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Problems in grading and staging prostatic carcinoma
Current Diagnostic Pathology (2002) 8, 65^75
c 2002 Elsevier Science Ltd doi:10.1054/cdip.2001.0101, available online at http://www.idealibrary.com on
MINI-SYMPOSIUM: UROPATHOLOGY
Problems in grading and staging prostatic carcinoma L. J. McWilliam*, I. S. D. Robertsw and D. R. Daviesw *Department of Histopathology, Manchester Royal In¢rmary, Oxford Road, Manchester M13 9WL, UK and wDepartment of Cellular Pathology, John Radcli¡e Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
KEYWORDS prostatic carcinoma, grading, staging, prognostic markers
Summary Prostatic carcinoma now forms a large part of most general histopathologists’daily workload.This article concentrates on discussion of the main prognostic and problematic areas in prostatic carcinoma reporting, where there are day-to-day practical di⁄culties in diagnostic categorization.The ¢rst is tumour grading, addressing dif¢cultiesin application of the Gleason system and problems of grading in needle biopsies, and the second is pathological staging, particularly with reference to radical prostatectomy specimens.Reproducibilityis a major problemin both grading and staging prostatic carcinoma and variation in observation in the reporting of pathology specimens may signi¢cantly a¡ect patient management.There are a number of new potential prognostic markersin prostatic carcinoma, some of which may be of value in supplementing traditional grading and staging information. Whilst some are of proven prognostic signi¢cance, we highlightthe di⁄culties involved in their routine application.
c 2002 Elsevier Science Ltd
INTRODUCTION Prostatic cancer is now the most commonly diagnosed malignancy a¡ecting middle aged to elderly men and is responsible in the UK for approximately 10 000 deaths per annum. The lifetime risk of developing histological prostate cancer is approximately 30% and of developing clinically apparent prostate cancer is estimated at 1 in 6. In the USA, it is currently the most common cancer in men with the number of new cases in 1997 being 334 000 and the number of deaths 41800.1,2 The incidence of the disease is continuing to rise globally.3^5 Early detection is considered to be important in terms of approaching disease treatment in a curative framework that improves prognosis when compared with diagnosis in later stages of the disease. The diagnosis and staging of prostatic carcinoma is based on a combination of clinical, serological, imaging and histological data (Table 1). Improved diagnostic techniques such as measurement of serum prostate speci¢c antigen (PSA), transrectal ultrasound (TRUS) and biopsy have helped to detect disease in earlier stages. As a result of this there has been an exponential rise in the number of needle core biopsies presenting to histopathology departments6 and also a steady rise in radical prostatecCorrespondence to: LJMW.Tel.: +44(0)161276 8803; Fax: +44(0)161276 6348; E-mail: [email protected]
tomy specimens in the UK over the last decade. This has been a taxing time for the histopathologist; particular di⁄culties may arise in the diagnosis of tiny foci of carcinoma in needle core biopsies, di¡erentiation of carcinoma from non-neoplastic glandular lesions and providing accurate grading and staging information. It is the latter two issues that will be addressed in this article. Grading and staging are prognostic of disease course and are important factors in clinical management.7^9 Various treatment options are available and depend to some extent on whether the disease is early or late (incurable) at the time of diagnosis. Options include watchful waiting, radical prostatectomy, radiation therapy, neoadjuvant and adjuvant therapy, androgen deprivation, chemotherapy, growth factor inhibitor and angiogenesis inhibitor therapy and immunotherapy. Cryotherapy, interstitial seed implantation and laser therapy are new treatment options becoming available for early disease.10 Prognosis in prostate cancer depends primarily on stage and grade plus other factors, such as pre-operative PSA level and co-morbidity, but is between 65% and 70% 5-year survival for T1 and T2 tumours treated by radiotherapy.The median survival for metastatic disease is 30 months. Additional histological features that may be of prognostic value include vascular invasion, perineural in¢ltration and neuroendocrine di¡erentiation, although the evidence for the signi¢cance of these is con£icting.
66
CURRENT DIAGNOSTIC PATHOLOGY
Table 1 TNM staging system for prostate cancer (1997 revision) Non-palpable cancer o5% of TURP tissue 45% of TURP tissue Detected by needle biopsy (raised PSA) Palpable cancer con¢ned within prostate One lobe Both lobes Local extra-capsular extension Extra-capsular Seminal vesicle Invasion of adjacent structures Bladder neck, rectum, external sphincter, levator muscle, pelvic wall Metastatic cancer Regionallymph node Non-regionallymph node Bone Other sites
T1a T1b T1c T2a T2b T3a T3b T4 Figure 1 High-grade PIN, micropapillary pattern. N1 M1a M1b M1c
PROSTATIC INTRAEPITHELIAL NEOPLASIA (PIN) Current recommendations are not to report low-grade PIN (previously PIN 1) as there is di⁄culty in separating this lesion from benign epithelium and reactive atypia and there is no clinical value in terms of likelihood of prostatic cancer presence or development. High-grade PIN (previously PIN 2 & 3) (Fig. 1) is a signi¢cant ¢nding and there is a high incidence of concurrent invasive adenocarcinoma. It is considered to be the precursor of most cases of prostate cancer.11,12 The presence of high-grade PIN in needle biopsy should always be reported and if PIN is mentioned in the report this should imply high grade by default. Its presence should prompt further biopsies and close follow-up.
GRADING AND SCORING OF PROSTATIC ADENOCARCINOMA INNEEDLE CORE BIOPSIES Numerous grading systems for prostatic adenocarcinoma (Table 2) have been used since the work of Broders13,14 and all identify relatively easily well and poorly di¡erentiated carcinomas. Most systems fall down in subdividing the majority of moderately di¡erentiated lesions which are the main problem group clinically in terms of prediction of likelihood of progression and biological potential. Problems faced by histopathologists have been the lack of a robust and reproducible universal system (Table 3) and, more recently, the limitations of grading biopsy material.
Table 2 Grading systems for prostatic adenocarcinoma Broders
Arch Pathol Lab Med1926; 2: 376^381
World Health Organization (Mosto¢) B˛cking Gleason
Cancer ChemoTher.Rep1975; 59:111^117 Cancer1982; 50: 288^294 Cancer Chemother.Rep.1966; 50:125^128 Hum Pathol1992; 23: 273^279 J.Urol1981; 17 (Suppl1): 33^37 Cancer1982; 49: 525^532
Gaeta Brawn
Gleason grading15 ^17 is the most widely used system in the USA and the UK. It is a predictor of recurrence after radical prostatectomy,18 PSA level,19 tumour volume and pathologic stage.20 It is important in predicting patient outcome in univariate and multivariate analyses.7,9 Implementation of Gleason grading and scoring does, however, have signi¢cant interobserver and intraobserver variation9,21^23 and many of the reasons for this are related to the problems outlined below. There is currently an ongoing UK study investigating observer variability in needle core biopsies co-ordinated by the Cancer Screening Evaluation Unit.
PROBLEMS IN REPORTING GLEASON GRADING INNEEDLE CORE BIOPSIES The Gleason system is based on the degree of architectural glandular di¡erentiation. It is assumed that readers are familiar with the architectural forms that de¢ne the Gleason patterns. These are summarized in Table 4. The Gleason sum or total score has conventionally been the sum of the primary pattern for the dominant grade by area and the secondary pattern for the non-dominant grade by area (and should be greater than 5% of the
PROBLEMS IN GRADING AND STAGING PROSTATIC CARCINOMA
67
Table 3 Reproducibility of grading systems Author
Reference
Grading Systems Studied
Findings
Gleason DF
Hum Pathol1992; 23: 273^279 Arch Pathol Lab Med1982; 106 : 265^267 Am J Clin Pathol1991; 96: 70^75 Hum Pathol1988; 19: 595^597
Gleason Gleason
Exact reproducibility in 50% of needle biopsies and 71score in 85% Similar ¢ndings to Gleason above
Gleason
Concordance rates ranging from 44^75%
Gleason Mosto¢ B˛cking MD Anderson (MDAH) Gleason Mosto¢ Gleason Mosto¢ B˛cking
MDAH most reproducible Gleason least reproducible (66% complete agreement)
Bain GO Di Loreto C De Las Morenas A
Ozdamar SO Cintra ML
Lessells AM
Int Urol Nephrol1996; 28: 73^77 Int Urol Nephrol1991; 23: 449^454
Hum Pathol1997; 28: 646^649
Gleason
70% agreement using Gleason No signi¢cant di¡erences in intra-observer agreement. Gleason ranges from 62^78% agreement Kappa values from 0.41to 0.54 with lumping of Gleason scores
Table 4 Gleason grading system for prostatic adenocarcinoma: histological patterns Pattern
Peripheral Borders of Tumour
Stromal Invasion
Appearance of Glands
Size of Glands
Architecture of Glands
Cytoplasm
1
Minimal
Simple, round monotonously replicated Simple, round, some variability in shape
Medium, regular
Closely packed, rounded masses
Similar to benign epithelium
Medium, less regular
Loosely packed, rounded masses
Similar to benign epithelium
3A
Circumscribed, pushing expansile Less circumscribed; early in¢ltration In¢ltration
Angular, with variation in shape
Medium to large
Variably packed, irregular masses
3B
In¢ltration
Marked
Angular, with variation in shape
Small
Variably packed, irregular masses
3C
Smoothed, rounded
Marked
Papillary and cribriform
Irregular
Round to elongate masses
4A
Ragged in¢ltration Ragged in¢ltration Smooth, rounded Ragged in¢ltration
Marked
Microacinar, papillary, and cribriform Microacinar, papillary, and cribriform Comedocarcinoma
Irregular
Di⁄culty to identify gland lumens
Sheets of glands
Fused, with chains and cords Fused, with chains and cords Round to elongate masses Fused sheets and masses
More basophilic than patterns 1and 2 More basophilic than patterns 1and 2 More basophilic than patterns 1and 2 Dark
2
4B 5A 5B
Mild, with de¢nite separation of glands by stroma Marked
Marked Marked Marked
Irregular Irregular
Clear (hypernephroid) Variable Variable
From:Bostwick DG. AJCP1994; 102 (Supp1)
total). If there is only one pattern the pattern score is doubled to give the sum score. The score should be reported as a composite score and its component patterns e.g. Gleason 9 = 4 + 5, with the ¢rst being the predomi-
nant pattern and the second being the next most extensive pattern.9 There are several problems that arise when trying to apply Gleason grading to needle core biopsies.These are summarized below.
