Ch. 18 The male genital system.

1. Penis. 1.1. malformations. Include abnormalities in the location of the distal urethral orifice, termed hypospadias and epispadias. Hypospadias is the more common of the two. It designates and abnormal opening of the urethra along the ventral aspect of the penis. It may be associated with other congenital anomalies, including inguinal hernias and undescended testes. 1.2. inflammatory lesions. A significant number are caused by STDs. The term balanitis and balanoposthitis refer to local inflammation of the glans penis, or of the glans penis and the overlying prepuce. Most cases occur as a consequence of poor local hygiene in uncircumcised males. In such cases, the distal penis is typically red, swollen and tender. Phimosis represent a condition in which the prepuce cannot be retracted easily over the glans penis. Most cases are accompanied by evidence of on going distal penile inflammation. When a stenotic prepuce is forcibly retracted over the glans penis, the circulation to the glans may be compromised with resultant a condition known as paraphimosis (spaanse kraag). 1.3. Neoplasms. More than 95% of penile neoplasms originate from squamous epithelium. Three clinical variant of carcinoma in situ, all strongly associated with HPV infection, occur on the penis: - Bowen disease: occurs in older uncircumcised males and appears grossly as a solitary, plaquelike lesion. It is not unique to the penis but may also occur elsewhere on the skin and on mucosal surfaces. - Erythroplasia of Queyrat: when bowens disease presents as an erythematous patch on the glans penis. Occurs in young, sexually active , males. - Squamous cell carcinoma: appears as a gray, cruster, papular lesion, most commonly on the glans penis or prepuce. Verrucous carcinoma is a variant characterized by a papillary architecture, less striking cytologic atypia, and rounded, pushing deep margins. 2. Scrotum, testis, and epididymis. Neoplasms of the scrotal sac are unusual. Squamous cell carcinoma is the most common, and had a high incidence of the disease in chimney sweeps. Hydrocele , the most common cause of scrotal enlargement, is an accumulation of serous fluid within the tunica vaginalis. 2.1. Cryptorchidism and testicular atrophy. Cryptorchidism represents failure of testicular descent into the scrotum. The diagnosis of cryptorchidism is difficult to establish with certainty before 1 year of age. By 1 year of age it is present in 1% of the male population. Failure of descent is also associated with a 3-5 fold increased risk of testicular malignancy. Individuals with unilateral cryptorchidism are also at increased risk for the development of cancer in the contralateral, normally descended testis, suggesting that some intrinsic abnormality may be responsible for the increased risk. 2.2. Inflammatory lesions. Are more common in the epididymis than in the testis proper. Causes of testicular inflammation include nonspecific epididymitis and orchitis, mumps, and TBC. Nonspecific epididymitis and orchitis usually begin as a primary urinary tract infection with secondary

ascending infection of the testis through the vas deferens or lymphatics of the spermic cord. The involved testis is swollen and tender. Mumps infection -> the infected testis is edematous and congested and contains a predominantly lymphoplasmacytic inflammatory infiltrate. 2.3. Testicular neoplasms. Most important cause of firm, painless enlargement of the testis. Represent a heterogeneous group of neoplasms composed of germ cell tumors and sex cord/stromal tumors. 95% of testicular tumors arise from germ cells, and all are malignant. The risk of neoplasia is increased in sibling of males with testicular cancers and it is more common in whites than in blacks. Germ cell tumors of the testis are divied into two groups: - Based on whether they contain a single histologic pattern (60%); - Or multiple histologic patterns (40%). Primitive cells that may either differentiate along gonadal lines to produce seminomas or transform into a totipotential cell population, giving rise to nonseminomatous germ cell tumors. Remain largely undifferentiated to form embryonal carcinomas. Most testicular tumors arise from in situ lesions characterized as intratubular germ cell neoplasia. Present in condition associated with a high risk of developing germ cell tumors. Individuals with testicular germ cell neoplasms present most frequently with painless enlargement of the testis. Some may have widespread metastases in the absence of a palpable testicular lesion. - Seminomas often remain confined to the testis. Metastases are most commonly encountered in the iliac and para-aortic lymph nodes; hCG produced by neoplastic syncytiothrophoblastic cells is always elevated in patients with choriocarcinoma. AFP is a glycoprotein normally synthesized by the fetal yolk sac and several other fetal tissues. Nonseminomatous germ cell tumors containing elements of yolk sac often produce AFP. - Nonseminomatous germ cell, tend to metastasize earlier, by both lymphatic and haematogenous routes. Most tumors have mixed patterns and hence elevation of both hCG and AFP. The treatment of testicular germ cell neoplasms is considered a success story. Seminomas are exquisitely radiosensitive, and they also respond well to chemotherapy. 3. Prostate. 3.1. Prostatitis. May be acute or chronic. The classification is based on a combination of clinical features, microscopic examination , and, in selected cases, culture of fractionated urine specimens - Acute bacterial prostatitis is caused by E. coli; - Chronic prostatitis may follow clinical episodes of acute prostatitis , or may develop insidiously, without previous episodes of acute infection. Clinical features are: - Dysuria; - Urinary frequency; - Lower back pain; - Pelvic pain. The prostate may be enlarged and tender, particularly in acute prostatitis.

3.2. Nodular hyperplasia of the prostate. Hyperplastic lesions arise in the inner transitional and central zones of the prostate, while most carcinomas (70-80%) arise in the peripheral zones (DUS! Daarom is moeite met plassen niet verdacht voor carcinoom. De perifere zone kan niet tegen de ureter drukken!) Clinical features: Occurs in only about 10% of men with the disease. Because nodular hyperplasia preferentially involves the inner portions of the prostate, its most common manifestations are those of lower urinary tract obstruction. Nodular hyperplasia is characterized by benign proliferation of stromal and glandular elements. DHT is the major hormonal stimulus for proliferation. 3.3. Carcinoma of the prostate. Second most common cause of cancer-related deaths in men older than 50 years of age, after carcinoma of the lung. Cancer of the prostate does not develop in males castrated before puberty, indicating that androgens probably contribute to its development. Clinical features: they are often clinically silent. Most cancers begin in the peripheral regions of the prostate. More extensive disease symptoms of prostatism , including local discomfort and evidence of lower urinary tract obstruction similar to that encountered in patients with nodular hyperplasia. Bone metastases, particularly to the axial skeleton, are common and may cause either osteolytic (destructing) or more commonly osteoblastic (bone-producting) lesions. PSA level of 4,0 ng/l has been used as the upper limit of normal. Values over 10ng/ml are suggestive of prostate cancer. PSA levels may also be elevated above 4ng/Ml in non-neoplastic conditions such as nodular hyperplasia and prostatitis. 4. Sexually transmitted disease (STDs). 4.1. Syphilis. Is a chronic venereal infection caused by the spirochete Treponema pallidum. T. pallidum is a fastidious spirochete whose only natural hosts are humans. The usual source is an active cutaneous or mucosal lesion in a sexual partner in the early stages of syphilis. The organism breaks in the skin or mucous membranes of the infected partner. Between 9-90 days after the initial infection, a primary lesions, termed chancre, appears at the point of entry. Two types of antibodies are formed: nontreponemal antibodies and antibodies to specific antigens. The chancre of primary syphilis resolves spontaneously over a period of 4-6 weeks and is followed in approximately 25% of untreated patients by development of secondary syphilis. The lesions of secondary syphilis resolve without any specific antimicrobial therapy, at which point patients are said to be in early latent phase syphilis. Late latent phase of the illness. This late symptomatic phase, or tertiary syphilis, is marked by the development of lesions in the cardiovascular system, central nervous system, or , less frequently other organs. 1. Primary syphilis: characterized by the presence of a chancre at the site of initial inoculation. Begins as a small, firm papule, which gradually enlarges to produce a painless ulcer. Regional lymph nodes are often slightly enlarged and firm, but painless. Serologic tests are often negative during the early stages. 2. Secondary syphilis: Approximately 2 months of resolution of the chancre, the lesions of secondary syphilis appear. A combination of generalized lymph node enlargement and a variety of mucocutaneous lesions are usually symmetrically distributed. Involvement of the palms of the hands and soles of the feet is common. Elevated lesions termed condylomata lata may occur. Less common manifestations include hepatitis, renal disease, iritis, and gastrointestinal abnormalities.

