Renal Pathology The glomerulus contains 2 epithelial cell layers: parietal cell layer (Bowmans capsule) and visceral

epithelial cells (podocytes). Podocytes cover the capillaries with pediceles (cell processes). Each adjacent pedicel belongs to a different cell (interdigitating). The minimal space b/w each pedicel is called the filtration slit, which separates particles based on size. The slit pore diaphragm located b/w 2 pediceles contains proteins secreted by podocytes including cadherin, FAT, nephrin, and podocin. Mutations in nephrin and podocin result in congenital nephrotic syndromes. The glomerular BM consists of a lamina rara interna (next to endothelium), lamina densa that is doubly thick, and lamina rare externa (next to podocytes). The lamina densa is (-) charged and therefore separates filtrate based on charge. Components of the BM include: o Perlecan: highly charged proteoglycan containing heparan sulfate. Imparts most of the charge to BMs. o Entactin: glycoprotein with Ca2+ binding properties o Laminin: glycoprotein formed by 3 different chains. Different isoforms exist. It binds collagen type IV, entactin, heparan sulfate, and cells (via integrins). o Collagen type IV: three chains form a collagen molecule but 6 different chains are known to exist. Type IV forms a network, not fibrils. Most of the chain is in a helical conformation but there is a nonhelical (non-collagenous) domain. Antibodies in Goodpasture syndrome react with an epitome in the NC1 domain of 3. Mesangial cells are mesenchymal cells that provide structural support to the glomerulus. They are modified smooth muscle cells that are similar to pericytes. They secrete a mesangial matrix that is similar to basement membrane. Their contractile properties allow them to have some regulation on blood flow. Substances trapped in the GBM flow to the mesangial matrix and are phagocytosed by mesangial cells. The capillary endothelial cells in the glomerulus rest on the glomerular BM and have fenestrations. New nephrons are not generated after renal injury. Surviving nephrons may undergo hypertrophy, and tubules may become longer (hypertrophy). Most glomerular diseases are due to immune mediated injury (Ab-mediated, cell-mediated, or activation of the alternative pathway). Circulating immune complexes (type III hypersensitivity) are trapped in the glomerular filter and can result in damage (nephritis). Any disease that causes an excess of immune complexes can cause damage (SLE, HBV, malaria, etc.). Immunofluorescence shows granular deposits. The immune complex deposits may be subendothelial, subepithelial, or mesangial deposits depending upon the physico-chemical properties of the complexes. Anti-GBM disease is due to antibodies against glomerular basement membrane components. It usually follows a short, flu-like illness. Immunofluorescence shows linear deposits along the GBM. If the Abs also react with alveolar basement membranes, the disease is called Goodpasture syndrome. In situ immune complexes result when antigens get trapped in the glomerular filter and circulating Abs to the Ags bind them. Immunofluorescence shows granular deposits. Some pts develop Abs against podocyte Ags and result in subepithelial, granular deposits with a membranous nephropathy. Epithelial cell injury (toxins, cytokines), hemodynamic changes, and neoplasms can also cause glomerular injury. Glomerular lesions may be classified as diffuse or focal (# of glomeruli involved) and global or segmental (portion of glomerulus involved). Patterns of glomerular response to injury: o Proliferative: Increased # of cells (inflammatory and glomerular) in the glomerulus o Membranous: thickening of the GBM and effacement of foot processes o Membrano-proliferative: combo of above o Crescents: proliferation of epithelial cells (at least 2 layers) which fill part of Bowmans capsule o Necrosis: nuclear fragmentation, cell death, and disruption of the GBM, often accompanied by fibrin deposition o Sclerosis: deposition of BM-like material resulting from an increase of mesangial matrix and/or GBM Nephrotic syndrome is due to a leaky glomerular filter and consists of massive proteinuria, hypoalbuminemia, anasarca, hyperlipidemia, lipiduria, and hypercoagulability. 1