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1. Should each needle core submitted be graded and scored or should a score be provided for each side, or an overall composite score that encompasses the entire sample? Current recommendations vary; some state a pattern and score for each needle biopsy,6 some advocate that each slide be scored separately and others that all needle cores (the entire specimen) should be considered in the assignment of score. The latter approach is recommended by the College of American Pathologists.9 Correlation of needle grade and subsequent prostatectomy grade shows highest accuracy for primary pattern but secondary pattern on biopsy is su⁄ciently accurate in predicting prostatectomy grade to provide useful predictive information, especially when combined with the primary pattern to create the Gleason sum score.24,25 2. If there is only a single small focus of carcinoma of one pattern present in a needle core biopsy, the current recommendation is to double this to give the score. This is not necessarily an accurate representation of the true score and is one of the reasons for needle score variation when compared with radical prostatectomy ¢ndings.24,25 It may be more accurate to say that there is only one pattern represented and a score cannot be assigned, rather than give a guesstimate that results in a high ‘discrepancy’ rate when grading of the biopsy is compared with the subsequent prostatectomy specimen. This approach does, however, risk confusing the urologists and oncologists by providing a pattern for some biopsies and a sum score for others. An alternative approach, which we use, is to provide a sum score in all cases, but with a caveat on the small amount of tumour present. 3. Should the conventional score criteria of grade by greatest area and second greatest area (as for TURP chips and radical specimens) be used for scoring needle cores7 or rather the most extensive grade plus the highest grade present in the sample to assign score? Should highest grade regardless of extent be quoted ¢rst in the score sum? Di¡erent practices for this are currently being used, though all recommend a mention of any higher grade present in the report, even if it is not part of the score.9 Current practice in needle biopsies in one institution is to incorporate the highest grade in the score regardless of its extent26 on the basis that a small amount of high-grade tumour on radical prostatectomy has prognostic signi¢cance, so it would also impact prognosis if found in a biopsy. Another institution states that the two highest grades present in needle biopsies or small sample should be recorded.27 It is clear that there are varied practices in grading and scoring of needle core biopsies that need to be standardized in order for valid comparative studies to occur. It would appear
CURRENT DIAGNOSTIC PATHOLOGY
from the available evidence to be reasonable to assign a score using conventional Gleason criteria, but also to state if there is a higher-grade tertiary component present. If a modi¢cation is made to the Gleason scoring system, it should be given a di¡erent name to avoid confusion. It is clear at present that further validation studies are required before changes to the Gleason score can be recommended. A compressed Gleason grade is sometimes used, particularly in clinical trials. If sum scores are to be compressed into three or four grades, it is important that Gleason scores 6, 7 and 8 are assigned to separate grades, as these tumours are associated with signi¢cantly di¡erent outcomes. For example, a system based on four grades would compress Gleason scores 2, 3 and 4 to grade 1, scores 5 and 6 to grade 2, score 7 to grade 3 and scores 8, 9 and 10 to grade 4. 4. Should patterns 1 and 2 be used at all in needle core biopsies? This is a very interesting question and is discussed by Epstein in a recent editorial.28 It is very di⁄cult to diagnose these two patterns in needle core material and one suspects that most practising pathologists would ¢nd needle biopsy grading considerably easier if these were omitted from consideration. As Epstein points out, grading of low-grade cancer in needle cores is not reproducible even amongst urological pathology experts. In our practice we very rarely diagnose patterns 1 and 2 in needle biopsies, and we would recommend great caution before doing so. It may be of some practical importance; a Gleason pattern 3 (sum score 6) might result in radical prostatectomy whilst pattern 2 (sum score 4) might result in watchful waiting. 5. Speci¢c problems arising in grade assignment that are most pertinent in day-to-day practice are centred around two main areas. K
K
Patterns 1 and 2 vs 3 Di¡erentiation of patterns 1 and 2 from 3 centre around the size, shape and proximity of glands and the margins of the lesion. Needle core biopsies, because of their nature, preclude in most instances being able to identify margins of wellde¢ned Gleason patterns 1 and 2 (Fig. 2). If the glands are separated by a distance of greater than one gland diameter, then this helps to rule out patterns 1 and 2 and if normal glands are present in between neoplastic glands then this automatically puts the pattern into 3 (Fig. 3). Pattern 3 vs 4 Di¡erentiation of patterns 3 and 4 can be di⁄cult, especially when trying to decide whether or not there is gland fusion. It is the source of greatest
PROBLEMS IN GRADING AND STAGING PROSTATIC CARCINOMA
Figure 2 A needle biopsy through an adenocarcinoma, the margins of which are not included in the biopsy.
69
Figure 4 Gleason pattern 4 adenocarcinoma, showing widespread glandular fusion.
Figure 5 Adenocarcinoma that is predominantly Gleason pattern 3, but with focal glandular fusion on the right.
Di¡erentiating cribriform pattern 3 from cribriform pattern 4 can also be di⁄cult. Pattern 3 has rounded margins (Fig. 6A) whereas cribriform pattern 4 may have ragged or irregular margins (Fig. 6B). Furthermore, in pattern 4 the cribriform glands are often larger than a normal duct and lumina may be inconspicuous. Useful website assistance and reviews29^31 are available to assist with the recognition of certain patterns (www.pathology.jhu.edu/prostate). Figure 3 Adenocarcinoma in which malignant acini in¢ltrate around benign prostatic ducts (A), that are highlighted by immunohistochemical staining of basal cells (B).
inter-observer variation.What is fusion and how do 29 we recognize it? Bostwick de¢nes it as acini with no intervening stroma for a length of at least four times the acinar width.Whilst most cases are clearcut (Fig. 4), this can be di⁄cult to assess if there is only a small amount of fusion or if there is very little stroma between tightly packed acini (Fig. 5).
PATHOLOGICAL STAGING Staging gives an estimate of the extent of spread of a tumour at the time of diagnosis.The results depend on the techniques used to produce the estimate: these may be clinical, biochemical, imaging or pathological. All the methods have limitations in producing an accurate re£ection of the true extent of the tumour but this does not matter as long as it is recognized that di¡erent methods yield di¡erent results. The information derived from
70
Figure 6 (A) Cribriform Gleason grade 3 with smooth contours. (B) Cribriform Gleason grade 4 with irregular contours and inconspicuous lumina.
staging can be useful in prognostication but it is also used to select the most suitable treatment for the patient. Urologists tend to use nomograms, based on logistic regression analysis, which take clinical and pathological data into account in selecting de¢nitive treatment for patients.32 The Whitmore Jewett system and its modi¢cation have been used for prostate cancer but theTNM system is now the most widely used (Table 133). Conventionally, theTNM system can be applied using clinical information only but this includes endoscopy, imaging and biopsy data. According to the rules of the TNM system, a pT number should be ascribed to give a pathological staging only when there is su⁄cient tissue to estimate the highest stage i.e. after de¢nitive surgery.The system used for prostate carcinoma, therefore, produces some apparently anomalous situations for pathologists. The clinical T1 stages (where a clinically impalpable and non-imaged tumour is found on TURP or needle biopsy) depend on pathological examination of specimens (T1a: tumour involving o5% of surface area, T1b involving 45% of surface area, T1c tumour in needle biopsy). There is no pT1 category.Where clinically inapparent tumour is detected bilaterally in needle biopsies it remains T1c. Even if invasion of extra-prostatic fat is detected on needle biopsy,
CURRENT DIAGNOSTIC PATHOLOGY
the tumour remains T1c if it is clinically impalpable and not imaged. pT staging is therefore limited in practice to radical prostatectomy specimens and forTobservations only categories pT2a (one lobe), pT2b (both lobes involved) and pT3, extra prostatic extension. pT4 is reserved for invasion of bladder or rectum or pelvic wall, detected in more extensive resections which are seldom seen in most centres. Even with such a limited number of categories, there are still problems for the pathologist. pT2 a and b are relatively straightforward, being unilateral or bilateral in the 1997 TNM system. The same letters and numbers are used to indicate di¡erent extents of involvement in the1992 version. It is therefore sensible for pathologists to indicate on the report as to which version is being used, for there is otherwise the potential for misleading urologists, clinical trials and cancer registries. Extra-prostatic extension may be di⁄cult to estimate because of problems of de¢nition of the capsule. Unfortunately, the ‘capsule’, consisting of smooth muscle and dense ¢brous tissue, is not well de¢ned, particularly antero-laterally and at the base and the apex of the prostate.34 Penetration of tumour into the capsule (i.e. outside the area where glands are normally found) does not count. Detecting extra-prostatic extension is easiest when tumour is seen in adipose tissue (which is very rarely present in the prostate). Perineural in¢ltration in itself is not diagnostic, for nerves are found within the prostate: in¢ltration around ganglion cells is more suspicious because they are only occasionally seen within the prostate. Perineural in¢ltration of nerves within fat is indicative of extra-prostatic extension, even if the fat is not directly in¢ltrated. In¢ltration of fat may be masked by a desmoplastic response to the tumour: in needle biopsies, this may be di⁄cult to detect but in radical prostatectomies the extension beyond the normal contour of the gland indicates extra-prostatic invasion. The capsule at the apex may be intimately mixed with striated muscle and benign glands may be found in striated muscle. In biopsies the location may not be clear but in radical prostatectomies the position of any striated muscle in¢ltration should make interpretation easier. Because of these problems with de¢nition of the capsule, the Mayo consensus conference35 recommended the term extra-prostatic extension to avoid the use of other ill-de¢ned terms such as capsular invasion, capsular penetration or capsular perforation. Extraprostatic extension is de¢ned as the extension of cancer beyond the edge or capsule of the prostate and is diagnosed when:
1. Carcinoma is present in adipose tissue. 2. Carcinoma is present in neurovascular bundles beyond the contour of the prostate.
