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)
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.  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 
and established in 1974.  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.  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.
I. Application of the Gleason Grading System in 18-Gauge Needle Biopsy Specimens.
Principles and Basis
- 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.
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.
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). 
- 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.
- 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. 
Criteria and Pitfalls for the Diagnosis of Each Pattern.
(A) Pattern 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.
- 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.
- 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
- 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.
- 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.
- Pitfalls in grading.
- 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.
- 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
- 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.
- 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
- Pitfalls in grading.
- Neoplastic acini may branch resulting in V and Y-shaped configurations. This is not gland fusion a
sina-qua-non of Gleason pattern 4.
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.
- 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
- Original Gleason criteria.
- 4A: fused glands, raggedly infiltrating.
- 4B: fused, raggedly infiltrating glands with large pale cells ("hypernephroid").
- 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
- Pitfalls in grading.
- Gland branching may be mistaken
- 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".
- 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
- Original Gleason criteria.
- 5A: almost solid,
rounded masses, necrosis (comedocarcinoma).
- 5B: anaplastic,
- 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.
- Pitfalls in grading.
- 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.
- 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.
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.  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. 
Problem areas for interobservor reproducibility
- 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. 
- 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. 
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.
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. The Gleason grade is underestimated in 33-45% of cases and overestimated in
4-32% of cases.  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
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. 
- Grading histologic variants of prostate
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.
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.
- 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. 
Most cancer in prostate with cribriform architecture is Gleason pattern 4 than 3 by consensus
- Grading after therapy (radiation or androgen
This is a controversial area as two issues need to be considered:
- 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
- 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. 
- "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
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.
ee reporting of prostate cancer
section for update.
- the radical prostatectomy may show a higher Gleason grade,
- there is poor interobservor reproducibility in low grade cancers even amongst
urologic pathology experts,
- 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. 
- 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.
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.
- Gleason system as a prognostic
Several studies have shown that the Gleason grade of a tumor correlates with:
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.  The "Partin
tables" are used frequently by many urologists in routine clinical practice when discussing treatment
options for prostate cancer.  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.
- preoperative PSA
- pathologic stage and tumor volume
- lymph node metastasis
- recurrence and survival
- other prognostic factors, e.g., ploidy, angiogenesis,
- 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.
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.
- 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
- 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
- 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.
- Patients with Gleason score 8-10 may become candidates for radiation
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,  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
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. 
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.
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
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.
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. 
From reference 2
TABLE 1. Categories in Diagnostic Reporting of Prostate Needle Biopsy
- Benign prostatic glands and stroma
- 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)
- 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
- 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*|
- 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
|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)|
- 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
|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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