Suba G PDF

HISTOMORPHOLOGICAL STUDY OF PROSTATIC
TURP SPECIMENS WITH SPECIAL REFERENCE

TO PROSTATIC INTRAEPITHELIAL NEOPLASIA
BY USING IMMUNOHISTOCHEMISTRY.
By
Dr. SUBA.G
A Dissertation submitted to the Rajiv Gandhi University of Health Sciences
Bangalore, Karnataka
In partial fulfillment of the requirements for the degree of
DOCTOR OF MEDICINE
in
PATHOLOGY
Under the guidance of
Dr. B.N.SWARNAGOWRI., MD, DCP.

Associate Professor
Department of Pathology
Dr. B. R. Ambedkar Medical College,
Bangalore- 560045, Karnataka
2010 -2013
i
Rajiv Gandhi University of Health Sciences,

Bangalore, Karnataka
DECLARATION BY THE CANDIDATE
I hereby declare that this dissertation entitled HISTOMORPHOLOGICAL

STUDY OF PROSTATIC TURP SPECIMENS WITH SPECIAL REFERENCE
TO PROSTATIC INTRAEPITHELIAL NEOPLASIA BY USING
IMMUNO
HISTOCHEMISTRY is a bonafide and genuine research work carried

by
me
under
the
guidance
out
of Dr. B. N.SWARNAGOWRI., M.D.,
DCP, Associate Professor, Department of Pathology, Dr. B. R. Ambedkar Medical

College, Bangalore.
Dr. SUBA.G
Date:
Postgraduate in Pathology
Dr. B.R. Ambedkar Medical college
Bangalore-560045
Place: Bangalore
ii
CERTIFICATE BY THE GUIDE

This is to certify that the dissertation entitled HISTOMORPHOLOGICAL
STUDY OF PROSTATIC TURP SPECIMENS WITH SPECIAL

REFERENCE TO PROSTATIC INTRAEPITHELIAL NEOPLASIA
BY USING IMMUNOHISTOCHEMISTRY is a bonafide research work
done by Dr. SUBA.G, in partial fulfillment of the requirement for the degree of
M.D, Pathology.
Dr. B.N.SWARNAGOWRI., M.D, DCP
Associate Professor
Bangalore-560045
Date:
Place: Bangalore
iii
CERTIFICATE BY THE CO-GUIDE

This
is
to
certify
HISTOMORPHOLOGICAL
that
the
dissertation
entitled
STUDY OF PROSTATIC TURP
SPECIMENS WITH SPECIAL REFERENCE TO PROSTATIC

INTRAEPITHELIAL NEOPLASIA BY USING IMMUNOHISTO
CHEMISTRY is a bonafide research work done by Dr. SUBA.G, in partial
fulfillment of the requirement for the degree of M.D, Pathology.
Dr. M. G. Desai., M.S, MCh (Uro)

Associate Professor& HOD
Department of Urology,
Dr. B.R. Ambedkar Medical College,
Bangalore-560045
Date:
Place: Bangalore
iv
CERTIFICATE BY THE HEAD OF THE DEPARTMENT

This
is
to
certify
HISTOMORPHOLOGICAL
that
the
dissertation
entitled

INTRAEPITHELIAL
NEOPLASIA
BY
USING
IMMUNO
HISTOCHEMISTRY is a bonafide research work done by Dr. SUBA.G

under the guidance of Dr. B.N.SWARNAGOWRI., M.D, DCP., Associate
Professor, Department of Pathology, Dr. B. R. Ambedkar Medical College, K.G.Halli,
Bangalore-560045.
Dr. Y.A.MANJUNATHA, M.D

Professor & HOD
Dr. B. R. Ambedkar Medical College
Bangalore-560045
Date:
Place: Bangalore
ENDORSEMENT BY THE HEAD OF THE DEPARTMENT AND

PRINCIPAL
This
is
to
certify
HISTOMORPHOLOGICAL
that
the
dissertation
entitled

INTRAEPITHELIAL
NEOPLASIA
BY
USING
IMMUNO
HISTOCHEMISTRY is a bonafide research work done by Dr. SUBA.G

under the guidance of Dr. B.N.SWARNAGOWRI., M.D, DCP., Associate
Professor, Department of Pathology, Dr. B. R. Ambedkar Medical College, K.G.Halli,
Bangalore-560045.
Dr. Y.A.MANJUNATHA, M.D
Dr. STANLEY JOHN, M.S(ENT)
Professor & HOD

Bangalore-560045
Principal
Bangalore-560045
Date:
Date:
Place: Bangalore
Place: Bangalore
vi
COPY RIGHT
DECLARATION BY THE CANDIDATE
I hereby declare that the Rajiv Gandhi University of Health Sciences,
Karnataka shall have the rights to preserve, use and disseminate this dissertation in
print or electronic format for academic or research purpose.
DR. SUBA.G
Date:
Bangalore-560045
Place: Bangalore
Rajiv Gandhi University of Health Sciences, Karnataka
vii
ACKNOWLEDGEMENT
It is most appropriate to begin my humble gratitude to the Almighty for his
abundant blessings that he bestowed upon me.
I attribute the successful completion of my dissertation to the guidance and
support of many people to whom I am very grateful and I take this opportunity to
thank everyone who made it possible.
I would like to express my profound gratitude and overwhelming respect to
Dr. B.N.Swarnagowri, Associate Professor, Department of Pathology whose
esteemed guidance,constant encouragement and timely advice helped me in successful
completion of the study.
I take this opportunity to thank and express my heartfelt gratitude to
Dr. Y.A.Manjunatha, Professor and HOD, Department of Pathology for his constant
guidance, invaluable help at every stage of the study.
I am grateful to Dr. Stanley John, Principal, Dr. B.R. Ambedkar Medical
College, for permitting me to carry out this study.
I am deeply indebted to my Co- guide Dr. M.G. Desai, Associate professor &
HOD, Department of Urology, whose immense help and encouragement helped me all
the time of this study.
I would like to thank my Professor Dr. H.T. Jayaprakash, Associate
professors Dr. A.N.Hemalatha, Dr. Shaista Choudhary, Assistant professors
Dr. Subha Sangeetha, Dr. Firdos Saba, Dr. Supriya, Dr. Sandeep and Dr. Rohini
Dhanya for their guidance and support.
I also extend my thanks to my colleagues Dr.Priyadarshini, Dr.Sharma,
Dr.Deepti, Dr.Samikshya and Dr.Shilpashree for their wonderful co-operation and
support throughout the study course.
viii
It is my privilege to thank my department technicians Mrs.Reeja, Mr.Suresh,

Mr.Mathew, Mrs. Jabeen for all the technical assistance they have offered.
I sincerely thank Mr. Sridhar, Biocare Medical, for helping me with the
immunohistochemical procedures.
No amount of words can measure up to the deep sense of gratitude and
thankfulness that I feel towards my family members especially my husband
Mr. R. Govindaraj whose patience, love and countless sacrifices enabled me to
complete this study.
Dr. SUBA.G
Date:
Place: Bangalore
Dr. B. R. Ambedkar Medical college

Bangalore-560045
ix
ABSTRACT
Background and Objectives:

In view of increasing trend in the occurrence of both neoplastic and nonneoplastic lesions of the prostate, this study was conducted to analyze the
histomorphology of various non-neoplastic and neoplastic lesions of the prostate and
to know the incidence of prostatic intraepithelial neoplasia in TURP (Transurethral
Resection of Prostate) specimens. Immunohistochemical markers p63 and P504S used
in this study were helpful in differentiating benign, premalignant and malignant
lesions.
Methods:
It is a prospective study performed over a period of two years from December
2010 to August 2012. 65 TURP specimens were collected from Dr. B. R. Ambedkar
Medical College and Hospital. The specimens were collected in 10% formalin and
processed in the Department of Pathology, Dr. B .R. Ambedkar Medical College. The
sections were stained with H&E and immunohistochemical markers p63 (monoclonal
antibody) and P504S (polyclonal antibody) separately.
Results:
In the present study BPH formed majority of cases (80%). The peak of BPH cases
were observed in the age group of 60-69 yrs. Among the premalignant lesions low
grade PIN was seen in 12.3% of cases, high grade PIN was seen in 13.8% of cases.
HGPIN was seen in 87.5% of adenocarcinoma cases and 3.8% of BPH of cases.
Commonest microscopic pattern of HGPIN was tufting type. Prostatic carcinoma was
seen in 9 cases (13.8%), majority of which were adenocarcinoma. Majority of prostatic
carcinoma cases were in the age group of 80-89 years. Gleasons score 8-10 was noted
in majority of the cases. Among the 9 carcinoma cases, urothelial carcinoma was
observed in 2 cases aged 81 and 85 years. Besides these various lesions like basal cell
hyperplasia, stromal nodule, cystic atrophy and transitional cell metaplasia were noted.
Immunohistochemical staining of basal cell nuclear marker p63 showed positivity in
all the BPH and HGPIN cases (100% positivity). None of the adenocarcinoma cases
showed positivity for p63 stain. P504S stain showed positivity in all the
adenocarcinoma cases (100% positivity) and 8 cases of HGPIN (88.9 % positivity).
None of the BPH cases expressed P504S stain. Both the cases of urothelial carcinoma
were positive for both p63 and P504S stain.
Interpretation and Conclusion:
BPH is the most common lesion of the prostate in the elderly. Granulomatous
prostatitis is rarely encountered. Conventional adenocarcinoma is the commonest type
of prostatic carcinoma. Gleasons score of 8-10 is the most common score in
adenocarcinoma of prostate. High grade PIN has a high degree of association with
prostatic carcinoma. Basal cell marker p63 is really helpful in differentiating benign
and HGPIN glands from malignant glands. P504S is of great value in differentiating
HGPIN and malignant glands from benign glands.
Keywords: Nonspecific granulomatous prostatitis, Benign prostatic hyperplasia,

Prostatic intraepithelial neoplasia, Prostatic adenocarcinoma, p63, P504S.
xi
LIST OF ABBREVIATIONS
AAH Atypical adenomatous hyperplasia
AMACR - Alpha-methyl-acyl-coA racemase
BCH Basal cell hyperplasia
BPH Benign prostatic hyperplasia
CA Carcinoma
CEA Carcino embryonic antigen
CP Chronic nonspecific prostatitis
CYA Cystic atrophy
DHT Dihydrotestosterone
FGF Fibroblast growth factor
Gs Gleasons score
H&E Haematoxylin and Eosin
HGPIN High grade prostatic intraepithelial neoplasia
HP diagnosis Histopathological diagnosis
HP No Histopathological number
IHC Immunohistochemistry
LGPIN Low grade prostatic intraepithelial neoplasia
MF- Miscellaneous findings
NSGP - Nonspecific granulomatous prostatitis
No Serial number
PIN Prostatic intraepithelial neoplasia
PAP - Prostatic acid phosphatase
PAS Periodic acid stain
PSA - Prostate specific antigen
xii
SN Stromal nodule
TCC - Transitional cell carcinoma
TGF Transforming growth factor
TM Transitional cell metaplasia
TURP - Transurethral resection of prostate
WHO World health organization
Yrs Years
xiii
TABLE OF CONTENTS
Page No
1. INTRODUCTION
2. OBJECTIVES
3. REVIEW OF LITERATURE
4. MATERIALS AND METHODS
43
5. OBSERVATION AND RESULTS
48
6. DISCUSSION
76
7. CONCLUSION
87
8. SUMMARY
88
9. BIBLIOGRAPHY
90
10. ANNEXURES
103
xiv
LIST OF TABLES
Page No
1. Diagnostic Criteria of prostatic intraepithelial neoplasia
16
2. Gleason's microscopic grading system of prostatic carcinoma
28
3. Distribution of cases according to Histopathological Diagnosis
55
4.
56
Distribution of cases according to Age Group.
5. Age wise distribution of cases according to Histopathological

Diagnosis.
57
6. Mean Age (yrs) of cases according to Histopathological Diagnosis.
58
7. Distribution of Prostatic Intraepithelial Neoplasia in different cases
59
8. Different Microscopic patterns of HGPIN
60
9. Distribution of cases of Prostatic Adenocarcinoma according to

Gleason's Grading System.
61
10. Distribution of Prostatic Adenocarcinoma cases based on Tumour

Quantification
62
11. Expression of p63 immunostaining in different cases
63
12. Expression of P504S immunostaining in different cases
64
13. Comparison of incidence of NSGP
76
14. Comparison of incidence of BPH
77
15. Comparison of age wise distribution of BPH
77
16. Comparison of mean age of BPH
78
17. Comparison of p63 positivity in BPH
78
18. Comparison of P504S negativity in BPH
79
19. Comparison of incidence of HGPIN in TURP specimens
79
xv
20. Comparison of association of LGPIN with BPH and Adenocarcinoma
80
21. Comparison of Association of HGPIN with BPH and Adenocarcinoma
80
22. Comparison of microscopic pattern of HGPIN
81
23. Comparison of p63 expression in HGPIN
81
24. Comparison of P504S Expression in HGPIN
82
25. Comparison of incidence of adenocarcinoma
82
26. Comparison of age incidence of carcinoma prostate above 65 years
83
27. Comparison of mean age of carcinoma prostate
83
28. Comparison of distribution of Gleasons score
84
29. Comparison of p63 Negativity in adenocarcinoma
85
30. Comparison of P504S positivity in adenocarcinoma
85
31. Comparison of age distribution of urothelial carcinoma
86
xvi
LIST OF FIGURES
PAGE NO
1. Schematic diagram of the Gleason grading system
29
2. Distribution of cases according to Histopathological Diagnosis
55
3. Distribution of age
56
4. Age wise distribution of cases according to Histopathological

diagnosis.
57
5. Mean Age (yrs) of cases according to Histopathological

diagnosis.
58
6. Distribution of Prostatic Intraepithelial Neoplasia in different

cases.
59
7. Different Microscopic patterns of HGPIN
60
8. Distribution of cases of Prostatic Adenocarcinoma

according to Gleason's Grading System.
61
9. Distribution of Prostatic Adenocarcinoma cases based

on Tumour quantification
62
10. Expression of p63 immuno staining in different cases
63
11. Expression of P504S immunostaining in different cases
64
12. Photomicrograph of Chronic Prostatitis (10x)
65
13. Photomicrograph of Non specific granulomatous prostatitis

showing multinucleated giant cell and histiocytes.(40x)
14. Photomicrograph of Benign prostatic hyperplasia (10x)
65
66
15 Benign glands in BPH showing positivity for basal cell

marker p63. (40x)
66
16 Photomicrograph of Basal cell hyperplasia (10x)
67
17 Basal cell hyperplasia showing p63 positivity (40x)
67
xvii
18 Photomicrograph of Low grade PIN (40x)
68
19 Photomicrograph of High grade PIN Tufting pattern. (40x)
68
20 Photomicrograph of High grade PIN Flat type (40x)
69
21 Photomicrograph of High grade PIN Micropapillary pattern (40x)
69
22 Photomicrograph of High grade PIN Cribriform pattern.(40x)
70
23 HGPIN showing p63 positivity (10x)
70
24 HGPIN showing P504S positivity (40x)
71
25 Photomicrograph of Adenocarcinoma Gleasons grade 2 (10x)
71
72
72
73
29 Photomicrograph of Adenocarcinoma showing strong cytoplasmic

