EUROPEAN UROLOGY 62 (2012) 20–39

available at www.sciencedirect.com journal homepage: www.europeanurology.com

Platinum Priority – Collaborative Review – Prostate Cancer Editorial by Maxine Sun, Marco Bianchi, Jens Hansen and Pierre I. Karakiewicz on pp. 40–41 of this issue

A Contemporary Update on Pathology Reporting for Prostate Cancer: Biopsy and Radical Prostatectomy Specimens Samson W. Fine a,*, Mahul B. Amin b, Daniel M. Berney c, Anders Bjartell d, Lars Egevad e, Jonathan I. Epstein f, Peter A. Humphrey g, Christina Magi-Galluzzi h, Rodolfo Montironi i, Christian Stief j a

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; b Department of Pathology and Laboratory Medicine, Cedars-Sinai

Medical Center, Los Angeles, CA, USA; c Department of Molecular Oncology and Imaging, St. Bartholomew’s Hospital Queen Mary University of London, London, UK;

d

Department of Urology, Ska˚ne University Hospital, Malmo¨, Sweden; e Department of Oncology-Pathology, Karolinska Institutet, Stockholm,

f

Sweden; Departments of Oncology, Pathology and Urology, Johns Hopkins Hospital, Baltimore, MD, USA;

g

Department of Pathology and Immunology,

Washington University School of Medicine, St Louis, MO, USA; h Department of Anatomic Pathology, Cleveland Clinic and Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA; i Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy; j Department of Urology, Ludwig Maximilians-Universita¨t Mu¨nchen, Munich, Germany

Article info

Abstract

Article history: Accepted February 29, 2012 Published online ahead of print on March 8, 2012

Context: The diagnosis of and reporting parameters for prostate cancer (PCa) have evolved over time, yet they remain key components in predicting clinical outcomes. Objective: Update pathology reporting standards for PCa. Evidence acquisition: A thorough literature review was performed for articles discussing PCa handling, grading, staging, and reporting published as of September 15, 2011. Electronic articles published ahead of print were also considered. Proceedings of recent international conferences addressing these areas were extensively reviewed. Evidence synthesis: Two main areas of reporting were examined: (1) prostatic needle biopsy, including handling, contemporary Gleason grading, extent of involvement, and high-risk lesions/precursors and (2) radical prostatectomy (RP), including sectioning, multifocality, Gleason grading, staging of organ-confined and extraprostatic disease, lymph node involvement, tumor volume, and lymphovascular invasion. For each category, consensus views, controversial areas, and clinical import were reviewed. Conclusions: Modern prostate needle biopsy and RP reports are extremely detailed so as to maximize clinical utility. Accurate diagnosis of cancer-specific features requires upto-date knowledge of grading, quantitation, and staging criteria. While some areas remain controversial, efforts to codify existing knowledge have had a significant impact on pathology practice. # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Keywords: Gleason grading Needle biopsy Prostate cancer Radical prostatectomy Reporting Staging

* Corresponding author. Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue—Room C513, New York, NY 10065, USA. Tel. +1 212 639 5066; Fax: +1 646 422 2070. E-mail address: fi[email protected] (S.W. Fine).

1.

Introduction

Prostate cancer (PCa) remains the most commonly diagnosed cancer in men in developed countries, although death from PCa has steadily declined over the past 10–15 yr [1]. Currently, most men in whom PCa is detected will die with,

rather than of, PCa. Characterization, clinical management, and follow-up of patients with PCa are highly dependent on a combination of laboratory factors (prostate-specific antigen [PSA] measurement), clinical factors (digital rectal examination), and pathologic factors [2–4]. Within the diagnostic armamentarium, pathologists play an important

0302-2838/$ – see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.eururo.2012.02.055

EUROPEAN UROLOGY 62 (2012) 20–39

role in identifying pathologic features in both prostatic needle biopsy and radical prostatectomy (RP) specimens that allow for appropriate risk stratification. As changes and modifications have occurred over the past 30 yr in the patient population diagnosed with PCa, as well as in the diagnostic material and pathologic criteria for PCa, we review the contemporary handling and reporting of PCabearing specimens. 2.

Evidence acquisition

A thorough literature review was performed for articles discussing PCa handling, grading, staging, and reporting that were published as of September 15, 2011. Electronic articles published ahead of print were also considered. Proceedings of recent international conferences addressing the reporting of PCa-bearing specimens were extensively reviewed. 3.

Evidence synthesis

3.1.

Pathology reporting for prostate cancer: biopsy specimens

Essential reporting elements for cancer-bearing prostatic needle biopsy specimens are summarized in Table 1. 3.1.1.

