—  LONG COURSE #02  —

The Pathology of Prostate Cancer: From Population Studies to the Molecule
Moderators: Dr. John R. Srigley and Dr. Rodolfo Montironi

Section 6 - Gleason Grading And Other Prognostic Factors In Needle Biopsies

Mahul B. Amin, MD
Chairman, Department of Pathology and Laboratory Medicine
Cedars-Sinai Medical Center


AN APPROACH TO GLEASON GRADING IN PROSTATIC NEEDLE BIOPSIES

Several systems have been proposed for application in prostate cancer grading and include the Gleason system, Mostofi (WHO) system, Böcking system, Gaeta system, MDAH system and the Broders (Mayo) system. [2, 3, 4] The de facto system used in the United States and in most other countries is the Gleason system that was based on the Veterans Administration Cooperative Studies. [6] The studies began in 1960 as prospective, randomized, controlled comparisons of treatments for prostate cancer available at that time, and the outcomes provided an invaluable clinical database of more than 4,000 patients between 1960 and 1975.

Pathologic material from this study formed the basis upon which the Gleason grading system was first proposed in 1966 [7] and established in 1974. [8] In the more than 30 years since the proposal of the system, and with almost completely different or more sophisticated therapeutic approaches to prostate cancer, the Gleason system remains as a paramount pathologic factor for prognostication, often influencing stratification of patients into different therapeutic modalities.

The Gleason grading system was based primarily on observations and applications in transurethral resection of prostate (TURP) specimens, 14-gauge needle biopsies and prostatectomies (most often simple prostatectomies). The 18-gauge needle biopsy technique used currently contains 36% of the width of the core compared to the 14-gauge needle biopsy, hence providing considerable lesser tissue for examination. [9] This review provides a simplified and practical approach to the application of the Gleason grading system in contemporary 18-gauge needle biopsies of the prostate gland and provides an update of the recent modifications to its application. While the basic principles and diagnostic criteria remain relatively unchanged, application of the system in contemporary 18-gauge needle biopsies requires extrapolation and modification of some of the principles in facilitate application in these more limited samples, while importantly preserving the important prognostic utility of the system. Several recent position papers have discussed this issue. [2, 3, 4, 5]

I. Application of the Gleason Grading System in 18-Gauge Needle Biopsy Specimens.


Principles and Basis
  1. The Gleason system is fairly unique in that it is based solely on architectural features of the cancer (pattern of growth and extent of glandular differentiation) and does not take into account cytologic characteristics. It can thus be practiced at low to intermediate powers of light microscopy. Only rarely is a high power evaluation required.

  2. The patterns of growth and degree of glandular differentiation form a morphologic continuum, along which 5 distinct patterns are separated based on arbitrary, although easily definable, cut points.

    • The pattern that is most prevalent in surface area = primary grade (five patterns = 1-5).

    • The next most prominent pattern = secondary grade (five patterns = 1-5).

    • The two grades are added to derive a Gleason score (2-10).

    • If only one pattern is seen, the grade is doubled to achieve the Gleason score.

    • In prostatectomy specimens approximately 50% will contain more than two grades (tertiary and quaternary patterns). [10]

    • In needle biopsies if three grades (patterns) are present, and if the second & third patterns are roughly equal, the higher of the two grades is included to derive the Gleason score.


  4. The central premise on which the scoring system is proposed, is based on the fact that "prostate carcinoma did not appear to be as bad as its worst part but behaved more in proportion to its average histology"; i.e., the observed number of deaths (survival) fell in between that expected for on the basis for the primary pattern above, than that based on the secondary pattern alone. [11]


Criteria and Pitfalls for the Diagnosis of Each Pattern.


(A) Pattern 1
  1. Original Gleason criteria.
    Single, separate, uniform glands closely packed, with definite edge. Gland size and gland spacing usually does not exceed one gland diameter.

  2. Application in 18-gauge needle biopsy specimens.
    Pattern 1 SHOULD NOT BE DIAGNOSED in these specimens as one needs to visualize the "definite edges" of an entire focus of carcinoma.

  3. Pitfalls in grading.
    An extremely small focus of cancer (e.g., 3-8 glands) should not be graded as pattern 1 simply because stroma is appreciable on all sides of the proliferation.


(B) Pattern 2
  1. Original Gleason criteria.
    Single, separate, uniform glands loosely packed, mostly circumscribed but with an irregular edge. Gland size and gland spacing often exceeds one gland diameter.

