Male Genitourinary tract Pathologies Flashcards
What are the key three zones of the prostate gland?
Peripheral zone - 70%
Transition zone -5%
Central zone - 25% - around ejaculatory duct
What region of the prostate gland enlarges the most with age?
Transitional zone (BPHP)
Which region of the prostate gland is most commonly affected in cancer?
Peripheral zone
What is the key function of the postate function?
Male male repoductive
Role in seminal fluid production - 30 weeks
If a fibro-muscular stroma around the prostate for muscular contraction during ejecaulation
Stoma contains emissions of seminal fluid prior to ejaculation
What drives the response of the prosatate?
Testosterone crosses the cell membrane and is reduced by 5-alpha reductase to DHT.
DHT is more potent -> binds to androgen receptors (which displaces from HSP).
(Note testosterone can also bind directly but is less potent)
Dimerises and phosphorylates-> acts as transcription factor on androgen response element
Leads to increased prostate growth, survival and inc PSA.
Androgen receptor is a major therapeutic target in what prostate diseases?
BPH
Prostate Cancer
What are the key parts of the androgen receptor?
N-terminal domain - contains Activator of function domain (regulated by other proteins to reg transcription)
DNA binding domain
Ligand binding domain
What is the function of the 5-alpha reductase enzyme?
Reduces testosterone to its more potent form DiHydro Testosterone (DHT).
What are the key symptoms of prostate disease?
Decreased urinary flow - in older men 60yrs> - inc frequency, dec stream, dec volume
How does prostate disease lead to decreased urinary flow?
Enlargement of the prostate
- compression of the intraprostatic urethra
- impaired urine flow
- increased risk or UTI
- acute retention of urine requiring urgent relief by catheterisation
What are the key epidemiology and morphology features of prostatisis?
Inflammation/infection of the prostate gland
Common
Anywhere in the gland
Morphology - Inflammatory infiltrate
What are the key epidemiology and morphology features of BPH?
75% of M over 70yrs
Occurs in the periurethral transition zone
Morphology : nodular hyperlasia of glands and stroma
What is the key epidemiology and morphology of prostatic carcinoma?
Commonest male cancer - peak 60-75
Occurs in the peripheral zone
Morphology - infiltrating adenocarcinoma
Where does prostatic cancer metastasise to?
Lymph nodes
Bone
Liver
Lung
What is the normal histology of the prostate gland?
Stroma with glands
Glands are lined by simple columnar or pseudostratified columnar epithelium
Stoma may have thick smooth muscle to aid expulsion from glands.
What are the histological features of prostatitis?
Increased size of cytoplasm of glandular cells
Increased inflammatory cells in the stroma
What are the histological features of BPH?
Increased cytoplasm of glandular cells
Overlapping of glands - without clear stroma between them.
How does the incidence of BPH vary with age?
20% in 40yrs (typically asymptomatic from autopsy)
70% in 60yrs
90% in 80yrs.
S curve increase with age
What is the medical treatment for BPH?
Finasteride
Binds to 5-alpha reductase inhibitor - prevents the conversion of testosterone to DHT
Reduces (NOT stop) activity at androgen receptors.
What are the surgical treatments for BHP?
Retroscope into urethra
TURP (trans-urethral resection of the prostate) - wire loop heated by electric current
HoLEP - Holmium Laser Enucleation of the Prostate -> new not widespread
Caution: risk of bleeding
What are the key risk factors for prostate cancer?
Age = main
Genetics - FH, particularly in 1stDR <50yrs
Rave - 3x African/Carribbean, lower is Japan/China
Diet - red meat increased, soya = protective.
What can PSA levels be effected by?
Prostate biospy
DRE
Ejaculation
BPH
Prostatitis
Intense exercise
(high risk of false positives)
What is the key diagnostic test of prostate cancer?
PSA blood test - AR regulated gene produced by prostatic ductal epithelium - normal upper limit 3-4ng/ml.
Digital rectal exam - for nodularity, enlargement, rigidity, masses.
What are the limitations of PSA blood test?
Non specific to prostate cancer
20% of patient will be missed
66% raised PSA and not prostate cancer
Some prostate cancers grow very slowly -> overdiagnoses
What second line investigation from positive DRE and PSA is done for suspected prostate cancer?
Trans rectal ultra sonography biopsy
Is very invasive -> frustrating for patients with false-positive PSA tests.