PROBLEMS IN GRADING AND STAGING PROSTATIC CARCINOMA
3. Carcinoma extends anteriorly (where there is little adipose tissue) beyond the contour of the prostate into skeletal muscle or between ¢bromuscular stroma and skeletal muscle. Bostwick and Montironi36 discuss the problems of reporting radical prostatectomy specimens. They do not report extra-prostatic extension at the apex or base, where the capsule is di⁄cult to de¢ne and at these sites limit observations to surgical margin status. A more recent review is that of Epstein.37 The CAP Consensus Statement recommended clari¢cation of theTNM categories of 1997 but did not contribute di¡erent de¢nitions.9 A plea for a return to the1992 T categories has been made because of evidence that it obscures the di¡erence between the outcome of patients with single lobe disease (T2a92 and T2b9238). Invasion of the seminal vesicles alters the stage but it is important to note that this means invasion of the muscle of the seminal vesicles, not the associated connective tissue.34 In selection of patients for radical prostatectomy, seminal vesicle biopsy may be carried out in an attempt at pre-operative staging; again, muscle invasion is the important observation. Seminal vesicle involvement and perineural in¢ltration in biopsies have been claimed to be predictors of lymph node positivity.39 Surgical margin positivity in a radical prostatectomy does not alter the stage. This is an observation which is distinct from that of extra-prostatic extension but is sometimes confused. Urologists are often keen for the pathologists to tell them whether a tumour is organ con¢ned (i.e. within the prostatic capsule) and specimen con¢ned (i.e. clear of the excision margins). Although we cannot always tell them whether it is organ con¢ned, we can usually tell if the tumour is present at an excision margin. In prostatic specimens, it is the convention to report margin positivity only when the tumour is seen abutting the inked margin. Inadvertent intra-operative cuts into the prostate may result in artifactual positivity at the inked margin but careful observations at the cutup stage can usually make the interpretation clear. In many radical prostatectomy specimens, the excision margin coincides with the capsule in some areas and extra-prostatic extension is uncertain.The Mayo consensus proposed aT2+ category for these.35 The predictive value of pathological ¢ndings has inspired many studies of biopsies, to detect features which select patients for certain treatment modalities, and of radical prostatectomy specimens to detect features which predict behaviour and indicate response to treatment. Not surprisingly, the authors do not all agree. Using observations of needle biopsies to predict the likely ¢ndings on radical prostatectomy (such as Gleason sum score, volume of tumour, extra-prostatic extension, lymph node metastasis) has met with limited success and varying results. The volume (or length of cores involved
71
by tumour) in the biopsy does not give a good estimate of the volume of tumour in a radical prostatectomy specimen, although small foci of tumour in the biopsy are more frequently associated with small volume tumour in the radical specimen.40 Perineural in¢ltration is often recorded on needle biopsies but some authors claim that it is not a good predictor of extra-prostatic extension.41 Others claim that this, together with the Gleason sum score, is the best predictor of lymph node metastasis. Vascular invasion is not an independent predictor in tumours with a volume less than 4 cm.3,42 The ¢ndings in radical prostatectomy include those which may be made on biopsy but other observations such as the volume of tumour, its extent and completeness of excision may be made.Tumour volume correlates with adverse features of tumour pathology and behaviour43 but the ¢gure is at best a rough estimate. It is clear that what is estimated is the volume of prostate in¢ltrated by tumour, rather than the volume of tumour cells. The methodology employed usually involves measuring the volume of the prostate, preparing whole mounts of the gland at 2, 3 or 4 mm intervals, outlining the areas involved by tumour on H & E slides (Fig. 7) and measuring the proportion of the gland involved by image analysis. Based on a number of assumptions, a ‘volume of tumour’ ¢gure is arrived at which is not the volume of tumour cells but which, nevertheless, has been claimed to be an independent variable.44 Others have not found this when other factors have been taken into account.45,46 Because volume measurement is timeconsuming and usually does not a¡ect actual treatment decisions, it is performed in only a minority of centres. Others have used simple estimates of size such as maximum tumour diameter which is claimed to be an independent variable.47 For peripheral zone cancer, it is claimed that the percentage of high-grade tumour and the volume of tumour determined in a radical prostatectomy are the best prognostic indicators of biochemical failure.44
Figure 7 Whole mount section of radical prostatectomy specimen with two separate carcinomas outlined (pT2b: 97, specimen con¢ned, organ con¢ned; the tumours do not reach the inked margin).
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The assessment of lymph node involvement is part of the staging process.When no lymph nodes are sent, their status cannot be assessed and are assigned pNX. When nodes are sent but no tumour deposits are identi¢ed, the code is pN0 and when tumour is identi¢ed pN1. It is generally accepted that lymph node involvement indicates an adverse prognosis but urologists di¡er in their attitude to treatment in the presence of lymph node metastases. Clinical and pathological methods have been used to predict lymph node involvement prior to operation. Perineural and seminal vesicle in¢ltration in the biopsy has been claimed to be a predictor of outcome but this is controversial.39 The use of frozen section at operation is also controversial. Its value depends on the urologist’s policy on cancelling the operation in the presence of positive nodes and the recognition that there is a substantial falsenegative rate with this technique. Selection of high- and low-risk patients seems to have led to a reduction in the demand for this technique.48
CURRENT DIAGNOSTIC PATHOLOGY
Table 5 New putative prognostic markers in prostatic carcinoma Reference DNA ploidy and chromosomal abnormalities Nuclear size, shape and chromatin texture Microvascular density
Cell proliferation markers Cytokine/growth factors, receptors and transducers Vascular endothelial growth factor Epidermal growth factorp21 Regulators of proliferation and apoptosis Hormone receptors
NEW PROGNOSTIC MARKERS IN PROSTATIC CARCINOMA In view of the problems associated with poor reproducibility of grading systems in current use there is a clear need for new techniques that enable more objective, consistent and accurate prediction of outcome in carcinoma of the prostate. A large and increasing number of morphometric and molecular techniques have been investigated for their potential value in identifying prognosis in terms of response to treatment, metastatic behaviour and androgen-independent growth. Some of the growing number of putative prognostic markers are listed inTable 5.49^ 67 It is beyond the scope of this review to discuss each in detail. The extent to which new prognostic markers have been studied is variable and investigation by more than one group has often led to con£icting results and directly opposing conclusions. This re£ects a lack of consistency in methodology. For example, the predictive value of microvascular density appears to depend at least in part upon the way in which the number of vessels are quanti¢ed and the method used for selecting ¢elds for analysis.Whilst individual studies have demonstrated associations with grade, stage, progression and metastatic behaviour, it is unclear for some as to whether the markers are of truly independent prognostic value. Those that have been demonstrated to be of prognostic signi¢cance in a multivariate analysis include markers of proliferative activity, DNA ploidy, p53 and bcl-2 expression, and microvascular density. The most useful prognostic markers in carcinoma of the prostate are those that may be applied to needle biopsies at the time of diagnosis, when the range of ther-
Adhesion molecules Others Heat shock proteins CaT1 Sialyl Lewis X
Lieber49 Mora et al50 Pan et al51 Jorgensen et al52 Bettencourt et al53 Brawer54 Volavsek et al55 Bubendorf et al56
Tsurusaki et al57 Hahn et al58 Fowler et al59 Lacombe et al60 Bubendorf et al61 Diaz et al62 Shurbaji et al63 Jenster64 Cardillo et al65 Pan et al51 Cornford et al66 Peng et al67 Jorgensen et al52
apeutic options is greatest. A clinically useful marker for the individual patient would supplement grading and staging data and provide information on the probability of local extra-prostatic spread or metastatic disease, and thus help to identify those individuals who might bene¢t from prostatectomy. Most studies of new putative prognostic markers are retrospective and use tissue obtained from radical prostatectomy specimens. Even when an association with outcome is demonstrated in this type of study, it is possible that tumour cell heterogeneity and sampling artefact associated with needle biopsies will limit the use of new prognostic markers in just the same way as creating ‘errors’ in grading and staging.This is illustrated by attempts to introduce measurement of DNA ploidy into routine use. There have been numerous studies investigating the signi¢cance of DNA ploidy in the development and progression of prostatic carcinoma. Tumour aneuploidy is certainly an adverse prognostic factor68 but there are practical di⁄culties in measuring ploidy routinely. The most common method employed is £ow cytometry but this requires large numbers of cells, limiting its use in needle biopsies. Measurement of nuclear DNA content by image analysis can be performed on biopsy material and is of potential value. It does,
PROBLEMS IN GRADING AND STAGING PROSTATIC CARCINOMA
however, su¡er from the same drawbacks as traditional grading systems: that is, heterogeneity of DNA ploidy within tumours, resulting in sampling errors, and lack of standardization of the technique. Fluorescence in-situ hybridization (FISH) may also be used to determine ploidy69 and has revealed details of chromosomal abnormalities in prostatic carcinoma, but at present is not widely available. Chromatin texture, determined morphometrically, has also been found to be an independent prognostic marker52 but its routine use in needle biopsies may be limited by variable ¢xation and crush artefact.70 Even for those markers that have been demonstrated in large groups to show a statistically signi¢cant association with progression to metastatic disease, the level of overlap between progressors and non-progressors may limit the usefulness in managing an individual patient. The development of neural networks, incorporating data from grade, morphometric analysis and histological biomarkers, in addition to clinical data and levels of serum markers, may prove to be a powerful tool for use in patient management. Simple algorithms combining grade, stage and serum PSA level are already widely used for determining the probability of extra-prostatic spread. Bauer et al.71 developed a formula to calculate the relative risk of recurrent disease following prostatectomy using a combination of traditional markers, PSA level and Gleason grade, and tumour expression of Ki67, p53 and bcl-2. Recent studies indicate that arti¢cial neural networks are superior to other statistical methods in predicting outcome.72,73 In summary, a number of newer histological markers have potential prognostic value. However, their role in the management of individual patients remains unclear and needs to be de¢ned in larger prospective studies. The introduction of many of these markers into routine practice may be limited by technical di⁄culties and expense. In particular, the issues of inter-laboratory variation and standardization have yet to be addressed; it is possible that many of the problems associated with reproducibility of current grading and staging systems will equally apply to other prognostic markers.