  2. Application in 18-gauge needle biopsy specimens.
    PATTERN 2 SHOULD BE DIAGNOSED WITH GREAT CAUTION in these specimens, and both edges of the carcinoma (as sampled in the needle biopsy) should clearly be smooth. Hence, even if the unsampled cancer of the focus has an irregular edge, the diagnosis of a Gleason grade 2 is tenable though this diagnosis must be made only on extremely rare occasions.

  3. Pitfalls in grading.
    1. An extremely small focus of cancer (e.g., 3-8 glands) should not be graded as pattern 2 simply because stroma is appreciable on all sides of the proliferation.

    2. It is conceivable that cancer judged as pattern 2 in the 18-gauge needle biopsy may actually represent pattern 3 if the entire focus was evaluable (e.g., in a prostatectomy), and the glands at the periphery of the unvisualized edges of the biopsy were clearly invasive into the prostate stroma. This is one of the reasons why there is often "undergrading" in needle biopsies compared to the prostatectomy specimen.


(C) Gleason Pattern 3
  1. Original Gleason criteria.
    • 3A: single, separate, uniform glands, scattered (infiltrative carcinoma).

    • 3B: single, separate, very small glands, scattered (infiltrative carcinoma).

    • 3C: papillary/cribriform masses, smoothly circumscribed.


  2. Application in 18-gauge needle biopsy specimens.
    • A small focus of cancer when seen in between benign glands is a pattern 3, as presence between benign glands indicates invasion beyond the confines of a circumscribed nodule of neoplasm.

    • Cribriform pattern 3 is recognized when the lumina within the cribriform proliferation are regular, evenly spaced and relatively cleanly punched out and the borders of the cribriform proliferation are smooth. Using this definition, most neoplastic cribriform proliferations are Gleason patter 4 and not 3.

    • Papillary pattern 3 is recognized when glands containing the papillary architecture are discrete, single and separate.

    • There is no apparent clinical utility of subgrading pattern 3 into pattern 3A, 3B and 3C, and hence are currently not routinely performed or reported in needle biopsies.


  3. Pitfalls in grading.
    1. Neoplastic acini may branch resulting in V and Y-shaped configurations. This is not gland fusion a sina-qua-non of Gleason pattern 4.

    2. Tightly packed or "squeezed" yet discrete or single acini should not be construed as fused glands. As long as an imaginary line can be drawn around each acinus it is a Gleason pattern 3.

    3. Not all cribriform proliferations are Gleason pattern 3. The differential diagnoses range from benign (clear cell cribriform hyperplasia) to cancer (acinar or ductal type). In needle biopsies with cancer most cribriform proliferations in the authors experience are Gleason pattern 4 (see below for criteria).


(D) Pattern 4
  1. Original Gleason criteria.
    • 4A: fused glands, raggedly infiltrating.

    • 4B: fused, raggedly infiltrating glands with large pale cells ("hypernephroid").


  2. Application in 18- gauge needle biopsy.
    Gland fusion is the defining feature of Gleason pattern 4. A unique variation is when cells resemble renal cell carcinoma (hypernephroid pattern). Although apparently straight forward, gland fusion may be difficult to recognize. Interanastomosis between glandular lumina and longer branched and interconnecting glands, some with more solid appearance must be present. Also included are ill-defined poorly formed glands with inconspicuous lumina where a tangential section of Gleason 3 glands cannot account for histology. As the presence of any amount of Gleason 4 confers an adverse prognosis, adherence to strict criteria is essential. I require at least more than one or two separate glandular structures to demonstrate fusion. Insistence on this quantitative guideline avoids overcalling branched glands as fusion, and in almost all cases of clear-cut Gleason pattern 4 fusion is seen in several and not merely between one or two isolated glandular units. Cribriform structures with irregularly sized and shaped lumina, with focal solid growth and irregular ragged outlines should be designated Gleason pattern 4.

  3. Pitfalls in grading.
    1. Gland branching may be mistaken for fusion.

    2. Xanthomatous (lipid rich or foamy gland) pattern of adenocarcinoma may be composed of single discrete glands, hence Gleason pattern 3, and should not be overgraded as "hypernephroid pattern".

    3. Irregular cribriform aggregates with ragged growth or solid architecture may contain foci of necrosis, which is indicative of Gleason pattern 5.


(E) Gleason Pattern 5
  1. Original Gleason criteria.
    • 5A: almost solid, rounded masses, necrosis (comedocarcinoma).

