SF28D-PA 03-04-09- Male Genital System- Penis, Testes & Epididymis- COARD ** The penis can be affected by the

following: iCongenital anomalies iiInflammations iiiTumors Penis: Congenital Anomalies - Congenital absence - Aberrations in size and form - Hypoplasia, hyperplasia and duplication - Hypospadias & epispadias - Phimosis ** Malformations of the urethral groove and urethral canal may create abnormal openings in two places of the penis: iVentral surface- hypospadia iiDorsal surface- epispadia ** Either of these two anomalies may be associated with failure of normal descent of the testes and with malformations of the urinary tract - These openings should be corrected because they are associated with urethral stricture and other infections - The abnormal opening is constricted resulting in urinary tract obstruction - An increased risk of ascending urinary tract infections - If the orifices are near the base of the penis, normal ejaculation and insemination are prevented or blocked - Therefore these lesions are possible causes of sterility in men Phimosis- when the orifice of the prepuce is too small to allow normal retraction - Interferes with cleanliness - Causes accumulation of secretions and detritus (smegma) under the prepuce - Favors the development of secondary infections and possible carcinoma - Phimosis can the congenital but more commonly associated with inflammation Penis- Inflammation ** Inflammations of the penis usually involve the glans and prepuce. There are two types of inflammation: iNon-specific- balanitis or balanoposthitis Balanoposthitis- refers to infection of the glans and prepuce caused by a wide variety of organisms - Common agents- Candida albicans, anaerobic bacteria, Gardnerella, pyogenic bacteria - Most cases occur as a consequence of poor local hygiene in uncircumcised males - Accumulation of desquamated epithelial cells, sweat and debris (smegma) acting as a local irritant iiSpecific- sexually transmitted diseases - Syphilis - Chancroid- soft ulcers - Granuloma inguinale- associated with granulation tissue - Lymphogranuloma venerum - Herpes simplex virus - HPV Tumors of the Penis Benign Tumors - Condyloma acuminatum - Bowenoid papulosis ** Condyloma acuminatum is a benign tumor caused by HPV. May occur on any moist mucocutanous surface of the external genitals in either sex - Can also occur on the perineal areas - These lesions occur most often occur on the coronal sulcus and the inner surface of the prepuce - The basement membrane is intact and there is no evidence of the underlying stroma - Etiologic agent: HPV types 6 & 11 - Gross pathology = papillary lesion - Histology = Hyperplastic epithelium overlying papillary processes - Recurrences are common but malignant transformation is uncommon Malignant Tumors ** The most frequent malignant tumor is carcinoma of the penis

Carcinoma- in- situ- is a histologic term used to describe epithelial lesions in which the cytologic changes of malignancy are confined to the epithelium - No evidence of local invasion or distant metastases - Therefore it is full thickness carcinoma that does not invade the basement membrane - Considered to be a precancerous condition because of its potential to evolve into invasive cancer - 5% go onto form invasive tumors ** In the external male genitalia, two lesions that display histologic features of carcinoma in situ have been described: Both these lesions have strong association with HPV infection iiiBowens disease- occurs in the genital region of both men and women. In men it normally involves the skin of the penile shaft and the scrotum Appears as a solitary, thickened, gray white, opaque plaque with shallow ulceration and crusting Manifests on the glans and prepuce as red plaques known as Erythroplasia of Queyrat Epidermis shows proliferation with numerous mitoses. Cells are dysplastic with large hyperchromatic nuclei The dermal-epidermal border is delineated by an intact basement membrane Bowenoid papulosis- occurs in sexually active adults Occurs in younger patients Presence of multiple rather than solitary pigmented popular lesions Histologically indistinguishable from Bowen disease Related to HPV 16 However Bowenoid papulosis almost never develops into an invasive carcinoma and in many cases it spontaneously regresses

Invasive Malignant Tumors ** The most common is squamous cell carcinoma of the penis - Rare tumor but is more common in populations without routine circumcision - Usually begins on the glans or inner surface of the prepuce - High associations with HPV 16, 18 - Treated with surgery +/- irradiation or chemotherapy ** Two macroscopic patterns are seen: iPapillary- resemble condylomata acuminata iiFlat- appear as areas of epithelial thickening accompanied by fissuring of the mucosal surface Testis & Epididymis - Congenital anomalies - Inflammation

Vascular lesions Tumors

Congenital Anomalies of Testis- Cryptorchidism Crytorchidism- refers to maldescent of the testis - Found in about 1% of boys at 1 year old - Represents a complete or incomplete failure of the intraabdominal testis to descend into the scrotal sac - Most patients the undescended testis is palpable in the inguinal canal - However the undescended testis due to is ectopic position is at risk of trauma and tumor development - Therefore surgical correction is recommended if they have not reached their correct position by age 2 years Note: The undescended testis is at higher risk for development of germ cell tumors Inflammation of the Testis & Epididymis ** Inflammation is more common in the epididymis than in the testis. - Gonorrhea and tuberculosis usually arise in the epididymis first - Syphilis tends to affect the testis first ** Non-specific Epidiymitis & Orchitis- usually related to infections in the urinary tract (cystitis, urethritis, genitoprostatitis) which usually reach the epididymis and the testis through the vas deferens or the lymphatics of the spermatic cord ** Granulomatous (Autoimmune) Orchitis- distinguished by granulomas that are restricted within the spermatic tubules Vascular Disturbances- Torsion of the Testis - Twisting of the spermatic cord may cut off the venous drainage and the arterial supply to the testis - Usually the thick-walled arteries remain patent - Therefore intense vascular engorgement and venous infarction follows 2

Torsion is an urologic emergency The first signs are pain + swelling The testis must be manually untwisted surgically within the first 6hrs for the organ to remain viable The predisposing factor is increased mobility of an already mobile structure. Associated with a problem with the ligament of the scrotum

Tumors of the Testis ** Testicular neoplasms are divided into two main categories: 1- Germ cell tumors- (90-95%) usually highly aggressive capable of rapid, wide dissemination - Seminoma - Yolk sac tumor - Teratoma - Combinations 2Non-germinal tumors (Sex cord stromal tumors) (4%)- derived from the stroma or the sex cord Generally benign Leydig cell tumor Sertoli cell tumor

Note: Mixed germ cell/sex cord stroma tumors are also possible Seminoma - The most common type of germinal tumor - Usually seen in young adults 30-40 years - Formed when neoplastic germ cells differentiate along gonadal lines - Homogenous, gray-white lobulated cut surface appearance - Tunica albuginea is usually not penetrated. Therefore they tend not to infiltrate the capsule - Microscopy: sheets of uniform cells separated into incomplete lobules by delicate septa. Also with a lymphocytic infiltrate - Seminomas are very sensitive to radiotherapy Yolk Sac Tumor (Endodermal Sinus Tumor) - Also known as infantile embryonal carcinoma - Most common testicular tumor in infants and children up to 3 years - If found in adults, the yolk sac elements are mixed with embryonal carcinoma - Non encapsulated mass with a mutinous appearance Microscopy: Lace like (reticular) network of medium-sized cuboidal or elongated cells - Schiller-Duval Bodies- structures that consists of a mesodermal core with a central capillary and a visceral and parietal layer of cells that resemble glomeruli - These cells secrete alpha feto protein (AFP) which can be detected in tumor tissue, CSF, urine, and serum Teratoma ** A teratoma is a group of complex tumors with various cellular or organoid components that resemble normal derivatives of more than one germ layer - Contains tissues of more than one germ layer - More common in children - Although they can occur at any age from infancy to adult Gross Appearance- usually large with variegated cut surface - Because they are composed of various tissues, their gross appearance tends to be heterogeneous - May have solid, sometimes cartilaginous and cystic areas Microscopic: Immature type or mature type - Mature Type- the tissue is recognizable and therefore it is benign - Immature Type- the type of tissue is unrecognizable and is usually a sign of malignancy Testicular Tumors: Clinical Features - Painless enlargement of the testis - Spread mainly by lymphatics at early stage to para-aortic nodes - Hematogenous spread occurs later to lungs, liver, bone + brain - Two categories are recognized for treatment and prognostic purposes

SF28D-PA- Renal Pathology #1- SHAH

** Glomerular disease that interferes with blood flow through the glomerular capillaries has an effect on the tubules. - Because all tubular capillary beds are derived from efferent arterioles - The medulla does not have its own arterial blood supply but is dependent on the blood from the glomerular efferent arterioles - Therefore even small interferences with the blood supply of the medulla may result in medullary necrosis from ischemia ** The glomerular capillary wall is composed of: iEndothelial cells- fenestrated iiBasement membraneiiiVisceral epithelial cells (podocytes) Note: The entire glomerular tuft of capillaries is supported by mesangial cells between the capillaries Functions: Ultrafiltration of blood - Ability to discriminate among various protein molecules depending on their size and charge - This is the glomerular barrier function Glomerular Disease ** The glomeruli may become injured in various disease processes as well as other factors iPrimary glomerulonephritis- disorders in which the kidney is the only or predominant organ involved iiSecondary glomerulonephritis- Systemic diseases which have an effect on the kidneys and injure the glomeruli - EX: DM, SLE, hypertension, polyarteritis nodosa, Fabry disease Note: However both the clinical manifestations and the glomerular histologic changes in primary and secondary forms are similar ** Glomerular disease encompasses a spectrum of morphological changes resulting from a wide variety of etiological factors - Many glomerular and some tubulo-interstital and vascular diseases are immunologically mediated - Therefore immune mechanisms underlies most forms of primary glomerulonephritis and some forms of the secondary types - Glomerular deposits of immunoglobulins along with various components of complement are found in the majority of patients ** The immunological mechanisms may be either: iPrimary immunopathogenetic- initiating the disease process iiSecondary immunopathogenetic- mediating the disease ** There are a variety of antigens that are related to the disease process - Heterologous: foreign proteins, products of bacteria, viruses, parasites - Autologous Primary Immunopathogenetic Mechanisms ** These are mechanisms related to initiating the disease process. Come in two types: - Antibody mediated - Cell mediated Antibody Mediated Primary Immunopathogenetic Mechanism - Demonstrates a granular pattern on immunofluoresence - Demonstrates a linear pattern on immunofluoresence Immune Complex Glomerulonephritis- is a heterogeneous group of diseases characterized by extracellular accumulation of immune complexes (ag-ab complexes) within the glomeruli ** The patterns on immune complex deposition within the glomeruli include: iGranular appearance on IF iiMesangial iiiSubendothelial ivSubepithelial- where the Ag-Ab complexes are formed in circulation OR in situ ** There are 2 forms of antibody-associated injury: 1- Injury by antibodies reacting in situ within the glomerulus- ether with intrinsic glomerular antigens or with antigens planted within the glomerulus from the circulation - Antibodies that bind to these planted antigens induce a discrete pattern of immunoglobulin deposition that is detected as granular staining by IF 2Injury resulting from deposition of circulating antigen-antibody complexes in the glomerulus The antigens that trigger the formation of circulating immune complexes may be endogenous This occurs in glomerulonephritis associated with SLE May be exogenous, as in the glomerulonephritis that follows certain infections 4