Specimen submission, gross description, and site designation

Concurrent with the rise of PSA screening and increasingly sensitive imaging techniques, the average number of prostate needle biopsy cores has risen from 2 to 6 to 12 over the past 20 yr [5–7]. With this expansion, the primary purpose of needle biopsy has shifted from the targeting of specific areas of concern on rectal examination to the systematic mapping of the gland for cancer involvement and quantity [7]. In modern practice this information is routinely used to determine (1) the indication or lack of indication for any form of therapy or follow-up, (2) the type of therapeutic options offered to the patient, (3) the extent of resection (ie, nerve sparing or not) for patients opting for surgery, and (4) the nature and dosing of radiation therapy. Given the import of these results, the submission, handling, and description of biopsy cores assume clinical significance. Whether needle cores are submitted in two containers (right and left sides) or in separate containers with specific site designations (eg, right lateral apex, right lateral mid, right lateral base) is not uniform among urologists or institutions. However, the potential importance of knowing the specific location of the biopsy, and

Table 1 – Essential reporting elements for cancer-bearing prostatic needle biopsy specimens  Gleason grades/score * Usual scenario: primary plus secondary patterns * Special scenario: see Tables 2–3  Number of positive cores  Tumor quantitation/extent (percentage of involvement and/or linear extent, in millimeters)  Treatment-related changes

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therefore the location of cancer, is well recognized; this information allows for avoidance of diagnostic pitfalls (eg, normal anatomic structures, such as the prostatic central zone and seminal vesicles [base biopsy], that may mimic prostatic intraepithelial neoplasia [PIN] or cancer, respectively) [8], detailed correlation with clinical and imaging studies, and effective treatment planning [7,9]. In addition, a number of studies have correlated the presence and amount of cancer in different regions with risk of higher pathologic stage and margin positivity [10]. On a practical level, processing and pathologic assessment of needle biopsies are greatly facilitated if biopsies are separated. Less material is lost when cutting single biopsies; reading biopsies one by one is easier and facilitates identification of minimal foci of cancer [11]. Therefore, when cores are submitted separately or assigned a clear site designation by container, the pathology report should reflect this labeling. Some urologists place multiple cores into each container and attempt site designation based on inking of each core. However, this practice may result in fragmentation and/or nonevident ink on the cores, so it is not recommended for site-specific designation. 3.1.2.

Gleason grading: background and historical context

The modern system for grading prostatic adenocarcinoma emerged from work by Donald F. Gleason in the 1960s based on a specimen cohort from the Veterans Administration Cooperative Research Group [12]. Nearly 50 yr later, the Gleason grading system remains novel in that it is based on the architectural pattern of the tumor alone (Gleason patterns 1–5); the sum of the two most common patterns— that is, primary Gleason pattern plus secondary Gleason pattern equals Gleason score (GS)—conveys the most clinical meaning. While additional morphologic descriptors were added to patterns 3, 4, and 5 in subsequent 1974 and 1977 publications [13,14], all these observations emanate from an era in which PSA screening was nonexistent, most patients presented with palpable and/or advanced disease, and prostatic tissue was typically obtained from transurethral resection (TUR) specimens or other large specimens. With the introduction of PSA screening, as well as the advent of thin-needle biopsy techniques and expanded sampling over the last two decades, it has become necessary for pathologists to diagnose and grade PCa on smaller and better characterized samples. As a result of increasing volumes coupled with the importance assigned to Gleason grading in modern predictive models [3,4], pathologists have garnered much experience in the application of the Gleason grading system. Not surprisingly, this has led to gradual evolution in practice. A well-documented example of this phenomenon is the group of lesions formerly diagnosed as GS 1 + 1 = 2. It is now well known that many such cases would have benefited from modern immunohistochemical staining with basal cell markers and today might be classified as adenosis (adenomatous hyperplasia), a benign entity [15]. Additional difficult and/or underrecognized areas in Gleason grading, such as what pattern to assign to small to medium-sized

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[(Fig._1)TD$IG]

cribriform glands, poorly formed glands, and variants of carcinoma, have also been encountered. In 2005, the International Society of Urologic Pathology (ISUP) convened a conference on Gleason grading to address emerging issues in the field based on existing data, as well as the personal and institutional experience of a large international group of urologic pathologists. The resulting manuscript, ‘‘The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma,’’ serves as a provisional diagnostic guide to modern Gleason grading [16]. Importantly, the modifications to Gleason grading codified in the 2005 ISUP paper represent collective changes introduced over the course of the 1990s and early 2000s based on muchexpanded experience with assessment of prostatic needle biopsy and RP specimens. A few publications since 2005 have addressed morphologic findings for which limited to no literature existed [17–19]. 3.1.3.

Fig. 1 – Gleason pattern 3: small to medium-sized discrete acini with focal tangential sectioning.

