METHODS
Of 114 isolated HGPIN cases were included; 64 with 6 (1st group) and 50 with 12 cores (2nd group). The
number of cores with HGPIN, laterality, structural PIN subtypes, prominent nucleolus, and nuclear
pleomorphism was examined in the first and follow-up biopsies. The relationship between the results of
follow-up biopsies and clinicopathological findings was evaluated statistically. Furthermore, a systematic
literature review was carried out.
RESULTS
Carcinoma was found in repeat biopsies in 15.6% of the cases in 6-core and 24% of cases with 12-core
biopsies (p=0.006). Carcinoma detection rate was significantly higher in cases with ?2 cores with HGPIN
than in cases with a single core of HGPIN (p=0.007). The rates of carcinoma and persistent HGPIN were
higher in multifocal and bilateral HGPIN cases, compared to unifocal, or multifocal but unilateral cases
(p=0.018). In both groups, prominent nuclear pleomorphism was significantly more common in cases
with carcinoma (p=0.023). The systematic literature review revealed 25.6% of carcinoma risk out of 5580
isolated HGPIN patients.
CONCLUSION
Carcinoma detection rate in repeat biopsies of 12-cores was significantly higher than cases with 6-core
biopsies. The HGPIN cases with ?2 cores, bilaterality, and presence of prominent nuclear pleomorphism
were found to be significant histopathological markers in predicting patients with carcinoma. Close follow-
up of high risk patients with repeat biopsies in addition to clinical parameters was recommended.
Keywords: Bilateral; carcinoma; high grade prostatic intraepithelial neoplasia; multifocal; prostate; prostatic intraepithelial neoplasia
Prostatic intraepithelial neoplasia (PIN) is a
histopathological lesion that accompanies prostate
cancer and is considered a cancer precursor. It is defined
as the limited proliferation of the secretory cells
of the ductal-acinar system of the prostate within the
gland and is characterized by the presence of atypical
cytological features. McNeal and Bostwick first emphasized
the potential malignant nature of this proliferative
change in 1965, and in 1986 they defined the diagnostic
criteria with Bostwick.[
The incidence of isolated HGPIN in initial biopsies
ranges from 0.6% to 24.6%.[
This study including cases with isolated HGPIN
detected in prostate needle biopsies evaluated in two
periods between 1996 and 2005 when 6-core protocol was applied and 2006-2018 when 12-core protocol
was applied in our institution. In patients diagnosed
with isolated HGPIN with one or more follow-up
biopsies in prostate needle biopsies in both periods,
the relationship between the foci of HGPIN and their
histopathological features with the development of carcinoma
was investigated. It was aimed to compare the
clinicopathological findings of the cases of these two
periods in which 6-core and 12-core needle biopsy
protocols were applied. At the same time, a systematic
literature review was conducted to compile the results
of the largest published case series on this subject.
At the first step, 6-core prostate needle biopsies evaluated
between January 1, 1996, and December 31, 2005,
were reviewed in the report archive of our department.
At the second step, 12-core prostate needle biopsies evaluated
and reported between January 1, 2006, and December
31, 2018, were reviewed. Cases with adenocarcinoma,
isolated HGPIN without repeat biopsy, atypical
small acinar proliferation (ASAP), and benign prostate
tissue (BPT) were excluded from the study; and only isolated
HGPIN cases with at least one repeat biopsy were
included into the study (Fig.
HGPIN: High-grade prostatic intraepithelial neoplasia,
BPT: Benign prostate tissue, Re-bx: Re-biopsy, repeated
tru-cut needle biopsy.
Hematoxylin-Eosin stained slides of both initial
and follow-up biopsies of each case were re-evaluated
according to the standard histopathological criteria
accepted for the diagnosis of HGPIN under light microscopy
(Olympus BX50).[
The relationship of histopathological findings
within the groups was evaluated using the Statistical
Package for the Social Sciences 25.0 package program
statistically using Monte Carlo Chi-square and independent
t-tests. If p<0.05, the difference between the
groups was considered significant. Continuous and
categorical variables were defined as mean±standard
deviation and percentage, respectively.
