Pathology of prostate

suitable for medical college pathology undergraduates

1. Prostate Pathology
Dr Guvera Vasireddy
Osmania medical college

2. Prostate
The prostate gland is a male reproductive organ whose main
function is to secrete prostate fluid, one of the components of
semen.
The muscles of the prostate gland also help propel this
seminal fluid into the urethra during ejaculation .
One component of prostate fluid an enzyme called Prostate
Specific Antigen (PSA) also aids in the success of sperm by
liquefying semen that has thickened after ejaculation.
This thinning action allows sperm to swim more freely,
according to the medical reference book "Prostate Specific
Antigen" (Informal Health Care, 2001).

3. Prostate and Bladder obstruction
Unfortunately, while the prostate is in a great location for delivering this
important fluid and squeezing things along when the time is right, its
position around the urethra can be a liability if the gland swells or
grows.
A swollen prostate compresses the urethra and irritates the walls of the
bladder, interfering with normal urination.
More than half of men in their 60s suffer from a growth of the prostate called
Benign Prostatic Hyperplasia (BPH), according to the OSU Medical Center.
By age 70 or 80, a man's chance of suffering BPH jumps to 90 percent.
Symptoms include frequent urination, dribbling or leaking urine and a
stuttered or weak stream.
A growing prostate can also signal cancer. It is estimated that more than
200,000 men will be diagnosed with prostate cancer in 2010, according to
the National Cancer Institute.

4. Prostate: anatomy and histology
Prostate weighs 20 grams in normal adult
Retroperitoneal organ ,encircling the neck
of bladder and urethra
Devoid of a distinct capsule
Four distinct zones
Tubulvalveolar organ
Glands lined two layers of cells, basal
cells and columnar secretory cells

5. Adult prostate
The normal prostate contains
several distinct regions,
including a central zone (CZ),
a peripheral zone (PZ), a
transitional zone (TZ), and a
periurethral zone.
Most carcinomas arise from
the peripheral glands of the
organ and may be palpable
during digital examination of
the rectum.
Nodular hyperplasia, in
contrast, arises from more
centrally situated glands and
is more likely to produce
urinary obstruction early than
is carcinoma.

6. Histologically the prostate is
composed of glands lined by
two layers of cells.
A basal layer of low cuboidal
epithelium covered by a layer
of columnar secretory cells.
In many areas there are small
papillary infoldings of the
epithelium.
These glands are separated
by abundant fibromuscular
stroma.
Testicular androgens control
the growth and survival of
prostatic cells.
Castration leads to atrophy of
the prostate caused by
widespread apoptosis.

7. H&E of normal gland HMW keratin stains basal layer

8. Benign Prostatic Hyperplasia BPH
Extremely common lesion in men over age 50
Hyperplasia of glands and stroma
Fairly large ,well delined nodules
20% in men over age 40,up to 70% by age 60,
and 90% by age 70
Related to the action of androgen

9. BPH and the role of DHT
DHT ,Dihydrotestesterone is the ultimate mediator for prostatic growth.
The main component of the “hyperplastic” process is impaired cell death
resulting in the accumulation of senescent cells in the prostate.
Androgens not only increase cellular proliferation, but also inhibit cell death.
The main androgen in the prostate, constituting 90% of total prostatic
androgens, is dihydrotestosterone (DHT).
It is formed in the prostate from the conversion of testosterone by the
enzyme type 2 5α-reductase, located almost entirely in stromal cells;
Epithelial cells of the prostate do not contain type 2 5α reductase, with the
exception of a few basal cells. Thus stromal cells are responsible for
androgen-dependent prostatic growth.

10. Other sources of DHT
Type 1 5α-reductase is not detected in the
prostate, or is present at very low levels.
However this enzyme may produce DHT
from testosterone in liver and skin, and
circulating DHT may act in the prostate by an
endocrine mechanism.
Nodular hyperplasia is not considered to be a
premalignant lesion

11. Mechanism of DTH induced growth
DHT binds to the nuclear androgen receptor (AR) present in
both stromal and epithelial prostate cells.
DHT is more potent than testosterone because it has a higher
affinity for AR and forms a more stable complex with the
receptor.
Binding of DHT to AR activates the transcription of androgen-
dependent genes.
DHT is not a direct mitogen for prostate cells, instead DHT-
mediated transcription of genes results in the increased
production of several growth factors and their receptors.