Microbial antigens that are implicated include bacterial products (streptococci), surface antigen of Hepatitis B, antigens of Treponema pallidum, plasmodium falciparum

** Once deposited in the kidney the immune complexes may eventually be degraded by neutrophils, monocytes and macrophages etc and the inflammatory reaction should subside - However in disease states such as SLE and hepatitis there is a continuous production of these antibodies - The result is repeated cycles of immune complex formation, deposition and injury - This leads to a more chronic type of glomerulonephritis Cell Mediated Primary Immunopathogenetic Mechanisms ** Sensitized T-cells cause some forms of glomerular injury. - T-cells are responsible for cell + antibody mediated responses - Therefore they participate in both induction and mediation of renal disease caused by immune responses - Participation is by antibody production or local cell-mediated immunity by CD4+ helper cells - Cytokine production- INF-gamma, TNF-alpha, IL-2 - Effect injury through macrophage activation - CD8+ T-cell cytotoxicity Secondary Pathogenetic Mechanisms Role of: - Complement - Neutrophils - Monocyte/macrophages - Coagulation Complement Pathway - Alternative complement pathway activation occurs in dense-deposit disease (membranoproliferative glomerulonephritis) - Accumulation of neutrophils and monocytes infiltrate the glomerulus due to the activation of complement - This complement activation results in the generation of chemotactic agents (mainly C5a) - Neutrophils release proteases which cause glomerular basement membrane degradation - Neutrophils also generate oxygen derived free radicals which cause cell damage - Also cause the release of arachiodonic acid metabolites which reduce GFR ** The chemotactic complement components induce leukocyte influx and lead to the formation of C5b- C9, which is the lytic component - C5b-9 is a direct mediator of immune injury - Causes cell lysis and stimulates mesangial cells to produce oxidants, proteases and other mediators that are proinflammatory cell products Role of Monocytes & Macrophages - When these cells infiltrate the glomerulus they release a large number of biologically active molecules - Oxygen-derived free radicals - Cytokines- induce leukocyte adhesion - Plasminogen activator inhibitor- is linked to increased thrombosis and fibrosis by inhibiting the degradation of fibrin and matrix proteins Role of Coagulation System ** The coagulation system is also a mediator of glomerular damage through intraglomerular fibrin deposition - Fibrin is often present in the glomeruli in glomerulonephritis - Fibrin may leak in to the Bowman space and serve as a stimulus for parietal cell proliferation (crescent formation) - This leads to endothelial cell damage and hypercellularity ** The hypercellularity is caused by: - Leukocyte infiltration- both monocytes and neutrophils - Proliferation of endothelial + mesangial cells - Crescent formation Classification of Glomerular Diseases 1- Clinical 2- Morphological 3- Etiological 4- Immunopathological- immune complex glomerulonephritis OR ant-GBM-antibody diseases ** Immune complex glomerulonephritis can be divided into: 1- Associated with infection- post-streptococcal glomerulonephritis, post-infectious glomerulonephritis 2- Associated with systemic disease- SLE (lupus nephritis) 3- Primary glomerular diseases- idiopathic membranous glomerulonephritis, mesangiocapillary glomerulonephritis 5

Anti-GBM-antibody disease = Goodpasture syndrome ** Disease with immune mechanisms without immune complex formation or anti-GBM antibody development: - Minimal change disease - Focal + segmental glomerulosclerosis SF28D-PA Renal Pathology #2: Renal Diseases- Specific Glomerular Diseases Azotemia- a biochemical abnormality that refers to an elevation of the blood urea nitrogen and creatinine levels - Largely related to a decreased GFR Prerenal Azotemia- occurs when there is hypo perfusion of the kidneys that impairs renal function in the absence of parenchymal damage - EX: hemorrhage, shock, volume depletion, congestive heart failure Post-renal azotemia- occurs when urine flow is obstructed below the level of the kidney Note: When azotemia becomes associated with a constellation of clinical signs, symptoms and biochemical abnormalities it is known as uremia - Uremia is characterized by a failure of renal excretory function along with a host of metabolic and endocrine alterations resulting from renal damage

** The clinical manifestations of renal (glomerular) disease are: 1- Acute nephritic syndrome- glomerular syndrome characterized by the acute onset of grossly visible hematuria, mild to moderate proteinuria and hypertension - Acute nephritic syndrome is the classic presentation of acute poststreptococcal glomerulonephritis - Other symptoms include: azotemia + edema 2Nephrotic Syndrome- characterized by heavy proteinuria, hypoalbuminemia, severe edema, hyperlipidemia + lipiduria Lipiduria is lipid in the urine Proteinuria >3.5 gms/24hrs Hypoalbuminemia <25gms/l

3- Acute Renal Failure- characterized by oliguria or anuria with a recent onset of azotemia - Can result from glomerular, interstitial or vascular injury or acute tubular necrosis 4- Chronic Renal Failure- characterized by prolonged symptoms and signs of uremia. The end result of all chronic renal parenchymal diseases 5- Microscopic Hematuria- manifestation of mild glomerular abnormality 6- Asymptomatic Proteinuria- manifestation of a mild glomerular abnormality Nephrotic Syndrome ** The manifestations of nephritic syndrome include: 1- Massive proteinuria- daily loss of 3.5gms + 2- Hypoalbuminemia- plasma albumin levels less than 3gms/dl 3- Generalized edema 4- Hyperlipidemia + lipiduria ** The initial insult in nephrotic syndrome is a derangement of the glomerular capillary walls resulting in an increased permeability to plasma proteins - This allows proteins to escape from the plasma into the glomerular filtrate and the result is massive proteinuria - This proteinuria leads to a depletion of serum albumin - Generalized edema is the result of the loss of colloid osmotic pressure of the blood. - This causes an accumulation of fluid in the interstitial tissues

** The causes of nephrotic syndrome include: iMembranous nephropathy iiMesangiocapillary glomerulonephritis iiiMinimal change disease ivFocal & segmental glomerulosclerosis vLupus nephritis viDiabetes mellitus 6

vii-

Amyloidosis

Acute Glomerulonephritis ** Acute glomerulonephritis is a group of glomerular diseases characterized by inflammatory alterations in the glomeruli. - Also characterized clinically by the syndrome of acute nephritis ** The nephritic patient usually presents with: - Hematuria - Red cell casts in the urine - Azotemia - Oliguria - Mild to moderate hypertension ** The acute nephritic syndrome may occur in multi-system diseases such as SLE and microscopic polyarteritis - However it is characteristic of acute proliferative glomerulonephritis and crescentic glomerulonephritis Acute Proliferative (Poststreptococcal, Postinfectious) Glomerulonephritis - Characterized histologically by diffuse proliferation of the glomerular cells - This proliferation is associated with an influx of leucocytes - The lesions are usually caused by immune complexes and the inciting antigen may be endogenous or exogenous - Group A beta hemolytic streptococci type 12,4, 1 - Rising ASO titer - Low serum complement - Generally associated with a good renal prognosis **Poststreptococcal glomerulonephritis usually appears 1-4 weeks after a streptococcal infection of the pharynx or skin (impetigo) - The latent period between infection and onset of nephritis is compatible with the time required for the production of antibodies and the formation of immune complexes - The glomeruli appear enlarged and hypercellular ** Non-streptococcal acute glomerulonephritis (Post-infectious-)- Occurs sporadically in association with: iBacterial infections- staphylococcal endocarditis, pneumococcal pneumonia iiViral Disease- hepatitis B, hepatitis C, mumps, HIV, infectious mononucleosis iiiParasitic Infections- malaria, toxoplasmosis ** In this type of glomerulonephritis, granular immunofluorescent deposits are seen ** Crescentic Glomerulonephritis (Rapidly Progressing)- is a syndrome associated with severe glomerular injury - Characterized clinically by a rapid and progressive loss of renal function - Associated with severe oliguria and renal failure - Histology- presence of crescents in the glomeruli. These are produced by the proliferation of the parietal epithelial cells lining the Bowmans capsule and the infiltration of monocytes and macrophages - RPGN is an anti-GBM antibody induced disease - Related to Goodpasture syndrome ** In Good-pasture syndrome the anti-GGM antibodies cross-react with pulmonary alveolar basement membranes to produce the clinical picture of pulmonary hemorrhage associated with renal failure Systemic Lupus Erythematosus - Multi-system disease of autoimmune origin - Acute or insidious onset mainly in the child-bearing age group - Chronic remitting + relapsing often febrile - Mainly injuring skin, joints, kidneys, serous membranes - Characterized by the production of a wide array of autoantibodies Diagnosis of SLE - Depends on the classic clinical manifestations Laboratory Findings: - LE cells - Antinuclear antibodies - Anti-ds-DNA antibodies/Anti-smith antibodies (diagnostic) - ANA-negative SLE (5%)

