Features and Prognostic Significance of Intraductal Carcinoma of the Prostate

EUROPEAN UROLOGY ONCOLOGY 1 (2018) 21 28 available at www.sciencedirect.com journal homepage: euoncology.europeanurology.com EUO Collaborative Review Prostate Cancer Features and Prognostic Significance of Intraductal Carcinoma of the Prostate Rodolfo Montironi a,y, Ming Zhou b,y, Cristina Magi-Galluzzi c, Jonathan I. Epstein d, * a Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy; b University of Texas Southwestern Medical Center, Dallas, TX, USA; c R.T. Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA; d The Johns Hopkins Medical Institution, Baltimore, MD, USA Article info Article history: Accepted March 13, 2018 Associate Editor: Gianluca Giannarini Keywords: Diagnosis Intraductal carcinoma Prognosis Prostate carcinoma Abstract Context: Intraductal carcinoma of the prostate (IDC-P) is an intraglandular/ductal neoplastic growth of glandular epithelial cells characterized by marked abnormality of the glandular architecture and/or cytological atypia that exceeds what is typically seen in high-grade prostatic intraepithelial neoplasia (HPGIN). It has been shown that IDC-P is a strong independent indicator of poor prognosis for prostate carcinoma (PCa). Objective: To review the pathological and genetic features, diagnostic criteria and differential diagnosis, and clinical significance of IDC-P. Evidence acquisition: PubMed was searched using keywords including prostate carcinoma, intraductal carcinoma, IDC, histology, diagnostic criteria, and prognosis. The references in relevant articles were also reviewed. Evidence synthesis: IDC-P is a distinct entity with characteristic morphological and genetic features. It is strongly associated with aggressive PCa with high Gleason score/grade groups and large tumor volume, and portends unfavorable clinical outcomes. Morphological diagnostic criteria have been established to distinguish it from other lesions with similar histological features. IDC-P is an uncommon finding in prostate biopsies, and is even rarer as an isolated finding without concomitant PCa. However, patients with isolated IDC-P in biopsy specimens are recommended to have either definitive treatment or immediate repeat biopsy. Conclusions: It is critical to recognize and report IDC-P, especially in prostate biopsies, where the clinical impact of such a diagnosis is greatest. Patient summary: Intraductal carcinoma is a unique form of aggressive prostate cancer. In this report, we review its pathological and genetic features and poor prognostic significance. It is critical for pathologists to recognize and report this lesion in prostate specimens, especially in prostate biopsies for patient management. 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved. y These authors contributed equally to this work and are joint first authors. * Corresponding author. Department of Pathology, The Johns Hopkins Medical Institution, 401 N. Broadway Street, Baltimore, MD 21231, USA. E-mail address: jepstein@jhmi.edu (J.I. Epstein). https://doi.org/10.1016/j.euo.2018.03.013 2588-9311/ 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.

