Immunophenotypic Characterization of Benign and Malignant Prostatic Lesions Original Article Col R Lakhtakia

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Original Article
Immunophenotypic Characterization of Benign and
Malignant Prostatic Lesions
Col R Lakhtakia* , Col R Bharadwaj+, Col VK Kumar# , P Mandal** , Brig SK Nema++
Background: Biopsy diagnosis is the gold standard for differentiating benign and malignant prostatic enlargements. This study
was aimed at supplementing biopsy diagnosis with immunophenotypic characters of prostatic lesions.
Methods: Twenty five cases each of nodular hyperplasia and adenocarcinoma prostate were compared for their morphologic
appearances and immunophenotyping, by studying antibodies to prostate specific antigen (PSA), transglutaminase, chromogranin
and high molecular weight keratin, proliferating cell nuclear antigen, cell death (apoptosis) and neovascularisation (CD 34).
Results: Markers of differentiation (PSA and transglutaminase) aided recognition of higher-grade tumours. PSA negativity
avoided metaplasia being overcalled as carcinoma. Loss of basal cells around malignant prostatic acini as determined by high
molecular weight keratin (HMWK), was useful in foci of atypical small acinar proliferation and in prostatic intraepithelial
neoplasia. Assessment of proliferation indices identified subsets of tumours, within conventional morphologic Gleason’s grades,
with a higher growth fraction. Cell death determination and study of tumour vessels did not offer any improvement on morphology.
Conclusion: Immunophenotypic assessment helps in refining morphologic diagnosis of prostatic lesions. Differentiation and
proliferation markers objectively assess tumour characteristics with their biologic growth potential and are recommended for
diagnostic use.They also help in assessement of response to therapy.
MJAFI 2007; 63 : 243-248
Key Words: Immunophenotyping; Prostate; Benign; Malignant
odular hyperplasia of prostate (NHP) is a common
disorder of men increasing from 20% at 40 years,
to 90% by the eighth decade of life. Prostatic carcinoma
is the second highest cause of cancer related deaths
amongst men in America [1]. In India, it constitutes
about 4% of all male cancers [2]. Though 90% of such
lesions may not manifest clinically in the lifetime of the
host [3], occult carcinoma may present with extensive
dissemination to bones and other organs. Digital rectal
examination (DRE), transrectal ultrasound (TRUS) and
serum prostate specific antigen (PSA) constitute
complementary techniques for early detection [4,5].
However, biopsy remains the gold standard for final
diagnosis [6]. There is a growing recognition that
prostatic carcinoma is predated by an ‘in situ’ ‘prostatic
intraepithelial neoplasia’ (PIN) by atleast 10 years [7].
The diagnosis of the spectrum of preneoplastic and
neoplastic lesions is being rendered more objective by
the use of immunohistochemistry for phenotyping and
prognosticating biologic behaviour. These include
markers of differentiation like prostate specific antigen
(PSA) and chromogranin, functional alterations
(transglutaminase), loss of basal cell layer around glands
(high molecular weight cytokeratin HMWCK),
proliferative potential (cell-cycle associated proteins like
proliferating cell nuclear antigen (PCNA) [8,9], cell death
(apoptosis)) and tumour microvasculature (CD 34) [10].
This study was undertaken to assess the pathologic
features and determinants of prostate cancer in Indian
patients that would provide an insight into its appearance
and behaviour.
Material and Methods
Fifty cases of prostatic enlargement, presenting to the
Army Hospital R&R, formed the study group. Clinical
symptoms and signs, DRE, TRUS and PSA levels were
recorded. Histological diagnosis separated two groups into
25 cases each of nodular hyperplasia prostate (including other
benign lesions) and adenocarcinoma prostate.
The quantitation of core biopsies, transuretheral resection
of prostate (TURP) chips and radical prostatectomy specimens
was done followed by routine formalin-fixation, paraffinembedding and staining with haematoxylin and eosin (H&E).
Periodic acid Schiff and mucicarmine were used in selected
cases (for glycogen and mucin). The immunohistochemical
Senior Advisor (Pathology), Command Hospital (CC), Lucknow. +Senior Advisor (Pathology), Command Hospital (SC). # Senior Advisor
(Pathology), Military Hospital Dehradun. ** Post graduate trainee (Path), Army Hospital (R&R), Delhi Cantt. ++Dy Comdt, Command
Hospital (CC), Lucknow.
