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Spring 06 review.doc

  1. 1. 1/16 Pathology Review #1 (Renal and part of Gynecology) Dr. Kirshenbaum email: gary.kirshenbaum-md@advocatehealth.com Tuesday, February 14, 2006 REVIEW OF NORMAL RENAL ANATOMY: Nephron: functional unit of kidney: • Glomerulus-arterial capillary net • Bowman’s capsule: surrounds the capillary net • Proximal and distal convoluted tubules • Loop of Henle Nephron → collecting ducts →minor calyxes → major calyxes→ renal pelvis → ureter → bladder General anatomy of the kidney: • Capsule: when we show you pictures of the kidney in class, we’ve removed the capsule • Hilum: medial part of kidney o Major structures: renal pelvis, renal artery, renal vein • Cortex and medulla o Cortex (outside): contains glomeruli  Make sure you’re getting renal cortex when you take a biopsy of the kidney to assess for glomerular disease! o Medulla (inside): collecting ducts • Blood vessels: series of branching arteries o Renal artery → anterior and posterior renal arteries→interlobar arteries→arcuate arteries → interlobular arteries → afferent arteriole→glomerulus→efferent arteriole→peritubular vasa recta→ renal veins RENAL PHYSIOLOGY: Normal renal function is a result of: • Glomerular filtration • Reabsorption in the tubules • Secretion in the tubules As a result of these three things, you can essentially divide renal function into a few major categories . . . Major renal functions: • Excreting the waste products of metabolism: o Urea: byproduct of protein metabolism  What we use to measure renal function in our patients: BUN in blood, or urea o Urates: byproduct of nucleic acid metabolism  What we measure: uric acid • Regulating the body’s concentration of water and electrolytes: o Na+/Cl: regulated by reabsorption in the tubules, mediated by amount of blood flow to kidney, then the RAAS system. o Water: under regulation by reabsorption in the tubules and collecting ducts under the effect of ADH o K+: regulated by secretion in the distal tubles under the effect of aldosterone and acid/base balance o Ca2+: regulated by reabsorption of Ca, under the effect of Vitamin D. Vitamin D 25(OH)D3 is
  2. 2. 2/16 hydroxylated into active Vitamin D 1,25 (OH)2D3.  In renal failure, Vitamin D isn’t activated, therefore, Ca2+ isn’t reabsorbed • Maintaining appropriate plasma acid/base balance: o Patients with renal failure will be acidotic • Endocrine organ: o Renin, prostaglandins, and erythropoietin are produced RENAL PATHOLOGY: Histological categories of kidney disease: • Glomerular disease • Tubular disease • Interstitial disease (usually goes with tubular disease) • Vascular diseases When you damage one of the above components, over time, the others will also get damaged. So if you have a primary glomerular disease, over time you’ll see secondarily vascular and tubular interstitial disease. From a clinical standpoint the patient will present with various different groups of signs and symptoms: Nephritic vs. Nephrotic Syndrome • Nephritic: o Hematuria o Hypertension • Nephrotic: (in pathophysiological order . . . ) o Proteinuria: loss of protein into urine o Hypoalbuniemia: as a result of proteinuria, you have a decrease in albumin o Edema: Decreased protein → decreased oncotic pressure → edema o Hyperlipidemia: decreased proteins → liver produces lipoproteins and lipids Acute vs. Chronic Renal Failure Chronic Renal Failure: • Most commonly due to glomerular disease (can be caused by vascular or tubular/interstitial disease) • The end result of many types of renal diseases and is the major cause of death from renal disease. • Azotemia: elevation of BUN and creatinine (diagnosis by lab tests) o Prerenal azotemia: before the kidney  related to decreased blood flow to the kidney  Ex. CHF or hypotension o Renal azotemia: primary renal disease o Postrenal azotemia: after the kidney  Due to obstruction of urine flow (urethral obstruction)  Ex. kidney stone  Clinical presentation: patient will have obstructive signs and symptoms: not going to be able to void, painful urination o Clinically, is it difficult to distinguish pre-renal from post renal azotemia?  No! They have two very different clinical presentations  More difficult to distinguish pre-renal from renal azotemia. We use lab tests to distinguish pre-renal from renal azotemia: • BUN/creatinine ratio: o >20:1 in pre-renal azotemia o <20:1 in renal azotemia.