    • 5B: anaplastic, raggedly infiltrating.


  2. Application in 18-gauge needle biopsy.
    Single cells, cords, trabeculae and sheets of neoplastic cells, all indicating loss of glandular differentiation signify Gleason pattern 5. Additionally when cribriform or papillary patterns of cancer are associated with central comedonecrosis a diagnosis of Gleason 5 is warranted. Necrotic cells and karyorexis are required.

  3. Pitfalls in grading.
    1. Poorly preserved and thick sections may result in tumor appearing more solid and glands apparent as cords and trabeculae – this may result in over-grading.

    2. Presence of pyknotic tumor nuclei in luminal eosinophilic secretions may be misinterpreted as comedonecrosis. Tumors with comedonecrosis usually have high nuclear grade often with brisk mitotic activity.


Summary of application.
Using these principles EVERY PROSTATE CANCER ONCE IT IS DIAGNOSED IN A NEEDLE BIOPSY CAN BE ASSIGNED A GLEASON SCORE, NO MATTER HOW SMALL. If only 2-3 discrete glands are present, the diagnosis is a Gleason pattern 3, score 6. SINGLE DISCRETE GLANDS ARE PATTERN 3, FUSED GLANDS ARE PATTERN 4 and CORDS AND SHEETS OF CARCINOMA ARE PATTERN 5. Awareness of these basic principles will facilitate the application of Gleason grading of Prostate cancer in needle biopsy.

II. Interobservor Reproducibility of Gleason Grading System.
Over 10 studies have been conducted assessing interobservor, and sometimes intraobservor reproducibility in Gleason grading for prostate cancer. [12, 13] Exact agreement on Gleason score between two pathologists in a series of cases has varied from 36-70.8%, increasing to 69-94% with agreement ± 1 Gleason score. Amongst Urologic pathologists the level of agreement was moderate to substantial (kappa .56 to .70, mostly substantial), whereas the level of agreement was barely moderate between general pathologists. [13] Clearly, greater educational efforts are needed to improve the practice of Gleason grading in needle biopsies, and exposure to "re-training" in meetings, courses and websites have been demonstrated to be beneficial. [14]

Problem areas for interobservor reproducibility
  1. Among general pathologists:
    • The main problem, as shown in the study by Allsbrook et al, and in my personal experience, is under-grading of needle biopsies. Designating pattern 1 and 2 for small foci of pattern 3, and under-grading pattern 4 (due to failure to recognize gland fusion); occasionally pattern 4 may be mistaken for pattern 5. [12]


  2. Among urologic pathologists:
    • the problem areas appear to be: (a) low-grade tumors (Gleason pattern 2), (b) small cribriform proliferations (?Gleason 3 or 4), and (c) in tumors whose histology is on the border of Gleason patterns. [13]


III. Correlation of Needle Biopsy Gleason Score with Prostatectomy Specimens.
There is an overall good concordance between Gleason grading in needle biopsy and in the corresponding prostatectomy specimen. Several studies have addressed this issue formally. [15, 16, 17, 18] Two features appear consistent between studies: (i) The accuracy of grade decreases with low-grade cancer and in small amounts of cancer in the needle biopsy (this is most commonly due to sampling error), and, (ii) When higher Gleason patterns are present in a needle biopsy (pattern 4 and 5) they are most often present in the prostatectomy specimen. When a Gleason score of 5-6 was assigned in needle biopsy specimens, the same grade was present in 64% of cases in radical prostatectomy specimens. When the score was ≥8 in needle biopsy, 87.5% of cases had a concordant score in the definitive surgical procedure. [15]The Gleason grade is underestimated in 33-45% of cases and overestimated in 4-32% of cases. [17] In extremely minute foci of cancer diagnosed on needle biopsy the correlation of Gleason score in needle biopsy is poor not only with prostatectomy score, but also with outcome. [18]

IV. Modifications to the original Gleason System. Over the years several modifications have been proposed in the application of the Gleason grading system. Not all of these have been accepted or uniformly used by the practicing pathology community. Some of the major modifications based on the International Society of Urologic Pathologists are summarized below and in the slides after the test. [2]
  1. Grading histologic variants of prostate cancer.
    Although formally not evaluated, the Gleason grading system principles can be extrapolated and employed in the grading of histologic variants of prostate cancer. Since gland fusion is present in signet ring cell carcinoma, mucinous carcinoma, and most ductal carcinoma of the prostate, they should be assigned at least a Gleason pattern 4; if single cells or sheets of cells are present in signet ring cell carcinoma and if comedo necrosis is present in ductal carcinoma, a Gleason grade 5 should be designated. Most ductal carcinomas are Gleason 4+4=8. Small cell carcinoma of prostate, sarcomatoid carcinoma, and lymphoepithelioma-like carcinoma of prostate should be assigned a pattern 5 based on the diffuse growth pattern and lack of glandular differentiation. [1, 19] The outcome of patients with these variants appears to correlate with the proposed Gleason system application; although the experience with many of the variants is limited.

