Exam 6 Worksheet - Renal & Male GU PDF

1 Exam 6 Worksheet Renal & Male GU 1. Acute Kidney Injury AKI (formerly ARF) is an abrupt reduction in renal function producing: ○ Accumulation of waste materials in the blood (B...

1 Exam 6 Worksheet Renal & Male GU 1. Acute Kidney Injury AKI (formerly ARF) is an abrupt reduction in renal function producing: ○ Accumulation of waste materials in the blood (BUN) ○ Disruption of in fluid, electrolyte, and acid-base balances ○ Increased serum creatinine ○ Decreased GFR Classified by the pathophysiology: Prerenal Postrenal Intrinsic/intrarenal ACUTE KIDNEY INJURY - PRERENAL AKI Patho: blood flow to the kidney is impaired. Volume depletion is the most common Hypotension Absolute: Hemorrhage, dehydration, burns Relative decrease: Neurogenic, anaphylactic, septic shock, third-spacing and edema. Primary renal abnormalities: ○ Occlusion or stenosis of renal artery ○ Drug-induced impairment of renal autoregulation ○ Decreased cardiac output: Cardiogenic shock, dysrhythmias, heart failure, MI Clinical manifestations Low GFR, usually including oliguria, high urine specific gravity and osmolality and low urinary sodium concentrations. Prolonged prerenal AKI results in intrinsic kidney injury. - (elderly with atherosclerosis, heart disease, preexisting renal insufficiency who use NSAIDS, ACEIs OR ARBs are at increased risk) ACUTE KIDNEY INJURY - INTRINSIC/INTRARENAL AKI Patho: Small vessels within the kidney are inflamed, obstructed or damaged. Due to primary dysfunction of the nephrons. Classified by the area involved: tubular, glomerular, interstitial or vascular.  2 Acute tubular necrosis (ATN) is the most common cause. Result of tubular cell injury, primarily due to ischemia or exposure to nephrotoxic substances. Sepsis is the most common cause of ischemic ATN ACUTE KIDNEY INJURY - POSTRENAL AKI Patho: Due to obstruction within the urinary collecting system distal to the kidney. Pressure increases in Bowman’s capsule, which impedes glomerular filtration. Damage and ability to regain function depends on the length of time the obstruction persists. If obstruction persists, intrinsic AKI will result. Clinical manifestations: vary based on the duration of the obstruction. Most common causes: BPH, kinked or obstructed catheters, intraabdominal tumors, strictures, calculi. CHRONIC KIDNEY DISEASE 2. Acute tubular necrosis ACUTE TUBULAR NECROSIS (ATN/ATI) Patho: Two pathophysiologic processes: Vascular: renal blood flow decreased; hypoxia and vasoconstriction. Tubular: inflammation and reperfusion injury, causes casts, obstructs urine flow, tubular back leak. Can repair itself or sustained injury will lead to end-stage renal disease. - ATI is the most common cause of acute kidney injury and attributed to ischemia and/or toxicity from an endogenous or exogenous substance. - Tubular epithelial cell injury and altered intrarenal hemodynamics are the primary contributors to ATI. - The clinical outcome is determined by the magnitude and duration of ATI. Tubule necrosis leads to impaired filtration and increased NaCl delivery to the macula densa. As a result, the tubuloglomerular feedback mechanism of GFR regulation is activated, and GFR is reduced. Recall that reduced GFR can lead to azotemia and uremia. Acute tubular necrosis can be caused by low blood flow to the kidneys or exposure to toxic substances. ATI is characterized by tubular epithelial injury at multiple points along the nephron, with large skip areas in between, often accompanied by rupture of basement membranes (tubulorrhexis) and occlusion of tubular lumens by casts. ACUTE TUBULAR NECROSIS (ATN/ATI): CLINICAL MANIFESTATIONS (3 PHASES) Prodromal/Initiation Normal or declining urine output. Serum BUN and creatinine begin to rise. Insult to the kidney has occurred and the duration of this phase will vary depending on: cause of the injury, amount of toxin ingested, duration and severity of hypotension. Oliguric/Maintenance May last up to 8 weeks with usual urine output 50-400 mL/day Characterized by oliguria and progressive uremia; decreased GFR, hypervolemia May have signs of fluid excess, hyperkalemia, uremic syndrome. Typically lasts 1-2 weeks May require dialysis Post-Oliguric/Recovery Termination of oliguric phase represents renal recovery. Not all recover. Urine volume increases (diuresis); tubular function impaired and azotemia continues Fluid volume deficit until kidneys recover. May last 2-10 days; full recovery one year. - Recovery phase is ushered in by a steady increase in urine volume that may reach up to 3?L/day. The tubules are still damaged, so large amounts of water, sodium, and potassium are lost in the flood of urine. Hypokalemia, rather than hyperkalemia, becomes a clinical problem. There is a peculiar increased vulnerability to infection at this stage. 3. Nephrotic vs Nephritic syndrome NEPHRITIC SYNDROME Patho: most causes are immunologically mediated glomerular injury Inflammation of the glomeruli Proliferative changes and leukocyte infiltration  3 Typical clinical presentation of proliferative types of Glomerulonephritis Post infectious (streptococcal), lupus Clinical Manifestations: Hematuria Oliguria Proteinuria Azotemia Hypertension Nephritic syndrome is the typical clinical presentation of most proliferative types of GN such as postinfectious GN, crescentic GN, and proliferative lupus GN. The lesions that cause the nephritic syndrome are characterized by proliferation of the cells within the glomeruli, often accompanied by an inflammatory leukocytic infiltrate. This inflammatory reaction severely injures the capillary walls, permitting blood to pass into the urine and inducing hemodynamic changes that lead to a reduction in GFR. The reduced GFR is manifested clinically by oliguria, fluid retention, and azotemia. Hypertension probably is a result of both the fluid retention and renin release from the ischemic kidneys. NEPHROTIC SYNDROME Patho: Increased glomerular permeability to proteins (damage to the glomeruli); caused by a derangement in glomerular capillary walls resulting in increased permeability to plasma proteins. Most common cause in adults is DM – most likely due to inflammation. 1. Increased permeability of the glomerular membrane allows large quantities of protein to leave the bloodstream and exit the body in the urine. 2. Hypoalbuminemia and proteinuria 3. ↓albumin stimulates the liver to ↑ production of cholesterol and lipoproteins = hyperlipidemia  4 Proteins required for hemostasis are lost in the urine, stimulating hepatic synthesis of clotting factors, ↑ risk of thrombus formation. As the serum albumin is lost, the oncotic pressure within the blood vessel declines and the hydrostatic pressure ↑, forcing fluids into the interstitial spaces. ↓in the circulating volume results in the activation of RAAS causing sodium and water retention, ↑ protein loss, and edema. Heavy proteinuria depletes serum albumin levels at a rate beyond the compensatory synthetic capacity of the liver, resulting in hypoalbuminemia. Increased renal catabolism of filtered albumin also contributes to hypoalbuminemia. The generalized edema is a direct consequence of decreased intravascular colloid osmotic pressure. - Heavy proteinuria depletes serum albumin levels at a rate beyond the compensatory synthetic capacity of the liver, resulting in hypoalbuminemia. Increased renal catabolism of filtered albumin also contributes to hypoalbuminemia. The generalized edema is a direct consequence of decreased intravascular colloid osmotic pressure. There is also sodium and water retention, which aggravates the edema. This seems to be due to several factors, including compensatory secretion of aldosterone, mediated by the hypovolemia-enhanced renin secretion; stimulation of the sympathetic system; and a reduction in the secretion of natriuretic factors such as atrial peptides. Edema is characteristically soft and pitting, and it is most marked in the periorbital regions and dependent portions of the body. If severe, it may also lead to pleural effusions and ascites. 