3. Tertiary syphilis: develops approximately 1/3 of untreated patients, usually after a latent period of 5 years. It is divided into three major categories; - Cardiovascular syphilis: accounts for more than 80% of cases. It is fundamentally and endarteritis of the vasa vasorum of the proximal aorta. It is characterized by slowly progressive dilation of the aortic root and arch. - Neurosyphilis: accounts for 10% of cases. - Benign tertiary syphilis: characterized by the development of gummas in various sites. They occur most commonly in bone, skin and the mucous membranes of the upper airway and mouth. Congenital syphilis: The likelihood of maternal transmission is greatest during the early stages of disease. In the absence of treatments, as many as 40% of infected infants die in utero. Manifestations include stillbirth, infantile syphilis, and late congenital syphilis. Infants who are still born manifestate hepatomegaly, bone abnormalities, pancreatic fibrosis and pneumonitis. Diagnosis: by direct demonstration of bacteria within the lesion in primary and secondary stages or by serologic tests. Nontreponemal antibody test (VDRL and RPR) are directed against treponemal cell wall and cross react with host tissues. They are the first tests to become + and are useful for screening, but they may be negative in advanced disease. False positive nontreponemal test may occur in SLE, in drug adicts, and during pregnancy. 4.2. Gonorrhea. Sexually transmitted infection of the lower genitourinary tract caused by Neisseria gonorrhoeae. Humans are the only natural reservoir. The organism is highly fastidious, and spread of infection required direct contact with the mucosa of an infected person. The bacteria initially attach to mucosal epithelium, particularly of the collumnar or transitional type, using a variety of membrane associated adhesion molecules and structures termed pili. The organism then penetrates through the epithelial cells and invades the deeper tissues of the host. Clinical features: infected males present with dysuria, urinary frequency, and a mucopurulent urethral exudate within 2-7 days after time of initial infection. Untreated infections may ascend to involve the prostate, seminal vesicles, epididymis, and testis. 4.3. Nongonococcal urethritis and cervicitis. Are the most common forms of STDs today. A variety of organisms has been implicated in the pathogenesis. Including C. trahomatis, Trichomonas vaginalis, U. urealyticum. C. trachomatis is a small gram-negative bacterium. It exists in two forms: the infectious form is capable of at least limited survival in the extracellular environment. The elementary body is taken up by host cells. Once inside the cell, the elementary body differentiates into a metabolically active form, termed reticulate body. Spectrum of clinical features. Thus, patients may develop epididymitis, prostatitis, pelvic inflammatory disease, pharyngitis, conjunctivitis, perihepatic inflammation. 4.4. Trichomoniasis. Is a sexually transmitted protozoan that is frequent cause of vaginitis. It can cause superficial lesions of the mucosa in females. It may be asymptomatic, but frequently it causes itching and profuse, forthy, yellow vaginal discharge. 4.5. Genital herpes simplex. In most cases it is causes by HSV-2. Genital HSV infection may occur in any sexual active population. As with other STDs. HSV is transmitted when the virus comes into contact with a mucosal surface or broken skin of susceptible host. It can produce primary or recurrent mucocutaenous lesions that are clinically indistinguishable. First episode, locally painful vesicular lesions are often accompanied by dysuria, urethral discharge, local lymph node enlargement and tenderness, and systemic manifestations.

4.6. HPV. Is the cause of number of squamous proliferations in the genital tract. Condylomata acuminata are caused by HPV 6 and 11.

Ch. 14 The kidney and its collecting system.

Diseases of the kidney are divided into four basic morphologic components: Glomeruli, tubules, interstitium, and blood vessels. 1. Clinical manifestations of renal diseases. Azotemia refers to an elevation of blood urea nitrogen and creatinine levels and is largely related to a deceased GFR. Prerenal azotemia is encountered when there is hypoperfusion of the kidneys, which decreases GFR in the absence of parenchymal damage. Postrenal azotemia can result when urine flow is obstructed below the level of the kidney. When azotemia progresses to clinical manifestations and systemic biochemical abnormalities, it is termed uremia. This is characterized not only by failure of renal excretory function but also by host of metabolic and endocrine alterations incident to renal damage. 1. Acute nephritic syndrome: is a glomerular syndrome dominated by the acute onset of usually grossly visible hematuria, mild to moderate proteinuria, edema, and hypertension; it is classic presentation of acute poststreptococcal glomerulonephritis. 2. Nephrotic syndrome: a glomerular syndrome characterized by heavy proteinuria, hypoalbuminemia, severe edema, hyperlipidemia, and lipiduria. 3. Asymptomatic hematuria or proteinuria: a manifestation of subtle or mild glomerular abnormalities. 4. Rapidly progressive glomerulonephritis results in loss of renal function in a few days or weeks and is manifested by microscopic hematuria. 5. Acute renal failure: dominated by oliguria or anuria with recent onset of azotemia. 6. Chronic renal failure: characterized by prolonged symptoms and sings of uremia. 7. Urinary tract infection. 8. Nephrolithiasis (renal stones); renal colic, hematuria, and recurrent stone formation. 2. Glomerular diseases. The visceral epithelium (podocytes) is an intrinsic part of the capillary wall, whereas the parietal epithelium lines Bowman space (urinary space). 1. A thin layer of fenestrated endothelial cells; 2. A glomerular basement membrane (GBM); 3. The visceral epithelial cells (podocytes); 4. Entire glomerular tuft is supported by mesangial cells lying between the capillaries. Major characteristics are an extraordinarily high permeability to water and small solutes and almost an incomplete impermeability to molecules of the size and molecular charge of albumin. The podocyte is crucial to the maintenance of glomerular barrier function: its filtration slit diaphragm presents a distal resistance to flow of water and a diffusion barrier to the filtration of proteins, and is largely responsible for synthesis of GBM proteins. Nephrin is the major component of the slit diaphragms between adjacent foot processes. The intracellular part of nephrin molecules bind to and interacts with several cytoskeletal and signalling proteins. It has an crucial role in maintaining the selective permeability of the glomerular filtration barrier.

(toelichting A+B+C: A, Deposition of circulating immune complexes gives a granular immunofluorescence pattern. B, Anti-GBM antibody GN is characterized by a linear immunofluorescence pattern. C, Antibodies against some glomerular components deposit in a granular pattern.)

2.1 Pathogenesis of Glomerular diseases. Two forms of antibody associated injury have been established: 1. Injury resulting from deposition of soluble circulating antigen-antibody complexes in the glomerulus. 2. Injury by antibody reacting in situ