Needle biopsy Gleason grading: usual scenarios

Nearly all prostatic carcinomas seen in needle biopsy specimens are of the usual (acinar or conventional) type, to which the Gleason grading system may be applied. Gleason patterns 1–2 (GS 2–4), which require nodular circumscription as a diagnostic criterion, are not easily evaluable in the limited tissue of needle biopsy. In light of poor correlation with prostatectomy grade and reproducibility among experts, GS 2–4 are for practical purposes not diagnosed in these specimens [15,16]. Conversely, Gleason pattern 5, including single cells, sheet of cells, and comedocarcinoma, is essentially unchanged from its original descriptions [12–14]. Overall, the 2005 ISUP recommendations convey a significant contraction of Gleason pattern 3 and a consequent expansion of Gleason pattern 4, with Gleason pattern 3 typically the lowest assigned grade. The most profound impact of these changes has been on grading of prostatic needle biopsies, with GS 7 now being the most commonly assigned score in many settings [20,21]. In modern terms, discrete and well-formed, infiltrative glands—even when small—have been retained within Gleason pattern 3 (Fig. 1). In contrast, practice patterns have diverged with regard to cribriform glands with rounded contours, as well as ill-defined glands with poorly formed lumina, originally considered Gleason pattern 3 [16]. A percentage of small to medium-sized cribriform lesions label with basal cell markers and are better recognized today as cribriform high-grade PIN [22]. Of many images presented to ISUP experts in 2005, only rounded, well-circumscribed glands having the same size as normal glands, as well as evenly spaced lumina and cellular bridges of uniform thickness, were diagnosed as pattern 3. A subsequent study in which 10 well-known uropathologists were asked to grade a highly selected set of images thought to be representative of cribriform Gleason pattern 3 found that nearly all cases were considered Gleason grade 4 [18] (Fig. 2). In routine practice, therefore, cribriform glands, regardless of size, are nearly always diagnosed as pattern 4. A related feature of PCa is glomerulations or glomeruloid structures, characterized by dilated glands with intraluminal

cribriform structures, a morphology not accounted for in the original Gleason system. While the 2005 ISUP group did not reach consensus on this histology, a recent study reported that 45 biopsies with glomerulations showed an association with Gleason pattern 4 cancers in the same biopsy in >80% of cases [19]. This evidence, along with the significant morphologic overlap with, and occasionally observed transitions to, cribriform Gleason pattern 4 carcinoma, favors classifying glomerulations as pattern 4 (Fig. 3). The 2005 ISUP conference also highlighted the controversy surrounding classification of ‘‘ill-defined glands with poorly-formed glandular lumina’’ (Fig. 4). While there is some consensus that such foci should be graded as pattern 4, this morphology represents a significant challenge for the Gleason grading system, with few instructive images in the existing literature. The ISUP panel cautioned that a ‘‘cluster of ill-defined glands in which a tangential section of pattern 3

[(Fig._2)TD$IG]

Fig. 2 – Medium-sized cribriform gland with somewhat irregular luminal spaces (on left) that would be assigned Gleason pattern 4.

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[(Fig._3)TD$IG]

Table 2 – Reporting recommendations for prostate cancer variants Variant Atrophic Pseudohyperplastic Foamy Vacuoles Mucinous (colloid) Ductal Sarcomatoid Signet ring cell Small cell/ neuroendocrine Squamous Basaloid

Fig. 3 – Glomerulations demonstrating significant morphologic overlap with and transition to cribriform Gleason pattern 4 carcinoma.

Gleason grade 3 3 3 or 4 (depending on architecture) 3, 4, or 5 (extract vacuoles/grade architecture) Either 4 (based on extracellular mucin alone) or 3 or 4 (extract mucin/grade architecture) 4* 5 (glandular component graded separately) 5 Not graded Not graded Not graded

* Like a number of other variants, ductal carcinoma is typically associated with acinar (conventional) adenocarcinoma. Recently, ductal carcinomas with stratified or ‘‘high grade PIN-like’’ morphology [17] have been described, typically associated with Gleason pattern 3. Finding ductal carcinoma with comedonecrosis would warrant assigning a Gleason pattern 5.

[(Fig._4)TD$IG] 3.1.4.

Needle biopsy Gleason grading: special scenarios

Although Gleason grading is and always has been fundamentally based upon a sum of the first and second most common patterns, uropathologists have evolved reporting strategies for some specific scenarios in which (1) morphologic patterns are not well addressed within the original Gleason system, (2) the classic grading might not be clinically precise, and (3) the patient has received prior therapy. While some of these recommendations are consonant with the original Gleason system, the method of applying these rules has been clarified over time. Tables 2–3 summarize these recommendations. 3.1.5.

Fig. 4 – Gleason score 3 + 4 = 7 carcinoma. Note multiple poorly formed glands with ill-defined lumina and/or incomplete nuclear complement.

glands cannot account for the histology’’ would be diagnosable as Gleason pattern 4 [16], a determination that in many cases necessitates evaluation of multiple levels and sections of such glands.

Needle biopsy Gleason grading: prostate cancer variants

The Gleason grading of a number of variants has been modified from the original system, as reflected in Table 2. The group of mucin-related tumors is a controversial and evolving area within Gleason grading. Carcinomas associated with extravasated mucin (either focal or abundant) and/or mucinous fibroplasia present a diagnostic challenge because of significant distortion of tumor architecture [23]. In the biopsy context, it is difficult to evaluate true mucinous (colloid) carcinoma, which requires the presence of >25% mucin pools for its diagnosis [24]. However, carcinomas with mucinous features, typically composed of

Table 3 – Reporting recommendations for special Gleason grading scenarios Scenario Only one grade present (eg, GG 3) Abundant high-grade cancer (eg, GG 4) with 5%, include lower-grade cancer (assign GS 4 + 3 = 7) Include the higher grade (assign GS 3 + 4 = 7) Classify as high grade (assign most common plus highest grade) Assign separate GS to each core Assign overall GS for the specimen

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[(Fig._5)TD$IG]