22 EUROPEAN UROLOGY ONCOLOGY 1 (2018) 21 28 1. Introduction Intraductal carcinoma of the prostate (IDC-P) is now considered a unique type of prostatic glandular neoplasia with a propensity to grow within and expand benign prostatic ducts and acini [1]. IDC-P is strongly associated with aggressive, high-grade, typically Gleason patterns 4/5, and high-volume invasive prostate carcinoma (PCa). It is therefore critical to report and distinguish IDC-P from other lesions with similar histological appearance, especially in prostate biopsies. Patients with a diagnosis of IDC-P in a biopsy are counseled to either undergo an immediate repeat biopsy or, as recommended by some experts, definitive therapy even in the absence of documented invasive PCa. Here we review the historical perspective, morphological features, diagnostic criteria and differential diagnosis, and genetics of IDC-P. The clinical significance of IDC-P in both radical prostatectomy and prostate biopsy specimens is emphasized. Reporting of IDC-P in prostate biopsies is also discussed. 2. Evidence acquisition A comprehensive PubMed search was performed up to January 2018 using keywords including prostate carcinoma, intraductal carcinoma, IDC, IDC-P, intraductal spread, histology, diagnostic criteria, prognosis, and therapy. The search was restricted to articles published in the English language. The references in relevant articles were also reviewed. 3. Evidence synthesis 3.1. Historical perspective In the earlier literature, intraductal carcinoma was used variably to describe the extension into prostatic ducts and acini of prostatic acinar and ductal carcinoma and urothelial and squamous carcinoma [2]. At present, the term IDC-P refers specifically to the proliferation of prostate adenocarcinoma cells within pre-existing prostatic glandular structures. Kovi et al. [3] were the first to perform a detailed analysis of this phenomenon. They described PCa cells invading adjacent benign prostatic ducts and supplanting the normal epithelial component while preserving the general architectural framework of the affected ducts and acini. In a later study, McNeal et al. [4] found that PCa with cribriform morphology was predominantly located within prostatic ducts and acini, with cancer cells following the normal duct contour and retaining basal cells. The majority of cribriform PCa with intraductal location was prognostically equivalent to Gleason patterns 4/5 PCa. The authors coined the term intraductal carcinoma of the prostate to emphasize the unique histological and clinical features of this lesion. Subsequently, McNeal and Yemoto [5] proved that IDC-P was a unique form of PCa with a peculiar propensity for intraductal spread and growth, as IDC-P was almost never seen in the absence of invasive carcinoma, and the concomitant invasive component was usually of high grade. The concept of intraductal carcinoma has evolved significantly since then. The current concept is that the vast majority of IDC-P represents intraductal extension of advanced-stage invasive PCa. Very rarely, IDC-P can be found without a concomitant invasive prostate PCa [6] and therefore may represent a stage of prostate carcinogenesis beyond high-grade prostatic intraepithelial neoplasia (HGPIN) but before invasive PCa develops. IDC-P is accepted as a distinct entity in the 2016 World Health Organization (WHO) classification of tumors of the urinary system and male genital organs [1]. 3.2. Morphological features of IDC-P Almost all cases of IDC-P have two morphological hallmarks, including expansile growth of atypical cells that forms a dense cribriform and/or solid architecture and at least partial preservation of basal cells around these glands. Architecturally, IDC-P can exhibit a plethora of patterns (Table 1), including a dense cribriform pattern (Fig. 1A C), solid tumor (Fig. 1D), and comedonecrosis (Fig. 1E), representing progressively increasing proliferation of cancer cells. It is not uncommon that IDC-P partially involves benign glands (Fig. 1F). Cytologically, neoplastic cells may exhibit either the typical cytology of PCa or, in a minority of cases, marked variation in nuclear size and pleomorphic nuclei that are six or more times the size of adjacent nuclei (Fig. 1G). In some cases with marked cytological atypia, the IDC-P cells line ducts/acini in a single layer or piled up cells without a cribriform and/or solid architecture. There are also lesions that may represent a lower-grade form of IDC-P, with a small and smooth glandular contour and uniform nuclei that are morphologically difficult to distinguish from HGPIN glands (Fig. 2; see the discussion below) [7]. 3.3. Diagnostic criteria for IDC-P The diagnosis of IDC-P is based on morphology. Several diagnostic criteria have been proposed. Cohen et al. [8] proposed a set of five major and three minor criteria. The first four major criteria are always present in IDC-P and are: (1) large-caliber glands that are more than twice the diameter of normal peripheral-zone glands; (2) preserved basal cells, as confirmed by basal cell markers; (3) cytologically malignant cells; and (4) an expansile cell mass that spans the glandular lumen. The fifth major criterion, central comedonecrosis, is diagnostic of IDC-P but is not always present. Minor criteria include glands with (1) right-angle branching or (2) smooth, rounded outlines, and (3) a two-cell population with an outer perimeter cell group composed of tall, pleomorphic, and mitotically active cells that stain poorly for prostate-specific antigen (PSA), and a central group that is cuboidal, monomorphic, and quiescent, with abundant cytoplasm containing abundant PSA and occasional extracellular mucin.