4. Pyelonephritis PYELONEPHRITIS Upper urinary tract infection of the renal pelvis and parenchyma usually due to an ascending urinary tract infection (via urethra, bladder, ureters) Acute and Chronic Most common causative organisms are subgroups of Escherichia coli Fungal infections, mycoplasmas, and other anaerobic bacteria are occasionally responsible. Uropathogenic bacteria possess a substance that allows the bacteria to bind to epithelial cells of the urinary tract. Some bacteria secrete proteins that aid in protection from phagocytosis. Bacteria undergo continuous mutation to overcome both host defenses and antimicrobials used in their treatment. Pyelonephritis is one of the most common diseases of the kidney and is defined as inflammation affecting the tubules, interstitium, and renal pelvis. It occurs in two forms. Acute pyelonephritis is generally caused by bacterial infection and is associated with urinary tract infection. Chronic pyelonephritis is a more complex disorder; bacterial infection plays a dominant role, but other factors (vesicoureteral reflux, obstruction) predispose to repeat episodes of acute pyelonephritis. Pyelonephritis is a serious complication of urinary tract infections that affect the bladder (cystitis), the kidneys and their collecting systems (pyelonephritis), or both. Bacterial infections of the lower urinary tract may be asymptomatic (asymptomatic bacteriuria) and remain localized to the bladder, but lower urinary tract infection can potentially spread to the kidney. More than 85% of urinary tract infections are caused by the gram-negative bacilli that are normal inhabitants of the intestinal tract. By far the most common is Escherichia coli. RISK FACTORS FOR URINARY TRACT INFECTIONS PYELONEPHRITIS Increasing age Vesicoureteral reflux Congenital anatomic anomalies of the urinary tract Female gender Pregnancy Diaphragms with spermicidal agents for contraception. Neurogenic bladder Instrumentation of the urinary tract (catheterization, cystoscopy) Urinary obstruction (calculi, BPH) Immunodeficiency conditions such as AIDS DM Obesity Sickle Cell Trait Uncircumcised ACUTE PYELONEPHRITIS Patho: Bacteria bind to epithelial cell receptors initiating an inflammatory response causing damage to kidney parenchyma. Usually unilateral. Risk factors: pregnancy, DM, anatomic abnormalities of urinary tract. Clinical manifestations: Sudden onset. Patients are acutely ill, presenting with fever, chills, +CVAT, dysuria, urgency, frequency. N/V, anorexia Fever-induced dehydration. Hallmarks: patchy interstitial suppurative inflammation, intratubular aggregates of neutrophils, neutrophilic tubulitis, and tubular injury. Dx: Presence of clinical manifestations UA: WBC, RBC, Leuk, + Nitrites Urine culture  5 - Acute pyelonephritis is a suppurative inflammation of the kidney caused by bacterial and sometimes viral (e.g., polyomavirus) infection, which can reach the kidney by hematogenous spread or, more commonly, through the ureters in association with vesicoureteral reflux. Complications: Abscess formation, septic shock, acute respiratory distress, recurrent/chronic pyelonephritis, and chronic kidney disease attributable to scarring produced by recurrent infections/inflammation. Renal scarring and the subsequent development of chronic kidney disease are more likely when there are preexisting anatomic or functional urinary tract abnormalities. CKD has been found to progress more rapidly following acute pyelo. Preexisting CKD can increase the severity of infection. CHRONIC PYELONEPHRITIS Patho: Reflux of infected urine into the renal pelvis is the typical cause. Kidneys are usually smaller than normal with caliceal deformity, chronic inflammation and parenchymal scarring. Those at risk = persons with bacteriuria associated with obstructive disorders, renal calculi, neurogenic bladder, vesicouretal reflux, or underlying renal disease. Clinical manifestations: Symptoms may mimic acute pyelo = flank pain, abd pain, fever, malaise or anorexia. Dx Tests: UA may parallel acute, but not as profound. US reveals both smaller than normal kidneys with distorted architecture and significant scarring. Renal tubules may be dilated or atrophied. - Chronic pyelonephritis is a disorder in which chronic tubulointerstitial inflammation and scarring involve the calyces and pelvis. The hallmarks of chronic pyelonephritis are coarse, discrete, corticomedullary scars overlying dilated, blunted, or deformed calyces, and flattening of the papillae. - Chronic pyelonephritis ensues when anatomic anomalies result in urine reflux or urine outflow obstruction; multiple episodes of this injury leads to irregular scarring of the kidney that is typically more prominent at the upper or lower poles where reflux is more common. 5. Differentiate the types of incontinence TYPES OF INCONTINENCE Incontinence is: ○ Report of any involuntary urine loss ○ Is never normal under any circumstances ○ Is not a normal part of aging  6 6. Interstitial cystitis INTERSTITIAL CYSTITIS (CHRONIC PELVIC PAIN SYNDROME) Unknown etiology that occurs most frequently in women. The associated pain syndrome is defined by the American Urological Association as “an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder ○ Associated with urinary tract symptoms of more than six weeks duration, in the absence of infection or other identifiable causes.” Characterized by intermittent, often severe, suprapubic pain; urinary frequency; urgency; hematuria; and dysuria. Typical cystoscopic findings include mucosal edema Diagnostics: biopsy to rule out carcinoma in situ (CIS), which clinically mimics interstitial cystitis. Treatment is largely empiric. Some cases are associated with chronic mucosal ulcers (Hunner ulcers); this is termed the late (classic, ulcerative) phase. Late in the course, transmural fibrosis may lead to a contracted bladder. 7. ADPKD CHRONIC KIDNEY DISEASE - COMPARISON OF TYPES AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD) DISEASE (ARPKD) Autosomal dominant (adult) polycystic kidney disease is a Chromosome 6p-mutations in the PKHD1 gene, hereditary disorder characterized by multiple expanding cysts of both kidneys that ultimately which maps to chromosome region 6p21–p23. destroy the renal parenchyma and cause renal failure 1:20,000 Most common; 1 in 400 to 1000 live births and accounting for about 5% to 10% of cases of Dx neonate to childhood ESRD requiring transplantation or dialysis. Symmetrically enlarged kidneys—collecting Two types gene defects ducts enlarge from medulla to cortex ○ PDK1 & PDK2 Cysts derived from epithelial cells of collecting Dx usually in 4th or 5th decade ducts Enlarge kidneys, often asymmetric.-will not progress at same rate, will develop ESRD, usually Liver: Abnormal portal ducts progressing to faster in MEN fibrosis Asymptomatic until renal insufficiency, Other findings include: Liver: multiple cysts, cysts on Usually no other systemic findings. abdominal organs,- liver, spleen, pancreas aneurysms, abnormal cardiac valves, hernias, and diverticuli. Clinical manifestations: Decreased ability to concentrate urine Hypertension-dx late in disease, increase risk of escalated loss of renal fxn, will develop proteinuria, and hematuria Pain: most common complaints, may be due to bleeding with kidney, movement of the kidney stones, UTI or stasis of urine Dx: Genetic history and ultrasonography 8. BPH BENIGN PROSTATIC HYPERPLASIA Is the most common benign prostatic disease in men older than age 50 years. Approximately 30% of white American men in that age group have moderate to severe symptoms of BPH, and histologic evidence of BPH is found in up to 90% of men by age 80. It is not a premalignant lesion. Etiology and Pathogenesis Arises as a result of the loss of homeostasis between cellular proliferation and cell death, resulting in an imbalance favoring cellular proliferation. BPH is characterized by proliferation of benign stromal and glandular elements. DHT, an androgen derived from testosterone, is the major hormonal stimulus for proliferation. BPH most commonly affects the inner periurethral zone and transition zone of the prostate, producing nodules that compress the prostatic urethra. Clinical Features: The main symptoms of BPH are due to urinary obstruction caused by prostatic enlargement and stromal smooth muscle–mediated contraction. Clinical symptoms and signs are related to urinary obstruction that also predisposes to recurrent urinary tract infections. 9. Testicular torsion ACQUIRE DISORDERS: TESTICULAR TORSION Twisting of the spermatic cord typically cuts off the venous drainage of the testis. If untreated, it frequently leads to testicular infarction and thus represents one of the few true urologic emergencies.  7 The thick-walled arteries remain patent, producing intense vascular engorgement followed by hemorrhagic infarction. There are two settings in which testicular torsion occurs. ○ Neonatal torsion occurs either in utero or shortly after birth. ○ “Adult” torsion is typically seen in adolescence and presents with the sudden onset of testicular pain. It often occurs without any inciting injury. ○ If the testis is manually untwisted within approximately 6 hours of the onset of torsion, the affected testis may be spared an orchiectomy. Clinical manifestations: Severe sudden pain in one testis, swelling of scrotum , nausea and vomiting Diagnostic tests: Doppler ultrasound; Testicular nuclear scanning (most definitive) 10.Epididymitis INFECTIOUS DISORDERS: EPIDIDYMITIS & ORCHITIS Epididymitis and possible subsequent orchitis are commonly related to infections in the urinary tract, which reach the epididymis and the testis through the vas deferens or the lymphatics of the spermatic cord. The cause of epididymitis varies with the age of the patient. ○ Epididymitis in childhood is usually associated with a congenital genitourinary abnormality and infection with gram-negative rods. ○ In sexually active men younger than age 35 years, the sexually transmitted pathogens C. trachomatis and Neisseria gonorrhoeae are most frequent. ○ In men older than age 35, common urinary tract pathogens, such as E. coli and Pseudomonas, are responsible for most infections. Clinical manifestations: Enlarged, reddened, tender scrotum, pain with radiation into inguinal area; fever, urethral discharge, cystitis, cloudy urine DX: Elevated WBC and urine positive for organism 11.Phimosis vs paraphimosis PHIMOSIS When the