GENITOURINARY PATHOLOGY Kidney Anatomy
Metanephric in origin Gerota’s fascia envelopes each kidney Weight at birth is 26 gm, increases to 150-160 in adults and then slowly decreases with age
Congenital Anomalies
Common-10% born with some degree of urinary tract malformation
Hypospadias results from faulty closure of urethal folds Epispadias results from defect in genital tubercle
Associated with exstrophy of urinary bladder
In general, congenital kidney disease is more commonly due to a developmental defect rather than a hereditary defect 20% of chronic renal failure in children is due to renal dysplasias and hypoplasias
Renal Agenesis
Bilateral agenesis is incompatible with life
Most stillborn Most of rest die within days of birth Pregnancy characterized by oligohydramnios M>F Associated anomalies are imperforate anus, musculoskeletal anomalies and abnormal development of Mullerian organs
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Infantile Polycystic Disease
Classic clinical picture is a child under 3 months age with hypertension, respiratory failure and a protuberant abdomen Autosomal recessive, variable penetrance Usually is bilateral and also involves liver Kidneys enlarged by large numbers small cysts-so retain reniform (normal) shape Liver has fibrosis and bile duct proliferation
Adult Polycystic Disease
Classic Clinical picture: 30 to 40 year old patient with hypertension who gradually goes into renal failure and has bilaterally enlarged (usually massive) kidneys
May also present with lithiasis, hemorrhage into a cyst or ureteral obstruction Autosomal dominant with variable penetrance Common-1 out of every 500 birth Accounts for 5-8% of all renal transplantation Always bilateral Genetic defect most often on short arm of chromosome 16
Incidence of disease increases with increasing age -so in the right clinical circumstances begin to screen for this in the teenage years. Kidneys are enlarged and bosselated
Largely replaced by cysts ranging from mm to several cm in diameter Pelvis and ureters normal
Cysts are also present in liver (33%) and may occur in spleen, pancreas and lungs
Symptoms from cysts in these organs is uncommon
Intracranial Berry aneurysms in Circle of Willis occur in 16%
Usually hypertensive
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Glomerular Disease
Generalizations:
Many renal morphologic patterns lead to same clinical syndrome One disease can lead to many differing patterns of injury One type pattern can be associated with many diseases
Clinical Findings of glomerular injury are:
Hematuria-rbc casts always indicate glomerular injury Proteinuria Oliguria-defined as <600ml/day Azotemia Edema Hypertension
Clinical Syndromes:
Acute nephritic syndrome-This is dominated by acute onset of hematuria, usually grossly visible, mild to moderate proteinuria and hypertension Rapidly progressive glomerulonephritis-Acute onset of hematuria and oliguria leading to renal failure in weeks Nephrotic syndrome-Characterized by proteinuria >3.5 gm per day, hypoalbuminemia, severe edema, hyperlipidemia and lipiduria Slowly developing chronic renal insufficiency Asymptomatic urinary abnormalities such as hematuria, proteinuria or both
In Blacks, perform sickle cell screen if have hematuria
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Most Common Renal Diseases
Idiopathic Nephrotic Syndrome in Children
Minimal Change Nephrotic Syndrome
Idiopathic Nephrotic Syndrome in Adults
Membranous Glomerulonephropathy
Glomerular Disease in world
Berger Disease
Most common renal disease in AIDS and in IV drug abusers :
Focal segmental glomerulosclerosis
Renal transplant patients
Membranous glomerulonephropathy
Most common cause of end stage renal failure in US
Diabetes Mellitus
Most common form of hematuria in children
Familial benign hematuria
Minimal Change Nephrotic Syndrome
Classic Clinical picture: Child presents with microscopic hematuria and marked proteinuria which is predominantly albumin Most common cause of idiopathic nephrotic syndrome in children
Disease can occur in adults
Also called Nil disease and Lipoid syndrome Hypertension can occur but not invariable Differential is with focal segmental glomerulosclerosis May have an immunologic basis due to a T cell derived permeability factor Light microscopy (LM) is normal-”nil disease” Immunofluorescence (IM)-Usually negative Electron microscopy (EM)-Fusion of foot processes of glomerular visceral epithelial cells
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Treatment:
Corticosteroids
Relapses common, but most have no proteinuria at end of a year Adults are less responsive to steroid therapy
Focal Segmental Glomerulosclerosis
Classic Clinical picture: Child or adult who presents with microscopic hematuria, proteinuria usually in nephrotic range, hypertension and evidence of renal insufficiency
Protein is both albumin and globulin
Prognostic Factors
Elevated serum creatinine at diagnosis adversely affects outcome Degree of proteinuria
<3.5 gm/day-80% survive 10 years 3.5 gm/day-end stage renal disease in 6-8 yrs. >14gm/day-end stage renal disease in <6 yrs.