P504S positivity (40x)
73
30 p63 stain is negative in Adenocarcinoma (40x)
74
31 Photomicrograph of Invasive Urothelial carcinoma (10x)
74
32 Urothelial carcinoma is positive for p63 nuclear stain (10x)
75
33 Urothelial carcinoma is positive for P504S cytoplasmic stain (10x)
75
xviii
INTRODUCTION
Prostate cancer is a leading cause of morbidity and mortality worldwide. The
incidence of prostatic carcinoma is increasing with age. It increases from 20% in men
in their 50s, to approximately 70% in men between the ages 70 and 80 yrs. In view of
the increased life expectancy the absolute number of clinically significant prostate
carcinomas will probably increase in the coming decades. To prevent an equal rise in
mortality, early detection of prostate cancer will become essential, as will the detection
of premalignant lesions such as prostatic intraepithelial neoplasia. Prostatic
intraepithelial neoplasia and Atypical Adenomatous Hyperplasia (AAH) are now
considered to be the most likely precursors of prostate cancer. AAH is usually a
microscopic finding, but occasionally it presents as a mass lesion. But Prostatic
Intraepithelial Neoplasia lesions can only be diagnosed by histopathological
examination of prostatic tissue. It is impossible to detect Prostatic Intraepithelial
Neoplasia clinically by direct rectal examination, Prostate Specific Antigen assay or
ultrasound.
In view of increasing trend of the occurrence of both neoplastic and non
neoplastic lesions of the prostate in the elderly, the current study aims at evaluating the
histomorphological features of Transurethral Resection specimens of prostate with
special reference to prostatic intraepithelial lesion, for a period of two years. Use of
immunohistochemical markers in this study helps in arriving at diagnosis and to
develop therapeutic strategies. A unique problem with transurethral resection
specimen is cautery effect, results in coagulation and loss of orientation of the tissue,
which affects the diagnosis of prostatic carcinomas and premalignant lesions. Hence
this study would be interesting and challenging as well.
OBJECTIVES OF THE STUDY
1. To study the histomorphological spectrum of non-neoplastic and neoplastic

lesions of the Prostate in TURP specimens.
2. To know the incidence of Prostatic Intraepithelial Neoplasia in TURP
specimens.
3. To study the association of Prostatic Intraepithelial Neoplasia in different
prostatic lesions.
4. To find out the expression of immunohistochemical markers, p63 and P504S
in BPH, Prostatic intraepithelial neoplasia and Carcinoma cases.
REVIEW OF LITERATURE
Embryology of the prostate
The prostate gland arises during the third month from interactions between the
urogenital sinus mesenchyme and the endoderm of the proximal part of the urethra.
Early outgrowths, some 14 to 20 in number, arise from the endoderm around the
whole circumference of the tube, but mainly on its lateral aspects and excluding the
dorsal wall above the utricular plate. They give rise to the outer glandular zone of the
prostate.
Later outgrowths from the dorsal wall above the mesonephric ducts arise from
the epithelium of mixed urogenital, mesonephric and possibly paramesonephric, origin
that covers the cranial end of the sinus tubercle. They produce the internal zone of
glandular tissue. The outgrowths, which are at first solid, branch, become tubular and
invade the surrounding mesenchyme. The latter differentiates into smooth muscle,
associated blood and lymphatic vessels and connective tissue and is invaded by
autonomic nerves.1
Anatomy:
The prostate is a fibromuscular glandular organ that surrounds the prostatic
urethra. It is about 3cm long and lies between the neck of the bladder above and the
urogenital diaphragm below. The prostate is surrounded by a fibrous capsule. The
somewhat conical prostate has a base which lies against the bladder neck above and an
apex, which lies against the urogenital diaphragm below. The two ejaculatory ducts
pierce the upper part of the posterior surface of the prostate to open into the prostate
urethra at the lateral margins of the prostatic utricle.
Superiorly the base of the prostate is continuous with the neck of the bladder.
The urethra enters the center of the base of the prostate. Inferiorly the apex of the
prostate lies on the upper surface of the urogenital diaphragm. The urethra leaves the
prostate just above the apex on the anterior surface. Anteriorly the prostate is related to
the symphysis pubis separated from it by the extra peritoneal fat in the retro pubic
space (cave of Retzius) and connected to the posterior aspect of the pubic bones by
puboprostatic ligaments. Posteriorly the prostate is related to the anterior surface of the
rectal ampulla and is separated from it by the rectovesical septum (fascia of
Denonvilliers).2
Structure of the prostate:

The numerous glands of the prostate are embedded in a mixture of smooth
muscle and connective tissue and their ducts open into the prostatic urethra. The
prostate is incompletely divided into five lobes. The anterior lobe lies in front of the
urethra and devoid of glandular tissue. The middle lobe lies between the urethra and
the ejaculatory ducts. It is rich in glands. The posterior lobe is situated behind the
urethra and below the ejaculatory ducts and contains glandular tissue. The right and
left lobes lie on either side of the urethra and contain many glands.2
Zones of the prostate:

The prostate consists of four zones:
The transition zone surrounds the proximal prostatic urethra and comprises about 5%
of the glandular tissue.
The central zone (20%) surrounds the ejaculatory ducts.
The peripheral zone makes up the bulk of the gland (approximately 70%).
The anterior fibromuscular stroma contains no glandular tissue and lies anteriorly.
Most cases of carcinoma of the prostate arise in the peripheral zone while the
transition zone harbours almost all cases of benign nodular hyperplasia.3
Blood supply:
The prostate is supplied by branches from the inferior vesical, middle rectal
and internal pudendal arteries.
The veins form a rich plexus around the sides and base of the gland. The
plexus communicates with the vesical plexus and with the internal pudendal vein and
drains into vesical and internal iliac veins.
Lymphatic drainage:
Lymphatics from the prostate drain chiefly into the internal iliac and sacral
nodes; and partly into the external iliac nodes.
Nerve supply:
The prostatic plexus of nerves is derived from the lower part of the inferior
hypogastric plexus. The prostate is supplied by both sympathetic and parasympathetic
nerves.4
Histology:
The prostate consists of branched tubulo-acinar glands embedded in a fibro
muscular stroma. There is a partial capsule enclosing the posterior and lateral aspects
of the prostate but the anterior and apical surfaces are bounded by the anterior fibro
muscular stroma. The supporting stroma is a mixture of collagenous fibrous tissue and
smooth muscle fibres. The glands show a convoluted pattern with the epithelium
thrown up into folds. Inspissated secretions may accumulate in some glands to form
spherical concretions (corpora amylacea), which increase in number with age and may
become calcified. The main epithelial type is tall columnar secretory cell with
prominent round basal nuclei and pale staining cytoplasm. There is also a population
of small flat basal cells at the base of the gland, in contact with the basement
membrane.3
INFLAMMATORY LESIONS:
Clinical prostatitis is classified into three broad categories including acute,
chronic, and granulomatous prostatitis.
Acute prostatitis:
Acute prostatitis is a clinical disease characterized by the sudden onset of
systemic signs and symptoms that can be localized to the prostate. Almost all cases
result from bacteria arriving in the gland via infected urine or urothelium and most
patients have coincidental cystitis or urethritis. Gram negative enteric bacteria such a
E.coli as the most common infectious agents. The histological manifestations of acute
prostatitis are those of any acute inflammation; stromal edema, vascular congestion
and leukocytic infiltration. Initially, individual prostatic glands are filled with
neutrophils but infiltration through the epithelium with destruction of the acinus or
duct soon occurs. Micro abscesses are common as the neutrophils destroy the glands.5
Chronic prostatitis:
The spectrum of chronic prostatitis includes chronic bacterial, chronic
abacterial and granulomatous prostatitis. Granulomatous prostatitis is usually
considered as a separate entity.
Clinical features of chronic prostatitis are frequency, urgency, dysuria, hemato
spermia and pain in lower back. Microscopically, it is characterized by aggregates of
lymphocytes, plasma cells and macrophages within the prostatic stroma. The
epithelium displays reactive atypia, with occasional prominent nucleoli.6
Granulomatous prostatitis:
Mohan et al7 stated that granulomatous prostatitis is an unusual benign
inflammatory process encountered only occasionally. It was first described by Tanner
and McDonald in 1943 who reported an incidence of 3.3% of granulomatous
prostatitis in inflammatory lesions. Clinically, it presents as a hard fixed nodule on
digital rectal examination and may cause an elevation of serum prostate-specific
antigen (PSA) levels, thus mimicking prostatic carcinoma.
Based on histopathology and probable etiology, granulomatous prostatitis has
been recently classified into following types: idiopathic (non-specific), infective
(specific), iatrogenic (post-surgery), malakoplakia and cases associated with systemic
granulomatous disease and allergy.
Non-specific granulomatous prostatitis (NSGP) is the most common type. Its
etiology is not clear and has been hypothesized to result from foreign body response to
colloidal substances, bacterial products, refluxed urine or from an immunological
response to extraductal prostatic secretions arising from ducts obstructed by
hyperplasia. The lesion consists of a lobular, dense infiltrate of lymphocytes, plasma
cells, and histiocytes. Many of the histiocytes have a foamy appearance, and some are
multinucleated. Neutrophils and eosinophils make up a smaller component of the
inflammatory infiltrate7.
Specific granulomatous prostatitis: It can be caused by Mycobacterium tuberculosis.
Tuberculosis of the prostate gland presents with diffuse caseating epithelioid cell
granulomas which are not confined to the periglandular/periductal region, as seen in
NSGP. Other infectious agents, such as Treponema pallidum, viruses and various
fungi, are rare causes of granulomatous prostatitis7.
8
Xanthogranulomatous prostatitis:
This is usually an incidental finding and has been associated with hyper
lipidemia. It represents one end of spectrum of granulomatous prostatitis and is
composed of foamy histiocytes with little or no other inflammatory cell infiltrate7.
Malakoplakia:
As highlighted by McClure8 in his report of 2 cases and review of literature,
malakoplakia is a chronic inflammatory condition described by Michaelis and Gutman
(1902) and characterized by von Hansemann (1903). Typically, there are aggregations
of macrophages containing round, often concentrically laminated basophilic intracyto
plasmic inclusions. These Michaelis-Gutman (M-G) bodies usually contain calcium
salts and, less frequently, iron. Malakoplakia is usually associated with a coliform
infection.
Prostatic abscess:
Dajani and OFlynn9 have stated that Prostatic abscess is an uncommon lesion
most often encountered in the elderly. Although bacteremia or sepsis originating
anywhere in the body has been implicated, simple bacterial prostatitis is the usual
predisposing factor. E. coli is the causative organism in the majority of cases. Jacobsen
and Kvist have highlighted that in the past, the majority of prostatic abscesses resulted
from gonorrhea.10 Trapnell and Roberts11 reported 36% of cases presented with acute
urinary retention and 31% with perineal or suprapubic pain. Prostatic fluctuation on
digital rectal examination is the most characteristic sign, transrectal ultrasound is the
most reliable diagnostic method, and transurethral drainage under antibiotic coverage
is the treatment of choice.
Atrophy:
Gardner and Culberson12 have developed a perspective that atrophy of prostatic
glands is a common process typically but not exclusively found in older patients.
Atrophy may be seen in the young adult prostate and is commonly admixed with areas
of nodular prostatic hyperplasia. As highlighted by Billis13 atrophy is common in the
peripheral zone and may also be seen in the central and transition zones. Glandular
atrophy is commonly associated with chronic prostatitis which may have an active
component characterized by intraglandular neutrophils. Atrophy can also be the result
of treatment with radiation and antiandrogens.
As highlighted by Srigley14 there are four main patterns of atrophy
recognized lobula(simple), sclerotic, cystic and linear or streaming. Combined
patterns are common. Regardless of the architectural subtype of atrophy, the
cytological features are similar. The cells are small and lack nuclear membrane
irregularity and chromatin abnormalities. Occasionally, small chromocenters are seen
but prominent nucleoli are absent. Double layering of cells is often seen but in some
instances it may be difficult to appreciate because of the marked secretory cell
atrophy.
BENIGN PROLIFERATIVE LESIONS:

Benign prostatic hyperplasia:
Prevalence:
Berry et al15 reported the prevalence of BPH about 8% during the fourth
decade, but it reaches 50% in the fifth decade and 75% in the eighth decade.
Etiology and pathogenesis:
10
Kumar, Abbas, Fausto and Aster have highlighted the fact that the main
component of the hyperplasic
process
is impaired cell death, resulting in the
accumulation of senescent cells in the prostate. The main androgen in the prostate,
constituting 90% of total prostatic androgens, is dihydrotestosterone (DHT). It is
formed in the prostate from the conversion of testosterone by the enzyme type 2 5
reductase. This enzyme is located almost entirely in stromal cells. DHT binds to the
nuclear androgen receptor present in both stromal and epithelial prostate cells,
activates the transcription of androgen dependent genes, results in increased
production of several growth factors and their receptors. Most important among these
are members of fibroblast growth factor family, particularly FGF-7. Other factors
produced are FGFs 1 and 2, and TGF , which promote fibroblast proliferation.
Although the ultimate cause is unknown, it is believed that DHT induced growth
factors act by increasing the proliferation of stromal cells and decreasing the death of
epithelial cells.
Morphology:
In the usual case of prostatic enlargement, the prostate weighs between 60 and
100gms. Nodular hyperplasia of the prostate originates almost exclusively in the inner
aspect of the prostate gland (transition zone). The early nodules are composed almost
entirely of stromal cells, and later predominantly epithelial nodules arise. The nodular
enlargements may encroach on the lateral walls of the urethra to compress it to a slit
like orifice.
On cross section, the nodules vary in colour and consistency. In nodules that
contain mostly glands, the tissue is yellow-pink with a soft consistency, and a milky
white prostatic fluid oozes out of these areas. In nodules composed primarily of
11
fibromuscular stroma, each nodule is pale gray, is tough, does not exude fluid, and is
less clearly demarcated from the surrounding uninvolved prostatic tissue.16
Microscopy:
The book, Rosai and Ackermans Surgical Pathology, by Juan Rosai17 shows
that the earliest microscopic change is a stromal proliferation about small sinusoidal
spaces in the periurethral regions and, to a lesser degree, in the periductal and
intralobular areas. This is followed by hyperplasia of the glandular component, so that
in the well developed disease the nodules are composed of varying proportions of both
elements. The glands are dilated or even cystic and often contain an inspissated
secretion of glycoproteic nature (corpora amylacea), which is sometimes calcified. The
epithelium ranges from flat to columnar, sometimes facing each other in the same
gland (functional polarization); the cytoplasm is pale, and the nuclei are regular and
centrally located. The nucleoli are inconspicuous. Papillary infoldings are common. A
continuous basal cell layer is seen immediately above a well-developed basement
membrane. Small clusters of lymphocytes are common in the interstitium and around
the ducts.
Stromal nodule:
Petersen, Sesterhenn and Davis18 have highlighted the fact that the stromal
nodule represents one end of the morphologic spectrum of nodular hyperplasia,
composed of fibroblastic, fibromuscular, muscular or immature mesenchymal cells in
order of decreasing frequency (62%4%). It is most commonly found as a wellcircumscribed nodule in the periurethral tissue proximal to the verumontanum.
Microscopically, the nodule comprises spindle cells, fibroblasts, and/or smooth muscle
12
cells in a hyalinized or myxoid stroma. Scattered blood vessels, commonly with thick
hyalinized walls are common.
Basal cell hyperplasia:
Thorson et al19 stated that basal cell hyperplasia is occasionally a component of
untreated usual, nodular glandular and stromal hyperplasia, or benign prostatic
hyperplasia, which arises in the transition zone in the prostate. The incidence of basal
cell hyperplasia in the setting of usual, nodular hyperplasia has been reported to range
from 3.1 to 8.9%. It has been noted that basal cell hyperplasia may be atrophy
associated and found in the peripheral zone. Diagnostic recognition of basal cell
hyperplasia in the peripheral zone is important because it may be mistaken for
prostatic intraepithelial neoplasia or adenocarcinoma.
Devaraj and Bostwick have developed a perspective which identifies the basal
cell hyperplasia as nodular expansion of uniform round glands associated with a
cellular stroma. It may be complete or incomplete. There is a lack of secretory
(luminal) cell differentiation in the complete form in which solid nests of dark-blue
cells are present. In the incomplete form, there are residual small lumina lined by
secretory cells with clear cytoplasm and these are surrounded by multiple layers of
basal cells. In each type, the basal cells are dark and have scant cytoplasm and display
round, oval or somewhat spindled hyperchromatic nuclei. Nucleoli are usually
indistinct but in some examples of the so-called atypical basal cell hyperplasia,
nucleoli may be more prominent.20
Clear cell cribriform hyperplasia:
Ayala et al21 stated that cribriform hyperplasia, frequently called clear cell
cribriform hyperplasia for descriptively accurate reasons, is an uncommon benign
prostatic proliferation originally described in the 1980s. This lesion is most commonly
13
observed as an incidental finding in TURP specimens from patients with nodular