Drug-induced SLE- a lupus erythematosus-like syndrome may develop in patients receiving a variety of drugs - Hydralazine, procainamide, isoniazide - These patients develop ANAs but do not have the symptoms of lupus Note: In SLE patients exacerbation of their erythema and skin manifestations occurs after exposure to ultraviolet light Renal Manifestations of SLE ** The kidney is a frequent target of injury in SLE. The principal mechanism of injury is immune complex deposition in renal structures - Glomeruli, tubular + peritubular capillary basement membranes, larger blood vessels - Associated with proteinuria and nephrotic syndrome - Also associated with hematuria and acute renal failure - The immune complexes may be mesangial, intra-membranous, subepithelial or subendothelial in location - Telescoped urinary sediments are seen - Hypertension in 25-45% of patients Membranous Glomerulonephritis ** Membranous glomerulonephritis is characterized by diffuse thickening of the glomerular capillary wall - Also characterized by the accumulation of electron-dense, immunoglobulin containing deposits along the subepithelial side of the basement membrane - 4th to 5th decades and M > F - Commonly a primary type of glomerulonephritis - However secondary membranous glomerulopathy can occur in association with other systemic diseases ** Some causes of secondary membranous glomerulopathy are: iDrugs- penicillamine, captopril, gold, NSAIDs iiUnderlying malignant tumors- especially carcinoma of the lung, colon and melanoma iiiSLE- about 15% of SLE glomerulonephritis is the membranous type ivInfections- chronic Hepatitis B, hepatitis C, syphilis, schistosomiasis, malaria vOther autoimmune disorders- thyroiditis Note: In about 85% of patients with membranous glomerulonephritis, no associated condition can be uncovered therefore the disease is idiopathic in these patients ** Membranous glomerulopathy is a form of chronic immune complex-mediated disease - The damage is caused by the direct action of C5b- C9, the pathway leading to the formation of the membrane attack complex - C5b- C9 causes activation of glomerular epithelial and mesangial cells inducing them to liberate proteases and oxidants - These substances cause capillary wall injury and increased protein leakage ** The glomeruli exhibit uniform, diffuse thickening of the glomerular capillary wall - As the disease advances the membrane thickens progressively encroaches on the capillary lumens and sclerosis of the mesangium may occur - The course of the disease is variable but it is generally indolent - The proteinuria is non-selective and does not usually respond well to corticosteroid therapy ** Progression of the disease is associated with: - Increasing sclerosis of the glomeruli - Rising BUN- reflects renal insufficiency - Development of hypertension Mesangiocapillary Glomerulonephritis (Membranoproliferative glomerulonephritis) - Characterized histologically by alterations in the basement membrane, proliferation of glomerular cells and leukocyte infiltration - The proliferation is predominantly in the mesangium - Accounts for 10-20% of cases of nephrotic syndrome in children and young adults - Some patients present only with hematuria or proteinuria in the non-nephrotic range - Others have a combined nephrotic-nephritic picture ** MPGN can be: iPrimary- idiopathic iiSecondary- associated with other systemic disorders and known etiologic agents ** There are two types of MPGN based on their ultra structural and immunofluorexcent features: 1- Type I MPGN- characterized by the presence of subendothelial electron-dense deposits - On immunofluoresence it is seen that C3 is deposited in a granular pattern 8

IgG and early complement components are also present

2- Type II MPGN- (rare)- the lamina densa of the GBM is transformed into an electron-dense structure due to the deposition of dense material - C3 is present in irregular granular foci in the basement membrane but is not in the dense deposits - IgG is usually absent, along with the early-acting complement components ** The clinical course of MPGN is related to a presentation of nephrotic syndrome along with a nephritic component - Manifested by hematuria, mild proteinuria - Disease follows a slow but unremitting course - 50% of people develop chronic renal failure within 10 years

Minimal Change Disease (Lipoid Nephrosis) ** Minimal change disease is a relatively benign disorder that is the most frequent cause of nephrotic syndrome in children - Common in children 2-4 years B: G = 2:1 - The disease sometimes follows a respiratory infection or routine prophylactic immunization - Characteristic feature is dramatic response to corticosteroid therapy - Remission with steroids in 95% of patients - Therefore generally related to a good prognosis ** The disease is characterized by diffuse effacement of the foot processes of the epithelial cells in the glomeruli ** Minimal change disease involves some immune dysfunction, eventually resulting in the elaboration of a cytokine that damages visceral epithelial cells and causes proteinuria - The ultra structural changes point to a primary visceral epithelial cell injury - Therefore the defects in the charge barrier contribute to the proteinuria - Related to disorders of T-lymphocytes - Producing vascular permeability factors i.e cytokines - This leads to visceral epithelial cell damage and subsequent proteinuria ** Increased incidence of minimal change disease in lympho-reticular malignancies such as Hodgkin disease ** In minimal change disease despite the proteinuria, there is usually no hypertension or hematuria - The proteinuria is usually highly selective, and most of the protein lost consists of albumin Chronic Glomerulonephritis ** Chronic glomerulonephritis is a pool of end-stage glomerular disease fed by a number of streams of specific types of glomerulonephritis ** Also defined as end-stage renal disease with marked decrease in renal function leading to chronic renal failure - However it is impossible to determine the underlying disease process - End stage renal disease have kidneys that are bilaterally symmetrical and chronically contracted on gross examinations ** Membranous glomerulonephritis, MPGN, IgA nephropathy + focal segmental glomerulosclerosis all may progress to chronic renal failure - However in some patients the chronic glomerulonephritis arises with no antecedent history of acute glomerulonephritis ** The kidneys are symmetrically contracted and have diffusely granular, cortical surfaces - The cortex is thinned and there is an increase in peripelvic fat - Hypertension often accompanies chronic glomerulonephritis - Atrophy of associated tubules, irregular interstitial fibrosis and mononuclear leukocytic infiltration of the interstitium ** Chronic glomerulonephritis develops insidiously and slowly progresses to renal insufficiency or death from uremia during a span of years - Present with non-specific complaints: loss of appetite, anemia, vomiting, weakness - If patients with chronic glomerulonephritis are not maintained with continued dialysis or they do not receive a renal transplant, the outcome is invariably death SF28D- PA Renal Pathology #3- Renal Cysts & Tumors- SHAH ** Cystic disease of the kidney are a heterogeneous group comprising hereditary, developmental & acquired disorders Cystic Disease of the Kidney - Fluid filled spaces within the kidney - May involve cortex or medulla of both 9

May be unilateral or bilateral May be unilocular or multilocular May be congenital or acquired May be sporadic or genetically determined The clinical significance may be trivial or grave

** The classifications of renal cystic disease are: 1- Cystic renal dysplasia 2- Polycystic kidney disease iAutosomal-dominant (adult) polycystic disease iiAutosomal- recessive (childhood) polycystic disease 3- Medullary cystic disease iMedullary sponge kidney iiNephronophthisis 45678Acquired (dialysis-associated) cystic disease Localized (simple) renal cysts Renal cysts- in hereditary malformation syndromes Glomerulocystic disease Extra parenchymal renal cysts- pyelocalyceal cysts, hilar lymphatic cysts

Classification of Renal Cystic Disease ** Polycystic kidney diseases: iAutosomal recessive polycystic kidney disease- classic in neonates and infants. With hepatic fibrosis in older children iiAutosomal dominant polycystic kidney disease- classic in adults ** Simple cortical cysts ** Acquired (dialysis-induced) cysts Autosomal Recessive PKD - Rare developmental anomaly that is genetically distinct from adult polycystic kidney disease - Abnormal gene (PKHD1) on chromosome 6p21 - The PKHD1 gene encodes a large novel protein called fibrocystin Classically presents in antenatal or in the neonatal period. However it can present in infancy or adulthood Perinatal, neonatal, infantile and juvenile subcategories have been defined depending on the time of presentation and presence of associated hepatic lesions Patients who survive infancy may develop a type of hepatic fibrosis 30% of patients die of respiratory failure due to pulmonary hypoplasia or sepsis Complications includes chronic lung disease, growth retardation, hyponatremia, UTIs, hypertension

Gross Morphology- The kidneys are enlarged and have a smooth, external appearance - Cut section shows numerous small cysts in the cortex and medulla - Therefore the kidney has a sponge like appearance - Cysts have a uniform lining of cuboidal cells - Disease is bilateral - Liver has cysts with portal fibrosis as well as proliferation of portal bile ducts - Diffuse fusiform dilatation of the collecting ducts - Normal reniform shape complete with fetal lobation and normal sized ureter Autosomal Dominant PKD - Hereditary disorder characterized by multiple expanding cysts of both kidneys - These cysts eventually destroy the renal parenchyma and cause renal failure - Most common inherited kidney disease - Affects 1:1000 individuals and account for 5-10% of patients in dialysis or with renal transplant - Abnormal gene on the short arm of chromosome 16 - The cysts initially involve only portions of the nephrons, therefore renal function is retained until about the 4th or 5th decade of life ** Many patients remain asymptomatic until indications of renal insufficiency announce the presence of underlying kidney disease - Dull loin pain - Hemorrhage or dilation of cysts may produce pain 10

Excretion of blood clots causes renal colic Flank masses that are apparent on abdominal palpation Hematuria, proteinuria, polyuria, hypertension Progressive renal failure - anemia and decreased GFR, increased urea and creatinine

Note: Progression of the disease is accelerated in blacks, especially in correlation with the sickle cell train ** Associated cysts in the liver found in the biliary type (75%) and in the pancreas (10%) - Vascular anomalies including intracranial aneurysms (10%), colonic diverticula and mitral valve prolapse (25%) ** Bilaterally enlarged kidneys (up to 4000 gms) - External surface appears to be composed mainly of a mass of cysts with no intervening parenchyma - Diffuse cystic change with uninvolved intervening parenchyma - Varying sized, numerous generally oval-to spherical unilocular cysts - The cysts are distributed in the cortex and medulla and obscure the normal reniform shape - Cysts filled with fluid that may range from clear, to turbid, to gelatinous to hemorrhagic fluid - Distorted pelvi-calyceal system - Cysts can arise from any part of the excretory nephron - Neoplastic change is uncommon but can occur Simple Cortical Cysts - Extremely common as age advances - Occur as multiple or single cortical cystic spaces - Acquired cysts may originate from diverticula of the distal convoluted or collecting tubules due to weakening of the basement membrane - The membrane are made up of cuboidal epithelium - Usually asymptomatic with normal renal function - However hemorrhage into the cysts may cause sudden distention and pain - Radiology- Renal cysts have smooth contours unlike renal tumors. Cysts tend to be avascular and give fluid signals on ultrasonography Acquired (Dialysis-Associated) Cystic Kidney Disease ** Kidneys from patients with end-stage renal disease who have undergone prolonged dialysis exhibit numerous cortical + medullary cysts - Cysts are 0.5 to 2 cm in diameter - Contain clear fluid and are lined by hyperplastic/flattened tubular epithelium - Usually contain calcium oxalate crystals ** These cysts may form as a result of obstruction of tubules by interstitial fibrosis - Most are asymptomatic - Complication: Neoplastic changes are common. Development of renal carcinoma in the walls of these cysts in 7% of dialyzed patients Renal Tumors In infants & children: - Nephroblastoma (Wilms tumor) In adults: - Renal cell carcinoma - Renal cell adenoma - Renal oncocytoma Nephroblastoma (Wilms Tumor) ** Wilms tumor is the most common genitourinary malignant embryonal tumor derived from nephrogenic blastemal cells - Can differentiate into several cell lines: blastemal, epithelial, stromal - May replicate developing kidneys ** Common in young children and uncommon in neonates + infants - 90% in < 6year olds - Peak: 3yrs in boys and 3.5 years in girls ** 5-10% of Wilms Tumors involve both kidneys: iSynchronous- simultaneously iiMetachronous- affecting one kidney after the other