Light microscopy:-Segmental sclerosis and hyaline masses IM-Deposition of IgM and C3 in sclerotic segment EM-Electron dense material in sclerotic segment, diffuse loss of foot processes Most common renal disease in:
AIDS IV drug abusers
Treatment: Prednisone and/or cyclosporine
<50% show complete or even partial remission of nephrotic syndrome
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Membranous Glomerulonephropathy
Classic Clinical picture: An adult presents with proteinuria in nephrotic range with microscopic hematuria (usually), hypertension (50%), and renal insufficiency(50%) Is the most common cause of idiopathic nephrotic syndrome in adults 1/3 of all patients develop progressive disease that leads to either dialysis or transplant in 5-10 years Renal vein thrombosis is a complication Most common de novo glomerular disease in renal transplant patients Light microscopy(LM)-Varies from normal glomeruli to diffuse uniform thickening of the glomerular capillary walls with no inflammation or increased cellularity EM-Diffuse granular staining with IgG, usually C3 and C5B-9 complex EM-Early have deposits subepithelially and late have diffuse thickening of the glomerular basement membrane Pathogenesis:
In most cases, immune complexes form in situ rather than circulating immune complexes being trapped and deposited along the glomerular capillary walls
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25% of cases are secondary to other conditions
Drugs-gold, mercury, penicillamine, captopril Tumors SLE, Rheumatoid arthritis Hepatitis B Syphilis Renal transplants
Treatment
Recent study showed no differences in survival with or without treatment
Membranoproliferative Glomerulonephritis
Classic Clinical Picture: Child or teenager who presents with acute onset of hematuria, hypertension and the nephrotic syndrome Are actually three histologic patterns which are indistinguishable on clinical grounds
Type I-Accounts for 2/3 of cases Type II-Dense Deposit Disease Type III -Uncommon
LMDiffuse hypercellularity Increase in mesangial matrix Glomerular capillary wall thickening Silver stains show “tram-tracking”-caused by original BM on outside, new BM on endothelial side and a lighter zone in between
IM
Types I and III-Granular deposits of C3, IgG and IgM Type II-C3 stains along the margin of , but not within, the dense deposits
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EM
Types I, III have deposits subendothelially and in the mesangium Type II ( Dense deposit disease) have a striking increase in density of glomerular capillary BM and mesangium
Pathogenesis
Chronic antigenemia is thought to be important Complement activation also plays a role
Certain disease states are associated with this type renal disease
Hepatitis B and Care especially noted Endocarditis Autoimmune diseases Diseases with paraprotein deposition
Treatment is with corticosteroids Prognosis
50% end with end stage renal disease in <10 years
Acute Post-streptococcal Glomerulonephritis
Classic Clinical Picture: 6-10 year old presents with acute onset of severe edema, hematuria (smoky urine,) proteinuria, oligoanuria and hypertension following a sore throat two weeks prior
The proteinuria is usually <5 gm/day Serum BUN and creatinine are elevated Antistreptolysin-O is raised
Other infectious agents may also cause disease. These include staphylococcal, streptococcal pneumonia, meningococcemia, mumps, varicella, infectious mononucleosis, malaria and toxoplasomosis
These are uncommon causes
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This disorder is common and usually follows a streptococcal pharyngitis May also follow a streptococcal impetigo
Treatment of the impetigo will not prevent the occurrence of the glomerulonephritis Less commonly occurs with impetigo than pharyngitis
LM
Hypercellularity with closure of glomerular capillary lumens RBC’s, RBC casts and PMN’s in tubular lumens Crescents-Defined as two or more layers of cells within Bowman’s space
Can either fibrous or totally resolve
IM
Granular deposits of IgG and C3
EM
Glomerular BM is normal Swollen or proliferating glomerular endothelial and mesangial cells and immune deposits in capillary wall
Prognosis
Recovery is rule but mild hematuria and proteinuria may persist for several months after clinical recovery 1% develop rapidly progressive glomerulonephritis and 1-2% develop chronic glomerulonephritis In young adults 40% develop rapid progressive glomerulonephritis or chronic
Rapidly Progressive Glomerulonephritis
Classic Clinical picture: An adult presents with acute onset of hematuria, proteinuria, oligouria, and the presence of cellular casts in his urine. Over the next two to three months he has a rapid decline in his clinical state and the development of anuria with renal failure.
