Prostate carcinoma- pathology and staging

1. PATHOLOGY AND STAGING OF PROSTATIC NEOPLASIA
Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai
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2. MODERATORS:
Professors:
 Prof. Dr. G. Sivasankar, M.S., M.Ch.,
 Prof. Dr.A. Senthilvel, M.S., M.Ch.,
Asst Professors:
 Dr. J. Sivabalan, M.S., M.Ch.,
 Dr. R. Bhargavi, M.S., M.Ch.,
 Dr. S. Raju, M.S., M.Ch.,
 Dr. K. Muthurathinam, M.S., M.Ch.,
 Dr. D.Tamilselvan, M.S., M.Ch.,
 Dr. K. Senthilkumar,M.S., M.Ch.
DEPT OF UROLOGY, GRH AND KMC, CHENNAI. 2

3. CLASSIFICATION
 Adenocarcinoma (acinar)
 Carcinoma with spindle cell
differentiation - carcinosarcoma,
sarcomatoid carcinoma
 Prostatic intraepithelial neoplasia
(PIN)
 Ductal adenocarcinoma
 Urothelial tumours
 Squamous tumours
 Adeno squamous carcinoma
 Squamous cell carcinoma
 Basal cell tumours
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4.  Neuroendocrine tumours
 Endocrine differentiation within
adenocarcinoma
 Carcinoid tumour
 Small cell carcinoma
 Paraganglioma
 Neuroblastoma
 Prostatic stromal tumours –
Stromal tumour of uncertain malignant
potential,
Stromal sarcoma
 Mesenchymal tumours
 Leiomyosarcoma
 Rhabdomyosarcoma
 Chondrosarcoma
 Angiosarcoma
 Malignant fibrous
histiocytoma
 Malignant peripheral nerve
sheath tumour 4
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5. Haemangioma Chondroma
Leiomyoma Granular cell tumour
Haemangiopericytoma Solitary fibrous tumour
Hemato lymphoid tumours
 Lymphoma
 Leukaemia
Metastatic tumours
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6. PROSTATIC INTRAEPITHELIAL NEOPLASIA
 Architecturally benign prostatic acini or ducts lined by cytologically
atypical cells
 SUBCLASSIFICATION
 Low-grade PIN (LGPIN)
 High grade PIN (HGPIN)
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7. LG PIN
 Current recommendation – pathologist should not comment on
LGPIN.
WHY?
 Cannot reproducibly distinguish between LGPIN and benign prostate tissue
 No greater risk of having carcinoma on repeated biopsy than are men with a
benign biopsy finding
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8. HG PIN
 Precursor to CA prostate
1.Increase in the size and number of HGPIN foci in prostates with cancer
2.Increasing amounts of HGPIN - greater number of multifocal CA’s
3.Biomarkers and molecular changes show similarity between HGPIN and
carcinoma
4.About 20% of HGPIN lesions harbor a TMPRSS2:ERG fusion gene
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9. CLINICAL IMPORTANCE
 Incidence of HGPIN – 4-5%
 Precursor to peripheral zone intermediate to high grade tumors
 LGPIN & HGPIN Diff – Prominent nucleoli
 The mean risk of cancer is 26.4% on subsequent biopsy within a year
following the diagnosis of HGPIN(not significant)….
 HGPIN in Single core
 Perform repeat bx 3 years
 Repeat biopsy within 1yr – unnecessary in absence of other clinical CA
indicators (DRE,PSA,TRUS)
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10.  HGPIN on >2 cores -
 Risk approx. same as an atypical suspicious for carcinoma
 Follow-up warranted – serum/ urine test repeat biopsy ( within 1
year)
 Repeat biopsy - sample the entire prostate with relatively increased
sampling of the initial sextant site where the HGPIN was found
 SIGNIFICANCE OF HGPIN ON TUR
 Not clear
 Elderly – No further work up
 Younger – aggressive work up to r/o clinically significant tumor
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11. HG PIN
Cytologically atypical cells with
prominent nucleoli
Architecturally benign gland
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12.  PINATYP - HGPIN with adjacent small atypical glands
 Risk of carcinoma - 40% (same as atypical suspicious of carcinoma)
 require immunohistochemistry for basal cell markers
 Repeat biopsy within 6 months.