  2. Cribriform carcinoma behaves more like Gleason pattern 4 than Gleason 3.
    McNeal and associates have suggested that cribriform cancer that often has a prominent intraductal component, biologically behaves like a Gleason pattern 4 rather than Gleason pattern 3 cancer. [21] Most cancer in prostate with cribriform architecture is Gleason pattern 4 than 3 by consensus conference criteria. [2, 9]

  3. Grading after therapy (radiation or androgen deprivation).
    This is a controversial area as two issues need to be considered:
    1. Grade inflation due to atrophic and shrunken, closely packed glands hence glands artificially appear to be fused or in cords – Gleason patterns 4 or 5 (uncoupling of architecture). [22]

    2. At this time of the clinical course of the disease, the biologic potency or tumor viability is more critical than the histologic grade of the tumor, which was presumably assigned at the time of primary diagnosis. [22]


  4. "Gleason score 2 adenocarcinoma of the prostate on needle biopsy – a diagnosis that should not be made." Gleason score 3-4 adenocarcinoma in needle biopsy – a diagnosis that rarely, if ever, should be made."
    The reasons for rarely and cautiously making the diagnosis of Gleason scores 2-4 diagnosis in needle biopsies:
    1. the radical prostatectomy may show a higher Gleason grade,

    2. there is poor interobservor reproducibility in low grade cancers even amongst urologic pathology experts,

    3. the diagnosis of Gleason score 2-4 may potentially lead to the patient being under-treated or counseled as to having a low-risk tumor. [23]
    Since Gleason score 2+2=4 or 2+3 cancers do in fact exist (albeit rarely) in needle biopsy specimens, an alternate approach would be to clearly point out to the clinician in a comment that the prostatectomy specimen may reveal a higher grade tumor, and therefore treatment planning should not be entirely based on the Gleason score in the needle biopsy alone. [18, 23]S ee reporting of prostate cancer section for update.

  5. Estimate the % of Gleason pattern 4 or % Gleason 4/5 in needle biopsy specimens.
    Reporting in this fashion is not formally suggested and this parameter remains optional. Since the presence of Gleason pattern 4 is a critical feature, both in terms of prognosis and possibly in terms of determining therapy, the power of this parameter may be enhanced by estimating the amount of Gleason pattern 4 as a percentage of the carcinoma present in a particular biopsy, or amongst all of the cancer in a set of needle core biopsies from a patient. [24, 25, 26] See reporting of prostate cancer section for update.


V. Clinical Utility of the Gleason Grading System.
In the thirty plus years since its first proposal, the Gleason grading system has undoubtedly emerged as an extremely powerful prognostic parameter in prostate cancer, and this feature has led it to become an important factor in planning definitive therapy in patients with prostate cancer. It is, therefore, imperative that a Gleason score be provided for every cancer. [27, 28]
  1. Gleason system as a prognostic factor.
    Several studies have shown that the Gleason grade of a tumor correlates with:
    1. preoperative PSA

    2. pathologic stage and tumor volume

    3. lymph node metastasis

    4. recurrence and survival

    5. other prognostic factors, e.g., ploidy, angiogenesis, etc. [1, 19]
    Based on 703 patients with clinically localized prostate cancer, Partin et al (Partin, J Urol, 1993) showed that combinations of 3 variables (serum PSA, Gleason score and clinical stage) allowed for construction of probability plots and normograms, which assist in the preoperative prediction of final pathologic stage for patients with clinically localized prostate cancer. [29] The "Partin tables" are used frequently by many urologists in routine clinical practice when discussing treatment options for prostate cancer. [30] In the Partin et al study, Gleason score alone was statistically significant (p<0.0001) in preoperatively predicting organ confined disease; although the predictive power increased when clinical stage and preoperative PSA were factored in.