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Typically 50% decline in renal function occurs over 3 month period Accompanied by proteinuria, hematuria and cellular casts Morphologic hallmark is crescent formation
Defined as two or more layers of epithelial cells within Bowman’s space Crescentic glomerulonephritis implies crescent formation in >50% of glomeruli
Three disease groups cause crescent formation:
Goodpasture’s syndrome--anti-glomerular basement membrane antibody Acute post-streptococcal glomerulonephritis “Pauci” immune with few or no glomerular immune deposits. That is this disease
IM- Scattered deposits of IgM and C3 EM-Subepithelial bumps and deposits in the mesangium Treatment is supportive
No effective treatment exists
Prognosis
Poor, >90% end up rapidly with end stage renal disease
Disease states associated with “pauci” immune rapidly progressive glomerulonephritis
Microscopic polyarteritis Wegener’s granulomatosis Churg-Strauss syndrome
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Goodpasture’s Syndrome
Classic Clinical picture:
A 22-year old male presents to the emergency room with history of coughing up “bright red blood.” He was previously well and on no medication or drugs. In the subsequent weeks, he has deterioration of his renal function while usually the pulmonary symptoms become quiescent.
The pathogenesis is an attack against the lung and the glomeruli by anti-glomerular basement membrane antibodies The diagnosis is confirmed by detection of serum anti-NCI collagen IV antibodies Clinical
M>F #:1 Usually young-with peak incidence in 20’s-30’s Pulmonary manifestations almost always precede the renal
LM-Crescent formation with rest of glomeruli normal IM-Smooth intense linear staining along glomerular capillary BM by IgG and usually C3 EM-Non-specific
Schonlein-Henoch Purpura
Classic Clinical picture: An 8-year old presents to the emergency room because of intense colicky pain and joints that are hurting. On observation you see several purpuric lesions.
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This is a systemic vasculitis characterized by skin, joint, and gi manifestations
May actually cause intussuception Renal involvement in <25%
Indicated by presence of hematuria and proteinuria
Almost always in children
LM-Broad range of changes from focal to diffuse
Nephritis is the major cause of morbidity and mortality Severity of disease related to degree of proteinuria Proportion of glomeruli with crescents is the most important prognostic factor
IM-Granular deposits of IgA. IgG, IgM, and C3 Prognosis
Short term is favorable with >85% going into complete remission Some suggestion that in long term there is progressive disease
Berger Disease (IgA Nephropathy
Classic Clinical picture: A 20-year old male presents to the emergency with bright red blood in the urine. This is the most common form of glomerular disease in the world Morphologically identical to Schonlein-Henoch purpura but the extra-renal manifestations are absent Hematuria may be gross or microscopic If microscopic is usually accompanied by proteinuria and hypertension Nephrotic syndrome is rare-If present should consider some other disease
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Prognostic factors-If present suggest poor outcome
Glomerular sclerosis Renal interstitial fibrosis Extension of mesangial IgA deposits to peripheral capillary walls Proteinuria >1 gm/day
Familial Benign Hematuria
Classic Clinical Picture: A 6-year old is found to have microscopic hematuria during a routine physical exam. No proteinuria is present and the workup is negative for any renal disease This is the most common form of hematuria in children LM, IM, and EM are all normal Prognosis is excellent with no progression and no therapy is needed
Amyloidosis
Classic Clinical picture: A 67-year old male enters the hospital because of Streptococcal pneumoniae pneumonia. While working him up and treating him, you find he has hypertension and massive proteinuria along with microscopic hematuria. Amyloidosis is defined as the deposition in tissue of homogeneous eosinophilic material with randomly oriented fibrils with a diameter of 8-12 nm on EM