orifice of the prepuce (foreskin) is too small to permit its normal retraction, the condition is designated phimosis. An abnormally small orifice may result from anomalous development but is more frequently the result of repeated bouts of infection that cause scarring of the preputial ring. Phimosis is important because it interferes with cleanliness and permits the accumulation of secretions and detritus under the prepuce, favoring the development of secondary infections and increasing the risk for penile carcinoma. ACQUIRED DISORDERS: PARAPHIMOSIS Etiology, clinical manifestations, and treatment Foreskin that has been retracted over the glans up onto the shaft of the penis cannot be replaced in its normal position Usually secondary to chronic inflammation under the foreskin Constriction causes venous congestion with edema 12.Testicular cancer CONGENITAL DISORDERS: CRYPTORCHIDISM A complete or partial failure of the intra-abdominal testes to descend into the scrotal sac ○ Associated with testicular dysfunction and an increased risk of testicular cancer (3-5X higher risk for testicular cancer) Found in approximately 1% of 1-year-old boys. ○ May be accompanied by other malformations of the genitourinary tract, such as hypospadias. Testicular descent occurs in two phases. ○ During the first transabdominal phase, the testis comes to lie within the lower abdomen or brim of the pelvis. Controlled by the hormone müllerian-inhibiting substance. In the second inguinoscrotal phase, the testes descend through the inguinal canal into the scrotal sac. ○ Androgen-dependent and is thought to be mediated by androgen-induced release of calcitonin gene–related peptide from the genitofemoral nerve. Failure to treat causes fibrotic tubules with deficiency in spermatogenesis, infertility - Bilateral or, in some cases, even unilateral cryptorchidism is associated with tubular atrophy and sterility. Orchiopexy reduces but does not completely eliminate the risk of sterility and cancer. 13. Wilms tumor NEPHROBLASTOMA - WILM’S TUMOR Most common primary renal tumor of childhood and the fourth most common pediatric malignancy in the United States Patho:  8 Precursor lesions called nephrogenic rests, persistent clusters of embryonic cells, are notable on histologic findings. Typically large, well-encapsulated tumors that grow rapidly. Undergo hemorrhagic and cystic changes. As the malignant cells proliferate, the normal architecture of the kidney is altered. The renal pelvis becomes depressed & tumor infiltrates into the renal veins and hilar nodes. Metastasis is typically via bloodstream to brain, liver, adrenal glands, and bone. - Pg 480 - Peak incidence for Wilms tumor is between 2- 5 years of age, and 95% of tumors occur before 10 years of age. Approximately 5% to 10% of Wilms tumors involve both kidneys, either simultaneously (synchronous) or one after the other (metachronous). Bilateral Wilms tumors have a median age of onset approximately 10 months earlier than tumors restricted to one kidney, and these patients are presumed to harbor a germline mutation in one of the Wilms tumor–predisposing genes Clinical Manifestations: Palpable abdominal mass Abdominal pain, HTN, hematuria May produce a tumor thrombus in the Inferior vena cava, which can lead to decreased venous return and lower extremity edema. Dx: Often identified on routine physical exam. Renal US CT of abdomen 14.Nocturnal enuresis ENURESIS Intermittent incontinence while asleep Inappropriate wetting of clothing or bedding Typically refers to incontinence in children, particularly at night Patho: Deficiency in vasopressin (antidiuretic hormone/ADH) Nocturnal over activity of the detrusor muscle Immature or abnormal arousal mechanisms Familial pattern Types: Primary nocturnal enuresis: child who has never achieved continence Secondary enuresis: develops after a period of at least 6 months of dryness Monosymptomatic nocturnal enuresis: child has nocturnal incontinence but no other signs of lower urinary tract malfunction Nonmonosymptomatic nocturnal enuresis: child has symptoms of urgency, frequency, or daytime incontinence with night incontinence 15.Glomerulonephritis ACUTE GLOMERULONEPHRITIS PATHO: Immune response to a variety of triggers (strep most common – post skin and throat infections). Attraction of immune cells to the area of inflammation = degradation of the basement membrane. ↓GFR due to ↓surface area for filtration. CHRONIC GLOMERULONEPHRITIS Patho: Lesions and sclerotic injury dominate = ongoing fibrotic changes. Nephrons atrophy and kidneys become small, scarred and nonfunctional. Clinical Manifestations: Persistent proteinuria with or without hematuria and slowly declining renal fx. Proteinuria and HTN may advance renal damage. Glomerular diseases that assume a progressive course ultimately develop into CKD. Decrease in number of functional Nephrons is a normal physiologic variation found in elderly patients 16.Prostatitis PROSTATITIS: INFLAMMATION OF THE PROSTATE  9 Acute bacterial typically results from bacteria similar to those that cause urinary tract infections. ○ Various strains of E. coli, other gram-negative rods, enterococci, and staphylococci. ○ The organisms reach the prostate through the reflux of contaminated urine from the posterior urethra or the urinary bladder, but occasionally distant foci of infection seed the prostate through lymphohematogenous routes. Chronic bacterial - often have a history of recurrent urinary tract infections caused by the same organism ○ Because most antibiotics penetrate the prostate poorly, bacteria find haven in the parenchyma and constantly seed the urinary tract. ○ Diagnosis of chronic bacterial prostatitis depends on the demonstration of leukocytosis in expressed prostatic secretions and positive bacterial cultures. Chronic abacterial prostatitis, the most common form of prostatitis, is often referred to clinically as chronic pelvic pain syndrome. ○ indistinguishable from chronic bacterial prostatitis in terms of signs and symptoms, but there is no history of recurrent urinary tract infection. Expressed prostatic secretions contain more than 10 leukocytes per high-power field, but bacterial cultures are uniformly negative. DISORDERS OF THE PROSTATE: PROSTATITIS Clinical manifestations ○ Fever, chills, low back pain, with acute prostatitis ○ Frequency, urgency, and dysuria ○ Rectal exam: tender, swollen prostate, ○ In chronic prostatitis: voiding symptoms with pain, in perineum, back, suprapubic area and occasionally testis, may be asymptomatic ○ Prostadynia (non-inflammatory chronic pelvic pain syndrome) Term is used when symptoms of prostatitis are present, but there is no evidence of prostate infection or inflammation. Diagnosis ○ Urinalysis: ↑ WBCs and bacteria ○ Need to culture urine to determine type 17.Peyronie’s PEYRONIE’S DISEASE Reactive rather than neoplastic Characterized by hard penile plaques that result from the deposition of collagen in the connective tissue between the corpora cavernosa and the tunica albuginea. The fibrosis is believed to be the product of microvascular trauma and subsequent organizing sclerosing chronic inflammation. Clinically, the lesion results in penile curvature toward the side of the lesion and pain during intercourse resulting in painful, incomplete erections 18.Renal cancer RENAL CELL CARCINOMA Renal cell carcinomas represent about 3% of all newly diagnosed cancers in the United States and account for 85% of renal cancers in adults. The tumors occur most often in older individuals, usually in the sixth and seventh decades of life, and show a 2 : 1 male preponderance. Risk Factors Cigarette smoking, obesity, HTN, DM, asbestos exposure. Heavy metal exposure, unopposed estrogen, pts with ERSD, CKD, cystic disease and tuberous sclerosis Histology Clear Cell - Most Originate in renal cortex from cells of proximal tubule, usually unilateral, random in occurrence, with rare familial patterns, Common most frequently associated with metastatic disease. Papillary Evolves from cells of the distal tubule, 2 subtypes of familial identified, less likely to metastasize, but if it does, prognosis is worse than clear cell. Chromophobe Originates from renal parenchyma, slow growth, infrequent metastasis. Medullary & Least common, occur in younger pts, develop rapidly, only 30% 5 year survival rate, associated with sickle cell trait. Collecting Duct Clinical Manifestations: Often asymptomatic until quite advanced then systemic symptoms Costovertebral pain, hematuria, palpable mass The most reliable clue is hematuria, but it is usually intermittent and may be microscopic; thus, the tumor may remain silent until it attains a large size, often greater than 10 cm  10 Dyspnea, cough, and bone pain develop secondary to metastasis Dx: Renal US and CT of abdomen 19.Glomerulopathies GLOMERULAR DISORDERS Result from alteration in the structure and function of the glomerular capillary circulation. Glomerulopathies are responsible for 90% of ESRD. Easier to categorize as primary and secondary, by location, or by the degree of proteinuria. Primary glomerulopathies: ○ Disease states in which the kidney is the only or dominant organ involved. Secondary glomerulopathies: Result of drug exposure, infection, multisystem