Minimal change disease is characterized by normal glomeruli on light microscopy but effacement of foot processes seen with electron microscopy. The cells of proximal convoluted tubules often contain protein droplets and lipids (old name is lipoid necrosis). It has a benign course with normal renal function and blood pressure. It is the most common cause of nephrotic syndrome in children. 80% respond to steroids. Focal and segmental glomerulosclerosis is sclerosis affecting not all glomeruli and only segments of each glomerulus. Initially only juxtamedullary glomeruli are affected. It usually presents with nephrotic syndrome. It can occur due to primary podocyte damage in HIV and IV drug use (heroin) or as secondary FSGN in a number of other diseases. o Collapsing glomerulopathy is a variant of FSGS characterized by collapse of all glomerular tufts, podocyte hypertrophy, and tubular dilation. It is often seen with HIV or drug toxicity. Tubuloreticular inclusions may be seen due to cytokines (SLE, HIV). There is rapid onset of nephrotic syndrome with rapid progression to renal failure. Membranous nephropathy is a slowly progressive disease characterized by GBM thickening, subepithelial immunoglobulin deposits, and effacement of foot processes. 85% of cases are due to in situ immune complex disease in which Abs react with podocyte Ags. In secondary cases Ags are trapped in the GBM and complexes are formed in situ. The complexes attract complement (MAC). It results in nephrotic syndrome. It is most common in males in the 40-60 age range. Risk factors for progression include male, severe proteinuria, HTN, and tubulointerstitial fibrosis/glomerular sclerosis. Membranoproliferative glomerulonephritis is characterized by changes in the GBM and mesangium with proliferation of glomerular cells (endothelial and mesangial cells). Most pts present with nephrotic syndrome, but some present with acute nephritis or mild proteinuria. o MPGN type I is more common (80%) and is due to circulating immune complexes in pts with persistent antigenemia (HBV, HCV, SLE, persistent infections). Immunofluorescence shows granular deposits of C3, IgG, C1q, and C4. EM shows subendothelial deposits. Cell processes of mesangial and inflammatory cells extend into the GBM, creating a split appearance. o MPGN type II (dense deposit disease) is due to excessive complement activation, resulting in hypocomplementemia. Immunofluorescence shows granular deposits of C3 along the GBM. There is a split appearance due to dense deposits in the GBM. Nephritic syndrome consists of acute onset of hematuria with RBC casts, HTN, oliguria, azotemia, proteinuria (mild to moderate), and edema (moderate). It is due to glomerular inflammation with cellular proliferation and inflammatory cells. Post-infectious glomerulonephritis is due to glomerular deposition of immune complexes resulting in diffuse proliferation/swelling of glomerular cells and infiltration of leukocytes (PMNs, mononuclear cells). It commonly follows group A streptococcus infection (poststreptococcal). It may also occur following infection with staphylococcus, pneumococcus, HBV, EBV, mumps, malaria, or toxoplasmosis. There is diffuse increased glomerular cellularity, granular deposits of IgG and complement, and subepithelial deposits. Crescent formation may occur and is a bad prognostic sign. o Most children have a complete recovery, while 40% of adults develop chronic GN. IgA nephropathy (berger disease) is characterized by deposition of IgA in the mesangium. It often follows URIs or GI infections. Defective glycosylation of IgA is implicated. Incidence is increased in patients with celiac disease, dermatitis herpetiformis, exposure to infectious agents, and chronic liver disease. Primary IgA nephropathy is more common in children/young adults. Pts present with gross hematuria a few days after a URI that subsides and returns every few months. It is the most common glomerulitis worldwide. Hereditary nephritis is a group of hereditary glomerular diseases with mutations in GBM proteins. Alport syndrome is due to mutations in genes encoding for one of the chains of collagen type IV (5), resulting in defective BMs. Pts have nephritis, nerve deafness (cochlea), and eye disorders (lens). Age of presentation is 5-20 years. It is usually X-linked so males are affected more frequently and severely .LM appears normal early on with some foam cells from lipid accumulation. EM shows thin, attenuated GBM. Later develop glomerulosclerosis, tubular atrophy, and interstitial fibrosis. The 2 BMs dont come together in development, resulting in split GBM. Rapidly progressive (crescentic) glomerulonephritis is a clinical syndrome (not disease) characterized by nephritic syndrome with rapid loss of renal function, oliguria, and death in weeks or months. Crescents are 2

