Intraductal Carcinoma of the Prostate

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1 General Intraductal Carcinoma of the Prostate The term intraductal carcinoma of the prostate was introduced first almost 40 years ago 12. McNeal and Yemoto, however, were the first to provide detailed morphological and clinical correlations in 1996 and proposed the unifying term intraductal carcinoma of the prostate (IDC-P) 9. In the Gleason era, atypical cribriform lesions were probably classified as Gleason pattern 4 or 5 cancer. But when basal cell markers became available, atypical cribriform lesions were found to have basal cell lining and were thought to represent a part of a prostatic intraepithelial neoplasia (PIN) morphologic spectrum. In recent times IDC-P could be identified as a lesion which is separate from PIN with specific morphologic, prognostic and molecular features 11. IDC-P was identified as an independently significant variable in the prediction of pathological stage, tumor volume, and treatment failure 9. Also, it has been observed that the concurrent invasive adenocarcinoma in IDC-P is associated with high Gleason score, large tumor volume, extraprostatic extension of carcinoma, positive surgical margins, and accelerated disease progression 1, 3, 5, 6, 10, 14. Therefore, a number of studies have advocated that if IDC-P is diagnosed in a biopsy specimen, an immediate re-biopsy or even definitive therapy is recommended in the absence of documented invasive carcinoma 5, 14. Diagnostic criteria IDC-P is defined as prostatic adenocarcinoma cells filling acini and prostatic ducts, with preservation of the surrounding basal cell layer 2. Morphologically, IDC-P is characterized by either solid nests or a dense cribriform pattern within acini and ducts or a loose cribriform/micropapillary pattern with marked nuclear atypia and/or necrosis. Histological features are summarized in Table Table 1: Histologic features that may be seen in intraductal carcinoma of the prostate (IDC-P) IDC-P glands, Number Many; often >6 per prostate gland Size Larger than normal glands; can be >1 mm Ductal-lobular structure Native ducts and acini are expanded and may show irregular and branching contours Intraductal growth pattern 1. Loose cribriform with cells forming narrow strands (often 2 cells thick); spanning lumen without stromal support and intersecting randomly to form an orderly lacework of empty spaces 2. Micropapillary with cells forming papillae with inconspicuous fibrovascular cores 3. Dense cribriform with cells forming small, round punched out lumens that comprise >50% of the luminal space 4. Solid cell mass Cytology 1. Cuboidal or low columnar 2. Significant nuclear atypia 3. Nuclei 6x larger (area!) than adjacent non-neoplastic nuclei 4. 2 cell populations with central small and uniform nuclei and peripheral pleomorphic nuclei may be seen in dense cribriform and solid patterns Comedonecrosis May be present Basal cell layer Preserved, at least focally Page 1 of 6

2 Looking at the criterion 'nuclei 6x larger' it should be emphasized that this means the nuclear area rather than the nuclear diameter. A 6x increase in nuclear diameter would be equivalent to 36x increase in nuclear area and would almost never be encountered in clinical practice. Hence, we recommend that that this criterion should be described as nuclear area >6x normal or nuclear diameter >2.5x normal to avoid ambiguity. "Nuclei 6x larger" area or diameter? Normal prostate Mean nuclear area: 26 μm 2 (6x = 156 μm 2 ) Intraductal carcinoma Max. nuclear area: 167 μm 2 Normal prostate Mean nuclear diameter: 6.8 μm (6x = 41 μm: nuc. area = 1320 μm 2 ) On the basis of these features, IDC-P may be differed from PIN, the most common precursor lesion to invasive prostatic carcinoma. Also, IDC-P is not an in-situ form or precursor of invasive ductal carcinoma and must be distinguished therefrom. Differential Diagnoses Among the differential diagnoses one should consider/rule out: High grade PIN Invasive duct carcinoma Intraductal urothelial carcinoma Cribriform or solid invasive acinar carcinoma To distinguish these entities various parameters are helpful which are listed in Table 2 4. Page 2 of 6