EUROPEAN UROLOGY ONCOLOGY 1 (2018) 21 28 23 Table 1 Intraductal carcinoma of the prostate (IDC-P): common histological deatures. IDC-P glands Size Ductal-acinar structure Growth pattern Cytology Comedonecrosis Basal cell layer Many; often >6 per prostate gland Larger than normal glands; may be >1 mm 1. Native ducts and acini are expanded and may show irregular and branching contours 2. Partial involvement is common 1. Loose cribriform: cancer cells form narrow strands without fibrovascular cores that intersect randomly to form irregular empty spaces; cellular columns span the entire glandular lumens (only diagnosable as IDC with either necrosis or marked pleomorphism) 2. Micropapillary: cancer cells form delicate papillae with inconspicuous fibrovascular cores 3. Dense cribriform: cancer cells form small, round punched out lumens that comprise 70% of the luminal space 4. Solid mass 1. Cuboidal or low columnar 2. Significant nuclear atypia including enlargement, anisonucleosis, and prominent nucleoli 3. Rarely, nuclei that are six or more times greater than adjacent non-neoplastic nuclei 4. Uncommonly, two-cell populations with central small and uniform nuclei and peripheral pleomorphic nuclei seen in dense cribriform and solid patterns May be present Preserved, at least focally, as observed microscopically or confirmed by immunohistochemistry [(Fig._1)TD$FIG] Fig. 1 A wide range of morphological patterns may be seen in intraductal carcinoma. (A) Dense cribriform structures partly involving a gland with (B) a retained basal cell layer on immunostaining for high molecular weight cytokeratin and P63. Note the invasive carcinoma in the vicinity. (C) Dense cribriform glands. (D) Solid glands showing two-cell populations with central small and uniform nuclei and peripheral more pleomorphic nuclei. (E) Glands with comedonecrosis. (F) Intraductal carcinoma partly involving benign glands. (G) Glands with cells with marked variation in nuclear size and shape that are six or more times greater than the adjacent nuclei. Guo and Epstein [9] described a set of diagnostic criteria for IDC-P in prostate biopsies that is the most widely used and has been accepted in the 2016 WHO classification [1].In addition to the presence of malignant epithelial cells expanding large prostatic acini and ducts with preservation of basal cells, diagnosis of IDC-P requires the presence of a solid or dense cribriform pattern (Fig. 1B) in which punched-out luminal spaces occupy <30% of the central cellular mass. If these features are not present, IDC-P can be diagnosed if loose cribriform or micropapillary patterns are identified with one of the following: (1) comedonecrosis (Fig. 1D) or (2) marked nuclear atypia, for which the nuclei are six or more times larger than adjacent benign nuclei (Fig. 1G). In summary, a constellation of architectural and cytological features is used to diagnose IDC-P. Stringent diagnostic criteria should be applied, especially for prostate biopsies, to ensure that an IDC-P diagnosis is associated with consideration of adverse clinicopathological outcomes. 3.4. Molecular genetics of IDC-P Many genetic changes in IDC-P have been reported. Earlier studies of the genomic instability in PCa, HGPIN, and IDC-P as determined by loss of heterozygosity and comparative genomic hybridization found that IDC-P and Gleason pattern 4/5 PCa show a similar frequency of genomic instability, which is more common than in Gleason pattern 3 PCa and HGPIN [10,11]. Furthermore, IDC-P harbors genetic changes that are more common in Gleason pattern 4/5 PCa than in HGPIN or Gleason pattern 3 PCa [11]. Several recent studies found that PCa with IDC-P and cribriform

24 [(Fig._2)TD$FIG] EUROPEAN UROLOGY ONCOLOGY 1 (2018) 21 28 Fig. 2 (A) Atypical intraductal proliferation that is morphologically more atypical than high-grade prostatic intraepithelial neoplasia, with several large loose cribriform glands lined with uniform nuclei, but is insufficient for intraductal carcinoma. (B) Retained basal cell layer on immunostaining for high molecular weight cytokeratin and P63. components is associated with higher genomic instability with a significantly higher percentage of genome alterations than PCa without this pattern [12,13]. The frequent alterations included deletions of 8p, 16q, 10q23, 13q22, 17p13, and 21q22, and amplification of 8q24, and