proliferations of parietal epithelial cells that often contain macrophages and fibrin and eventually necrosis. Most cases are due to immunologic glomerular injury. o Type I CrGN (linear IgG deposits) may be due to 2 diseases. Anti-GBM disease is due to Abs against 3 chain of type IV collagen and pts exclusively have renal involvement. It is a crescentic and necrotizing glomerulonephritis that presents with nephritic syndrome, prominent hematuria, and rapid renal failure. Goodpasture syndrome is the term used when patients have renal and pulmonary involvement (pulmonary hemorrhages and hemoptysis). Both benefit from plasmapheresis. o Type II CrGN (granular deposits) is immune complex mediated and consists of granular deposits in the GBM and mesangial matrix. There are crescents with segmental necrosis, mesangial proliferation, and leukocyte exudate. Plasmapheresis is not beneficial. It is seen in PSGN, SLE, and IgA nephropathy. o Type III CrGN (Pauci-immune) involves the presence of crescents without IgG or complement deposits. Many pts have ANCA antibodies, and some have microscopic polyangitis or Wegener granulomatosis. Most cases only have renal disease and are considered idiopathic. Chronic glomerulonephritis is the end stage of glomerular disease that presents as chronic renal failure. The kidneys are symmetrically contracted and diffusely granular. The glomeruli are fibrotic, sclerosed, and many are obliterated. There is interstitial fibrosis with loss of many tubules. Lupus nephritis is due to the presence of numerous autoimmune Abs that can result in several patterns of glomerular injury. Five classes are noted. Class III and IV are most common, and class I is rare. o Class I: Normal o Class II: Mild increase in mesangial matrix and mesangial deposits with mild proteinuria and occasional hematuria. o Class III: Focal and segmental glomerulosclerosis with immune complexes in mesangium and GBM. Occasionally tuft necrosis and crescents. Proteinuria and hematuria are usual. o Class IV: Diffuse proliferative with variable GBM thickening with mesangial and GBM deposits. Tuft necrosis and crescents are common. Hematuria and severe proteinuria are present. o Class V: Membranous nephropathy with subepithelial immune complexes. Nephrotic syndrome is presenting symptom. Diabetes mellitus is a common cause of end-stage renal disease. Damage may consist of lesions of arterial/arterioles supplying kidney, glomerular lesions, and/or tubulointerstitial lesions. o Diffuse thickening of the GBM with proteinuria. o Diffuse glomerulosclerosis with increased mesangial matrix and thickened GBM resulting in large glomeruli and proteinuria. o Nodular glomerulosclerosis involves focal deposits of mesangial matrix in a concentric fashion (Kimmestiel-Wilson nodules). Seen in advanced diabetic renal disease with proteinuria. o Diabetic tubulointerstitial disease may consist of ischemic injury due to vascular changes resulting in atrophy and fibrosis or as pyelonephritis, which is infection in tubules and ducts with small abscesses. Papillary necrosis is a combination of ischemia and infection in which renal papilla and pyramids undergo acute necrosis resulting in renal failure. Amyloid is protein aggregates in bundles of -pleated fibrillar protein that exhibit apple-green birefringence under polarized LM after staining with Congo red and the presence of rigid, nonbranching fibrils on EM. Gamma globulins are a common source and are the cause of renal amyloidosis, in which amyloid is deposited in GBM, mesangium, and vascular walls. This results in proteinuria and nephrotic syndrome with eventual compression of capillary loops and renal failure. Associated with chronic inflammatory diseases. Benign HTN (systemic HTN) causes fibrointimal proliferation and medial muscular hypertrophy in intrarenal arteries while causing hyaline arteriolosclerosis in afferent arterioles. Both lead to decreased glomerular blood flow. Nephrosclerosis is due to chronic reduction in blood flow (benign HTN) and results in non-functional glomeruli from ischemia. The tubule becomes atrophic, and the number of nephrons decreases over the years. o Benign hypertensive nephrosclerosis is sequence of changes consisting of decreased # of nephrons, decreased GFR, and eventual chronic renal failure (takes decades). Malignant HTN is due to a rapid rise in blood pressure that if uncontrolled results in renal failure within weeks or months. Afferent arterioles undergo fibrinoid necrosis while fibromuscular arteries develop a loose 3