Fig. 5 – Carcinoma with mucinous features. Note that although some truly fused glands (pattern 4) are present, much of the cancer consists of discrete glands (pattern 3) with varying degrees of distortion by extravasated mucin.

irregular cribriform glands in a mucinous background, may be diagnosed. Such cases may also show individual glands in the same background or simulated ‘‘gland within gland’’ patterns representing single distorted acini and caused by encroachment of acellular mucin in and adjacent to neoplastic glands (Fig. 5). A similar finding is carcinoma with mucinous fibroplasia (collagenous micronodules), indicating the delicate ingrowth of fibrous tissue in and among glands, which may result in fused- or cribriformappearing glands. While colloid carcinoma with cribriform glands is routinely graded as 4 + 4 = 8 in RP specimens, there is no consensus regarding cases with discrete glands in a background of extravasated mucin or mucinous fibroplasia. At the 2005 ISUP conference, some attendees suggested that the mucin or mucinous fibroplasia be extracted and the underlying architecture graded [16]. As such, a percentage of these cases would be graded as GS 3 + 3 = 6. While early studies of mucinous carcinoma from the pre-PSA era showed associations with Gleason patterns 4–5 nonmucinous PCa and adverse outcomes [24,25], more recent studies have recognized the variability in the epithelial component of mucin-containing carcinomas and have reported no death from disease and limited biochemical recurrence without clinical evidence of local or distant recurrence in patients who had mucinous carcinoma treated by RP [26,27]. In theory, the latter results support grading based on the architectural configuration rather than by the presence of extracellular mucin in these tumors, a finding that should be confirmed in larger series. 3.1.6.

Increasing clinical precision with Gleason grading

on needle biopsy

There are certain circumstances in which reporting primary plus secondary Gleason grades may be inexact, as the traditional GS is unlikely to be representative of cancer in the gland (Table 3). For instance, in the context of abundant

high-grade cancer, lower-grade patterns should not be incorporated in the GS. If the pathologist encounters a 15mm core with 13 mm of cancer in which 0.5 mm displays Gleason pattern 3 and the remainder is Gleason pattern 4, the pathologist should diagnose GS 4 + 4 = 8 [16]. Conversely, any amount of high-grade tumor should be included in the GS, as it very often reflects more significant high-grade tumor in the gland. Hence, a 15-mm core with 13 mm of cancer in which 0.5 mm displays Gleason pattern 4 and the remainder is Gleason pattern 3 should be diagnosed as GS 3 + 4 = 7 [16]. To apply the second rule correctly, the possibility of tangential cuts of pattern 3 glands masquerading as fused or poorly formed glands must be excluded. Although Gleason himself noted the presence of more than two patterns in approximately 50% of RP specimens, quantitating this phenomenon in needle biopsy has been more difficult, with the few existing reports suggesting an incidence of 1.5–4% [28,29]. How to address tertiary Gleason patterns in the biopsy context is controversial, as any incorporation of the third most common pattern is by definition contrary to Gleason’s original approach [12]. Nonetheless, in some cases, the pathologist encounters a core with three patterns of cancer—most typically, patterns 3, 4, and 5 (eg, 3 + 4 = 7 or 4 + 3 = 7 with a minor component of 5). As an example of a pathology recommendation based on empirical experience and heavily influenced by clinical practice, the ISUP group recommended that such cases be classified overall as high grade (primary grade plus highest grade) because of the possibility that the highest grade is a more significant component in the gland. Consequently, the highest grade would be used by clinicians when assessing risk using a variety of predictive models, which only allow for two grades. For example, a core with 10 mm of cancer that is composed of 65% pattern 3, 25% pattern 4, and 10% pattern 5 would be diagnosed as GS 3 + 5 = 8 [16]. A subsequent study has supported this ‘‘first plus worst’’ approach, finding earlier time to, and higher percentage of patients with, biochemical recurrence in patients with GS 7 with tertiary pattern 5 compared with GS 7 alone [29]. When cores are submitted in separate containers and/or have a clearly designated location, it is presumed that the urologist–oncologist will be interested in this information for treatment planning. Therefore, the pathologist should assign a separate GS to each sampled core, rather than an overall or averaged score for the entire biopsy session [16,30,31]. Such practice avoids weakening the predictive power of the highest GS (eg, one core showing 4 + 4 = 8 and multiple cores showing 3 + 3 = 6; overall GS would assign 3 + 4 = 7) and is buoyed by studies demonstrating that the highest GS in a specimen correlates with grade and stage at RP [32,33]. There is no uniform manner of grading cores of differing GS in the following contexts: (1) multiple cores in one container without site designations and (2) multiple fragmented cores in one container even with site designation. These settings are problematic, as the relationship of each core or fragment to another is unclear, and the potential for overgrading is increased. So as not to impose a seemingly precise assessment in an inherently imprecise

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scenario, logic dictates that the pathologist would assign an overall GS in these cases. 3.1.7.