In addition, a systematic literature review was conducted,
including reports of the largest case series (consisting
of at least 100 cases of HGPIN having correlation
results with repeated biopsies). The PubMed database
was searched for the relevant literature between 1990
and 2020. Search terms were "prostate" and "needle
biopsy" and "HGPIN." In addition, a manual search
was performed by reviewing the relevant publications
presented in PubMed and the citations in the related references. Additional articles were found or removed
by manually reviewing the full text and references of
the matching articles. To identify relevant observational
studies, inclusion criteria were as follows: (1) An observational
study design; (2) the definition of the HGPIN
group and the number of cases clearly stated; (3) the
final histopathological malignancy rate in the HGPIN
group was reported; and (4) studies written in English
as a full text publication. Relevant results, including the
total number of prostate needle biopsy, total number
of HGPIN cases, the rate of diagnosis of HGPIN from
prostate needle biopsy, and the rate of final histopathological
malignancy diagnosis in HGPIN, were reviewed
and analyzed in the articles included into the study.
Group I Cases (With 6-Core Biopsy Protocol)
When the 6-core biopsy protocol was applied between
January 1, 1996, and December 31, 2005, a total of
1402 prostate needle biopsies were evaluated. Adenocarcinoma
was diagnosed in 399 cases (28.4%), and
isolated HGPIN was diagnosed in 211 (15%); 17 were
diagnosed with isolated ASAP (1.2%), and 775 (55.2%)
were diagnosed with BPT (Table
Patient age ranged from 48 to 86 years in 64 isolated HGPIN cases in the first group; the mean patient age was 64.4 (SD=8.743). sPSA levels before the first biopsies ranged from 1.1 ng/ml to 20 ng/ml; averaging 7.1 ng/ml. The follow-up period of the patients varied between 1 month and 54 months, and the average follow- up period was 12.4 months.
Carcinoma was detected in ten cases (15.6%) at
repeat biopsies; the presence of isolated HGPIN continued
in 19 cases (29.7%) and 35 cases (54.7%) was
diagnosed with BPT (Table
Multifocal HGPIN was present in 50% of the cases in the first group. The ratio of cases with bilateral HGPIN was also higher (37.5%) in the first group. On the other hand, the ratio of cases with carcinoma detected at repeat biopsies was lower (15.6%) than the expected range in the first group.
The rates of carcinoma and persistent HGPIN were
higher in multifocal and bilateral HGPIN cases compared
to unifocal or multifocal but unilateral cases
(p=0.018) (Table
The difference between the diagnostic groups was
statistically significant (p=0.023) in terms of the presence
of significant nuclear pleomorphism in the glands
in which HGPIN was detected in the first biopsies. The frequency of marked pleomorphism observed in
the group diagnosed with BPT on repeat biopsies was
much lower than the other groups. The distribution of
the presence of prominent nuclear pleomorphism according
to the diagnostic groups is shown in Table
No statistically significant difference was found between the groups with and without carcinoma development in repeat biopsies in terms of the ratio of cores showing involvement with HGPIN in both the first and repeat biopsies, the extent and number of glands containing HGPIN in each core and the ratio of involvement in the gland (p>0.05).
There was no statistically significant difference between the groups with and without carcinoma in terms of HGPIN pattern type either (p>0.05). Considering the types of PIN patterns detected in both the first and second biopsies, a single type (pure) pattern was observed in 65.3% of the cases, and multiple (composite) HGPIN patterns were observed in 34.7% of the cases. One type of PIN pattern was observed in all cases with carcinoma on repeat biopsy. (p=0.013).
