defined by the presence of tall, columnar cells and is often cribriform with slitlike spaces. Intraductal spread can also be seen in prostatic duct adenocarcinoma. D, Urothelial carcinoma extending into the prostatic glands often has an eosinophilic, squamoid appearance; immunostains can be helpful in distinguishing this entity from IDC-P (hematoxylin-eosin, original magnifications 340 [A] and 310 [B through D]. cells that obviously represent prostatic ductal adenocarcinoma, it likely represents intraductal spread of prostatic ductal adenocarcinoma. 34 In terms of molecular aberrations, TMPRSS2:ERG gene fusions are present in prostatic ductal adenocarcinoma but at a lesser frequency. 2 The diagnosis of prostatic ductal adenocarcinoma is clinically important because it is thought to be equivalent to Gleason score 8 cancer 35 39 and is associated with adverse pathologic parameters, such as increased rates of extraprostatic extension and seminal vesicle invasion as well as lower biochemical-free survival following radical prostatectomy. 31,32,40 44 A recently described pattern of prostatic ductal adenocarcinoma, PIN-like (prostatic intraepithelial neoplasia-like) prostatic ductal adenocarcinoma 45,46 exhibits dilated glands lined with pseudostratified, columnar epithelium and may also mimic entities on the HGPIN/IDC-P spectrum. The PIN-like prostatic ductal adenocarcinoma has been reported to behave less aggressively than classic prostatic ductal adenocarcinoma, more analogous to a Gleason score 6 cancer. Usually, PIN-like prostatic ductal adenocarcinoma has uniform-appearing, elongated nuclei, in contrast to the pleomorphism seen in IDC-P; counterintuitively, the nuclei in PIN-like prostatic ductal adenocarcinoma often lack prominent nucleoli. The epithelium may be pseudostratified, but cribriforming and solid nests should not be present. Basal markers can be quite helpful in this differential diagnosis because PIN-like prostatic ductal adenocarcinoma is negative for basal markers. Urothelial Carcinoma Involving Prostatic Ducts A final mimicker of IDC-P is urothelial carcinoma involving prostatic ducts (Figure 2, D). The prostatic ducts may become distended with urothelial carcinoma cells and exhibit comedonecrosis, which is morphologically similar to IDC-P. A key morphologic difference between IDC-P and urothelial carcinoma involving prostatic ducts is the dense, pink squamoid cytoplasm typical of urothelial carcinoma. Arch Pathol Lab Med Vol 139, October 2015 Intraductal Carcinoma of the Prostate Magers et al 1239

Additionally, greater nuclear pleomorphism, variably prominent nucleoli, increased mitotic activity, and stromal inflammation favor urothelial carcinoma involving prostatic ducts over IDC-P. 2 Unlike other mimickers of IDC-P, IHC staining with a panel of immunomarkers can readily distinguish these 2 entities. Moreover, IDC-P expresses prostatic markers, such as PSA, prostate-specific acid phosphatase, prostate-specific membrane antigen, P501S, and NKX3.1; basal cell markers should only highlight the intact basal layer. Urothelial carcinoma involving prostatic ducts expresses urothelial markers, including 34bE12, p63, and GATA3. 3,47 Identification of urothelial carcinoma involving prostatic ducts is important because these patients usually require cystoprostatectomy with or without chemotherapy. 2 Figure 2, A through D, highlights the major differential diagnoses for IDC-P. CONCLUSIONS Frequently, IDC-P is associated with aggressive, invasive prostate adenocarcinoma, which requires immediate, definitive therapy. The most critical distinction in the differential diagnosis is that of IDC-P from HGPIN, because it has both therapeutic and prognostic implications. Atypical intraductal proliferations on biopsy have atypia beyond HGPIN but short of IDC-P. Thus, IDC-P lies on the malignant end of a spectrum with HGPIN on the preneoplastic, benign end and atypical intraductal proliferation is in a borderline/intermediate category. Several diagnostic criteria schemes have been proposed that aid the surgical pathologist in accurately classifying these entities. Application of these criteria and careful assessment of morphology is paramount because IHC is generally not helpful, except to confirm the presence of basal cells. Current studies have suggested utility of PTEN IHC in the distinction of HGPIN from IDC-P; however, the use of PTEN in routine practice still seems limited. On core biopsies, we do not assign IDC-P a Gleason score. When IDC-P is admixed with invasive carcinoma, we include IDC- P in the tumor volume assessment. References 1. Robinson BD, Epstein JI. Intraductal carcinoma of the prostate without invasive carcinoma on needle biopsy: emphasis on radical prostatectomy findings. J Urol. 2010;184(4):1328 1333. 