This manuscript reviews the possible pitfalls that may appear when the extent of prostate cancer is assessed by studying core biopsies and radical prostatectomy specimens.
The data presented are the result of a review of the literature and the author's experience contrasted with and implemented in discussion with a group of European urologists during a meeting in Monte Carlo, Monaco.
A core biopsy of the extent of prostate cancer is made by means of indirect data with Gleason score and tumour volume as the main ones, in addition to intraprostatic perineural invasion. Consequently, they can only determine the risk of invasion but not the extent of prostate cancer. Radical prostatectomy pathologic staging, on the other hand, is a direct determination of prostate cancer, but the urologist must be perfectly aware of a series of limitations, such as quantity of periprostatic fat tissue, handling artefacts, and diagnosis of morphologic criteria, before deciding on further treatment.
Although pathologic staging appears easy and totally reproducible among observers, we must be aware of its limitations in the interests of improving the evaluation and being able to make more solidly based decisions. Excellence results from a close relationship between the pathologist and urologist that leads to better handling of the specimens and improvement of the morphologic criteria.
Keywords: Pathologic staging, Pathology prostate cancer, Prostate cancer, Prostate needle biopsy, Radical prostatectomy specimen.
There is a general idea that pathologic prostate cancer (PCa) staging is always true and indisputable because the pathologist does an objective search for the truth. However, in daily practice, we know that pathologic staging also has its limitations, either because the sample is only representative of one part of the organ studied or because of a series of factors that make it hard to be categorically certain of the pathology study. This paper reviews the possible pitfalls in pathologic staging of PCa and attempts to establish the pathologic characteristics with clinical implications.
2. Limitations of the staging system
Currently, the staging classification most frequently used throughout the literature is that of the International Union Against Cancer (UICC), 2002 version, and the first pitfalls to be considered in pathologic PCa staging are related in particular to category pT (Table 1) .
|T1a||Incidental < 5%||}|
|T1b||Incidental > 5%|
|T1c||Incidental biopsy (PSA)|
|pT2a||Tumour prostate confined to one half of one lobe or less|
|pT2b||Tumour prostate confined to more than half one lobe, but not both lobes|
|pT2c||Tumour involves both lobes|
|pT3a||Tumour extends through prostate capsule|
|pT3b||Tumour invades seminal vesicles|
|pT4||Tumour invades other structures or organs|
According to this classification, the pT2 category in PCa (intraprostatic cancer) is subdivided into a, b, and c, a subclassification that attempts to reflect the increment in tumour volume, which is an already known prognostic factor . Furthermore, it should be pointed out that the pT2c category includes all cases with evidence of neoplasia in both prostatic lobules, meaning that most radical prostatectomy pieces fall within this category, because 87% of cases are multifocal; of these, the majority are bilateral , and thus this stratification does not necessarily reflect a definite biologic risk. In this regard, several modifications in the TNM staging system have been proposed by the Morphology-Based Prognostic Factors Committee .
Another possible pitfall may lie in the criterion for establishing a pT3a category defined as “tumour extends through prostate capsule.” The problem arises in relation to what structures are interpreted as “capsule” and what adipose tissue is really considered periprostatic. The prostate “capsule” is a fibromuscular band that should be considered as an extension of the internal parenchyma more than a true anatomic capsule . We must add to these anatomic considerations that the perineural invasion of the subcapsular nerve trunks is the principal way to transcapsular extension  and direct invasion through the “capsule” is much less frequent . Faced with all these concerns, it is difficult to know if some adipose tissue accumulations located among the fibromuscular bundles are simply fat accumulations in the “capsule” or real extraprostatic adipose tissue (Fig. 1). These problems are the consequence of uncertainty or misunderstanding about the precise anatomy and the irregular adipose tissue distribution around the prostatectomy specimen .
3. Staging problems in core needle biopsies
Obviously, any attempt to determine staging via needle biopsies is limited because of the many possible carcinoma foci (which cannot be detected by ultrasound) and the tiny proportion of prostatic tissue that can be obtained by this method . In addition, the quality of the biopsy (eg, fixation technique and length of the biopsy) will also influence the pathologic features.
3.1. Location of prostate cancer
Pitfalls of pathologic staging may be partially influenced by the distribution of the cancer foci in the prostate. It is potentially important to know the specific location of the core biopsy and, by extension, of the tumour . Apart from the biologic and prognostic differences, depending on whether tumours originate in the transition zone or in the peripheral zone , the topographical distribution of the cancer has some interesting features depending on the tumour volume; thus, in the paper by Egawa et al , tumours with a smaller volume were preferably located in the apical portion and as volume increases, the base portions are also affected. The tumour location was anterior (retropubic) in 14% of cases, posterior (near the rectum) in 58%, and in both positions in 28% of cases, with some differences among African American men as compared to Caucasians (16% vs. 11%, p
3.2. Needle biopsy representation
Another source of pitfalls is the fact that most biopsies are done without having a suspicious area, meaning that the biopsy is done at random, following some guidelines determined by the patient's age, the volume of the prostate, and the serum prostate-specific antigen (PSA); taking all these variables into account, 12 cylinders is the minimum number of cores currently recommended .