3 Table 2: High-grade prostatic intraepithelial neoplasia (HGPIN) versus intraductal carcinoma of the prostate (IDC-P) 8 Features HGPIN IDC-P Growth pattern Frequently micropapillary, tufted; rarely loose cribriform, flat Frequently solid, dense cribriform, 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 Pleomorphism Uniformly atypical Marked pleomorphism/ anaplasia Comedonecrosis Extremely rare (if present, Nonfocal comedonecrosis only focal) Mitoses Rare Easily identifiable ERG IHC Uncommon (0% 18%); typically ERG+ when adjacent to ERG+ cancer or when associated with subsequent biopsies with ERG+ cancer Frequently positive in IDC-P, with or without invasive cancer (30% 58%) PTEN IHC No loss of PTEN Loss of PTEN in 61% 84% LOH Rare (9%) Frequent (60%) Significance No definitive therapy; repeat biopsy only if multifocal Definitive therapy usually recommended Legend: IHC: immunohistochemistry; LOH: Loss of heterozygosity Table 3: Ductal adenocarcinoma versus intraductal carcinoma of the prostate (IDC-P) 14 Features Ductal Adenocarcinoma IDC-P Cell morphology Tall columnar Cuboidal/short columnar Cell layering Pseudostratified Simple Nuclear size Variable, at least 2-3x normal At least 6x normal Nuclear atypia Mild pleopmorphism Marked pleomorphism Mitoses Variable Present, often multiple Basal cells Usually absent Present Ductal-lobular architecture Markedly distorted by invasive large glands that are closely spaced with irregular contours Native ducts are expanded and show some irregular contours Necrosis Occasional Frequent, non-focal Intraluminal growth patterns Flat Loose cribriform (large slit like spaces) Papillary (true fibrovascular cores) Solid Loose cribriform (large round spaces) Micropapillary Dense cribriform (small round spaces) Page 3 of 6

4 Table 4: Intraductal urothelial carcinoma versus 13, 16 intraductal carcinoma of the prostate (IDC-P) Features Urothelial carcinoma IDC-P Ductal-lobular structure Preserved (usually) Expanded Gland size Increased (>2x normal) Variable Lumen-spanning cell mass Present Present Intraductal growth pattern Solid (typically) Cribriform Micropapillary/trabecular Cribriform Solid Basal cell markers (p63, CK5/6, CK 34βE12) Positive in tumor cells Positive in basal cells, negative in tumor cells Prostate markers Negative Positive (PSA, PAP, NKX3.1) Urothelial makers Positive Negative (GATA-3, CK20, Uroplakin) ERG Negative Often positive Grading of IDC-P Whether IDC-P should be graded or not, and if so how it should be graded was debated at the 2014 Chicago ISUP consensus meeting on grading of prostate carcinoma 4. This issue was not discussed in the 2005 grading consensus meeting. Since IDC-P is sometimes difficult to recognize in HE sections, immunohistochemistry was advised for cases where the results would change the case s overall grade. In the literature there are controversial recommendations whether or not IDC-P should be graded 4, 13, 15. The arguments for and against grading of IDC-P are as follows 4 : Pro Even when IDC-P alone is present on biopsy, 90% will have a Gleason score >7 at radical prostatectomy. When IDC-P and invasive cancer are present on biopsy, there is almost always a Gleason score >7, so there is already a Gleason pattern 4. Sometimes it is difficult to distinguish between IDC-P vs. cribriform Gleason pattern 4 cancer and one may need to do immunohistochemistry on multiple parts to distinguish. There are several studies demonstrating a correlation of IDC-P with an increased stage and prognosis. Contra Approximately 10% of IDC-P found at radical prostatectomy are not closely associated with an invasive carcinoma and appear to be a precursor lesion as opposed to invasive cancer extending into ducts. In the uncommon setting of IDC-P only on biopsy, in about 10% no invasive carcinoma is found at radical prostatectomy. If a Gleason score 4+4=8 were given on biopsy, the patient would have been labeled as having a poor prognosis when in fact the patient is 100% cured with IDC-P only. In the uncommon setting of IDC-P and an invasive cancer Glesason score 3+3 on biopsy, approximately 20% have only a Gleason score 3+3=6 cancer at radical prostatectomy and would have been incorrectly labeled as having a pattern 4 on biopsy. Page 4 of 6