or vascular abnormalities. ○ Goodpasture syndrome, lupus, diabetic nephropathy, HTN 20.Vesicoureteral reflux LOWER URINARY TRACT CONGENITAL DISORDERS: VESICOURETERAL REFLUX Reflux of urine from the bladder to the ureter and renal pelvis ○ Due to incompetence of the valvular mechanism at the ureter-bladder junction Most common and serious congenital anomaly. Vesicoureteral reflux predisposes to ascending pyelonephritis and loss of renal function Classified as primary or secondary etiology ○ 5 grades - The level of severity is determined by urine flow and the extent of the associated dilation. In Grade I VUR the urine flows back into one or both of the ureters but does not reach the kidney. In Grade II VUR urine flows back up to the kidney, but does not cause dilation of the renal pelvis. In Grade III VUR there is mild to moderate dilation of the ureter and the renal pelvis. In Grade IV VUR, the ureter, the renal pelvis and calyces are dilated. In Grade V VUR there is severe dilation of the ureters, renal pelvis and calyces. Clinical manifestations may include recurrent UTI, voiding dysfunction, renal insufficiency, or hypertension in children May resolve spontaneously or require surgery 21.Obstructive uropathies URINARY TRACT OBSTRUCTION (OBSTRUCTIVE UROPATHY) Obstructive lesions of the urinary tract increase susceptibility to infection and to stone formation, and unrelieved obstruction almost always leads to permanent renal atrophy, termed hydronephrosis or obstructive uropathy. Obstruction may be sudden or insidious, partial or complete, unilateral or bilateral; it may occur at any level of the urinary tract from the urethra to the renal pelvis. It can be caused by intrinsic lesions of the urinary tract or extrinsic lesions that compress the ureter. The common cauÅses are: ○ Congenital anomalies ○ Urinary calculi ○ Benign prostatic hypertrophy ○ Tumors ○ Inflammation: prostatitis, ureteritis, urethritis, retroperitoneal fibrosis ○ Sloughed papillae or blood clots ○ Pregnancy ○ Uterine prolapse and cystocele ○ Functional disorders: neurogenic (spinal cord damage or diabetic nephropathy) and other functional abnormalities of the ureter or bladder (often termed dysfunctional obstruction) - Fortunately, many causes of obstruction are surgically correctable or medically treatable. Hydronephrosis-dilation of the renal pelvis and calyces associated with progressive atrophy of the kidney due to obstruction to the outflow of urine. Obstruction also triggers an interstitial inflammatory reaction, leading eventually to interstitial fibrosis Clinical Features: ○ Acute obstruction- pain attributed to distention of the collecting system or renal capsule. Most of the early symptoms are produced by the underlying cause of the hydronephrosis. ○ Unilateral complete or partial hydronephrosis may remain silent for long periods because the unaffected kidney can maintain adequate renal function. ○ Bilateral partial obstruction, the earliest manifestation is inability to concentrate urine, reflected by polyuria and nocturia. Some patients develop distal tubular acidosis, renal salt wasting, secondary renal calculi, and chronic tubulointerstitial nephritis with scarring and atrophy of the papilla and medulla. Hypertension is common. ○ Complete bilateral obstruction of rapid onset results in oliguria or anuria and is incompatible with survival unless the obstruction is relieved. Curiously, after relief of complete urinary tract obstruction, postobstructive diuresis occurs. This can often be massive, with the kidney excreting large amounts of urine that is rich in sodium chloride. - Even with complete obstruction, glomerular filtration persists for some time because the filtrate subsequently diffuses back into the renal interstitium and perirenal spaces, from where it ultimately returns to the lymphatic and venous systems. Because of this continued filtration, the affected calyces  11 and pelvis become dilated. The high pressure in the pelvis is transmitted back through the collecting ducts into the cortex, causing renal atrophy, but it also compresses the renal vasculature of the medulla, causing a diminution in inner medullary blood flow. The medullary vascular defects are initially reversible, but lead to medullary functional disturbances. Accordingly, the initial functional alterations caused by obstruction are largely tubular, manifested primarily by impaired concentrating ability. Only later does the GFR begin to fall. OBSTRUCTION - NEPHROLITHIASIS Patho: Crystallization and stone formation occurs with solutes found in the urine. Certain solutes tend to form crystals if their concentration in the urine becomes great enough. Stones begin their development in the loop of Henle, distal tubule, or collecting duct. Usually unable to form large enough to cause obstruction if urine is flowing freely. Increased concentration of stone constituents, changes in urinary pH, decreased urine volume, and the presence of bacteria influence the formation of calculi. Four main types of calculi: ○ Most common → calcium stones (about 70%), composed largely of calcium oxalate or calcium oxalate mixed with calcium phosphate - Urolithiasis affects 5% to 10% of people in the United States in their lifetime, and the stones may form anywhere in the urinary tract, but most arise in the kidney. OBSTRUCTION - NEPHROLITHIASIS GENERAL RISK FACTORS Hyperparathyroidism Gout Certain medications HTN UTI Chronic inflammatory bowel disease Excess dietary meat Excess dietary sodium Excess dietary oxylate Family history Obesity Insulin resistance/type II DM Dehydration IBS, chronic diarrhea Prolonged immobility Congenital defects of kidney Vesicouretal reflux Clinical manifestations: May be asymptomatic Flank pain and colic-usually unilateral Nausea, vomiting, abd distention Hematuria Chills, fever, bladder irritability if infection is present. Dx: Urinary pH – more acidic, hematuria. CBC, serum electrolytes, BUN and creatinine Parathormone level Gold standard for renal calculi WAS IVP (intravenous pyelogram). CT has replaced – able to view other organs and surrounding tissues. Female GU & Breast 1. Breast cancer BREAST CANCER The lifetime risk of breast cancer is 1 in 8 for women living to age 90 in the United States. Rare in women younger than age 25 and increases in incidence rapidly after age 30 PATHOGENESIS OF FAMILIAL BREAST CANCER ¼ to 1/3 of breast cancers occur due to inheritance of a susceptibility gene or genes. Risk is autosomal dominant and stems from alleles with loss-of-function mutations. High-risk genes associated with familial breast cancer include several involved with DNA repair and genomic stability, most notably BRCA1, BRCA2, and TP53 Mutations in BRCA1 and BRCA2 are responsible for 80% to 90% of single gene familial breast cancers and about 3% to 6% of all breast cancers.  12 pg.1049 Breast cancer is the most common non-skin malignancy in women and the second most common cause of cancer deaths in the United States. The most important risk factors for sporadic cancers in women are estrogenic stimulation and age. Breast cancers cluster into three major molecular groups, luminal (ER-positive), HER2, and triple negative, each with distinctive biologic and clinical features. Luminal cancers are further divided into two groups, A and B, that differ mainly in terms of proliferation, which is low in group A and high in group B. HER2 cancers are defined by overexpression of the HER2 receptor, usually due to HER2 gene amplification, and respond well to HER2 inhibitors. TNBCs lack ER and HER2 expression, are often associated with defects in DNA repair or genomic stability (e.g., due to silencing of BRCA1 or TP53 mutation), and carry a relatively poor prognosis. CANCER OF THE BREAST Clinical manifestations Painless, hard, poorly moveable lump Dimpling of the skin Nipple retraction Changes in breast contour Bloody discharge from nipple - FIG 33.10 Page 685 Skin dimpling caused by an underlying malignant tumor  13 2. Fibrocystic breasts FIBROCYSTIC BREASTS There are three principal nonproliferative morphologic changes: 1. Cystic change, often with apocrine metaplasia ○ Cysts. Small cysts form by the dilation of lobules and in turn may coalesce to form larger cysts. Unopened cysts contain turbid, semi translucent brown- or blue-colored (blue-dome cysts) ○ Cysts are lined either by a flattened atrophic epithelium or by metaplastic apocrine cells. ○ Over time, these cysts can enlarge and become palpable, leading to the characteristic “lumpy” feel associated with FBD. ○ Larger cysts may fluctuate in size with hormonal changes, often increasing in size and causing discomfort premenstrually. ○ Cysts may cause concerns when they are solitary and firm. The diagnosis is confirmed by the disappearance of the mass after fine-needle aspiration of its contents. 2. Fibrosis ○ Chronic hormonal stimulation leads to overgrowth of stromal (connective) tissue, resulting in dense, fibrotic tissue in the breast. This fibrosis often develops in response to tissue damage, which may occur from cyst rupture or microtrauma within the breast tissue. ○ The resulting chronic inflammation and fibrosis contribute to palpable nodularity of the breast. 