The Pathology of Prostate Cancer: From Population Studies to the Molecule
Moderators: Dr. John R. Srigley and Dr. Rodolfo Montironi
Section 1 -
Dr. John R. Srigley
Department of Pathology and Molecular Medicine
Hamilton, Ontario, Canada
Dr. Rodolfo Montironi
Institute of Pathological Anatomy and Histopathology, School of Medicine
Polytechnic University of the Marche Region (Ancona)
The incidence of prostate cancer has tripled during the past decade, chiefly because of the widespread
use of serum prostate-specific antigen testing, digital rectal examination and transrectal ultrasound.
Needle biopsy of the prostate plays a central role in the morphologic evaluation of prostate cancer .
The increase in prostate cancer detection has induced a sharp increase in the number of radical
The pathologist has a fundamental and challenging role in the evaluation of tissue specimens and has
to define a series of lesions such as cancer, its mimics, and its well known precursor high-grade
prostatic intraepithelial neoplasia. In difficult cases when a specific cancer diagnosis is not feasible
for a host of reasons, a term indicating diagnostic uncertainty needs to be used.
The diagnostic features of adenocarcinoma of the prostate have been dealt with in recent studies and
reviews. Architectural and cytological features suggestive of carcinoma have been defined. The list
includes features such as small glands infiltrating in between larger benign glands, lack of basal cells,
and nuclear enlargement and nucleolar prominence. There are also a number of adjunctive findings that
are seen with carcinoma, some of them almost pathognomic for prostate cancer: mucinous fibroplasia
(collagenous micronodules) and glomeruloid structures. There are also features that should make
pathologists hesitate in diagnosing carcinoma. The list of such features is quite long and includes
small glands with minimal atypia merging in with similar glands which seem more recognizably benign.
Many histological benign mimickers of cancer can lead to misdiagnosis of cancer. One distinguishing
feature is that benign glands contain basal cells, which are absent in cancer, and pathologists have used
immunohistological markers to label basal cells. cDNA microarrays have also identified markers specific
for prostate cancer. These markers, although improving the accuracy of diagnosis, have their
limitations, and this technique should be used in conjunction with sections stained routinely.
a-methylacyl-CoA racemase (AMACR) is a marker that is substantially upregulated in prostate cancer.
Because negative staining for basal cell markers, especially in a small focus of atypical glands, is not
always diagnostic of prostate cancer, positive staining for AMACR can increase confidence in a diagnosis
of malignant disease.
This procedure has some pitfalls in diagnostic use. Pseudohyperplastic, atrophic, and foamy gland
adenocarcinoma of the prostate, variants that are especially difficult to diagnose, are positive for
AMACR in only 62–77% of cases. Up to 20% of small foci of adenocarcinoma on needle biopsy can be
negative for AMACR. AMACR also labels high-grade prostatic intraepithelial neoplasia glands and
occasional benign glands.
In prostatic needle biopsies, two histologic entities are predictive of subsequent prostatic
High-grade prostatic intraepithelial neoplasia (PIN) is an isolated finding in less
than 1% to greater than 20% of needle biopsies and has long been known to be a significant risk factor
for PCa. Repeat biopsies for high-grade PIN detected PCa in 21% to 48% of men in most pre-year 2000
studies. The identification of high-grade PIN without concurrent PCa generally warrants follow-up with
repeat biopsy. Between 1% and 5.3% of contemporary needle biopsies contain a minute collection of small
acini that raises the suspicion of carcinoma, but which falls below the diagnostic threshold. These
cases are reported under different terms such as atypical glands suspicious but not diagnostic of
malignancy or atypical small acinar proliferation suspicious for but not diagnostic of malignancy (or
or atypical foci suspicious for carcinoma . The histologic finding of atypical foci is a strong
predictor of PCa on repeat biopsy. Therefore, its isolated histologic identification also warrants
repeat biopsy. Based on repeat biopsy, about half of atypical foci cases prove to be marginally sampled
carcinoma, whereas half represent benign reactive or atrophic acini with sufficient atypia or confounding
findings that carcinoma cannot be definitely excluded. PIN and atypical foci may occur together within a
biopsy set in the absence of prostate cancer.
Substantial effort has been expended in the recent years in describing the available factors and
determining their predictive value for staging, cancer recurrence, and patient survival in prostate
carcinoma . A wealth of clinical information is available in even the smallest tissue specimens of
the prostate, such as biopsies. This includes information on histologic type, Gleason score, extent of
involvement, local invasion (extraprostatic extension and seminal vesicle involvement), perineural
invasion (focal vs. multifocal, and diameter of nerve bundles), lymphovascular invasion, and location and
distribution of tumor .