2. Epstein JI, Netto GJ. Biopsy Interpretation of the Prostate. 5th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2015. 3. Zhou M. Intraductal carcinoma of the prostate: the whole story. Pathology. 2013;45(6):533 539. 4. Catalona WJ, Kadmon D, Martin SA. Surgical considerations in treatment of intraductal carcinoma of the prostate. J Urol. 1978;120(2):259 261. 5. Kovi J, Jackson MA, Heshmat MY. Ductal spread in prostatic carcinoma. Cancer. 1985;56(7):1566 1573. 6. Cohen RJ, Wheeler TM, Bonkhoff H, Rubin MA. A proposal on the identification, histologic reporting, and implications of intraductal prostatic carcinoma. Arch Pathol Lab Med. 2007;131(7):1103 1109. 7. Guo CC, Epstein JI. Intraductal carcinoma of the prostate on needle biopsy: histologic features and clinical significance. Mod Pathol. 2006;19(12):1528 1535. 8. Shah RB, Magi-Galluzzi C, Han B, Zhou M. Atypical cribriform lesions of the prostate: relationship to prostatic carcinoma and implication for diagnosis in prostate biopsies. Am J Surg Pathol. 2010;34(4):470 477. 9. Cohen RJ, McNeal JE, Baillie T. Patterns of differentiation and proliferation in intraductal carcinoma of the prostate: significance for cancer progression. Prostate. 2000;43(1):11 19. 10. Watts K, Li J, Magi-Galluzzi C, Zhou M. Incidence and clinicopathological characteristics of intraductal carcinoma detected in prostate biopsies: a prospective cohort study. Histopathology. 2013;63(4):574 579. 11. Cohen RJ, Chan WC, Edgar SG, et al. Prediction of pathological stage and clinical outcome in prostate cancer: an improved pre-operative model incorporating biopsy-determined intraductal carcinoma. Br J Urol. 1998;81(3): 413 418. 12. Van der Kwast T, Al Daoud N, Collette L, et al. Biopsy diagnosis of intraductal carcinoma is prognostic in intermediate and high risk prostate cancer patients treated by radiotherapy. Eur J Cancer. 2012;48(9):1318 1325. 13. Dawkins HJ, Sellner LN, Turbett GR, et al. Distinction between intraductal carcinoma of the prostate (IDC-P), high-grade dysplasia (PIN), and invasive prostatic adenocarcinoma, using molecular markers of cancer progression. Prostate. 2000;44(4):265 270. 14. Wilcox G, Soh S, Chakraborty S, Scardino PT, Wheeler TM. Patterns of high-grade prostatic intraepithelial neoplasia associated with clinically aggressive prostate cancer. Hum Pathol. 1998;29(10):1119 1123. 15. Rubin MA, de La Taille A, Bagiella E, Olsson CA, O Toole KM. Cribriform carcinoma of the prostate and cribriform prostatic intraepithelial neoplasia: incidence and clinical implications. Am J Surg Pathol. 1998;22(7):840 848. 16. McNeal JE, Yemoto CE. Spread of adenocarcinoma within prostatic ducts and acini. Morphologic and clinical correlations. Am J Surg Pathol. 1996;20(7): 802 814. 17. Kimura K, Tsuzuki T, Kato M, et al. Prognostic value of intraductal carcinoma of the prostate in radical prostatectomy specimens. Prostate. 2014; 74(6):680 687. 18. O Brien B, Cohen R, Wheeler T, Moorin R. A post-radical-prostatectomy nomogram incorporating new pathological variables and interaction terms for improved prognosis. BJU Int. 2011;107(3):389 395. 19. Lotan TL, Gumuskaya B, Rahimi H, et al. Cytoplasmic PTEN protein loss distinguishes intraductal carcinoma of the prostate from high-grade prostatic intraepithelial neoplasia. Mod Pathol. 2013;26(4):587 603. 20. Bettendorf O, Schmidt H, Staebler A, et al. Chromosomal imbalances, loss of heterozygosity, and immunohistochemical expression of TP53, RB1, and PTEN in intraductal cancer, intraepithelial neoplasia, and invasive adenocarcinoma of the prostate. Genes Chromosomes Cancer. 2008;47(7):565 572. 21. Tomlins SA, Rhodes DR, Perner S, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005;310(5748):644 648. 22. Clark JP, Cooper CS. ETS gene fusions in prostate cancer. Nat Rev Urol. 2009;6(8):429 439. 23. Han B, Suleman K, Wang L, et al. ETS gene aberrations in atypical cribriform lesions of the prostate: implications for the distinction between intraductal carcinoma of the prostate and cribriform high-grade prostatic intraepithelial neoplasia. Am J Surg Pathol. 2010;34(4):478 485. 24. Tomlins S, Palanisamy N, Siddiqui J, Chinnaiyan A, Kunju L. Antibodybased detection of ERG rearrangements in prostate core biopsies, including diagnostically challenging cases: ERG staining in prostate core biopsies. Arch Pathol Lab Med. 2012;136(8):935 946. 25. Morais CL, Han JS, Gordetsky J, et al. Utility of PTEN and ERG immunostaining for distinguishing high-grade PIN from intraductal carcinoma of the prostate on needle biopsy. Am J Surg Pathol. 