fibroelastotic proliferation. Hyperplastic arteriolosclerosis results in a small lumen in small muscular arteries and arterioles, followed by ischemia and necrosis. Renin is released due to glomerular ischemia, which results in a cycle of continuously elevated BP and renin release. Pts present with ICP (papilledema, headache, N/V) with proteinuria and hematuria followed by cardiac and renal failure. Renal artery stenosis may be due to atherosclerosis or fibromuscular dysplasia (c.t. disease in young females). It is a curable cause of HTN. Renin is released from ischemic kidney, resulting in hypertensive nephrosclerosis in contralateral kidney. Thrombotic microangiopathies are characterized by widespread microvascular thrombosis. Pts present with microangiopathic hemolytic anemia, thrombocytopenia, and often renal failure. There are fibrin microthrombi in the small vasculature and glomeruli are often affected. If lots of vessels are affected, there is cortical renal necrosis. It is seen in childhood and adult HUS and thrombotic thrombocytopenic purpura (TTP). o Hemolytic uremic syndrome is due to widespread endothelial injury and activation, resulting in a procoagulant endothelium that causes intravascular thrombosis. In childhood, it is usually due to Shiga toxin, which glomerular endothelial cells have a receptor for. 10% of childhood cases are due to an inherited mutation that inactivates factor H (regulator of complement). Minor endothelial injuries result in uncontrolled complement activation and intravascular thrombosis. HUS presents with bleeding tendency (hematemesis, melena), microangiopathic hemolytic anemia, and acute renal failure. Tx is dialysis. o Thrombocytopenic purpura is a rare disease in which there are inherited/acquired defects in cleavage of von Willebrand factor multimers, which interact with platelets and cause disseminated platelet-fibrin thrombin and thrombocytopenia. Same presentation as HUS but pts need plasmapheresis to remove vWF multimers. Acute pyelonephritis is a suppurative inflammation of the kidney (renal parenchyma and pelvis) due to bacterial infection. The infection may reach the kidneys via hematogenous spread or as an ascending infection from the urinary tract (more common).One or both kidneys may be involved, resulting in swollen kidneys and commonly abscess formation. UTIs are more common in females aged 5 to 50, males older than 50 (prostatic hyperplasia), vesicoureteral reflux, preexisting renal lesions, pregnancy, diabetes mellitus, and in immunocompromised. o Common organisms are E. coli, Proteus, Klebsiella, and Enterobacter. o Sx include sudden pain at CVA with chills, fever, malaise, pyuria, and bacteriuria. Usually unilateral. Dx based on leukocytes in urine. o Complications include pyonephrosis (pus accumulation in renal pelvis), perinephric abscess (extension to perirenal adipose tissue and retroperitoneum), scar formation, and acute papillary necrosis. Chronic pyelonephritis is chronic tubuloinsterstitial inflammation with gross scarring and deformities of the pelvicalyceal system. Characterized by uneven scarring and scarring of the renal pelvis or calyces. Glomeruli are not directly affected but the glomeruli of affected nephrons become sclerotic. Thyroidization due to proteinaceous material accumulating in tubular lumen is characteristic. Leads to renal HTN and end-stage renal disease. o Chronic obstructive pyelonephritis is recurrent infections due to obstruction resulting in scarring and chronic pyelonephritis. It may be uni- or bilateral. o Chronic reflux pyelonephritis is more common and due to the presence of congenital vesicoureteral reflux and intrarenal reflux with multiple bouts of acute pyelonephritis. Reflux may be uni- or bilateral. Drug-Induced interstitial nephritis is probably a hypersensitivity reaction. It frequently occurs due to synthetic penicillins, diuretics (thiazides), NSAIDs, sulfas, lithium, cimetidine, cyclosporine, and analgesics. Interstitial changes are variable and may include inflammatory cells (mononuclear), eosinophils, sometimes PMNS, nonnecrotizing granulomas, and glomerular changes such as loss of pediceles (NSAIDs) leading to nephrotic syndrome. Presents with fever, eosinophilia, rash, and renal abnormalities (hematuria, leukocyturia, proteinuria). Discontinue drug. Analgesic nephropathy occurs in some pts who ingest large quantities of mixed analgesic, resulting in chronic interstitial nephritis often with renal papillary necrosis. Drugs include phenacetin, aspirin, acetaminophen, and codeine. Cell damage occurs due to covalent binding and oxidative damage. Drugs that interfere with PG synthesis cause vasoconstriction and ischemia. 4