hyperplasia. In a comparative study of 173 patients to know the pathology of androgen
deprivation therapy in prostatic carcinoma, Civantos et al22 reported that less
frequently clear cell cribriform hyperplasia is observed in patients previously receiving
androgen blockade therapy. Frauenhoffer et al23 reported that clear cell cribriform
hyperplasia is microscopically characterized by ducts and acini within the transition
zone that contain a cribriform proliferation of secretory luminal cells and a peripheral
basal cell layer. The proliferating cells have benign cytologic features and diploid
DNA. The luminal cells are PSA positive, and the peripheral basal cells stain with
34BE12.
Sclerosing adenosis:
Luque et al24 stated that sclerosing adenosis of the prostate is a microglandular
lesion, rst described as adenomatoid tumour,that can mimic prostate cancer.
Young and Clement recognized its resemblance to the homonymous lesion of the
breast. Sclerosing adenosis of the prostate usually is an incidental nding in
transurethral resections or simple prostatectomies performed in the clinical setting of
benign prostatic hyperplasia; the condition accounts for 2% to 2.8% of the cases in this
population.
Microscopically, the lesion can be partially well circumscribed, and the

available margins resemble an inltrative lesion, but the stroma is distinctive; usually
it is cellular and myxoid with no smooth muscle cells present. Other features of
diagnostic importance include the nding of a double cell population of clear secretory
and amphophilic basal cells, sometimes presenting as fusiform cells inltrating the
14
stroma. Nucleoli are readily identiable in foci of sclerosing adenosis, but not in the
size and extent of prostatic carcinoma.
PREMALIGNANT LESIONS OF THE PROSTATE:
Prostatic intraepithelial neoplasia:

Andrews GS 1949 initially reported the observation of prostatic intraductal foci
with cytologically atypical hyperplasia. Subsequent studies of atypical hyperplasia
in the prostate appeared in the literature with the suggestion that these foci may be
premalignant, and histogenetically function as the source of invasive prostate
adenocarcinoma. Prostatic intraepithelial neoplasia (PIN), first described in 1969 by
McNeal, is a neoplastic proliferation of prostatic epithelial cells that is confined to preexisting prostatic ducts or acini (glands).
PIN was further characterized and initially termed intraductal dysplasia by
McNeal and Bostwick in 1986. The currently used term prostatic intraepithelial
neoplasia was later introduced by Bostwick and Brawer in 1987, and endorsed by
consensus at a 1989 conference.25
Definition:
Prostatic intraepithelial neoplasia (PIN) is best characterized as a neoplastic
transformation of the lining epithelium of prostatic ducts and acini. By definition, this
process is confined within the epithelium therefore, intraepithelial.26
Grading of PIN:
Prostatic intraepithelial neoplasia was originally graded from 1 to 3, but
current recommendations recognize two grades of PIN (low grade and high grade).
Grade 1 was defined as low-grade PIN, whereas grades 2 and 3 were currently
15
considered together as high-grade PIN; currently, conventional use of the term 'PIN'
without qualification refers to only high-grade PIN.27
Table 1: Diagnostic Criteria of prostatic intraepithelial neoplasia28
Features
Architecture
Low grade PIN
High grade PIN
Epithelial cell crowding
Similar to low-grade PIN, but
and stratification, with
more crowding and stratification
irregular spacing.
with four patterns tufting, flat

micro-papillary and cribriform
Nuclear membrane
Thin
Thick
Chromatin
Normal
Increased density and clumping
Nuclei
Enlarged, with marked
Enlarged, some variation in size
size variation
and shape
Not discernible
Prominent, similar to those in
Nucleoli
prostate carcinoma, multiple.

Basal cell layer
Continuous and intact
Discontinuous, may show some

disruption
Basement Membrane
Intact
Intact
Feneley and Busch have developed a perspective which identifies that the risk
of carcinoma on rebiopsy of patients with low grade PIN seems to be similar to that
without PIN, while the findings of high grade PIN in prostate biopsy suggests the
likelihood of coexisting prostate carcinoma and warrants further search for concurrent
invasive carcinoma.29
16
Incidence and prevalence of PIN:

Bostwick et al30 stated that the incidence of PIN in prostate biopsies averages 9%
(range 4%-16%), representing 115000 new cases of PIN diagnosed each year in
United States. In an autopsy study, Mc Neal and Bostwick studied 400 prostate
specimens and observed HGPIN in 82% of prostates bearing cancer, compared to 43%
of benign prostates in patients aged 50 or more.31
De La Torre et al32 reported that the prevalence of HGPIN in radical
prostatectomy specimens is remarkably high reflecting the strong association between
the lesion and prostate cancer. They have found HGPIN in 85-100% of radical
prostatectomy specimens.
In a series of 100 cystoprostatectomy specimens, Troncoso et al33 found 49% and
61% of the prostates to harbour HGPIN and carcinoma, respectively. In 48 men who
underwent cystoprostatectomy for reasons other than prostate cancer, Wiley et al34
found 83% and 46% of the prostates to contain HGPIN and incidental carcinoma,
respectively.
Incidence of PIN in TURP specimens:

Gaudin et al35 studied 158 cases of TURP specimens and found HGPIN in 3.2% cases.
In a study of 698 TURP specimens, Pacelli and Bostwick found the overall incidence
of HGPIN 4.2%, including 2.8% in BPH and 10.2% with coexistent cancer.36
Skjorten et al37 found 33% of HGPIN in 731 TURP specimens.
Rekhi et al38 found 18.6% cases of low grade PIN and 11.2% cases of high grade PIN
out of 29.9% cases of PIN seen in 177 specimens of benign prostatic hyperplasia. Out
of 23 cases of adenocarcinoma of prostate, 20 cases (86.9%) had foci of high grade
PIN only 1 case (5.8%) revealed low grade PIN.
17
Sakr et al39 observed that the incidence of PIN is higher in prostate with
carcinoma than that without carcinoma and PIN is frequently found in the peripheral
zone where prostatic carcinoma often occurs.
Qian and Bostwick have developed a perspective which identifies, 64.5% of
cases of PIN were multicentric, 63% located in the non-transition zone, while 36%
were in all zones.40
In a study of 110 prostate specimens, to document the prevalence of HGPIN in
a low-risk Indian population, Desai and Borges observed a majority of prostate
carcinoma specimens (85.24%) were found to harbour HGPIN. Conversely, none of
the benign prostate samples were found to have HGPIN.41
Architectural patterns of HGPIN:

There are four morphological patterns of high-grade PIN: tufting,
micropapillary, flat and cribriform. They may be present as a single type, or mixed.
Tufting Pattern: This is the commonest pattern, seen in 87% to 97% of high grade
PIN. The neoplastic cells grow towards the lumen, forming wave- or mound-like
structures.
Micropapillary Pattern: This occurs in 85% of high-grade PIN. Atypical secretory
epithelial cells present in 85% of high-grade PIN. Atypical secretory epithelial cells
present as bulb or micropapillary structures, typically lacking fibrovascular cores. The
micropapillary pattern commonly occurs in dilated ducts and acini.
Flat Pattern: This is present in 28% of high-grade PIN. The acini and ducts are lined
with one or two layers of atypical cells without significant architectural abnormality.
18
Cribriform Pattern: This pattern presents in 32% of high-grade PIN. Roman bridge
and cribriform patterns are present. The cells close to the centre of the gland show
more benign features.42
Histologic variants:
Signet-ring variant:
High grade prostatic intraepithelial neoplasia (PIN) with signet-ring cells is
exceedingly rare with only three reported cases. In all cases signet-ring cell PIN was
admixed with adjacent, invasive signet-ring carcinoma. Histologically, cytoplasmic
vacuoles displace and indent PIN cell nuclei. The vacuoles are mucin-negative by
histochemical staining (mucicarmine, Alcian blue, PAS).
Mucinous variant:
Mucinous high grade PIN exhibits solid intraluminal masses of blue tinged
mucin that fill and distend the PIN glands, resulting in a flat pattern of growth. This is
a rare pattern, with five reported cases. It is associated with adjacent, invasive, typical
acinar adenocarcinoma (of Gleason score 5-7), but not mucinous adenocarcinoma.43
Foamy variant:
Berman et al44 stated that foamy variant shows bland nuclei and abundant
xanthomatous cytoplasm, identical morphologically to that seen in foamy gland
prostate carcinoma. However, unlike invasive carcinoma, the foamy glands in PIN are
large with papillary infoldings and a discontinuous basal cell layer that may be
highlighted by immunostaining for high-molecular-weight cytokeratin. The benign
appearance of the neoplastic cells makes it more difficult to recognize as a lesion of
intraepithelial neoplasia under low power magnification. Ki67 immunostaining shows
19
an increased proliferation rate in foamy high-grade PIN glands when compared with
normal glands. More than half of foamy variant PIN coexists with invasive carcinoma.
Small-cell neuroendocrine variant:
Extremely rare examples with small cell neuroendocrine cells exist. Small
neuroendocrine cells forming rosette-like structures, and are often observed in the
centre of glands, while glandular-type PIN cells are commonly located in the
peripheral zone. The small neoplastic cells are positive for the neuroendocrine
markers, chromogranin and synaptophysin. This variant is also usually present
concomitantly with invasive small-cell adenocarcinoma. Reyes et al reported a case of
small cell neuroendocrine variant which displayed a mixed intraepithelial glandular,
small-cell neoplastic proliferation. Histologically, the neoplastic cells were identical to
surrounding invasive small-cell carcinoma. Both the small-cell high grade PIN and
invasive small-cell carcinoma were positive for chromogranin, synaptophysin and
neuron-specific enolase.43
Inverted (hobnail) high-grade PIN:
This is characterized by polarization of enlarged secretory cell nuclei toward
the glandular lumen. The nuclei usually demonstrate less prominent nucleoli than in
non involved epithelium, and can give a false impression of a non-neoplastic process.
In an analysis of 15 cases of inverted high-grade PIN by Argani and Epstein, all were
mixed with typical micropapillary-tufting high-grade PIN. Seven cases were
associated with concurrent prostatic adenocarcinoma and two other cases with atypical
glands suspicious for carcinoma. In six other cases, inverted high-grade PIN appeared
on its own. Two patients had radical prostatectomies following biopsy, revealing the
inverted high-grade PIN localized in the peripheral zone of the prostate where more
typical forms of high-grade PIN and carcinoma were present: these results suggested
20
that the inverted variant always coexists with a typical pattern of high grade PIN and is
frequently present with concomitant invasive adenocarcinoma.45
Atypical Adenomatous Hyperplasia (AAH):
Atypical adenomatous hyperplasia (AAH), one of the most frequently