Group II Cases (With 12-Core Biopsy Protocol)
During the 13-year period when 12-core biopsy protocol
was applied between 2006 and 2018, 2038 out
of 5323 prostate needle biopsies evaluated in our department
were diagnosed as adenocarcinoma (38.3%),
225 as isolated HGPIN (4.2%), 73 as ASAP (1.4%), and
2987 (56.1%) was diagnosed with BPT (Table
In the cases of the second group, the patient's age ranged from 55 to 94; mean patient age was 73.9 (SD=7.785). The age distribution of patients with carcinoma on repeat biopsy varied between 50 and 90 (mean 70.9; SD: 10.389). No statistically significant difference was found between the patient groups with and without carcinoma on repeat biopsies in terms of mean patient age (p>0.05).
sPSA levels before the first biopsies ranged from 0.3 ng/mL to 44.2 ng/mL; it averaged 9.6 ng/mL. The follow- up period of the patients varied between 1 month and 107 months, and the average follow-up period was 28.7 months.
Carcinoma was detected in 12 cases (24%) at repeat
biopsies. Isolated HGPIN presence continued in
three cases (6%), and 35 cases (70%) were diagnosed
with BPT (Table
Multifocal HGPIN was present in 30% of the cases
and the ratio of cases with bilateral HGPIN was also
lower (14%) in the second group. On the other hand,
the ratio of cases with carcinoma detected in repeat
biopsies was higher (24%) in the second group. In
multifocal and bilateral HGPIN cases, the rates of
carcinoma and persistent HGPIN were higher than
multifocal but unilateral or unifocal cases (p=0.018)
(Table
The difference between the diagnostic groups
was statistically significant (p=0.023) in terms of the
presence of significant nuclear pleomorphism in the
glands with HGPIN detected in their first biopsies.
The frequency of marked pleomorphism observed in
the group diagnosed with BPT in the final biopsy was
much lower than the other groups. The distribution of
the presence of prominent pleomorphism by diagnostic
groups is shown in Table
There was no statistically significant difference between the groups with and without carcinoma development at repeat biopsies in terms of the ratio of cores that showed involvement with HGPIN in both the first and repeat biopsies, the extent and number of glands containing HGPIN in each core, and the ratio of involvement in the gland. There was no statistically significant difference between the groups with and without carcinoma in terms of HGPIN pattern type either (p>0.05).
Comparison of the Findings of the Cases between
the Study Groups I and II
While 28.4% of the cases in the first period in which
the 6-core biopsy protocol was applied were diagnosed
with adenocarcinoma, it was observed that the rate of
adenocarcinoma diagnosis increased to 38.3% in the second period when the 12-core protocol was applied.
While the rate of HGPIN diagnosis in 6-core biopsies
was 15.0%, we observed that the rate of HGPIN in 12-
core biopsies decreased to 4.2%. We did not see any significant
changes in other diagnostic groups (i.e., BPT
and ASAP).
Multifocal HGPIN was present in 50% of the cases in the first group and in 30% of the cases in the second group, the ratio of cases with bilateral HGPIN was also higher in the first group. On the other hand, the ratio of cases with carcinoma detected at repeat biopsies was higher (24%) in the second group than that (15.6%) in the first group.
Carcinoma was detected in repeat biopsies in 10
(15.6%) of the cases in the first group (6 cores) and in
12 cases (24%) with 12-core biopsies (p=0.006) (Table
2). The rate of carcinoma detection in repeat biopsies
was found to be significantly higher in patients with ≤2
cores with HGPIN than the patients with single-core
HGPIN (p=0.007) (Table
HGPIN: High-grade prostatic intraepithelial neoplasia.