are clustered to genetic regions involved in aggressive PCa [12]. Of the genes that are affected by somatic copy number alterations, some are known to be associated with aggressive PCa, such as loss of PTEN, CDH1, and BCAR1 and gain of MYC [12]. Chua et al. [13] compared RNA expression profiles between 63 PCas with IDC-P and/or cribriform pattern and 93 PCas without such a pattern and identified one gene, SchLAP1, whose expression was more than threefold higher in PCa with an IDC-P/cribriform pattern out of >25 000 genes tested. SchLAP1, a long noncoding RNA, has been previously associated with poor prognosis in PCa following radical prostatectomy [14]. Surprisingly, IDC-P/cribriform PCa can be further stratified into two subgroups based on the expression of SchLAP1: tumors with positive expression had significantly higher biochemical relapse rate than those with no SchLAP1 expression. A recent study using patient-derived xenograft (PDX) tissue from three carriers of a germline BRCA2 mutation carriers revealed that PDX from BRCA2-mutant tumors had a significantly higher incidence of IDC-P compared to sporadic PCa (42% vs 9%; p = 0.015) [15]. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant PCa. This dysregulation is enriched in BRCA2-mutant PCa harboring IDC-P [16], suggesting a link between BRCA2 mutation, MED12L/ MED12 dysregulation, and aggressive biological behavior in PCa with IDC-P. TMPRSS2-ERG gene fusion is the most common recurrent chromosomal alteration and is present in approximately 50% of PCa treated with radical prostatectomy [17,18]. The

EUROPEAN UROLOGY ONCOLOGY 1 (2018) 21 28 25 ERG gene is rearranged in 75% of IDC-P and the ERG gene fusion status between IDC-P and adjacent invasive PCa is concordant in 100% cases [7], supporting a clonal relationship between IDC-P and PCa. Loss of cytoplasmic PTEN protein is found in 84% of IDCs, and such a loss is concordant between IDC and adjacent acinar carcinoma in 92% of cases [19]. 3.5. Ontogeny of IDC-P IDC-P is almost always intermixed with or in close vicinity to PCa. Not infrequently, a benign gland partially involved by IDC-P may be found, with the appearance of invasive carcinoma colonizing a native benign gland (Fig. 1F). Such a topographic relationship between the two suggests that IDC-P originated from invasive PCa. Molecular studies show that IDC-P and adjacent PCa share the same patterns of genomic changes that are distinct from HGPIN. TMPRSS2- ERG gene fusion has been identified in 75% of IDC-P and none of HGPIN. ERG gene status is concordant between IDC- P and adjacent invasive PCa in 100% of cases, supporting the hypothesis that IDC-P represents intraductal spread of high-grade PCa [7,20]. The most convincing evidence comes from whole-genome sequencing analysis for subclonality of IDC-P, which shows IDC-P and adjacent invasive PCa share an original genetic ancestry before diverging later in tumor evolution [16]. Rarely, IDC-P has been reported either without or with only a miniscule amount of concomitant adjacent invasive PCa [6,8,21]. In a study of the 901 radical prostatectomies, IDC-P was found to be associated with adjacent invasive carcinoma in 141 (15.6%). However, in 14 cases (1.5%) IDC-P was distant from invasive cancer [21]. It is likely that in a small subset of cases IDC-P may represent a precursor to invasive PCa, typically more aggressive invasive cancer than that seen associated with HGPIN. 3.6. Differential diagnosis of IDC-P IDC-P should be differentiated from other atypical prostate lesions with cribriform and solid architecture, which range from normal histological structures and benign proliferative lesions to premalignant lesions and frank malignancies. Normal histological variations, such as central-zone prostate glands, and benign glandular proliferations, such as cribriform clear-cell hyperplasia, can be present as cribriform structures. However, these lesions do not have nuclear atypia, mitotic figures, or comedonecrosis, and are unlikely to be mistaken for IDC-P. The most important differential diagnosis, particularly in prostate biopsies, is between isolated IDC-P and cribriform HGPIN, as the management for these two lesions is drastically different [22]. The architectural and cytological atypia are always more pronounced in IDC-P. The diagnostic criteria described by Guo and Epstein [9] can reliably