encountered mimics of prostate adenocarcinoma, was originally described by McNeal
in the 1960s. AAH was defined as a localized proliferation of small glands within the
prostate that may be mistaken for carcinoma. The acini tend to be closely packed,
preponderantly small, and lined by uniform cuboidal or columnar cells with clear
cytoplasm. The nuclei are not enlarged and nucleoli are generally small. Only
uncommonly will a prominent nucleolus be identified. The periphery of the focus
shows an expansile edge with only minimal foci of stromal invasion present. Basal
cells are present and can usually be detected in routine stained slides. Basal cell
specific immunostains disclose a discontinuous basal cell population in the acini of
AAH. The frequency of identification of AAH is highest in prostatectomy specimens
(23%), intermediate in TURP specimens, and lowest in needle biopsies (1%) that
sample the peripheral zone.18 In all specimens AAH is an incidental microscopic
finding; however, Humphrey et al46 reported one mass formative example of AAH in
a suprapubic prostatectomy.
MALIGNANT LESIONS OF PROSTATE
Carcinoma prostate:
Prostate cancer is one of the most important cancers in men. With a world
incidence of 25.3 per 100,000 it is the second most common cancer in men, with large
differences between countries.47The number of cases has continuously increased over
21
the past decades, partly due to the higher life expectancy. An additional factor is the
Western lifestyle, characterized by a highly caloric diet and lack of physical exercise.
Epidemiological data that black people are most susceptible, followed by white
people, while Asian people have the lowest risk.26
Incidence:
Butler et al48 found one or more foci of carcinoma in 32.2% of 220 cases and
majority of them showed involvement of lateral lobes.
Lee and Shanmugaratnam studied 156 cases and found latent carcinoma in 13
(8.3) cases in the age range of 42-87 yrs.49
Rullis et al50 gives an incidence of 66.7% in 57 cases in men over 80 yrs of
age.
As highlighted by Franks51, Prostate cancer is rare before the age of 50, after
which time the incidence increases rapidly until the age of 80. The rate of increase
then seems to slow.
Jasani et al52 have studied 180 cases of prostate and observed adenocarcinoma
in 58 (32%) cases.
Etiology:
There are three etiologic factors which seem to be closely associated with
prostatic cancer: age, race and the endocrine system. There seems to be no direct
relationship between steroid hormone levels- estrogens, androgens, or adrenal steroids
and the development of cancer. These hormones stimulate the development and
maintenance of the prostatic epithelium so that a sufficient number of cells are present
in which malignant change can occur.51
Androgens play an important role in prostate cancer. Like their normal
counterparts, the growth and survival of prostate cancer cells depends on androgens,
22
which bind to the androgen receptor (AR) and induce the expression of pro-growth
and pro-survival genes.16 Prostate growth, differentiation and function are primarily
controlled by androgens but estrogens modulate these effects in several ways.
Prostate contains estrogen receptor alpha and beta, which are localized
characteristically in stroma and epithelium, respectively. The physiological function of
these receptors is not known but there is evidence to show the role of estrogen in
prostate carcinogenesis. Recent results concerning antiestrogen inhibition of prostate
cancer development beyond PIN-type lesions in transgenic mouse models further
suggests a role for estrogens in prostate cancer progression. These studies also suggest
that direct inhibition of estrogen action at the level of prostate may provide an
important novel way to treatment of prostate cancer.53
Definition of terms:
As highlighted by Franks51 biologically-that is in the patient-three types of
prostate cancer have been identified.
1. Clinical cancer: Any case in which a firm clinical diagnosis of prostatic cancer
is made and confirmed by histology should be described as a clinical cancer.
2. Latent cancer: These tumors by definition exist but do not become
manifest, i.e. they produce no clinical evidence of disease. They are found
incidentally.
3. Occult cancer: These tumors manifest themselves by their metastases. The
primary tumor remains hidden (occult).
Localization:
In a study of 208 total prostates removed surgically for early carcinoma of the
prostate and studied by the step-section technique, Byar and Mostofi found that 97%
were located either peripherally or both peripherally and centrally; 80% were bilateral,
23
and 85% were multifocal.54 McNeal et al55 studied 104 prostate glands obtained at
radical prostatectomy for adenocarcinoma. Among the 88 cancers whose probable
zone of origin could be identified, 68% arose in the peripheral zone, 24% arose in the
transition zone, and 8% arose in the central zone. Transition zone carcinomas had
usually been diagnosed by transurethral resection.
Pathologic features:
Morphology:
Prostatic carcinomas can be divided into two major categories:
1. Adenocarcinoma of peripheral (secondary) ducts and acini.
2. Carcinoma of large (primary) ducts.
The majority of the tumors belong to the first category. Large primary duct
carcinomas are normally found in a periurethral location. Outer zone is the site of
predilection for the ordinary adenocarcinoma.17
Gross appearance:
Grossly evident cancers are firm, solid, and range in colour from white-grey to
yellow-orange, the latter having increased cytoplasmic lipid; the tumours contrast with
the adjacent benign parenchyma, which is typically tan and spongy. Gross
haemorrhage and necrosis are rare.26
Histopathology:
Microscopically prostatic adenocarcinoma exhibit a wide spectrum of
appearances, ranging from anaplastic tumours to highly differentiated neoplasms.
Totten et al described four major cytoarchitectural patterns:
Small glands,
Medium sized glands,
Diffuse individual cell infiltration and Cribriform
24
A feature common to virtually all prostate cancers is the presence of only a single cell
type without a basal cell layer.
Architectural features:
Prostate cancers contain glands that are more crowded than in benign prostatic
tissue. They grow in a haphazard fashion. Glands oriented perpendicular to each other
and irregularly separated by bundles of smooth muscle are indicative of an infiltrative
process. Another pattern characteristic of an infiltrative process is the presence of
small atypical glands situated in between larger benign glands. With the loss of
glandular differentiation there is formation of cribriform structures, fused glands, and
poorly formed glands. Tumours composed of solid sheets, cords of cells, or isolated
individual cells characterize undifferentiated prostate cancer.
Nuclear features:
Nuclear enlargement with prominent nucleoli is a frequent finding. Some
neoplastic nuclei lack prominent nucleoli, yet are enlarged and hyperchromatic.
Mitotic figures may be relatively common in high-grade cancer, yet are infrequent in
lower grade tumours.
Cytoplasmic features:
Glands of adenocarcinoma of the prostate tend to have a discrete crisp, sharp
luminal border without undulations or ruffling of the cytoplasm. In contrast,
equivalently sized benign glands have an irregular luminal surface with small papillary
infoldings and a convoluted appearance. Neoplastic glands may have amphophilic
cytoplasm, which may be a useful diagnostic criterion of malignancy. Prostate cancer
of all grades typically lacks lipofuscin, in contrast to its presence in some benign
prostatic glands.
25
Stromal invasion:
Invasion is another important criterion for the diagnosis of prostatic carcinoma.
The acini of normal and hyperplastic glands are surrounded by a delicate basement
membrane and invested by smooth muscle strands. Malignant acini do not have this
orderly connective tissue framework. The earliest sign of invasion is the absence or
break in continuity of the basement membrane. Stromal invasion can be recognized by
the loss of acinar stromal interaction as evidenced by distribution of the acini without
regard to regular whorls of the smooth muscle fibres, irregularity of the shape of the
acini, pointed edges of the acini and the presence of outgrowths of individual or
groups of neoplastic cells near the acini or scattered in the stroma.
Malignant specific features:
These
are
perineural
invasion,
mucinous
fibroplasia
(collagenous
micronodules), and glomerulations. Mucinous fibroplasia or collagenous micronodules

is typified by very delicate loose fibrous tissue with an ingrowth of fibroblasts.
Glomerulations, consist of glands with a cribriform proliferation that is not
transluminal. Rather, these cribriform formations are attached to only one edge of the
gland resulting in a structure superficially resembling a glomerulus.26
Grading:
Multiple grading systems for prostate adenocarcinoma have been proposed in
past years, including the WHO system (Mostofi, 1975), the M.D. Anderson system
(Brawn and associates, 1982), and the Gleason system (Gleason, 1966, 1977).
The microscopic grading system developed by Gleason in conjunction with the
Veterans Administration Cooperative Urological Research Group is currently
preferred to the other grading systems that have been proposed over the years. It is
based on the degree of glandular architectural differentiation and the growth pattern of
26
the tumour in relation to the stroma as evaluated on low-power examination. The

predominant tumour pattern (referred to as primary) is graded from 1 to 5, and the
secondary pattern (if present) is graded similarly, with the two numbers being added
to obtain the Gleason score or sum. If the tumour has the same pattern throughout (i.e.,
it has only a primary pattern), the number is multiplied by 2 in order to obtain the
final score.
Some tumours have a tertiary pattern. This is to be reported only if it is a grade
5. In cases of multicentric involvement by tumour, there is often a great heterogeneity
of the Gleason score. The interobserver reproducibility in Gleason grading has been
found to be in an acceptable range both among urologic pathologists and among
general pathologists.
There is a reasonably good correlation between the tumour grade determined
by biopsy and that in the prostatectomy specimen, but upgrading occurs in 3045% of
the cases and downgrading in about 5%. The best correlation is obtained when the
highest Gleason score from all the positive biopsy sites is used. As expected, the
frequency and magnitude of this discrepancy are directly related to the quantity of
tumour tissue present in the biopsy. Parenthetically, the accuracy of the grading is
similar whether one uses the traditional 14-gauge needle biopsy or the automated
spring-loaded 18-gauge biopsy gun.
Microscopic grading of prostatic adenocarcinoma has been found to correlate

well with PAP and PSA levels, clinical and pathologic staging, frequency of apoptotic
bodies, p53 over expression, incidence of lymph node and bone metastases, survival
rate, and response to therapy. The correlation of the Gleason's grading system with the
mortality rate is particularly impressive. Patients with a score of 24 almost never
develop aggressive disease, whereas most patients with a score of 810 die of prostatic
27
carcinoma. Thus, by combining staging and grading, the best predictive values are
obtained.17
Table 2: Gleason's microscopic grading system of prostatic carcinoma17
Stage
1
Description
Single, separate, uniform glands in closely packed masses with a definite,
usually rounded, edge limiting the area of tumor.
Single, separate, slightly less uniform glands, loosely packed (separated by

small amounts of stroma), with less sharp edge.
3a
Single, separate, much more variable glands; may be closely packed but
usually irregularly separated; ragged, poorly defined edge
3b
Like 3a, but very small glands or tiny cell clusters
3c
Sharply and smoothly circumscribed rounded masses of papillary or loose

cribriform tumor (papillary intraductal tumor).
4a
Raggedly outlined, raggedly infiltrating, fused glandular tumour.
4b
Like 4a, with large pale cells (hypernephroid).
5a
Sharply circumscribed, rounded masses of almost solid cribriform tumor,

usually with central necrosis (comedocarcinoma).
5b
Ragged masses of anaplastic carcinoma with only enough gland formation

or vacuoles to identify it as adenocarcinoma.
28
Figure1. Schematic diagram of the Gleason grading system.56
WHO Histological Classification of Tumors of Prostate26

Epithelial tumors
Glandular neoplasms
Adenocarcinoma (acinar)
Atrophic
Pseudohyperplastic
Foamy
Colloid
Signet ring
Oncocytic
Lymphoepithelioma-like
29
Carcinoma with spindle cell differentiation (carcinosarcoma, sarcomatoid carcinoma)

Prostatic intraepithelial neoplasia (PIN)
Ductal adenocarcinoma
Cribriform
Papillary
Solid
Urothelial tumors
Urothelial carcinoma
Squamous tumors
Adenosquamous carcinoma
Squamous cell carcinoma
Basal cell tumors
Basal cell adenoma
Basal cell carcinoma
Neuroendocrine tumors
Endocrine differentiation within adenocarcinoma
Carcinoid tumor
Small cell carcinoma
Paraganglioma
Neuroblastoma
Prostatic stromal tumors
Stromal tumor of uncertain malignant potential
Stromal sarcoma
Mesenchymal tumors
Leiomyosarcoma
30
Rhabdomyosarcoma
Chondrosarcoma
Angiosarcoma
Malignant fibrous histiocytoma
Malignant peripheral nerve sheath tumor
Hemangioma
Chondroma
Leiomyoma
Granular cell tumor
Hemangiopericytoma
Solitary fibrous tumor
Hematolymphoid tumors
Lymphoma
Leukemia
Miscellaneous tumors
Cystadenoma
Nephroblastoma (Wilms tumor)
Rhabdoid tumor
Germ cell tumors
Yolk sac tumor
Seminoma
Embryonal carcinoma and teratoma
Choriocarcinoma
Clear cell adenocarcinoma
Melanoma
31
Tumors of the seminal vesicles

Epithelial tumors
Adenocarcinoma
Cystadenoma
Mixed epithelial and stromal tumors
Malignant
Benign
Mesenchymal tumors
Leiomyosarcoma
Angiosarcoma
Liposarcoma
Malignant fibrous histiocytoma
Solitary fibrous tumor
Hemangiopericytoma
Leiomyoma
Miscellaneous tumors
Choriocarcinoma
Male adnexal tumor of probably Wollfian origin
Metastatic tumors
HISTOLOGICAL VARIANTS OF PROSTATIC ADENOCARCINOMA:

Prostatic ductal adenocarcinoma or Endometrioid carcinoma:
Melicow and Pachter first described this tumour in 1967. It accounts for <1%
of prostatic adenocarcinomas.57 It often involves the central ducts of the gland and
may present as an exophytic papillary lesion in the prostatic urethra. These tumors do
32
metastasize to bone and have a worse prognosis than usual acinar adenocarcinoma.58
Histologically it is characterized by tall columnar pseudostratified epithelial cells with
abundant, usually amphophilic cytoplasm that could also be pale or clear. The cells
were arranged either along papillae or in complexes of large acini or as single
glands.59
Mucinous (colloid) carcinoma:
These tumors have an incidence of approximately 0.2%. Grossly, the tumors
may have a mucoid or gelatinous cut surface. Histologically, pools of extravasated
mucin are present in the stroma with suspended nests, cords or groups of carcinoma
cells forming acini. Of approximately 1,600 carcinomas of the prostate gland seen,
only six mucinous prostatic adenocarcinomas were identified. They have a worse
prognosis than usual acinar adenocarcinoma. In a literature review of 60 mucinous
carcinomas.58 Saito and Iwaki found the 3- and 5-year survivals to be 50 and 25%,
respectively.60
Signet ring cell carcinoma:
Warner et al61 stated that Signet ring cell changes were first described in 1981
and are estimated to occur in 2.5% of cases of adenocarcinoma of the prostate. It is
characterized by an intracytoplasmic vacuole compressing the nucleus into a crescent
shape at the cellular level. The cytoplasmic vacuoles can contain lipids or mucin and
stain positive with mucicarmine in about 50% of cases, PAS in about 60%, and alcian
blue in 60%. Remmele et al62 described the criterion for the diagnosis is the presence
of more than 50% of the signet ring cells in the tumour.
33
Adenosquamous carcinoma:
Adenosquamous carcinoma of the prostate is an unusual histological variant of
prostate cancer, with only 12 well-established cases previously reported. It is most
often seen in association with hormonal therapy.63 There are several theories to
explain the histogenesis of adenosquamous carcinoma, 1) there is a metaplastic
transformation of adenocarcinoma cells; 2) it is a collision type tumour, with the
squamous component developing from metaplastic foci after radiation or hormonal
therapy or 3) there is a possible deviation from pluripotent stem cells capable of
multidirectional differentiation. Histologically it is composed of malignant squamous
elements and a disorderly admixture of adenocarcinomatous elements.64
Squamous cell carcinoma:
Malik et al65 stated that primary squamous cell carcinoma of the prostate is a
rare tumour, making up 0.5% to 1% of all prostate carcinomas. It is an aggressive
neoplasm with a median post diagnostic survival of approximately 14 months and is
thought to arise from posterior urethral epithelium. Mott and colleagues described
criterion to define the histologic characteristics of squamous cell carcinoma; 1) a
clearly malignant neoplasm as judged by invasion, disordered growth and cellular
anaplasia; 2) definite squamous features of keratinisation, squamous pearls and
intercellular bridges; 3) lack of glandular or acinar pattern; 4) no prior estrogen
therapy; and 5) the absence of primary squamous cell carcinoma elsewhere,
particularly in the bladder.
Adenoid cystic carcinoma:
Adenoid cystic carcinoma is an extremely uncommon tumour of the prostate
gland. It was first described by Billroth in 1859. Adenoid cystic carcinoma is a slow
34
growing, indolent tumour and account for less than 0.01% of malignant tumours of the
prostate.66 Kramer et al67 have stated that adenoid cystic carcinoma may represent an
ectopic salivary gland carcinoma in the prostate or it may be a manifestation of the
neoplastic potential of the prostatic epithelium. Kuhajda and Mann have studied a case
of adenoid cystic carcinoma of the prostate with immunoperoxidase staining for both
prostate-specific acid phosphatase and prostate-specific antigen, which have been
shown to be specific for normal prostatic epithelium and prostatic carcinoma. The
negative staining for these antigens in this tumor distinguishes adenoid cystic
carcinoma from the usual acinic adenocarcinomas of the prostate.68
Sarcomatoid carcinoma:
Primary carcinosarcoma of the prostate is a rare tumor. According to Mostofi
and Price, only a tumor displaying definite sarcoma, metaplastic cartilaginous or
osseous components in addition to the usual adenocarcinoma can qualify as prostatic
carcinosarcoma.69Clinically, these patients tend to be older and in roughly half of
cases have a history of prostatic adenocarcinoma treated by radiation. These are
associated with a very poor prognosis.70
Small-cell (neuroendocrine) carcinoma:
As highlighted by Trotz71, primary small cell carcinoma of the prostate is
uncommon and is usually discovered incidentally in histologic samples of
adenocarcinomas. Three theories of histogenesis have been proposed, 1) small cell
carcinomas of the prostate arise from amine precursor uptake decarboxylation cells of
local endodermal origin, 2) these tumours arise from dedifferentiation of prostatic
adenocarcinomas, suggesting that small cell carcinomas are part of a spectrum of
prostatic adenocarcinomas rather than a separate disease entity. 3) The most widely
accepted view is that prostatic small cell carcinomas arise from totipotential stem cells
35
of the prostate, which have the ability to differentiate into either epithelial or
neuroendocrine type carcinomas.
Tetu et al72 observed that small cell prostate cancers have been reported to
produce
paraneoplastic
syndromes
associated
with
the
production
of
adrenocorticotrophic hormone. Microscopically the tumour may be pure small cell