Systematic Literature Review
Our systematic review of the literature revealed an
overall malignancy rate of 25.6% (ranging from 13% to 38%) among the largest studies of at least 100
cases with a diagnosis of isolated HGPIN and with
re-biopsy correlation results. In addition, significant
variations were observed in the use of diagnosis of
HGPIN in different centers with reporting rates varying
between 1% and 10%. The studies included (a
total of 5580 cases with repeat biopsy correlation in
the systematic analysis of the largest case series) are
by Herawi et al.,[
The clinical significance of HGPIN is related to its
predictive value as a marker for prostate carcinoma. In
different studies conducted in large case series from
1990 to 2020, the incidence of isolated HGPIN detected
in prostate needle biopsies varies in a wide range
between 0.6% and 24.6%. The average frequency of
HGPIN is 7.7%, with a median of 5.2%.[
After the initial diagnosis of HGPIN, the rate of
prostate carcinoma detection has dropped from 50% to 40% in the early 1990s to 35-20% in later studies. The
change in prostate sampling from the sextant to the
extended or dual sextant protocol has been thought to
be largely responsible for this reduction.[
The lower rates of carcinoma detection in repeat
biopsies performed following the diagnosis of isolated
HGPIN have been thought to be the result of
the biopsy approach aimed at more expanded sampling
(mean 12 cores).[
The probable reason for the higher incidence rates
of isolated HGPIN detected in the first group of our
study is that the biopsies we evaluated were sampled
with the 6-core method. In 2006, the standard sampling
method with ≥12 cores started to be used in prostate
needle biopsies in our hospital. In the first group, the
first biopsies of all ten patients with carcinoma on repeat
biopsy were performed before 2006, and the number of
cores sampled in the first and repeat biopsies of the patients
was 6. However, in our study, while the frequency
of isolated HGPIN cases diagnosed after the standard
12-core sampling method in 2006 and later decreased
as expected; the rate of carcinoma detected on repeat
biopsies has increased and our results partially support
the accuracy of the approach described above. We think
that the significant difference between the mean ages of
the two groups might also be important in this result.
Most of the studies did not report the total number
of patients diagnosed with isolated HGPIN and
the Gleason score of carcinomas detected on followup
biopsies during the study period. Girasole et al.[
Merrimen et al.[
Afterward, Roscigno et al.[
All the above data including ours, demonstrates
the potentially dangerous dilutional effect of labeling
HGPIN as a single entity, and might explain why
HGPIN without stratifying it into unifocal or multifocal
disease was not a predictor of prostate carcinoma in
many studies.
From the histomorphological point of view, the
only detailed histopathological study in the literature
that questions the relationship between the presence
of prominent nuclear pleomorphism and carcinoma
is made by Kronz et al. In their series of 245 cases,
cancer was detected in 33% of the follow-up biopsies
of HGPIN cases with distinctly pleomorphic nuclei.
However, in their study, a statistically significant correlation
could not be demonstrated between the presence
of prominent nuclear pleomorphism and detection
of carcinoma at repeat biopsies in patients with
HGPIN. The detailed histopathologic examination by
Kronz et al.[
In our study, the frequency of significant nuclear
pleomorphism observed in the glands with HGPIN in
their first biopsies was significantly lower in the group
diagnosed with BPT in follow-up biopsies compared to
other diagnostic groups. The frequency of prominent
nuclear pleomorphism in the first biopsies of cases
with persistent HGPIN and carcinoma in repeat biopsies
was significantly higher than in cases with BPT in
repeat biopsies.
In the publications examining the relationship between
the structural pattern in glands with HGPIN and
the risk of carcinoma in follow-up biopsy, the structural
type of the observed patterns was taken as a basis,
and the relationship between the pure or compound
pattern and the risk of carcinoma was not evaluated
separately. In our study, all of the pure and compound
patterns observed in the first and second biopsies were
evaluated in detail of pattern types and frequency; it
was coded according to both the type of structural
pattern and whether the pattern observed was pure or
compound. When the type of structural PIN pattern
was examined, no significant difference was found between
the groups with and without cancer at followup.
In the first group, it was noteworthy that pure PIN
pattern was observed in all cases with tumors found in
follow-up biopsies. In the second group with 12-cores,
a similar relationship could not be demonstrated. In
cases with pure PIN pattern, especially the cribriform
pattern may harden differential diagnosis with cribriform
carcinoma. Again, HGPIN-like ductal adenocarcinoma
may pose difficulties in differential diagnosis.
The differential diagnostic problems are more easily
overcome in recent years with the clarification of the
diagnostic criteria of these entities and the help of immunohistochemical
tests.
On the other hand, persistent HGPIN in repeat
biopsies has been previously reported in 5-43% of
cases. According to Gokden et al.[
The decision to repeat prostate biopsy was at the
discretion of the individual clinician, which is reflected
in the large number of patients that did not undergo
repeat biopsy during the study period. The concern of
increased detection must be weighed against the risk of
missing clinically significant malignancy.