11

** The pathogenesis and etiology is widely unknown. However has a worldwide incidence, therefore no associated environmental factors - Variable incidence in racial groups - Blacks > Caucasian > Asians ** The risk of Wilms tumor is increased in association with at least 3 recognizable groups of congenital malformations associated with distinct chromosomal loci - Familial tendencies- 1% autosomal dominant with variable penetrance and expressivity - Genetic predispositions= WT-1 gene, WT-2 gene ** Most children present with a large abdominal mass that may be unilateral - If large they may extend across the midline and down into the pelvis - Hematuria, abdominal pain, intestinal obstruction and the appearance of hypertension are other patterns of presentation Gross Morphology- Present as a large, solitary well-circumscribed mass - Tumor has a peritumoral fibrous capsule - Variable size and weight - 10% are bilateral or multicentric - Tumor is soft and homogenous. - Tan to gray with occasional foci of hemorrhage, cyst formation or necrosis

Microscopy: Demonstrates a classic triphasic combination of cell types - Blastemal, stromal and epithelial - The tumor appears as sheets of small blue cells - May contain other heterologous elements such as squamous/mucinous epithelium, smooth muscle, adipose tissue, cartilage, neurogenic tissue ** The histology may be favorable or unfavorable depending on the state of nuclear anaplasia - Marked nuclear enlargement - Abnormal mitoses - Pleomorphic nuclei Note: Tumors with diffuse anaplasia and with extrarenal spread have the least favorable outcome ** Nephroblasmtomas have the potential to spread to regional lymph nodes. Also to distant lymph nodes in the lung and liver ** The prognosis and treatment of nephroblastoma depends on: - Stage, age and histology ** Surgery with chemotherapy for Stage I + II with favorable histology ** Surgery with chemotherapy and radiotherapy for higher stages and unfavorable histology Renal Cell Carcinoma - Once known as hypernephroma because of their gross yellow color and resemblance of the tumor cells to clear cells of the adrenal cortex - 3% of all adult malignancies - No racial predisposition - Arises from mature renal tubules - Tobacco is the most significant risk factor - Obesity, hypertension, exposure to heavy metals, asbestos, unopposed estrogen therapy - Increased incidence in patients with chronic renal failure and acquired cystic disease ** Most renal carcinoma is sporadic but unusual forms of autosomal dominant familial caners occur: 1Clear Cell Type- most common type and accounts for 70-80% of renal cancers Tumor made up pf cells with clear cytoplasm and are nonpapillary Can be familial, sporadic or associated with Von Hippel Lindau disease 98% of these tumors, irregardless of cause, there is a loss of sequences on the short arm of chromosome 3 This occurs by deletion or unbalanced chromosomal translocation

2- Papillary Type- Characterized by a papillary growth pattern and also occurs in both familial and sporadic forms - These tumors are associated with trisomies 7 + 17 Note: Renal carcinomas are generally sporadic but there are rare familial associations - Also associated with acquired cysts and patients on chronic hemodilaysis 12

** The 3 classic, diagnostic features of renal cell carcinoma are: - Hematuria - Palpable abdominal mass - Costovertebral pain (flank pain)

** The most reliable of the three is hematuria. However the hematuria may be intermittent or only visible on microscopy - Therefore renal carcinoma may be clinically occult - 30% of persons present with a metastatic lesion - Therefore the patients present with a large mass and constitutional symptoms - Renal cancers have a tendency to metastasize widely before giving rise to any local signs or symptoms ** The most common locations of metastasis are: - Lungs - >50% - Bones- 33% - Regional lymph nodes - Liver + adrenals - Brain ** The prognosis is influenced by multiple factors: - Nuclear grade - Tumor size - Infiltrative margins - Histological type - Tumor stage Renal Cell Adenoma - Incidental findings at autopsy (22%) - Well demarcated and unencapsulated - Pale yellow gray, discrete cortical mass SF28D-SU 26-03-09- Urological Disorders- Clinical Features- CHIN History - Pain - Hematuria - Lower urinary tract symptoms - Associated symptoms - Sexual function ** The history should define onset, severity, character, location, degree of disability and associated features - Genitourinary pain usually results from urinary tract obstruction or inflammation - Genitourinary tumors do not usually cause pain unless they are obstructive or extend beyond the primary organ Pain- Renal/Ureteral - Renal pain fibers are stimulated by distention of the renal capsule or renal collecting system - Afferent signals travel with autonomic nerves - Visceral type referred pain from the kidney and ureter are felt in T8-L2 - Referred pain and reflex muscle spasm along distribution associated nerves (ilioinguinal, genitofemoral) - Therefore pain is often referred down to the scrotum and labia Renal Pain - Ipsilateral costovertebral/renal angle - May radiate to upper abdomen - May be constant or colicky Constant Pain- is normally associated with tumor or kidney stone Colicky Pain- pain that is the result of contraction of a hollow viscus (peristalsis) against some other structure ** Because the kidney is an upper GI structure and has similar innervation, renal pain may be related to upper GI symptoms Note: Musculoskeletal pain in the back may mask kidney problems Ureteral Pain - Flank, groin, scrotal/labial pain and hyperalgesia - Usually colicky type (ureteral spasm) 13

Classic loin to groin pain May mimic appendicitis or diverticulitis Stones in the lower ureter present with irritative urinary symptoms Usually acute and secondary to obstruction Mid-ureteric obstruction may cause pain radiant to the ipsilateral lower abdominal quadrant Lower ureteral irritation- can give irritative voiding

** The causes of ureteral pain include: - Stones - Clots - Tumors - Strictures Vesical Pain - May be due to overdistention (urinary retention), inflammation or infection - Inflammatory conditions (cystitis) produce intermittent suprapubic discomfort - However in general bladder pain tends to be constant Note: Pain from the bladder neck or trigone area may be referred to the distal urethra - Therefore pain originating in the trigone tends to be referred to the end of the urethra Penile Pain - Flaccid penile pain at the penile tip is usually referred from the bladder - Peyronies Disease- scarring of the tunica albuginea which leads to deviation of the penis during erection - The result is a painful erection Prostatic Pain - Inflammation or infection with capsular distention - Prostatic pain tends to be poorly localized: lower abdominal, inguinal, perineal or rectal pain - Usually associated with storage voiding symptoms Testicular/Scrotal Pain- Scrotal pain may be primary or referred. ** In primary scrotal pain it is important to differentiate between epididymitis and testicular torsion iEpididymitis/Orchitis- infection of the epididymis that involves the testicles. Usually a gradual onset iiTesticular Torsion- spinning of the testicles leading to ischemia. Sudden onset, associated with nausea and vomiting - Referred pain to the abdomen because the testicles are initially an abdominal structure iiiTorsion of testicular appendages

Note: Testicular tumors do not usually cause pain unless they are unusually large ** Chronic pain in the testicles is usually non-inflammatory: - Varicocoele - Hydrocoele - Tumor (rare) Hematuria ** Hematuria is the presence of blood in the urine. May signal a problem anywhere in the GU tract, therefore hematuria should always be considered significant - Therefore must rule out GU malignancy ** Must define the following in relation to hematuria: - Gross hematuria- seen as spots of blood in the urine or blood stained urine - Microscopic hematuria- the blood is only detectable after centrifuge. However must be seen on more than one sample - Microhematuria- 3 red cells/hpf on 2 of 3 urine analysis - Note: The degree of hematuria as an associated risk for significant pathology Associated pain Presence of clots- minor bleeding does not cause clotting Shape of clots: String clots (vermiform)- compressed due to peristalsis in the journey from the urethra Vermiform clots in association with flank pain suggests upper urinary tract bleeding

- Timing- of the hematuria in the urinary stream is indicative of its site of origin iInitial- seen at the start of urination and then eventually clears. Indicates that the blood is sitting in the urethra and usually indicates inflammation 14

Gonococcal urethritis

iiTotal- the urinary stream is entirely blood-stained (evenly) from start to finish. - Usually due to bladder or upper urinary tract pathology iiiTerminal- blood is seen at the end of the stream. - Indicative of bladder neck or prostatic pathology - Result of irritation of the outlet of bladder neck or trigone - The bladder dome collapses as the bladder empties and this dome presses against the neck of the bladder resulting in pain or bleeding ** Hematuria may be painless or painful: - Flank - Abdominal - Urethral ** The pain normally signifies the source of the bleeding - EXCEPT: in the passage of ureteric clots Note: Total, painless hematuria is the most common presentation for urological disorders Causes of Hematuria Renal: - Tumor - Stones - Infection - Trauma - Papillary necrosis- more common in patients with sickle cell - AV malformations or renal artery aneurysm Ureter: - Stone - Tumor - Trauma Bladder: - Infection - Tumor - Stone - Trauma - Foreign body - Non-infectious cystitis- eg. Radiation for prostatic or cervical disease Note: The most common cause of hematuria is usually infection Urethral (including prostate) - Tumor - Benign prostatic hyperplasia - Infection - Stricture - Trauma - Foreign body - Stones General Medical Conditions: - Coagulation disorders - Glomerulonephritis - Exercise induced- marathon, triathlon - Anticoagulants- eg warfarin Evaluation of Hematuria: iUrinalysis- including microscopy to determine glomerular vs. non-glomerular bleeding - Glomerular bleeding = referral to nephrology, because the problem is in the upper urinary tract - Non-glomerular bleeding- the pathology is originating in the collecting system iiUrine culture- to determine infective processes iiiCystoscopy- of the lower urinary tract ivImaging- of the upper urinary tract by CT scan, IVP vUrinary cytology- examining cells in the urine for neoplastic type cells 15

Lower Urinary Tract Symptoms ** The lower urinary tract is defined as the bladder and urethra. The normal function of the LUT is the storage and emptying of urine ** Symptoms of LUT disease (LUTS) may be divided into: iStorage (irritative) symptoms iiVoiding (obstructive) symptoms Storage (Irritative) Symptoms ** Frequency is defined as 7 or more voids per day. Due to either: iIncreased urinary output iiDecreased functional bladder capacity ** Nocturia- is nocturnal frequency - Waking from sleep to void - Similar pathogenesis to frequency - Note: Nocturia may be associated with cardiac failure rather than a LUT problem ** Dysuria- painful micturition - Initial- pain at initiation of voiding indicates urethritis - Stranguria- sudden sharp suprapubic pain at the end of micturition **Urgency: the sudden desire to void that is difficult to postpone - May be due to unstable bladder contractions - Related to an infective/inflammatory process, neurogenic or obstruction - Neurogenic bladder- seen in diabetics Voiding (Obstructive) Symptoms 1- Weak stream/Decreased force of urination- most commonly results from bladder outlet obstruction 2- Hesitancy- delay in the initiation of micturition - Also associated with bladder outlet obstruction 3- Intermittency- involuntary starting and stopping of the urinary stream - Usually due to prostatic occlusion 4- Post void dribbling- release of drops of urine at the end of micturition - Usually results from bladder outlet obstruction 5- Straining- use of abdominal musculature to assist in voiding 6- Incomplete bladder emptying- may be a cause of urinary frequency