PRACTICE POINTS K
K
K
K K
Gleason scoring of needle biopsies should be performed if possible All needle cores should be included as a composite score Any higher pattern not forming part of the score should be mentioned in the report Presence of high-grade PIN should be stated If TNM staging is used, the version (92 or 97) should be stated
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RESEARCH DIRECTIONS K
K
K
K
Application of new prognostic markers in large prospective multicentre studies Development of neural networks for improving prognostication Reduction in the variation in grading of prostatic carcinoma Standardization of new techniques used in prognostication
REFERENCES 1. Parker S L, TongT, Bolden S, Wingo P A. Cancer statistics 1997. CA Cancer J Clin1997; 47: 5^27. 2. Wingo P A, Tong T, Bolden S. An adjustment to the 1997 estimate for new prostate cancer cases.CA Cancer J Clin1997; 47: 239^342. 3. Alexander F E, Boyle P. The rise in prostate cancer: myth or reality? In Garroway M J (ed). The Epidemiology of Prostate Disease. Berlin: Springer,1995; 192^207. 4. Boyle P, Maissonnevve P, Napallcou P. Incidence of prostate cancer mortality will double by the year 2030: the argument for. Eur Urol 1996; 29: 3^9. 5. Majeed A, Babb P, Jones J, Quinn M. Trends in prostate cancer incidence, mortality and survival in England and Wales 1971^1998. BJU Int 2000; 85: 1058 ^1062. 6. Standards and Minimum Datasets for Reporting Common Cancers Minimum Dataset for Prostate Cancer Histopathology Reports.The Royal College of Pathologists, April 2000. 7. Bostwick D G.Grading prostate cancer. Am J Clin Pathol1994; 102 (Suppl 1): S38 ^S56. 8. Partin A W, Yoo J, Carter H B et al. The use of prostate speci¢c antigen, clinical stage and Gleason score to predict pathologic stage in men with localised prostate cancer. J Urol 1993; 150: 110 ^114. 9. Bostwick D G, Grignon D J, Hammond M E et al. Prognostic factors in prostatic cancer. Arch Pathol Lab Med 2000; 124: 995^1000. 10. Weiss R M, George N J R, O’Reilly P H. Comprehensive Urology. London: Mosby, 2001; 395^ 424. 11. McNeal J E, Villers A, Redwine E A et al. Microcarcinoma in the prostate: its association with duct acinar dysplasia. Hum Pathol 1991; 22: 644 ^ 652. 12. Bostwick D G. High grade prostatic intraepithelial neoplasia. The mostly likely precursor of prostate cancer. Cancer 1995; 75: 1823^1836. 13. Broders A C. Carcinoma grading and practical application. Arch Pathol Lab Med1926; 2: 376 ^381. 14. Broders A C.The grading of carcinoma. Minn Med 1925; 8: 72^73. 15. Gleason D F. Classi¢cation of prostatic carcinomas. Cancer Chemother Rev 1966; 50: 125^128. 16. Mellinger G T, Gleason D, Bailar J. The histology and prognosis of prostatic cancer. J Urol 1967; 97: 331^337. 17. Gleason D F, Mellinger G T. The Veterans Administration Co-operative Urological Research Group. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol 1973; 111: 58 ^ 64. 18. Humphrey PA, Frazier H A, Lollmer RT, Paulson D F. Strati¢cation of pathologic features in radical prostatectomy specimens that are predictive of elevated initial postoperative serum prostate speci¢c antigen levels. Cancer 1993; 71: 1821^1827. 19. Blackwell K L, Bostwick D G, Zincke H et al. Prostate speci¢c antigen: its use as a practical preoperative marker of tumour burden and pathologic stage in adenocarcinoma of the prostate. J Urol 1994; 151: 1565^1570.
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20. Bostwick D G. Signi¢cance of tumour volume in prostate cancer. In Rous S (ed). Urology Annual. Philadelphia: Norton Medical books,1994; 1^22. 21. Lessels A M, Burnett R A, Howatson S R et al.Observer variability in the histopathological reporting of needle biopsy specimens of the prostate. Hum Pathol 1997; 28: 646 ^ 649. 22. Steinberg D M, Sawageot J, Piantodosi S, Epstein J I. Correlation of prostate needle biopsy and radical prostatectomy Gleason grade in academic and community settings. Am J Surg Pathol 1997; 21: 566^567. 23. Grignon D, Pajak T, Winter K et al. Central review vs institutional Gleason grading and its impact on phase III clinical trial analysis: a review of RTOG protocol 8531. Mod Path 1997; 10: 77A. 24. Bostwick D G.Gleason grading of prostatic needle biopsies: correlation with grade in 316 matched prostatectomies. Am J Surg Pathol 1994; 18: 796^ 803. 25. Cookson M S, Flesher N E, Soloway S M, Fair W R. Correlation between Gleason score of needle biopsy and radical prostatectomy specimen: accuracy and clinical implications. J Urol 1997; 157: 559^562. 26. Pan C, Potter S R, Partin A W, Epstein J I. The prognostic signi¢cance of tertiary Gleason patterns of higher grade in radical prostatectomy specimens. Am J Surg Path 2000; 24: 563^569. 27. Deshmukh N, Foster C S. Grading prostate cancer. In: Foster C S, Bostwick D G, (eds). Pathology of the Prostate. Philadelphia: WB Saunders,1998; 191^227. 28. Epstein J I. Gleason score 2^ 4 adenocarcinoma of the prostate on needle biopsy. Am J Surg Pathol 2000; 24: 477^ 478. 29. Bostwick D G, Dundore P A. Biopsy Pathology of the Prostate, Ist Edn. London: Chapman & Hall Medical,1997. 30. Allsbrook W C, Mangold K A, Yang X, Epstein J I. The Gleason grading system: an overview. J Urol Pathol 1999; 10: 141^157. 31. Epstein J I. Prostate Biopsy Interpretation, 2nd Edn. Philadelphia: Lippincott-Raven,1995. 32. Partin A W, Kattan M W, Subong E N et al. Combination of prostate-speci¢c antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA1997; 18:1445^1451. 33. Sobin LH, Wittekind C (eds). TNM Classi¢cation of Malignant tumours, 5th Edn. New York: Wiley-Liss,1997; 170 ^173. 34. Young R H, Srigley J R, Amin M B, Ulright T M, Cubilla A L. Atlas of Tumour Pathology. Tumours of the Prostate Gland, Seminal Vesicles, Male Urethra and Penis, Third Series. Fascicle 28. Washington: AFIP,1998; 116^122. 35. Sakr W A, Wheeler T M, Blute M et al. Staging and reporting of prostate cancerFsampling of the radical prostatectomy specimen. Cancer 1996; 2: 366 ^368. 36. Bostwick D G, Montironi R. Evaluating radical prostatectomy specimens: therapeutic and prognostic importance. Virchow’s Arch1997; 430:1^16. 37. Epstein J I. Pathological assessment of the surgical specimen. Urol Clin North Am 2001; 28: 567^594. 38. Han M, Walsh P C, Partin A W, Rodriguez R A. Ability of the 1992 and1997 American Joint Committee on cancer staging systems for prostate cancer to predict progression-free survival after radical prostatectomy for StageT2 disease. J Urol 2000; 164: 89^92. 39. Stone N N, Stock R G, Parikh D, Yeghiayan P, Unger P. Perineural invasion and seminal vesicle involvement predict pelvic lymph node metastasis in men with localised carcinoma of the prostate. J Urol 1998; 160: 1722^1726. 40. Beerlage H P, de ReijkeT M, de la Rosette, J J M C H.Considerations regarding prostate biopsies. Eur Urol 1998; 34: 303^312. 41. Egan A J, Bostwick D G. Prediction of extra prostatic extension of prostate cancer based on needle biopsy ¢ndings: perineural invasion lacks signi¢cance on multivariate analysis. Am J Surg Pathol 1999; 23: 239^240.