Complications include accentuating chronic renal failure, calculi, urinary tract obstruction, UTI, papillary necrosis, and increased incidence of transitional cell carcinoma. Acute tubular necrosis is a clinicopathologic entity characterized by severe tubular damage and acute renal failure. It is a reversible condition with supportive care (dialysis). Oliguric phase is due to severe tubular damage with tubules blocked by cells and protein as well as interstitial edema and inflammatory cells. Prevent hyperkalemia and fluid overload. Polyuric phase 1-3 weeks after initial episode involves removal of dead cells and debris by phagocytosis as casts in urine. GFR increases but new cells cannot reabsorb water and electrolytes (hypotonic urine), therefore they need to be replaced. Recovery phase occurs as tubular cells become differentiated and are capable of concentrating urine. o Most common cause of acute renal failure. o Ischemic ATN is due to shock, hypovolemia, hypotension and affects shorter segments with a predilection toward the straight proximal tubule. It results in edema, casts, necrotic cells, PMNs in vasa recta, and epithelial regeneration. o Nephrotoxic ATN is more rare and due to hemoglobinuria, myoglobinuria, heavy metals (mercury, lead), organic solvents (chloroform, glycols), drugs (cyclosporine, antibiotics), pesticides (paraquat, phenol) or fungal toxins. It primarily affects long segments of the proximal convoluted tubule and has nonspecific features. Simple cysts are common and of no clinical consequence, but they need to be distinguished from neoplasms when found. They have smooth contours, are avascular, and have a fluid (not solid) signal. Acquired cysts may form in pts with acquired chronic renal disease with fibrosis and scarring or in pts with endstage kidney disease on dialysis. Hydronephrosis is dilation of the renal pelvis and calyces due to the obstruction of urine flow. Autosomal dominant (adult) polycystic kidney disease (ADPKD) is a congenital disease. There are 2 types due to mutations in polycistin-1 and 2, both of which have the same clinical and pathological characteristics. The kidneys are very enlarged and compress abdominal viscera, push up diaphragm, and contain hundreds of cysts. Cysts are also common in the liver (80%), pancreas, and intestine. Pts may also have heart-valve defects and aneurysms (especially intracranial). Presents with HTN, hematuria, polyuria, flank pain, and recurrent UTIs. o Polycystins regulate tubular and vascular development in the kidneys, liver, pancreas, heart, and brain. o 85-90% of cases are type I (mutation in polycystin-1). 10% are type II, which have later onset of Sx and longer life expectancy. Autosomal recessive (childhood) polycystic kidney disease (ARPKD) is a rare congenital disease that often causes fetal or neonatal death due to pulmonary compression by the kidneys. Those babies that survive rapidly develop renal failure and hepatic fibrosis. It is due to a mutation in the PKHD1 gene that encodes fibrocystin. Medullary cystic disease exists in 2 forms caused by mutations in MCKD1 or MCKD2. Both forms are autosomal dominant and more mild than ADPKD. Cysts are restricted to the medulla, and patients present with salt wasting and polyuria. o Nephronophthisis-medullary cystic disease exists in 4 variants (infantile, juvenile, adolescent, and adult). The juvenile form is most common and includes extrarenal manifestations including retinitis pigmentosa, liver fibrosis, mental retardation, and cerebellar malformations. The kidneys are small with small cysts at the cortico-medullar junction. There is frequently tubulointerstitial nephritis, thickened tubular BM, and eventual interstitial fibrosis. 5 genes identified are NPHP 1-5 which code for nephrocystins (components of epithelial cell cilia). Renal adenoma is small (<2 cm), papillary pattern frequent, well circumscribed,and pale yellow. They should be considered as neoplasms with low malignant potential. Renal fibroma (mesenchymal) is less than 1 cm, contains fibroblasts and dense fibrous tissue. It is most likely a hamartoma rather than a true neoplasm. Angiomyoliipoma is a benign renal tumor composed of smooth muscle, vessels, and adipose tissue. They are sometimes seen in patients with tuberous sclerosis (often multiple tumors). It is a hamartoma. The high adipose tissue content gives it a characteristic pattern by CAT. Renal oncocytoma is composed of large epithelial cells with abundant mitochondria. They may achieve a large size and have a characteristic mahogany brown color as well as a characteristic radiologic pattern. Most are o 5