carcinoma like that seen in the lung or may have mixed pattern of adenocarcinoma
with small cell carcinoma. They follow an aggressive course with prognosis regardless
of the small cell component or tumour cell type. Di Sant'agnese et al73 stated that the
tumour cells stain positively for the neuroendocrine markers. Electron microscopy
shows presence of neurosecretory granules in few carcinomas.
Urothelial (transitional cell) carcinoma:
The frequency of primary urothelial carcinoma ranges from 0.7 to 2.8% of
prostatic tumors in adults. Most patients are in the age range of 4590 years.74 Primary
prostatic urothelial carcinoma arises from the urothelium lining the prostatic urethra
and the proximal portions of prostatic ducts. It has been postulated that these may
develop through a hyperplasia to dysplasia sequence, possibly from reserve cells
within the urothelium.75
Most cases represent secondary involvement from a TCC of the urinary
bladder. When TCC of the urinary bladder involves the prostate, there are two patterns
of involvement: 1) mucosal pagetoid spread though the prostatic urethra, prostatic
ducts and acini with or without stromal invasion 2) direct invasion though bladder
wall.76
TCC of the prostate typically shows a solid growth pattern. Peritumoral
inflammation, prominent nuclear pleomorphism, solid cell nests containing a high
36
mitotic count and tumour necrosis are important diagnostic criteria for the diagnosis of
TCC.77
Mesenchymal tumours:
Leiomyoma:
Leiomyoma is a rare entity described in the prostate. It is probably of
embryologic origin.78The differential diagnosis of a leiomyoma vs stromal nodule in
benign hyperplasia may be difficult. Both leiomyomas and stromal nodules may
contain abundant smooth muscle, but leiomyomas typically demonstrate wellorganized fascicles that are not commonly seen in stromal nodules. Leiomyomas
demonstrate virtually no mitotic activity and minimal to no nuclear atypia.79
Leiomyosarcoma of prostate:
Leiomyosarcoma of the prostate is rare, affecting men between the ages of 40
78 years and most frequently presents with urinary obstruction.80 Lesions may range in
size from 3 to 21 cm and are often highly infiltrative. Microscopically, these hyper
cellular lesions are composed of intersecting bundles of spindled cells with atypia
ranging from moderate to severe.
The vast majority of leiomyosarcomas in the literature have been high grade
with frequent mitoses and necrosis. Low-grade leiomyosarcomas are distinguished
from leiomyomas by moderate amount of atypia, focal areas of increased cellularity,
scattered mitotic figures, and a focally infiltrative growth pattern around benign
prostate glands at the perimeter.79Leiomyosarcomas commonly express vimentin,
actin, and desmin. Cytokeratin expression is observed in about one-quarter of cases.
Patients with leiomyosarcoma commonly have a poor outcome.80
37
Primary lymphoma of the prostate:

Primary lymphoma of the prostate is rare. It represents 0.09% of prostate
neoplasias and 0.1% of all non - Hogkin lymphomas. Secondary involvement of the
gland is the most common presentation in such cases. Primary lymphomas of the
prostate occur in men aged 60 years in average. The most frequent presentation forms
are obstructive urinary symptoms, and obstruction can lead to renal failure.81
The definition of primary lymphoma of the prostate is based on several criteria.
The main symptoms are urinary. The disease occurs predominantly in the prostate,
with or without extension to adjacent tissues and there is no involvement of lymph
nodes, liver, spleen or blood up to 1 month after diagnosis. Prostatic lymphomas,
despite being rare, must be included in differential diagnostic of cases with obstruction
of the lower urinary tract.82
Prostatic acid phosphatase and Prostate specific antigen:
Prostatic acid phosphatise is a sialoglycoprotein produced by benign and
malignant prostatic epithelial cells. Serum levels can be measured by enzymatic or
immunological techniques and has been used primarily to assist staging and
monitoring of patients with prostatic carcinoma.83 Higher levels have been noticed in
the prostatic malignancies.84
Prostate specific antigen (PSA) is serine protease produced at high
concentrations by normal and malignant prostatic epithelium. Only minor amounts of
PSA leak out into circulation from the normal prostate, but the release of PSA is
increased in prostatic disease.85 This is currently replacing the prostatic acid
phosphatise as the preferred serum marker for prostatic carcinoma and is an excellent
marker for monitoring response to therapy, including residual and recurrent disease
38
and may predict tumour stage.83 It is considered to be the sensitive marker for early
stage disease.84
Immunohistochemistry:
p63 immunostaining:
The p63 antibody is a recently developed antibody to prostate basal cells.86
Protein p63, which shares homology with the suppressor gene of tumor p53, seems to
play a critical role as a regulator of growth and development of cutaneous epithelium,
uterine cervix, breast and the urogenital tract, and in particular, of prostate
development.87 In contrast to p53, the p63 gene encodes for atleast six major isotypes.
Three isotypes (TAp63, Tap63 and Tap63) contain the transactivating (TA)
domain and are able to transactivate p53 reporter genes and induce apoptosis. In
contrast, the other three isotypes (Np63, Np63, and Np63) are transcribed
from an internal promoter localized within intron 3, lack the TA domain, and act as
dominant-negative to suppress transactivation by both p53 and Tap63 isotypes.88
Signoretti et al88 in their study, first confirmed that p63 represents a selective
marker of basal cells within the prostatic epithelium by analyzing p63 expression in a
series of normal prostates and in normal prostate basal cells. Second, because it has
been demonstrated that prostate cancers express markers of secretory cells and are
usually negative for basal cell markers, they analyzed p63 expression in a series of 130
prostatic carcinomas and in prostate cancer cell lines. Finally, to assess the role of p63
in prostate development they histologically analyzed the periurethral region in day
1, p63(/) male mice. Their results show that p63 is a reliable prostate basal cell
marker and that the Np63 isotype is the most abundantly represented in normal
prostate basal cells. Because p63 protein is consistently undetectable in prostate
cancers, they propose that p63 expression may be used in the differential diagnosis
39
between benign and malignant lesions of the prostate. Finally and most importantly,
their results indicate that p63 expression is necessary for the normal development of
the mouse prostate, suggesting that p63-positive basal cells may represent/include
prostate stem cells.
Bostwick and Qian had developed a perspective which identifies increasing
grades of PIN are associated with progressive disruption of the basal cell layer. Basal
cell layer disruption is present in 56% of cases of high-grade PIN, and is more
frequent in acini adjacent to invasive carcinoma than in distant acini. The amount of
disruption increases with increasing grades of PIN.27 In their immunohistochemical
study of 28 cases of PIN and 41 cases of adenocarcinoma, Kruslin et al89found that
p63 was positive around the whole circumference in 12 out of 28 cases with PIN, and
discontinuously positive in the remaining cases, suggesting initial disruption of the
basal cell layer: positivity was observed in all normal glands, and negative in all
carcinomas.
Shah et al90 observed 95% of p63 positivity in TURP cases removed for BPH
and none of the needle biopsy specimens of prostatic carcinoma demonstrated p63
immunoreactivity.
Signoretti et al88 studied 130 prostate cancer specimens for p63 staining and
found p63 negativity in 126 (97%) cases.
Interpretation of p63 staining in prostatic glands91
Negative
or
Positive Complete
Positive Partial (< 25% of the glands circumference is stained).
40
Interpretation of p63 staining in urothelial carcinoma92

The percentage of tumor cells was scored as follows.
Score 0 = no reactivity - Negative
Score 1 = < 10% of cancer cell nuclei positive
Score 2 = 10-- 25 % of cancer cell nuclei positive
Score 3 = 25--50 % of cancer cell nuclei positive
Score 5 = 75--90% of cancer cell nuclei positive
Score 6 = >90% of tumor cell nuclei positive.
P504S (AMACR) immunostaining:
AMACR (alpha-methyl-acyl-coA racemase), a cytoplasmic protein recently
identified by cDNA library subtraction in conjunction with high-output microarray
analysis of prostatic carcinoma, has been considered as a marker that is substantially
upregulated in prostate cancer.93AMACR is known to be involved in the betaoxidation of branched-chain fatty acids and fatty acid derivatives.94 AMACR has been
located in peroxisomes and mitochondria and in human cells, and the enzyme is
strongly expressed in normal liver and kidney cells.95The racemic mixtures of
branched fatty acids and fatty acid derivatives must first be converted by AMACR in
peroxisomes, and mitochondria into (S) isomers, before undergoing beta oxidation.96
Mitochondrial beta-oxidation of fatty acids donates electrons to the respiratory chain
coupled with phosphorylation of ADP to ATP. Peroxisomes transform branched-chain
fatty acids by acyl-CoA oxidase with the production of oxidized substrate and
hydroxide hydrogen.94
A monoclonal antibody to AMACR, known as P504S has been developed and
is available commercially for use on routine formalin-fixed, paraffin embedded tissue
41
specimens.97 AMACR overexpression has been detected in many human tumors such
as colon and mammary tumors, malignant melanomas and papillary renal carcinomas.
Western blot analysis demonstrated 36-fold overexpression of P504S in prostatic
carcinomas when compared with benign glandular tissues. Using a highly specific
antibody (P504S) directed against the enzyme, Jiang et al found that strong immuno
staining for the enzyme was consistently present in prostatic carcinoma and in highgrade prostatic intraepithelial neoplasia of the peripheral zone of the prostate.98
Molinie et al98 studied immunohistochemistry of 260 prostate cases and found
97% of prostatic cancer showed AMACR overexpression.
Yu et al99 studied 42 cases of prostate cancer and 12 cases of HGPIN for the immuno
staining of AMACR and basal cell markers p63 and 34betaE12. They observed the
positivity rate of AMACR in prostate carcinoma and in HGPIN about 100% and
91.67% respectively.
Jiang et al100 found AMACR negativity in 254 (91.7%) out of 277 cases of benign
prostate.
Interpretation of AMACR staining101
Positive staining pertains to dark diffuse or granular, cytoplasmic or luminal,
but circumferential. The percentage positivity was graded from 0+ to 3+ as follows:0% cells - 0+, negative
1-10% cells - 1+, mild
11-50% cells - 2+, moderate
> 51% cells - 3+, strong
42
MATERIALS AND METHODS

This is a prospective study which includes 65 cases, done for a period of 2
years, i.e., from December 2010 to August 2012 at DR .B. R. AMBEDKAR
MEDICAL COLLEGE AND HOSPITAL. All the 65 cases were TURP specimens.
The clinical history and the details of the patient were collected from the
requisition form at Ambedkar Medical Hospital. The tissue samples were processed in
the Department of Pathology, DR .B.R. AMBEDKAR MEDICAL COLLEGE.
FIXATION FOR LIGHT MICROSCOPY
All the specimens obtained were fixed in buffered neutral formalin for a period of
12- 24 hrs and then the entire specimen was submitted for processing.
Fixation by 10% buffered formalin
40% formalin
100 ml
Water
900 ml
Sodium dihydrogen phosphate monohydrate
4 gms
Anhydrous disodium hydrogen phosphate
6.5 gms
Grossing:
The weight of the specimen was noted and the findings were recorded as per
the format. The entire bits were submitted for processing.
43
TECHNIQUE OF PROCESSING
1. Dehydration 3 changes of graded alcohol and 2 changes of acetone.
2. Clearing by chloroform.
3. Paraffin impregnation 2 changes at 60C
4. Embedded in paraffin wax, labelled and blocks were made after trimming
excess paraffin
5. Sections were cut at a microtome setting of 4 microns.
6. The sections were floated on a water bath at 60C temperature.
7. Sections were mounted on a slide using a very thin layer of glycerol egg
albumin as an adhesive.
8. For immunohistochemical study sections were mounted on Poly-L-Lysine
coated slides.
Technique of staining
For light microscopy one slide from each block was routinely stained with
H&E to arrive at a diagnosis.
H&E STAINING102
Method of H&E staining:
1. Deparaffinize sections, hydrate through graded alcohol.