  2. Gleason system as one of the parameters influencing definitive therapy.
    The decision for definitive therapy is based on multiple factors including the clinical stage, patient age, preoperative PSA, patients general health, life expectancy, etc. The Gleason grade in needle biopsy specimens is rapidly emerging as another variable that can potentially help stratify patients into different therapeutic modalities. The following examples are guidelines used in some institutions used in conjunction with other clinical parameters and in no ways or means set in stone.
    1. Frozen section sampling of lymph nodes.
      The presence of Gleason score 8-10 may be prompt frozen section evaluation of pelvic lymph nodes that if positive may abort a prostatectomy, and if negative at frozen section may allow for the procedure to be completed.

    2. Watchful waiting (WAWA) as an option for prostate cancer.
      Patients determined to have a small amount of cancer after thorough sampling (several biopsies) and who have a "low" Gleason score (scores 4-6) may be candidates for waitful watching. Fleshner et al have even recommended a rebiopsy to be considered in all patients being considered for waitful watching. [31]

    3. Gleason score 7 the critical crossroad.
      The presence of a Gleason pattern 4 (score 7 or more) will, in most cases, prompt intervention by the employment of at least one of the many therapeutic modalities available for prostate cancer.

    4. Patients with Gleason score 8-10 may become candidates for radiation therapy.
    Due to the higher probability of extraprostatic extension, seminal vesicle or lymph node involvement, patients with Gleason score 8-10 may benefit more from radiation to the prostate rather than surgery.


VI. Reporting of Prostate Cancer in Needle Biopsies.
The information provided in the surgical pathology report of a prostate needle biopsy with carcinoma has become critical in the subsequent management and prognostication of the cancer. The surgical pathology report should thus be comprehensive and yet succinct in providing relevant information consistently to urologists, radiation oncologists and oncologists and, thereby, to the patient. The attached tables reflect the current recommendations of the "2004 WHO-Sponsored International Consultation Consensus," which was co-sponsored by the College of American Pathologists. This information is incorporated into the latest CAP Cancer Protocols, [5] which, for the first time in this publication, require essential elements in needle biopsies to be reported in a pathology report, as required by the American College of Surgeons Commission on Cancer guidelines. (Tables 1-6) It builds on the existing work of several organizations, including the College of American Pathologists, the Association of Directors of Anatomic and Surgical Pathologists, the Royal Society of Pathologists, the European Society of Urologic Pathology, and the European Randomized Study of Screening for Prostate Cancer.

While the prime goal of the needle biopsy is to diagnose prostatic adenocarcinoma, once carcinoma is detected further descriptive information regarding the type, amount of cancer and grade forms the cornerstone for contemporary management of the patient and to assess potential for local cure and the risk for distant metastasis. The information provided in the needle biopsy report regarding the attributes of carcinoma is used depending on the individual patient's medical condition and preference, and the treating physician's evaluation to determine a) whether any form of treatment is indicated and, if so, b) the type of therapy. Further, the information in the biopsy report that may be valuable in further potentially determining treatment strategies includes the field and/or type of radiation therapy (brachytherapy, external beam, etc.), the need of adjuvant hormonal therapy, the eligibility for clinical trials, the type of surgery (nerve sparing, bladder neck sparing), and sometimes the intraoperative course (using frozen sections for lymph nodes, neurovascular bundle involvement, apical and bladder neck margin or type of operation, e.g., nerve sparing, etc.).

The Gleason score of adenocarcinoma of the prostate is the quintessential prognostic factor in predicting findings in radical prostatectomy (pathologic stage), biochemical failure, local recurrences, lymph node or distant metastasis in patients receiving no treatment, radiation therapy, radical prostatectomy and other therapies including cryotherapy and neoadjuvant therapy. The needle biopsy Gleason score also correlates with virtually all other adverse pathologic parameters including tumor volume and inked margin status in radical prostatectomy specimens, serum PSA levels and many molecular markers. Specifically, high Gleason scores of 7-10 are associated with worse prognoses, and tumors with Gleason scores 5- 6 are usually associated with lower progression rates after definitive therapy. The predictive value of Gleason score is enhanced when combined with other clinical parameters including digital rectal examination and serum PSA levels. In recent years, nomograms have been developed to predict pathological stage on radical prostatectomy, and disease progression after surgery or radiation therapy. Nomograms typically include pretreatment variables including clinical stage, Gleason score, serum PSA, amount of cancer in needle biopsy, etc. Based on statistical modeling of cumulative, prospectively accrued data on large consecutive series of patients, the nomograms have reasonable discriminatory ability to predict (depending on the nomogram patient cohort and statistical modeling) the pathologic stage, seminal vesicle involvement, lymph node metastasis, biochemical failure, small volume organ-confined tumors, response to radiotherapy, etc. Such nomograms are used with increasing frequency in clinical practice by urologists and radiation oncologists to counsel their patients regarding therapeutic options and potential risk for failure based on therapy they may choose. Inclusion of the needle biopsy Gleason score in all clinically valid nomograms is testimony to the prognostic and predictive power of this grading system and its central role in contemporary prostate cancer patient management. Further, Gleason score is also often used to determine eligibility for clinical trials, including those for watchful waiting.