benign, and necrosis and hemorrhage are uncommon. There are 3 histological grades, and grade III is malignant carcinoma. o Composed of large cells with abundant, granular (mitochondria), eosinophilic cytoplasm. Clear cell carcinoma accounts for 80% of all renal cancers. They are most common in 6th and 7th decades. Characterized by lipid-laden cells with clear cytoplasm and uniformly sized nuclei. Presents with hematuria and flank pain. It is associated with inactivation of von Hippel-Lindau (VHL) gene on chromosome 3p, which downregulates angiogenesis. Sporadic cases are more common than pts with von Hippel-Lindau syndrome. o Macroscopically see round masses with a yellow-orange color and areas of hemorrhage and necrosis. Tend to be large at diagnosis (<3 cm benign, >3 cm malignant). o Paraneoplastic syndromes that may be seen include hypercalcemia, HTN, polycythemia (erythropoietin), and Cushing syndrome (glucocorticoids). Chromophobe renal carcinomas are less common (5% of renal cancers) and cells have an eosinophilic cytoplasm with variable nuclear size. They have extreme hypodiploidy with multiple losses of entire chromosomes. They have a better prognosis than clear cell carcinomas. Papillary renal cell carcinomas are 10-15% of renal cancers and may be multiple (heredity forms). Grossly, they often have abundant necrosis and hemorrhage. They form papillae with a fibrovascular core. Cells have an eosinophilic cytoplasm but some clear cells are often present. There is overlap with benign papillary tumors. They are frequently multifocal and bilateral. MET proto-oncogene is involved in familial and sporadic forms. Sporatic forms are also due to trisomy 7, 16, and 17. Renal carcinomas do not commonly spread to adjacent organs but spread hematogenously to lung, bone, brain, and skin. Hematuria is the most common presenting manifestation of renal cell carcinomas. Wilms tumor (nephroblastoma) is the 3rd most common cancer in children but is uncommon in adults. It arises from metanephric remnants and appears as a large, rounded mass with a fleshy white appearance. Presents as an abdominal mass or occasionally with hematuria. They often replace most of the kidney and frequently have metastasis by time of diagnosis. 90% cure rate even with metastasis. o 3 genes are implicated, one of which is WT1, a tumor suppressor gene on chromosome 11. o Since they are embryological derivatives, tumors contain several cell types including primitive small cells, immature glomerular structures, epithelial tubules, and spindle stromal and striated muscle cells. They occasionally contain other components such as cartilage, osteoid, neural tissue, or squamous epithelium. Transitional carcinomas arise from the urothelium of the renal pelvis and often present with hematuria. Ureteral and/or vesical seeding of the tumors is common. o Papillary carcinoma of the renal pelvis has morphology similar to urinary bladder carcinomas. o Squamous cell carcinoma occasionally arises from the renal pelvis. They are associated with calculi and chronic inflammation in the pelvis. Metastasis to the kidney is not common, but it is still more common than primary carcinoma of the kidneys. Metastasis is usually of hematogenous origin and tends to be multiple and bilateral. Lichen sclerosis is a non-neoplastic vulvar epithelial disorder characterized by thinning of the epidermis, hydropic degeneration of basal cells, superficial hyperkeratosis, and dermal fibrosis with a scant perivascular, mononuclear inflammatory cell infiltrate. Leukoplakia is seen grossly. It is most common in postmenopausal women and carries an increased risk of developing squamous cell carcinoma. The labia become atrophic. Bartholin cysts are caused by obstruction of the excretory ducts of Bartholins glands and are painful. Trichomonas vaginalis is an STI due to a large flagellated protozoa. It results in a thick gray-green vaginal discharge with mucosal irritation, severe itching, dyspareunia, and dysuria. of infected women are asymptomatic carriers. Can be seen on wet mount or pap smear. Candida albicans infection results in a curdy white vaginal discharge with discomfort and itching. Thrush (small plaques on the mucosa) is seen. Untreated infection waxes and wanes and can resolve spontaneously. Predisposing factors include DM, pregnancy, and oral contraceptives. Herpes simplex infection is an STI caused by HSV II. It is common in adolescents and presents as painful papules/vesicles on vulva, vagina, and cervix. Histologically characterized by nuclear inclusions and multinucleation. Incubation period is 1 to 3 weeks. The infection becomes latent and remains in sacral ganglia. Active infection at time of birth is indication for Cesarean section to avoid a fatal infection in the infant. 6