3.3. Prostate needle biopsy assessment of extraprostatic extension
Needle biopsy can only provide certainty that there is extraprostatic invasion when cancer can be demonstrated in structures around the prostate, but the finding of adipose tissue invaded by carcinoma is an infrequent event. One must be very cautious in interpreting muscle tissue as bladder neck or seminal vesicle unless there is a certain indication by ultrasound that the sample comes from one of these structures (Fig. 2) . So, most commonly, only the risk that PCa will infiltrate the periprostatic structures can be determined.
Attempts have been made to correlate different factors with the risk of periprostatic invasion. Factors that appear to be significant by themselves are the Gleason grade and the tumour volume. Among the category pT3 carcinomas in radical prostatectomy, the Gleason score on needle biopsy was 2–4 in 28% of cases, Gleason score 5–7 in 55% of cases, and Gleason score 8–10 in 83% of cases  and . The tumour volume correlated with the risk of periprostatic invasion using the percentage of positive cores (32% of positive cores with cancer among the pT2 carcinomas and 50% of positive cores among the pT3 carcinomas)  or any other method as number of positive cylinders, total length of tumour, and percentage of tissue involved . Other markers, such as intraprostatic perineural invasion (in 5.4% of pT2 cases and in 18.3% of the pT3 patients) , lymphovascular invasion, microvascular density, and some molecular markers, have not been sufficiently studied or are dependent on Gleason score or tumour volume  and .
Even with all the limitations mentioned, the data provided by prostate needle biopsy are fundamental for making treatment decisions. This means that a close relationship between urologists and pathologists is needed to obtain the most from the needle biopsy information and to recognise future prognostic markers . This correlation begins with the urologic and pathologic handling of the specimen.
3.4. Requirements and handling of needle biopsy specimen
It is obvious, yet needs to be remembered, that a pathologic evaluation needs good material, not just in terms of how it is preserved (fixed) and its representative aspect (number of core biopsies), but also in terms of its pre-embedded handling, to allow all of the tissue obtained to be studied. To do this, fixed fixation is crucial to keep the cores stretched, avoiding floating fixation that favours the classical curved biopsies, which makes it necessary to make multiple paraffin block levels to see a complete section of the tissue obtained .
Another important aspect is the number of microscopic sections to be made in each paraffin block. In pathologic studies of different specimens usually only one level is evaluated, and the perfect situation would be to analyse as many levels as the tissue permits, but this is impossible. That is the reason for the recommendation to review at least three different levels of each core, thereby improving the final diagnosis in 2% of the patients studied . It is recommended to take two or three additional sections in case the pathologist needs to perform special techniques, such as immunohistochemical staining for high-molecular-weight cytokeratins (for basal cells) or α-methylacyl-coenzyme A racemase.
4. Staging problems in radical prostatectomy specimens
Next to the Gleason score, pathologic staging of radical prostatectomy specimens is the most important prognostic marker. It would seem that studying the radical prostatectomy specimen should not involve any pathologic staging evaluation problem, but in a recent study, a centralised review of 552 radical prostatectomy specimens found high inter-pathologist agreement in the identification of seminal vesicle invasion (94%, κ
What is the reason for the high degree of consensus in the assessment of seminal vesicle invasion? Possibly, the agreement by all the pathologists to accept invasion of the seminal vesicle only when its muscle or epithelium is invaded, without considering as such just the invasion of adipose tissue around the seminal vesicle .
Why do pathologists disagree on the determination of periprostatic invasion?
Of course, one of the causes may be overlooking the zone with invasion, but this plays a minor role. The main reason consists of differences in the criteria for establishing invasion due to lack of a good anatomic delineation between the prostate and its environment; whereas some pathologists only consider a carcinoma to be extraprostatic when it makes direct contact with the adipose tissue (Fig. 3), others find malignant glands in the fibrous tissue outside the edge of the extraprostatic area (periprostate or in the neurovascular bundle), even without fat tissue, to fulfil the requirement of extraprostatic extension (Fig. 4) . A consensus on the criteria to identify extraprostatic invasion by PCa appears to be urgent to achieve uniformity among observers.
4.1. Pitfalls in the evaluation of the radical prostatectomy specimen margins
In the study by Van der Kwast and colleagues, consensus on the determination of margin status was 69.4% (κ
All these variables explain inter-pathologist discrepancies in the positive/negative margin diagnosis and the differences in clinical significance of a positive margin. That is the reason in the literature we can find that positive margins have the same impact on PSA recurrence as periprostatic invasion , that no correlation is found between the extension of surgical margin positivity and PSA recurrence , and in other studies that positive margins are more predictive of PSA recurrence than of extraprostatic extension .