distinguish IDC-P and cribriform HGPIN in most cases. Although some experts have suggested that immunohistochemical detection of ERG protein and cytoplasmic PTEN loss may be of help in distinguishing HGPIN from IDC-P [7,19,23], there are conflicting data that ERG protein is expressed in some isolated HGPINs [24 26]. Therefore, these tests are not recommended for current clinical use in this setting. It is also questionable if a diagnosis of cribriform HGPIN should ever be made on biopsy as it can be difficult to exclude IDC-P in this setting because of sampling error, and a diagnosis of HGPIN on biopsy is often not followed up with repeat biopsy or monitoring. Most cases for which cribriform HGPIN is a consideration on biopsy should be diagnosed as atypical intraductal proliferation, for which the differential diagnosis is between cribriform HGPIN and IDC-P, with repeat biopsy recommended (see the discussion below). Cribriform and solid Gleason pattern 4 or 5 PCa closely mimics IDC-P. The former, unlike IDC-P, lacks a basal cell lining. The distinction between the two is usually not critical because IDC-P is usually associated with high-grade and high-volume overtly invasive PCa (see below for IDC-P work-up). A confusing issue is the distinction between ductal adenocarcinoma and intraductal carcinoma. IDC-P refers to location within ducts, as opposed to ductal adenocarcinoma, which is based on cytological features of the tumor. Ductal adenocarcinoma is defined by a tall-pseudostratified columnar epithelium as opposed to acinar (usual) PCa, which has a simple cuboidal/low columnar lining of epithelium. Ductal adenocarcinoma involves large atypical glands with expansile growth, usually with papillary, cribriform, or solid growth patterns with frequent necrosis. The papillae in ductal adenocarcinoma have true fibrovascular cores. The majority of ductal adenocarcinomas are invasive with a lack of basal cells. However, invasive ductal adenocarcinoma is also prone to intraductal spread that is mechanistically similar to aggressive acinar PCa. Residual basal cells can be found in ductal adenocarcinoma with intraductal extension into pre-existing benign glands [22]. In a fashion analogous to the majority of IDC-P cases composed of acinar (usual) PCa, almost all IDC-P cases composed of ductal adenocarcinoma have associated invasive ductal adenocarcinoma. However, just as with IDC-P with acinar cytology, there are rare cases of IDC-P with ductal cytology without concomitant invasive PCa, in which the IDC-P is probably a precursor lesion to invasive ductal adenocarcinoma. Colorectal adenocarcinoma and urothelial carcinoma, when secondarily involving the prostate, may extend into native prostate glands and be mistaken for IDC-P. Immunohistochemistry plays a key role in their differential diagnosis. IDC-P is positive for prostate markers such as PSA, P501S, and NKX3.1, and negative for urothelial markers including GATA3, P63, and high molecular weight cytokeratin. 3.7. Clinical significance of IDC-P Since the diagnostic criteria and reporting guideline for IDC- P were only recently established, its incidence is very probably underestimated in published studies. A recent

26 EUROPEAN UROLOGY ONCOLOGY 1 (2018) 21 28 publication indeed found that IDC-P is more prevalent than common perception [27], with an average incidence increasing from 2.1% in low-risk patient cohorts to 23.1%, 36.7%, and 56.0% in cohorts with moderate-risk, high-risk, and metastatic or recurrent disease. IDC-P is also highly prevalent in tumors following androgen deprivation therapy or chemotherapy (59.7%). Studies so far have established that the presence of IDC-P is associated with an aggressive form of PCa and is an independent adverse pathological factor in both radical prostatectomy and needle biopsy specimens and may influence response to current therapeutic regimens for advanced-stage PCa. Since the initial studies by Kovi et al. [3] and McNeal and Yemoto [5], other studies have consistently found that the presence of IDC-P correlates with other adverse pathological features in the associated invasive PCa, including higher Gleason score, larger tumor volume, and greater probability of extraprostatic extension, seminal vesicle invasion, and pelvic lymph node metastasis on radical prostatectomy. It also independently predicts progression-free