** In general lower urinary tract symptoms are: - Non-specific and may have various causes - Occur with equal frequency in both sexes above the age of 55 - Further evaluation is usually necessary to define pathology - Ex: Frequency + urgency may be due to infection, neurologic disease or urothelial cancer Urinary Incontinence ** Urinary incontinence is defined as the involuntary loss of urine. The condition is classified into the following: 1- Stress Incontinence- sudden leakage of urine with increased abdominal pressure - Ex: coughing, laughing, sneezing 2- Urge Incontinence- the precipitous loss of urine preceded by the strong desire to void. - Often due to irritation of the bladder which leads to unstable bladder contractions 3- Overflow Incontinence- Paradoxical urine loss that is due to urinary retention - Therefore in a chronically distended bladder that does not fully empty there is increased pressure and this leads to overriding of the sphincter 4- Enuresis (Nocturnal) Incontinence- urinary incontinence that occurs during sleep - EX: bed wetting 5- Continuous Incontinence- persistent urinary loss that may be urethral or non-urethral 16

Commonly due to fistulae (vesicovaginal) or female ectopic ureter

Associated Symptoms Gastrointestinal Symptoms 1- Nausea & vomiting- commonly seen with renal/ureteral colic due to stone disease - The renal system shares a common autonomic innervation with the proximal GI tract - Therefore renal symptoms will produce upper GI symptoms 2- Fever & Chills- signifies an infective process - Most commonly seen with pyelonephritis, acute bacterial prostatitis and epididymitis 3- Pneumaturia- the passage of gas with urination. May result from instrumentation - Commonly occurs with enterovesical fistulae - Therefore pneumaturia is the result of an abnormal connection between the bowel and urinary bladder 4- Faecaluria- passage of fecal debris with the urine Other Associated Symptoms: 1- Hematospermia- presence of blood in the seminal fluid - Usually results from inflammation of the prostate and seminal vesicles 2- Urethral discharge- thick, copious, yellow purulent discharge is indicative of gonococcal urethritis - Note: Non-specific urethritis usually has scant, watery discharge

Sexual Dysfunction 1- Impotence (ED)- the inability to attain and maintain an erection sufficient for sexual satisfaction. - May have organic or psychogenic causes 2- Ejaculatory Disorders-d iPremature Ejaculation- persistent occurrence of ejaculation at or soon after penetration that causes distress iiDelayed iiiAnejaculation Note: Delayed ejaculation and anejaculation are often psychogenic in cause 3- Loss of libido- related to a decreased testosterone level 4- Priapism- defined as persistent erection not associated with sexual stimulation that lasts for more than 4 hours - If the penis remains erect for more than 4-6 hours the result is ischemia of the corpus cavernosa - Usually painful and associated with blood dyscrasias - Ex: sickle cell disease - Requires emergent intervention Print Slide #43 Physical Examination: Kidneys ** The kidneys are difficult to palpate in normal adults. However a palpable mass may be due to: - Renal tumor - Cystic diseases - Gross hydronephrosis ** The presence of costovertebral angle tenderness suggests: - Infection or inflammation - Obstruction Physical Examination: Bladder - Detected with suprapubic palpation and percussion - The normal adults bladder cannot be detected with <150 ml of residual urine - A distended bladder may be visible in thin patients with >500 ml of urine - Suprapubic tenderness may indicate cystitis Physical Examination: Prostate ** The use of a digital rectal examination to examine for: - Sensation, sphincter tone - Prostatic size 17

Tenderness Nodularity and firmness

Physical Examination: Penis ** Examine the foreskin for any abnormalities such as: iPhimosis- inability to retract the foreskin iiParaphimosis- foreskin that has been retracted and is now unable to return to its normal position. The result is ischemia and edema ** Also examine the penis for lesions and plaques

** Examine the scrotum and contents for: - Testicular size + consistency - Epididymis - Spermatic cord - Tenderness Rule out: hernia, varciocoele, hydrocoele or testis tumor

Common Clinical Scenarios- Summary Renal Tumor- Triad - Flank pain - Mass - Hematuria Differentials: - Renal cystic disease - Severe obstruction - Chronic infection SF28D-ME 26-03-09- Urinary Tract Infections- PROF. WAN Urinary Tract Infection- is an inflammatory response of the urothelium to bacterial invasion. - Usually associated with bacteruria or pyuria Bacteruria- presence of bacteria in the urine - May be symptomatic or asymptomatic Pyuria- the presence of white blood cells, usually pus cells in the urine - Generally indicative of an inflammatory response to bacteria ** UTIs are the commonest bacterial infection. Women have an increased incidence of UTI at the onset of sexual intercourse - 30% risk of UTI by age 25 - 50% lifetime risk Note: Men with obstruction to outflow (enlarged prostate) are more prone to UTIs ** UTIs are an uncomplicated infection in a healthy individual with a structurally and functionally normal urinary tract ** Complicated Infections- are those associated with factors that increase the chance of acquiring bacteria and decreasing the efficacy of therapy - Associated with structurally or functionally abnormal urinary tract - Immunocompromised host - Increased bacterial virulence - Antimicrobial resistance

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Diagnosis 1- Urinalysis (dipstick)- 3+ wbc/hpf, nitrites, leukocyte esterase 2- Urine culture- 100,000 colonies/cc but in symptomatic women the presence of 100 colonies/cc is diagnostic - Note: Urine samples will invariable have some bacteria in it because the urine comes into contact with the skin as it exits. - There are bacteria living on the skin as well as genital bacteria (choliform bacteria) 3- Midstream Urine- is the best sample because; the initial flow will contain the genital bacteria from the skin. This should be the sample that is cultured 4- Catheter Specimen- also a means of getting a sterile urine sample 5- Suprapubic aspirate- done mainly in children or adults with grossly distended bladders Bacterial Virulence Factors ** Bacteria have fimbriae and these have receptors for the bladder wall and kidney, which assists them in facilitating infection 1- Adherence- Type I Pili- (mannose sensitive)- adheres to bladder mucosa. Normally causes cystitis 2- Adherence- Type P Pili (mannose resistant)- binds to glycoprotein receptors on urothelium of the upper tract - Normally causes pyelonephritis ** In addition infection may be the result of epithelial cell receptivity. 1- Vagina- increased adherence in susceptible women: early pregnancy, post-menopausal 2- Bladder- the fimbria binds to uroplakin molecules on the bladder cells Host Factors 1- Adherence- glycolipid, glycoprotein receptors 2- Blood group antigens- Groups Le a-b, a+b are slightly more susceptible to UTI than Le a-b+ 3- Bladder- immune response 4- Normal periurethral flora- lactobacilli, coagulase negative staph, corynebacteria, streptococcus 5- Prostatic Zinc- Theorized that zinc acts as a prostatic anti bacterial agent. Therefore men with lower zinc levels are more prone to infections. However taking exogenous zinc has not been proven to decrease UTI incidence 6- Normal ureteral peristalsis + bladder emptying- bacteria in the urine tends to multiply quickly, therefore any obstruction to outflow often results in severe UTI Print Slide #17 +18 Note: The majority of UTIs are due to E. coli - Anaerobes do not usually cause infection IVP- Intravenous pyelogram - Contrast media + x ray - Useful for obstruction diagnosis Cystoscopy- used to visualize the urethra, bladder wall, and ureteric orifices - Invasive test Types of Infections - Cystitis 19

Prostatitis Pyelonephritis Epididymitis

Acute Bacterial Cystitis ** The common etiologic agents of cystitis are the choliform: - E. coli, Proteus, Klebsiella, enterobacter - Women are more likely to develop cystitis because of the short urethra ** Predisposing factors to cystitis include: - Bladder calculi - Urinary obstruction - Diabetes mellitus - Instrumentation - Immune deficiency ** All forms of clinical cystitis are characterized by a triad of symptoms: iFrequency/Urgency- urination every 15-20 mins iiSuprapubic pain- lower abdominal pain localized over the bladder region (suprapubic region) iiiDysuria- pain or burning on urination Note: Hematuria may also be present ** Associated with these localized changes, there may be systemic signs of inflammation - Fever, chills, general malaise - However in the usual case bladder infections do not give rise to constitutional symptoms ** Diagnose by using a dipstick or urine microscopy. If this is the first infection there is no need for a urine culture ** Treat with a 3-day course of antibiotics: 1- Beta lactams- ampicillin, amoxil, cephalosporins (1st generation) 23Nitrofurantoin- specific to the urinary system and requires 5 days of treatment The other types of antibiotics may affect the normal flora of the GI However this type works only in the urinary tract TMP/SMX

4- Aminoglycosides- gentamicin (IV)- used for resistant infections - Ex: nosocomial UTI - A 3rd generation cephalosporin may also be used for these resistant infections 5- Fluorquinolones Recurrent UTI - Identify and treat the predisposing factor - Do a urine culture, +/- ultrasound ** Recurrent UTIs in young women may be related to sexual intercourse because the bacteria from the urethra enters the bladder - Therefore in susceptible individuals a UTI may develop each time the person has sexual intercourse - Therefore use of prophylactic low dose antibiotic therapy is indicated - Ex: nitrofurantoin - Older women may become prone to UTIs as a result of hormonal changes - Use of local estrogen therapy may help to prevent UTIs Note: Cranberry juice may prevent adherence of the bacteria to the bladder wall

Acute Bacterial Prostatitis ** Usually uncommon, however it tends to be severe - Occurs in men 20s- 40s - Fever, chills, lower back pain, perineal pain, suprapubic pain - Along with frequency, urgency, dysuria, poor stream - Hematuria - Malaise and generally ill looking - Tender prostate