Received : 11.07.2005; Accepted : 22.12.2005
Lakhtakia et al
staining [11] was carried out by the labeled streptavidin-biotin
method using monoclonal antibodies and kits (DAKO
Corporation, USA). Antibodies to PSA, transglutaminase,
chromogranin, HMWCK (34 ?E 12), PCNA, and CD 34 Class
I were used. Positive staining for PSA, transglutaminase and
chromogranin was observed as cytoplasmic staining of
prostatic epithelial cells. HMWCK stained the basal cells,
PCNA was seen as nuclear brown staining and CD34 stained
endothelial cells. The detection and quantification of
apoptosis was based on labelling of DNA strand breaks
(TUNEL technology).
On histopathological findings morphologic patterns of
hyperplasia, metaplasia, PIN and adenocarcinoma, Gleason’s
grade, spread and TNM staging were recorded. The following
immunophenotypic features were used:
(a) PSA: A semi-quantitative score from 0-4+ .
(b) HMWCK: for detection of basal cells around prostatic
(c) Transglutaminase for decreased expression.
(d) Chromogranin for neuroendocrine differentiation.
(d) CD 34 to stain endothelial cells for MVD.
(e) PCNA counts: PCNA =
labelling index (LI):
No. of cells
1000 cells
X 100
The statistical analysis was done by Mann Whitney or
Wilcoxon Two sample test/T-test for normal variance/ Kruskal
Wallis one way analysis of variance as and wherever
The mean age of the patients with NHP was 65.6 years
(range 48-89 years) and of prostatic adenocarcinoma 73.8
years (range 54-93 years) (statistically significant). Carcinoma
was diagnosed on trucut biopsies at a mean age of 68.9 years.
Patients with PIN had a mean age of 70.4 years (range 56-77
years). Symptoms were referable to outflow obstruction of
urine viz. frequency of micturition, hesitancy, dysuria, thin
stream of urine, terminal dribbling and urinary retention. Two
patients with prostatic adenocarcinoma had bony metastases.
Mean duration of symptoms in NHP was 13.2 months (range
1-22 months) and in prostatic carcinoma 11.3 months (4-21
months). The difference was not significant. A suspicious
DRE was recorded in five (20%) NHP and 18 (72%) cases of
carcinoma. TRUS findings were suspicious in 1/9 patients of
NHP and 10/12 patients of cancer. The serum PSA levels in
NHP ranged from 0.85 to 42.4ng/ml (mean value 7.8 ± 0.8) and
in carcinoma prostate from 3.2 to 180 ng/ml (mean 44.5± 45.3).
The difference was statistically significant (Table 1).
Nineteen trucut biopsies, 30 transurethral resection of
prostate specimens (TURP) and one radical prostatectomy
were evaluated and a diagnosis of NHP was made in 25
cases(Fig 1A,B). They also showed metaplasia (transitional,
squamous or mucinous) in six, basal cell hyperplasia in two,
prostatitis in six, atrophy in 10 and atypical adenomatous
hyperplasia (AAH) in one case. In 14 benign cases where
serum PSA was marginally elevated, seven showed significant
inflammation while in others no associated cause for rise
could be detected. Prostatic Intraepithelial Neoplasia (PIN)
(Fig 1C) was seen in four cases associated with prostatic
adenocarcinoma (TURP 3, trucut 1), (3 high grade and 1 low
grade). One low grade PIN (4%) was associated with NHP
Prostatic adenocarcinoma (Fig 1D), was seen in 11 trucut
biopsies, 13 TURP specimens (incidental) and one planned
radical prostatectomy. In TURP the mean percentage of chips
involved was 16.6% (range 9-20) (Stage T1b N0 M0).