12. Growth factors
Most important among these are members of the fibroblast
growth factor (FGF) family, and particularly FGF-7
(keratinocyte growth factor;).
FGF-7, produced by stromal cells, is probably the most
important factor mediating the paracrine regulation of
androgen-stimulated prostatic growth.
Other growth factors produced in BPH are FGFs 1 and 2, and
TGFβ, which promote fibroblast proliferation.
Although the ultimate cause of BPH is unknown, it is believed
that DHT-induced growth factors act by increasing the
proliferation of stromal cells and decreasing the death of
epithelial cells.

13. Simplified scheme of
the pathogenesis of
prostatic hyperplasia.
The central role of
the stromal cells in
generating
dihydrotestosterone
(DHT) should be noted.
DHT may also be
produced in skin and
liver by both type 1 and
2 5α-reductase.

14. BPH , Morphology
The prostate weighs between 60 and 100 grams
Enlargement occurs almost exclusively in the inner aspect of
the prostate gland
Nodules ,vary in color and consistency
Histologic hallmark of BPH is nodularity due to glandular
proliferation or dilation and to fibrous or muscular proliferation
Aggregation of small to large and cystically dilated glands
Needle biopsy don’t sample the transitional zone BPH occur

17. Clinical features
The increased size of the gland, and the smooth muscle-mediated
contraction of the prostate cause urethral obstruction.
The increased resistance to urinary outflow leads to bladder hypertrophy
and distension, accompanied by urine retention.
The inability to empty the bladder completely creates a reservoir of residual
urine that is a common source of infection.
Increased urinary frequency, nocturia, difficulty in starting and stopping the
stream of urine, overflow dribbling, dysuria (painful micturition).
Increased risk of developing bacterial infections of the bladder and kidney.
In many cases, sudden, acute urinary retention appears for unknown
reasons that requires emergency catheterization.

18. Management
Decreasing fluid intake, especially before bedtime;
moderating the intake of alcohol and caffeine containing
products; and following timed voiding schedules.
α-blockers, which decrease prostate smooth muscle tone via
inhibition of α1-adrenergic receptors.
Inhibitors of 5-α-reductase.
Transurethral resection of the prostate (TURP).
High-intensity focused ultrasound, laser therapy,
hyperthermia, transurethral electro vaporization, and
transurethral needle ablation using radiofrequency.

19. Prostate cancer

20. Epidemiology
Cancer of the prostate is a disease of men over age 50 and
adenocarcinoma is the most common form.
One in six lifetime probability of being diagnosed with prostate
cancer.
Prostatic cancer is uncommon in Asians and occurs most
frequently among blacks.
Increased consumption of fats has been implicated.
Dietary products suspected of preventing or delaying prostate
cancer development include lycopenes (found in tomatoes),
selenium, soy products, and vitamin D.

21. Prostate Cancer Risk Factors
Established
•Advancing age
•Presence of androgens
•Family history (1
st
degree relative)
•African ancestry
Potential
•High dietary fat
•Obesity
•Inherited mutations (BRCA1 or BRCA2 genes)
•Vitamin D or E deficiency
•Selenium deficiency?

22. Screening Recommendations
•Discuss with the patient and if he decides to be screened
•Annual PSA and DRE
•Age 50-70 yrs (with at least 10 yr life expectancy)
•Begin screening at age 40 if risk factors
•African ancestry
•First degree relative(s) with prostate cancer
•A shared decision-making approach to PSA screening
seems most appropriate

23. Prostate Cancer: Screening with PSA
No clear cut-point between normal and abnormal PSA levels.
Even PSA cut-off of 1.1 ng/ml misses up to 15% of prostate
cancer (The Cancer Prevention Trial – 2003)
Positive predictive value for PSA > 4ng/ml = 30% (i.e. About 1 in
3 men with elevated PSA have prostate cancer detected at time
of biopsy
PPV increases to 45-60% for PSA > 10ng/ml
Nearly 75% of cancers detected in the grey zone (PSA 4-10) are
organ confined; potentially curable.
<50% of prostate cancers organ confined if PSA >10

24. What is PSA (Prostate Specific
Antigen)?
A Serine protease
(enzyme) found in the
prostate
Secreted by prostate
epithelial cells
Found in ejaculate
As diagnostic tool for:
Screening
Staging
Prognostic indicator
Surveillance

25. Other causes of an elevated PSA
1.Age
2.Prostate size (BPH)
3.Infection/inflammation
4.Recent instrumentation (biopsy, catheterization,
etc.)
5.Physiological variation
6.Recent ejaculation