survival and biochemical recurrence following radical prostatectomy [21,28 32]. IDC-P is also an independent predictor of biochemical recurrence in patients receiving neoadjuvant hormone therapy [29,33,34]. The incidence of IDC-P in prostate needle biopsy varies significantly according to the Gleason grade and tumor volume of PCa in the biopsies. It ranged from 2.8% in a prospectively collected biopsy series [35] to 73.9% in cohorts with locally advanced high-risk PCa [33,36,37]. IDC-P without concomitant PCa is an exceedingly rare finding, occurring in <0.06% of prostate biopsy specimens [6,9]. IDC-P is typically seen in biopsies that contain PCa with high Gleason grade and tumor volume and is associated with adverse findings on radical prostatectomy and poor outcomes. IDC-P in prostate biopsies correlated with seminal vesicle invasion on subsequent radical prostatectomy [35]. The association with adverse findings on radical prostatectomy is true even when the concomitant PCa is Gleason score 6. A recent biopsy study on IDC-P evaluated 73 cases with IDC-P and Gleason score 6 as the highest grade on biopsy [38]. Of the 62 patients with follow-up, four had metastatic disease at diagnosis that was treated with chemotherapy and androgen deprivation. Of the 16 radical prostatectomies, three (19%) had only Gleason score 3 + 3 = 6. The rationale for separating out Gleason 3 + 3 = 6 with IDC-P on biopsy as the highest grade versus Gleason 3 + 4 = 7 is not in how it will affect patient management based on the biopsy. Rather, there are uncommon cases with Gleason 3 + 3 = 6 with IDC-P on biopsy for which radical prostatectomy shows the same finding with no Gleason pattern 4. In these cases, there would no risk of metastatic potential, so assigning the patient Gleason 3 + 4 = 7 on biopsy would be inaccurate and confusing as to the patient s true grade, given discrepancies between the biopsy and prostatectomy grade. Inclusion of IDC-P in prostate biopsies in a preoperative model could improve prediction of the pathological stage in radical prostatectomy specimens [36] and significantly improved the predictive accuracy of a postoperative nomogram that used preoperative clinicopathological variables to predict PSA recurrence after radical prostatectomy [30]. For patients with high-risk PCa undergoing radical prostatectomy, it has been shown that IDC-P in biopsy specimens is an independent prognostic factor. IDC- P diagnosed in prostate biopsies provides independent prognostication of early biochemical recurrence and metastatic failure after radiation therapy in intermediateand high-risk PCa [37]. Although there is some evidence that IDC-P has independent prognostic significance even in high-grade and advanced cancers, its presence currently does not affect treatment or prognosis to an extent that warrants the cost and expense of identifying it in these settings. In two studies, Epstein and associates [6,9] reported on 66 prostate biopsies in which IDC-P was diagnosed without invasive carcinoma. Of the 21 radical prostatectomies available for review, the pathological stage was pt3a in eight (38%), pt3b in three (13%), and pt2 in eight (38%). Isolated IDC-P without identifiable invasive cancer was seen in two radical prostatectomy specimens (10%). The median Gleason score was 8. The authors recommended definitive therapy for men with IDC-P on needle biopsy, even in the absence of pathologically documented invasive PCa. The appropriate clinical management for patients with IDC-P has not been established. Findings that IDC-P is enriched after androgen deprivation and/or chemotherapy [27] have led to speculation that IDC-P may be resistant to current therapeutic regimens for aggressive PCa. It is possible that IDC-P may contain cancer cells that can withstand androgen deprivation [39], or IDC-P may simply be a marker of aggressive PCa. Regardless of the underlying mechanism, these findings suggest that multimodal and novel therapy options are needed to treat PCa with IDC-P. It is thus interesting to note that in patients with metastatic castration-resistant PCa harboring IDC-P, abiraterone showed better efficacy than docetaxel as first-line therapy [40]. Active surveillance would not be recommended for the rare cases with Gleason score 3 + 3 = 6 associated with IDC- P on biopsy. 