within the glomerulus, either with insoluble fixed glomerular antigens or with molecules planted within the glomerulus.. Antibodies directed against glomerular cell components may cause glomerular injury. 2.2. Nephritis caused by circulating immune complexes. The antigen is not of glomerular origin. It may endogenous (as with SLE), or exogenous (when it follows a certain bacterial infection). Often the inciting antigen is unknown. Antigen-antibody complexes are formed in situ or in the circulation and are then trapped in the glomeruli, where they produce injury, in large part through the activation of complement and the recruitment of leukocytes. The glomerular lesions usually consist of leukocytic infiltration (exudation) into glomeruli and variable proliferation of endothelial, mesangial, and parietal epithelial cells. When fluoresceinated anti-immunoglobulin or anti-complement antibodies are used, the immune complexes are seen as granular deposits in the glomerulus. 2.3. Nephritis caused by in situ immune complexes. Anti-GBM: antibodies are directed against fixed antigens in the GBM. Spontaneous antiGBM antibody GN in humans results from the formation of autoantibodies directed against the GBM. Deposition of these antibodies creates a linear pattern of staining. Antigen responsible is a component of the noncollagenous domain of the alfa3 chain of colalgen type IV. Sometimes the anti-GBM antibodies cross-react with lung alveoli, resulting in simultaneous lung and kidney lesions (goodpasture-syndrome). Several factors affects glomerular localization of antigen, antibody, or complexes. The molecular charge and size of these reactants are clearly important. The pattern of localization is also affected by changes in glomerular hemodynamics, mesangial function, and the integrity of the charge-selective barrier in the glomerulus. 2.4. Mediators of immune injury. A major pathway of antibody-initiated injury is complement leukocyte mediated. It leads to the generation of chemotactic agents (mainly C5a) and the recruitment of neutrophils and monocytes. Neutrophils release proteases, which cause GBM degradation; oxygenderived free radicals, which cause cell damage; and arachidonic acid metabolites, which contribute to reduction in GFR. The membrane attack complex also up-regulates transforming growth factor-beta (TGF-B) receptors on podocytes. TGF-B stimulates synthesis of extracellular matrix, thus giving rise to altered GBM composition and thickening. Other mediators of glomerular damage include: 1. Monocytes and macrophages, which infiltrate the glomerulus in anti-body- and cellmediated reactions and, release a vast number of biologically active molecules; 2. Platelets which aggregate in the glomerulus during injury and release prostaglandins and growth factors; 3. Resident glomerular cells can be stimulated to secrete mediators such as cytokines. 4. Fibrin-related products can cause leukocyte infiltration and glomerular cell proliferation. 2.5. Other mechanism of glomerular injury. - Podocyte injury (plaatje): can be induced by antibodies to visceral epithelial cell antigens; by toxins; or by still poorly characterized factors, as in some cases of focal and segmental glomerulosclerosis. Morphologic changes in the podocytes, which include effacement of foot processes, vacuolization, and retraction and detachment of cells from GBM. Podocyte injury is key in development of proteinuria. - Nephron loss: once any renal disease destroys sufficient functiong nephrons to reduce GFR to 30-50% of normal, progression to end-stage renal failure often proceeds inexorably. Develop proteinuria, and their kidneys show widespread glomerulosclerosis.

2.6. The nephrotic syndrome. 1. Massive proteinuria >3,5 gm 2. Hypoalbumineia, less than 3gm/dl 3. Generalized edema 4. Hyperlipidemia and lipiduria. At the onset there is little or no azotemia, hematuria hypertension. The generalized edema of the nephrotic syndrome is consequence of the drop in plasma colloid osmotic pressure as a result of hypoalbuminemia, and primary retention of salt and water by the kidney. As fluid escapces from the vascular tree into the tissues, there is a concomitant drop in plasma volume, with diminished glomerular filtration. Compensatory secretion of aldosterone ->promotes retention of salt and water by kidneys, thus further aggravating the edema. 2.7. Minimal-change disease (Lipoid nephrosis) (plaatje B). It is characterized by glomeruli that have a normal appearance by light microscopy but show diffuse effacement of podocyte foot processes when viewed with the electron microscope. The proteinuria has been attributed to a T-cell derived factor that causes podocyte damage and effacement of foot processes.

or a

Clinical course: the insidious development of the nephrotic syndrome in an otherwise healthy child. NO hypertension, and renal function is preserved in most individuals. The prognosis in children is good. More than 90% of cases respond to a short course of corticosteroid therapy. Less than 5% develop chronic renal failure after 25 years. 2.8. Focal and segmental glomerulosclerosis. A lesion characterized histologically by sclerosis affecting some but nog all glomeruli and involving only segments of each affected glomerulus. It can occur 1.) in association with other known conditions, such as HIV; 2.) secondary event in other forms of GN, 3.) as a maladaptation after nephron loss, 4.) in inherited or congenital forms. 5.) primary disease. It accounts for 20-30% of all cases of the nephrotic syndrome. The primary accounts for 20-30% of all cases of the nephrotic syndrome. The injury to the podocytes is thought to represent the initiating event of primary FSGS. Permeability increasing factors produced by lymphocytes have been proposed. The deposition of hyaline masses in the glomeruli represents the entrapment of plasma proteins and lipids in foci of injury where sclerosis develops. There is little tendency for spontaneous remission of idiopathic FSGS, and responses to corticosteroid therapy are usually poor. 2.9 Membranous nephropathy (glomerulonephritis). Well-developed cases show diffuse thickening of the capillary wall. Is idiopathic in about

85% of cases. Scondary to other disorders including: 1.) infections, 2.) malignant tumors, 3.) SLE and other auto immune disorders, 4.) exposure to inorganic salts, 5.)drugs (penicilamine, captopril, NSAIDs). React with an antigen located in the GBM, resulting in granular deposits and proteinuria. In the absence of neutrophils, monocytes, or platelets and in the virtually uniform presence of complement, current work points to a direct action of C5b-C9 on the podocyte. Complex causes activation of glomerular mesangial cells and podocytes. The onset in idiopathic cases is characterized by the insidious development of the nephrotic syndrome. Proteinuria is nonselective, with urinary loss of globulins as well as smaller albumin molecules, and does not usually respond to corticosteroid therapy. (plaatje B.) 2.10 Mebranoproliferative Glomerulonephritis. Most cases of type I MPGN seem to be caused by circulating immune complexes, akin to chronic serum sickness, but the inciting antigen is not known. Type I MPGN also occurs in association with Hep b and C antigenemia. Pathogenesis of type II MPGN, also known as densedeposit disease, is less clear. It appears to be excessive complement activation. Some patients have an autoantibody against C3 convertase which is believed to stabilize the enzyme and lead to uncontrolled cleavage of C3 and activation. The principal mode of presentation is the nephrotic syndrome. Prognosis is generally poor. 2.11 Nephritic syndrome. A clinical complex, usually of acute onset, characterized by 1. Hematurie with dyspmorphic red cells and red blood cells casts in urine, 2. Some degree of oliguria and azotemia, and 3. Hypertension. This inflammatory reaction injures the capillary walls, permitting escape of red cells into the urine and induces hemodynamic changes that lead to a reduction in the GFR. It may be produced by systemic disorders such as SLE, or it may be the result of primary glomerular disease. - Acute postinfectious (Poststreptococcal) glomerulonephritis: is typically caused by glomerular deposition of immune complexes resulting in diffuse proliferation and swelling of resident glomerular cells and frequent infiltration of leukocytes. The prototypic exogenous pattern is seen in poststreptococcal GN. The classic case of poststreptococcal GN develops in a child 1-4 weeks after the individual recovers from a group A streptococcal infectio. In most cases the initial infection is localized to the pharynx or skin. The onset tends to be abrupt, heralded by malaise, a slight fever, nausea, and the nephritic syndrome. Characteristically there is gross hematuria, the urine appearing smoky brown rather than bright red. In most children recovery occurs. Some children develop rapidly progressive GN due to severe injury with crescent or chronic renal disease due to secondary scarring. - IgA Nephropathy (Berger disease): Begins a s an episode of gross hematuria that occurs within 1-2 days of nonspecific upper respiratory tract infection. Hematuria lasts several days and then subsides, only to recur every few months. It is often associated with loin pain. It being one of the most common causes of recurrent microscopic or gross hematuria. The pathogenic hallmark is the deposition of IgA in the mesangium.

