Pathology

1. Journal club
Prepared by: Dr. Ashish Adhikari
NAIHS,2nd Year Resident

3. Article details
• Authors: Okubo Y, Sato S, Hasegawa C, et al.
• Published date: Feb 3, 2023.
• Published place: Kangawa Cancer Center, Yokohama, Japan
• Published site: Elsevier Human Pathology (2023)
• DOI: https://doi.org/10.1016/j.humpath.2023.01.008

4. Content
• Introduction
• Aim
• Materials and methods
• Results
• Discussion
• Conclusion
• Take home message
• Critical analysis

5. Introduction
Number of prostate cancer patients is increasing worldwide and accurate diagnosis and
understanding of pathophysiology of this cancer are essential.
A prostate biopsy is particularly important for definitive diagnosis and grading.
The highest-grade group is significant factor for prognosis and decision of treatment
strategies.
Specific morphologic features such as Cribriform structure and Intraductal carcinoma of
prostate (IDC-P) have been widely recognized as poor prognostic factors.

6. Introduction
However, it is not fully understood whether these specific morphologic features, if only
partially observed in HE stained prostate biopsy specimen affect other prognostic factors.
Therefore, they have summarized characteristics of biopsy specimens associated with the
cribiform pattern and IDC-P.

7. Contd…
 In this study,
Cribiform pattern:
• Sheet arrangement of epithelial
cells with lumen punched out and
majority of epithelial cells not in
contact with intervening
capillaries or stroma, according to
ISUP classification. Only, presence
of cribriform pattern was evaluated
without distinguishing between
large and small cribriform patterns.
 IDC-P: Lesion meeting following
three criteria:
 Continuous or discontinuous
basal cell layers observed in HE
stained specimens.
Adenocarcinoma showing a solid
or dense cribriform pattern.
In the same core, invasive and
proliferative adenocarcinoma
observed adjacent to IDC-P.

9. Contd…
 Both cribiform pattern and IDC-P were considered positive even if
only a portion of cores was identified, regardless of number, amount,
or percentage of cores that could be confirmed.
 The Cribriform pattern is categorized as Gleason pattern 4, and
whether or not to include IDC-P findings in GG/Gleason Grade is
controversial with a report staining that IDC-P area should not be
included in GG determination.

10. Contd…
 In contrast, there was a positive response at the ISUP conference to the
proposal that IDC-P with invasive cancer should be included in the grading.
 In this study, it was decided that cases with Cribriform pattern only in
IDC-P area should also be categorized as having a cribriform pattern.
 However, regarding IDC-P area, they did not include it in assessment of
GG components because it is controversial.
 In addition, cases in which radical prostatectomy was conducted at their
institution after biopsy, were selected to obtain data, such as final GG in
radical prostatectomy specimens, tumor size and the presence or absence
of lymph node metastases, extra-prostatic extension, resection margin
and lympho-vascular invasion.

11. AIMS
 To study the clinicopathological significance of the presence or absence of
the cribiform pattern and IDC-P regardless of their percentage and number of
cores

12. Materials and Methods
Study Design and Characteristics:
 Type of study: Retrospective study
 No. of cases: 850 prostate biopsy cases
 Center: Department of Pathology, Kanagawa Cancer Centre,2-3-2, Nakao, Asahi,
Yokohama, Japan
 Time period: May 2021 to November 2022

13.  Inclusion Criteria:
 TRUS-guided systematic
10 region needle biopsy
 Diagnosed with
Adenocarcinoma
 Exclusion Criteria:
 MRI-TRUS Biopsy
 Diagnosed with Small Cell
Carcinoma,Sarcoma, other
tumours,post hormone
therapy cases and cases with
no tumours detected.

14. Materials and Methods
Various clinicopathological data were extracted;
Age
Serum PSA
Body mass index
GG
Number of biopsies obtained
Number of positive cores(number of tissue specimen with confirmed cancer cells)
Number of highest GG core
Lesion length of the highest GG core
Presence or absence of necrosis
Presence or absence of cribriform pattern and IDC-P

15. Materials and Methods
Basic Conditions for Statistical Analysis :
The Kolmogrov-Simrnov test was first used to confirm normality in the analysis of
continuous variables.
To evaluate the relationship of continous variables;
If the normal distribution was confirmed T-test
If otherwise, Mann Whitney U Test

16. Materials and Methods
To evaluate the correlations between continous variables;
If the normal distribution was confirmed Pearson’s Correlation
Coefficient
If otherwise, Spearman’s Rank Correlation
Chi-square test was used to analayse categorical variables.
In addition, Multivariate logistic regression analysis was used when dependent variable was
categorical variable. P<0.05 was considered significant difference.
All statistical analyses were conducted using IBM SPSS Statistics.