Histological pattern in 24 (96%) was acinar while one (4%)
was a signet ring cell adenocarcinoma. Focal mucinous
differentiation was seen in two (8%) cases (<25% of the
tumour area). Perineural invasion was noted in eight (32%)
and vascular invasion in three (12%) cases . Invasion around
parasympathetic ganglia was seen in the radical
prostatectomy. One (4%) was low Gleason’s grade (score 24), 17 (68%) intermediate grade (score 5-7) and seven (28%)
were high-grade tumours (score 8-10). The commonest pattern
was Gleason’s score 3. The PSA range of tumours of different
grades is shown in Table 2. Thirteen (52%) were in stage I
(T1b N0 M0), three (12%) cases in stage I (T1c N0 M0), eight
(32%) cases in stage II (T2 N0 M0) and one (4%) case in
stage III (T3 N0 M0).
Immunophenotypic Characterisation
Tissue PSA staining was intense (4+) in benign lesions
(except atrophic glands). With increasing grade of carcinoma
serum PSA levels rose (Fig. 2A) while PSA staining was patchy
and weak. The staining pattern of PSA and intensity of PSA
expression in different grades of carcinoma is depicted in
Tables 3, 4. Metaplastic epithelia (transitional/squamous) did
not show staining. Chromogranin staining was not detected
in any of our cases (controls being positive).
Transglutaminase staining patterns paralleled the findings
of PSA staining. With increasing grade of tumour i.e. lack of
differentiation transglutaminase activity became weaker,
becoming absent in solid areas and poorly differentiated areas.
Benign acini had a continuous layer of basal cells
Table 1
Serum PSA levels in NHP and Carcinoma prostate
PSA levels ng/ml
NHP n (%)
25 (100)
Carcinoma prostate (%)
23 (100)
Table 2
Relationship of Gleason’s grade with serum PSA levels.
Grade of tumour
Low grade
Intermediate grade
High grade
Serum PSA range
(n=number of cases)
Mean value
3.98 (1)
3.2-110.10 (17)
20.83-180.2 (7)
34.26 ± 37.5
75.29 ± 52.8
p value*
0.02 *
* Mann-Whitney or Wilcoxon two sample test (p value <0.05 was
considered significant)
MJAFI, Vol. 63, No. 3, 2007
Immunophenotyping of Prostatic Lesions
Fig. 1A :
Fig. 1C :
Fig. 1B :
Fig. 1D :
Fig. 1A : Trucut biopsy showing suspicious haphazard glands surrounded by severe inflammation (H&E x 10). Fig. 1B: A focus of atypical
adenomatous hyperplasia (arrow-heads) in nodular hyperplasia (H&E x10). Fig. 1C: High grade prostatic intraepithelial neoplasia
(PIN) with prominent nucleoli. (H&E x 20). Fig. 1D: Poorly differentiated adenocarcinoma prostate (Gleason’s score 4+5) in a trucut
biopsy (H&E x 10)
Table 3
Intensity of PSA staining in benign prostatic lesions and
Table 4
Prostatic adenocarcinoma: PSA expression and its relation
to Gleason’s grade
Intensity of
Intensity of
n (%)
adenomatous Low grade
n (%)
n (%)
High grade
n (%)
22 (88)
3 (12)
1 (100)
2 (100)
1 (33.3)
2 (66.7)
25 (100)
1 (100)
2 (100)
3 (100)
surrounding the prostatic glandular epithelium. In atrophic
glands, though difficult to visualize on H&E, the basal cells
could be visualized by HMWCK (Fig.2B). Basal cell
hyperplasia noted on H&E was better demonstrated with IHC.
In low grade PIN the basal cell layer was continuous. In high
grade PIN there were focal disruptions in 2/3 cases while it
was continuous but with reduced intensity in one. Basal cells
were absent in carcinoma.
Staining for PCNA was heterogeneous, however only the
MJAFI, Vol. 63, No. 3, 2007
Total cases Low grade Intermediate
n (%)
n (%)
grade n (%) grade n (%)
6 (240)
9 (36)
6 (24)
3 (12)
1 (4)
1 (100)
5 (29.4)
8 (47.1)
4 (23.5)
25 (100)
1 (100)
17 (100)
7 (100)
strongly stained nuclei were included in the count (Fig. 2C).
The LI was low in benign lesions with a gradual increase from
PIN to ascending grades of adenocarcinoma (Tables 5 A, B).