The retrospective structure and the use of biopsy
protocols, which are now known to provide insufficient
sampling of the prostate gland in most of the studies,
are among the limitations of the studies in the literature.
However, the number of cores taken in the first
biopsy is determined by the clinician who is monitoring
the patient and may be affected by various clinical
parameters such as PSA level, prostate volume, or DRE
findings. Saturation biopsy protocols have been well
studied in the repeat biopsy population, particularly in
patients with elevated PSA levels. Increasing the number
of samples and varying the distribution of biopsy
sites has demonstrated a higher cancer detection rates,
varying from 17% to 41% without an increase in clinically
insignificant cancers. For that reasons, saturation
biopsy protocol might be considered for the second
and/or more repeat biopsies in multifocal and bilateral
HGPIN and/or persistent HGPIN cases.
In our systematic literature review, the incidence of
carcinoma on follow-up repeat biopsies ranged from
13% to 38% (average 25.6%) for the largest series after
the initial diagnosis of isolated HGPIN (totally 5580
isolated HGPIN cases with re-biopsies) on prostate
needle biopsy. In these series, variable core numbers
and follow-up intervals have been reported after the diagnosis
of HGPIN on needle biopsy. The length of the
follow-up period and the number of repeated biopsy
sessions might also have affected the rates of carcinoma
detection at repeat biopsy.
Although the necessity and timing of prostate
biopsy after isolated HGPIN diagnosis remains controversial;
current data suggest that increased sampling
in repeat biopsies will enable more detection
of prostate carcinoma in patients with a diagnosis of
HGPIN. Concerns about increased detection of Gleason
pattern score 6 cases must be weighed against the
risk of missing clinically significant malignancies.
When the Gleason pattern scores and Gleason grade
groups of tumors were examined in cases with carcinoma
in repeat biopsies; it was observed that Gleason
pattern score ≥7 (Grade group ≥ 2) tumors, which are
considered more important clinically, constitute 1/3rd
(33.3%) of our cases in 12-core biopsy group.
The conclusions drawn may be somewhat limited
by our relatively small study population and the retrospective nature of our study. However, our data show
that bilateral and multifocal HGPIN carries a significantly
higher risk of carcinoma (25.8%) in repeat biopsies.
In addition to this, a much higher ratio (35.5%)
of both multifocal and bilateral persistent HGPIN has
been re-diagnosed. Therefore, we also believe that sequential
repeat biopsies are necessary in this specific
high-risk population.
It was concluded that in cases with isolated HGPIN in prostate needle biopsies, the number of cores with HGPIN, bilaterality and prominent nuclear pleomorphism within the gland involved with HGPIN are histopathological findings that help to predict patients who will be diagnosed with carcinoma at repeat biopsies; a closer follow-up of cases in which these histopathological features were observed should be recommended with repeat biopsies as well as clinical parameters.
Note: The study was presented orally at the 4th International Hipocrates Congress on Health Sciences on September 25, 2020.
Part of this study was presented as a poster at the 14th Urooncology Congress held in Antalya on November 6-10, 2019.
Some findings of the cases in the first group of this study, although presented in Dr. Gupse Turan's academic thesis; it has not been published before in the same form.
Acknowledgement: The authors thank Professor Dr. Özdal Dillioğlugil and his team for the clinical follow-up of the cases.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved by the Kocaeli University Faculty of Medicine Non-Invasive Research Ethics Committee (No: GOAEK 2020/15.09, Date: 11/09/2020).
Financial Support: None declared.
Authorship contributions: Concept - G.T., S.K.Ö.; Design - G.T., S.K.Ö.; Supervision - G.T., S.K.Ö.; Funding - None; Materials - G.T., S.K.Ö.; Data collection and/or processing - G.T., S.K.Ö.; Data analysis and/or interpretation - G.T., S.K.Ö.; Literature search - G.T., S.K.Ö.; Writing - G.T., S.K.Ö.; Critical review - G.T., S.K.Ö.