20

** Diagnose with a digital rectal exam that elicits a tender prostate - Urine culture - Leucocytosis ** Treatment tends to be long to prevent development of chronic prostatitis - Antibiotics (fluoroquinolones) 4-6 weeks - Analgesics - Catheter/ suprapubic cystostomy- urinary retention tends to occur because the prostate is edematous - IV fluids, bed rest Chronic Bacterial Prostatitis - Frequency, urgency, dysuria - Perineal, suprapubic, genital or lower back pain - In chronic prostatitis the prostatic tenderness is not always present on DRE Print Slide #28, 30 ** Treatment with a 6-week course of fluoroquinolones - Use of alpha adrenergic blockers - Skeletal muscle relaxants and analgesics Treatment of Chronic Pelvic Pain Syndrome (Chronic non-bacterial prostatitis) - Antibiotics- fluoroquinolones, TMP/SMX - Analgesics- NSAIDs - Alpha blockers - Allopurinol Note: Chronic non-bacterial prostatitis is more common than acute bacterial prostatitis Epididymitis - Swollen painful scrotum - Important to exclude testicular torsion especially in children - Urine microscopy and culture - Scrotal Doppler- may be helpful to determine the blood supply and venous drainage of the testes - If the blood supply is intact it is epididymitis - If there is decreased or no blood supply = testicular torsion ** Treat epididymitis with antibiotics and analgesics Acute Pyelonephritis - Fever, flank pain, dysuria ** Acute pyelonephritis is a bacterial infection of the kidney - Usually due to reflux of infected urine from the bladder to the kidneys - In children with pyelonephritis look for a congenital cause

** Other predisposing factors include: - Ascending infection - Vesciourteral reflux - Ureteral obstruction - P fimbria ** Uncomplicated pyelonephritis occurs in adults with normal urinary tract - Males below 50 - Females Print Slide #38-39 ** For the treatment of acute pyelonephritis begin empirical therapy before the culture results are returned ** The predisposing factors for the development of complicated pyelonephritis are: iObstruction- relieved by draining the kidney using either a ureteral stent or percutaneous nephrostomy iiDiabetes- danger of emphysematous pyelonephritis - Emphysematous pyelonephritis- is infection by a gas-producing organism iiiPregnancy- danger of premature delivery ivSilent pyelonephritis- occurs in transplant patients and the elderly vImmunosuppression 21

vi-

Structural + functional abnormalities- congenital etc

** The complications of pyelonephritis include: - Bacteremia - Septic shock - Renal abscess - Kidney Scarring - Renal insufficiency - Perinephric abscess- outside the kidney Chronic Pyelonephritis - Small scarred kidney - Related to previous bacterial infections - Rarely due to uncomplicated infections - May be due to other etiology: reflux, obstruction, analgesic abuse - Often asymptomatic or presents with hypertension or renal failure - Pyuria and abnormal renal function tests ** Treatment of chronic pyelonephritis involves: - Long term antibiotics - Anti-reflux surgery - Removal of stones - Correction of obstruction - Nephrectomy Pregnancy - 25-35% risk of pyelonephritis in untreated bacteruric women - Pregnant women with pyelonephritis have a higher incidence of prematurity, low birth weight infants and infant mortality Fourniers Gangrene - Necrotizing fasciitis of male genitalia - Mixed organisms: E. coli, Klebsiella, enterococci, bacterioides, clostridia, microaerophilic streptococci ** Predisposing factors include: diabetes, periurethral abscess, and periurethral urinary extravasations ** Treatment with: - Emergency debridement - Urinary diversion- via catheter, suprapubic tube - Colostomy- if colorectal problem is present - Antibiotics SF28D-PA 03/04/09- Pathology of the Breast- SHIRLEY ** The breast is made up of specialized epithelium and stroma that give rise to both benign and malignant lesions - 6-20 major ductal systems originate at the nipple - The keratinizing squamous epithelium of the overlying skin continues into the ducts and becomes a double layer of cuboidal epithelium - Successive branching of the large ducts eventually leads to the formation of the terminal duct lobular unit Note: Most disease affects the lobule and the first part of the duct (terminal duct lobular unit) Clinical Presentations of Breast Disease ** The most common symptoms reported by women are: pain, palpable mass or nipple discharge - A breast mass usually does not become palpable until it is about 2 cm in diameter - The likelihood that a palpable mass is malignant increases with the age of the patient ** Therefore breast diseases may present as: - Palpable lumps - Pain - Inflammatory masses - Nipple discharges - Non-palpable abnormalities on breast ultrasound/mammography ** Mammographic screening and ultrasound have the ability to detect small, nonpalpable breast carcinomas that are not yet associated with breast symptoms - Facilitates early detection 22

The sensitivity and specificity of mammography increases with age Screening begins at age 40 Younger women only undergo mammography if they have had a prior palpable cancer or a strong family history of breast cancer

** Methods of pathological diagnosis include: - Fine needle aspiration cytology- does not require anesthesia. However only gives the cells without the underlying tissue - Incisional biopsy- use of a larger needs to excise a portion of the lump - Excisional biopsy- removal of the lump Note: Hook-wire localization biopsies or image-guided biopsies are done for lesions detected on ultrasound or mammography - This is non-palpable lesions which include masses and calcifications ** Most women who present with breast complaints will have benign lesions - However breast cancer is one of the most common malignancies affecting women in the Caribbean Benign Breast Disease Non-Neoplastic Diseases: Inflammation ** Inflammatory disease of the breast often present as an erythematosus, swollen, painful breast Acute Mastitis - Occurs as a complication of breast feeding (during lactation) - Most arise in the first month of nursing - The breast is vulnerable to bacterial infection cause of the development of cracks + fissures in the nipples - This allows for entry of bacteria such as Staphylococcus aureus or streptococcus which live on the skin - Usually unilateral - However acute inflammation in the breast can lead to abscess formation Treatment: Surgical drainage (under general anesthesia) of the entire breast and antibiotic therapy - Emphasis on nipple care to prevent cracks and fissures Periductal Mastitis (Recurrent Subareolar Abscess) - Can occur in both women and men - Present with a painful erythematous subaerolar mass - Occurs secondary to squamous metaplasia of the lining of the lactiferous duct - 90% of affected patients are smokers - Theory: Vitamin A deficiency associated with smoking alters the differentiation of the ductal epithelium - Condition is not associated with lactation **Keratinizing squamous epithelium extends to an abnormal dept into the orifices of the nipple ducts - Therefore keratin becomes trapped in the ductal system - Causes dilation and eventual ruptures of the duct - This is followed by a chronic + granulomatous inflammatory response - If secondary infection with skin bacteria occur, acute inflammation will also be present ** A fistula tract under the smooth muscle of the nipple and opening onto the skin at the edge of the nipple can occur in recurrent cases Treatment: Removing the involved duct and fistula tract - Specific antibiotic therapy Mammary Duct Ectasia Tends to occur in older women (5th- 6th decade) Usually in multiparous women Periductal chronic inflammation that leads to destruction of the walls of the ducts Affects large ducts Become filled with lipid-laden macrophages and necrotic debris As the inflammation subsides there is periductal fibrosis This fibrosis presents as a poorly defined periareolar mass that can be clinically mistaken with carcinoma Can also present as a thick nipple secretion, +/- the mass

Note: Because the mammographic appearance can resemble carcinoma, carcinoma must be excluded by FNAC or histologic evaluation (biopsy)

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Fat Necrosis - Uncommon lesion - Associated with a history of trauma, prior surgical intervention or previous radiation therapy - Characterized by a central focus of necrotic fat cells - Surrounded by foamy macrophages and neutrophils - Can progress to chronic inflammation with infiltrating lymphocytes and the formation of multinucleated giant cells - Can also present as a palpable mass that may be confused with carcinoma Non-Neoplastic Diseases: Non-proliferative (Fibrocystic) Changes ** These represent the single most common disorder of the breast - Presents as an overall lumpy breast - The areas have an ill-defined diffuse increase in consistency as well as discrete nodularities - Thought to be caused by hormonal imbalances. Relative increases in estrogens or decreases in progesterone ** The main pathologic features are: iCystic change + Apocrine Metaplasia- Small cyst form by the dilation of lobules (terminal ducts) - Cystic lobules can coalesce to form larger cysts - Lined by flattened atrophic epithelium or cells altered by apocrine metaplasia - Thesis cells are large polygonal cells with eosinophilic cytoplasm that resemble the apocrine epithelium of sweat glands - Calcification can occur in the cyst lumens iiAdenosis- an increase in the number of acini per lobule. Therefore adenosis is an increase in glandular proliferation

iiiFibrosis- Cysts rupture and the contents are released into the adjacent stroma - The result is chronic inflammation and fibrous scarring ** These non- proliferative changes are usually diagnosed between the ages of 20 and 40 years - Often multifocal and bilateral - Therefore the classic description is a generalized lumpiness to both breasts, that is generally accentuated during menstruation ** The cysts yield clear fluid on aspiration as compared to cysts that develop during the lactation period (galactoceles) - These galactoceles give turbid fluid on aspiration - Benign features are confirmed on FNAC or biopsy Non-Neoplastic Disease- Proliferative Disease without Atypia ** These changes rarely form palpable masses. They are detected as: a- Mammographic densities- complex sclerosing lesions, sclerosing adenosis b- Calcifications- sclerosing adenosis c- Incidental findings- in biopsies performed for other reasons ** This group of disorders is characterized by proliferation of ductal epithelium and/or stroma without cellular abnormalities suggestive of malignancy 1Epithelial Hyperplasia- Normal ducts and acini are lined by two cell layers: epithelium + myoepithelium Epithelial hyperplasia is defined by the presence of more than 2 cell layers Clinically significant hyperplasia is the presence of 4 or more cell layers The proliferating epithelium fills and distends the ducts and lobules However there is NO atypical architectural or cytological features present Therefore although there is proliferation there is no abnormal histological changes

2- Sclerosing Adenosis- special type of glandular proliferation characterized by increased number of acini and stromal fibrosis. - These changes occur within lobules which compress and distort the acini - The number of acini per terminal duct is increased to at least twice the number found in uninvolved lobules - The normal lobular arrangement is maintained - Calcifications are frequently present in the lumens of the acini - Note: Sclerosing adenosis is associated with an increased risk of breast cancer\

Non-Neoplastic Disease- Atypical Hyperplasia - Certain types of epithelial hyperplasia are characterized by the presence of atypical architecture and/or cytologic features - Atypical hyperplasia is a cellular proliferation resembling ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS) 24

However it lacks sufficient features for a diagnosis of carcinoma in situ Can affect ducts (atypical ductal hyperplasia) or lobules (atypical lobular hyperplasia) Requires a biopsy to look at the underlying tissue framework