26. Free/Total PSA Ratio:
A Way to Improve Specificity
Prostate cancer maybe
associated with more
protein-bound PSA
(less free PSA) than in
BPH
F/T ratio is lower in
patients with prostate
cancer
Can improve test
specificity
Useful when total PSA
in 4-10 ng/ml range
BPH
Prostate Ca

27. Prostate Cancer Screening: Pros and Cons

28. Charles Brenton Huggins Charles Brenton Huggins (1901–1998)(1901–1998)
Only Canadian-born doctor ever to
receive the Nobel Prize in Physiology or
Medicine.
Nobel Prize received in 1966.
For his discoveries concerning
hormonal treatment of prostatic
cancer.
Born in Halifax, Nova Scotia.
B.A (Acadia)
©The Nobel Foundation©The Nobel Foundation

29. Prostate Cancer: Presentation
Early stages usually asymptomatic
Most cases detected by serum PSA screening
Palpable nodule or firmness on DRE
Advanced stages
Urinary retention/renal failure
Bone pain
Anemia
Weight loss, fatigue
Spinal cord compression

30. Prostate Cancer: Diagnosis
Indications for trans rectal ultrasound (TRUS) guided biopsy
Palpable nodule on DRE
Elevated serum PSA
Biopsy involves 10-18 needle cores taken mostly from the
peripheral zone of the prostate
Transrectal ultrasound alone/CT scan/MRI not sensitive
enough to make the Diagnosis

31. The 2016 and 2004 WHO
classifications of prostatic carcinoma

32. Adenocarcinoma of Prostate
The most common form is
adenocarcinoma
Three variants
1. Acinar adenocarcinoma
2. Intraductal carcinoma
3. Ductal adenocarcinoma

33. Variants of acinar adenocarcinoma (AC) of
the prostate in the 2016 WHO classification

34. Adenocarcinoma: Gross Morphology
70% arises in the peripheral zone of the
gland
Palpable in rectal exam
Gritty and firm
Spread by direct local invasion and
through blood stream and lymph
Local extension most commonly involves
the seminal vesicles and the base of the
urinary bladder

37. Adenocarcinoma
Well defined gland pattern
Histologic diagnosis in some cases is one
of the most chalenges for pathologists
Peri-neural invasion is common and
typical

38. Adenocarcinoma: microscopic
pathology
Well-defined, readily demonstrable gland patterns, that are
typically smaller than benign glands.
Lined by a single uniform layer of cuboidal or low columnar
epithelium.
Cancer glands are more crowded, and characteristically lack
branching and papillary infolding.
The outer basal cell layer typical of benign glands is absent.

39. Adenocarcinoma: microscopic
pathology
The cytoplasm of the tumor cells ranges from pale-clear as
seen in benign glands to a distinctive amphophilic
appearance.
Nuclei are large and often contain one or more large nucleoli.
There is some variation in nuclear size and shape, but in
general pleomorphism is not marked.
Mitotic figures are uncommon.
α-methylacyl-coenzyme A-racemase (AMACR) is up-
regulated in prostate cancer and can be detected by
immunohistochemistry

40. perineural invasion by
malignant glands
malignant glands with enlarged nuclei,
prominent nucleoli, and dark cytoplasm

44. Pseudohyperplastic variant
foamy gland (xanthomatous) variant
mucinous (colloid) adenocarcinoma signet ring cell variant
Other morphological variants

45. Adenocarcinoma
Hematogenous extension occurs chiefly
to the bones
The bony metastasis are typically
osteoblastic .

46. Adenocarcinoma ,Clinical Course
Microscopic cancers are asymptomatic,
discovered incidently
Patients with clinically localized disease
do not have urinary symptoms
Most arise peripherally ,away from
urethra, therefore ,urinary symptoms
occur late.
Prognosis depends mainly on the extent
of the disease at the time of the diagnosis.