2.
Stain in alum haematoxylin.
3. Wash in running tap water until sections blue for 5 minutes or less.
4. Differentiate in 1% acid alcohol for 5-10 seconds.
5. Wash well in tap water until sections are again blue.
44
6. Blue by dipping in an alkaline solution (ammonia water) followed by a tap

water wash.
7. Counterstained in 1% Eosin Y for 15 seconds.
8. Wash in running tap water for 1-5 minutes.
9. Dehydrate, clear and mount in DPX.
Results:
Nuclei blue to black.
Cytoplasm and other substances pink.
IMMUNOHISTOCHEMICAL STAINING102
The antibodies and other consumables were obtained from Biocare Medical,
Bangalore.
p63 STAINING:
1. Deparaffinize sections, hydrate through graded alcohol

2. Pressure cooker antigen retrieval method: Retrieve sections under pressure
using Biocares Decloaking Chamber by placing the slides in antigen retrieval
buffer solution. Allow the solution to cool for 10 minutes then wash in distilled
water.
3. Rinse in TBS buffer.
4. Drain off excess TBS buffer and block endogenous peroxidase activity by using
peroxidase block 10 - 15mts.
45
6. Primary antibody (p63 monoclonal antibody): Incubate for 60 minutes at room

temperature.
8. Probe: Incubate for 30 minutes at room temperature with a Probe.
9. Rinse in TBS buffer
10. Polymer: Incubate for 30 minutes at room temperature with a Polymer.
11. Rinse in buffer.
12. Chromogen: Incubate for 5 minutes at room temperature when using Biocares
3 , 3-diaminobenzidine (DAB).
14. Counterstain with Haematoxylin.
15. Dehydrate, clear and mount with DPX.
Cellular localization: Nucleus (basal cells of prostatic glands, urothelium)

Positive control: Normal prostate
P504S STAINING:
1. Deparaffinize sections, hydrate through graded alcohol
2. Pressure cooker antigen retrieval method: Retrieve sections under pressure
using Biocares Decloaking Chamber by placing the slides in antigen retrieval
buffer solution. Allow solution to cool for 10 minutes then wash in distilled
water.
4. Drain off excess TBS buffer and block endogenous peroxidase activity by
using peroxidase block 10 - 15mts.
46
6. Primary antibody (P504S polyclonal antibody): Incubate for 60 minutes at

room temperature.
8. Probe: Not applicable for P504S staining.
9. Polymer: Incubate for 30 minutes at room temperature with a Polymer.
11. Chromogen: Incubate for 5 minutes at room temperature by using Biocares
3, 3-diaminobenzidine (DAB).
13. Counterstain with Haematoxylin.
14. Dehydrate, clear and mount with DPX.
Cellular localization: Granular and cytoplasmic.
Positive control: Prostate cancer.
Normal tissue: Not applicable.
Statistical analysis:
Statistics was done using SPSS 10.5 version software system. Results were
expressed in numbers and percentages.
47
OBSERVATION AND RESULTS

A total number of 65 cases were studied. The cases were distributed in the age
group of 4585 years. The maximum number of patients were in the age group of 6069 yrs. Out of 65 cases, 52 were BPH, 3 were non-specific granulomatous prostatitis,
1 was prostatic abscess, 7 were prostatic adenocarcinoma, 1 case was urothelial
carcinoma and 1case had both prostatic adenocarcinoma and urothelial carcinoma.
Foci of low grade PIN was identified in 8 cases. All the low grade PIN foci were
associated with BPH. High grade PIN was identified in 9 cases. Out of these 2 HGPIN
foci were seen in BPH and 7 were seen associated with adenocarcinoma.
Miscellaneous features like cystic atrophy, chronic non-specific prostatitis, stromal
nodule, basal cell hyperplasia and transitional cell metaplasia were also seen
associated with these lesions. Immunohistochemistry was done using p63 and P504S
markers in the cases of BPH, Prostatic intraepithelial neoplasia, and carcinoma.
INFLAMMATORY LESIONS:
In the present study 3 (4.6%) cases of non specific granulomatous prostatitis
and 1 (1.5%) case of prostatic abscess were identified out of 65 cases (Table 3, Fig 2).
Chronic non-specific prostatitis formed majority among inflammatory lesions and
predominantly it was seen in BPH cases and also in few cases of prostatic
adenocarcinoma.
Light microscopic findings:
Chronic non-specific prostatitis revealed benign appearing glands lined by
inner luminal secretory cell layer and outer basal cell layer and infiltrated by sheets of
48
lymphocytes and plasma cells. Destruction of glandular lining was noted at places
with necrotic debri and inflammatory cells in the lumen.
The cases of non-specific granulomatous prostatitis showed dense infiltrate of
lymphocytes, plasma cells, foamy histiocytes and few multinucleated giant cells. Foci
of glands showed destruction of epithelial lining.
BENIGN PROSTATIC HYPERPLASIA
There were totally 52 (80%) cases of BPH out of 65 cases. All these cases of
BPH were in the age group of 45-85 yrs. The peak incidence was observed in the age
group of 60-69 yrs. The mean age of BPH in this study belongs to 66.88 yrs. (Tables
3, 5, 6) (Figs 2, 4, 5)
Light microscopic findings:
Sections consisted of proliferation of both glandular and stromal components.
The glands were variable in size, at places showed cystic dilation and contained an
inspissated secretion called corpora amylacea. The lining epithelium was flat to
columnar, the cytoplasm was pale, and the nuclei were regular and basally located
with inconspicuous nucleoli. The epithelium showed papillary infoldings. The outer
basal cell layer composed of flattened to cuboidal cells placed on an intact basement
membrane.
p63 stain: In all the 52 cases of BPH the basal cell nuclei of the glands showed
positivity for p63 immunostaining which was complete positivity. The percentage of
positivity was 100%. (Table 11, Fig 10)
49
P504S stain: In all the 52 cases of BPH, the glands were negative for the P504S
immunostaining. The percentage of negativity was 100%. (Table 12, Fig 11)
Basal cell hyperplasia:
Basal cell hyperplasia was identified in 6 cases out of 65 cases. There were two
patterns of basal cell hyperplasia identified. The complete basal cell hyperplasia
showed solid nests of basal cells without central lumen and the incomplete form
showed small lumina lined by secretory cells with clear cytoplasm and these are
surrounded by multiple layers of basal cells. These basal cells were positive for p63
staining and negative for P504S stain.
Stromal nodule showed spindle cell proliferation in a hyalinized stroma with

scattered thick walled blood vessels.
Foci of transitional cell metaplasia was seen in 4 cases of BPH and was
characterized by the presence of a stratified epithelium composed of oval to spindle
cells perpendicularly oriented to the lumina, and having scanty pale eosinophilic to
clear cytoplasm. The nuclei were elongated, vesicular with inconspicuous nucleoli.
PREMALIGNANT LESIONS OF THE PROSTATE:
PROSTATIC INTRAEPITHELIAL NEOPLASIA:

In the present study low grade PIN was identified in 8 (12.3%) cases out of 65
cases. All of these were associated with BPH.
High grade PIN was seen in 9 (13.8%) cases out of 65 cases. Out of these 7
cases were associated with adenocarcinoma and 2 cases were seen in BPH. 87.5% of
adenocarcinoma and 3.8% of BPH were associated with HGPIN. (Table 7, Fig 6) High
50
grade PIN has high association with adenocarcinoma. This reflects a greater possibility of high
grade PIN as a precursor lesion to carcinoma prostate.
Microscopy:
Low grade PIN showed crowding and stratification of glandular secretory
epithelium. The nuclei were variably increased in size with thin nuclear membrane and
inconspicuous nucleoli. The basal cells were intact.
High grade PIN consisted of crowding and stratification of glandular secretory
epithelium. The nuclei were enlarged with variation in size and shape and the nucleoli
were prominent. The basal cells were intact but few cases showed discontinuity.
p63 stain:
Basal cell nuclei of HGPIN glands showed positivity for p63 stain in all the
9(100%) cases. Out of the 9 cases, complete positivity was seen in 8 cases and 1 case
showed partial positivity. (Table 11, Fig 10)
P504S stain:
Out of 9 cases of HGPIN 8 (88.9%) cases showed moderate to strong positivity
which was cytoplasmic and circumferential and 1(11.1%) case showed negativity for
P504S immunostaining. (Table 12, Fig 11)
Microscopic patterns of HGPIN:

There were four patterns identified in HGPIN usually with multiple patterns in
each case.
Tufting Pattern was seen in 6 out of 9 cases. The percentage was 66.7%.
Microscopy showed the neoplastic cells grow towards the lumen, forming wave- or
mound-like structures.
51
Flat Pattern comprised of 5 out of 9 cases. The percentage was 55.6%.

Microscopy consisted of the glands lined with one or two layers of atypical cells
without significant architectural abnormality.
Micropapillary pattern composed of glands lined by atypical secretory
epithelial cells arranged in micropapillary structures, lacking fibrovascular cores was
identified in 3 out of 9 cases of HGPIN. The percentage was 33.3%
Cribriform Pattern showed glands with epithelium forming cribriform pattern was
identified in 1 out of 9 cases. The percentage was 11.1%. (Table 8, Fig 7)
In this present study the commonest pattern identified was tufting type and the
next common pattern was flat type.
MALIGNANT LESIONS OF PROSTATE:
In this present study there were 7 (10.8%) cases of Adenocarcinoma, 1 (1.5%)

case of Adenocarcinoma with Urothelial carcinoma and 1 (1.5%) case of Urothelial
carcinoma out of 65 cases identified. All the 9 malignant lesions constituted 13.8% of
cases. Malignant lesions in the age group of 60-69 yrs, 70-79 yrs, 80-89 yrs were
constituting 1 (11.1%) case, 3 (33.3%) cases, 5 (55.6%) cases respectively. The peak
incidence was seen in 9th decade. The mean age of malignant cases was 76.78 yrs.
(Tables 3, 5, 6) (Figs 2, 4, 5).
ADENOCARCINOMA
Microscopy:
All the cases of adenocarcinoma showed architectural disturbance, stromal
invasion and nuclear anaplasia in the form of variable size and shape, hyperchromatic
with prominent nucleoli. Two cases showed perineural invasion.
52
Microscopic grading system followed in this study was Gleasons microscopic

grading system of prostatic carcinoma.
Gleasons grade 2 pattern composed of single, separate, slightly less uniform glands,
loosely packed and separated by small amounts of stroma was seen in 1 case.
Gleasons grade 3 pattern composed of single, separate, more variable glands,
irregularly separated with ragged, poorly defined edge was seen in 3 cases.
Gleasons grade 4 pattern showed fused glands was seen in 5 cases.
Gleasons grade 5 pattern showing tumour cells arranged in sheets with no gland
formation was seen in 5 cases, and malignant glands with comedonecrosis was seen in
1 case.
Gleasons Grading system:
The gleason score 5,7,8,9,10 constituted 1 ( 12.5%) case, 1 ( 12.5%) case, 2( 25%)
cases, 3 ( 37.5%) and 1 ( 12.5%) case respectively. Majority of patients diagnosed as
conventional adenocarcinoma had graded as score 9 (3cases, 37.5%) followed by
score 8 (2 cases, 25%). (Table 9, Fig 8)
Tumour quantification:
1 (12.5%) case of adenocarcinoma showed < 5% and remaining 7 (87.5%)
cases showed
>5% of tumour quantification. (Table 10, Fig 9)
p63 stain:
Present study showed p63 negativity in all the 8 cases of adenocarcinoma. The
percentage of negativity was 100%. (Table 11, Fig 10)
53
P504S stain:
All the 8 cases of adenocarcinoma showed strong cytoplasmic, granular
positivity. The percentage of positivity was 100%. (Table 12, Fig 11)
UROTHELIAL CARCINOMA:
There were 2 cases of urothelial carcinoma found in this study and both were
in 9th decade of age (81 and 85 years old). One of that case had both adenocarcinoma
and urothelial carcinoma. Specimens were taken from these patients by TURP.
Microscopy showed infiltrating sheets and solid nests of neoplastic transitional
epithelial cells with moderate to scanty cytoplasm with pleomorphic and hyper
chromatic nuclei having prominent nucleoli. The patient whom had only urothelial
carcinoma showed invasion into bladder.
Expression of p63 and P504S immunostaining in urothelial carcinoma
Both the cases showed score 5 p63 positivity (75--90% of cancer cell nuclei
positive) and strong cytoplasmic positivity for P504S stain.
54
Table 3: Distribution of cases according to Histopathological Diagnosis

HP Diagnosis
Frequency
Percent
Adenocarcinoma
10.8
52
80.0
NSGP
4.6
Prostatic abscess
1.5
1.5
Adenocarcinoma+ Urothelial carcinoma
1.5
65
100.0
BPH
Total
Fig 2: Distribution of cases according to Histopathological Diagnosis

(N=65)
90
80
80
70
Percentage
60
50
40
30
20
10.8
10
4.6
1.5
1.5
1.5
Prostatic abscess
Urothelial
carcinoma
Adenocarcinoma
with Urothelial
carcinoma
0
Adenocarcinoma
BPH
NSGP
55
Table 4: Distribution of cases according to Age Group.
Age
Frequency
Percent
40-49 yrs
3.1
50-59 yrs
10
15.4
60-69 yrs
25
38.5
70-79 yrs
15
23.1
80-89 yrs
13
20.0
Total
65
100.0
Fig 3: Distribution of age (N=65)

40-49 yrs
3.1%
80-89 yrs
20.0%
50-59 yrs
15.4%
70-79 yrs
23.1%
60-69 yrs
38.5%
The maximum number of patients in this study were in the age group of 60-69 yrs.
56
Table 5: Age wise distribution of cases according to Histopathological Diagnosis.
Histopathological
diagnosis
Carcinoma
(adenocarcinoma+
Urothelialcarcinoma)
BPH
0.0%
11.1%
33.3%
55.6%
100.0%
2
3.8%
0
9
17.3%
1
21
40.4%
2
12
23.1%
0
8
15.4%
0
52
100.0%
3
0.0%
0
0.0%
2
33.3%
0
0.0%
10
66.7%
1
100.0%
25
0.0%
0
0.0%
15
0.0%
0
0.0%
13
100.0%
1
100.0%
65
3.1%
15.4%
38.5%
23.1%
20.0%
100.0%
50-59
yrs
0
0.0%
Prostatic abscess
Total
120.0%
80-89
yrs
5
Total
70-79
yrs
3
40-49
yrs
0
NSGP
Age
60-69
yrs
Fig 4: Age wise distribution of cases according to Histopathological

Diagnosis (N=65)
40-49 yrs
50-59 yrs
100.0%
100.0%
60-69 yrs
70-79 yrs
80-89 yrs
80.0%
66.7%
60.0%
55.6%
40.4%
40.0%
33.3%
33.3%
23.1%
17.3%
20.0%
15.4%
11.1%
3.8%
0.0%
0.0%0.0%
Carcinoma (N=9)
0.0%
BPH (N=52)
0.0%0.0%
NSGP (N=3)
57
0.0%0.0%
0.0%0.0%
Prostatic abscess (N=1)
Table 6: Mean Age (yrs) of cases according to Histopathological Diagnosis.
HP diagnosis
Mean
SD
Min
Max
Carcinoma (adenocarcinoma+
76.78
7.138
65
85
BPH
52
66.88
10.099
45
85
NSGP
61.00
4.583
56
65
Prostatic abscess
60.00
60
60
Total
65
67.88
10.170
45
85
urothelial carcinoma)
Fig 5: Mean Age (yrs) of cases according to Histopathological

Diagnosis (N=65)
90
80
76.78
70
66.88
61
60
NSGP (N=3)
Age (yrs)
60
50
40
30
20
10
0
Carcinoma (N=9)
BPH (N=52)
58
Table 7: Distribution of Prostatic Intraepithelial Neoplasia in different cases
PIN
Type of case
LGPIN
HGPIN
Neg.
Total
0.0%
87.5%
12.5%
100.0%
42
52
15.4%
3.8%
80.8%
100.0%
0.0%
0.0%
100.0%
100.0%
0.0%
0.0%
100.0%
100.0%
Adenocarcinoma
BPH
NSGP
Prostatic abscess
120.0%
Fig 6: Distribution of Prostatic Intraepithelial Neoplasia in different

cases (N=65)
LGPIN
100.0%
HGPIN
100.0%
100.0%
Neg.
87.5%
80.8%
80.0%
60.0%
40.0%
20.0%
12.5%
15.4%
3.8%
0.0%
0.0%
Adeno Carcinoma (N=8)
0.0% 0.0%
BPH (N=52)
NSGP (N=3)
59
0.0% 0.0%
Table 8: Different Microscopic patterns of HGPIN (N= 9)
Microscopic pattern
No of cases
Percentage
Flat
55.6%
Tufting
66.7%
Cribriform
11.1%
Micropapillary
33.3%
Fig 7: Different Microscopic patterns of HGPIN ( N= 9 )