The prominent mesangial deposition of IgA suggests entrapment of IgA immune complexes in the mesangium, and the absence of C1q and C4 in glomeruli points to activation of the alternative complement pathway. Increased IgA synthesis in response to respiratory or gastrointestinal exposure to environmental agents may lead to deposition of IgA and IgA-containing immune complexes in the mesangium, where they activate the alternative complement pathway and initiate glomerular injury. The subsequent course is highly variable. Many individuals maintain normal renal function for decades. Slow progression to chronic renal failure occurs in 25-50% of cases during a period of 20 years. (Plaatje: IgA nephropathy showing characteristic immunofluorescence deposition of IgA in mesangial regions) - Hereditary nephritis: Disease caused by mutations in GBM proteins. Alport syndrome, in which nephritis is accompanied by nerve deafness and various eye disorders. 2.12 Rapidly progressive (crescentic) glomerulonephritis. Characterized by rapid and progressive loss of renal function with features of the nephritic syndrome, often with severe oliguria and death from renal failure within weeks to months. Crescents are produced in part by proliferation of the parietal epithelial cells of Bowmans capsule in response to injury and in part by infiltration of monocytes and macrophages. In most cases the glomerular injury is immunologically mediated. - Anti-Glomerular basement membrane antibody (type I) crescentic glomerulonephritis: Characterized by linear deposits of IgG and, C3 on the GBM. The anti-GBM can also bind to pulmonary alveolar capillary -> clinical picture of pulmonary hemorrhages associated with renal failure = Good pasture. Anti-GBM antibodies are present in the serum and are helpful in diagnosis. Type I-CrGN individuals benefit from plasmapheresis, which removes pathogenic antibodies from the circulation. - Immune complex-mediated (type II) crescentic glomerulonephritis: can be a complication of any of the immune complex nephritides, including poststreptococcal GN, SLE, IgA nephropathy. Charactersitic granular (lumpy bumpy) pattern of staining of the GBM and/or mesangium. - Pauci-Immune (type III) crescentic glomerulonephritis: Defined by the lack of the antiGBM antibodies or significant immune complex deposition detectable by immunofluorescence and electron microscopy. Clinical course: the oliguria and azotemia are more pronounced. Some of these persons become anuric and require long-term dialysis or transplantation. The prognosis can be roughly related to the number of crescents. 2.13 Chronic glomerulonephritis. By the time chronic GN is discovered, the glomerular changes are so far advanced that it is difficult to discern the nature of the original lesion. 20% of cases arise with no history of symptomatic renal disease. Clinical course: chronic GN develops insidiously and is discovered only late in its course. It is first detected with proteinuria, hypertension, or azotemia on routine medical examination. As the glomeruli become obliterated, the avenue for protein loss is progressively closed and the nephrotic syndrome thus becomes less severe with more advanced disease. Without treatment there is a poor prognosis. 3. Disease affecting tubules and interstitium. 3.1. Tubulointerstitial Nephritis.

Refers to a group of inflammatory diseases of the kidneys that primarily involve the interstitium and tubules. In most cases it is caused by bacterial infection, the renal pelvis is prominently involved hence the more descriptive term pyelonephritis. Interstitial nephritis is generally reserved for cases of TIN that are nonbacterial in origin. Tin can be divided into acute and chronic. - Acute pyelonephritis. A common supprurative inflammation of the kideny and renal pelvis, is caused by bacterial infection. Enteric gram negative rods are the causative organisms. There are two routes: * Through the bloodstream (hematogenous) and, * from the lower urinary tract (ascending ifnection), this is the most important and common route by which the bacteria reach the kidney. The first step is adhesion of bacteria to mucosal surfaces, followed by colonization of the distal urethra. From there the organisms must gain acces to the bladder, by expansive growth of the colonies and by moving against the flow of urine. Ordinarily, bladder urine is sterile, and remains so, as a result of the antimicrobial properties of the bladder mucosa and the flushing action. Incompetence of the vesicoureteral orifice that allows bacteria to ascend the ureter into the pelvis. The normal ureteral to ascend into the bladder is a competent one-way valve that prevents retrograde flow of urine. An incompetent orifice allows the reflux of bladder urine into the ureters, termed vesicouretreral reflux (VUR). Present in 20-40% of young children with UTI. Predisposing conditions: - Urinary obstruction; - Instrumentation; - Vesicoureteral reflux; - Pregnancy. The onset of uncomplicated acute pyelonephritis is usually sudden, with pain at the costovertebral angle and systemic evidence of infection such as chills, fever and malaise. Urinary findings include pyruria and bacteriuria. Even without antibiotic treatment, the disease tends to be benign and self-limited. Disease is usually unilateral. - Chronic pyelonpehritis: Defined as morphologic entity in which predominantly interstitial inflammation and scarring of the renal parenchyma is associated with grossly visible scarring and deformity. Chronic can be divided into two: 1. Chronic obstructive pyelonephritis: : recurrent infections superimposed on diffuse or localized obstructive lesions lead to recurrent bouts of renal inflammation and scarring. The disease can be bilateral, resulting in fetal renal insufficiency. 2. Chronic reflux-associated pyelonephritis: common form. Reflux may be unilateral or bilateral. Clinical course: many persons come to medial attention relatively late in the course of the disease, because of the gradual onset. Often the renal disease is heralded by the development of hypertension. - Drug induced interstitial nephritis: 1. Acute drug-induced: an adverse reaction to any of an increasing number of drugs. Most frequently occurs with synthetic penicillins, other synthetic antibiotics, diuertics. The drug acts as haptents that, during secretion by tubules, covalently bind to some cytoplasmic or extracellular component of tubular cells and become immunogenic. The resultant tubulointerstitial injury is then caused by IgE- and cell-mediated immune reactions. The disease begins about 15 days after exposure to the drug and is characterized by fever, eosinophelia, a rash in about 25% of persons. A rising serum creatinine or acute renal failure with oliguria develops in about 50% of cases. 2. Analgesic nephropathy; individuals who consume large quantities of analgesics may develop chronic interstitial nephritis, often associated with renal papillary necrosis. This is the initial event, and the interstitial nephritis in the overlying renal parenchyma is a

secondary phenomenon -> oxidative damage. Common clinical features include chronic renal failure, hypertension, and anemia. The anemia results in part from damage to red cells by phenacetin metabolites. 3.2. Acute tubular necrosis (ATN). Damaged tubular epithelial cells. It is the most common cause of acute renal failure. Urine flow falls within 24hours to less than 400mL per day. ATN is reversible renal lesion that arises in a variety of clinical settings. Most of these have in common a period of inadequate blood flow to peripheral organs, marked hypotension and shock. Ischemic ATN: mismatched blood transfusion, and other hemolytic crises. Nephrotoxic ATN: caused by a variety of poisons, including heavy metals. The decisive events: 1. Tubular injury and 2. Persistent and severe disturbances in blood flow resulting in diminished oxygen and substrate delivery to tubular cells. Tubular epithelial cells are particularly sensitive to anoxia and are also vulnerable to toxins. Loss of polarity seems to be functionally important early event. This leads to redistribution of membrane proteins from the basolateral to the luminal surface of tubular cells, resulting in decreased sodium reabsorption by proximal tubules and hence increased sodium delivery to distal tubules. Further damage to the tubules and the resultant tubular debris can block urine outflow and eventually increase intratubular pressure, thereby decreasing GFR. Fluid from the damaged tubules could leak into the interstitium, resulting in increased interstitial pressure and collapse of the tubules. Ischemic renal injury is also characterized by severe hemodynamic alterations that cause reduced GFR. The major one intrarenal vasoconstriction. Vasoconstriction is mediated by sublethral endothelial injury, leading to increased release of the endothelial vasoconstrictor endothelin and decreased production of vasodilator NO and prostaglandins. Clinical course: - Inition phase: dominated by inciting medical surgery, or obstetric event in the ischemic form of ATN. The only indication of renal involement is a slight decline in urine output with a rise in serum creatinine. - Maintaince phase: begins anyhwer from the second to the sixth day. Urine output falls markedly, usually between 50-400 mL per day (oliguria). Signs and symptoms of uremia and fluid overload. - Recovery phase: ushered by a steady increase in urine volume,reaching as much as 3L/day over the course of a few days. Because tubular function is still deranged, serious electrolyte imbalances can occur. - Final phase: there is a gradual return of the individuals well being. Urine volume returns to noram; however, subtle functional impairment of the kidneys may be visible for months. Patients who do not die from the underlying precipitating problem have 90-95% chance of recovering from ATN. 4. Disease involving blood vessels. 4.1. Benign Nephrosclerosis. Used for the renal changes in benign hypertension, always associated with hyaline arteriolosclerosis. Many renal disease cause hypertension, which in turn is associated with benign nephrosclerosis. This renal lesion is often seen superimposed on other primary kidney diseases. This lesion only rarely causes severe damage. 4.2. Malignant hypertension and malignant nephrosclerosis. Occurs in only about 5% of persons with elevated blood pressure. The basis for this turn for the worse is unclear, but the following is suggested; the initial event seems to be some form of vascular damge to the kidneys. The result is increased permeability of the small vesssels to fibrogen and other plama proteins. This leads to the appereance of fibronoid necoris of arterioles and small arteries. Mitogenic factors cause intimal smooth hyperplasia of vessels, resulting in the hyperplastic arteriolosclerosis typical of malignant hypertension. The kidneys become markedly ischemic. Renin-angiotensin system

