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PROSTATE CANCER: PATHOLOGY & TNM STAGING

Adenosis

Characteristically found in the transition zone
Not associated with increased risk of harboring or developing adenocarcinoma of the prostate

Prostatic intraepithelial neoplasia (PIN)

Classified into low-grade PIN and high-grade PIN
- Low-grade PIN
  - Diagnostic reports should not comment on low-grade PIN since pathologists cannot reproducibly distinguish between low-grade PIN and benign tissue
- High-grade PIN (HGPIN)
  - Precursor lesion to many peripheral intermediate to high-grade prostate cancers; however, PIN is not necessary for cancer to arise
    - Biomarkers and molecular changes show similarity between HGPIN and carcinoma
      - ≈20% of HGPIN lesions harbor the TMPRSS2:ERG fusion gene, a common molecular abnormality detectable in ≈50% of prostate cancers
    - Low-grade cancers are not closely related to HGPIN
  - Size and number of HGPIN foci are increased in prostate cancer compared to benign prostates
  - Increasing amounts of HGPIN is associated with cancer multifocality
  - Likelihood of cancer diagnosis on subsequent biopsy within a year following the diagnosis of HGPIN: 26.4%; not significantly higher than the risk of cancer on repeat biopsy after a benign diagnosis, which ranges from 10-25%
Diagnosis and Evaluation
- PSA levels are not increased, since elevated PSA is due to disrupted prostate epithelium, which does not occur with PIN
Management of HGPIN
- Because of the lack of large studies on its long-term risk of cancer and the potential medicolegal consequences of not following up on an HGPIN diagnosis, it has been suggested to repeat biopsy with timing based on number of cores demonstating HGPIN:
  - 1 core: 3 years following a diagnosis of HGPIN
  - ≥ 2 cores: within 1 year following a diagnosis of HGPIN
    - Associated with a sufficiently high risk of subsequent cancer
- If a repeat biopsy is performed, it should sample the entire prostate with relatively increased sampling of the initial sextant site where the HGPIN was found
- The significance of HGPIN on TUR pathology is not clear

Atypia

Findings suggestive of, but not diagnostic of, carcinoma; also described as atypical small acinar proliferation (ASAP)
- Small glands, consistent with cancer, are noted, but in an insufficient number to confirm the diagnosis of prostate cancer.
The incidence of atypical needle biopsy specimens is ≈5%
Likelihood of cancer diagnosis after finding atypia on biopsy is ≈40-50%, much higher than HGPIN
Management
- Consider expert review to attempt to resolve the diagnosis as either definitively benign or malignant before subjecting the patient to repeat biopsy
  - Cases diagnosed as atypical have the highest likelihood of being changed on expert review
- All patients with an initial diagnosis of atypia or ASAP on needle biopsy should undergo a repeat biopsy, typically within 6 months, regardless of the serum PSA level

Prostate Adenocarcinoma

Location

Most (85%) cancers arise from the peripheral zone
- Majority of cT1c tumors are in the posterior or posterolateral region
Multifocal in >85% of cases

Spread of the tumour

Because the prostate lacks a discrete histologic capsule, extra-prostatic extension (EPE), rather than capsular invasion or penetration, is the preferable term to describe a tumor that has extended out of the prostate into the periprostatic soft tissue
EPE preferentially occurs posteriorly and posterolaterally, paralleling the location of most adenocarcinomas.
- Transition zone tumors require larger volumes than peripheral zone tumors for comparable rates of EPE and/or distant metastases
Most frequent sites of metastasis (in descending order):
1. Lymph nodes
2. Bone
3. Lung
4. Bladder
5. Liver
6. Adrenal gland