What scale is used to stratify prostate cancer?
Gleason Pattern Scale
Adding the two most typical grades to calculate the Gleason score
What is theWhat are the different stages of a Gleason Grade in prostate cancer?
1 - small unfirm glands
2 - more stroma between glands
3 - infiltartion of cells from glands at margin
4 - irregular massess of neoplastic cells with few glands
5 - lack of or occasional glands, sheets of cells
What are the key features of bony mets from prostate gland?
Direct - stromal invasion into pelvic side wall
Lymphatics - to sacral, iliac and paro-aortic
Bloods to bone (pelvis, lumboscaral femur)
Mets are osteosclerotic NOT osteonecrotic -> difficult to treat and painful
What are the different treatment approaches for prostate cancer?
Watchful waiting - may not progress, to frail for treatment, avoid side effects of drugs/surg.
What are the surgical treatment for prostate cancer?
Radical Prostatectomy
Major operation - must be deemed fit for surgery
Keyhole or robot-assisted
Orchiectomy - remove testes -> reduce androgen production
What are some potential complications of a radical prostatectomy?
Infertility
Erectile dysfunction
Impotence
Urinary incontinence
What are the key chemotherapy Zoladex used in prostate cancer?
LRHR agonist (chemical castration) = Zoladex/Gosalerine
LRHR is released from hypothalamus -> activates PG to release LH -> targets testis to release testosterone.
Increase LRHR signs leads to desensitization to signal -> leads to suppression.
This reduces the testosterone and DHT available to bind to AR.
How does Casodex/Bicalutamide treat prostate cancer?
Potent AR inhibitor -> binds to AR -> AR can move into nucleus but not longer able to activate gene expression
This leads to tumour shrinkage.
Requires 50-200mg daily
What is the caution with the use of Casodex use in prostate cancer?
With long term use 2-3yrs becomes an agonist of AR -> leads to increased growth
Independent of AR cells populations develop -> become primary population as dependent cells killed off -> survival advantageous.
How does the androgen receptor become Casodex resistant?
Promiscus /outlaw - Ligand binding domain mutation
Allows other hormoens to bind to AR - multiple potential agonists (oestrogens, progesterone, glucocorticoids and casodex)
Mutations - T877A
Hypersensitivity - increased number of androgen receptors.
What treatment is used for replases of prostate cancer?
Taxanes/Docetaxal -> targets cell division nad microtubules
Common in combination with prednisolone for relief of bone pain, inflammation and nausea.
What are the next generation antiandrogens? (Enzalutamide)
Reserved for patients with mestastasis, CRPC disease.
Inc survival 4 months
Stops testosterone binding to andorgen receptor, also stop migration into the nucleus.
Still some resistance
How does Abiraterone Acetate (zytiga) treat prostate cancer?
Prevents testosterone biosynthesis
Inhibits CYP17 -> prevents conversion of progestens to andorgens
However can lead to mineralocorticoid excess, decrease cortisol hence high ACTH
Must be treated with prednisolone/dexamethasone to lower ACTH
What is the site of sperm production?
Seminferous tubules in the testes
Spermatagonia -> along the basement membrane of the germinal epithelium.
Supported by sertoli cells and leydig cells.
What is the function of sertoli cells?
Epithelial supporting cells of the seminiferous tubules
Are tall simple columnar, from BM to lumen
Surround germ cells -> provide nutrients, and phagocytose excess cytoplasm
What is the function og leydig cells?
Support spermatogenesis in the testes
Local production of testosterone in response to LH
What is cryptorchidism?
Development lesion -> undescended testicles seen in 5% newborn.
Small seminiferous tubules as high temp = low sperm = replaced by sertoli cells = inc cancer risk
Usually resolve or surgical descend pre puberty
What is the key pathology of hydrocele?
Intrascrotal swelling of serous fluid in tunica vaginalis
Acute -rapid production due to damage/infection and inflammation
Congenital
Secondary inflammation - infection, underlying testis or epididymis lesion, tumours
What is a haematocele?
Intrscrotal haemorrhage in the tunica vaginalis
Cause - trauma, neoplasm
Minor - anti-inflams, antibiotics, ice pack
Major - emergency surgery
What is a variocele?