receives a powerful stimulus and indeed persons with malignant hypertension have markedly elevated levels of renin. This then sets up a self-perpetuating cycle in which ANG-II causes intrarenal vasoconstriction. Aldosterone levels are also elevated. Clinical course: Diastolic pressure is >120 mmHg, papilledema, encephalopathy, cardiovascular abnormalities and renal failure. Early symptoms are related to increased intracranial pressure and include headache, nausea, vomiting and visual impairment. Soon renal failure makes its appearance. About 50% of patients survive 5-years. 90% of deaths are caused by uremia. 4.3. Thrombotic microangiopathies. Lesions seen in various clinical syndromes, characterized by widespread thrombosis in the microcirculation and clinically by microangiopathic hemolytic anemia. Central to pathogenesis of HUS is endothelial injury and activation. TTP is now known to be caused by an acquired defect in proteolytic cleavage of vWF multimers. Childhood HUS is characterized by the sudden onset, usually after a gastrointestinal or flulike prodromal episode. This disease is one of the main cases of acute renal failure in children. The renal failure is managed properly with dialysis, most patients recover in a matter of weeks. About 25% of children eventually develop renal insufficiency due to the secondary scarring. 5. Cystic disease of the kideny. A heterogeneous group comprising hereditary, developmental but nonhereditary, and acquired disorders. 1. They are reasonably common and often present diagnostic problems for clinicians ; 2. Some forms are major causes of chronic renal failure; 3. They can occasionally be confused with malignant tumors. - Simple cysts: innocuous lesions occur as multiple or single cystic spaced. They are 15cm in adiamter; translucent; lined by a gray, glistening, smooth membrane; and filled with clear fluid. They are usually confined to the cortex. They are common post-mortem findings. Renal cysts have cmooth contours, are almost always avascular, and give fluid rather than solid tissue signals on ultrasonography. Dialysis associated acquired cysts: occur in kidenys of patients with end-stage renal disease who have undergone prolonged dialysis. Present in both cortex and medulla and may bleed. 5.1. Autosomal dominant polycystic kidney disease. Characterized by multiple expanding cysts of both kidenys that ultimately destroy the intervening parenchyma. 1-500/1000 persons and accounts for 10% of cases of chronic renal failure. The polycystin -> mutations in this protein cause cyst formation, and it is thought that the resultant defects in cell matrix interactions may lead to alterations in proliferation, adhesion, differentiation, and matrix production. Clinical course: Usually does not produce symptoms until the fourth decade, by which time the kidneys are quite large. Most common presenting complaint is flank pain or a heavy, dragging sensation. Intermittent gross hematuria commonly occurs. 5.2. Autosomal recessive polycystic kidney disease. Rare developmental anomally. It occurs 1-20.000 live births. Perinatal and neonatal forms are most common; serious manifestations are usually present at birth. 6. Urinary outflow obstruction. 6.1. Renal stones. Urolithiasis is calculus formation at any level in the urinary collecting system. About 80% of renal stones are composed of either calcium oxalate or calcium oxalate mixed iwth calcium phosphate. Another 10% are composed of magnesium ammonium phosphate. The most important cause is increased urine concentration of the stones constituents, so that it exceeds their solubility in urine. 50% of patients who develop calcium stones have hypercalciuria that is not associated with hypercalcemia.

- A high pH favors crystallization of calcium phosphate and stone formation; - Magnesium ammonium phosphate (struvite) stones almost always occur in persons with a persistently alkaline urine due to UTIs. IN particular, the ureaspillting bacteria, such as proteus vulgaris and the staphylococci. - Gout and diseases involving rapid cell turnover lead to high uric acid levels in the urine and the possibility of uric acid stones. This low pH favors uric acid stone formation. Clinical course: stones may be present without producing either symptoms or significant renal damage. Smaller stones may pass into the ureter, producing a typical intense pain. 6.2. Hydronephrosis. Refers to dilation of the renal pelvis and calyces, with accompanying atrophy of the parenchyma, caused by obstruction to the outflow of urine. Most common causes: - Congenital: atresia of the urethra, valve formations. - Acquired: foreign bodies (calculi), tumors, inflammation, neurogenic, normal preganancy. Bilateral hydronephrosis occurs only when the obstruction is below the level of the ureters. Even with complete obstruction, glomerular filtration persists for some time. Because of the continued filtration, the affected calyces and pelvis become dilated. The unusually high pressure thus generated in the renal pelvis causes compression of the renal vasculature. The most severe effects are seen in the papillae. The initial functional disturbances are largely tubular, manifested primarily by impaired concentrating ability. Serious irreversible damage occurs in about 3 weeks with complete obstruction. 7. Tumors. Tumors of the lower urinary tract are about twice as common as renal cell carcinomas. 7.1 Renal cell carcinoma. Derived from the renal tubular epithelium, located predominantly in the cortex. Renal carcinomas represents 80-85% of all primary malignant tumors, and 2-3% of all cancers in adults. They are most common from the sixth to seventh decades, and men are affected about twice as commonly as women. The risk is high in smokers, hypertensive or obese patients. - Clear cell carcinomas: Most common type, accounting for 70% to 80%. They are made up of cells with clear or granular cytoplasm. In association with von Hippel-Lindau disease. VHL disease is autosomal dominant and is characterized by predisposition to a verity of neoplasms. A germ-line mutation of the VHL gene on chromsome 3p25. The loss of both copies of this tumor suppressor genes gives rise to clear cell carcinoma. - Papillary renal cell carcinomas: 10-15% of all renal cancers. Show a papillary growth pattern. Frequently multifocal and bilateral and appear as early-stage tumors. MET gene is a tyrosine kinase receptor for growth factor called hepatocyte growth factor. It is an increased gene dosage due to duplications of chromsome 7 that seems to spur abnormal growth in the proximal tubular epithelial cell precursors of papillary carcinomas. - Chromphobe renal carcinomas: representing 5%. Arise from intercalated cells for colecting ducts. These tumors are unique in having multiple losses of entire chromosomes, including 1,2,6,10,13,17 and 21. Showing extreme hypodiploidy. Clinical course: Most frequent presenting manifestation is hematuria, occurring in > 50%. The tumor may declare itself simply by virtue of its size, when it has gown large enough to produce flank pain and palpable mass. Extra-renal effects are fever and polycythemia. PV affects 5-10% of persons. It results from elaboration of EPO by the renal tumor. Paraneoplastic syndromes. The prevalent locations for metastases are the lung and the bones. 7.2. Tumors of the urinary bladders and collecting system. Painless hematuria is the dominant clinical presentation. They affect men about 3x as frequently , between 50-70 yers. Tumors are 50 times more common in those exposed to

Beta-naphtylamine. Except for the clearly benign papillomas, lesions that invade the uretral or urethral orifices cause urinary tract obstruction. In general, with low-grade shallow lesions, the prognosis after removal is good, but when deep penetration has occurred, the 5-year survival rate is <20%. Overall 5-year survival is 57%.

Ch.19 The female genital system and breast. I. Vulva.