CURRENT DIAGNOSTIC PATHOLOGY
42. McNeal J E, Yemoto C E M. Signi¢cance of demonstrable vascular space invasion for the progression of prostatic adenocarcinoma. Am J Surg Pathol 1996; 20: 1351^1360. 43. McNeal J E.Cancer volume and site of origin of adenocarcinoma of the prostate: relationship to local and distant spread. Hum Pathol 1992; 23: 258 ^266. 44. StameyTA, McNeal J E,Yemoto C H, Sigal B M, Johnstone I M. Biological determinants of cancer progression in men with prostate cancer. JAMA1999; 281: 1395^1400. 45. Epstein J I, Carmichael M, Partin A W et al. Is tumour volume an independent predictor of of progression following radical prostatectomy? A multivariate analysis of 185 clinical stage B adenocarcinomas of the prostate with 5 years of follow up. J Urol 1993; 149: 1478 ^1481. 46. Ohori M, Abbass F, Wheeler T M et al. Pathological features and prognostic signi¢cance of prostate cancer in the apical section determined by whole mount histology. J Urol 1999; 161: 500 ^504. 47. Renshaw A A, Richie J R, Loughlin K R et al. Maximum diameter is a simple, inexpensive and independent predictor of prostate-speci¢c antigen failure in radical prostatectomy specimens. Am J Clin Pathol 1999; 111: 641^ 644. 48. Link R E, Morton R A. Indications for pelvic lymphadenectomy in prostate cancer. Urol Clin North Am 2001; 3: 491^ 498. 49. Lieber M M. Practical clinical utility of DNA ploidy for managing patients with prostate carcinoma.Urology1995; 45: 558. 50. Mora L B, Moscinski L C, Diaz J I et al. Stage B prostate cancer: correlation of DNA ploidy analysis with histological and clinical parameters. Cancer Control 1999; 6: 587^591. 51. Pan Y, Matsuyama H, Wang N et al. Chromosome 16q24 deletion and decreased E-cadherin expression: possible association with metastatic potential in prostate cancer. Prostate 1998; 36: 31^38. 52. JorgensenT, KanagasingamY, Kaalhus O et al. Prognostic factors in patients with metastatic (stage D2) prostate cancer: experience from the Scandinavian Prostatic Cancer Group StudyF2. J Urol 1997; 158:164 ^170. 53. Bettencourt M C, Bauer J J, Sesterhenn I A, Connelly R R, Moul J W. CD34 immunohistochemical assessment of angiogenesis as a prognostic marker for prostate cancer recurrence after radical prostatectomy. J Urol 1998; 160: 459^ 465. 54. Brawer M K. Quantitative microvessel density: a staging and prognostic marker for human prostatic carcinoma. Cancer 1996; 78: 345^349. 55. Volavsek M, Masera A, Ovcak Z. Incidental prostatic carcinoma. A predictive role of neoangiogenesis and comparison with other prognostic factors. Pathol Oncol Res 2000; 6: 191^196. 56. Bubendorf L, Sauter G, Moch H et al. Ki67 labelling index: an independent predictor of progression in prostate cancer treated by radical prostatectomy. J Pathol 1996; 178: 437^ 441. 57. Tsurusaki T, Kanda S, Sakai H et al.Vascular endothelial growth factor-C expression in human prostatic carcinoma and its relationship to lymph node metastasis. Br J Cancer 1999; 80: 309^313. 58. Hahn D, Simak R, Steiner G E et al. Expression of theVEGF-receptor Flt-1 in benign, premalignant and malignant prostate tissues. J Urol 2000; 164: 506^510. 59. Fowler J E, Lau J L T, Ghosh L, Mills S E, Mouzner T. Epidermal growth factor and prostatic carcinoma: an immunohistochemical study. J Urol 1988; 139: 857^ 861. 60. Lacombe L, Maillette A, Meyer F et al. Expression of p21 predicts PSA failure in locally advanced prostate cancer treated by prostatectomy. Int J Cancer 2001; 95: 135^139. 61. Bubendorf L, Sauter G, Moch H et al. Prognostic signi¢cance of Bcl-2 in clinically localized prostate cancer. Am J Pathol 1996; 148: 1557^1565. 62. Diaz J I, Pow-Sang J M, Mora L B et al. Cytometric analysis of Fas and Bcl-2 expression in normal prostatic epithelium and prostate cancer. Urol Oncol 2000; 5: 149^154.
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63. Shurbaji M S, Kalb£eisch J H,Thurmond T S. Immunohistochemical detection of p53 protein as a prognostic indicator in prostate cancer. Hum Pathol 1995; 26: 106^109. 64. Jenster G. The role of the androgen receptor in the development and progression of prostate cancer. Semin Oncol1999; 26: 407^ 421. 65. Cardillo M R, Petrangeli E, Salvatori L, Ravenna L, Di Silverio F. Transforming growth factor beta1and androgen receptors in prostate neoplasia. Anal Quant Cytol Histol 2000; 22: 403^ 410. 66. Cornford P A, Dodson A R, Parsons K F et al. Heat shock protein expression independently predicts clinical outcome in prostate cancer. Cancer Research 2000; 60: 7099^7105. 67. Peng J-B, Zhuang L, Berger U V et al. CaT1 expression correlates with tumor grade in prostate cancer. Biochem Biophys Res Commun 2001; 282: 729^734. 68. Zincke H, Bergstrahl E J, Larson-Keller J J et al. Stage D1 prostate cancer treated by radical prostatectomy and adjuvant hormonal treatment. Evidence for favorable survival in patients with DNA diploid tumors. Cancer 1992; 70 (Suppl): 311^323.
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69. Brown J A, Slezak J M, Lieber M M, Jenkins R B. Fluorescence in situ hybridization aneuploidy as a predictor of clinical disease recurrence and prostate-speci¢c antigen level 3 years after radical prostatectomy. Mayo Clin Proc 1999; 74: 1214 ^1220. 70. Veltri R W, O’Dowd G J, Orozco R, Miller M C. The role of biopsy pathology, quantitative nuclear morphometry, and biomarkers in the preoperative prediction of prostate cancer staging and prognosis. Semin Urol Oncol 1998; 16: 106 ^117. 71. Bauer J J,Connelly R R, Sesterhenn I A et al. Biostatistical modeling using traditional variables and genetic biomarkers for predicting the risk of prostate carcinoma recurrence after radical prostatectomy. Cancer 1997; 79: 952^962. 72. Han M, Snow P, Brandt J M, Partin A W. Evaluation of neural networks for the prediction of pathological stage in prostate carcinoma.Cancer 2001; 91: 1661^1666. 73. Bostwick D G, Burke H B. Prediction of individual patient outcome in cancer. Cancer 2001; 91: 1643^1646.
c 2002 Elsevier Science Ltd doi:10.1054/cdip.2001.0101, available online at http://www.idealibrary.com on
MINI-SYMPOSIUM: UROPATHOLOGY
Problems in grading and staging prostatic carcinoma L. J. McWilliam*, I. S. D. Robertsw and D. R. Daviesw *Department of Histopathology, Manchester Royal In¢rmary, Oxford Road, Manchester M13 9WL, UK and wDepartment of Cellular Pathology, John Radcli¡e Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
KEYWORDS prostatic carcinoma, grading, staging, prognostic markers
Summary Prostatic carcinoma now forms a large part of most general histopathologists’daily workload.This article concentrates on discussion of the main prognostic and problematic areas in prostatic carcinoma reporting, where there are day-to-day practical di⁄culties in diagnostic categorization.The ¢rst is tumour grading, addressing dif¢cultiesin application of the Gleason system and problems of grading in needle biopsies, and the second is pathological staging, particularly with reference to radical prostatectomy specimens.Reproducibilityis a major problemin both grading and staging prostatic carcinoma and variation in observation in the reporting of pathology specimens may signi¢cantly a¡ect patient management.There are a number of new potential prognostic markersin prostatic carcinoma, some of which may be of value in supplementing traditional grading and staging information. Whilst some are of proven prognostic signi¢cance, we highlightthe di⁄culties involved in their routine application.
c 2002 Elsevier Science Ltd
INTRODUCTION Prostatic cancer is now the most commonly diagnosed malignancy a¡ecting middle aged to elderly men and is responsible in the UK for approximately 10 000 deaths per annum. The lifetime risk of developing histological prostate cancer is approximately 30% and of developing clinically apparent prostate cancer is estimated at 1 in 6. In the USA, it is currently the most common cancer in men with the number of new cases in 1997 being 334 000 and the number of deaths 41800.1,2 The incidence of the disease is continuing to rise globally.3^5 Early detection is considered to be important in terms of approaching disease treatment in a curative framework that improves prognosis when compared with diagnosis in later stages of the disease. The diagnosis and staging of prostatic carcinoma is based on a combination of clinical, serological, imaging and histological data (Table 1). Improved diagnostic techniques such as measurement of serum prostate speci¢c antigen (PSA), transrectal ultrasound (TRUS) and biopsy have helped to detect disease in earlier stages. As a result of this there has been an exponential rise in the number of needle core biopsies presenting to histopathology departments6 and also a steady rise in radical prostatecCorrespondence to: LJMW.Tel.: +44(0)161276 8803; Fax: +44(0)161276 6348; E-mail: [email protected]
tomy specimens in the UK over the last decade. This has been a taxing time for the histopathologist; particular di⁄culties may arise in the diagnosis of tiny foci of carcinoma in needle core biopsies, di¡erentiation of carcinoma from non-neoplastic glandular lesions and providing accurate grading and staging information. It is the latter two issues that will be addressed in this article. Grading and staging are prognostic of disease course and are important factors in clinical management.7^9 Various treatment options are available and depend to some extent on whether the disease is early or late (incurable) at the time of diagnosis. Options include watchful waiting, radical prostatectomy, radiation therapy, neoadjuvant and adjuvant therapy, androgen deprivation, chemotherapy, growth factor inhibitor and angiogenesis inhibitor therapy and immunotherapy. Cryotherapy, interstitial seed implantation and laser therapy are new treatment options becoming available for early disease.10 Prognosis in prostate cancer depends primarily on stage and grade plus other factors, such as pre-operative PSA level and co-morbidity, but is between 65% and 70% 5-year survival for T1 and T2 tumours treated by radiotherapy.The median survival for metastatic disease is 30 months. Additional histological features that may be of prognostic value include vascular invasion, perineural in¢ltration and neuroendocrine di¡erentiation, although the evidence for the signi¢cance of these is con£icting.