The difference of mean LI of NHP vs PIN and PIN vs carcinoma
was statistically significant. The difference in LI between low
grade vs intermediate and high grade carcinoma was
CD 34 staining showed randomly distributed thin walled
vessels in NHP, more concentrated in areas of inflammation
(Fig. 2D). In both trucut and TURP biopsies microvessel
density (MVD) count was erratic (because of crushing in the
Lakhtakia et al
Fig. 2A :
Fig. 2C :
7/26/2007, 2:11 PM
Fig. 2B :
Fig. 2D :
Fig. 2 A: Staining for prostate specific antigen (PSA) in foci of PIN in a background of invasive carcinoma: intensity 3+ to 4+ ( IHC with DAB
x 10). Fig. 2B: Complete loss of basal cells in malignant acini (in contrast entrapped benign acini have an intact basal cell layer
(identified by HMWCK on IHC with DAB x 10). Fig. 2C: Proliferating cell nuclear antigen (PCNA) expression in a prostatic
adenocarcinoma showing a high PCNA LI (IHC with DAB x 10). Fig. 2D: CD 34 stain marks the endothelial cells of vessels
concentrated at the advancing edge of a carcinoma (IHC with DAB x 10).
former and small separate chips in the latter). However
morphological observations showed randomly distributed
vessels in low-grade tumours and accentuation in numbers
Table 5A
PCNA LI in Prostatic lesions
Type of lesion
LI range
Low grade Ca
Intermediate grade Ca 17
High grade Ca
Mean LI
p value*
0.76 ± 0.1} 0.02
3.09 ± 1.7}
12.59 ± 5.5} 0.03
22.02 ± 8.3}
* - p<0.05 considered significant
Table 5B
Prostatic lesions: PCNA LI by IHC
Mean PCNA LI (%)
p value*
0.76 ± 0.1}
3.09 ± 1.7}
14.94 ± 7.7}
< 0.001
Carcinoma prostate
* - p<0.001 is significant
at the advancing edge of high-grade tumours. Apoptotic cells
were occasional in prostatic hyperplasias and metaplasias.
In tumours, apoptotic rate varied from 2.5-12.2/1000 cells (low
grade tumours) to 4-15.5/1000 cells (high grade tumours).
Tumours with solid areas (high grade) showed less apoptosis
compared to better-differentiated areas.
Carcinoma prostate, common among men in the West,
is uncommon in our country ranking seventh and eighth
among male cancers in Bangalore, Mumbai and Delhi
respectively [1,2]. The course of most prostate
malignancies is often unpredictable. Heredity appears
to be the most constant risk factor apart from hormonal
influence [12]. The age specific prevalence of NHP
and adenocarcinoma is remarkably similar with a gradual
increase over 40 years [1]. The mean age of
presentation of our patients was sixth and seventh
decade of life.
TRUS, DRE and PSA levels form the basis for early
detection of prostate carcinoma. In our experience the
MJAFI, Vol. 63, No. 3, 2007
Immunophenotyping of Prostatic Lesions
sensitivity and specificity of TRUS was better than DRE
[13]. The mean serum PSA concentration in healthy
men has been reported to be < 4ng/ml. Up to 43%
patients of NHP have levels of 4-10 ng/ml and 12% >10
ng/ml [14, 15]. In our study serum PSA levels of NHP
had a mean of 7.8 ± 8 ng/ml with 14 cases showing
borderline and three high PSA due to inflammation,
infarcts or instrumentation. PSA may not be the sole
reliable criterion for diagnosis of malignancy as only
about 75% cancers have an abnormal PSA, and 20%
of prostate cancers with aggressive features have levels
< 4 ng/mL (American Urological Association) [16]. In
our series 2/23 cases had normal PSA levels. The
likelihood of cancer above 50 years of age, goes up
from 20 to 30% for levels between 2.5-4.0 ng/mL and
above 4.0 ng/mL respectively [17]. Among benign
lesions, atypical adenomatous hyperplasia (AAH) that
varies in incidence from 19.6% (TURP specimens) to
24% (autopsy series in 20-40 year old men) is a cause
for misdiagnosis [18,19] and we had only one (4%) such
case. Basal cell hyperplasia seen in 2/25 (8%) of our
cases, has a potential for being misdiagnosed as
Bostwick et al [20], proposed the term prostatic
intraepithelial neoplasia (PIN), for an intraluminal
proliferation of secretory cells of the prostatic ductacinar system with atypical cytology, and recommended
its categorization into low and high grade. Many studies
have shown the association of high grade PIN with
prostate cancer [7, 20]. We found PIN associated with
16% of prostate cancers (majority high grade) and only
4% of NHP (low grade). Fenely et al [21], observed
PIN in 11% cases in hospital practice, 20% in prostate
cancer screening and 25% in urology practice. Our study
supports the notion that low grade PIN occurs with NHP
and can be ignored, whereas high grade PIN signifies
coexistence with, or subsequent development of
carcinoma. Our study was dominated by acinar patterns
of prostatic adenocarcinoma . Perineural invasion was
a common finding involving eight (32%) patients while
vascular invasion was seen in only three (12%). Both
connote a poor prognosis.