Histology
- Malignant glands lack basal cells and this differentiates them from benign glands.
  - The basal cells can be labeled with high-molecular-weight cytokeratin and TP63
- Grade
  - The Gleason system is based on the glandular pattern of the tumor at relatively low magnification
  - Architectural patterns are identified and assigned a grade from 1 to 5, with 1 being the most differentiated and 5 being undifferentiated
    - Pattern 1: Circumscribed nodule of closely packed but separate, uniform, rounded to oval, medium-sized acini (larger glands than pattern 3)
    - Pattern 2: like pattern 1, fairly circumscribed, yet at the edge of the tumor nodule there may be minimal infiltration; glands are more loosely arranged and not quite as uniform as Gleason pattern 1
    - Pattern 3: discrete glandular units; typically smaller glands than seen in Gleason pattern 1 or 2; infiltrates in and among non-neoplastic prostate acini; marked variation in size and shape
    - Pattern 4: fused microacinar glands; ill-defined glands with poorly formed glandular lumens; large cribriform glands; cribriform glands; hypernephromatoid
    - Pattern 5: Essentially no glandular differentiation, composed of solid sheets, cords, or single cells, comedocarcinoma with central necrosis surrounded by papillary, cribriform, or solid masses
  - Prior to 2005, Gleason score was the sum of the most common and second most common grades. In 2005, the International Society of Urological Pathology (ISUP) revised the scoring and it differed for biopsy and radical prostatectomy specimens; for biopsy specimens, Gleason score is the sum of the most common pattern and highest grade; it was felt important to include the higher grade because the biopsy likely underestimates the burden of high grade tumour. For radical prostatectomy, there was no consensus on if Gleason score should be sum of the first and second most common pattern or similar to biopsy specimens. Some pathologists now use tertiary pattern to describe a small component of a third, usually more aggressive, pattern
    - Gleason score 2 to 4 on needle biopsy should not be assigned a diagnosis of prostate cancer
    - The pathologic definition of Gleason score 6 has changed over time and the contemporary Gleason score 6 have better prognosis
  - In 2014, ISUP adopted a new grading system to replace the previously used Gleason score system
    - Grade Group 1 (Gleason score ≤6) – Only individual discrete well-formed glands
    - Grade Group 2 (Gleason score 3+4=7) – Predominantly well-formed glands with lesser component of poorly- formed/fused/cribriform glands
    - Grade Group 3 (Gleason score 4+3=7) – Predominantly poorly-formed/ fused/cribriform glands with lesser component of well-formed glands (for cases with>95% poorly-formed/fused/cribriform glands or lack of glands on a core or at RP, the component of <5% well-formed glands is not factored into the grade and should be 4+4).
    - Grade Group 4 (Gleason score 4+4=8; 3+5=8; 5+3=8): Only poorly-formed/fused/cribriform glands OR Predominantly well-formed glands and lesser component lacking glands (poorly-formed/fused/cribriform glands can be a more minor component) OR predominantly lacking glands and lesser component of well-formed glands (poorly-formed/fused/cribriform glands can be a more minor component.
    - Grade Group 5 (Gleason scores 9-10) – Lacks gland formation (or with necrosis) with or w/o poorly formed/fused/cribriform glands
      - UrologySchool.com Summary: in general, most common and second most common (if second most common >5% of tissue)
    - Advantages
      1. Grade group 1 patients could be reassured that they have the lowest tumor grade possible
      2. Separates Gleason score 7 into Gleason 3+4 and 4+3, consistent with differences in prognosis
      3. Unified approach for biopsy and prostatectomy specimens

Staging

Clinical staging is the assessment of disease extent using pre-treatment parameters (DRE, PSA values, needle biopsy findings, and radiologic imaging)
Patthologic stage is determined after prostate removal and involves histologic analysis of the prostate, seminal vesicles, and pelvic lymph nodes if lymphadenectomy is performed.
TNM Staging (AJCC 8th edition§)
- T staging
  - TX: Primary tumor cannot be assessed
  - T0: No evidence of primary tumor
  - T1
    - cT1a: tumour incidental histological finding in ≤5% of tissue resected
    - cT1b: tumour incidental histological finding in >5% of tissue resected
    - cT1c: tumour identified by needle biopsy (e.g. because of elevated PSA)
    - pT1 does not exist; if a patient undergoes radical prostatectomy, cT1a to cT1c are converted to pT2 or pT3 if the tumor is organ confined or shows extraprostatic extension, respectively
  - T2
    - cT2a: tumour involves ≤ 1/2 of one lobe
    - cT2b: tumour involves > 1/2 of one lobe, but not both lobes
    - cT2c: tumour involves both lobes
      - cT2 staging is based on DRE findings only, not imaging