80.0%
70.0%
66.7%
60.0%
55.6%
40.0%
Percentage
50.0%
33.3%
30.0%
20.0%
11.1%
10.0%
0.0%
Flat
Tufting
Cribriform
Tufting type is the commonest pattern seen in this study.
60
Micro papillary
Table 9: Distribution of cases of Prostatic Adenocarcinoma according to

Gleason's Grading System.
Gleason Score Frequency
Valid Percent
12.5
12.5
25.0
37.5
10
12.5
Total
100.0
Fig 8: Distribution of cases of Prostatic Adenocarcinoma according

to Gleason's Grading System (N=8)
10
12.5%
9
37.5%
5
12.5%
7
12.5%
8
25.0%
61
Table 10: Distribution of Prostatic Adenocarcinoma cases based on

Tumour quantification.
Tumour quantification
Frequency
Valid Percent
<5%
12.5
>5%
87.5
Total
100.0
Fig 9: Distribution of Prostatic Adenocarcinoma cases based on

Tumour quantification (N=8)
<5%
12.5%
>5%
87.5%
62
Table 11: Expression of p63 immunostaining in different cases.
IHC-p63 Stain
Type of Case
Total
HGPIN
Positive
9
Neg.
0
Adenocarcinoma
100.0%
0
0.0%
8
100.0%
8
BPH
0.0%
52
100.0%
0
100.0%
52
100.0%
0.0%
100.0%
Fig 10: Expression of p63 immuno staining in different cases

120.0%
Positive
100.0%
Neg.
100.0%
100.0%
100.0%
Percentage
80.0%
60.0%
40.0%
20.0%
0.0%
0.0%
HGPIN (N=9)
0.0%
0.0%
BPH (N=52)
All the BPH and HGPIN cases showed positivity for p63
All the adenocarcinoma cases showed negativity
63
Table 12: Expression of P504S immunostaining in different cases
IHC- P504S stain
Total
Type of case
HGPIN
Positive
8
Negative
1
Adenocarcinoma
88.9%
8
11.1%
0
100.0%
8
BPH
100.0%
0
0.0%
52
100.0%
52
0.0%
100.0%
100.0%
Fig 11: Expression of P504S immunostaining in different cases

120.0%
Positive
Neg.
100.0%
100.0%
100.0%
88.9%
Percentage
80.0%
60.0%
40.0%
20.0%
11.1%
0.0%
0.0%
HGPIN (N=9)
0.0%
BPH (N=52)
All the adenocarcinoma cases and 8 HGPIN cases showed P504S positivity
None of the BPH cases were positive.
64
Fig 12: Photomicrograph of Chronic Prostatitis (10x)
Fig 13: Photomicrograph of Non specific granulomatous prostatitis showing

multinucleated giant cell and histiocytes. (40x)
65
Fig 14: Photomicrograph of Benign prostatic hyperplasia (10x)
Fig 15: Benign glands in BPH showing positivity for basal cell marker p63. (40x)
66
Fig 16: Photomicrograph of Basal cell hyperplasia (10x)
Fig 17: Basal cell hyperplasia showing p63 positivity (40x)
67
Fig 18: Photomicrograph of Low grade PIN (40x)
Fig 19: Photomicrograph of High grade PIN Tufting pattern. (40x)
68
Fig 20: Photomicrograph of High grade PIN Flat type (40x)
Fig 21: Photomicrograph of High grade PIN Micropapillary pattern (40x)
69
Fig 22: Photomicrograph of High grade PIN Cribriform pattern (40x)
Fig 23: HGPIN showing p63 positivity (10x)
70
Fig 24: HGPIN showing P504S positivity (40x)
Fig 25: Photomicrograph of Adenocarcinoma Gleasons grade 2 (10x)
71
72
Fig 28: Photomicrograph of Adenocarcinoma Gleasons grade 5(10x)
Fig 29: Photomicrograph of Adenocarcinoma showing strong cytoplasmic P504S

positivity (40x)
73
Fig 30: p63 stain is negative in Adenocarcinoma (40x)
Fig 31: Photomicrograph of Invasive Urothelial carcinoma (10x)
74
Fig 32: Urothelial carcinoma is positive for p63 nuclear stain (10x)
Fig 33: Urothelial carcinoma is positive for P504S cytoplasmic stain (40x)
75
DISCUSSION
The present study was carried out on 65 cases of TURP specimens. The
specimens were examined for analyzing various histomorphological lesions of
prostate, with special emphasis given to prostatic intraepithelial neoplasia. There were
2 immunohistochemical markers (p63, P504S) used in benign, prostatic intraepithelial
neoplasia and malignant cases.
Among the inflammatory lesions, chronic prostatitis formed majority of cases
and was seen associated with BPH. Non specific granulomatous prostatitis was
identified in 4.6% (3 cases) of cases. Herranz et al103 showed in their study that 1.5%
(11 cases) of patients had nonspecific granulomatous prostatitis. In present study the
percentage is slightly higher.
Table 13: Comparison of incidence of NSGP

Authors
Percentage
Herranz et al103
1.5%
Present study
4.6%
In the benign proliferative lesions, BPH was seen in the majority of patients.
Out of 65 TURP specimens BPH was diagnosed in 52 (80%) of cases and it was the
major type of lesion found in this study. Comparison of the incidence of BPH in
prostate specimens with other studies in the following table.
76
Table 14: Comparison of incidence of BPH
Authors
Percentage
Kshitij et al52
85.8 %
Haroun et al104
64.48%
Djavan et al105
83%
Jasani et al52
56%
Pacelli and Bostwick36
81.7%
Present study
80%
Incidence of BPH is correlated with Pacelli and Bostwick study.

All these cases of BPH were in the age group of 45-85 years. The peak
incidence was observed in the age group of 60-69 years. Jasani et al52 showed in their
study the age wise distribution as, 3.92% below 50 years , 96.08% at 51-70 years and
no cases were found above 70 years. In the present study the age incidence was 7.8%
below 50 years, 59.6% at 51-70 years and 32.6% above 70years.
Table 15: Comparison of age wise distribution of BPH

Authors
<50 years
51-70 years
>70 years
Jasani et al52
3.92%
96.08%
0%
Present study
7.8%
59.6%
32.6%
Mean age of BPH

In the present study the mean age of BPH patients was 66.88 years. It is
comparable with the study done by Mwakyoma HA106
77
Table 16: Comparison of mean age of BPH

Authors
Mean Age ( years)
Mwakyoma HA106
67
Present study
66.88
Expression of p63 staining in BPH
In all the 52 (100%) cases of BPH the basal cell nuclei of the glands showed
positivity for p63 immunostaining which was complete positivity. Comparison with
other studies is given in the following table.
Table 17: Comparison of p63 positivity in BPH
Authors
Percentage of positivity
Shah et al90
95%
Kruslin et al89
100%
Present study
100%
p63 positivity in BPH is correlated with Kruslin et al study.
Expression of P504S staining in BPH
In all the 52 cases of BPH, the glands were negative for the P504S
immunostaining. The percentage of negativity was 100%. It is comparable with other
studies in the following table.
78
Table 18: Comparison of P504S negativity in BPH
Authors
Percentage of negativity
Jiang et al100
91.7%
Kumaresan et al101
100%
Present study
100%
P504S negativity in BPH is correlated with Kumaresan et al study.
Premalignant lesions of the prostate

Present study showed 12.3% (8 cases) of low grade PIN and 13.8% (9 cases) of
high grade PIN in 65 TUPR specimens studied. Comparison of this result with other
studies is given in the following table.
Table 19: Comparison of incidence of HGPIN in TURP specimens
Authors
Percentage
Gaudin et al35
3.2%
Pacelli and Bostwick36
4.2%
Skjorten et al37
33%
Present study
13.8%
Association of LGPIN with BPH and Adenocarcinoma

The present study showed 8 cases of LGPIN associated with BPH and no
LGPIN case was seen in adenocarcinoma. 15.4% of BPH cases showed LGPIN in this
study. Rekhi et al38 found LGPIN in 18.6% cases of BPH and 5.8% of cases of
adenocarcinoma.
79
Table 20: Comparison of association of LGPIN with BPH and Adenocarcinoma
Authors
LGPIN in BPH
LGPIN in Adenocarcinoma
Rekhi et al38
18.6%
5.8%
Present study
15.4%
0%
Association of HGPIN with BPH and Adenocarcinoma

In the present study HGPIN was observed in 3.8% of the cases of BPH and
87.5% of the cases of adenocarcinoma. Comparison with other studies in the following
table.
Table 21: Comparison of Association of HGPIN with BPH and Adenocarcinoma
Authors
HGPIN in BPH
HGPIN in Adenocarcinoma
Rekhi et al38
11.2%
86.9%
Desai and Borges41
0%
85.24%
Present study
3.8%
87.5%
Microscopic patterns of HGPIN

In present study there were four microscopic patterns identified in HGPIN
usually with multiple patterns in each case. The percentage of tufting, flat,
micropapillary and cribriform patterns were 66.7%, 55.6%, 33.3% and 11.1%
respectively. The commonest pattern identified was tufting type followed by flat type.
80
Bostwick et al107 in their study found the percentage of tufting, flat, micropapillary
and cribriform patterns 87%, 28%, 85% and 32% respectively. The commonest pattern
was tufting type followed by micropapillary type.
Table 22: Comparison of microscopic pattern of HGPIN
Authors
Tufting
Flat
Micropapillary
Cribriform
Bostwick et al107
87%
28%
85%
32%
Present study
66.7%
55.6%
33.3%
11.1%
p63 Expression in HGPIN

In the present study all the 9 (100%) cases of HGPIN showed positivity for p63
staining. Kruslin et al89 showed in their study that 100% positivity for p63 staining in
28 cases of HGPIN.
Table 23: Comparison of p63 expression in HGPIN
Authors
Percentage of p63 positivity
Kruslin et al89
100%
Present study
100 %
P504S Expression in HGPIN

The present study showed moderate to strong positivity for P504S stain in 8
(88.9%) cases of HGPIN and 1 (11.1%) case showed negativity. This is comparable
with other studies in the following table.
81
Table 24: Comparison of P504S Expression in HGPIN
Authors
Percentage of P504S positivity
Molinie et al98
70%
Wu et al108
90%
Yu et al99
91.67%
Kunju et al97
89%
Present study
88.9%
MALIGNANT LESIONS OF PROSTATE

In this present study there were 8 (12.3%) cases of adenocarcinoma out of 65
TURP specimens identified. Of these 1 case was associated with urothelial carcinoma.
Comparison with other studies given in the following table.
Table 25: Comparison of incidence of adenocarcinoma
Authors
Percentage
Kshitij et al52
8.35%
.Haroun et al104
27.1%
Jasani et al52
32%
Djavan et al105
17%
Arun chitale et al52
11%
Present study
12.3%
Incidence of adenocarcinoma is comparable with Arun chitale et al study.
82
Age incidence of carcinoma prostate:

In present study all the 9 (100%) cases (adenocarcinoma and urothelial
carcinoma) were seen above 65 years. The peak incidence was seen in 9th decade. The
mean age was 76.78 years. Xie et al109 found in their study that the percentage of
carcinoma prostate was 84.2% over 65 years of age. Shimada et al110 found 75% of
carcinoma prostate above 65 years.
This variation in age incidence could be due to small sample size of cases of
carcinoma in the present study.
Table 26: Comparison of age incidence of carcinoma prostate above 65 years
Authors
Age
Percentage
Xie et al109
>65 years
84.2%
Shimada et al110
>65 years
75%
Present study
>65 years
100%
Table 27: Comparison of mean age of carcinoma prostate

Authors
Mean age ( years)
Lyn et al111
65
Mwakyoma HA106
75.6
Mwakyoma and Mabandi112
68
Present study
76.78
83
Distribution of Gleasons score in prostatic carcinoma

The distribution of patients in the present study was 0%, 25% and 75% in
Gleasons score of 2-4, 5-7 and 8-10 respectively. Mwakyoma and Mabandi112 in their
study showed the distribution of patients were 5.3%, 61.1% and 33.6% in Gleasons
score of 2-4, 5-7 and 8-10 respectively. Divrik et a1113 observed in their study that the
distribution of patients were 9.7%, 76.7% and 13.6% in Gleasons score of 2-4, 5-7
and 8-10 respectively. The present study showed more number of patients in
Gleasons score 8-10.
Table 28: Comparison of distribution of Gleasons score

Gleasons score
Authors
2-4
5-7
8 - 10
Mwakyom and Mabandi112
5.3%
61.1%
33.6%
Divrik et al113
9.7%
76.7%
13.6%
Present study
0%
25%
75%
p63 Expression in adenocarcinoma

Present study showed p63 negativity in all the 8 cases of adenocarcinoma. The
percentage of negativity was 100%. It is comparable with other studies mentioned in
the following table.
84
Table 29: Comparison of p63 Negativity in adenocarcinoma

Authors
Percentage of p63 Negativity
Molinie et al98
100%
Signoretti et al88
97%
Shah et al90
100%
Ud Din et al92
100%
Present study
100%
P504S Expression in adenocarcinoma

All the 8 cases of adenocarcinoma showed strong positivity to P504S stain.
The percentage of positivity was 100%. It is comparable with other studies in the
following table.
Table 30: Comparison of P504S positivity in adenocarcinoma
Authors
Percentage of P504S positivity
Molinie et al98
97%
Jiang et al114
100%
Yu et al99
100%
Rubin et al115
97%
Yang et al116
100%
Present study
100%
85
in 9th decade of age. Greene et al74 in their study found the age distribution of
urothelial carcinoma between 45 90 years.
Table 31: Comparison of age distribution of urothelial carcinoma
Authors
Age range
Greene et al74
45- 90 years
Present study
81 and 85 years
Expression of p63 and P504S immunostaining in urothelial carcinoma