Gleason’s grading system, based on the degree of
architectural differentiation, is used for behaviour
prediction [22]. In our series there was one (4%) low
grade, 17 (68%) intermediate and seven (28%) high
grade tumours. The commonest pattern had a score of
3. Current clinical and pathological staging (TNM) of
early prostatic adenocarcinoma separates patients into
2 groups: those with palpable and non-palpable tumours
[23] based on DRE which has low sensitivity, specificity
and poor predictive value [4]. Thirteen (52%) cases in
our study were detected on TURP and three (12%)
MJAFI, Vol. 63, No. 3, 2007
cases had only PSA elevation without palpable prostate.
Mai et al [24], showed incidental carcinoma in 8% cases.
He also noted that there was no T1c cases in the nonPSA era but detected 28 such cases when serum PSA
estimation became available.
Immunophenotyping revealed strong PSA staining for
benign lesions as reported by others [8]. In atrophic
glands and foci of inflammation, negativity may raise
the possibility of carcinoma but morphological correlation
solves the issue. PSA staining intensity was directly
proportional to tumour differentiation. In intermediate
grade tumours a subset stained poorly and is likely to be
biologically aggressive. Others have reported similar
findings [8,25]. Transglutaminase expression paralleled
PSA. In NHP, though serum PSA levels were variable,
majority had good PSA staining (88%). In two cases of
prostate carcinoma where PSA levels were < 4ng/ml
and 12 cases where it was 4-10 ng/ml, staining in tissues
was 4+ to 3+. Thus tissue expression of PSA did not
always correlate directly with serum levels. The
discrepancy may be due to differences between the
amount of PSA produced and secreted and/or the
sensitivity of detection of various isoforms [25].
HMWCK, highlighting basal cells was useful in
separating AAH from carcinoma (being consistently
absent in the latter) [26]. It is less useful in PIN. We
improved HMWCK staining by combining antigen
retrieval by trypsin treatment and microwave heating.
Proliferative activity (PCNA LI) was statistically
higher in PIN and adenocarcinoma as compared to
benign lesions and in higher grade tumours. Proliferation
indices have correlated well with grades of tumour [27],
though some have found lower LI. Apoptotic rate was
consistently low in benign lesions and only marginally
higher in PIN. In carcinomas it showed variability. This
may be a reflection of poor cell viability rather than a
protective intracellular signal to control the tumour
burden. However, inhibitors of apoptosis have a direct
bearing on drug resistance by tumour cells [28]. MVD
counts were plagued by erratic staining and reliability
of counting in TURP chips. The close relation of vessels
to foci of PIN (with normal PSA) may be a
neovascularisation promoting survival of this
premalignant stage. There is a suggestion that high
grade PIN that will progress to malignancy may have
higher MVD [10].
Our morpho-immunophenotypic evaluation of
prostatic lesions underscores the sound basis of good
histological evaluation by routine H&E stains. Basal cell
identification is useful in morphologically atypical cases.
High grade PIN should alert the clinician to coexistence
of carcinoma or need for close follow-up because PIN
cannot be suspected by clinical examination, TRUS or
PSA levels. Prognostication can be further enhanced
by corroboration with markers of differentiation and
assessment of proliferation indices. The application of
tumour angiogenesis needs further study to establish
guidelines for significance of counts. Future directions
of prostate biology research are aimed at exploring a
stem cell origin, biological markers for diagnosis and
prognosis besides novel therapeutic approaches targeting
angiogenesis, immunosurveillance and stromal-epithelial
interactions [29,30].
Conflicts of Interest
None identified
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