What truly matters when there are positive margins is to know what the patient's risk is of having residual carcinoma foci in the prostate lodge. What we know today is that a positive margin does not necessarily mean residual cancer, and so some cases with positive margins, followed for 10 yr, have a PSA recurrence of 52% but local recurrences could be documented in only 6% of them , exactly as continues to happen in other, more recent studies .
Why do positive margins not always mean residual disease? Are all of these cases false-positive margins? Were the small, residual cancer foci destroyed by ischaemia or inflammation? There is obviously no definite answer to all these questions, but two remarks need to be made. The first is that clearly, the prognostic significance is not going to be the same if the positive margin is directly on the carcinoma without evidence of invaded adipose tissue or if there is an invasion of the adipose tissue in the positive margin area. The second remark refers to an observation that Epstein  had already made some years ago, that is, when the positive margin is smooth, the risk of residual carcinoma is 12.5% compared to 60% when the margin is microscopically irregular (Fig. 7). This observation was confirmed by a recent series of cases in which an incidence of 30.6% for biochemical recurrence was found for cases with positive smooth margins versus 65.5% for microscopically irregular positive margins , probably because smooth positive margins do not tend to be real positive margins, but rather a consequence of dissection by anatomic cleavage planes, whereas a microscopically irregular positive margin can represent surgical dissection through the tumour.
4.2. Requirements and handling of radical prostatectomy specimen
Because of everything discussed, a meticulous study of the radical prostatectomy specimen according to guidelines that have been agreed on is crucial . As with needle biopsy, specimen quality and correct pathologic handling of the specimen ensure that the small details mentioned above can be detected. In general, it is recommended to ink the entire prostate surface without sectioning the specimen after carefully removing all surgical suture material, making complete sections of the organ and complete paraffin embedded blocks, or a very wide sampling. In case of a partial embedded study, once again the close relationship of the pathologist and urologist is basic for an adequate selection of sampling and areas if the tumour is not observed macroscopically.
All the limitations discussed create a series of dilemmas and to be able to make decisions, urologists must be aware of the relativity in which they move, and therefore, a number of concerns have to be considered (Table 2). Urologists must keep in mind that with needle biopsy only the risk of extraprostatic invasion can be evaluated (particularly when quantifying the tumour volume) and rarely will this invasion be observed directly in the biopsy. They need to consider that generally <50% of the area of the prostatectomy specimen is really covered by adipose tissue , making pathologic staging relative. On the other hand, there is the possibility that the patient has residual, nonneoplastic tissue  without evidence of carcinoma that can account for occasional elevated PSA persistence after prostatectomy. However, the presence of benign prostatic glandular tissue at surgical margins does not predict PSA recurrence . Urologists must remember that there is not yet a consensus on the criteria for extraprostatic invasion; this, together with the absence of anatomic entity of the prostatic “capsule” explains the possible discrepancies among observers. Urologists must also be aware that the “capsular” incision expression is a complex topic that includes different definitions  that make understanding and correlation with the patient's evolution difficult. As a result, it would possibly be more useful to refer to margin characteristics, correlating them with post-prostatectomy evolution.
|Staging system||pT categories|
|Anatomic definition of prostate capsule|
|Core needle biopsy||Multifocality|
|Quality and extent of biopsy: fixation method, length|
|Tumour location in prostate|
|At random sampling method|
|Determination of extraprostatic extension|
|Quality of biopsy: pre-embedded handling|
|Number and level of section in paraffin block|
|Radical prostatectomy specimen||Determination of periprostatic invasion: criteria, anatomic delineation|
|Quality of specimen: handling|
|Margin characteristics: status positive or negative (criteria, retraction, lacerations), smooth or irregular|
Despite all this, scrupulous pathologic handling and microscopic study of prostate samples can provide some guidelines for clinical decisions, as explained hereafter. Samples without clear evidence of extraprostatic invasion, with negative margins, or smooth positive margins, can be deemed to be from patients at low risk for PSA recurrence. In contrast, patients with extraprostatic tumours, with or without positive margins, and patients without invasion of the adipose tissue but with microscopically irregular positive margins, are at high risk for PSA recurrence.
In the end, let us remember that the final evaluation of a patient's prognosis is based on a variety of factors, among which the pathology findings are included. The pathologic analysis should be done by a pathologist aware of the urologist's requirements, and the clinical dilemmas need to be resolved by direct pathologist–urologist contact to avoid over-treatment, but without missing patients who do need treatment.
Conflicts of interest
The author has nothing to disclose.
The author is grateful to Ismar Healthcare NV for their assistance in editing of the manuscript. The publication was supported by Astellas Pharma Europe.
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Section of Pathology, Fundació Puigvert, Department of Morphology, Facultat de Medicine, Universitat Autonoma de Barcelona (UAB), Cartagena 340-350, 08025 Barcelona, Spain
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