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13. INTRADUCTAL CARCINOMA OF PROSTATE (IDC-P)
 Architectural or cytologic atypia that clearly exceeds that seen in HGPIN.
 Frequently associated with high-grade cancer and poor prognostic parameters
at radical prostatectomy.
 90 % chances of malignancy on repeat biopsy
 Patients with IDC-P only on biopsy - definitive therapy ( EAU – repeat biopsy)
 Borderline between IDC-P and HGPIN - Repeat biopsy
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14. ADENOCARCINOMA
 85%– nonpalpable > posterior portion in peripheral zone
 15% - predominantly anterior tumors, some in transition zone, anterior horn
of peripheral zone
 Anterior prostate tend to have better prognosis and less seminal vesicle
involvement than tumour located posteriorly
 Multifocal in >85%
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15. SPREAD OF TUMOR
 Lacks a discrete histologic capsule - extraprostatic extension
 Peripherally located adeno CA’s of the prostate - perineural space invasion
 EPE preferentially occurs posteriorly and posterolaterally
 Seminal vesicle invasion - a tumor extends into the muscle wall of the seminal
vesicle
 Local spread – rarely involves rectum
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16. SEMINALVESICLE INVASION
 Most common route - tumor penetration out of the prostate at the base
of the gland  extension into the periseminal vesicle soft tissue
seminal vesicles.
 Direct extension (less commonly)
 Through the ejaculatory ducts
Almost never are there discontinuous metastases to seminal vesicle
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17. METASTATIC SPREAD
 Lymph nodes
 Bones
 Lungs
 Other – bladder, liver, adrenal gland
 Lung Metastatic lesions - Usually multiple small nodules or diffuse
lymphatic spread
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18. TUMOR VOLUME
 Size correlates with its stage
 EPE is uncommon in tumors < 0.5 cm3
 Tumors < 4 cm3 uncommonly show lymph node metastases or seminal
vesicle invasion
 Tumor volume is also proportional to grade
 Transition zone tumors extend out of the prostate at larger volumes
than do peripheral zone tumors because of their lower grade and
greater distance from the edge of the gland. 18
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19. TUMOR GRADE
 Dr Donald Gleason
 Gleason score devised in 1960’s • Most powerful predictor of prognosis
on biopsy
 Gleason scoring system – based on glandular pattern > at low
magnification
 No role of cytological features
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20.  Original Gleason system – most common & second most common grades
combined
 Updated & modified (2005)
> most common + highest grade
>> < 5% of Gleason grade 2 or 3 not to incorporated
>>> Gleason score of 2-4 not to be reported
WHY 1) graded higher as reviewd by uropathology expert
2) poor reproducibility
3) not necessarily a/w favourable finding at radical prostatectomy 20
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21.  RP specimen
> Most common with second most common combined
>> < 5% involvement to be discarded
>>> Mention tertiary higher grade if present, even if < 5 %
>>>> recommended to assign separate grade to each dominant tumour
nodule
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22. GLEASON GRADING SYSTEM 2014
Pattern 1
 Circumscribed nodule of
closely packed but
separate glands
 uniform,rounded to oval,
medium-sized acini (larger
glands than pattern 3) 22
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23. GLEASON GRADING SYSTEM 2014
Pattern 2
 Fairly circumscribed,minimal
infiltration at edge of tumor
nodule
 Glands are more loosely
arranged and not quite as
uniform 23
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24. GLEASON GRADING SYSTEM
Pattern 3
 Discrete glandular units
 Typically smaller glands than
seen in pattern 1 or 2
 Infiltrates in and among non-
neoplastic prostate acini
 Marked variation in size and
shape
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25. GLEASON GRADING SYSTEM 2014
Pattern 4
 Fused microacinar glands
 Ill-defined glands with poorly
formed glandular lumens
 Large cribriform glands
 Hypernephromatoid
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26. GLEASON GRADING SYSTEM
Pattern 5
 No glandular differentiation,
composed of solid sheets,
cords, or single cells
 Comedocarcinoma with
central necrosis surrounded
by papillary,cribriform,or
solid masses
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27. GLEASON’S GRADE GROUP
only individual descrete well formed glands
predominantly well formed glands with lesser component
of poorly formed/fused/cribriform gland
Predominantly poorly formed glands with lesser