1. Vulvitis. The five most important of these infectious agents are HPV, producing condylomata acuminata and vulvar intraepithelial neoplasia; HSV, causing a vesicular eruption; gonococcal suppurative infection of the vulvovaginal glands; syphilis, with its primary chancre at the site of inoculation; and candidal vulvitis. 1.1. Contact dermitis. Reactive inflammation to an exogenous stimulus, whether an irritant or an allergen. Presents as well-defined erythematous weeping and crusting. 2. Non-neoplastic epithelial disorders. The epithelium of the vulvar mucosa may undergo atrophic thinning or hyperplastic thickening. 2.1. Lichen Sclerosus. Characterized by thinning of the epidermis and disappearance of rete pegs, hydropic degeneration of the basal cells, superficial hyperkeratosis, and dermal fibrosis with a scant perivascular, mononuclear inflammatory cell infiltrate. Appear clinically as smooth, white plaques or papules that in time may extent and coalesce. It occurs in all age groups but is most common in postmenopausal women. 2.2. Lichen simplex chronicus. Previously called hyperplastic dystrophy, end stage of many inflammatory dermatoses and is marked by epithelial thickening. Appears clinically as an area of leukoplakia. 3. Tumors. 3.1. Condylomas and Low-Grade Vulvar intraepithelial neoplasia (VIN). Condylomas are essentially anogenital warts. Most fall into two distinctive biological forms: - Condylomata lata ; are flat, moist, minimally elevated lesions that occur in secondary syphilis; - Condylomata acuminata; may be papillary and distinctively elevated or somewhat flat

and rugose. Considered to be hallmarks of HPV infection. HPV can be transmitted venereally and indentical lesions occur in men on the penis and around the anus -> NOT precancerous!! 3.2. High-grade vulvar intraepithelial neoplasia and carcinoma of the vulva. Represents about 3% of all genital tract cancers in women occurring mostly in women older than age 60 years. 90% of carcinomas are squamous cell carcinomas. Two biological forms of vulvar carcinoma; - Most common is seen in relatively younger patients, particularly in cigarette smokers. HPV, type 16, is present in 75%-90% of cases. - Other subgroup occurs in older women. It is not associated with HPV but is often preceded by years of non-neoplastic epithelial changes, principally lichen sclerosus. Women with a tumor less than 2cm in diameter have about a 75% 5-year survival after radical excision. 3.3. Extramammary paget disease. A form of intraepithelial carcinoma. The majority of cases of vulvar paget have no demonstrable underlying carcinoma. Present as red, scaly, crusted plaque and may appear as inflammatory dermatosis.

II. VAGINA
1. Vaginitis. A relatively common clinical problem that is usually transient and not serious. It produces a vaginal discharge (leukorrhea). Candidal vaginitis produces a curdy white discharge. It is present in about 5% of normal adults, symptomatic infection almost always involve predisposing influences. T. vaginalis produces a watery, copious gray-green discharge in which parasites can also be identified microscopically. Can also be identified in about 10% of asymptomatic women.

III. Cervix.
Serve as a barrier to the ingress of air and the microflora of the normal vaginal tract. 1. Cervicitis. Remodelling occurs continuously with regeneration of both squamous and columnar epithelium. The region in which this takes place is known as the transformation zone. Frequently, overgrowth of the regenerating squamous epithelium block the orifices of endocervical glands in the transformation zone to produce small nabothian cysts lined by columnar mucussecreting epithelium. Difficult to differentiate noninfectious from infectious cervicitis. Often present are indigenous and incidental vaginal aerobes and anaorbes, streptococci, etc. Much more important are Chlamydia trachomatis, Ureoplasma urealyticum, T. vaginalis, candida spp., Neisseria gonorrhoeae. Among these pathogens, C. trachomatis is by far the most common and accounts for as many as 40% of cases of cervicitis.

Cervicitis commonly comes to attention on routine examination or because of marked leukorrhea. Only the identification of known pathogens is helpfull. (Plaatje: development of the cervical transformation zone) 2. Tumors of the cervix. 2.1. Cervical intraepithelial neoplasia (CIN) and squamous cell carcinoma. Was once the most frequent form of cancer in women around the world. Since the introduction of PAP-smear 50 years ago, the incidence of cervical cancer has plummeted. It remains the most successful cancer screening test ever developed. Cancer mortality is reduced by as much as 99%. Many of the cases of cervical carcinoma now occur in women who do not have had regular screening. Nearly all invasive cervical squamous cell carcinomas arise from precursor epithelial changes referred to as CIN. Not all cases of CIN progress to invasive cancer. 2.2. Cervical intraepithelial neoplasia. On the basis of histology, precancerous changes are graded as follows: CIN I: mild dysplasia; CIN II: moderate dysplasia; CIN III: severe dysplasia and CIS. The precancerous lesions are dived into two groups: low-grade and high-grade squamous intraepithelial lesions (SIL). The low-grade lesions correspond to CIN I or flat condylomas and the high-grade lesions to CIN II or III Peak age incidence of CIN Is about 30 years, whereas that of invasive carcinoma is about 45 years. Important risk factors for the development of CIN: - Early age at first intercourse; - Multiple sexual partners; - A mal partner with multiple previous sexual partners; - Persistent infection by high-risk HPV (including 16,18,45 and 31, account for the majority of cervical carcinomas). HPV types 16 and 18 usually integrate into the host genome and express large amount of E6 and E7 proteins, which block or inactivate tumor supressor gene p53 and RB. Among the well defined risk factor are cigarette smoking and exogenous or endogenous immunodeficiency. 2.2.1. Invasive carcinoma of the cervix. Most common cervical carcinomas are squamous cell carcinomas (75%), followed by adenocarcinomas and adenosquamous carcinomas (20%), and small-cell neuroendocrine carcinomas (<5%). The squamous cell lesions are increasingly appearing in younger women, now with peak incidence at about 45 years. The vast majority of cervical neoplasms are diagnosed in the preinvasive phase and appear as white areas on colposcopic examination after application of dilute actic acid. Once cancer develops, the outlook hinges on stage, with 5-year survival as follows: 0 stage = 100%; stage 1 = 90%, Stage 2= 82%, Stage 3= 35% and stage 4 = 10%.

IV. Body of uterus.

1. Endometritis. Part of the wider spectrum of pelvic inflammatory disease, a condition with consequences for the integrity of the fallopian tubes and subsequent fertility. Endometritis is classified as acute or chronic based on whether there is a predominant neutrophilic or lymphoplasmacytic response. Generally the diagnosis of chronic endometritis requires the presence of plasma cells. Acute endometritis is frequently due to N. gonorrhoeae or C. trachomatis. 2. Adenomyosis. Refers to growth of the basal layer of the endometrium down into the myometrium. The uterine wall often becomes thickened and the uterus enlarged and globular as a result of the presence of endometrial tissue and reactive hypertrophy of the myometrium. 3. Endometriosis. Characterized by endometrial glands and stroma location outside the endomyometrium. It occurs in as many as 10% of women in their reproductive years and in nearly half of women with infertility. It is a common cause of dysmenorrhea, and pelvic pain, and may present as pelvic mass filled with degenerating blood. Three possibilities have been invoked to explain the origin of these dispersed lesions: - The regurgitation theory, currently the most accepted, proposes that menstrual backflow through teh fallopian tubes with