Enlargement of blood vessels to the testes (more common in left)
1 in 7 men
Primary -> no underlying cause
Secondary -> venous obstruction such as kidney tumour causing back pressure
Risk - may raised intrascrotal temp causing subfertility
What is orchitis?
Inflammation of the testes
What is mumps orchitis?
Acute infection (paramyoxivirus) in children
Adults
Vascular dilation and oedema with lymphocyte infiltrate
Risk of ischaemia and necrosis of seminiferous tubules
Rare = sub fertility
What is idiopathic granulomatous orchitis?
Chronic of unknown cause
Firm testicular enlargement
Managed with pain relief
What is STI orchitis?
Syphyllis - treponema pallidum (rare)
Gonorrhea, chlamydia
Causes inflammation of the testis.
What are the key features of a testicular torsion?
Most common in males under 25yrs
Twisting of cord cuts off blood supply and prevents venous drainage
Medical emergency - 6hrs to save the testicle.
Can be sudden without trauma.
What are the common causes of testicular atrophy?
Progressive atherosclerotic narrowin of blood supply in old age
End stage orchitis
Cryptorchidism
Hypopituitarism
Malnurihsed
Irridiation
Prolonged administration of anti-androgens
Alcoholism
Kleinfelter syndrome
What is the epidemiology of testicular tumours?
Most common cancer in young men
Highly treatable if detected early
What are the different classifications of testicular tumours?
- Germ cell tumours
- Sex cord-stromal tumours
What are the different types of germ cell tumours in the testes?
Seminomatous tumours - (spermatocytic) seminoma - more immature cells
Non-seminamatous - embryonal, yolk sac, choriocarcinoma, teratoma - more mature cells, further differentiated into sperm
What are the different types of sex cord stromal tumours?
Leydig cell tumours
Sertoli cell tumour
What are the main risk factors for testicular cancer?
Undescended tests
Kleinfelter syndrome (XXY)
Genetic - FH and polymorphism Xq27
Race - caucasian
Enviro -
What are the key symptoms of testicular cancer?
Painless unilateral enlargement of the testis
Secondary hydrocele
Symptoms from mets (bone and lungs)
Retroperitoneal mass
Gynaecomastia
What are the locations of the testicular tumours?
What are the key features of a seminoma?
Most common germ cell tumour
Peak 30-50yrs
Enlarged tests - Homogenous white solid tumour replaces testes mass
10% secrete hCG
25% c-KIT activating mutation
What are the histological features of a seminoma of the testes?
Large neoplastic cells
Vacuolated cytoplasm
Stroma has variable lymphocytic infiltrate
Positive cor c-KIT expression
What are the key features of an embryonal carcinoma?
Most common in 20-30yrs
Very aggressice
Pleomorphic epithelial cells
Hyperchromatic nuclei
Necrosis is very common
Very pluripotent in nature - can de-differentiation
Stain positive for Oct4
Negative for c-KIT expression
What are the features of yolk sac tumour?
Most common testicular tumour in infants and child up to 3yrs
Painless
Low risk of metastases
Responds very well to chemotherapy
What are the features of teratomas?
Group of complex testicular tumours with various cellular and organoid components from more than one germ layer.
Infants and children ->2nd most common
Rare in adults.
What is the pathology of a teratoma?
Epithelial lined cystic structures
Glands, cartilage, muscle, immature strome
gut, muscle like etc
Lots of different cell differentiations lines
Gross - cystic and haemorrhagic
What are the features of mixed testicular tumors?
Common types
60% are moxed
Teratoma and embryonal
Yolk sac, seminoma, embryonal
Embryonal with teratoma
Prognosis based on most progressive
What are the key features of Leydig tumours?
Produce androgens and oestrogens
20-60yrs
Benign - 10% invasive
What are the key features of sertoli tumour?
Hormonally silent
Small nodules
10% are invasive most are benign
What are the different stages of testicular cancer?
Stage 1 - in testes only
Stage 1s - raised markers in blood after surgery
Stage 2 - spread to nearby lymph or pelvis
Stage 3 - spread to lymph nodes or other organs
What is the key treatment for tesitcular cancer?
Surgical removal of testicle
Seminomas - + single chome and short radio
Non-seminomous - follow up, short chemo
Stage2/3 - 3/4 chemo and surg for mets
What is the typical chemotherapy regime used for testicular cancer?
IV central line at day clinic
Bleomycin
Bleomycin, Etoposide, Cisplatin (BEP)
