Prostate cancer – overview & epidemiology

Most common non skin cancer in males.

Up to 1 in 8 men (12.5 %) will be diagnosed in their lifetime.

Up to 1 in 40 men (2.5 %) will die from prostate cancer.

Second leading cause of cancer death in men in Aust (5^th worldwide)

In Aust:

• Incidence / number of diagnoses peaked 2009
• Incidence rates increase with age to a peak at 70 – 74, then decrease
• There may be slightly worse mortality rates in rural and remote Australians
• Lower incidence/diagnosis in Indigenous Australians, but perhaps poorer survival

Incidental prostate cancer:

• 20 – 25 % or more at radical cystoprostatectomy
• 5 – 10 % at TURP
• Autopsy systematic review – 20 – 40 % aged 50 – 70, to a prevalence of 59 % by 80 years

Geographic distribution:

• Wide variation between areas
• Highest incidence in Aust/NZ and North America, followed by Western and Northern Europe – age-standardised rates around 100 / 100 000
  • Largely due to PSA testing and ageing populations
• Incidence much lower in Eastern and South-Central Asia – age-standardised rates 5 – 10 / 100 000
• Mortality rates vary less, but are higher in populations of African descent and lower in Asia

Risk factors:

Both genetics and environment play a role in the development of prostate cancer.

The main definitive proven risk factors for prostate cancer are:

• Age
• Family history & genetic predisposition
• Ethnicity

There are many proposed associations with developing prostate cancer but none have been definitively proven and currently there are no definitive modifiable risk factors.

Ethnicity

• African-Americans and Jamaicans of African descent have the higher rates of prostate cancer incidence in the world, and at least twice as high mortality.
• Thought to be multi-factorial – partly biologically more aggressive, partly social (different screening and treatment patterns)
• Men with Asian backgrounds who are born in the US have a lower incidence of prostate cancer than white Americans, but a higher incidence compared to men of their background born in Asia

Family History

• Whilst only 5 – 10 % of prostate cancers are thought to be truly hereditary in nature or caused by high risk inherited factors, there is a definite increase in risk in men with relatives with prostate cancer.
• Relative risk increases with number of affected family members, degree of relation, and younger age at diagnosis.
• First degree relative – 2 x risk
• 2 x first degree relatives – at least 4 x risk

Proposed associations (EAU guidelines)

Vasectomy	“Disproven” 2017 meta-analysis
Metformin	“not advised as preventive measure”
Tomatoes/lycopenes	Trend towards favourable effect in meta-analyses – no significance decrease in incidence in RCTs
Meat	No association in meta-analysis
Vitamin D	U shaped association – low and high vit D levels associated with increased CaP risk
Vitamin E/selenium	Association with low nail selenium/vit E levels and aggressive CaP – but selenium and vitamin E supplementation had no effect on incidence
Testosterone	“Hypogonadal men receiving T supplements do not have an increased risk of CaP”
UV exposure	Decreased risk 0.91 HR
Circumcision	Small protective association
Higher ejaculatory frequency	>21 / month vs 4-7 – associated lower risk
“The current body of evidence will not support a causal relationship between dietary or other factors and development of prostate cancer” “Consequently, no effective preventative strategies can be suggested”

5-ARIs & prostate cancer

PCPT:

• 18 000 men; 9000 available for results; normal DRE and PSA < 3 ; biopsy at 7 years, or if PSA > 4 / abnormal DRE
• 25 % reduction in overall prostate cancer in men taking finasteride vs placebo
• Most of the reduction in cancer was of Gleason 6 cancers
• Of the cancers found, there was a higher prevalence of Gleason 8 – 10 cancers in the finasteride group
• ? smaller prostate secondary to finasteride increased the chance of finding the higher risk cancer
  • Higher rates of upgrading to Gleason 7 + in those who underwent RP for Gleason 6 or less
• 15 year follow up – no difference in overall survival between groups (including subgroup analysis of those diagnosed with cancer)

REDUCE:

• Included 6700 men with a negative biopsy 6 – 12 months before enrolment
• Dutasteride reduced risk of prostate cancer by 23 % over 4 years
• No overall difference in detection of Gleason 7 – 10 cancers over the study period, there was an increased risk for Gleason 8 – 10 in years 3 – 4 in the dutasteride group

Prostate cancer – pathology

High grade prostatic intraepithelial neoplasia (HGPIN)

Architecturally benign prostatic acini or ducts, lined by cytologically atypical cells.

Incidence of 4 – 5 % on biopsies (subjective finding based on nucleolar prominence). Risk of cancer (pre MRI studies):

• 20 – 30 % risk of cancer on subsequent biopsy within 1 year – not different to negative/normal biopsy
• 80 % of cancers detected on repeat biopsy are Gleason 6
• > 2 cores with HGPIN may be higher risk

Considered pre-malignant.

HGPIN can occasionally mimic intraductal carcinoma; consider specialist pathology review if concerns.

Atypical small acinar proliferation (ASAP)

Focus of atypical glands on a biopsy specimen which is quantitatively or qualitatively insufficient for definitive diagnosis of prostate cancer.

Risk of cancer (pre MRI data)

• 40 – 60 % of men with ASAP on biopsy will have cancer on repeat biopsy
• 80 – 90 % of subsequent cancers are Gleason 6, and they are usually in the same area as the ASAP

The emergence of MRI and active surveillance for low risk prostate cancer has meant the significance of these findings is much less.