66
CURRENT DIAGNOSTIC PATHOLOGY
Table 1 TNM staging system for prostate cancer (1997 revision) Non-palpable cancer o5% of TURP tissue 45% of TURP tissue Detected by needle biopsy (raised PSA) Palpable cancer con¢ned within prostate One lobe Both lobes Local extra-capsular extension Extra-capsular Seminal vesicle Invasion of adjacent structures Bladder neck, rectum, external sphincter, levator muscle, pelvic wall Metastatic cancer Regionallymph node Non-regionallymph node Bone Other sites
T1a T1b T1c T2a T2b T3a T3b T4 Figure 1 High-grade PIN, micropapillary pattern. N1 M1a M1b M1c
PROSTATIC INTRAEPITHELIAL NEOPLASIA (PIN) Current recommendations are not to report low-grade PIN (previously PIN 1) as there is di⁄culty in separating this lesion from benign epithelium and reactive atypia and there is no clinical value in terms of likelihood of prostatic cancer presence or development. High-grade PIN (previously PIN 2 & 3) (Fig. 1) is a signi¢cant ¢nding and there is a high incidence of concurrent invasive adenocarcinoma. It is considered to be the precursor of most cases of prostate cancer.11,12 The presence of high-grade PIN in needle biopsy should always be reported and if PIN is mentioned in the report this should imply high grade by default. Its presence should prompt further biopsies and close follow-up.
GRADING AND SCORING OF PROSTATIC ADENOCARCINOMA INNEEDLE CORE BIOPSIES Numerous grading systems for prostatic adenocarcinoma (Table 2) have been used since the work of Broders13,14 and all identify relatively easily well and poorly di¡erentiated carcinomas. Most systems fall down in subdividing the majority of moderately di¡erentiated lesions which are the main problem group clinically in terms of prediction of likelihood of progression and biological potential. Problems faced by histopathologists have been the lack of a robust and reproducible universal system (Table 3) and, more recently, the limitations of grading biopsy material.
Table 2 Grading systems for prostatic adenocarcinoma Broders
Arch Pathol Lab Med1926; 2: 376^381
World Health Organization (Mosto¢) B˛cking Gleason
Cancer ChemoTher.Rep1975; 59:111^117 Cancer1982; 50: 288^294 Cancer Chemother.Rep.1966; 50:125^128 Hum Pathol1992; 23: 273^279 J.Urol1981; 17 (Suppl1): 33^37 Cancer1982; 49: 525^532
Gaeta Brawn
Gleason grading15 ^17 is the most widely used system in the USA and the UK. It is a predictor of recurrence after radical prostatectomy,18 PSA level,19 tumour volume and pathologic stage.20 It is important in predicting patient outcome in univariate and multivariate analyses.7,9 Implementation of Gleason grading and scoring does, however, have signi¢cant interobserver and intraobserver variation9,21^23 and many of the reasons for this are related to the problems outlined below. There is currently an ongoing UK study investigating observer variability in needle core biopsies co-ordinated by the Cancer Screening Evaluation Unit.
PROBLEMS IN REPORTING GLEASON GRADING INNEEDLE CORE BIOPSIES The Gleason system is based on the degree of architectural glandular di¡erentiation. It is assumed that readers are familiar with the architectural forms that de¢ne the Gleason patterns. These are summarized in Table 4. The Gleason sum or total score has conventionally been the sum of the primary pattern for the dominant grade by area and the secondary pattern for the non-dominant grade by area (and should be greater than 5% of the
PROBLEMS IN GRADING AND STAGING PROSTATIC CARCINOMA
67
Table 3 Reproducibility of grading systems Author
Reference
Grading Systems Studied
Findings
Gleason DF
Hum Pathol1992; 23: 273^279 Arch Pathol Lab Med1982; 106 : 265^267 Am J Clin Pathol1991; 96: 70^75 Hum Pathol1988; 19: 595^597
Gleason Gleason
Exact reproducibility in 50% of needle biopsies and 71score in 85% Similar ¢ndings to Gleason above
Gleason
Concordance rates ranging from 44^75%
Gleason Mosto¢ B˛cking MD Anderson (MDAH) Gleason Mosto¢ Gleason Mosto¢ B˛cking
MDAH most reproducible Gleason least reproducible (66% complete agreement)
Bain GO Di Loreto C De Las Morenas A
Ozdamar SO Cintra ML
Lessells AM
Int Urol Nephrol1996; 28: 73^77 Int Urol Nephrol1991; 23: 449^454
Hum Pathol1997; 28: 646^649
Gleason
70% agreement using Gleason No signi¢cant di¡erences in intra-observer agreement. Gleason ranges from 62^78% agreement Kappa values from 0.41to 0.54 with lumping of Gleason scores
Table 4 Gleason grading system for prostatic adenocarcinoma: histological patterns Pattern
Peripheral Borders of Tumour
Stromal Invasion
Appearance of Glands
Size of Glands
Architecture of Glands
Cytoplasm
1
Minimal
Simple, round monotonously replicated Simple, round, some variability in shape
Medium, regular
Closely packed, rounded masses
Similar to benign epithelium
Medium, less regular
Loosely packed, rounded masses
Similar to benign epithelium
3A
Circumscribed, pushing expansile Less circumscribed; early in¢ltration In¢ltration
Angular, with variation in shape
Medium to large
Variably packed, irregular masses
3B
In¢ltration
Marked
Angular, with variation in shape
Small
Variably packed, irregular masses
3C
Smoothed, rounded
Marked
Papillary and cribriform
Irregular
Round to elongate masses
4A
Ragged in¢ltration Ragged in¢ltration Smooth, rounded Ragged in¢ltration
Marked
Microacinar, papillary, and cribriform Microacinar, papillary, and cribriform Comedocarcinoma
Irregular
Di⁄culty to identify gland lumens
Sheets of glands
Fused, with chains and cords Fused, with chains and cords Round to elongate masses Fused sheets and masses
More basophilic than patterns 1and 2 More basophilic than patterns 1and 2 More basophilic than patterns 1and 2 Dark
2
4B 5A 5B
Mild, with de¢nite separation of glands by stroma Marked
Marked Marked Marked
Irregular Irregular
Clear (hypernephroid) Variable Variable
From:Bostwick DG. AJCP1994; 102 (Supp1)
total). If there is only one pattern the pattern score is doubled to give the sum score. The score should be reported as a composite score and its component patterns e.g. Gleason 9 = 4 + 5, with the ¢rst being the predomi-
nant pattern and the second being the next most extensive pattern.9 There are several problems that arise when trying to apply Gleason grading to needle core biopsies.These are summarized below.