Grading irradiated cancer

Radiation therapy (external beam and/or brachytherapy [‘‘seeds’’]) is commonly used to treat clinically localized or locally advanced PCa. In the setting of a rising PSA after radiation therapy, a biopsy is typically performed in an attempt to distinguish local (in the prostate) recurrence from metastatic disease and for histologic confirmation if a salvage RP is to be attempted. Occasionally, the pathologist will not be informed of a history of radiation therapy, so it is essential to recognize the changes in benign and malignant glands that occur with this intervention, which have been well described elsewhere [34]. While in the past, benign tissue with marked therapeutic effect may have been diagnosed as atypical, increased recognition that these changes are therapy related has aided pathologists in their correct identification. Cancerous foci exhibiting profound treatment effect secondary to radiation typically display infiltrative, poorly formed glands or single cells with moderate to abundant vacuolated clear cytoplasm and prominent nucleoli [34] (Fig. 6). When only irradiated cancer is seen, the case may be signed out as ‘‘adenocarcinoma with profound treatment effect’’ and not graded. When usual-type adenocarcinoma is solely present after therapy, such that the observed cancer is indistinguishable from that of a patient who had not received radiation, the cancer is graded. Although not codified in the literature, in cases in which both gradable cancer and cancer with treatment effect are seen, a reasonable approach is to assign a GS and add a note stating, ‘‘The assigned Gleason score reflects the gradable portion of the carcinoma (%); the remaining cancer shows profound treatment effect.’’ Determining whether gradable cancer is present is crucial for clinical management, as studies of postradiation biopsies with 10-yr follow-up indicate that the biochemical recurrence-free and distant failure rates for patients having only cancer with profound treatment effect are similar to

[(Fig._6)TD$IG]

the rates for patients with benign biopsies, as opposed to patients with gradable cancer [35]. Said another way, the presence or absence of gradable cancer in a biopsy after radiation therapy is a major indicator of clinical outcome. 3.1.8.

Needle biopsy Gleason grade as a measure of risk

Independent of these recent modifications, accumulated evidence from >40 yr of application has shown the biopsy GS to be the most significant predictor of pathologic outcomes at RP, as well as one of the key predictors of clinical outcomes after RP and radiation therapy [4,21,36–41]. Furthermore, GS on needle biopsy may be used to determine therapeutic choices, the extent of neurovascular bundle resection, or performance of a pelvic lymph node (LN) dissection. Consequent to the evolution previously described, the value of grouping GS (ie, GS 6, 7, 8–10), such that each group behaved worse than the group below it, was recognized. Further substratification of GS 7 based on primary grade (ie, GS 3 + 4 = 7 vs GS 4 + 3 = 7) has also been shown to influence pathologic and clinical outcomes [42–44] and is routinely reported. It has also been demonstrated that tumors with biopsy GS 9–10 are associated with a much worse prognosis than tumors with GS 8, such that GS 8–10 might not be considered a homogeneous group [45]. As Gleason grading is incorporated into every predictive tool that has been designed for PCa [4,39,40], the accurate and reproducible application of this system has clinical meaning. In the past two decades, major educational and media efforts, including Web sites, publications, and courses, have resulted in significantly better correlation for GS on biopsy among community and academic pathologists, such that >80% of cases showed exact agreement in a recent large series [37]. Few formal studies have evaluated the impact of the 2005 ISUP conference [20,21,46–49], and the studies that have done so were small cohorts with limited follow-up. As many of the ‘‘changes’’ or ‘‘consensus’’ positions represent modifications by groups of pathologists over time, such an exercise may also not be fruitful, as using 2005 as a dividing line between an ‘‘old’’ and a ‘‘new’’ system may be biased and inaccurate. While these studies have generally documented a higher percentage of biopsy specimens with GS 7 in cohorts after 2005 and a somewhat improved biopsy– prostatectomy GS correlation and prediction of biochemicalfree progression after RP, more robust data with long-term follow-up addressing these questions are awaited. 3.1.9.

Fig. 6 – Adenocarcinoma with profound radiation treatment effect. Note poorly formed glands and single cells with vacuolated clear cytoplasm.

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Extent of involvement

For core biopsy specimens, the absolute number of cores examined and involved is routinely reported. In cases with one core submitted per container, this assessment is simple. In the event of multiple cores per container, the degree to which tissue fragmentation has taken place will affect this determination. Once a diagnosis of cancer has been rendered for a given core, there are multiple measures of tumor quantification that have been reported to correlate with pathologic grade and stage, as well as predict biochemical recurrence [50–53]. Many of these evaluations are tedious, are not routine in contemporary practice, and may add little to the predictive

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accuracy of more simple measurements. However, there is overwhelming consensus that in addition to the number of cores involved, some quantitation of tumor extent on a percore basis should occur, whether by visual estimation of linear extent in millimeters, percentage of the core involved, or both [54]. The latter may be reasonable, given that a variety of clinical nomograms and protocols use different measures. When multiple cores are submitted in the same cassette, there is a higher likelihood of fragmentation [11], such that it may be most prudent to report the percentage of the overall fragmented specimen involved by cancer in these cases. Within a given core, foci of cancer may be present continuously or discontinuously along the length of the specimen. In the former case, length in millimeters, percentage of core involvement, or both are readily assessed. When multiple foci of carcinoma are separated by intervening benign prostatic glands and stroma, some pathologists will ‘‘collapse’’ the tumor by disregarding the intervening tissue [50], while others will measure the farthest distance between the outermost foci and report the entire length or percentage as if there were one unbroken focus (eg, three small foci of carcinoma discontinuously involving 80% of the core) [55]. This method may result in vastly differing tumor quantitation, which may affect nomogram predictions or eligibility for active surveillance. Two contemporary studies of this specific issue convey different findings. The first study showed that in cores with discontinuous foci of cancer separated by 5 mm of intervening benign stroma, different methods used to estimate cancer length have equal prognostic significance [50]. In contrast, a recent report has suggested that for cancer-bearing cores in which the needle biopsy GS is reflective of the entire tumor in the RP specimen, quantitating discontinuous foci as one unbroken focus correlates better with pathologic outcomes [55]). Given the limited evidence, it is not possible to draw a definitive conclusion at this time. 3.1.10.