The Gleason score of adenocarcinoma of the prostate is the quintessential prognostic factor. The
Gleason grading system is recommended as the international standard for grading prostate cancer. The
Gleason score is a scalar measurement that combines discrete primary and secondary groups (patterns or
grades) into nine groups (scores 2 to 10). Gleason score should be reported as the composite score and
its component patterns, e.g., Gleason 7 = 4 + 3. The method of reporting needle biopsies needed
clarification of a few issues including some not addressed in the original Gleason system. A recent
consensus conference organized by the members of the International Society of Urological Pathology
(ISUP) has dealt with the current application of the
Gleason system .
Molecular knowledge of prostate cancer can improve prediction of prognosis, but has not yet yielded
information that is ready to be routinely incorporated into clinical practice
Among the risk
factors for prostate cancer are inherited susceptibility and diet. At the cellular and molecular level,
genetic aberrations drive the formation and aggressiveness of prostate cancer. Every carcinoma focus is
presumed to arise from a single cell that accumulates genomic changes affecting regulatory genes
resulting in a growth or survival advantage. Additional changes lead to local invasion and metastasis.
Mutations in classic oncogenes or tumour suppressor genes are uncommon in primary prostate cancer, and
mutations specific for prostate cancer (eg, prostate gatekeeper genes) have not been identified.
However, several molecular or genetic changes have been found. Although none of them are unequivocally
linked to prostate cancer initiation or progression, some are directly involved in prostatic
In summary, 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. P roper examination of radical prostatectomy (RP) specimens by the
pathologist is critical in accurately determining the prediction of patient outcome. The pathology
report should include relevant clinical information as well as provide prognostically useful data derived
from the evaluation of the RP specimen . Since the yearly incidence of prostate cancer greatly
exceeds the death rate, and since clinically apparent prostate cancers can have a widely variable course,
finding genes that control aggressiveness is of particular interest.
The 2006 Prostate Cancer Long Course will provide a state-of-the-art update on the pathology of
prostate cancer. The global scope of the prostate cancer problem will be presented along with
epidemiological considerations. Theoretical aspects including models of cellular and molecular
pathogenesis will be discussed. The pragmatic aspects of diagnosing precursor lesions such as prostatic
intraepithelial neoplasia (PIN) will be reviewed. The morphological diagnosis of adenocarcinoma in
needle biopsies will be emphasized along with the reporting of prognostic factors, especially Gleason
grade in needle biopsies and radical prostatectomy specimens. The use of ancillary technologies
including immunohistochemistry and molecular pathology will be integrated in the program. While the
emphasis will be on prostatic adenocarcinoma, other types of carcinoma affecting prostatic tissue will
also be reviewed. Finally, we will look at some futuristic considerations utilizing molecular and
bioinformatic technology. At the end of the program, attendees should have a reasonable understanding of
the current scope of prostate cancer pathology.
- Amin MB, Boccon-Gibod L, Egevad L, Epstein JI, Humphrey PA, Mikuz G, Newling D, Nilsson S, Sakr W, Srigley JR, Wheeler TM, Montironi R. Prognostic and predictive factors and reporting of prostate carcinoma in prostate needle biopsy specimens. Scan J Urol Nephrol Suppl 2005;216: 20-33
- Epstein JI, Allsbrook WCJ, Amin MB , Egevad LL, and The ISUP Grading Committee (2005a) The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason grading of prostatic carcinoma. Am J Surg Pathol 2005;29:1228-1242.
- Epstein JI, Amin M, Boccon-Gibod L, Egevad L, Humphrey PA, Mikuz G, Newling D, Nilsson S, Sakr W, Srigley JR, Wheeler TM, Montironi R. Prognostic factors and reporting of prostate carcinoma in radical prostatectomy and pelvic lymphadenectomy specimens. Scand J Urol Nephrol Suppl 2005;216:34-63.
- Herawi M, Kahane H, Cavallo C, Epstein JI. Risk of prostate cancer on first re-biopsy within 1 year following a diagnosis of high grade prostatic intraepithelial neoplasia is related to the number of cores sampled. J Urol 2006;175:121–4.
- Montironi R, Vela-Navarrete R, Lopez-Beltran A, Mazzucchelli R, Bono A. 2005 Update on pathology of prostate biopsies with cancer. Eur Urol 2006;49:241–47.
- Schlesinger C, Bostwick DG, Iczkowski KA. High grade prostatic intraepithelial neoplasia and atypical small acinar proliferation: predictive value for cancer in current practice. Am J Surg Pathol 2005;29:1201–7.
- Srigley JR, Amin M, Boccon-Gibod L, Egevad L, Epstein JI, Humphrey PA, Mikuz G, Newling D, Nilsson S, Sakr W, Wheeler TM, Montironi R. Prognostic and predictive factors in prostate cancer: historical perspectives and recent international consensus initiatives. Scan J Urol Nephrol Suppl 2005;216:8-19