pT2: organ-confided disease
- Subdividing pT2 disease has no prognostic significance
- PT2x means that the tumor is organ confined everywhere in the prostate except in the area of the positive margin where EPE cannot be assessed because there is an intraprostatic incision and the edge of the prostate is not visualized in this area

T3: palpable tumor beyond prostate
- cT3a: extra-prostatic extension (unilateral or bilateral)
- cT3b: tumour invades seminal vesicle(s)
- pT3a: extra-prostatic extension (unilateral or bilateral) or microscopic invasion of bladder neck
  - Bladder neck invasion has not been associated with any independent increased risk of recurrence following radical prostatectomy§
- pT3b: tumour invades seminal vesicle(s) (specifically muscle wall of the seminal vesicle)
T4: tumour invades external sphincter, rectum, bladder, levator muscles or pelvic wall

N staging
- N(+) Involvement of regional lymph nodes
- NX Regional lymph nodes cannot be assessed
- N0 No lymph node metastases
- N1 Regional lymph node metastasis
M staging
- M(+) Distant metastatic spread
- MX Distant metastases cannot be assessed
- M0 No evidence of distant metastases
- M1 Distant metastases
  - M1a Involvement of non-regional (outside of pelvis) lymph nodes
  - M1b Involvement of bones
  - M1c Involvement of other distant sites (liver, lungs, brain, etc.)

Assessment of Prostate Biopsy Specimens

Prognostic factors (3):
1. Grade and tumor extent, generally predict adverse findings in the radical prostatectomy specimen
  - However, as a result of sampling error, favorable findings on needle biopsy do not necessarily predict favorable findings in the radical prostatectomy specimen
  - Factors associated with upgrading from the needle biopsy to the radical prostatectomy (4):
2. Intraductal carcinoma
  - Associated with high-grade cancer and poor prognostic parameters at radical prostatectomy
  - Patients with intraductal carcinoma only on biopsy should be treated with definitive treatment
3. Perineural invasion

Assessment of Radical Prostatectomy Specimens

Prognostic factors (7):
1. Lymph node involvement
  - Poor prognostic factor, associated with a high risk of distant disease.
  - The 15-year biochemical–recurrence-free, metastases-free, and cancer-specific survival for men undergoing radical prostatectomy with positive nodes is 7.1%, 41.5%, and 57.5%, respectively.
2. Grade group
  - 5-year post-operative biochemical relapse-free survival by grade group::
    - Grade group I: 97%
    - Grade group II: 88%
    - Grade group III: 70%
    - Grade group IV: 64%
    - Grade group V: 34%
3. Tertiary high-grade pattern
  - The grade group should be recorded along with a note stating whether there is a tertiary high-grade pattern.
  - Associated with increased risk of biochemical recurrence
4. Vascular invasion
5. Extent of EPE (focal vs. non-focal)
  - Associated with the risk of progression after radical prostatectomy
6. Seminal vesicle invasion
  - Poor prognostic factor, associated with a high risk of distant disease.
  - 5-year progression rate after surgery: 65%
7. Positive margins (malignant tissue present at resection margin)
  - Mean rate of positive margins from RALP is 15%
  - Only ≈50% of men with positive margins progress after RP
  - Most studies show that margin length does not affect the risk of recurrence, although one conflicting study exists
  - Factors that can aid in the decision as to whether or not to administer adjuvant radiation therapy are the extent of positive margins and the grade of the tumor at the margins, and these factors have been shown to be prognostic
Non-prognostic factors