17. Materials and Methods
 Statistical analysis using data obtained from Biopsy Specimens:
 Univariate analaysis was conducted for data obtained from biopsy specimens.
Factors affecting the cribiform pattern and IDC-P were extracted by multivariate logistic
regression analysis.
Dependent variable was the presence or absence of the cribiform pattern and IDC-P.
 Age , Serum PSA value, BMI,
 Number of biopsies obtained,
 Number of positive cores, Percentage of positive cores,
 Highest GG, Number of highest GG core,
 Lesion length of the highest GG core and
 Presence or absence of the cribiform pattern and IDC-P

18. Materials and Methods
Statistical analysis using Data from Biopsy and Surgical Specimens:
 Univariate analysis was performed on clinicopathological data obtained from surgical
specimens only (Tumour size, presence or absence of lymph node metastases, EPE, RM
and LVI ) for presence or absence of cribriform pattern or IDC-P in biopsy specimens,
respectively.
Further analysis was conducted using multivariate logistic regression analysis.
Specifically, conclusive GG and presence or absence of cribiform pattern or IDC-P in
biopsy specimens were used as dependent variables, and variable that exhibited significant
differences in the above univariate analysis were used as explanatory variables.

19. Compliance with Ethical Standards:
Study was conducted in accordance with principles of Declaration of Helsinki and
approved by the Ethics Review Committee of the Kanagawa Cancer Centre(approval
number : 2019-36; June 26, 2019)
Informed consent was obtained from all participants.

20. Results
Reviewed 850 prostate biopsies diagnosed as Prostatic Adenocarcinoma
259 cases(Kangawa Centre) 591 cases(From other centre)
 The specimens from other hospitals were re-reviewed using a virtual slide system.
 Out of 850 cases, 125 cases underwent Radical Prostatectomy.

21. Results

22. Results

23. Results

24. Results

25. • Total Cases: 316 IDC ( Current study)
• Krishan et al
Results
Presence of cribriform patterns, IDC-P in biopsy specimens was risk factor for increased GG,
lymphnode metastasis, EPE, and LVI and significantly increased tumor size.

26. Results

27. Discussion
In this study, both cribriform pattern and IDC-P increased in frequency as GG
increased; however, difference was that cribriform pattern exceeded 10% at GG3,
whereas IDC-P was less frequent than the cribriform pattern overall and was more easily
confirmed from GG4. Further statistical analysis showed that the cribriform pattern and
IDC-P were each a risk factor independent of each other, suggesting a relationship
between them.
Showed concordance with the study done by Chen et al 2016 and McNeal et al 1985
on the study Intraductal Carcinoma of Prostate: from obscure to significant and
Cribriform adenocarcinoma of Prostate, respectively.

28. Discussion
 Other independent risk factors for biopsy specimens were cribriform pattern for the
lesion length of the highest GG core and IDC-P for the number of highest GG cores.
Further analysis is required; however, it is worth noting that it is not a simple number of
positive cores or the longest lesion in the biopsy specimen but the number of cores
showing highest GG and length of lesion.
 Showed concordance with study done by Okubo Y et al 2016 who also stated that both
lesion length of Highest GG core and number of highest GG core in biopsy specimens
were significant factor for tumor size in radical prostatectomy specimens as well as
improving GG concordance rate between biopsy and radical prostatectomy specimen.

29. Discussion
 Positive cores exhibiting the highest GG in biopsy
specimens are more likely to indicate a
representative lesion of the tumor.
Chen et al 2016
 Important to have a larger number of cores, with
longer lesion lengths for more accurate diagnosis
and potential resources for future novel studies,
include tissue base analysis. This reveal
importance of detecting cribriform pattern and
IDC-P which are considered poor prognostic
factors.
Ida et al 2021
Basourakos et al
2021
Showed concordance with this study

30. Discussion
In this study, odds ratio for number of biopsies obtained for IDC-P was less than 1.
Therefore, they examined number of biopsies obtained for cases with high serum PSA
values (>100 ng/mL in this study), which clinicians considered highly malignant before
biopsy, and found that only significantly fewer biopsies were obtained than the overall
mean (Mann-Whitney U test, P < 0.001).
It is presumed that number of biopsies obtained does not reduce chances of IDC-P
identification but only reflects fact that high-risk cases were originally biopsied in small
numbers.
This study postulated the use of MRI targeted biopsy for efficient methods showing
concordance with the study done by Ahdoot et al 2020 and Shoji et al 2019.