Note: Atypical hyperplasia falls between benign and malignant - Therefore no diagnostic clinical or radiological means to determine the difference - Must biopsy and look at the histology NOT the cytology - Need to excise the entire lump to determine its architecture Benign Tumors Fibroadenoma - The most common benign tumor of the female breast - Composed of both proliferating glandular and stromal elements - However in a lesion one element can predominate - Patients usually present before 30 years - Classic presentation is a firm, mobile lump (breast mouse) - Frequently multiple and bilateral ** The epithelium of the fibroadenoma is hormonally responsive. Therefore a slight increase in size may occur in the late phase of each menstrual cycle - Regression usually occurs after menopause ** Fibroadenomas grow, as spherical nodules re are sharply circumscribed and freely movable in the breast tissue - 20% of these lesions are complex fibroadenomas - These are characterized by specific histologic features and carry an increased risk for carcinoma Duct Papillomas - Benign papillary epithelial tumors that occur mainly in large ducts - Papillary are fibro vascular stalks lined by layers of proliferating epithelial and myoepithelial cells with no atypical features - Most patients present with a serous or bloody nipple discharge Note: The epithelial features must be benign to distinguish it from papillary carcinoma Relative Risk for Invasive Breast Cancer for Benign Breast Lesions ** Benign lesions have different levels of risk for the development of invasive breast cancer - The magnitude of the risk may be modified by other factors: - Ex: menopausal status, family history No Increased Risk (NIR) - Mastitis - Fat necrosis - Mammary duct Ectasia - Non-proliferative (fibrocystic) changes - Simple fibroadenomas Slightly Increased Relative Risk (1.5- 2 x) - Moderate or florid epithelial cell hyperplasia - Sclerosing adenosis - Duct papillomas - Complex fibroadenoma Note: These cases should be followed closely in both breasts Moderately Increased Relative Risk (4-5X) - Atypical ductal hyperplasia - Atypical lobular hyperplasia Note: These patients should be started on prophylactic tamoxifen - This slows the rate of development of breast cancer vs. women who receive no prophylactic therapy - Women with a strong family history of breast cancer may opt for prophylactic double mastectomy Summary - Non-proliferative changes- do not increase the risk of cancer - Proliferative disease- is associated with a mild/slightly increased risk 25

Proliferative disease with Atypia- confers the highest risk of carcinoma

Carcinoma of the Breast ** Carcinoma of the breast is the most common non-skin malignancy in women - Accounts for 18% of all female cancers - Incidence rates are highest in North America, Australia, Western Europe - In Jamaica it is the most common invasive tumor of women Risk Factors 1- Age- The incidence increases with age. Uncommon before age 25 years except in familial cases - The incidence increases to the time of menopause and then slows after menopause 2Family History- 10% of breast cancer is due to inherited genetic predisposition First degree relative = mother, sister, daughter A woman with a first degree relative that has breast cancer is at an increased risk in comparison to other women At least 2 genes that predispose to breast cancer have been identified (BRCA 1 and BRCA2)

3- Benign Breast Disease- Certain types of benign breast disease confer a higher risk of developing breast cancer 4- History of Other Cancer- a history of cancer in the other breast or a history of ovarian or endometrial cancer increases a womans risk for breast cancer 5- Hormonal Factors- Factors associated with exposure to increased levels of estrogen increase a womans risk for breast cancer - These factors include: early age at menarche, late age at menopause, nulliparity, late age at first child birth, postmenopausal hormone replacement therapy - High fat intake is also a risk factor because obese persons have higher levels of circulating estrogens 6- Environmental Factors- High fat intake, excessive alcohol consumption, exposure to ionizing radiation ** The etiology of breast cancer in most women is unknown but is most likely due to a combination of the risk factors above - Genetic, hormonal, + environmental factors See Page 5 of notes

Classification of Breast Carcinoma ** Almost all breast malignancies are adenocarcinomas. Carcinomas are divided into: iIn situ carcinoma- refers to a neoplastic population of cells limited to ducts and lobules by the basement membrane - Does not invade lymphatics and blood vessels and cannot metastasize - The myoepithelial cells are often preserved in situ iiInvasive carcinoma- has invaded the basement membrane into the stroma Cells may also invade the vasculature and lymphatics

Note: The majority of Jamaican cancers are ductal because of a lack of screening - Therefore cancers are often detected at the invasive stage rather than the in situ stage - Populations that have more active screening have higher percentages of lobular rather than ductal carcinoma Ductal Carcinoma In-situ (DCIS) - Increased incidence in countries related to increased use of mammographic screening and early cancer detection - These lesions are non-invasive - Therefore proliferating malignant cells within the duct system do not breach the underlying basement membrane - Usually involves a single ductal system **DCIS most frequently presents as mammographic calcifications ** DCIS can be divided into 5 architectural sub-types: iComedocarcinoma- solid sheets of pleomorphic cells with high-grade nuclei and central necrosis iiiiiSolid- cells fill spaces Cribriform- cells arranged around punched-out spaces. The intraepithelial spaces are evenly distributed and regular in shape Papillary- grows into spaces and lines fibrovascular cores Micropapillary- protrusions without a fibrovascular core 26

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** DCIS can be of different grades: - Low - Intermediate - High- comedo form is associated with a high grade ** DCIS is often multifocal; therefore the malignant population can spread widely throughout the duct system without breaching the basement membrane ** Women with DCIS are at risk of recurrent DCIS following treatment - Also at increased relative risk for the development of invasive cancer (8-10 x) especially in the same affected breast Treatment: No chemotherapy because the cancer is localized and has not spread to the circulation - Therefore treat with radiotherapy and surgery Lobular Carcinoma In-situ (LCIS) - Usually an incidental finding on biopsy - Because LCIS is not associated with calcifications or a stromal reaction that would form a density - Relatively uncommon lesion as compared to DCIS - Malignant proliferation of small, uniform epithelial cells within the lobules which do not breach the basement membrane ** The risk is the same on both sides even is the tumor only arise on one side - Therefore the treatment should be systemic as opposed to DCIS - Lobule is increased in size - The uniform cells are low grade in appearance ** The risk of developing invasive cancer is bilateral, therefore treatment should be systemic Invasive (Infiltrating) Ductal Carcinoma ** In patients not undergoing mammographic screening, invasive carcinoma almost always presents as a palpable mass - By the time the cancer becomes palpable over half the patients will have axillary lymph node metastases Usually presents as a hard/irregular palpable lump with or without evidence of local spread

** Evidence of local spread includes: - Tethering of the skin to the carcinoma- Dimpling of the skin - Retraction of the nipple- if the tumor involves the central portion of the breast - Peau dorange appearance- thickening of the skin into an orange peel appearance due to blockage of the lymphatics of the area of skin drainage - Pagets disease of the nipple- ulceration and inflammation due to intraductal spread to the nipple - The nipple must be biopsied

** Invasive ductal carcinoma is the commonest form of breast cancer, especially in poorer populations ** Can also present as an axillary mass. This represents spread to regional lymph nodes - Or present with evidence of distant metastases ** Special histologic types of IDC confer a better prognosis and these include: iMedullary carcinoma- sheets of malignant cells in a dense lymphoid stroma Circumscribed tumor and can be mistaken clinically/radiologically for a fibroadenoma Lymphatic or vascular invasion is never seen

iiTubular carcinoma- characterized by infiltrating tubular structures iiiMucinous/colloid carcinoma- malignant cells in pools of mucin - Tends to grow slowly and express hormone receptors ivPapillary carcinoma- papillary formations like benign papillomas but with the features of invasion

Note: These special types of IDC carry a better prognosis that the more common scirrhous cancer - Scirrhous cancers demonstrate a desmoplastic response with proliferating stroma Invasive Lobular Carcinoma (ILC) - Less common than its ductal counterpart 27

However can present with similar features ILC is more likely to be bilateral and multicentric (multiple lesions in the same breast)

** The histologic hallmark is the pattern of single infiltrating tumors cells - The cells are often formed in single file or in loose clusters or sheets - Indian File- Small uniform cells arranged as strands within a fibrous stroma - Bulls-eye: Cells infiltrate and surround uninvolved ducts. Therefore malignant cells form a ring in the shape of a bulls eye ** ILC tend to metastasize more frequently to the CSF, serosal surfaces and pelvic organs - Because of their propensity for serosal surfaces, these patients tend to have a long term problem with pleural effusion and ascites Prognostic Factors 1- Stage- Various staging systems exist. The stage represents how far the cancer has spread from its foci of origin - Tumor size + axillary node status are important parameters 2Inflammatory Carcinoma- Specific clinical presentation with inflammatory signs Breast swelling and skin thickening Associated with underlying IDC or ILC that features prominent lymph-vascular invasion Poor prognosis- 3 year survival of 3-10%

3- Tumor Grade- The grade is a histologic assessment of the differentiation of the tumor - Nuclear grade, tubule formation + mitotic rate 4- Hormone Receptors- Tumors that express receptors for estrogen + progesterone can be treated with hormonal manipulation - Therefore hormone positive tumors have a slightly better prognosis than hormone receptor negative tumors 5- Molecular Markers- Newest category of prognostic markers that can be detected by immunohistochemistry - c-erb-B2, HER2/neu Other Breast Tumors ** The two types of stroma in the breast: interlobular + intralobular give rise to distinct types of neoplasms Phyllodes Tumor - Arise from intralobular stroma - Range in size from a few cm to massive lesions that involve the entire breast - Most are low-grade lesions that can recur locally but do not metastasize - Others are high-grade lesions that exhibit aggressive clinical behavior - Ex: spread to distant sites. These are sometimes called cytosarcoma phyllodes Pathology of the Male Breast ** The normal male breast consists of the nipple and a rudimentary duct system that ends in terminal buds without lobule formation Gynecomastia - Enlargement of the male breast related to hormonal imbalances - Usually due to a relative increase in estrogens - May be physiologic- seen at puberty or old age - Pathologic- associated with cirrhosis, functional testicular tumors, drugs (alcohol, marijuana, anabolic steroids) - Can be unilateral or bilateral - May present as diffuse enlargement or as a defined mass Carcinoma - Rare occurrence - Presents earlier in males because they have less fat. - Therefore lumps + discharges are more apparent - As a result of early detection male carcinoma of the breast has a better prognosis - Skin involvement is more frequent - Breast epithelium in men is limited to large ducts near the nipple - Therefore the carcinoma usually presents as a palpable subaerolar mass - Nipple discharge is a common symptom - Ulceration through the skin is more common in men than in women SF28D-ME- 27-03-09- UTIs in Children- NEWTON-DUNCAN 28