68
1. Should each needle core submitted be graded and scored or should a score be provided for each side, or an overall composite score that encompasses the entire sample? Current recommendations vary; some state a pattern and score for each needle biopsy,6 some advocate that each slide be scored separately and others that all needle cores (the entire specimen) should be considered in the assignment of score. The latter approach is recommended by the College of American Pathologists.9 Correlation of needle grade and subsequent prostatectomy grade shows highest accuracy for primary pattern but secondary pattern on biopsy is su⁄ciently accurate in predicting prostatectomy grade to provide useful predictive information, especially when combined with the primary pattern to create the Gleason sum score.24,25 2. If there is only a single small focus of carcinoma of one pattern present in a needle core biopsy, the current recommendation is to double this to give the score. This is not necessarily an accurate representation of the true score and is one of the reasons for needle score variation when compared with radical prostatectomy ¢ndings.24,25 It may be more accurate to say that there is only one pattern represented and a score cannot be assigned, rather than give a guesstimate that results in a high ‘discrepancy’ rate when grading of the biopsy is compared with the subsequent prostatectomy specimen. This approach does, however, risk confusing the urologists and oncologists by providing a pattern for some biopsies and a sum score for others. An alternative approach, which we use, is to provide a sum score in all cases, but with a caveat on the small amount of tumour present. 3. Should the conventional score criteria of grade by greatest area and second greatest area (as for TURP chips and radical specimens) be used for scoring needle cores7 or rather the most extensive grade plus the highest grade present in the sample to assign score? Should highest grade regardless of extent be quoted ¢rst in the score sum? Di¡erent practices for this are currently being used, though all recommend a mention of any higher grade present in the report, even if it is not part of the score.9 Current practice in needle biopsies in one institution is to incorporate the highest grade in the score regardless of its extent26 on the basis that a small amount of high-grade tumour on radical prostatectomy has prognostic signi¢cance, so it would also impact prognosis if found in a biopsy. Another institution states that the two highest grades present in needle biopsies or small sample should be recorded.27 It is clear that there are varied practices in grading and scoring of needle core biopsies that need to be standardized in order for valid comparative studies to occur. It would appear
CURRENT DIAGNOSTIC PATHOLOGY
from the available evidence to be reasonable to assign a score using conventional Gleason criteria, but also to state if there is a higher-grade tertiary component present. If a modi¢cation is made to the Gleason scoring system, it should be given a di¡erent name to avoid confusion. It is clear at present that further validation studies are required before changes to the Gleason score can be recommended. A compressed Gleason grade is sometimes used, particularly in clinical trials. If sum scores are to be compressed into three or four grades, it is important that Gleason scores 6, 7 and 8 are assigned to separate grades, as these tumours are associated with signi¢cantly di¡erent outcomes. For example, a system based on four grades would compress Gleason scores 2, 3 and 4 to grade 1, scores 5 and 6 to grade 2, score 7 to grade 3 and scores 8, 9 and 10 to grade 4. 4. Should patterns 1 and 2 be used at all in needle core biopsies? This is a very interesting question and is discussed by Epstein in a recent editorial.28 It is very di⁄cult to diagnose these two patterns in needle core material and one suspects that most practising pathologists would ¢nd needle biopsy grading considerably easier if these were omitted from consideration. As Epstein points out, grading of low-grade cancer in needle cores is not reproducible even amongst urological pathology experts. In our practice we very rarely diagnose patterns 1 and 2 in needle biopsies, and we would recommend great caution before doing so. It may be of some practical importance; a Gleason pattern 3 (sum score 6) might result in radical prostatectomy whilst pattern 2 (sum score 4) might result in watchful waiting. 5. Speci¢c problems arising in grade assignment that are most pertinent in day-to-day practice are centred around two main areas. K
K
Patterns 1 and 2 vs 3 Di¡erentiation of patterns 1 and 2 from 3 centre around the size, shape and proximity of glands and the margins of the lesion. Needle core biopsies, because of their nature, preclude in most instances being able to identify margins of wellde¢ned Gleason patterns 1 and 2 (Fig. 2). If the glands are separated by a distance of greater than one gland diameter, then this helps to rule out patterns 1 and 2 and if normal glands are present in between neoplastic glands then this automatically puts the pattern into 3 (Fig. 3). Pattern 3 vs 4 Di¡erentiation of patterns 3 and 4 can be di⁄cult, especially when trying to decide whether or not there is gland fusion. It is the source of greatest
PROBLEMS IN GRADING AND STAGING PROSTATIC CARCINOMA
Figure 2 A needle biopsy through an adenocarcinoma, the margins of which are not included in the biopsy.
69
Figure 4 Gleason pattern 4 adenocarcinoma, showing widespread glandular fusion.
Figure 5 Adenocarcinoma that is predominantly Gleason pattern 3, but with focal glandular fusion on the right.
Di¡erentiating cribriform pattern 3 from cribriform pattern 4 can also be di⁄cult. Pattern 3 has rounded margins (Fig. 6A) whereas cribriform pattern 4 may have ragged or irregular margins (Fig. 6B). Furthermore, in pattern 4 the cribriform glands are often larger than a normal duct and lumina may be inconspicuous. Useful website assistance and reviews29^31 are available to assist with the recognition of certain patterns (www.pathology.jhu.edu/prostate). Figure 3 Adenocarcinoma in which malignant acini in¢ltrate around benign prostatic ducts (A), that are highlighted by immunohistochemical staining of basal cells (B).
inter-observer variation.What is fusion and how do 29 we recognize it? Bostwick de¢nes it as acini with no intervening stroma for a length of at least four times the acinar width.Whilst most cases are clearcut (Fig. 4), this can be di⁄cult to assess if there is only a small amount of fusion or if there is very little stroma between tightly packed acini (Fig. 5).
PATHOLOGICAL STAGING Staging gives an estimate of the extent of spread of a tumour at the time of diagnosis.The results depend on the techniques used to produce the estimate: these may be clinical, biochemical, imaging or pathological. All the methods have limitations in producing an accurate re£ection of the true extent of the tumour but this does not matter as long as it is recognized that di¡erent methods yield di¡erent results. The information derived from
70
Figure 6 (A) Cribriform Gleason grade 3 with smooth contours. (B) Cribriform Gleason grade 4 with irregular contours and inconspicuous lumina.
staging can be useful in prognostication but it is also used to select the most suitable treatment for the patient. Urologists tend to use nomograms, based on logistic regression analysis, which take clinical and pathological data into account in selecting de¢nitive treatment for patients.32 The Whitmore Jewett system and its modi¢cation have been used for prostate cancer but theTNM system is now the most widely used (Table 133). Conventionally, theTNM system can be applied using clinical information only but this includes endoscopy, imaging and biopsy data. According to the rules of the TNM system, a pT number should be ascribed to give a pathological staging only when there is su⁄cient tissue to estimate the highest stage i.e. after de¢nitive surgery.The system used for prostate carcinoma, therefore, produces some apparently anomalous situations for pathologists. The clinical T1 stages (where a clinically impalpable and non-imaged tumour is found on TURP or needle biopsy) depend on pathological examination of specimens (T1a: tumour involving o5% of surface area, T1b involving 45% of surface area, T1c tumour in needle biopsy). There is no pT1 category.Where clinically inapparent tumour is detected bilaterally in needle biopsies it remains T1c. Even if invasion of extra-prostatic fat is detected on needle biopsy,
CURRENT DIAGNOSTIC PATHOLOGY
the tumour remains T1c if it is clinically impalpable and not imaged. pT staging is therefore limited in practice to radical prostatectomy specimens and forTobservations only categories pT2a (one lobe), pT2b (both lobes involved) and pT3, extra prostatic extension. pT4 is reserved for invasion of bladder or rectum or pelvic wall, detected in more extensive resections which are seldom seen in most centres. Even with such a limited number of categories, there are still problems for the pathologist. pT2 a and b are relatively straightforward, being unilateral or bilateral in the 1997 TNM system. The same letters and numbers are used to indicate di¡erent extents of involvement in the1992 version. It is therefore sensible for pathologists to indicate on the report as to which version is being used, for there is otherwise the potential for misleading urologists, clinical trials and cancer registries. Extra-prostatic extension may be di⁄cult to estimate because of problems of de¢nition of the capsule. Unfortunately, the ‘capsule’, consisting of smooth muscle and dense ¢brous tissue, is not well de¢ned, particularly antero-laterally and at the base and the apex of the prostate.34 Penetration of tumour into the capsule (i.e. outside the area where glands are normally found) does not count. Detecting extra-prostatic extension is easiest when tumour is seen in adipose tissue (which is very rarely present in the prostate). Perineural in¢ltration in itself is not diagnostic, for nerves are found within the prostate: in¢ltration around ganglion cells is more suspicious because they are only occasionally seen within the prostate. Perineural in¢ltration of nerves within fat is indicative of extra-prostatic extension, even if the fat is not directly in¢ltrated. In¢ltration of fat may be masked by a desmoplastic response to the tumour: in needle biopsies, this may be di⁄cult to detect but in radical prostatectomies the extension beyond the normal contour of the gland indicates extra-prostatic invasion. The capsule at the apex may be intimately mixed with striated muscle and benign glands may be found in striated muscle. In biopsies the location may not be clear but in radical prostatectomies the position of any striated muscle in¢ltration should make interpretation easier. Because of these problems with de¢nition of the capsule, the Mayo consensus conference35 recommended the term extra-prostatic extension to avoid the use of other ill-de¢ned terms such as capsular invasion, capsular penetration or capsular perforation. Extraprostatic extension is de¢ned as the extension of cancer beyond the edge or capsule of the prostate and is diagnosed when:
1. Carcinoma is present in adipose tissue. 2. Carcinoma is present in neurovascular bundles beyond the contour of the prostate.