Tumor volume
- Correlates well with pathologic stage and Gleason grade in clinical T2 cancers; however, it is not an independent predictor of cancer progression once grade, stage, and margins are accounted for
Perineural invasion
- Very common in a radical prostatectomy specimen
- Not prognostic and should not be included in the pathology report
  - Recall that perineural invasion on biopsy specimen was associated with risk of EPE

Assessment of Adenocarcinoma with Treatment Effect

Endocrine therapy
- Results in atrophic changes with squamous metaplasia in the prostate
- Grade often appears artifactually higher
Radiation therapy of the prostate
- May either show no recognizable difference from non-radiated cancer or may show the effects of radiation damage
Pathologists should not assign a Gleason score to carcinomas with treatment effect

Other histologic subtypes of prostate cancer

Neuroendocrine/anaplastic phenotype
- Small cell prostate cancer is a rare form of extrapulmonary high-grade neuroendocrine carcinoma
  - Accounts for <0.5% to 1% of all prostate cancers
- Rapidly growing disease with the following clinical characteristics should prompt evaluation for the neuroendocrine/ anaplastic phenotype (4):
  1. Brain metastasis
  2. Pelvic masses
  3. Visceral involvement
  4. Osteolytic metastasis with hypercalcemia (associated with high serum PTHrP)
- Diagnosis and Evaluation
  - Labs:
    - PSA
      - Despite evidence of rapid disease progression, neuroendocrine/anaplastic tumors either stop expressing PSA in the presence of major tumor progression or even have undetectable PSA levels at the time of this transformation.
    - Biopsy
      - It has been suggested that biopsies of disease sites in patients with clinically aggressive disease and relatively low serum PSA levels may demonstrate evidence of a neuroendocrine phenotype
      - Not assigned a Gleason grade
    - Serum chromogranin A and urine serotonin metabolites might be detected
- Management
- Prognosis
  - Despite high initial response rates with chemotherapy and radiation treatment, the prognosis of these patients remains poor and is dependent on various factors, including extent and location of metastases.
  - In general, survival is < 12 months.
Prostatic duct adenocarcinomas

0.4-0.8% of prostatic adenocarcinomas arise from the periurethral prostatic ducts.
Usually grow as an exophytic lesion in the urethra.
Can give rise to either hematuria or obstructive symptoms; often both are present.
More likely to present with advanced stage and a lower PSA§
- Usually underestimated clinically because serum PSA levels and DRE are often normal.
Agressive; most should be regarded as grade group 4 because of their shared morphologic features with Gleason score 8 acinar adenocarcinoma and a similar prognosis

Pure primary squamous carcinoma
- Rare
- Agressive, associated with poor survival
Mucinous prostate adenocarcinomas

Not more aggressive than non-mucinous prostate cancer
- Behaves like usual prostate carcinomas, including a propensity to develop bone metastases with advanced disease.
Treated by radical prostatectomy

Urothelial carcinoma of the Prostate
Sarcomas
- Account for 0.1% to 0.2% of all malignant prostatic tumors
Leukemia and lymphoma

Questions

What is the next step in management in a patient with atypia on prostate biopsy? HG PIN? Adenosis?
What is the significance of perineural invasion on prostate biopsy specimen? Radical prostatectomy specimen?
Describe the TNM staging of prostate cancer

Answers

What is the next step in management in a patient with atypia on prostate biopsy? HG PIN? Adenosis?
- Atypia: repeat biopsy within 6 months
- HG PIN: repeat biopsy in 3 years if single core, within 1 year if 2 or more cores
- Adenosis: benign pathology, repeat based on clinical indicatiosn (PSA, positive DRE)
What is the significance of perineural invasion on prostate biopsy specimen? Radical prostatectomy specimen?
- Biopsy: associated with increased incidence of EPE
- Prostatectomy: non-prognostic
Describe the TNM staging of prostate cancer
- See above

Next Chapter: Diagnosis and Evaluation

References

Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 110