Perineural invasion

Perineural invasion, defined as cancer tracking along or circumferentially around a nerve, is a relatively ubiquitous finding in RP specimens. In needle biopsies, an incidence between 11% and 38% has been reported in large cohort series [56]. There appears to be functional bidirectional communication between nerves and prostatic carcinoma cells accounting, at least in part, for perineural growth, which is a major route of extraprostatic extension [57]. However, there has been significant controversy over the past two decades as to whether this finding on needle biopsy predicts extraprostatic spread at RP and/or biochemical recurrence after therapy (surgical or radiation) [58–65]. Reviews by Bismar et al. and Harnden et al. reveal that while most studies find perineural invasion to be predictive of extraprostatic extension in univariate analysis, its importance is not retained once PSA, clinical stage, and biopsy GS (common preoperative parameters) are considered in multivariate analysis [51,56]. Similarly, there are conflicting data as to whether perineural invasion predicts recurrence after surgery or radiation therapy. Importantly, the meta-analysis by Harnden et al. has shown that studies that analyzed

perineural invasion in specific patient groups stratified by PSA levels, clinical stage, GS, and/or biopsy tumor extent have found it to be an independent prognostic factor [56]. It is also clear from these collective studies that surgeons react in different ways to a report of perineural invasion on needle biopsy. While some groups initially considered this finding an indication to abandon nerve-sparing surgery, recent data suggest that bilateral nerve sparing may be performed without compromising oncologic efficacy in the majority of patients [60]. Taking into account the relative ease of identifying perineural invasion, its proposed significance in at least some patient groups, and the variation in therapeutic choices among centers and clinicians, many pathologists routinely report this finding. 3.1.11.

High-risk lesions and putative precursors: small foci of

atypical glands, suspicious for carcinoma

Atypical small acinar proliferation (ASAP) and small focus of atypical glands, suspicious for carcinoma are terms that refer to a gland or focus of glands that is suspicious for cancer but lacks sufficient architectural and/or cytologic atypia for a definitive diagnosis. This diagnosis is rendered in 10% of secretory cells at 40 magnification,’’ ‘‘in >10% of secretory cells at 20 magnification,’’ and ‘‘in >10% of secretory cells regardless of magnification.’’ These answers represented 16%, 17%, 19%, 11%, 9%, and 13% of replies, respectively, clearly demonstrating the great variability in the application of this diagnosis [67]. These findings indicate the need for more specific diagnostic criteria to increase the reproducibility of a PIN diagnosis. While the incidence of high-grade PIN does not appear to be dependent on the number of cores sampled, with studies

27

in the 6- and 12-core eras showing similar variability in PIN detection [66], a significantly decreased incidence of cancer detection following a high-grade PIN diagnosis has been observed [77–79]. While the literature reveals a huge span of cancer incidence after high-grade PIN diagnosis, ranging from 2.3% to 100%, a more careful look reveals an incidence of approximately 50% in studies from the 1990s, which dropped to approximately 20% after 2000 [66]. This change approximates the shift toward more extended biopsy schema, which is now the norm. Furthermore, recent studies that examined the risk of cancer on rebiopsy following a diagnosis of highgrade PIN compared with that following a benign diagnosis have shown no statistically significant differences [66,80]. This finding has led some practitioners to propose that early repeat needle biopsy is not required for men within 1 yr of a PIN diagnosis, especially if there is only one core with high-grade PIN [79]. When the initial biopsy is multifocal (more than one core with PIN), the risk of cancer on immediate repeat biopsy is approximately 40% [81,82] and justifies repeat biopsy within the first year. However, the long-term risk of cancer with unifocal high-grade PIN on initial biopsy remains unknown. Until data exist, it may be reasonable to perform a repeat biopsy between 1 and 3 yr later, as suggested by some groups [83,84]. 3.1.13.