CMV rarely causes genital tract infection but may cause spontaneous abortion or infection of the newborn. Pelvic inflammatory disease is an infection of pelvic organs (vulva, vagina, cervix, endometrium, adnexa) due to microorganisms extending beyond the uterine corpus. It may be due to ascending inflammation or a complication of primary endometrial infection. The principal organisms are N. gonorrhea and Chlamydia trachomatis but most infections are polymicrobial (mycoplasma, strep, staph may also be present). Presents with vaginal discharge, pelvic pain (chandelier sign when cervix manipulated), fever, and adnexal tenderness. o Complications include rupture of tubo-ovarian abscess, peritonitis, sepsis, infertility, and bowl obstruction (from adhesions). Ectopic pregnancy is an abnormal implantation site of the fetus and usually occurs in the fallopian tubes (95%). Patients present with sudden abdominal pain and shock 6-12 weeks following a menstrual period. It is a medical emergency that can lead to exsanguination if untreated. Tx is surgery or cytotoxic drugs (methotrexate). Human papilloma virus (HPV) is an STI due to a DNA virus that causes verrucae and condylomata. Most cases are diagnosed by Pap smear. It can result in cervical intraepithelial neoplasia (CIN), which is a spectrum of intraepithelial changes ranging from mild atypia to invasive squamous cell carcinoma. o HPV 16,18, 31 and 45 (high risk) genomically integrate viral DNA. E6 and E7 genes are involved in p53 and Rb suppression and up-regulating Cyclic E and p16INK4 (proliferation promoters). o HPV 6 and 11 (low risk) are seen in 80% of macroscopically visible condylomata. o Koilocytic changes are seen due to increasing cell life span (condyloma). They consist of cytomegaly, nucleomegaly, perinuclear halo, irregular nuclear membrane, stippled chromatin, and increased mitotic activity. o CIN I (low grade or flat condylomas) involves changes in lower 1/3 of squamous epithelium. CIN II and CIN III (high grade) involve progressively larger amounts of dysplasia extending toward the superficial epithelium and less differentiation. CIS (carcinoma in situ) shows no differentiation at all. o CIN risk factors include early age at first intercourse, multiple sexual partners, a male partner with multiple previous sexual partners, high parity, family history, and immune status. o VLPs are used as vaccination. o Clinical stage is the best prognostic indicator of survival (stage I-IV). Proliferative phase of menstrual cycle is dominated by estrogen and lasts for approximately 14 days. The glands are straight and mitotically active with pseudo-stratified epithelium. There is no mucin production. The stroma is composed of spindle cells with scant cytoplasm and a high mitotic rate. The stroma is edematous. o Anovulation results in continually increased estrogen levels and maintenance of the proliferative phase. When the estrogen levels fall breakthrough bleeding occurs. Secretory phase of menstrual cycle is dominated by progesterone and lasts for 14 days. Postovulation there are basal secretory vacuoles, decreased mitotic activity, and a simple epithelial layer. The late phase (premenstruation) consists of tortuous dilated glands that lack mitotic activity, prominent secretory activity, stromal spiral arteries, and decidualizaton. o Luteal phase defect is caused by inadequate progesterone due to inadequate development or early regression of the corpus luteum. Menstruation occurs 6-9 days after ovulation. It can cause infertility (3%). Menstrual phase consists of progressively decreasing estrogen and progesterone levels with extravasation of RBCs into the stroma, leukocytic infiltration of the stroma, fibrin thrombi, and disintegrating glands and stroma. It lasts 3 to 7 days and results in flow of 35 mL of blood. Postmenopausal endometrium consists of inactive simple or cystic glands, an inactive stroma, and the number of glands and quality of stroma progressively decrease. Endometrium can be reversed by exogenous hormones or endogenous hormones produced by tumors. Adenomyosis is the presence of endometrium in the myometrium. Presents with chronic pelvic pain, menstrual abnormalities, and fertility problems. Endometrial hyperplasia occurs due to prolonged excess of estrogen without progesterone. It results in endometrial proliferation that can be preneoplastic. Carcinoma can develop due to PTEN tumor suppressor gene inactivation, making the gland less sensitive to estrogen. o Associated with Stein-Leventhal syndrome (polycystic ovary syndrome), perimenopause, estrogen producing tumors, and obesity. 7