subsequent implantation; - Metaplastic theory, endometrial differentiation of coelomic epithelium, which is the origin of the endometrium itself; - Vascular or lympathic dissemination theory, invoked to explain extrapelvic or intranodal implants. The clinical manifestations depend on the distribution of the lesions. 4. Dysfunctional uterine bleeding and endometrial hyperlasia. Most common problem for which women seek medical attention. - Menorrhagia (profuse or prolonged bleeding); - Metrorrhagia (irregular leeding); - Ovulatory (Intermenstrual) or Postmenopausal bleeding. 4.1. Dysfunctional uterine bleeding. Abnormal bleeding in the absence of a well-defined organic lesion in the uterus. The probable cause depends somewhat on the age of the women. - Failure of ovulation: Anovulatory cycles are very common at both ends of reproductive life. Regardless of the basis for the failure ovulation, it leads to an excess of oestrogen relative to progesterone. The endometrium goes through a proliferative phase that is not followed by the normal secretory phase; - inadequate luteal phase: the corpus luteum may fail to mature normally or regress prematurely, leading to a relative lack of progesterone. - Contraceptive induced bleeding; - Endomyomterial disorders (e.g. chronic endometritis, endometrial polyps etc.) 4.2. Endometrial hyperplasia. An excess of oestrogen relative to progestin will induce exaggerated endometrial proliferation (hyperplasia). In time the hyperplasia may become autonomously proliferating, no longer needing estrogenic influences, eventually giving rise to carcinoma. Simple hyperplasia carrier a negligible risk while a person with atypical hyperplasia with cellular atypia has a 20% risk. A common risk factor is obsesity, because adipose tissue processes steroid precursors into estrogens. 5. Tumors of the endometrium and myometrium. 5.1. Endometrial polyps. Sessile, usually hemisperhic lesions that are 0,5 to 3 cm in diameter. They are composed of endometrium resembling the basalis. They have cystically dilated glands. May occur at any age, they develop more commonly at the time of menopauze. Clinical significance lies in the production of abnormal uterine bleeding and the risk of giving rise to cancer. 5.2. Leiomyoma and leyiomyocarcoma. Benign tumors that arise from the smooth muscle cells in the myometrium -> leiomyoma. Because they are firm, they are more often referred to as fibroids. They are found in 3050% of women during productive life. Estrogens and possibly oral contraceptives stimulate their growth. Leiomyomas of the uterus may be entirely asymptomatic and be discovered during routine examination. Most frequent manifestation is menorrhagia. - Leiomyosarcomas typically arise de novo. Recurrence after removal is common with these cancers, and many mastastasize, typically to the lungs, yielding a 5-year survival rate of about 40%. 5.3. endometrial carcinoma. Appears most frequently between the ages 55-65 and is distinctly uncommon in women under 40 years of age. Two clinical settings in which endometrial carcinomas arise: in perimenopausal women with estrogen excess and in older women with endometrial atrophy. Well defined risk factors: - Obesity; increased estrogens; - Diabetes; - Hypertension; - Infertility.

First clinical indication is marked leukorrhea and irregular bleeding. This cause for concern in in postmenopausal woman, since it reflect erosion and ulceration of the endometrial surface. Stage I carcinoma is associated with a 5-year survival rate of 90%. 6. Fallopian tubes. Inflammation of the tube are almost always microbial in origin. All forms of salpingitis may produce fever, lower abdominal or pelvic pain, and pelvic masses when the tubes become distended with either exudate or , later, burned-out inflammatory debris and secretions. Adherence of the tube to the ovary and adjacent ligamentous tissues results in a tubo-ovarian abcess. Primary adenocarcinomas of the fallopian tubes may be of papillary serous or endometrioid histology. Fallopian tube carcinomas seem to be increased with BRCA mutations.

V. Ovaries.
1. Follicle and luteal cysts. Follicle and luteal cysts originate in un ruptured graafian follicles or in follicles that have ruptured and immediately sealed. They are often multiple and develop immediately subjacent to the serosal covering of the ovary. (1-1,5 cm) filled with clear serous fluid. 2. Polycystic ovaries. Oligomenorrhea, hirsutism, infertility, and sometimes obesity may appear in young women secondary to excessive production of estrogens and androgens by multiple cystic follicles in the ovaries. Ovaries are usually twice normal in size, are gray white with a smooth outer cortex, studded with subcortical cysts 0,5-1,5cm. Excessive production of androgens, high concentrations of LH, and low concentrations of FSH. 3. Tumors of the ovary. Pathogenesis: risk factors are nulliparity and family history. Hereditary ovarian cancers seem to be caused by mutations in the BRCA genes, BRCA1 and BRCA2. Average lifetime risk for ovarian cancer approximates 30% in BRCA1 carriers. The risk in BRCA2 is somewhat lower. HER2/NEU positive is associated with a poor prognosis. K-ras protein is overespressed in up to 30% of tumors.

4. Surface epithelial-stromal tumors. Derived from the coelomic mesothelium that covers the surface of the ovary. Repeated ovulation and scarring the surface epithelium is pulled into the cortex of the ovary, forming small epithelial cysts. These can undergo metaplasia and neoplastic transformation into epithelial tumors. Limited invasive potential. Serous tumor: most frequent. Benign lesions are usually encounterd between age 30-40 years, and malignant serous tumors are more commonly seen between 45-65. Prognosis with clearly invasive serous cystadenocarcinoma after surgery, radiation and chemotherapy is poor and depends heavily on the stage of the disease at the time of diagnosis. Mucinous tumors: in most respects analogous to the serous tumors, differing in that the epithelium consists of mucin-secreting cells similar to those of the endocervical mucosa. Prognosis is somewhat better than that of the serous counterpart, the stage rather than the histologic type is the major determinant of treatment success. Endometrioid tumors: may be solid or cystic, but sometimes they develop as a mass projecting from the wall of an endometriotic cyst. Brenner tumor: Uncommon, solid, usually unilateral ovarian consisting of an abundant stroma containing nests of transitional-like epithelium. Generally smoothly encapsulated and gray-white on transection and range from a few cm to 20cm. 5. Other ovarian tumors. 5.1. Teratomas. Neoplasms of germ-cell origin. They display the distressing behaviour of arising in the first two decades of life, the younger the greater malignancy. 5.2.Benign Cystic Teratomas: marked by differentiation of totipotential germ cells into mature tissues representing all three germ cell layers:

ectoderm, endoderm, and mesoderm. Unilateral, more often on the right. Often filled with hair, that when removed , reveal a hair-bearing epidermal lining. (plaatje) 5.3. Immature malignant teratomas. Early in life, mean age being 18. Are often bulky, are predominantly solid or near-solid on transection, and are punctuated here and there by areas of necrosis. Microscopically , distinguishing feature is a variety of immature or barely recognizable areas of differentiation toward cartilage, bone, muscle, nerve and other structures. 5.4. Specialized teratomas. Struma ovarii is composed entirely of mature thyroid tissue that, interestingly, may hyperfunction and produce hyperthyroidism. Appear as small, solid, unilateral brown overian masses. 5.6. Clinical correlations for all ovarian tumors. Pose formidable clinical challenges, because they produce no symptoms or signs until they are well advanced. Ovarian tumors of surface cell origin are usually asymptomatic until they become large enough to cause local pressure symptoms (e.g. pain, gastrointestinal complaints, urinary frequency). Fibromas and malignant serous tumors often cause ascites, the latter resulting from metastatic seeding of the peritoneal cavity, so that tumor cells can be identified in the ascitic fluid.

VI. Diseases of pregnancy.

1. Placental inflammations and infections. Infections reach the placenta by two pathways: - Ascending infections, by far the most common. They are bacterial and are associated with premature birth and premature rupture of the membranes. The chorioamnion shows polymorphonuclear leukocytic infiltration with edema and congestion of the vessels; - Hematogenous spread of bacteria and other organisms; the villi are most often affected. E.g. syphillis or TBC. Transplacental infections can give rise to TORCH-complex. 2. Ectopic pregnancy. Implantation of the fertilized ovum in any site other than the normal uterine location. Occurs in as many as 1% of the pregnancies. In more than 90% of theses cases, implantation is in the oviducts (tubal pregnancy). Any factor that retard the passage of the ovum along its course through the oviducts to the uterus predisposes to an ectopic pregnancy. In about half of the cases, such obstruction is bases on chronic inflammatory changes. Gestation within the abdominal cavity occurs when the fertilized egg drops out of the fimbriated end of the oviduct and implants on the peritoneum. Until rupture occurs, an ectopic pregnancy may be indistinguishable from a normal one. The endometrium undergoes characteristic hyper secretory and decidual changes. 3. Gestational trophoblastic disease. Three overlapping morphologic categories. All elaborate hCG. 3.1. Hydatidiform mole: Complete and partial. A voluminous mass of swollen, sometimes cystically dilated, chorionic villi, appearing grossly as grapelike structures. Two distinctive subtypes: - The complete mole does not permit embryogenesis and therefore never contains fetal parts. - Partial mole is compatible with early embryo formation and therefore contains fetal parts, has come normal chorionic villi, and is almost always triploid. The two patterns result from abnormal fertilization; in a complete mole an empty egg is fertilized by 2 spermatozoa, resulting in triploid karyotype with a preponderance of paternal genes. 1-2000 pregnancies.