This deposition has a distinctive staining with Congo Red
Two distinct groups
2/3 are related to the plasma cell dyscrasias 1/3 are familial
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Prognosis is poor in both groups with a median survival of 13.2 months from diagnosis LM-Deposition of acellular material along mesangium early and then along tubular basement membranes and around blood vessels EM-Distribution of very long randomly oriented extracellular amyloid fibrils is diagnostic
Systemic Lupus Erythematosus
Classic Clinical picture: A young women presents to your office with complaints of severe arthralgias and the sudden appearance of a rash on her face after going to the beach for a day. During the workup, you find rbc casts in her urine. This is an autoimmune disease characterized by inflammation in various organ systems in association with antibody production against nuclear, cytoplasmic, and cell membrane antigens Most patients have some degree of renal involvement with 20% having severe renal disease WHO has 5 classes of LE which range from minimal to severe. Most have rbc casts, hematuria and proteinuria which usually is in the nephrotic range Recurrence of SLE in the kidney is unusual following renal transplantation LM:
“Wire Loops”-this is synonymous with SLE Glomerular hypercellularity Fibrinoid necrosis Crescent formation Neutrophilic infiltrate into glomeruli
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IM:
See deposits of IgG, IgA< IgM, Clq, C3 and C4
Diabetes Mellitus
55-year old diabetic comes in for monthly visit and you find proteinuria and rbc casts in her urine Diabetic nephropathy is defined by the presence of a persistently positive test for protein in the absence of other renal disease
Once diagnosed, means that end stage renal disease will occur over the next 10 years in 75% of patients Is the most common cause of end stage renal disease in the US
LM-Kimmelstiel-Wilson nodules are diagnostic. These are the acellular “Christmas balls” that occur in the mesangium.
Usually occur in the periphery and are rimmed by capillary lumen
Also have hyalinization or sclerosis of afferent and efferent arterioles.
Efferent changes occur in the absence of hypertension and are diagnostic of diabetes
ACE inhibitors are said to prevent these lesions
Acute Tubular Necrosis
Classic Clinical picture:
A thirty year old male is brought to the ER because of a motorcycle wreck. He has multiple broken bones and a pulmonary contusion. He is in hemorrhagic shock. He is taken to the OR and treated. On admission to the ward he is found to be anuric.
Typically have severe oliguria or anuria secondary to acute damage to tubular epithelium
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This is a reversible disorder and if the patient recovers from the disease causing the renal injury, the renal injury usually reverts to normal Causes
Ischemic injury including atherosclerotic disease, shock, hepatorenal syndrome and severe rhabdomyolysis Nephrotoxic substances including heavy metals, pesticides and mushroom poisoning
Acute Pyelonephritis
Classic Clinical picture:
A 24-year old pregnant female comes in with sudden onset of a fever of 103 and severe back pain A 78-year old male comes in with sudden onset of fever of 101 and back pain and history of difficulty in urinating
Microscopically see an infiltrate of PMN’s in the interstitial and when sever have abcess formation
Especially in diabetic patients may be complicated by necrotizing papillitis or papillary necrosis
Predisposing factors
Prostatic hyperplasia Pregnancy Neoplasia of prostate or cervix Vesicoureteral reflux Paraplegia Renal stone which obstructs
Most common pathway is ascension of bacteria up the urinary stream from the urinary bladder cavity Usually (>85%) is E. coli
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Chronic Pyelonephritis
Classic Clinical picture
A 68-year old male with long standing difficulty urinating comes in with history of multiple bouts of acute pyelonephritis and now has some proteinuria after treatment of this bout of pyelonephritis
Usually does not occur unless there is both repeated bouts of acute pyelonephritis and an associated urinary tract obstructive disease