Simple adenomatous hyperplasia displays glandular clouding and irregularly shaped glands with stroma. There is minimal glandular complexity and no cytologic atypia. 1% become endometrioid adenocarcinoma. o Complex adenomatous hyperplasia consists of complex glandular architecture with stroma. There is marked glandular complexity and crowding but no cellular atypia. The stroma is scanty. 3% develop endometrioid adenocarcinoma. o Atypical hyperplasia consists of crowded glands with almost no stroma. Architectural features are like complex hyperplasia, but there is cytological atypia. Epithelial cells are enlarged and hyperchromatic with prominent nucleoli and increased nuclear/cytoplasmic ratio. 25% become endometrioid adenocarcinoma. Endometrioid adenocarcinoma is linked to prolonged estrogen stimulation and defects in the PTEN tumor suppressor pathway. Divided into grades I-III based on differentiation and amount of solid area. Higher nuclear atypia indicates a higher grade. It is the most frequent cancer in the female genital tract in U.S. o Survival is related to stage, grade, age, progesterone receptor activity (high levels of E and P receptors in tumor is better), depth of endometrial invasion, extent of lymphovascular invasion, and the results of peritoneal washing. o Is associated with HNPCC and Cowdens syndrome (PTEN mutation). Brenner tumor is an uncommon, usually unilateral ovarian tumor containing abundant stroma and nests of transitional-like epithelium resembling the urinary tract. Most are benign. Leiomyoma is a benign tumor arising from smooth muscle cells in the myometrium. They are the most common benign tumors in females and are common after age 30. They regress after menopause. They are often multiple, and estrogen promotes their growth. They are well circumscribed but not encapsulated. They consist of elongated and eosinophilic smooth muscle cells with elongated, cigar-shaped nuclei. The nuclei are uniform, and mitotic figures are absent or sparse. They may cause bleeding, cramping pains, or interfere with labor. Surface epithelial ovarian tumors account for 90% of ovarian cancers. Germ cell and sex cord/stromal cell tumors are less common (10% of malignant ovarian tumors). Germ cell tumors tend to be benign in adults and malignant in children. Serous cystadenocarcinoma is the most common malignant tumor of the ovary, occurring in 1-2% of women. They consist of invasive cell nests forming papillary fronds and psammoma bodies. The most important prognostic factor is surgical stage at the time of detection. o Benign serous cystadenocarcinoma consists of a single layer of tall, ciliated columnar epithelium that lines the cyst(s). Granulosa cell tumor is a functional ovarian neoplasm that secretes estrogen and can cause postmenopausal bleeding, endometrial hyperplasia, and endometrioid carcinoma. Most occur after menopause, and development of the tumor is linked to loss of oocytes. Grossly appears as a mustard-yellow mass with areas of necrosis. Cells contain coffee-bean shaped nuclei and Call-Exner bodies. They secrete inhibin (suppresses FSH) and calretinin, a neuronal protein. Dysgerminoma is an ovarian tumor composed of primordial germ cells. Most patients are between 10 and 30 years of age. Teratoma is a tumor of germ cell origin that differentiates into somatic structures. They usually arise from all 3 germ layers, and they may contain sebaceous content, hair, skin, fat, keratin, etc. They commonly arise in the 1st two decades and are more likely to be malignant the younger the patient. Still, more than 90% are benign. Yolk sac tumor is a highly malignant tumor of women under 30 years that resembles the mesenchyme of the primitive yolk sac. Choriocarcinoma is a tumor that mimics the epithelial covering of placental villi, such as cytotrophoblasts and syncytiotrophoblasts. o