3.2. Invasive mole. Are complete moles that are more invasive locally but do not have the aggressive metastatic potential of a choriocarcinoma. Retains hydropic villi, which penetrate the uterine wall deeply, possibly causing rupture and sometimes life-threatening haemorrhage. 3.3. Choriocacinoma. Very aggressive malignant tumor that arises either from gestational chorionic epithelium or from totipotenial cells within the gonads or elsewhere. About 25% arise after abortion. Most cases are discovered by the appearance of a bloody, brownish discharge accompanied by a rising titer of hCG, and the absence of marked uterine enlargement. By the time most choriocarcinomas are discovered there is usually widespread dissemination via the blood, most often to the lungs (50%), vagina (30-40%), brain, liver and kidneys. Present-day chemotherapy has achieved that nearly 100% of cases can be cured. By contrast, there is relatively poor response to chemotherapy in choriocarcinomas in the gonads (ovary and testis). 4. Preeclampsia/eclampsia. Development of hypertension, accompanied by proteinuria and edema in the third trimester of pregnancy is referred to as preeclampsia. This syndrome occurs in 5-10% of pregnancies. In those severely affected, convulsive seizures may appear, and the symptom complex is then termed eclampsia. Full-blown eclampsia may lead to disseminate intravascular coagulation. The triggering event initiating these syndromes are unknown, but a basic feature underlying all cases is inadequate maternal blood flow to the placenta secondary to inadequate development of the spiral arteries. In the third trimester, musculoelastic walls of the spiral arteries are replaced by fibrinous material, permitting them to dilate into wide vascular sinusoids. In preeeclampsia, this does not happen. It appears insidiously in the 24h to 25th week of gestation, with the development of edema, proteinuria an rising blood pressure.

VII Breast.
Supernumerary nipple or breasts may be found along the embryonic ridge (milk line). These congenital anomalies are subject to the same disease that affects the definitive breasts. Congenital inversion of the nipple is of significance because similar changes may be produced b an underlying cancer. Galactocele is a cystic dilation of an obstructed duct that arise during lactation. 1. Fibrocystic changes. Diagnosis of fibrocytic disease have little clinical significance except that they cause nodularity; fibrocystic changes is preferred, since it does not stigmatize the

subject with a disease. 1.1. Nonproliferative change. Cysts and fibrosis: increase in fibrous stroma associated with dilation of ducts and formation of cysts of various sizes. 1.2 Proliferative change. Epithelial hyperplasia: are often accompanied by other histologic change. Does not often produce clinically discrete breast mass. Sclerosing adenosis. Less common than cysts and hyperplasia. Its clinical and morphologic features may be deceptively similar to those of carcinoma. Lesions contain marked intralobular fibrosis and proliferation of small ductules and acini. Associated with a minimally increased risk. 1.3. Relationship of fibrocystic changes to breast carcinomas. - Minimal or no increased risk of breast carcinoma: Fibrosis, cystic changes, apocrine metaplasia, mild hyperplasia, fibroadenoma. - Slightly increased (1,5-2): moderate hyperplasia, ductal papillomatosis, sclerosing adenosis. -Significantly increased risk: atypical hyerplasia. - A family history of breast cancer may increase the risk in all categoreies (e.g. to -10 fold).

2. Inflammations. None are associated with increased risk of cancer. Acute mastitis develops when bacteria gain access to breast tissue through the ducts. Mammary duct ectasia; non bacterial chronic inflammation of the breast associated with inspissation of breast secretions in the main excretory ducts. Is of principal importance because it leads to induration of breast substance and, to retraction of the skin or nipple. Traumatic fat necrosis; uncommon and innocuous lesion that is significant only because it produces a mass. 3. Tumor of the breast. 3.1. Fibroadenoma. Most common benign neoplasm of the femal breast. Increase in estrogen activity is thought to contribute to its development. Appear in young women. Clinical features: solitary discrete, movable masses. Enlarge late in the menstrual cycle and during pregnancy. 3.2. Phyllodes tumor. Much less common than fibroadenomas and are thought to arise form the periductal stroma and not from preexisting fibroadenomas. Tumors are usually benign. Most ominous change is the appearance of increased stromal cellularity with anaplasia and

high mitotic activity, accompanied by rapid increase in size, usually with invasion of adjacent breast tissue by malignant stroma. 3.3. Intraductal papilloma. Neoplastic papillary growth within a duct. Lesions are solitary. Present clinically as a result of 1.) the appearance of serous or bloody nipple discharge, 2.) presence of a small subareolar tumor a few millimeters in diameter, or 3.) rarely, nipple retraction. 3.4. Carcinoma. Differences among countries in the incidence and mortality rates of breast cancer. Risk for this form of neoplasia is significantly higher in North America and Northern Europe than in Asia and Africa. Is uncommon in women younger than age 30. Women are more likely to carry a breast cancer susceptibility gene if they develop breast cancer before menopauze, have bilateral cancer, have other significant family history, or belong to certain ethnic groups. BRCA genes are thought to function in DNA repair. They act as tumor suppressor genes. Other risk factors are ; - Prolonged exposure to exogenous estrogens postmenopaussaly. - Oral contraceptives. - Ionizing radiation. Pathogenesis. Three important sets of influences: 1. Genetic changes: HER2/NEU proto-oncogen, found amplified in 30% of invasive breast cancers -> A member of the epidermal growth factor receptor family, associated with poor prognosis; 2. Hormonal influences: Endogenous estrogen excess, or more accurately, hormonal imbalance, clearly has a significant role. Estrogens stimulate the production of growth factors by normal breast epithelial cells and by cancer cells; 3. Environmental variables: include irradiation and exogenous estrogens. Spread of breast cancer. Occurs through lymphatic and hematogenous channels. Outer quadrant and central located lesions typically spread first to the axillary nodes. Those in the inner quadrants often involve the lymph node along the internal mammary arteries. Favoured locations are the lungs, skeleton, liver, and adrenals and (less common) the brain, spleen, and pituitary. Clinical course: Often discovered as a deceptively discrete, solitary, painless, and movable mass. Involvement of regional lymph nodes is in about half patients at that time. With mammographic screening, frequently detected before they become palpable. Only 15% of these have nodal metastases. Prognosis is influenced by the following variables: 1. Size of the primary carcinoma. 2. Lymph node involvement and the numer of lymph nodes involved by metastases. 3. Distant metastases. 4. Grade of carcinoma: evaluates tubule formation, nuclear grade, and mitotic rate. 5. Histologic type of carcinoma. 6. Presence or absence of estrogen or progesterone receptors. (better prognosis.) 7. Proliferative rate of cancer. 8. Aneuploidy: carcinomas with an abnormal DNA content. 9. Overexpression of HER2/NEU. Ductal carcinoma in situ (DCIS): is a precursor to invasive ductal carcinoma and is typically found on mammographic examination as calcification or as a mass. When carcinoma develops in a women with a previous diagnosis of LCIS, it occurs usually in the same breast. Lobular carcinoma in situ (LCIS): is frequently and incidental finding and does not tend to produce mass lesion. When carcinoma develops, it occurs in the affected or unaffected breast with the same frequency and may be lobular or ductal carcinoma.