3. Adenosis ○ This is an increase in the number of glands within the lobules, causing them to become larger and more prominent. ○ Sclerosing adenosis, a variant of adenosis, involves both glandular and stromal proliferation, which can mimic the appearance of cancer in imaging. FIBROCYSTIC BREAST DISEASE Clinical manifestations Tenderness or pain in one or both breasts immediately before onset of menstrual cycle Firm, regular in shape, mobile on palpation Located in upper outer quadrant of breasts Size fluctuates throughout menstrual cycle Lumps are typically bilateral, though one breast may be more affected. Risk Factors: Hormonal factors, including the use of hormone replacement therapy, are associated with higher risk; genetic predisposition may also play a role. 3. STI’s- lesion appearance, associated pathogens, & sequelae (gonorrhea, chlamydia, bacterial vaginosis, herpes, condylomas) SEXUALLY TRANSMITTED INFECTIONS - STIs may become established locally and then spread from the urethra, vagina, cervix, rectum, or oral pharynx. Organisms that cause STIs depend on direct contact for person-to-person spread because these pathogens do not survive in the environment. Transmission of STIs often occurs from asymptomatic people who do not realize that they have an infection. Infection with one STI-associated organism increases the risk for additional STIs. This is mainly because the risk factors are the same for all STIs. In addition, the epithelial injury caused by N. gonorrhoeae or C. trachomatis can increase the chance of co-infection with the other, as well as the risk of HIV infection if there is concomitant exposure. The microbes that cause STIs can be spread from a pregnant woman to the fetus and cause severe damage to the fetus or child. Perinatally acquired C. trachomatis causes conjunctivitis, and neonatal HSV infection is much more likely to cause visceral and CNS disease than is infection acquired later in life. Syphilis frequently causes miscarriage. - Untreated HIV infection may be fatal to children infected with the virus prenatally or perinatally. Diagnosis of STIs in pregnant women is critical, because intrauterine or neonatal transmission of STIs can often be prevented by treatment of the mother or newborn. Antiretroviral treatment of pregnant women with HIV infection and their newborn infants can reduce the transmission of HIV to offspring from 25% to less than 1%.  14 NEISSERIA GONORRHOEAE Overview Neisseria gonorrhoeae is a Gram-negative diplococcus and a major cause of sexually transmitted infections(STI), with over 450,000 reported cases annually in the United States. Gonorrhea commonly affects the genital tract but can also infect the pharynx, anorectum, and eyes (in neonates), and may lead to systemic dissemination in some cases. Infections often remain localized but have the potential to spread if untreated. Transmission and Pathogenesis Primarily transmitted through sexual contact; can also be passed to newborns during childbirth. Neisseria spp. adhere to and invade non-ciliated epithelial cells at the site of entry (nasopharynx, urethra, or cervix).​ Adherence of N. gonorrhoeae to epithelial cells is initially mediated by long pili, which bind to CD46, a protein expressed on all human nucleated cells. ​ Neisseria spp. use antigenic variation as a strategy to escape the immune response Clinical Manifestations Men: ○ Urethritis with dysuria, purulent discharge, and redness/swelling at the infection site. ○ Symptoms are typically symptomatic and prompt treatment-seeking. Women: ○ Often asymptomatic, leading to undetected infections. ○ When symptoms do occur, they may include purulent vaginal discharge, dysuria, and abnormal bleeding. ○ High risk of pelvic inflammatory disease (PID) if untreated, potentially leading to infertility or ectopic pregnancy. Other Sites: ○ Pharynx: May cause pharyngitis with mild or no symptoms. ○ Anorectum: Particularly in those who engage in receptive anal intercourse; may cause discomfort and discharge. - Transmission - Direct contact with infectious mucous membrane exudate from infected person incubation time 3 to 10 days GONOCOCCAL INFECTION Disseminated Gonococcal Infection (DGI): Occurs when N. gonorrhoeae spreads to the bloodstream, typically in individuals with untreated infections. Symptoms: Septic arthritis, often in large joints, accompanied by a characteristic rash of hemorrhagic papules and pustules. Neonatal Infections: Neonates can acquire gonorrhea during birth, leading to conjunctivitis (ophthalmia neonatorum), which, if untreated, can cause blindness. Prevention: Instillation of silver nitrate or antibiotics (e.g., erythromycin ointment) in the newborn's eyes can prevent conjunctival infection. Rarely may lead to neonatal sepsis in untreated cases. Diagnosis: Culture and Polymerase Chain Reaction (PCR) tests are used for diagnosis; PCR is highly sensitive and specific. Screening Recommendations: Annual screening for sexually active women under 25 and those at risk, as well as for men who have sex with men. Complications and Long-Term Sequelae Men: Urethral strictures, abscesses, and fistula formation may occur if untreated. Women: Chronic pelvic pain, infertility, and risk of ectopic pregnancy due to PID. Systemic Complications: If disseminated, may result in arthritis, endocarditis, or meningitis.  15 CHLAMYDIA TRACHOMATIS Chlamydia trachomatis is the most common bacterial STI worldwide, with high rates of asymptomatic infection, particularly in young adults. This infection often coexists with other STIs like Neisseria gonorrhoeae, increasing its public health significance. Pathogen Characteristics Small, Gram-negative bacterium that acts as an obligate intracellular pathogen due to its dependence on the host cell for ATP and amino acids. Has a unique biphasic life cycle involving two forms: Elementary Body (EB): Infectious but metabolically inactive form; enters host cells via phagocytosis. Reticulate Body (RB): Metabolically active, replicative form within host cells, which transforms back to EBs to infect new cells. Mechanism of Infection EBs use a type III secretion system to inject the TARP protein into host cells, leading to actin remodeling and facilitating phagocytic entry. Within host cells, EBs differentiate into RBs within membrane-bound inclusions that support replication and eventually release new EBs through cell lysis or extrusion. Patients may develop epididymitis, prostatitis, pelvic inflammatory disease, pharyngitis, conjunctivitis, perihepatic inflammation, and proctitis. ○ Unlike N. gonorrhoeae urethritis, C. trachomatis urethritis in men may be asymptomatic and so may go untreated. Both N. gonorrhoeae and C. trachomatis frequently cause asymptomatic infections in women. C. trachomatis urethritis can be diagnosed using amplified nucleic acid tests performed on genital swabs or urine specimens. Genital infection with the L serotypes of C. trachomatis causes lymphogranuloma venereum, a chronic, ulcerative disease. Lymphogranuloma venereum ○ Epidemiology: Endemic in regions of Asia, Africa, the Caribbean, and South America but sporadic in the United States and Western Europe. Presentation: ○ Initial phase: Painless genital papule or ulcer, often unnoticed. ○ Secondary phase: Tender inguinal/femoral lymphadenopathy that can rupture. ○ Tertiary phase (if untreated): Fibrosis and strictures in the anogenital tract, including rectal strictures in women. ○ If not treated, the infection can subsequently cause fibrosis and strictures in the anogenital tract. Rectal strictures are particularly common in women. - In 2016, approximately 1.6 million cases of genital chlamydia were reported to the CDC. The rate of genital chlamydia in the United States has risen fairly steadily over the past 10 years. Genital C. trachomatis infections (other than lymphogranuloma venereum, discussed later) are associated with clinical features that are similar to those caused by N. gonorrhoeae. GARDNERELLA VAGINALIS AND BACTERIAL VAGINOSIS (BV) Gardnerella vaginalis is a Gram-variable (often appears Gram-negative) coccobacillus that is strongly associated with bacterial vaginosis (BV). BV represents a shift in normal vaginal flora rather than a single infection, often involving a polymicrobial environment with G. vaginalis and other bacteria. Pathogenesis ○ Disruption of Lactobacilli: Normal vaginal flora dominated by Lactobacillus species (which produce lactic acid to maintain acidic pH) is diminished, allowing overgrowth of G. vaginalis and other bacteria. ○ Anaerobic Environment: G. vaginalis and anaerobes (e.g., anaerobic peptostreptococci, Mobiluncus species) contribute to the characteristic symptoms and biofilm formation associated with BV. - In pregnant patients, bacterial vaginosis has been implicated in premature labor. GARDNERELLA VAGINALIS AND BACTERIAL VAGINOSIS (BV): CLINICAL MANIFESTATIONS Characteristic Discharge:  16 ○ Thin, green-gray vaginal discharge with a malodorous “fishy” smell, especially noticeable after intercourse. Other Symptoms: ○ While BV is often asymptomatic, some patients may experience mild vaginal irritation or itching. Diagnosis Microscopy: ○ Wet Mount (Wet-Prep): Reveals “clue cells” – epithelial cells with a stippled appearance due to bacteria coating the cell surface. ○ Amine (“Whiff”) Test: Adding KOH to the discharge releases a fishy odor, aiding in diagnosis. ○ Pap Smear: Superficial and intermediate squamous cells may appear with a shaggy coat of coccobacilli, typical in BV HERPES SIMPLEX VIRUS HSVs are DNA viruses that include two primary serotypes: HSV-1 and HSV-2. ○ HSV-1: Primarily causes perioral infections (cold sores). ○ HSV-2: Typically associated with genital infections. Transmission and Infection Phases ○ Active Infection: Vesicles and ulcers are highly contagious during this phase due to the presence of numerous viral particles. ○ Latency: Following initial infection, the virus migrates to regional lumbosacral nerve ganglia and establishes latency, allowing for possible reactivation later. - Because of viral latency, HSV infections persist indefinitely, and any decrease in immune function due to stress, trauma, concurrent viral infection, or hormonal changes can trigger reactivation of the virus and recurrence of the skin and mucosal lesions. - By 40 years of age, approximately 30% of women are seropositive for antibodies against HSV-2. Symptomatic Presentation Complications and Severe Manifestations Incubation Period: Lesions typically appear 3 to 7 days post-transmission. Neonatal HSV Infection: Systemic Symptoms: May include fever, malaise, and tender lymph nodes (particularly ○ Risk of neonatal transmission is highest if the inguinal nodes in genital HSV infections). mother has an active infection during delivery, Progression of Lesions: especially if it's a primary infection. ○ Early signs: Red papules. ○ Severe consequences for the neonate include ○ Develop into vesicles and eventually into painful, coalescent ulcers. blindness, deafness, seizures, and meningitis. Genital Infections: Cesarean delivery is recommended if an active infection is ○ Cervical and vaginal lesions often present with purulent discharge and pelvic present at birth to prevent neonatal transmission. pain. ○ Urethral lesions can lead to painful urination and urinary retention. Diagnostic Methods Clinical Evaluation: Diagnosis often based on characteristic clinical presentation. Laboratory Tests: ○ Tissue Culture: Aspiration from lesions inoculated into a tissue culture, where viral cytopathic effects appear within 48-72 hours. ○ Molecular Testing: PCR (polymerase chain reaction) for viral DNA. ELISA (enzyme-linked immunosorbent assay) and Direct Immunofluorescence for viral proteins. Serologic Testing for anti-HSV antibodies, which indicate recurrent or latent infection. Prevention and Management Transmission Risk: HSV is primarily transmitted during active infection, but subclinical shedding allows occasional latent phase transmission. Preventive Measures: Condoms and antiviral therapies reduce but do not eliminate transmission risk. CONDYLOMA ACUMINATUM Etiology: Caused by low-risk HPV types (mainly 6 and 11), which are unlikely to progress to malignancy. Appearance: Lesions are often soft, pink, or skin-colored and have a cauliflower-like appearance. Histopathology: Shows koilocytosis (HPV-induced changes in squamous cells) with wrinkled nuclei and perinuclear halos, helping distinguish from other conditions. Differentiation: Important to differentiate from condyloma lata (secondary syphilis), which appears smoother and flatter. Diagnosis may require serologic testing for syphilis or HPV DNA testing to confirm. Prevention: HPV vaccination (covering types 6 and 11) can reduce the risk of condyloma acuminatum. 4. Rectocele RECTOCELE Protrusion of anterior rectal wall into a weakened area of posterior vagina Weakening of connective tissue and muscles in the pelvic floor, especially the rectovaginal septum. Reduced collagen and elasticity with aging contributes to loss of support. Hormonal Influence: Postmenopausal estrogen deficiency leads to thinning and weakening of pelvic tissues, increasing the risk of rectocele. Increased Intra-abdominal Pressure - Clinical manifestations- Depends on severity, Constipation, Painful bowel evacuation, Painful intercourse RECTOCELE CONT.  17 Causes: Childbirth Injury: Trauma during vaginal delivery can damage pelvic floor muscles and connective tissues. Aging: Natural decline in tissue elasticity and muscle tone. Multiparity: Multiple pregnancies increase pelvic floor stress. Obesity: Additional weight contributes to increased intra-abdominal pressure. Postmenopausal Status: Lower estrogen levels contribute to tissue thinning. Symptoms: Vaginal bulge or protrusion Pelvic pressure or discomfort Difficulty with bowel movements Feeling of incomplete bowel evacuation Fecal incontinence in severe cases Severity and Classification Grading: ○ Based on the extent of rectal wall protrusion into the vaginal canal. ○ Severe cases may require surgical intervention. Complications ○ Fecal Incontinence: Loss of control due to rectal wall displacement. ○ Incomplete Evacuation: Difficulty in completely emptying the bowels. ○ Recurrent UTIs: Due to incomplete emptying and pelvic floor dysfunction. 5. DUB (Dysfunctional Uterine Bleeding) DYSFUNCTIONAL UTERINE BLEEDING In many cases of DUB, there's an imbalance between estrogen and progesterone, which affects the growth and shedding of the endometrial lining. Abnormal endometrial bleeding not associated with tumor, inflammation, pregnancy, trauma, or hormonal effects Most common around time of menarche and menopause Adolescents Immaturity in functioning of the pituitary and ovary Perimenopause Progressive function and failure of the ovary to produce estrogen ANOVULATORY CYCLE The most frequent cause of dysfunctional bleeding is anovulation (failure to ovulate). This occurs when ovulation does not happen, so there’s no corpus luteum to produce progesterone. Without progesterone, the endometrial lining keeps growing because estrogen levels are still elevated. Eventually, the lining becomes too thick and unstable, causing irregular or heavy bleeding. ○ Endometrial Hyperplasia: When estrogen is unopposed by progesterone, the endometrial lining can become excessively thick (hyperplasia), which leads to irregular bleeding. Most common at menarche and in the perimenopausal period. Less commonly, anovulation is the result of the following: ○ Endocrine disorders, such as thyroid disease, adrenal disease, or pituitary tumors ○ Ovarian lesions, such as a functioning ovarian tumor (granulosa cell tumors) or polycystic ovaries ○ Generalized metabolic disturbances, such as obesity, malnutrition, or other chronic systemic diseases DYSFUNCTIONAL UTERINE BLEEDING: OVULATORY BLEEDING This occurs when ovulation happens, but the corpus luteum either produces insufficient progesterone or it’s not functioning properly. Without enough progesterone, the lining of the uterus is not properly maintained, leading to abnormal shedding and bleeding. Chronic Anovulation: Conditions like polycystic ovary syndrome (PCOS) can prevent regular ovulation, leading to estrogen dominance and abnormal bleeding patterns. 6. Endometriosis ENDOMETRIOSIS Defined by the presence of “ectopic” endometrial tissue at a site outside of the uterus. The abnormal tissue most commonly includes both endometrial glands and stroma The disorder is principally a disease of women in active reproductive life, most often in their 30-40's, and affects approximately 10% of women. There are three types of endometriosis: ○ Superficial peritoneal endometriosis, ○ Ovarian endometriosis ○ Deep infiltrating endometriosis It occurs in the following sites, in descending order of frequency: (1) ovaries (2) uterine ligaments (3) rectovaginal septum  18 (4) cul de sac (5) pelvic peritoneum (6) serosa of the large and small bowel and appendix (7) mucosa of the cervix, vagina, and fallopian tubes (8) laparotomy scars. - The superficial and ovarian forms of endometriosis are uncommonly associated with the development of malignancy, whereas it is extremely rare for the deep infiltrating form to undergo malignant transformation. ENDOMETRIOSIS: PATHOGENESIS Proposed origins of endometriotic lesions fall into two main categories: (1) those that propose an origin from the uterine endometrium (2) those that propose an origin from cells outside the uterus that have the capacity to give rise to endometrial tissue The regurgitation theory proposes that endometrial tissue implants at ectopic sites via retrograde flow of menstrual endometrium. The benign metastasis theory holds that endometrial tissue from the uterus can “spread” to distant sites (e.g., bone, lung, and brain) via blood vessels and lymphatic channels. The metaplastic theory suggests that endometrium arises directly from coelomic epithelium (mesothelium of pelvis or abdomen), from which the müllerian ducts and ultimately the endometrium itself originate during embryonic development. ○ In addition, mesonephric remnants may undergo endometrial differentiation and give rise to ectopic endometrial tissue. The extrauterine stem/progenitor cell theory proposes that stem/progenitor cells from the bone marrow differentiate into endometrial tissue. - Retrograde menstruation through the fallopian tubes is common, and the regurgitation theory provides a plausible explanation for the origin of ectopic endometrial tissue in the peritoneal cavity, which constitutes