component of well formed gland
-poorly formed/fused/cribriform/glands or
-predominantly well formed gland and only lesser
component lacking glands
-predominantly lacking glands and second most common
component of well formed glands
lack gland formation( or with necrosis) with or without
poorly formed/fused/cribriform glands
 Grade Group I - < 6
 Grade Group II – 3+4
 Grade Group III – 4+3
 Grade group IV – 8
 Grade groupV – 9-10
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28. GLEASON SCORE CAN BE USED FOR
 Pathologic stage
 side-specific EPE
 EPE into the neurovascular bundle
 progression after radical prostatectomy
 candidates for brachytherapy
 prognosis after radiotherapy
 candidates for active surveillance
 intervention criteria following active surveillance
 Prognosis following cryotherapy
 Prognosis following high-intensity focused ultrasound (HIFU) and
candidates for focal therapy
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29. Lymph Node Metastases: It is related to the clinical stage, preoperative
PSA level, and biopsy grade
Margin:
- MC -Apex
- 50% of men with positive margins progress after RP but adjuvant
radiation therapy depend on extent of positive margins and the grade of
the tumor at the margins
vascular invasion –poorer prognosis
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30.  SV invasion
• Extraprostatic Extension
• Focal or non-focal
• Degree co-relates with BCR and risk of progression after RP
• SV invasion> much more prognostic value > Poorer prognosis (65% 5
year progression)
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31. Perineural invasion inTRUS Bx
• Possible route of extraprostatic spread
• Higher incidence of EPE seen
• Prognostic in men undergoing EBRT > Brachy
Perineural invasion in RP
• Very common > NOT PROGNOSTIC
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32. Treatment Effect
• Gleason score should not be used ( artifactuary higher grade)
• Radiation atypia in benign prostate gland > persists for upto 72 months
• Cryotherapy and HIFU results in infarction of benign and malignant
prostate tissue and if residual cancer is seen > no t/t effect present >
gleason score can be assigned
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33. SUBTYPES OF ADENOCARCINOMA
Mucinous adeno CA
- behaves like usual prostate carcinoma
- not more aggressive
- RXWith RP
Small cell CA
 50% - A/W adenocarcinoma of the prostate
 Poor prognosis > average survival < 1 year
 Not assigned Gleason grade
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34. Prostatic duct adenocarcinoma
 I: 0.4-0.8% arise from prostatic ducts
 5% - both ductal and acinar differentiation
 From large primary periurethral prostatic ducts - exophytic lesion into the
urethra, most commonly in and around the verumontanum  obstructive
symptoms or hematuria.
 Often underestimated clinically - DRE and serum PSA levels may be normal
 Regarded as Gleason pattern 4 - cribriform morphology
 Exceptions:
 PIN like duct adenocarcinoma – Gleason 3
 Ductal adenocarcinoma with comedonecrosis – Gleason 5
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35. Primary squamous carcinoma
 Rare
 Poor survival
 Osteolytic metastases
 Do not respond to hormonal therapy
 More commonly squamous differentiation occurs in primary & metastatic
deposits of adenocarcinoma treated with estrogen therapy
Sarcomatoid carcinoma ( carcinosarcoma) reported within the prostate>>
carries dismal prognosis
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36. Mesenchymal tumors
 0.1-0.2%
 Most frequent – Rhabdomyosarcoma  almost exclusively in childhood
 Most common in adults – leiomyosarcomas
 Spindle cell lesion –at any age- closely resembles leiomyosarcoma>>
inflammatory myofibroblastic tumor
 STUMP – prostatic stromal tumors of uncertain malignant potential
 Indolent
 Unpredictable behaviour
 Close follow-up & consideration of definitive resection in younger
individuals
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37. INTRADUCATAL Urothelial carcinoma
 I: 1-4% -PCa
 Propensity to infiltrate bladder neck & surrounding tissue in >50%
 20% - distant metastases to bone(osteolytic), lung, liver
 More commonly involves prostatic ducts & acini in pt with H/o CIS of
bladder treated with intravesical chemotherapy 37
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38.  Direct extension from the overlying urethra, which is usually involved by
CIS
 Direct invasion from bladder urothelial carcinoma into the stroma of the
prostate
Urothelial carcinoma involving the prostate is substaged into
 pT1 - invasive carcinoma involves the suburethral tissue
 pT2 -CIS involving prostatic acini with prostatic stromal invasion.