Hence, while the pivotal role of Gleason score in the needle biopsy is not in question, the method of reporting in needle biopsies needs clarification of a few issues including some not originally addressed in the original Gleason system. The current recommendations of reporting of the Gleason score in needle biopsies as summarized in Table 4. The most significant new recommendation is to separately report the Gleason score for each recognizable core irrespective of whether the cores are individually submitted [in individual container signifying specific anatomic location, e.g., right base], or submitted together; [more than one core, possibly sampling different areas of the prostate, e.g., three cores from the left apex, mid and base sent in one container]. The needle biopsy core(s) with the highest Gleason score is often given the most weight in clinical decision making and hence should be identifiable as a separate Gleason score, information which would be lost if individual cores were not graded. If extreme fragmentation makes grading of individual cores difficult, the emphasis should be to identify and provide information on the core with the highest Gleason score. A recent survey of the surgical members of the Society of Urologic Oncology indicated that 81% used the highest Gleason score in a positive biopsy, regardless of the overall percentage involvement, to determine their treatment plan. This paradigm was also used in the creation and validation of Kattan nomograms, Partin tables that are currently in wide clinical use. Assigning a global (composite) score is optional.

Another important change is the recognition and reporting of the tertiary pattern in needle biopsies. Tertiary patterns are uncommon but when the worst Gleason grade is the tertiary pattern, it should influence the final Gleason score. Examples : a case with primary Gleason pattern 3 , secondary pattern 4 , and tertiary pattern 5 should be assigned a Gleason score of 8; a case with primary Gleason pattern 4, secondary pattern 3, and tertiary pattern 5 should also be assigned a Gleason 8 (secondary score being 4 based on the average of patterns 5 and 3 = 4) or Gleason score 9 (pattern 4+5).

The data regarding the importance of the percentage of Gleason 4 pattern in Gleason score 7 tumors is rapidly expanding. In recently generated nomograms, patients with Gleason score 4+3 vs. 3+4 are stratified differently, underscoring the importance of the relative amount of pattern 4. [48] Whether or not the actual percentage of 4 pattern tumor should be included in the report is not clear based on published data to date and, if this emerges as an important parameter, meaningful discriminatory cut-off points for percentage of pattern 4 will need to be defined.

The diagnosis of Gleason 2-4 should not be made on needle biopsies. The reasons for not making this diagnosis are compelling: 1) Gleason score 2-4 cancer is extraordinarily rare in needle biopsies as compared to transurethral resection specimens; 2) there is poor reproducibility among experts for lower grade tumors; 3) the correlation with the prostatectomy score for Gleason 2-4 tumors is poor and approximately half of the prostatectomies in one study had extraprostatic extension; and 4) a "low" score of Gleason 2-4 may misguide clinicians and patients into believing that there is an indolent tumor.