47. Prostate Cancer
Prognostic factors
Depends upon grade, stage and
treatment
Early stage/well-differentiated Ca treated
by radical prostatectomy:
 85% + 10 year survival
Metastatic disease
<10% 5 year survival

48. Adenocarcinoma: Gleason’s Grading
Gleason grading system is the best known
for grading
Five grades on the basis of glandular pattern
and degree of differentiation as seen under
low magnification
Grading is of particular important in prostate
cancer, because it is the best marker ,along
with the stage ,for predicting prognosis

49. Adenocarcinoma: Gleason’s Grading
Gleason grade is from 1-5 based on glandular
architecture
Gleason score is the total primary grade (1-5) +
secondary grade (1-5) = 2-10
4-6/10=well-differentiated
7/10=moderately differentiated
>8/10=poorly differentiated

54. Grading and grouping
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 a lesser component of poorly-formed/fused/cribriform
glands.
Grade Group 3 (Gleason score 4+3=7) – Predominantly poorly-
formed/fused/cribriform glands with a lesser component of well-
formed glands.
Grade Group 4 (Gleason score 8) - Only poorly-
formed/fused/cribriform glands or - Predominantly well-formed
glands with a lesser component lacking glands†† or - Predominantly
lacking glands with a lesser component of well-formed glands.
Grade Group 5 (Gleason scores 9-10) – Lacks gland formation (or
with necrosis) with or w/o poorly-formed/fused/cribriform glands.

55. Prostate Cancer:
Staging
Can spread to adjacent organs (seminal
vesicles, bladder), lymph nodes, bone
Most bone mets are osteoblastic
Prior to initiating treatment consider
Bone scan (PSA>10, Gleason Score >7)
CT scan pelvis/abdomen (PSA >10, Gleason
Score >7))
These tests are typically not required in
asymptomatic men with low risk prostate cancer

56. Adenocarcinoma
Grading and Staging
Staging in prostate cancer depends on
the TNM system .
Clinical staging includes combined clinical
and radiological findings and PSA levels.
Pathological staging includes tumor extent
on biopsy and Gleason's grade.
AJCC staging combines the both.

58. Tumor extent

59. N and M
Status of Regional Lymph Nodes (N)
N0 NO REGIONAL NODAL METASTASES
N1 METASTASIS IN REGIONAL LYMPH NODES
Distant Metastases (M)
M0 NO DISTANT METASTASES
M1 DISTANT METASTASES PRESENT
M1a Metastases to distant lymph nodes
M1b Bone metastases
M1c Other distant sites

61. Prostate Cancer – Treatment - Survival
Considerations
Patient’s age
Co-morbid health
conditions
Tumor stage
Tumor grade (Gleason
score)
Often a patient choice
Surgery and

62. Adenocarcinoma
Treatment
Surgery ,radiotherapy ,and hormonal therapy
90% of treated patients expected to live for 15
years
Currently the most acceptable treatment for
clinically localized cancer is radical surgery
Too locally advanced cancers can be treated by
radiotherapy
Hormonal therapy (Antiandrogen therapy) could
induce remission .

63. Early Stage Prostate Cancer
Treatment
Early stage Cancer
1.Radical Prostatectomy
2.External Beam Radiotherapy
3.Radioactive Seeds (Brachytherapy)
4.Active Surveillance
5.Observation – Watchful Waiting

64. Prostate Cancer Treatment:
1. Radical Prostatectomy

65. Advanced Prostate Cancer:
Treatment
Androgen Deprivation
(Hormonal Rx)
Orchidectomy
LHRH analogues
Antiandrogens
Supportive therapies
Analgesics
Steroids
Bisphosphonates/Vitamin D/Calcium
for bone health
Chemotherapy
 Taxotere, Docetaxel
Last line of treatment

66. Osteoblastic Bone Metastases

67. Spinal Cord Compression
Metastatic prostate cancer is a
common cause of spinal cord
compression
Clinical recognition is critical
Signs and symptoms
Back pain
Neurological symptoms in
saddle distribution
Lack of rectal tone, fecal and
urinary incontinence
Paraplegia below the level of
compression
MRI is diagnostic

68. Spinal Cord Compression
Treatment
Emergency decompression laminectomy
by spinal surgeons
Emergency radiation to affected level
Dexamethasone/steroids
Emergency bilateral orchidectomies if
patient not already on androgen
deprivation

69. Prostate Cancer Prevention
Modifiable
Factors
Diet
Saturated fats
Red Meat
BBQ meats
Lifestyle
Exercise
Drug therapy
5 a reductase
inhibitor
Vitamin D

70. Prostate Cancer Prevention
Two major studies using 5 a reductase inhibitors
vs placebo
Similar reduction in prostate cancer diagnosis
in the treatment arms (23-24%)
Not currently approved by Health Canada for
prostate cancer prevention
PCPT (Thompson et al NEJM 2003)
Finasteride
Reduce (Andriole et al NEJM 2010)
Dutasteride