PROBLEMS IN GRADING AND STAGING PROSTATIC CARCINOMA
3. Carcinoma extends anteriorly (where there is little adipose tissue) beyond the contour of the prostate into skeletal muscle or between ¢bromuscular stroma and skeletal muscle. Bostwick and Montironi36 discuss the problems of reporting radical prostatectomy specimens. They do not report extra-prostatic extension at the apex or base, where the capsule is di⁄cult to de¢ne and at these sites limit observations to surgical margin status. A more recent review is that of Epstein.37 The CAP Consensus Statement recommended clari¢cation of theTNM categories of 1997 but did not contribute di¡erent de¢nitions.9 A plea for a return to the1992 T categories has been made because of evidence that it obscures the di¡erence between the outcome of patients with single lobe disease (T2a92 and T2b9238). Invasion of the seminal vesicles alters the stage but it is important to note that this means invasion of the muscle of the seminal vesicles, not the associated connective tissue.34 In selection of patients for radical prostatectomy, seminal vesicle biopsy may be carried out in an attempt at pre-operative staging; again, muscle invasion is the important observation. Seminal vesicle involvement and perineural in¢ltration in biopsies have been claimed to be predictors of lymph node positivity.39 Surgical margin positivity in a radical prostatectomy does not alter the stage. This is an observation which is distinct from that of extra-prostatic extension but is sometimes confused. Urologists are often keen for the pathologists to tell them whether a tumour is organ con¢ned (i.e. within the prostatic capsule) and specimen con¢ned (i.e. clear of the excision margins). Although we cannot always tell them whether it is organ con¢ned, we can usually tell if the tumour is present at an excision margin. In prostatic specimens, it is the convention to report margin positivity only when the tumour is seen abutting the inked margin. Inadvertent intra-operative cuts into the prostate may result in artifactual positivity at the inked margin but careful observations at the cutup stage can usually make the interpretation clear. In many radical prostatectomy specimens, the excision margin coincides with the capsule in some areas and extra-prostatic extension is uncertain.The Mayo consensus proposed aT2+ category for these.35 The predictive value of pathological ¢ndings has inspired many studies of biopsies, to detect features which select patients for certain treatment modalities, and of radical prostatectomy specimens to detect features which predict behaviour and indicate response to treatment. Not surprisingly, the authors do not all agree. Using observations of needle biopsies to predict the likely ¢ndings on radical prostatectomy (such as Gleason sum score, volume of tumour, extra-prostatic extension, lymph node metastasis) has met with limited success and varying results. The volume (or length of cores involved
71
by tumour) in the biopsy does not give a good estimate of the volume of tumour in a radical prostatectomy specimen, although small foci of tumour in the biopsy are more frequently associated with small volume tumour in the radical specimen.40 Perineural in¢ltration is often recorded on needle biopsies but some authors claim that it is not a good predictor of extra-prostatic extension.41 Others claim that this, together with the Gleason sum score, is the best predictor of lymph node metastasis. Vascular invasion is not an independent predictor in tumours with a volume less than 4 cm.3,42 The ¢ndings in radical prostatectomy include those which may be made on biopsy but other observations such as the volume of tumour, its extent and completeness of excision may be made.Tumour volume correlates with adverse features of tumour pathology and behaviour43 but the ¢gure is at best a rough estimate. It is clear that what is estimated is the volume of prostate in¢ltrated by tumour, rather than the volume of tumour cells. The methodology employed usually involves measuring the volume of the prostate, preparing whole mounts of the gland at 2, 3 or 4 mm intervals, outlining the areas involved by tumour on H & E slides (Fig. 7) and measuring the proportion of the gland involved by image analysis. Based on a number of assumptions, a ‘volume of tumour’ ¢gure is arrived at which is not the volume of tumour cells but which, nevertheless, has been claimed to be an independent variable.44 Others have not found this when other factors have been taken into account.45,46 Because volume measurement is timeconsuming and usually does not a¡ect actual treatment decisions, it is performed in only a minority of centres. Others have used simple estimates of size such as maximum tumour diameter which is claimed to be an independent variable.47 For peripheral zone cancer, it is claimed that the percentage of high-grade tumour and the volume of tumour determined in a radical prostatectomy are the best prognostic indicators of biochemical failure.44
Figure 7 Whole mount section of radical prostatectomy specimen with two separate carcinomas outlined (pT2b: 97, specimen con¢ned, organ con¢ned; the tumours do not reach the inked margin).
72
The assessment of lymph node involvement is part of the staging process.When no lymph nodes are sent, their status cannot be assessed and are assigned pNX. When nodes are sent but no tumour deposits are identi¢ed, the code is pN0 and when tumour is identi¢ed pN1. It is generally accepted that lymph node involvement indicates an adverse prognosis but urologists di¡er in their attitude to treatment in the presence of lymph node metastases. Clinical and pathological methods have been used to predict lymph node involvement prior to operation. Perineural and seminal vesicle in¢ltration in the biopsy has been claimed to be a predictor of outcome but this is controversial.39 The use of frozen section at operation is also controversial. Its value depends on the urologist’s policy on cancelling the operation in the presence of positive nodes and the recognition that there is a substantial falsenegative rate with this technique. Selection of high- and low-risk patients seems to have led to a reduction in the demand for this technique.48
CURRENT DIAGNOSTIC PATHOLOGY
Table 5 New putative prognostic markers in prostatic carcinoma Reference DNA ploidy and chromosomal abnormalities Nuclear size, shape and chromatin texture Microvascular density
Cell proliferation markers Cytokine/growth factors, receptors and transducers Vascular endothelial growth factor Epidermal growth factorp21 Regulators of proliferation and apoptosis Hormone receptors
NEW PROGNOSTIC MARKERS IN PROSTATIC CARCINOMA In view of the problems associated with poor reproducibility of grading systems in current use there is a clear need for new techniques that enable more objective, consistent and accurate prediction of outcome in carcinoma of the prostate. A large and increasing number of morphometric and molecular techniques have been investigated for their potential value in identifying prognosis in terms of response to treatment, metastatic behaviour and androgen-independent growth. Some of the growing number of putative prognostic markers are listed inTable 5.49^ 67 It is beyond the scope of this review to discuss each in detail. The extent to which new prognostic markers have been studied is variable and investigation by more than one group has often led to con£icting results and directly opposing conclusions. This re£ects a lack of consistency in methodology. For example, the predictive value of microvascular density appears to depend at least in part upon the way in which the number of vessels are quanti¢ed and the method used for selecting ¢elds for analysis.Whilst individual studies have demonstrated associations with grade, stage, progression and metastatic behaviour, it is unclear for some as to whether the markers are of truly independent prognostic value. Those that have been demonstrated to be of prognostic signi¢cance in a multivariate analysis include markers of proliferative activity, DNA ploidy, p53 and bcl-2 expression, and microvascular density. The most useful prognostic markers in carcinoma of the prostate are those that may be applied to needle biopsies at the time of diagnosis, when the range of ther-
Adhesion molecules Others Heat shock proteins CaT1 Sialyl Lewis X
Lieber49 Mora et al50 Pan et al51 Jorgensen et al52 Bettencourt et al53 Brawer54 Volavsek et al55 Bubendorf et al56
Tsurusaki et al57 Hahn et al58 Fowler et al59 Lacombe et al60 Bubendorf et al61 Diaz et al62 Shurbaji et al63 Jenster64 Cardillo et al65 Pan et al51 Cornford et al66 Peng et al67 Jorgensen et al52
apeutic options is greatest. A clinically useful marker for the individual patient would supplement grading and staging data and provide information on the probability of local extra-prostatic spread or metastatic disease, and thus help to identify those individuals who might bene¢t from prostatectomy. Most studies of new putative prognostic markers are retrospective and use tissue obtained from radical prostatectomy specimens. Even when an association with outcome is demonstrated in this type of study, it is possible that tumour cell heterogeneity and sampling artefact associated with needle biopsies will limit the use of new prognostic markers in just the same way as creating ‘errors’ in grading and staging.This is illustrated by attempts to introduce measurement of DNA ploidy into routine use. There have been numerous studies investigating the signi¢cance of DNA ploidy in the development and progression of prostatic carcinoma. Tumour aneuploidy is certainly an adverse prognostic factor68 but there are practical di⁄culties in measuring ploidy routinely. The most common method employed is £ow cytometry but this requires large numbers of cells, limiting its use in needle biopsies. Measurement of nuclear DNA content by image analysis can be performed on biopsy material and is of potential value. It does,
PROBLEMS IN GRADING AND STAGING PROSTATIC CARCINOMA
however, su¡er from the same drawbacks as traditional grading systems: that is, heterogeneity of DNA ploidy within tumours, resulting in sampling errors, and lack of standardization of the technique. Fluorescence in-situ hybridization (FISH) may also be used to determine ploidy69 and has revealed details of chromosomal abnormalities in prostatic carcinoma, but at present is not widely available. Chromatin texture, determined morphometrically, has also been found to be an independent prognostic marker52 but its routine use in needle biopsies may be limited by variable ¢xation and crush artefact.70 Even for those markers that have been demonstrated in large groups to show a statistically signi¢cant association with progression to metastatic disease, the level of overlap between progressors and non-progressors may limit the usefulness in managing an individual patient. The development of neural networks, incorporating data from grade, morphometric analysis and histological biomarkers, in addition to clinical data and levels of serum markers, may prove to be a powerful tool for use in patient management. Simple algorithms combining grade, stage and serum PSA level are already widely used for determining the probability of extra-prostatic spread. Bauer et al.71 developed a formula to calculate the relative risk of recurrent disease following prostatectomy using a combination of traditional markers, PSA level and Gleason grade, and tumour expression of Ki67, p53 and bcl-2. Recent studies indicate that arti¢cial neural networks are superior to other statistical methods in predicting outcome.72,73 In summary, a number of newer histological markers have potential prognostic value. However, their role in the management of individual patients remains unclear and needs to be de¢ned in larger prospective studies. The introduction of many of these markers into routine practice may be limited by technical di⁄culties and expense. In particular, the issues of inter-laboratory variation and standardization have yet to be addressed; it is possible that many of the problems associated with reproducibility of current grading and staging systems will equally apply to other prognostic markers.
PRACTICE POINTS K
K
K
K K
Gleason scoring of needle biopsies should be performed if possible All needle cores should be included as a composite score Any higher pattern not forming part of the score should be mentioned in the report Presence of high-grade PIN should be stated If TNM staging is used, the version (92 or 97) should be stated
73
RESEARCH DIRECTIONS K
K
K
K
Application of new prognostic markers in large prospective multicentre studies Development of neural networks for improving prognostication Reduction in the variation in grading of prostatic carcinoma Standardization of new techniques used in prognostication
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