REPORTING OF HGPIN AND ATYPICAL FOCI SUSPICIOUS BUT NOT DIAGNOSTIC OF MALIGNANCY

Since the clinical significance or biologic relevance of low-grade prostatic intraepithelial neoplasia is not known and appears insignificant, this diagnosis should not be made in needle biopsies. The diagnoses of high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical foci suspicious for cancer in needle biopsies have no prognostic significance, although their presence is predictive of subsequent cancer detection in 27-31% (recent data) and 30-60% of patients, respectively. [33, 34] Due to the lower predictive value for cancer in recent years, studies have focused on HGPIN parameters in needle core biopsies that may be more useful in subsequent detection of cancer. Whether the extent of involvement of HGPIN is a better predictor of subsequent prostate cancer detection is controversial. [35, 36] The pattern of HGPIN (micropapillary, cribriform, etc.) is not correlated with increased prostate cancer recognition. Atypical small acinar proliferation (ASAP) is not a diagnostic entity and is not synonymous with HGPIN. It represents descriptive diagnostic terminology in which there is architectural and/or cytologic atypia that does not reach an individual pathologists' threshold required for the diagnosis of cancer. If pathologists use this diagnostic terminology, it must be supplemented by stating that malignancy cannot be excluded. [37, 38, 39, 40, 41, 42, 43, 44, 45] The reasons for this include the equation by some urologists of the term ASAP with HGPIN and because all of the atypical foci are not always "small" acinar but may include glands with larger diameter (such as pseudohyperplastic pattern of cancer or adenocarcinoma with ductal features). Further, with the judicious use of highly sensitive markers for the basal cell layer and markers related to cancerous epithelium (AMACR/P504S), the incidence of atypical biopsies may be reduced, such that when the term is used in contemporary times it is for the most part used for lesions that fall short of the threshold for diagnosing cancer. If urologists equate the term ASAP with HGPIN and since the diagnosis of HGPIN has diminished relevance as a marker lesion to detect adenocarcinoma (as recent data seem to indicate), if the term ASAP is used by pathologists and misunderstood by urologists, a clinically significant suspicion for cancer may trigger a less than adequate clinical follow-up. The importance of close clinical follow-up and re-biopsy in patients with atypical diagnosis must, hence, be re-stressed to urologists. [45]


From reference 2

TABLE 1. Categories in Diagnostic Reporting of Prostate Needle Biopsy Specimens *

Benign
  • Benign prostatic glands and stroma
    Optional:
    • Benign mimickers of cancer

    • Chronic and acute inflammation

    • Granulomatous prostatitis

    • Atypical adenomatous hyperplasia (adenosis)

    • Severe atrophy
High-grade prostatic intraepithelial neoplasia (HGPIN)
Optional: Extent of HGPIN (focality - focal or multifocal, number of cores involved, laterality - unilateral or bilateral)
Atypical glands, suspicious for cancer, malignancy cannot definitively be excluded
Adenocarcinoma of prostate
  • Location and distribution of tumor (site of biopsy if specified - see Table 2)

  • Histopathologic type (see Table 3)

  • Gleason score including primary and secondary pattern (see Table 4)

  • Extent of involvement (see Table 5)

  • Local invasion
    • Seminal vesicle (cancer involving specimen directed at and/or containing seminal vesicle)

    • Extraprostatic extension (tumor in periprostatic adipose tissue)


  • Perineural invasion (report only if identified)
    Optional:
    • Extent (focal, multifocal)

    • Caliber of nerve bundles


  • Lymphovascular invasion (report only if identified)

  • Therapy-related changes (if clinical history of radiation or hormonal therapy)

TABLE 2. Potential Importance of Diagnostic Reporting of Location and Distribution of * Prostate Cancer in Accordance with Site of Sampling
  • Map distribution of prostate cancer for planning field of radiation therapy (e.g., in brachytherapy)
  • Laterality useful in planning of nerve-sparing radical prostatectomy

  • Tumor involvement of base biopsies may influence bladder neck-sparing radical prostatectomy

  • Extensive cancer in base biopsies correlates with extraprostatic extension

  • Dominant side of prostate biopsy correlates with ipsilateral positivity of surgical margins and extraprostatic extension

  • Knowledge of location of cancer may help target additional tissue or block sampling in cases with no apparent cancer in radical prostatectomy sections

  • Knowledge of biopsy site helps recognize potential diagnostic pitfalls (e.g., seminal vesicle epithelium or central zone epithelium, seen most frequently in base biopsies and the rare Cowper's glands in apex biopsies)

  • Allows detailed correlation with digital rectal examination and imaging studies
Additional benefits
  • In a patient with atypical glands without cancer, knowledge of site allows for more focused repeat biopsies

  • Biopsy samples with site-specific labeling usually contain only one or two cores, which is advantageous for block and slide preparation and allows for complete visualization of cores and detection of small foci of cancer

  • Limited number of cores in site-specific labelled specimens reduces fragmentation, thereby allowing for more confident assessment of number of cores involved

TABLE 3. Diagnostic Reporting of Histologic Type in Prostate Needle Biopsy * Specimens
Adenocarcinoma of prostate (refers to conventional, acinar, microacinar or usual type, most common morphology hence no qualifier necessary; category includes morphologic variations such as atrophic, foamy, pseudohyperplastic patterns of prostate cancer, etc.)
Small cell carcinoma of prostate
Sarcomatoid carcinoma of prostate
Adenocarcinoma of prostate with ductal features*
Adenocarcinoma of prostate with signet ring cell features*
Adenocarcinoma of prostate with mucinous differentiation*
Adenosquamous carcinoma
Urothelial carcinoma
- involving prostatic ducts and acini without stromal invasion
- involving prostatic ducts and acini with stromal invasion
Basal cell (adenoid cystic) carcinoma