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39. ADENOCARCINOMA VS UROTHELIAL CARCINOMAS
Adenocarcinoma
 95% – PSA staining
 Other newer prostate specific
marker for adenoca – P501S
(prostein) & NKX 3.1
Urothelial carcinoma
 CK7
 CK 20
 GATA 3 – most sensitive &
specific
 Others – uroplakin,
thrombomodulin, p63
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40. Lymphoma MC- Chronic Lymphocytic Leukemia
Metastasis to Prostate
- Lymphomas, Leukemias
- Adenocarcinomas of the lung
- Melanoma, Seminoma
- Malignant rhabdoid tumors
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41.  Differential Diagnosis
IHC can be used
• Benign > + for p63 and HMWCK
• Malignant > AMACR,TMPRSS2:ERG fusion
Adenosis (Atypical adenomatous hyperplasia)
• D/D for low-grade cancer
•TZ of prostate, Multifocal
• No increased risk for cancer
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42. SUMMARY
 Most common visceral malignancy in men with second leading cause of
cancer-related deaths
 Both genetics and environment are important in the origin and evolution
of prostate cancer
 LGPIN should not be commented on in diagnostic reports
 Regardless of the serum PSA level, all patients with an initial atypical
diagnosis on needle biopsy should undergo repeat biopsy
 Gleason grade, whether it is assessed on needle biopsy,TUR, or radical
prostatectomy specimens, remains one of the most influential prognostic
factors
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43. STAGING OF CA PROSTATE
 Historical -Whitmore and Jewett staging system
 Commonly used - TNM staging
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47.  Predicting tumor extent > Combined use of pre-treatment parameters
- S. PSA
- DRE
-Gleason Score
-Imaging
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48. PREDICTING TUMOR EXTENT
PSA level and Tumor Extent
< 4ng/mL - 80% organ confined
4-10ng/mL - 66% organ confined
>10mg/mL - < 50% organ confined
LN involvement
• PSA > 20 ng/mL - 25 %
• PSA > 50 ng/mL - 75 %
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49. DRE
Positive DRE - Risk of high grade (GS 8-10) tumor
DRE increases PPV of S.PSA
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50.  COMBINED STAGING
 Risk Stratification
• D’Amico risk groups
• CAPRA Score - Cancer of the Prostate Risk Assessment score – disease free survival
(PSA, Gleason score,T stage, age at diagnosis, ethnicity)
 Assessment of LN mets
• Roach Formula
1) Risk of positive LN - ( 2/3 x PSA + {Gleason score – 6 }x 10
2) Risk of SV invasion = PSA ( 10 X {gleason score -6 })
3) Positive capsular penetration = ( 1.5 x PSA + (10 X gleason score -3 )
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51.  Briganti Nomogram
- Preoperative PSA
- Clinical stage at mpMRI ( organ confined, extracapsular extension, SV
invasion)
- Maximum lesion diameter at mpMRI
- Biopsy grade group at mpMRI targeted biopsy
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52. IMAGING
 What to assess?
 T stage - To detect extraprostatic extension
 N stage
• Current indications for LN staging
- cT3 or higher
- > 10% nomogram probability of LN mets
 M stage
• T1 + PSA > 20ng/mL • T2 + PSA > 10ng/mL
• cT3 or cT4 disease • Gleason 8-10
• Symptomatic patients
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53. T STAGING
TRUS
• No more accurate than DRE in predicting organ confined disease
• Cannot differentiateT2 fromT3
mpMRI
• Most useful
• T2W imaging
• Low sensitivity, hence not recommended for Low risk patients
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54. N STAGING
CT/MRI
• LN’s with short axis > 8mm in pelvis, >10mm outside pelvis ---Malignant
• Sensitivity < 40%
• Not recommended in low-risk patients
• Lymphotropic MRI - Uses paramagnetic nanoparticles
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55. Nuclear imaging
• 11C- or 18F-choline PET/CT
• 68Ga- or 18F-labelled PSMA PET/CT
• ProstaScint Scan
- Indium 111 capromab pendetide scan
- MAB to PSMA
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56. M STAGING
99mTc-Bone scan has been the most widely used method
18F-NaF PET or PET/CT - similar specificity, superior sensitivity to bone
scan
Diffusion-weighted whole-body and axial MRI are more sensitive than
bone scan
68Ga-PSMA PET/CT - Initial results show very good sensitivity and
specificity
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