EAU guideline – “In a contemporary series of biopsies the likelihood of finding a csPCa after follow-up biopsy after a diagnosis of atypical small acinar proliferation and high-grade prostatic intraepithelial neoplasia (PIN) was only 6-8%, not significantly different from follow-up biopsies after a negative biopsy”

Non adenocarcinoma cancer

Rare, < 5 %

• Urothelial carcinoma
• Small cell carcinoma
• Sarcoma

Adenocarcinoma of the prostate

Location:

• 70 % in the peripheral zone
• 20 % transition zone
• Approximately 15 % can be considered “anterior tumours” either in the TZ or anterior horns of peripheral zone.
• May be multifocal in up to 85 % of cases

Spread:

• Extraprostatic extension preferentially occurs posteriorly and posterolaterally
• Seminal vesicle invasion is often penetration out of the gland at the base, into and through peri-vesicular soft tissue and into the SVs
  • Direct spread via ejaculatory ducts is rare. Separate deposits in SV is very rare.
• Local extension to rectum is rare
• Extension into the trigone in advanced disease and can cause ureteric obstruction
• Most common sites of metastases are lymph nodes then bones

Volume:

• Size of tumour generally correlates with stage
• EPE uncommon in tumours < 0.5 cm³
• Nodal or SV invasion uncommon in tumours < 4.0 cm³

Diagnostic criteria for cancer

• Prostate adenocarcinoma does not have a basal cell layer (normal prostate glands do)
• Increased cellularity with crowded cells, often enlarged nuclei and cytoplasm
• Cancer stains positive for PSA/PAP. Basal cells stain positive for HMWK.
  

Gleason Grade

Based on the glandular pattern of the tumour at relatively low magnification. Cytologic features play no role in Gleason grading.

Graded from 1 – 5; with 5 being the most poorly or undifferentiated.

Gleason score is obtained from adding two numbers:

• On biopsy – the most common pattern + second most common pattern (or higher grade pattern if present even in small amount – i.e. only 5% pattern 4, should still be 3+4)
• On radical – the most common pattern + second most common pattern

Gleason score on biopsy has validated significance for:

• Pathological stage
• EPE
• Recurrence or progression after surgery or radiation
• Candidacy for surveillance or brachytherapy
• Prognosis after focal therapy
  

3	Discrete, well formed glands
4	Poorly formed, fused or cribriform glands
5	Sheets or cords, single cells, solid nests, necrosis

ISUP Grade Group

Has been validated in terms of prognostication and is in common use since 2014.

ISUP/WHO Grade group	Gleason score
1	Gleason 6 (or lower)
2	Gleason 3+4=7
3	Gleason 4+3=7
4	Gleason 8
5	Gleason 9 – 10

What is clinically significant prostate cancer?

EAU – ISUP grade 1 disease bears the hallmarks of cancer histologically, but does not behave in a clearly malignant fashion (0.28 % EPE, no SVI/LNI reported).

ISUP grade 1 disease can be described as clinically insignificant, but should be observed not ignored, as it may progress or be undersampled at biopsy, subsequently becoming significant.

ISUP grade 2 disease is commonly used as threshold for clinically significant, but there is no clear consensus.

Radical prostatectomy prognostic features

• Gleason score / ISUP grade group correlates well with biochemical recurrence risk
• Tertiary high grade increases risk of BCR
• LN + (7 % BCR-free at 15 years if lymph node positive)
• EPE – focal (few glands outside prostate) or nonfocal (more extensive)
• SVI – 65 % progression rate at 5 years
• Positive margins (although 50 % positive margins don’t progress)
  • Intraprostatic incision
  • Extent/length of positive margin
  • Grade of tumour at margin
• Tumour volume has not been shown to provide prognostic information independently

Treatment effect – Gleason score should not be assigned for cancer with histologic treatment effect (i.e. post hormones or radiation).

If there is cancer present without treatment effect, this can be graded.

Other subtypes:

Intraductal carcinoma:

• Architecturally and cytologically atypical proliferation of epithelial cells within pre-existing ducts and acini
• EAU – “an extension of cancer cells into pre-existing prostatic ducts and acini, distending them, with preservation of basal cells”
• Often associated with higher grade disease and poorer prognosis
• May occasionally look like HGPIN on biopsies (similar cellular atypia, but HGPIN has architecturally benign glands)
• Occasionally seen on biopsies in the absence of usual type acinar adenocarcinoma – 90 % repeat biopsies will show adenocarcinoma, usually higher grade. Treatment justified.

Ductal carcinoma

• 0.4 – 0.8 % adenocarcinoma arises from the prostatic ducts
• Represents a distinct morphologically different subtype (cf. acinar) – previously called endometrioid
• May grow from primary prostatic ducts exophytically into urethra and cause haematuria or retention
• Poorer prognosis, higher rates of recurrence and poorer survival
• Should be graded as Gleason 4
• Often non PSA producing
• May be more avid on FDG PET cf. PSMA

Small cell

• Aggressive with average survival < 1 year
• Do not assign Gleason grade
• Treated with chemotherapy

Other

• Urothelial carcinoma
  • Reportedly 1 – 4 % of non adenocarcinomas of the prostate
  • Propensity to invade bladder neck and soft tissue – often T3/T4 at diagnosis
  • 20 % of patients present with distant metastases
  • More often it is CIS of the bladder spreading into prostatic ducts rather than primarily arising in prostatic urethra
• Sarcoma
  • 0.1 – 0.2 %
  • Rhabdomyosarcoma – almost exclusively in childhood
  • Leiomyosarcoma – in adults
• STUMP
  • Stromal tumour of uncertain malignant potential – usually non aggressive but cases exist of rapid re-growth after resection, or co-existence or transformation to sarcoma
• SCC
• Lymphoma / leukaemia (usually secondary cf. primary)