* Final diagnosis of ductal, signet ring cell or mucinous carcinoma only assignable upon examination of radical prostatectomy specimens
TABLE 4. Diagnostic Reporting of Gleason Score in Prostate Needle Biopsies *
Report primary pattern and secondary pattern and assign Gleason score
If one pattern is present, double it to yield Gleason score
A Gleason score is usually assignable even if the cancer is extremely small
In a needle biopsy with more than 2 patterns, the worst pattern must be reflected in the Gleason score even if it is not the predominant or secondary pattern (see text)
Provide Gleason score for each separately identifiable specimen
A diagnosis of Gleason score 2 should not be made and Gleason score 3-4 should rarely ever be made (see text)
Do not report Gleason score after hormonal or radiation therapy except if cancer shows no treatment effect
Provide Gleason score for all adenocarcinoma variants - ductal, signet ring and mucinous

Do not assign a Gleason score for small cell carcinoma and sarcomatoid carcinoma cases, specify the histologic variant pattern.
Provide Gleason score for adenocarcinoma morphologic patterns (e.g., hypernephroid, foamy gland, atrophic, pseudohyperplastic)
Optional:
  • Provide composite (global) Gleason score for all cores for the patient

  • Provide percent of tumor with Gleason pattern 4 in Gleason score 7

  • Provide percent of tumor with Gleason patterns 4 and 5 in tumors with Gleason score 8-10

TABLE 5. Diagnostic Reporting of Extent of Involvement by Carcinoma in Prostate * Needle Biopsy Specimens
Number of cores involved ( if possible include % of cores involved)
Amount of cancer in biopsy (either method optional)
  • Linear measurement in mm (total tumor length in all biopsies, longest single length of tumor)

  • Percent of sampled tissue (overall % of cancer in all biopsies, % of each core involved)
Optional: Composite (global) percentage of cancer in all needle biopsy tissue

TABLE 6. Some Observed Problems in Prostate Cancer Needle Biopsy Reports *
All benign biopsies designated as "benign fibromuscular and glandular hyperplasia" (erroneous, as most biopsies are targeted at the peripheral zone; also this may be misleading as findings may be interpreted as correlates of elevated PSA levels)
All benign biopsies designated as "benign" or "negative for malignancy" [biopsies with scant tissue or only stroma need some description of amount of tissue or characteristics of tissue to notify limitation of sampling. Also, reporting possible causes of elevated PSA (significant inflammation) or potential correlates of hypoechoic lesion (severe atrophy) may be beneficial]
Focal, minimal inflammation is designated as "chronic and/or acute prostatitis" (chronic or acute inflammation is not synonymous with clinical chronic or acute prostatitis; comment on chronic and/or acute inflammation should be reserved for significant inflammation in an attempt to suggest potential correlation with elevated PSA levels)
"Prostatic adenocarcinoma, Gleason score 3/5" (unclear if Gleason score 3+3=6 or score 3+5=8)
"Prostatic adenocarcinoma, Gleason grade 4" (unclear if Gleason score 2+2=4 or score 4+4=8)
"Prostatic adenocarcinoma, well differentiated, too small to grade" (a small focus does not equate to well-differentiated carcinoma - most cancers Gleason grade 3+3=6, hence, not well differentiated and in most cases, no matter how small, a Gleason grade is assignable)
Biopsy targeting seminal vesicle diagnosed as "left seminal vesicle: prostatic adenocarcinoma, Gleason score 3+3=6" (misleading - if the seminal vesicle tissue is not sampled, the report may be misread as involvement of seminal vesicle). Presence or absence of seminal vesicle epithelium should be commented upon.
"Prostatic adenocarcinoma, Gleason score 3+3=6 involving skeletal muscle or ganglia" - with comment suggesting extraprostatic extension (erroneous, as involvement of neither indicates pT3 disease)
Adenocarcinoma of prostate, Gleason score 4+4=8 with therapy effect (do not grade if therapy effect due to artifactual upgrading due to therapy)
Adenocarcinoma of prostate, Gleason score 5+5=10 in a case of small cell carcinoma (small cell carcinoma should be specified in diagnosis as it has therapeutic and prognostic implications - Gleason grading should not be performed)

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