** The urinary tract includes the: - Kidney - Ureter - Bladder - Urethra Lower Urinary Tract = bladder + urethra - Clinically associated with irritative symptoms - Burning, increased frequency and urgency Upper Urinary Tract = Kidney + ureter - Clinically associated with systemic symptoms + signs - Fever, malaise, rigor, anorexia, weight loss ** A urinary tract infection is a state where organisms are multiplying within the urinary tract ** A UTI is diagnosed when more than 105 colonies/ml of urine is detected from a midstream catch OR when there is any growth from a bladder tap - This is because a bladder tap should result in a sterile sample. - Unlike a mid-stream catch which may contain some of the bacteria from the skin - Note: Less than 105 colonies/ml is considered to be a possible infection - Less than 104 colonies/ml is NOT an infection ** Gram-negative aerobic bacteria are the organisms that cause the majority of urinary tract infections - EX: E. coli, Klebsiella, enterobacter - E. Coli is responsible for up to 80% of UTIs ** If the child is ambulatory it is better to treat specifically after the culture returns - Therefore delay empirical therapy in favor of specific therapy ** However is the child has an ill appearance (septic)- treat empirically immediately - Presumptive treatment must cover for E. coli and other gram-negative bacilli Note: The proximity of the genitourinary tract to the anus is a factor for the development of UTIs in children ** Urine collection can be done in two ways: iAspiration- sterilize the skin over the suprapubic region and then aspirate through the skin - This usually provides the most sterile sample - Disadvantage- possibility of iatrogenic injury as the needle enters - Bladder taps are simpler in children because the bladder is mostly outside of the pelvis i.e. above the suprapubic line iiReceptacle Collection- non-sterile because the urine contacts the skin and the bacterial living on the skin will enter the sample

** In children the route of infection may be spread to the kidneys by ascending via the urethra or via a hematogenous route - UTI in children should prompt the physician to further investigate the urinary tract for an underlying congenital anomaly and to check for the presence of renal scarring ** Contamination of the urinary stream rarely leads to infection if there is normal unidirectional flow of urine from the kidney to the exterior - Therefore the disruption of this ordered flow is the major underlying factor of UTIs in children ** Disruption of normal unidirectional flow leads to STASIS within the urinary tract - Stasis is the main predisposing factor for UTIs in children Note: 20-30% of UTIs in children have a clear underlying cause Note: UTIs in children is NOT caused by prostatic obstruction ** Urinary tract stasis may be caused by: Mechanical Obstruction- to flow of urine leading to stasis and pooling of urine at various sites Can be the result of strictures at any point extending from the kidney to the urethral meatus. Two examples of mechanical obstruction are: - Pelvic-Ureteric Junction Obstruction- Treatment with Andersen-Hynes Pyeloplasty - Vesicoureteric Junction Obstruction- block between the ureter and the bladder

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** Stasis can also occur is there is a problem of flow secondary to abnormal emptying (abnormal peristalsis) - The detrusor muscle is abnormally thick and cannot contract normally - Problem with the bladder nerve supply (neurogenic bladder) Note: These two mechanisms lead to stasis and are causes of recurrent UTIs - Therefore they require surgical intervention to treat **Three causes of urinary tract stasis in children are: 1- Posterior Urethral Valves (congenital cause)- Affects male children - The commonest congenital cause of LUT obstruction in the male child - The valves are leaflets of urethral tissue in the area of the prostate that causes blockage of the bladder - Leads to a backflow of urine to the kidneys - Treatment: Fulguration of the valves - Surgical operation to destroy the valves 2Retrograde Flow- Vesicoureteric reflux- Urine flows back from the bladder up the ureter More common in female children Normally when the ureter enters the bladder a segment of the ureter is intramuscular This portion helps to compress the ureter when the bladder is full Therefore is sub-urothelial course helps to prevent backflow as a part of a normal anti-reflux mechanism However if the ureteric orifices are larger than normal or the ureter has a shorter intramucosal course the individual will be prone to reflux

** Vesicoureteric Reflux- is graded from 1-4 iGrade I- backflow of urine from the bladder to the lower 1/3 of the ureter - Most common type - Tends to resolve as the child gets older and does not usually require surgery iiiiiiv3Grade II- backflow of urine to the level of the kidney BUT there is no dilatation of the ureter Grade III- backflow or urine to the level of the kidney with dilatation of the ureter Grade IV- backflow of urine to the level of the kidney associated with dilatation and torturosity of the ureter Duplex Systems- detected with the use of IVU (x-ray with contrast) Usually not clinically significant But a small percentage have problems with recurrent UTIs A duplex system is the duplication of some segment of the urinary tract Duplex Ureter- the pelvis branches and then joins before reaching the bladder

** In a duplex system in which the two segments empty at 2 different points; the kidney is then divided into 2 moieties: upper + lower moieties - The upper moiety of the kidney tends to drain to a lower part of the urinary tract - The upper moiety tends to empty at a more abnormal point and therefore has a greater tendency to become obstructed (predisposed to UTI development) The lower moiety of the kidney drains to an upper part of the urinary system. Therefore the lower moieties tends to have more normal emptying Note: Abnormalities of the lower moiety tends to be reflux NOT obstruction

Summary - UTIs normally occur once and do not return - But surgical causes of UTI have a predisposition to recur due to the phenomenon of stasis - Stasis may be due to obstruction or abnormal flow - The commonest cause of upper tract infection in children is vesicoureteric reflux - This can lead to renal scarring and hypertension later in life - The younger the child, the more atypical the means of clinical presentation SF28D-SU 30-03-09- Urinary Bladder: Trauma, tumor & Stones- TULLOCH Bladder Trauma - The bladder is an extraperitoneal and intrapelvic organ in adults. Can extend up into ht abdomen if it is distended - In the child the bladder is an intra-abdominal organ ** The bladder is relate to the bony pelvis, rectum, musculature - The base is firmly anchored and the body is mobile 30

** The mechanism of bladder trauma is via: iBlunt/Penetrating injury- >80% iiIatrogenic- 15% iiiIntoxication- 2% ivSpontaneous- 1%- occurs in an augmented or man-made bladder (constructed bladder) ** The extent of the trauma also determines the bladder injury: iContusion- blood seen in the urine but the bladder is still intact. These heal without intervention needed iiRupture or Penetration- as a result of accelerating/decelerating injuries that impact on the bony pelvis iiiIntraperitoneal injury- bladder becomes directed into the abdominal cavity ivExtraperitoneal injury- extravasations of the urine into the extraperitoneal spaces Clinical Diagnosis of Bladder Trauma - No specific symptoms or signs - However there is a history of trauma- because the bladder is a well-protected structure - External signs of injury - Inability to void- may occurs if the bladder is ruptured or the urethra is torn - Hematuria- urethral injury Note: Because the bladder is a well-protected organ, damage to the bladder is usually concomitant with damage to other vital structures - Therefore in unstable patients the goal is to preserve life - ABCs - Surgery = resuscitation ** Investigations in a stable patient involve: - Plain x-ray- to look for fractures of the pelvic ring - KUB x-ray - Retrograde Urethrogram- insertion of contrast into the urethra. Used to exclude damage to the urethra. - Standard Cystogram- use of contrast to determine if there is any bladder compromise Extraperitoneal Rupture- no leakage of urine into the peritoneal cavity Intraperitoneal Rupture- leakage of urine into the peritoneal cavity Note: All intraperitoneal ruptures must be repaired because of the toxic effects of urine on the peritoneal tissues - Most extraperitoneal ruptures should also be surgically repaired; along with all penetrating injuries to the bladder Note: Some small extraperitoneal injuries can be repaired by drainage alone because they will seal off and heal eventually on their own Bladder Trauma: Facts - Bladder filling influences the type of injury - Bladder rupture occurs in 10% of pelvic fractures - Pelvic fractures occur in 90% of bladder ruptures - Therefore rupture of the bladder is invariably associated with pelvic fracture - However the associated injuries to bladder trauma are their main cause of morbidity Bladder Tumors - Transitional cell carcinoma- 90%- the lining of the bladder is transitional epithelium Squamous cell carcinoma- <10%- associated with chronic irritation of the bladder which leads to metaplasia of the lining from transitional epithelium to squamous cell epithelium EX: In Egypt there is a parasite that infects the bladder leading to metaplasia of the lining Adenocarcinoma- 1%- usually associated with the dome of the bladder because the urachus is there The urachus has an adenocolumnar lining

** Bladder tumors are the 2nd most common GU cancer - The most common GU cancer is prostate cancer - Peak incidence 50-70 years - Males > females 3:1 ** The risk factors for the development of bladder tumors are: - Industrial toxins (aniline dyes) - Heavy smokers 31

Schistosoma hemotobium- parasite that is associated with squamous cell cancer Pelvic irradiation Drugs- cyclophosphamide

** Bladder tumors tend to present most frequently with intermittent painless hematuria (80%) in the appropriate age group ** Bladder irritability- increased frequency + urgency ** Bladder tumors tend to present late with symptoms such as: - Ureteric obstruction- blocs the ureteric orifices and can lead to post-obstructive renal failure - Lymph edema - Pelvic masses Bladder Tumor: Diagnosis iUrine culture/cytology- looks for cancer cells that have been shed in the urine. However only aggressive cancers shed cells into the urine iiIVP iiiCystoscopy/Bimanual Examination- used to examine the lining of the urethra, ureter, bladder, renal pelvis ivCT Scan Bladder Cancer Staging - The cancer begins in the lining and spreads to the external - Low grade- tumor still resembles the source of the tissue - Intermediate grade - High grade- malignant appearance however it no longer resembles its parent tissue. Can spread to the muscle and then to adjacent organs

Superficial Bladder Tumor- no muscle involvement - Can be treated less aggressively - Treatment is local - Remove the growth and apply chemotherapeutic agents to the bladder lining - TURBT, Intravesical therapies Muscle Invasion: - Cystostomy- remove the bladder - Chemotherapy- systemic - Radiation- rarely used Note: Treatment and follow up is life-long because bladder cancers have a tendency to recur - High grade tumors- recur frequently - Lower grade tumors- recurrence less frequent

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Bladder Stones ** Bladder stones are the calculus material remaining after voiding from a hollow viscus - If the same material occurred in a solid organ it would be known as a calcification ** Uncommon in the west and are usually secondary to obstruction ** Bladder stones are endemic in areas with diets that have: - Low phosphorous - Oxalate rich vegetables - Ammonium and oxalate in urine ** Bladder stones can be secondary to several processes: 1Voiding Dysfunction- which predisposes to stasis Benign prostatic enlargement Urethral stricture disease Neurogenic Bladder- both sexes

2- Foreign Body- non-absorbable sutures acts as a nidus for stones and calcifications Bladder Stones: Symptoms & Signs ** Can be asymptomatic ** Symptomatic: - Primary condition is made worse by the stone - Painful voiding - Hematuria - Infections Urine analysis- shows pyuria, hematuria + bacteruria ** Diagnoses with the use of: - Plain x-ray - Pelvic ultrasound - CT scan - Cystoscopy ** Treatment: - Remove stones and treat the cause - Medical dissolution- of uric acid stone - Lithotripsy- Cystoscopic, percutaneous, open surgery Note: Encourage hydration, which will promote a flow of urine. This will help to mitigate the formation of the stone

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