Acute Interstitial Nephritis, Mononuclear
There is no classic clinical picture with the interstitial diseases. A large number of agents have been shown to cause an infiltrate of lymphocytes into the interstitium and cause damage to the renal tubules Known causes include:
Acute hypersensitivity methicillin and ampicillin Direct tubular damage by mercuric chloride Antibiotic damage by aminoglycosides
Acute Interstitial Nephritis, Eosinophils
Have in addition to lymphocytes and plasma cells eosinophils. In this disease may have clinically skin rash with pruritus, fever, arthralgias and an eosinophilia Most common are drugs
Beta-lactam antibiotics NSAIDS
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Urolithiasis
Classic Clinical picture: A 44-year old physician presents to the ER with intense colicky pain on the left side of his abdomen which radiates into his left groin. A urinalysis reveals fresh rbc’s in the urine Common US problem
Affects 1-6% of population, usually >30 yrs M>F Accounts for 1 in 1000 admissions to hospital
Majority of stones are calcium containing stones-3/4 of all stones
10% are associated with hypercalcemia and/or hypercalciuria
Staghorn calculi are magnesium ammonium phosphate stones arising in an alkaline urine caused by a urea-splitting bacteria such as proteus Hyperuricemia may also cause stone formation
50% of patients with uric acid stones do not have elevated serum uric acid Gout and leukemias both may cause this type stone
Renal Cell Carcinoma
Classic Clinical picture: A 65-year old male presents with intermittent bouts of abdominal pain and on exam has a palpable abdominal mass and hematuria on urinalysis
This is the classic picture but occurs<10% of time and typically today the lesion is found accidentally when CT of abdomen is done for other reasons (Steven Spielberg)
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Clinical
Common
31000 new cases and 12000 deaths in 1996
Predominantly older person disease
Rare before 40
Arises in renal cortex and accounts for 90% of all renal cancers M>F
Incidence is slowly increasing in US 5 year survival is also increasing - probably because we are detecting renal cell carcinomas earlier Risk factors
Cigarette smoking-now accounts for 1/3 of all cases Obesity Hypertension Occupational exposure to petroleum products, heavy metals or asbestos Patients requiring renal dialysis, especially if have polycystic disease Renal transplant patients have increased risk for renal cell carcinoma to develop in their native kidney Von Hippel-Lindau patients have increased risk
Pathologic types:
Clear cell carcinoma
Most common 80-85% of all Associated with deletion of one or both copies of chromosome 3
Chromophilic
14% of tumors May be multifocal and bilateral Trisomy 7 and trizomy 17 Have better prognosis than clear cell
Chromophobe tumors
4% of tumors Hypodiploid number of chromosomes Usually excellent prognosis
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Oncocytomas
Rare Rarely metastasize
Sarcomatoid
Rare Very aggressive
Collecting-Duct carcinomas
Rare Very aggressive
Metastasis may occur before tumor is detected.
Is noted for unusual site of metastasis such as thyroid, skin, sinuses, skeletal muscle Usual sites however are lung, bone, liver and brain Tumor has a proclivity for extending into renal vein
Paraneoplastic syndromes occur in <5% of patients. Presence of these does not mean tumor has metastasized!
Erythrocytosis (polycythemia) Hypertension Hypercalcemia Feminization or masculinization Hepatic dysfunction Amyloidosis Cushing’s syndrome Eosinophilia Leukemoid reactions (>20,000 wbc’s)
Prognosis:
58% 5 year survival 20-30% relapse after radical nephrectomy Most relapse with distant metastasis rather than local recurrence
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Wilm’s Tumor
Classic Clinical picture: A mother is bathing her 4-year old daughter when she feels an abdominal mass. Is thought to be a malignancy arising from metanephric blastema that undergoes malignant transformation either before or after birth Is a common childhood tumor with peak incidence 2-4 years
Only 3% of tumors occur after age 10 yr.