Both the cases showed positivity for p63 and P504S stain.
Langner et al117 performed p63 stain in 53 urothelial carcinoma and found
positivity in 51 (96.2%) cases. Kunju et al118 found p63 positivity in 92% of urothelial
carcinoma cases. In the present study both the cases showed positivity for p63 stain.
(Score 5 = 75--90% of cancer cell nuclei positive)
Beach et al119 found 5 (83%) out of 6 cases of invasive urothelial carcinoma
showed P504S positivity. In the present study both the cases showed strong
cytoplasmic positivity for P504S stain.
86
CONCLUSION
BPH is the most common lesion of the prostate in the elderly.
Chronic nonspecific prostatitis is the commonest inflammatory condition of the

prostate. Granulomatous prostatitis is rarely encountered.
Conventional adenocarcinoma is the commonest type of prostatic carcinoma.
Gleasons score of 8-10 is the most common score in adenocarcinoma of

prostate.
High grade PIN has a high degree of association with prostatic carcinoma. This
reflects a greater possibility of high grade PIN as a precursor lesion to
carcinoma prostate.
Basal cell marker p63 is really helpful in differentiating benign and HGPIN
glands from malignant glands.
P504S is of great value in differentiating HGPIN and malignant glands from

benign glands.
In view of high degree of association of HGPIN with prostatic carcinoma, it is

suggested that these HGPIN patients need close follow-up, observations and
investigations to rule out existence of carcinoma, especially in the peripheral
zone.
87
SUMMARY
The present study was conducted at Dr. B. R. Ambedkar Medical College from
December 2010 to August 2012. The aim of the study was to analyze the various
neoplastic and non-neoplastic lesions of prostate and special emphasis was given to
prostatic intraepithelial lesions. p63 and P504S markers were used to differentiate
benign, PIN and malignant cases.
The most common inflammatory lesion in the present study was chronic nonspecific prostatitis. Non specific granulomatous prostatitis was seen in 4.6% of
the cases, which was slightly higher than other studies. Prostatic abscess was
seen in 1.5% of the cases.
BPH was the most common benign proliferative lesion amounting to 80% of
the cases.
BPH was observed highest in the age group of 60-69 yrs and the mean age was
66.88 yrs.
BPH showed 100% positivity for p63 stain and 100% negativity for P504S
stain.
Other benign proliferative lesion encountered was BCH which was seen in 6
cases.
Stromal nodule which is a benign stromal proliferative lesion, seen associated

with BPH.
Among PIN, low grade PIN was identified in 15.4% of BPH cases.
High grade PIN was observed in 3.8% of BPH cases and 87.5% of adenocarcinoma
cases.
88
HGPIN showed 100% positivity for p63 stain and 88.9% positivity for P504S
stain.
Various patterns of HGPIN like tufting, flat, micropapillary and cribriform

types were identified. The commonest pattern identified was tufting type.
The malignant lesions were seen in 9 out of 65 cases amounting to 13.8%.
Adenocarcinoma of the prostate formed majority of malignant cases.
All the malignant cases were in the age range of 65 - 85 years. The peak
incidence was seen in 9th decade. The mean age was 76.78 years.
All the Gleason grades were identified except for the grade 1 pattern.
Most of the patients were found to be with score 8-10 of Gleasons grading
system.
All the cases of adenocarcinoma showed negativity for p63 stain.
100% positivity was seen for P504S stain in adenocarcinoma.
in 9th decade of age.
Both the cases of urothelial carcinoma showed positivity for p63 and P504S
staining.
89
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102
PROFORMA
Patient Name:
Age:
Sex:
IP No:
Residence:
Clinical details:
HISTORY:
a) Present History:
Frequency, Dysuria, Urgency, Hematuria, Retention of urine,
Any other:
b) Past History:
c) Personal History:
CLINICAL EXAMINATION:
Per Rectal examination:
Others:
INVESTIGATIONS:
a) CBC
b) Urine Examination:
i)
Microscopy
ii)
Albumin
103
iii)
Glucose
iv)
Culture
c) Serum Prostate Specific Antigen

d) USG
e) X-Ray
f) CT scan
Clinical diagnosis:
Surgery: Date/Type
Nature of the Specimen: TURP
Histopathological Details:
a) Gross description:
Weight
Appearance
b) Microscopy :
i)
Glandular hyperplasia
present /absent
ii)
Stromal hyperplasia
present/ absent
iii)
Cellular details :
1) Luminal epithelial cells: size/shape/ stratification/ crowding
2) Cytoplasm : scanty/abundant/clear
3) Nucleus : size/ shape/ hyperchromasia
4) Nucleolus : absent/ prominent
iv)
Basal cells : present/ absent
104
v)
Stroma : inflammatory cells/ benign stromal lesions
vi)
Granuloma: present/absent
vii)
Prostatic intraepithelial neoplasia:

LGPIN:
present/ absent
HGPIN: present/absent
Microscopic pattern: flat/ tufting/cribriform/ micropapillary
viii)
Other changes:
1) Metaplasia: transitional /squamous
2) Atrophy: present/absent
3) Infarct: present/absent
4) Basal cell hyperplasia: present/absent
5) Others ( specify):
Reporting of Malignant tumour:

Architectural disturbances in malignant tumour:
1. Size of the malignant glands: uniform/variable
2. Arrangement of malignant glands: variably separated by stroma/ closely
packed with back-to-back arrangement.
3. Margins of the glands: well defined/ irregular/ infiltrating
4. Gland fusion: present/absent.
5. Arrangement of neoplastic cells: cords/ columns/ sheets/cribriform
6. Squamous cell differentiation of neoplastic cells: present/absent
7. Transitional cell differentiation of neoplastic cells: present/absent
8. Mucin : present/ absent
If present: intracellular/extracellular
105
9. Others : Signet ring cells/ Small cells

10. Any other changes: present/ absent
Reporting in malignancy is done under the following headings:
Microscopy:
1) Histologic Type:
a) Adenocarcinoma ( conventional)
b) Others (specify)
2) Histologic grade:
Gleason Pattern
Primary (Predominant) Pattern
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Secondary (Worst Remaining) Pattern
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Total Gleason Score:

3) Tumour quantification:
a) Tumor incidental histologic finding in no more than 5% of tissue resected
with Gleason score 2 to 6
106
b) Tumor incidental histologic finding in more than 5% of tissue resected or

Gleason score 7 to 10
4) PIN: present/ absent
If present: low grade/ high grade
5) Perineural invasion: present/absent
6) Lymphatic invasion: Present/absent
7) Other associated findings: BPH/ AAH/etc.
Interpretation of p63 stain in prostatic glands: (stains nucleus of basal cells)
i)
Positive / Negative
ii)
If positive : Complete/ Partial
Interpretation of p63 staining in urothelial carcinoma

The percentage of tumor cells was scored as follows.
Score 0 = no reactivity - Negative
Score 1 = < 10% of cancer cell nuclei positive
Score 2 = 10-- 25 % of cancer cell nuclei positive
Score 5 = 75--90% of cancer cell nuclei positive
Score 6 = >90% of tumor cell nuclei positive.
107
P504s stain: (cytoplasmic stain)

Graded as follows:
i)
0+ Negative ( 0% cells)
ii)
1+ Mild
iii)
2+ Moderate ( 11- 50% cells)
iv)
3+ Strong
( 1-10% cells)
( > 51% cells)
108
No
Age (Yrs)
HP No
60
1281/10
2
3
62
59
IHC-p63 Stain
IHC- P504S stain
BPH
Positive
Neg
SN
1297/10
1325/10
NSGP
BPH
Positive
Neg
CP, SN
65
1354/10
Adenocarcinoma(Gs-10)
(Tumour quantification- >5%)
HGPIN-Positive
CA - Neg
HGPIN-Positive
CA- Positive
55
1388/10
BPH
Positive
Neg
CP
6
7
8
9
10
11
60
75
65
85
64
60
1396/10
1401/10
1423/10
1430/10
2/11
5/11
Prostatic abscess
BPH
BPH
BPH
BPH
BPH
Positive
Positive
Positive
Positive
Positive
Neg
Neg
Neg
Neg
Neg
SN,CYA
CP
CP, SN
TM,CYA
CP,CYA
12
70
12/11
HGPIN- Positive
CA- Neg
HGPIN- Positive
CA- Positive
Positive
Neg
CYA
Positive
Positive
Neg
Neg
SN,BCH
CYA
Positive
Neg
CP,CYA
Positive
Neg
CP,SN
Positive
Neg
Positive
Positive
HGPIN -Positive
CA - Neg
Neg
Neg
HGPIN- Positive
CA- Positive
CP,
TM,BCH
SN
CP, CYA
Perineural
Invasion
Positive
Neg
CYA
13
46
14
15
16
17
HP Diagnosis
LGPIN
HGPIN ( Pattern)
(Micropapillary,Tufting)
( Tufting)
BPH
57
70
65
62
17/11
23/11
37/11
40/11
61/11
BPH
BPH
NSGP
BPH
18
63
138/11
BPH
19
76
196/11
BPH
20
21
22
83
55
80
222/11
236/11
242/11
BPH
BPH
Adenocarcinoma( Gs-9)
23
68
281/11
BPH
(Flat, Micropapillary)
MF
24
81
295/11
Adenocarcinoma(Gs-5) with
Urothelialcarcinoma (Tumour
quantification of adenoca - <5%)
25
26
27
77
58
50
299/11
313/11
364/11
BPH
BPH
BPH
28
29
80
70
383/11
384/11
BPH
30
57
391/11
BPH
31
32
33
34
35
65
50
65
75
75
428/11
442/11
498/11
541/11
629/11
BPH
BPH
BPH
BPH
36
37
38
39
40
41
42
69
70
85
45
80
70
85
669/11
694/11
738/11
747/11
762/11
771/11
777/11
BPH
BPH
BPH
BPH
BPH
BPH
BPH
43
44
45
46
60
60
73
56
790/11
798/11
804/11
826/11
BPH
BPH
BPH
NSGP
Tufting)
( Tufting,
Micropapillary)
(Flat,
HGPIN- positive
HGPIN- positive
AdenoCA - Neg
AdenoCA - Positive
Urothelial CA-Positive Urothelial CA-Positive
Positive
Positive
Positive
Neg
Neg
Neg
Positive
HGPIN-positive
CA - Neg
Neg
HGPIN-Positive
CA- Positive
CYA
Positive
Neg
CP,SN
Neg
Neg
Neg
Neg
CA- Positive
TM
CYA
SN
CYA
Perineural
Invasion
CP,SN
CYA
Positive
Positive
Positive
Positive
CA -Neg
Positive
Positive
Positive
Positive
Positive
Positive
Positive
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Positive
Positive
Positive
Neg
Neg
Neg
CYA
SN
CYA,BCH
SN
CYA
CYA,BCH
CYA
47
48
49
50
51
52
53
54
55
56
67
55
65
72
80
83
65
68
65
61
844/11
853/11
863/11
907/11
915/11
920/11
955/11
1001/11
1060/11
1161/11
BPH
BPH
BPH
BPH
(Tufting)
BPH
BPH
BPH
BPH
BPH
Positive
Positive
Positive
Positive
HGPIN-Positive
CA-Neg
Neg
Neg
Neg
Neg
HGPIN-Positive
CA- Positive
Neg
Neg
Neg
Neg
BPH-Neg
HGPIN - Neg
Neg
CA- Positive
57
67
1183/11
BPH
Positive
Positive
Positive
Positive
BPH- Positive HGPINPositive
Positive
58
85
1231/11
CA- Positive
59
75
1298/11
BPH
60
61
62
63
64
72
65
85
1359/11
44/12
45/12
116/12
64
65
82
75
158/12
169/12
BPH
BPH
BPH
BPH
BPH
( Flat)
KEYS:
- Present
Neg - Negative
( Flat,Tufting)
Cribriform)
BPH-Positive HGPINPositive
Positive
Positive
Positive
(Flat,
HGPIN-Positive
CA-Neg
Positive
Positive
BPH- Neg
HGPIN - Positive
Neg
Neg
Neg
HGPIN-Positive
CA- Positive
Neg
Neg
SN
CYA,TM
CYA
CP,SN
CYA
CYA,CP
BCH
CYA,CP
SN,BCH
CYA
CYA

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HISTOMORPHOLOGICAL STUDY OF PROSTATIC

TURP SPECIMENS WITH SPECIAL REFERENCE

Under the guidance of

Dr. B.N.SWARNAGOWRI., MD, DCP.

Rajiv Gandhi University of Health Sciences,

I hereby declare that this dissertation entitled HISTOMORPHOLOGICAL

HISTOCHEMISTRY is a bonafide and genuine research work carried

of Dr. B. N.SWARNAGOWRI., M.D.,

DCP, Associate Professor, Department of Pathology, Dr. B. R. Ambedkar Medical

CERTIFICATE BY THE GUIDE

STUDY OF PROSTATIC TURP SPECIMENS WITH SPECIAL

Dr. B.N.SWARNAGOWRI., M.D, DCP

CERTIFICATE BY THE CO-GUIDE

STUDY OF PROSTATIC TURP

SPECIMENS WITH SPECIAL REFERENCE TO PROSTATIC

Dr. M. G. Desai., M.S, MCh (Uro)

CERTIFICATE BY THE HEAD OF THE DEPARTMENT

STUDY OF PROSTATIC TURP

SPECIMENS WITH SPECIAL REFERENCE TO PROSTATIC

HISTOCHEMISTRY is a bonafide research work done by Dr. SUBA.G

Dr. Y.A.MANJUNATHA, M.D

ENDORSEMENT BY THE HEAD OF THE DEPARTMENT AND

STUDY OF PROSTATIC TURP

SPECIMENS WITH SPECIAL REFERENCE TO PROSTATIC

HISTOCHEMISTRY is a bonafide research work done by Dr. SUBA.G

Dr. Y.A.MANJUNATHA, M.D

Dr. STANLEY JOHN, M.S(ENT)

Professor & HOD

Rajiv Gandhi University of Health Sciences, Karnataka

It is my privilege to thank my department technicians Mrs.Reeja, Mr.Suresh,

Dr. B. R. Ambedkar Medical college

Background and Objectives:

Interpretation and Conclusion:

Keywords: Nonspecific granulomatous prostatitis, Benign prostatic hyperplasia,

4. MATERIALS AND METHODS

5. OBSERVATION AND RESULTS

1. Diagnostic Criteria of prostatic intraepithelial neoplasia

2. Gleason's microscopic grading system of prostatic carcinoma

3. Distribution of cases according to Histopathological Diagnosis

Distribution of cases according to Age Group.

5. Age wise distribution of cases according to Histopathological

6. Mean Age (yrs) of cases according to Histopathological Diagnosis.

7. Distribution of Prostatic Intraepithelial Neoplasia in different cases

8. Different Microscopic patterns of HGPIN

9. Distribution of cases of Prostatic Adenocarcinoma according to

10. Distribution of Prostatic Adenocarcinoma cases based on Tumour

11. Expression of p63 immunostaining in different cases

12. Expression of P504S immunostaining in different cases

13. Comparison of incidence of NSGP

14. Comparison of incidence of BPH

15. Comparison of age wise distribution of BPH

16. Comparison of mean age of BPH

17. Comparison of p63 positivity in BPH

18. Comparison of P504S negativity in BPH

19. Comparison of incidence of HGPIN in TURP specimens

20. Comparison of association of LGPIN with BPH and Adenocarcinoma

21. Comparison of Association of HGPIN with BPH and Adenocarcinoma

22. Comparison of microscopic pattern of HGPIN

23. Comparison of p63 expression in HGPIN

24. Comparison of P504S Expression in HGPIN

25. Comparison of incidence of adenocarcinoma

26. Comparison of age incidence of carcinoma prostate above 65 years