the vast majority ofcases. However, it cannot explain endometriosis in women who are amenorrheic because of a variety of underlying etiologies (e.g., gonadal dysgenesis); endometriosis in the urogenital tract of men treated with high-dose estrogens for prostate cancer; and endometriosis in distant sites like the brain, lung, and bone. In addition, the relatively low incidence of endometriosis, despite the common occurrence of retrograde menstruation (up to 90% of women), suggests that additional factors are involved in the pathogenesis of the disorder. - Molecular analyses have provided additional insights. The endometriotic implants show certain differences when compared to the endometria of women without endometriosis ENDOMETRIOSIS: PATHOPHYSIOLOGY Ectopic Endometrial Tissue Growth Inflammatory Process Hormonal Influence Endometrial-like tissue implants in areas The immune response plays a significant Estrogen is thought to be a key driver in the outside the uterus. This tissue responds to role in endometriosis pathophysiology. growth of endometriotic lesions. The ectopic hormonal fluctuations of the menstrual cycle, Ectopic tissue releases inflammatory tissues express estrogen receptors and, in similar to normal endometrial tissue, by cytokines and prostaglandins, causing response to circulating estrogen, can thickening, breaking down, and bleeding. chronic inflammation in the surrounding proliferate and develop new blood vessels Unlike regular menstrual flow, blood from these tissues. (angiogenesis). ectopic sites cannot exit the body, leading to This inflammation not only promotes pain Additionally, research shows these tissues inflammation, scar tissue (adhesions), and cyst but also creates an environment that have a higher concentration of estrogen and formation (often called endometriomas when fosters further implantation and growth of can produce estrogen locally, which further affecting the ovaries). endometrial-like cells outside the uterus. supports their growth and persistence. - Release of proinflammatory and angiogenic factors, including PGE2, IL-1β, TNFα, IL-6 and IL-8, NGF, VEGF, MCP-1, MMPs, and TIMPs. Some of these factors are released by associated macrophages, which are recruited to endometriotic implants by proinflammatory factors. Like metastatic tumors, the ability of endometriotic implants to survive and grow is dependent on angiogenesis, which is mediated by typical proangiogenic factors such as VEGF. Similarly, the ability to implant requires remodeling of the extracellular matrix, which is carried out by factors such as matrix metalloproteases. These factors may also contribute to avoidance of immune clearance. - Increased estrogen and retinoic acid production by endometriotic stromal cells, due in large part to high levels of the key steroidogenic enzyme aromatase, which is absent in normal endometrial stroma. Estrogen enhances the survival and persistence of endometriotic tissue, and inhibitors of aromatase are beneficial in the treatment of endometriosis. A link between inflammation and estrogen production is made plausible by the ability of prostaglandin E2 to stimulate local synthesis of estrogen. It also has been shown that retinoic acid produced in the stromal cells promotes epithelial cell survival via paracrine signaling. In addition, epigenetic alterations (DNA methylation) have been described that lead to increased responsiveness to estrogen and decreased responsiveness to progesterone, alterations that promote endometrial proliferation and survival. These abnormalities are present not only in ectopic endometriotic tissue, but also, albeit to a lesser degree, in the uterine endometrium of patients with endometriosis, suggesting that there is a fundamental defect in the endometrium. - Mutations in tumor suppressor genes and oncogenes, such as KRAS, PIK3CA, PPP2R1A, and ARID1A, have been identified in the epithelial cells of deeply infiltrating endometriosis. ENDOMETRIOSIS: PATHOPHYSIOLOGY CONT. Neuroangiogenesis and Pain Mechanisms ○ Endometriosis is associated with neuroangiogenesis, the formation of new blood vessels and nerve fibers, within lesions. This process is partly responsible for the severe and chronic pelvic pain seen in endometriosis patients. ○ Nerve fibers in endometriotic lesions are sensitized by inflammation, making these areas hyperresponsive to pain stimuli and leading to a heightened perception of pain.  19 Genetic and Epigenetic Factors ○ Genetic predisposition is evident, as endometriosis often runs in families. Studies have identified several genes associated with an increased risk, although no single gene is responsible. ○ Epigenetic changes, like DNA methylation, have been observed in endometriotic tissue, potentially affecting gene expression involved in hormone signaling, inflammation, and cell adhesion. Immune Dysfunction ○ Endometriosis is linked with immune system dysregulation, as the immune system may fail to recognize and eliminate ectopic endometrial cells. ○ These cells produce molecules that attract immune cells, which, paradoxically, contribute to chronic inflammation without effectively clearing the lesions. Clinical Features ○ Symptoms usually include severe dysmenorrhea ○ Dyspareunia (pain with intercourse) ○ Pelvic pain due to the intrapelvic bleeding and periuterine adhesions ○ Menstrual irregularities are common ○ Infertility is the presenting complaint in 30% to 40% of women. ○ In addition, although uncommon, malignancies can develop within endometriomas, suggesting that these lesions contain “at-risk” epithelium. ENDOMETRIAL HYPERPLASIA An important cause of abnormal bleeding and a frequent precursor to the most common type of endometrial carcinoma. Defined as an abnormal proliferation of the endometrial glands relative to the stroma, resulting in an increased gland-to-stroma ratio Inactivation of the PTEN tumor suppressor gene is a common genetic alteration in both endometrial hyperplasias and endometrioid endometrial carcinoma. Associated with prolonged estrogenic stimulation of the endometrium (anovulation, increased estrogen production from endogenous sources, or exogenous estrogen) Associated conditions include: ○ Obesity (peripheral conversion of androgens to estrogens) ○ Menopause ○ Polycystic ovarian syndrome ○ Functioning granulosa cell tumors of the ovary ○ Excessive ovarian cortical function (cortical stromal hyperplasia) ○ Prolonged administration of estrogenic substances (estrogen replacement therapy) - Typical hyperplasia has a wide-range of appearances, but the cardinal feature is an increased gland-to-stroma ratio. The glands show variation in size and shape and may be dilated (Fig. 22.23A). Although there may be back-to-back glands focally, some intervening stroma is usually retained (see Fig. 22.23B). These lesions are caused by persistent estrogen stimulation and rarely progress to adenocarcinoma (approximately 1% to 3%). Hyperplasia may evolve into cystic atrophy when estrogen is withdrawn. - Atypical hyperplasia (endometrial intraepithelial neoplasia) is composed of complex patterns of proliferating glands displaying nuclear atypia. The glands are commonly back-to-back and often have complex outlines due to branching structures. Individual cells are rounded and lose the normal perpendicular orientation to the basement membrane. In addition, the nuclei have open (vesicular) chromatin and conspicuous nucleoli. The features of atypical hyperplasia have considerable overlap with those of well-differentiated endometrioid adenocarcinoma (discussed later), and accurate distinction from cancer may not be possible without hysterectomy (Fig. 22.23C–D). Indeed, up to 50% of women with a diagnosis of atypical hyperplasia are found to have carcinoma when a hysterectomy is performed. 7. Uterine fibroids (leiomyomas) LEIOMYOMA Origin and Development ○ Monoclonal Tumors: Leiomyomas are monoclonal, meaning they arise from a single cell that undergoes a mutation and proliferates ○ Smooth Muscle Cells: They develop from the smooth muscle cells of the myometrium, the muscular layer of the uterus Genetic and Molecular Factors ○ Genetic Mutations: Common genetic alterations include mutations in the MED12 gene, overexpression of HMGA2, and fumarate hydratase deficiency ○ Epigenetic Changes: Histone acetylation and DNA methylation also play roles in the tumorigenesis of leiomyomas Hormonal Influence ○ Estrogen and Progesterone: These hormones significantly influence the growth of leiomyomas. Estrogen promotes the proliferation of smooth muscle cells, while progesterone supports the maintenance and growth of the fibroids ○ Receptors: Leiomyomas have a higher density of estrogen and progesterone receptors compared to normal myometrium Extracellular Matrix (ECM) ○ ECM Components: Leiomyomas contain an increased amount of extracellular matrix, including collagen, fibronectin, and proteoglycans ○ Fibrotic Processes: The ECM contributes to the fibrotic nature of these tumors, making them firm and often causing distortion of the uterine cavity Growth Factors and Angiogenesis ○ Growth Factors: Various growth factors, such as transforming growth factor-beta (TGF-β), are involved in the proliferation and maintenance of leiomyomas ○ Angiogenesis: Increased blood vessel formation supports the growth and sustenance of these tumors.  