5 In other organ systems, intraductal lesions are not graded with the same grading system as the invasive component. In summary, there is currently no consensus whether or not IDC-P should be graded. The recommendation of the ISUP 2014 consensus conference is currently not to grade IDC-P but to report it with a special comment 4 (see below). Reporting of IDC-P Since IDC-P on needle biopsy can have an influence on the decision for a further therapy, a comment should be given in the report (table 5) 8 : Table 5: ations for reporting IDC-P in needle biopsies Finding Reporting criteria IHC necessary? ation Report IDC-P if High grade cancer No Definitive therapy recognized (Gl. 8-10) and IDC-P morphologically Gleason score 7 and 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 Report IDC-P with a comment that IDC-P is often associated with high-grade invasive cancer and that the welldifferentiated 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 Required if overall Gleason score is affected (i.e., to differentiate invasive carcinoma from IDC-P) Required if overall Gleason score is affected (i.e., to differentiate invasive carcinoma from IDC-P) Required if invasive carcinoma needs to be excluded Required if invasive carcinoma needs to be excluded definitive therapy definitive therapy or immediate rebiopsy (within 3 mo) definitive therapy or immediate rebiopsy (within 3 mo) immediate biopsy (within 3 mo) Because IDC-P does have some independent, adverse prognostic significance (i.e., for progression-free and cancer-specific survival) even on radical prostatectomy 7, the presence of IDC-P should be included in the report if it is recognized. Our strategy for radical prostatectomy specimens is similar to the strategy on core needle biopsies. We typically do not perform basal marker IHC to confirm IDC-P if it is associated with unequivocal, concomitant, invasive, high-grade prostatic adenocarcinoma. Basal marker IHC is only performed if we feel that its presence is discrepant to the Gleason score, and so, it is typically only be performed in select cases of concomitant Gleason score 6 or 7 cancer. Page 5 of 6

6 References 1. Cohen RJ, McNeal JE, Baillie T. Patterns of differentiation and proliferation in intraductal carcinoma of the prostate: significance for cancer progression. Prostate. 2000;43: Cohen RJ, Wheeler TM, Bonkhoff H, et al. A proposal on the identification, histologic reporting, and implications of intraductal prostatic carcinoma. Arch Pathol Lab Med. 2007;131: 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: Epstein JI, Egevad L, Amin MB, et al. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: Definition of Grading Patterns and Proposal for a New Grading System. Am J Surg Pathol. 2015;(epub). 5. Guo CC, Epstein JI. Intraductal carcinoma of the prostate on needle biopsy: Histologic features and clinical significance. Mod Pathol. 2006;19: Henry PC, Evans AJ. Intraductal carcinoma of the prostate: a distinct histopathological entity with important prognostic implications. J Clin Pathol. 2009;62: Kimura K, Tsuzuki T, Kato M, et al. Prognostic value of intraductal carcinoma of the prostate in radical prostatectomy specimens. Prostate. 2014;74: Magers M, Kunju LP, Wu A. Intraductal Carcinoma of the Prostate: Morphologic Features, Differential Diagnoses, Significance, and Reporting Practices. Arch Pathol Lab Med. 2015;139: McNeal JE, Yemoto CE. Spread of adenocarcinoma within prostatic ducts and acini. Morphologic and clinical correlations. Am J Surg Pathol. 1996;20: Miyai K, Divatia MK, Shen SS, et al. 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: Montironi R, Cheng L, Lopez-Beltran A, et al. A better understating of the morphological features and molecular characteristics of intraductal carcinoma helps clinicians further explain prostate cancer aggressiveness. Eur Urol. 2015;67: Rhamy RK, Buchanan RD, Spalding MJ. Intraductal carcinoma of the prostate gland. J Urol. 1973;109: Robinson B, Magi-Galluzzi C, Zhou M. Intraductal carcinoma of the prostate. Arch Pathol Lab Med. 2012;136: Robinson BD, Epstein JI. Intraductal carcinoma of the prostate without invasive carcinoma on needle biopsy: emphasis on radical prostatectomy findings. J Urol. 2010;184: Shah RB, Magi-Galluzzi C, Han B, et al. Atypical cribriform lesions of the prostate: relationship to prostatic carcinoma and implication for diagnosis in prostate biopsies. Am J Surg Pathol. 2010;34: Tsuzuki T. Intraductal carcinoma of the prostate: a comprehensive and updated review. Int J Urol. 2015;22: Page 6 of 6