3.8. Work-up and reporting of IDC-P Both the International Society of Urological Pathology (ISUP) and WHO recommend IDC-P not be assigned a Gleason grade and a comment as to its invariable association with aggressive PCa be made [1,41]. However, the specifics of working up and reporting IDC-P depend on the presence and grade of the concomitant PCa in the specimens. In most cases, IDC-P is present together with a concomitant Gleason pattern 4 or 5 PCa. In these cases, IDC- P should be mentioned in the reports if recognized morphologically. Immunohistochemical staining for basal cell markers is not routinely performed to confirm the diagnosis, as the presence of invasive high-grade PCa will dictate therapy. However, staining should be performed in the setting in which the distinction between invasive PCa and IDC-P may potentially affect the Gleason score. A rare

EUROPEAN UROLOGY ONCOLOGY 1 (2018) 21 28 27 but classical scenario is large atypical glands suspicious for IDC-P found in the background of Gleason score 6 or 3 + 4 PCa, or without co-existing PCa. After the nature of large atypical glands suspicious for IDC-P is clarified, the invasive PCa component can be appropriately graded. IDC-P can be included in the overall cancer volume measurement. When IDC-P is identified in biopsies without concomitant PCa, pathologists should diagnose IDC-P with a comment stating that IDC-P is usually associated with high-grade and highvolume PCa and that definitive therapy may be indicated [6]. However, some pathologists may still recommend immediate repeat biopsy instead of definitive treatment in these rare situations. Finally, any lumen-spanning lesion comprising cytologically atypical cells that do not satisfy the diagnostic criteria for IDC-P but that exceed the criteria for HGPIN should be reported as atypical intraductal proliferation ; the Guo and Epstein [9] stringent criteria are highly specific for the diagnosis of IDC-P since they recommend that definitive therapy be performed for this diagnosis even in the absence of invasive carcinoma. As a result of the high specificity, the sensitivity of these criteria for the diagnosis of IDC-P is lower and they do not encompass the entire morphological spectrum of IDC-P. A significant proportion of intraductal carcinomas may exhibit low-grade features that fall short of the Guo and Epstein criteria (Fig. 2) and may resemble HGPIN [7,21,42,43]. Accumulating molecular evidence suggests that such lesions with borderline morphology could represent IDC-P [41,44]. A recent study by Morais et al. [23] found that these borderline lesions between HGPIN and IDC-P, when diagnosed on biopsies, are associated with a substantial increase in the risk (50%) of invasive carcinoma and/or IDC-P on repeat biopsy. Although IDC-P has a morphological spectrum wider than the accepted classical morphology, low-grade IDC-P terminology is not recommended for use in clinical practice in order to restrict the term IDC-P in surgical pathology reports to lesions that are with rare exception associated with aggressive invasive PCa. Rather, lesions with a morphology of low-grade IDC-P that is morphologically more atypical than HGPIN but not sufficient for IDC-P should be reported as atypical intraductal proliferation, for which immediate repeat biopsy is warranted in this setting to rule out unsampled invasive carcinoma. 4. Conclusions IDC-P is a distinct clinicopathological entity with architectural or cytological features that exceed what is seen with HGPIN. IDC-P is typically associated with aggressive PCa, with high Gleason grade and large tumor volume, and independently predicts clinical outcomes. It is critical for pathologists to recognize and report IDC-P in prostate specimens, especially in prostate biopsy, for patient management. Author contributions: Jonathan I. Epstein had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Montironi, Zhou, Magi-Galluzzi, Epstein. Acquisition of data: Montironi, Zhou, Magi-Galluzzi, Epstein. Analysis and interpretation of data: Montironi, Zhou, Magi-Galluzzi, Epstein. Drafting of the manuscript: Montironi, Zhou, Magi-Galluzzi, Epstein. Critical revision of the manuscript for important intellectual content: Montironi, Zhou, Magi-Galluzzi, Epstein. Statistical analysis: None. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Montironi, Epstein. 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