High-risk lesions and putative precursors: intraductal

carcinoma

Intraductal carcinoma is characterized by malignant epithelial masses conforming to the contours of often expanded native ducts and/or acini displaying basal cells. Early descriptions from RP specimens drew attention to the fact that in contradistinction to high-grade PIN, intraductal carcinoma is rare in areas away from carcinoma [85]. This dichotomy is also reflected in needle biopsies, in which intraductal carcinoma is rarely seen in the absence of invasive cancer [86]. Further studies revealed associations with high GS and tumor volume, as well as increased rates of extraprostatic extension, seminal vesicle invasion, and recurrence after prostatectomy [86–88]. Based on this evidence, most experts have argued that intraductal carcinoma is part of the evolution of PCa (a late event) or, alternatively, an aggressive precursor (which may or may not arise from PIN) [87,89]. Recent follow-up series of needle biopsies containing exclusively intraductal carcinoma have shown that the overwhelming number have invasive cancer with GS >7 and pT3 disease at subsequent RP [86,90]. These associations reveal the critical importance of separating high-grade PIN from intraductal carcinoma on needle biopsy. Diagnosing intraductal carcinoma may be difficult, as the description of this condition may overlap with that of highgrade PIN in a given case. A number of authors have proposed more specific architectural and cytologic features that they feel to be beyond what is acceptable for a PIN diagnosis [86,90]. The most commonly agreed-on criteria are intraductal foci with dense cribriform (more solid than cribriform) to solid masses with or without comedonecrosis. Although not always present, the other feature that has been repeatedly associated with intraductal carcinoma is marked nuclear atypia in the form of striking nucleomegaly,

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[(Fig._7)TD$IG]

Fig. 7 – Intraductal carcinoma: solid growth of malignant cells with marked nuclear atypia. Note the evident basal cells at multiple points in the periphery of the duct.

hyperchromasia, and/or overt pleomorphism (should be well beyond the increased nuclear size, hyperchromasia, and prominent nucleoli seen in high-grade PIN) (Fig. 7). However, in the absence of these collective findings, the threshold for diagnosing this pattern of carcinoma is more blurred. For instance, some experts would not consider an intraductal carcinoma diagnosis in the presence of loosely cribriform or micropapillary intraductal lesions, always classifying them as high-grade PIN, while others would accept these architectures within the intraductal carcinoma spectrum only when accompanied by marked nuclear atypia [88,90]. In practice, the identification of rounded or circumscribed masses of malignant cells with complex architecture and/or obvious nuclear atypia and a preserved basal cell layer should raise the diagnostic possibility of intraductal carcinoma. Given the well-established correlation with high-grade, high-stage disease at RP, when detected, the presence of intraductal carcinoma should be noted in needle biopsy reports; some experts recommend definitive therapy when intraductal carcinoma is diagnosed on biopsy [86,90]. 3.2.

Pathology reporting for prostate cancer: transurethral

resection specimens

Even though it is not the primary diagnostic modality for PCa, TUR may yield incidental cancers in 4–16% of patients who undergo surgery for benign prostatic hypertrophy (BPH) [91,92]. However, the prevalence of this finding has progressively decreased in recent years secondary to PSA testing and biopsy diagnosis prior to TUR, as well as a rise in medical and ablative therapies for BPH [93]. When cancers are detected in TUR specimens, processing issues and quantitation of tumor may have clinical import, since these incidental cancers are designated cT1a or cT1b depending on whether 5% or >5% of the tissue is involved. Importantly, TUR cancers with GS >6 are designated cT1b, regardless of percentage of involvement. Since much of the tissue resected

emanates from the region anterior to the urethra and likely represents prostatic transition zone [94], pathologists should exercise caution in diagnosing lower-grade cancer in this setting given the not infrequent finding of PCa mimics, such as adenosis and basal cell hyperplasia, in this region. In current practice TUR specimens are weighed and measured in aggregate and submitted in multiple cassettes. However, there is no consensus regarding the degree of sampling required, with some pathologists submitting all tissue and others using subtotal sampling protocols. Additionally, among pathologists who submit less than all tissue in the initial processing, more or all of the tissue may be examined in younger men, in specimens of greater weight, or in cases with 5% involvement correlated with adverse clinical behavior [93], evidence that led to the initial 1992 TNM designations of cT1a and cT1b. However, T-staging for incidental TUR-based cancer may be limited by the amount of tissue removed surgically and the amount of tissue submitted, so it may be difficult to tell whether the detected cancer accurately reflects the cancer in the whole gland. Furthermore, cT1b is a heterogeneous group with widely varying percentage of involvement, GS, and when determined, pathologic stage at RP [93]. Therefore, the time-honored dictum of ‘‘follow T1a, treat T1b’’ has come under scrutiny, with multiple studies demonstrating that (1) this division imprecisely predicts final pT stage and (2) when controlling for PSA, GS, and year of surgery, clinical T stage is not independently predictive of biochemical recurrence [92,94,98–100]. While total sampling or careful gross examination of TUR chips [93,94] may somewhat improve the predictive value of TUR-detected cancer descriptors, Rajab et al, in a cohort of 914 incidental TUR cancers, have shown that the percentage of positive TUR chips, especially when stratified by 25% intervals (ie, 0–25%, 26–50%, 51–75%, >75%), is significantly more effective than cT stage in anticipating adverse outcomes [99]. In a different vein, Capitanio et al. have advanced an algorithm for determining which TURdetected cancers have the highest likelihood of pT0 (no residual carcinoma) at RP and might benefit from surveillance. The latter group determined that patients with PSA 1.0 ng/ml, and that this effect was strongest in patients with pre-TUR PSA 95% of adverse features [117] and represents a practical alternative for institutions not wishing to submit the entire gland. Centers opting for any subtotal submission of the gland should balance its benefits against the additional effort expended in keeping track of remaining tissue, subsequent embedding of

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additional blocks, dictating amended reports, and/or a delayed final diagnosis [107]. 3.3.2.