2015;39(2):169 178. 26. Khani F, Epstein JI. Gleason 3 þ 3 ¼ 6 and intraductal carcinoma (IDC-P) on prostate biopsy specimens [abstract 933]. Mod Pathol. 2015;28(suppl 2):234A 27. Miyai K, Divatia MK, Shen SS, Miles BJ, Ayala AG, Ro JY. Heterogeneous clinicopathological features of intraductal carcinoma of the prostate: a comparison between precursor-like and regular type lesions. Int J Clin Exp Pathol. 2014;7(5):2518 2526. 28. Amin MB, Schultz DS, Zarbo RJ. Analysis of cribriform morphology in prostatic neoplasia using antibody to high-molecular-weight cytokeratins. Arch Pathol Lab Med. 1994;118(3):260 264. 29. Bostwick DG, Amin MB, Dundore P, Marsh W, Schultz DS. Architectural patterns of high-grade prostatic intraepithelial neoplasia. Hum Pathol. 1993; 24(3):298 310. 30. Han JS Lee S, Epstein JI, Lotan TL. PINDCIS: Clinical significance of borderline lesions between high grade prostatic intraepithelial neoplasm (HGPIN) and intraductal carcinoma of the prostate (IDC-P) on needle biopsy [abstract 893]. Mod Pathol. 2013;26(suppl 2):215A. 31. Samaratunga H, Duffy D, Yaxley J, Delahunt B. Any proportion of ductal adenocarcinoma in radical prostatectomy specimens predicts extraprostatic extension. Hum Pathol. 2010;41(2):281 285. 32. Seipel AH, Wiklund F, Wiklund NP, Egevad L. Histopathological features of ductal adenocarcinoma of the prostate in 1,051 radical prostatectomy specimens. Virchows Arch. 2013;462(4):429 436. 33. Aydin H, Zhang J, Samaratunga H, et al. Ductal adenocarcinoma of the prostate diagnosed on transurethral biopsy or resection is not always indicative of aggressive disease: implications for clinical management. BJU Int. 2010;105(4): 476 480. 34. Herawi M, Epstein JI. Immunohistochemical antibody cocktail staining (p63/hmwck/amacr) of ductal adenocarcinoma and Gleason pattern 4 cribriform and noncribriform acinar adenocarcinomas of the prostate. Am J Surg Pathol. 2007;31(6):889 894. 35. Bostwick DG, Kindrachuk RW, Rouse RV. Prostatic adenocarcinoma with endometrioid features: clinical, pathologic, and ultrastructural findings. Am J Surg Pathol. 1985;9(8):595 609. 36. Epstein JI, Woodruff JM. Adenocarcinoma of the prostate with endometrioid features: a light microscopic and immunohistochemical study of ten cases. Cancer. 1986;57(1):111 119. 1240 Arch Pathol Lab Med Vol 139, October 2015 Intraductal Carcinoma of the Prostate Magers et al

37. Greene LF, Farrow GM, Ravits JM, Tomera FM. Prostatic adenocarcinoma of ductal origin. J Urol. 1979;121(3):303 305. 38. Ro JY, Ayala AG, Wishnow KI, Ordonez NG. Prostatic duct adenocarcinoma with endometrioid features: immunohistochemical and electron microscopic study. Semin Diagn Pathol. 1988;5(3):301 311. 39. Christensen WN, Steinberg G, Walsh PC, Epstein JI. Prostatic duct adenocarcinoma. Findings at radical prostatectomy. Cancer. 1991;67(8):2118 2124. 40. Fine SW. Variants and unusual patterns of prostate cancer: clinicopathologic and differential diagnostic considerations. Adv Anat Pathol. 2012;19(4): 204 216. 41. Brinker DA, Potter SR, Epstein JI. Ductal adenocarcinoma of the prostate diagnosed on needle biopsy: correlation with clinical and radical prostatectomy findings and progression. Am J Surg Pathol. 1999;23(12):1471 1479. 42. Morgan TM, Welty CJ, Vakar-Lopez F, Lin DW, Wright JL. Ductal adenocarcinoma of the prostate: increased mortality risk and decreased serum prostate specific antigen. J Urol. 2010;184(6):2303 2307. 43. Amin A, Epstein JI. Pathologic stage of prostatic ductal adenocarcinoma at radical prostatectomy: effect of percentage of the ductal component and associated grade of acinar adenocarcinoma. Am J Surg Pathol. 2011;35(4):615 619. 44. Meeks JJ, Zhao LC, Cashy J, Kundu S. Incidence and outcomes of ductal carcinoma of the prostate in the USA: analysis of data from the Surveillance, Epidemiology, and End Results program. BJU Int. 2012;109(6):831 834. 45. Tavora F, Epstein JI. High-grade prostatic intraepithelial neoplasialike ductal adenocarcinoma of the prostate: a clinicopathologic study of 28 cases. Am J Surg Pathol. 2008;32(7):1060 1067. 46. Hameed O, Humphrey PA. Stratified epithelium in prostatic adenocarcinoma: a mimic of high-grade prostatic intraepithelial neoplasia. Mod Pathol. 2006;19(7):899 906. 47. Wu A PN, Siddiqui J, Kunju LP. Utility of GATA-3 and ERG immunohistochemistry in distinguishing between intraductal urothelial carcinoma in the prostate and intraductal carcinoma of the prostate [abstract 1067]. Mod Pathol. 2015;28(suppl 2):268A. Arch Pathol Lab Med Vol 139, October 2015 Intraductal Carcinoma of the Prostate Magers et al 1241