20 LEIOMYOMA CONT. Common signs and symptoms include : ○ Abnormal bleeding ○ Urinary frequency due to compression of the bladder ○ Sudden pain from infarction of a large or pedunculated tumor ○ impaired fertility. ○ In pregnant women, increase frequency of spontaneous abortion, fetal malpresentation, uterine inertia, and postpartum hemorrhage ○ If large mass: Abdominal pain and pressure, backache, constipation, urinary frequency/urgency ○ Malignant transformation to leiomyosarcoma is extremely rare. 8. Cervical cancer HUMAN PAPILLOMAVIRUS (HPV) INFECTIONS Prevalence: HPV is one of the most common sexually transmitted infections worldwide, affecting a significant proportion of sexually active individuals. Serotypes: Over 100 HPV types exist, with certain types associated with different clinical outcomes: Low-risk types (e.g., HPV-6, HPV-11) are commonly associated with genital warts. High-risk types (e.g., HPV-16, HPV-18) are associated with cervical dysplasia and cervical cancer, as well as other cancers (oropharyngeal, anal, penile). Persistent human papillomavirus infection important risk factor for cervical cancer Viral Entry and Epithelial Transformation: HPV infects the basal epithelial cells of the skin or mucosa through microabrasions. E6 and E7 Oncoproteins: High-risk HPV types produce these proteins, which inhibit tumor suppressor proteins p53 and Rb, promoting cellular dysregulation and malignant transformation. Latency and Persistence: HPV can persist in basal cells, remaining undetected for years, which complicates understanding the timing of infection and transmission. - High-risk HPVs cause several types of cancer. - Cervical cancer: Virtually all cases of cervical cancer are caused by HPV, and just two HPV types, 16 and 18, are responsible for about 70 percent of all cases - Anal cancer: About 95 percent of anal cancers are caused by HPV. Most of these are caused by HPV type 16. Clinical Manifestations Anogenital Warts: ○ Often painless but can become irritating and pruritic. ○ Tend to bleed easily (friable), especially in areas subject to friction. Cervical Dysplasia and Cancer: ○ Often asymptomatic in early stages. ○ Progression can lead to abnormal vaginal bleeding, especially post-coital bleeding. Non-genital Manifestations: ○ HPV can also cause oral and pharyngeal lesions, which have been increasingly linked to oropharyngeal cancers. ○ Plantar and common warts: Non-genital HPV types (e.g., HPV-1, HPV-2) cause common skin warts on hands and feet.​​ - Clinical manifestations - Female lesions - Vagina, Cervix, Anogenital - Male lesions - Anterior urethra and Anogenital Diagnostic and Screening Tools Cervical Screening (Pap Smear): ○ Detects abnormal epithelial changes in cervical cells, helping to identify precancerous or cancerous changes. HPV DNA Testing: ○ Detects high-risk HPV types, often used in conjunction with Pap smears for cervical cancer screening. Visual Inspection: ○ Lesions, particularly anogenital warts, can be diagnosed visually, often supported by acetic acid application (turns HPV-infected areas white). Complications and Long-term Effects Cancer Development: ○ Persistent high-risk HPV infection is the leading cause of cervical cancer and contributes to other anogenital and oropharyngeal cancers. Recurrent Respiratory Papillomatosis (RRP): 9. Septate vagina VAGINA Developmental Anomalies Septate or Double Vagina: ○ This rare anomaly results from incomplete fusion of the müllerian ducts, often presenting with a double uterus (uterus didelphys). ○ Associated Factors: may stem from genetic syndromes, in utero exposure to diethylstilbestrol (DES), or other disruptions in epithelial-stromal signaling during fetal development. Gartner duct cysts are relatively common lesions found along the lateral walls of the vagina that are derived from wolffian (mesonephric) duct rests. ○ They consist of 1- to 2-cm fluid-filled submucosal cysts. ○ Other cysts, including mucus cysts, which occur in the proximal vagina, are derived from müllerian epithelium.  21 10. Dysmenorrhea Metrorrhagia Bleeding between menstrual periods Causes ○ Slight bleeding from endometrium during ovulation, uterine malignancy, cervical erosions, endometrial polyps, estrogen therapy Hypomenorrhea Deficient amount of menstrual flow; reduced flow Causes ○ Endocrine or systemic disorders interfering with hormones, partial obstruction of menstrual flow Oligomenorrhea Infrequent menstruation Menstrual cycles that are longer than 35 days, typically resulting in fewer than 9 periods per year. Cause: Endocrine/systemic disorder causing failure to ovulate Polymenorrhea Increased frequency of menstruation Cycles 4.5 can result in dysbiosis promoting the overgrowth of normal flora and increases the risk of STI transmission. 14. PCOS PCOS Hypothalamus-Pituitary-Ovary Role of Insulin Resistance Ovarian Hyperandrogenism Diagnostics Risks & Complications Axis Dysregulation Elevated GnRH Insulin resistance in Increased LH and Ultrasound Metabolic pulse frequency from muscle and adipose insulin stimulate Findings Syndrome: the hypothalamus tissues requires the the theca cells in "String of pearls" Due to insulin increases LH pancreas to compensate ovaries to produce appearance of resistance and secretion. by producing more excess androgens. multiple small obesity. High LH/FSH ratio insulin. Hyperinsulinemia Excess androgens cysts on the Infertility: (typically >2:1) favors increases androgen disrupt the normal ovaries. Resulting from androgen production production in the ovaries follicular Enlarged anovulation. over estrogen. and reduces hepatic development, ovaries with an Endometrial Reduced FSH levels production of sex preventing increased Hyperplasia impair follicular hormone-binding globulin ovulation and number of and Cancer: maturation, (SHBG). causing immature follicles. Due to contributing to cyst Lower SHBG results in follicles to Histology prolonged formation. more free (active) accumulate as Accumulation of exposure to androgens in the “cysts.” immature unopposed bloodstream, Leads to clinical follicles in estrogen. exacerbating symptoms manifestations various stages Mood like hirsutism and acne. such as hirsutism, of development Disorders: acne, and, often, due to halted Higher male-pattern hair folliculogenesis. prevalence of loss. anxiety and depression 15. PID PELVIC INFLAMMATORY DISEASE (PID) Pelvic Inflammatory Disease (PID) is an ascending infection that originates in the vulva or vagina and spreads to involve multiple structures within the female genital system, causing symptoms such as pelvic pain, adnexal tenderness, fever, and vaginal discharge. Common Causes: Neisseria gonorrhoeae and Chlamydia trachomatis are major pathogens associated with PID. However, PID is often polymicrobial, with other organisms like staphylococci, streptococci, coliforms, and Clostridium perfringensfrequently contributing to infection. Pathophysiology: Onset: For gonococcal infections, inflammatory changes generally emerge 2 to 7 days after exposure. Primary Infection Sites: The initial infection usually begins in the endocervical mucosa but can also affect Bartholin, vestibular, or periurethral glands. Upward Spread: The infection ascends to involve the fallopian tubes and tubo-ovarian regions, where the tubal lumen becomes filled with purulent exudate that may escape from the fimbriated ends, potentially spreading to the ovary and leading to salpingo-oophoritis. Abscess Formation: Pus can accumulate within the ovary and tube (tubo-ovarian abscess) or the tubal lumen (pyosalpinx). PID CHRONIC CHANGES Healing and Scarring: Over time, as the infection resolves, the tubal plicae—denuded of epithelium—adhere and fuse, resulting in scar tissue formation that creates glandlike spaces and blind pouches, a condition known as chronic salpingitis. Hydrosalpinx Development: Fusion of the fimbriae and blockage of the tube may lead to hydrosalpinx, where tubal secretions accumulate, causing tubal distention. Suppurative Salpingitis: Acute inflammation of the fallopian tubes, or acute suppurative salpingitis, often ensues, marked by pus-filled tubes.  24 PELVIC INFLAMMATORY DISEASE COMPLICATIONS Acute Complications: Peritonitis Bacteremia, potentially leading to endocarditis, meningitis, or suppurative arthritis. Chronic Sequelae: Infertility due to tubal obstruction Increased risk of ectopic pregnancy Chronic pelvic pain Dyspareunia (pain during intercourse) Abscess formation Intestinal obstruction caused by adhesions between bowel and pelvic organs. Clinical Manifestations of PID Symptoms: ○ Abdominal tenderness and pelvic pain ○ Pain or tenderness in the cervical or adnexal areas upon palpation ○ Fever and elevated white blood cell (WBC) count ○ Purulent vaginal discharge 16. Endometrial cancer/Endometrial hyperplasia ENDOMETRIAL HYPERPLASIA An important cause of abnormal bleeding and a frequent precursor to the most common type of endometrial carcinoma. Defined as an abnormal proliferation of the endometrial glands relative to the stroma, resulting in an increased gland-to-stroma ratio Inactivation of the PTEN tumor suppressor gene is a common genetic alteration in both endomet