Multifocality

The tendency of PCa to develop in a multifocal fashion is well established, with reported rates between 60% and 90% in surgically removed glands [118]. Although the biologic basis for multifocality still requires clarification [119,120], this aspect of PCa has a significant impact on RP reporting, especially in assigning zonal origin, identifying the index or dominant tumor nodule, and grading and staging.

will be the stage-determining lesion, up to one-third of cases may not conform to this rule [118]. While it is relatively easy to report a dominant nodule location in the former case, some studies have questioned the prognostic significance of this data element. Furthermore, in the onethird of cases in which size, grade, and stage do not converge in a single tumor nodule, there is no consensus as to how the index lesion should be designated [108]. This situation, of necessity, will lead to diagnostic challenges in Gleason grading and staging, as will be described. 3.3.5.

3.3.3.

Zonal origin

Numerous studies have claimed that transition-zone tumors should be considered and reported separately from peripheral-zone tumors [121,122]. In part, these observations were based on a series of studies from the late 1980s and early 1990s in which investigators argued that transition-zone tumors could be identified using distinctive histology, including well-differentiated glands of variable size and contour, composed of tall cuboidal to columnar cells with clear to pale pink cytoplasm, basally oriented nuclei, and occasional eosinophilic luminal secretions [121]. These studies concluded that this ‘‘clear cell’’ appearance was a marker of transition-zone tumors, which were associated with a more indolent course, higher cure rate, and overall more favorable prognosis [122]. Paradoxically, while transition-zone tumors may be of larger volume and associated with higher serum PSA values than peripheral tumors, most reports have maintained that transition-zone tumors show lower GSs [123,124]. Few studies, however, compared tumors arising in the transition zone with tumors arising in the anterior peripheral zone, the predominant glandular tissue of the apical prostate. A recent large-scale histopathologic analysis of 197 anterior dominant tumors, in which zone of origin was determined using an anatomy-sensitive approach emphasizing the variability in anterior prostatic anatomy from apex through base, showed that the majority of dominant anterior tumors in the prostate are actually of anterior peripheral– zone origin. In comparing 97 cases of anterior peripheral– zone origin and 70 cases of transition-zone origin, no significant differences in GS, incidence of extraprostatic extension, or overall surgical margin positivity rate were observed [125]. Other groups have also reported no significant differences in GS between transition- and peripheral-zone tumors [126,127]. Therefore, while it is important to recognize anterior prostatic tumors, which represent an increasing percentage of dominant lesions [125], there is less definitive evidence at this time to specify zone of origin in the pathology report. 3.3.4.

Defining the index, or dominant, tumor

The notion of an index, or dominant, tumor was originally proposed at Stanford University by McNeal and Stamey, who measured the volume of the largest tumor nodule and correlated this volume with outcome [128].While empirical experience and logic dictate that the dominant nodule by size will most often be associated with the highest GS and

Grading of specimens with separate tumor nodules

While the general principles, historical background, and recent modifications in morphology in regard to Gleason grading are equally applicable to biopsy and RP specimens, a number of reporting elements specific to prostatectomy remain. One such element is the grading of cases with separate tumor nodules. This phenomenon is best illustrated with two examples. The first example is a gland with multiple tumor nodules in which the largest nodule has GS 4 + 4 = 8, while multifocal smaller nodules with GS 3 + 3 = 6 are also present. Assigning an overall GS in such a case may result in a diagnosis of 4 + 3 = 7 or even 3 + 4 = 7, depending on the extent of the multifocal disease. In light of limited data, the 2005 ISUP conference [16] recommended assigning a separate GS to each dominant tumor nodule. In this case, the reported GS would only reflect the dominant nodule by size—that is, GS 4 + 4 = 8—without the need to record smaller foci of lower-grade tumor. A second example of a challenging scenario is a prostate gland with multiple tumor nodules in which the largest nodule has GS 3 + 3 = 6, while a smaller nodule shows GS 3 + 4 = 7. Here, grading on the basis of the dominant nodule by size alone may underestimate the biologic potential of the tumor. Hence, the ISUP group recommended reporting two GSs—one for the largest nodule (ie, GS 3 + 3 = 6) and one for the nodule with the highest grade (ie, GS 3 + 4 = 7). This approach would lead to separate GSs for at most two nodules in the overwhelming majority of cases [16]. However, given the lack of evidence in the literature, we may posit that another reasonable approach in this case may be to assign one GS of 3 + 4 = 7, as this approach may be used in a more straightforward fashion by clinicians in prognostic nomograms. A similar strategy may be used when no dominant nodule is present and scattered small foci of GS 3 + 3 = 6 and 3 + 4 = 7 make up the tumor. 3.3.6.

Tertiary Gleason grades

The definition of tertiary Gleason grade in RP specimens is not analogous to that of needle biopsy because (1) the entire tumor is available for examination and (2) the multifocal nature of PCa affects its assessment [16]. Technically, the extent of a tertiary component can vary from