Clinical
Usually diagnosed when family member detects mass. Average size is >10 cm Abdominal pain-1/3 Hematuria-1/7
Microscopic exam:
Have epithelial components which form immature glomeruli and tubules and stroma that forms the background
Prognosis:
5 year survival is 85% as compared to 15% in 1920 Related to:
Stage Patient age-is better if <2 yr Histologic differentiation
Neuroblastoma
Classic Clinical picture: A 3-year old male is brought in with a large flank mass. The mother states he is weak and does not eat well. On exam you find generalized lymphadenopathy The most common solid tumor of children with peak incidence of 4 years It arises from adrenal medulla
Is associated with retinoblastoma
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Microscopic exam: Rosettes of neuroblasts Early metastasis is common to liver, bone marrow and skin
Transitional Cell Carcinoma Renal Pelvis
Classic Clinical picture: A 65-year old male presents with painless hematuria Clinical
5-10% of all renal tumors Mean age is 65 Increased incidence in:
Dye workers Cigarette smokers Analgesic abuse
Is an exophytic lesion (protrudes into renal pelvic cavity) Usual complaint is painless hematuria
Ureters
Lumen restricts stones to size <0.5 cm Are three points of narrowing
Ureteropelvic junction Point of entry into bladder Point where cross iliac vessels
Cystitis
Classic Clinical picture: A 33-year old housewife presents with sudden onset of pain on urination associated with marked increase in frequency of urination. She has no fever or tenderness. Etiology
Organisms
Bacterial-most commonly E coli Fungus Parasites Viruses
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Cytotoxic anticancer drugs may also induce a cystitis
Cyclophosphamide or busulfan may cause severe hemorrhagic cystitis
Radiation
Dose dependent Begins 4-6 weeks after therapy begins and stops 3 months after therapy ends
Autoimmune cystitis (Hunner’s Ulcer)
Rare Usually middle-aged women Usually associated with allergies and/or eosinophilia
Endometriosis Urinary Bladder
Most common site within urinary tract Patient presents with pelvic pain and hematuria
On cystoscopy see a mass which on biopsy reveals endometrial glands, stroma and hemosiderin laden macrophages
Urinary Bladder Carcinoma
Classic Clinical picture: A 78-year old man comes in with painless hematuria Incidence: 3-5% of cancer deaths in US 52,900 new cases in 1996 with 11,700 deaths M>F 3:1 Cigarettes are a major predisposing factor Disease of older adults with greatest incidence in 6th and 7th decade Types:
Transitional-90% Squamous cell carcinoma
In Egypt Schistosoma haematobium is a cause of bladder cancer and causes almost exclusively squamous cell carcinoma
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Adenocarcinoma
Prognosis
Depth of invasion of tumor at time of initial diagnosis History of prior urothelial tumors
If a patient has had a low grade tumor and it has not recurred at 3 years, his chance of recurrence returns to that of a patient who has never had a urothelial tumor
Prostatic Hyperplasia
Classic Clinical picture; A 70-year old male comes to see you because he cannot urinate. He has had difficulty for some time in starting his stream but yesterday he got a cold and after taking a antihistamine he has been unable to urinate. Normal prostate weighs 20 gm at age 40. Beginning at 40, prostate gradually increases in size
4% of men >70 have prostates that weigh >100 gm Clinical prostatism usually begins in 7th decade
Pathogenesis is not known
Almost certainly related to testosterone and estrogen metabolism
Is not a premalignant lesion
Prostatic Adenocarcinoma
No classic picture. Is increasing in number of cases diagnosed
Increased awareness of disease Increased utilization of serum PSA Increased utilization of prostatic needle biopsies
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It is the most common cancer today and is the second most common cause of cancer death
Only 25% of tumors are ever clinically significant Only 3% of men will die from this disease
Incidence
Uncommon in men <50 Increased incidence in Blacks Asians have decreased incidence
Are three prognostic groups
Unimportant
Less than 0.5 cm in diameter Gleason grade 1, 2, or 3 Tumor is confined to prostate
Curable
More than 0.5 cm in diameter, Gleason 1, 2 or 3 and confined to prostate Any size with Gleason 4 or 5 which is confined to prostate Any size, any grade with tumor extending through capsule if surgical margins are negative
Advanced
Any size, any grade with extensive extracapsular extension, with seminal vesicle extension or with lymph node metastasis
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