31. Discussion
Multi-variate logistic regression analysis showed that the presence of the cribriform
pattern and IDC-P in biopsy specimens were both independent risk factors for the high
GG and lymph node metastasis in radical prostatectomy specimens.
 Incidence of cribriform pattern
and IDC-P increase as GG
increases.
 Both the cribriform pattern and IDC-P
may be predictors of lymph node
metastasis, regardless of percentage
or number of cores, using only HE-
stained specimens without
immunostaining.
 In this study, 9 cases were positive for LN metastasis so, its reasonable to interpret the
cribriform pattern and IDC-P in biopsy specimen as strong predictors.

32. This study focused on clinical significance of the cribriform pattern and IDC-P, which can
be easily diagnosed by pathologists in their routine work. Therefore, even least presence
of the cribriform pattern and/or IDC-P was regarded as positive, and cribriform patterns
were not distinguished as large or small.
Moreover, IDC-P was diagnosed only with HE-stained specimens, and not with any special
immunostaining for basal cell markers such as 34bE12 or p63. Thus, it is indeniable that
subtle lesions might have been missed or the sensitivity was poor due to HE-stained only
biopsy specimens.
This study postulated that we should emphasize cribriform patterns and IDC-P
diagnosed in routine work with HE stained biopsy specimen regardless of percentage or
number of cores.

33. Discussion
IDC-P area was not included in the GG determination in this study, but IDC- P area, especially
those showing a cribriform pattern, might be included in the GG determination. However, further
discussion is needed.
Meanwhile, incidence of necrosis was approximately six times higher in cases showing cribriform
lesions , and this was significantly higher in the univariate analysis, but not in the multivariate
analysis. In contrast, necrosis and IDC-P were not significantly related in both univariate and
multivariate analyses.
 Presence of cribriform pattern in biopsy
specimen as poor prognostic factor regardless
of its size with no difference in clinical
outcomes between large and small cribriform
pattern in biopsies
Hafner et al 2020
Rijstenebrg et al 2022

34. LIMITATIONS
This study had used ISUP classification and previous literature as reference for the
cribriform pattern and IDC-P, however exact definitions are controversial.
Solid growth was not included in this study.
As prostate biopsy specimens from other hospitals were included, so biopsy technique
and number of cores obtained were not the same. Therefore, the percentage of the
cribriform pattern and IDC-P, as well as number of cores in which they were found were
not calculated.
Most cases analyzed were recent, no data were available on the clinical and prognosis of
disease.

35. Conclusion
Cribiform pattern and IDC-P incidence increased with increasing GG, IDC-P is
infrequent overall and usually identifiable from more or equal to GG4.
The presence of the cribriform pattern and IDC-P in a HE-stained biopsy specimen was a
significant factor indicating lymph node metastasis, regardless of the percentage or
number of cores.

36. Take Home Message
Presence of cribriform pattern and IDC-P provide valuable information in biopsy
specimens, regardless of percentage or number of cores, and should be included in
pathology report, at least for its presence or absence.
Further validation is required to establish the extent to which detailed information on
the Cribriform pattern and IDC-P (such as the percentage, number of cores confirmable
and the presence of necrosis) should be described in routine pathology reports to
predict poor prognosis other than lymph node metastasis more accurately.

37. Thank you

38. High grade PIN
• Essential:
- Crowded, stratified atypical secretory cells in
preexisting normal sized or expanded glands ; enlarged,
hyperchromatic and sometimes pleomorphic nuclei,
conspicuous nucleoli; basal layer present but often
discontinuous.
- Absence of necrosis, marked nuclear pleomorphism
and brisk mitotic activity are features that distinguish
it from IDC.

39. Intraductal carcinoma of prostate
• Expansile epithelial proliferation in the preexisting
duct-acinar system; lumen- spanning solid, cribriform,
and / or comedo patterns, loose cribriform or
micropapillary patterns with enlarged pleomorphic
nuclei; residual basal cells.
• Desirable: IHC demonstrating at least partial basal cell
retention.