  3. 3. 3/16 • FENa (Fractional excretion of Na+) o FENa is the Na+ clearance/creatinine clearance. o Clearance = UxV/P where U is urinary concentration, V is urinary flow in ml/min, and P is plasma concentration. o Prerenal azotemia: FENa < 1%  Not enough blood flow to the kidney→ activation of RAAS → increase Na+ reabsorption → Na+ clearance decreases → therefore the FENa ratio is <1%. o Renal azotemia: FENa >1%  Creatinine clearance decreases → FENa is >1% Uremia = azotemia + signs and symptoms Clinical Manifestations of Chronic Renal Failure: • Volume regulation: Increase in urine production (initially) due to loss of ability to concentrate urine but with time other functions like glomerular filtration are lost → oligouria or anuria • Acid/base balance: decrease in secretion of H+ ions → decrease in HCO3 → acidosis o Henderson-Hasselbach equation: pH is directly correlated with HCO3/pCO2  HCO3 (metabolic component): decreased in renal failure due to loss of H+  pCO2 (respiratory component): to maintain the pH, you must decrease pCO2 by hyperventilation • GI: nausea, vomiting, GI bleeding • Cardiovascular symptoms: o Fluid retention causes CHF o Hypertension develops as a result of the alteration of renin-angiotensin-aldosterone. o Uremic pericardiditis: remember from cardiopathology that the most common cause of pericarditis is idiopathic (undiscovered virus, probably). Also consider uremia in your differential. • Hematopoeitic manifestations: anemia due to decreased erythropoietin • Calcium/bone metabolism: Unactivated Vitamin D → decreased Ca2+→ increased PTH → secondary hyperparathyroidism → Ca2+ pulled out of bones (renal osteodystrophy) • Skin changes: o Pale skin color due partly to anemia o Itchting: • Neurologic: patients present confused or semi-comatose o Probably due to accumulation of urea, but we’re not sure Acute renal failure: • Presents with oliguria/anuria • Most commonly caused by Acute Tubular Necrosis (ATN) due to ischemia or drugs • Initial event (shock/hypotension) → oliguria/anuria→ patient recovers → ability to concentrate urine is the last function to recover → polyuria • Hyperkalemic, acidotic • Main difference between acute and chronic renal failure is urine production! o Chronic: polyuria then oliguria o Acute: oliguria then polyuria CONGENITAL ANOMALIES: Review these on your own • Agenesis: no kidney develops • Hypoplasia: not enough kidney developed
  4. 4. 4/16 • Abnormal location • Fused/horseshoe kidney • Cysts: most frequently seen, frequently tested o Simple cyst: most common cyst that you’ll encounter in your practice (not congenital)  Must distinguish from tumor o Adult Polycystic Kidney Disease:  About 1/500  Autosomal dominant: mutation in chromosome 16 (PKD1) mostly, sometimes chromosome 4 (PKD2)  Bilateral  Asymptomatic until 3rd or 4th decade o Sometimes present with mass “dragging sensation”  Often presents with other congenital anomalies: o Liver cysts o Berry aneurysms in the Circle of Willis o Mitral valve prolapse (Barlow’s syndrome) o Infantile Polycystic Kidney Disease:  Autosomal recessive: mutation on short arm of chromosome 6  Present in newborn with rapidly progressive renal failure  Bilateral  Almost always associated with liver cysts o Minor cystic diseases: (review on your own):  Cystic renal dysplasia  Medullary cystic disease • Medullary sponge (not that serious) • Uremic medullary cystic disease (more severe) GENERAL GLOMERULAR DISEASE: Some basic concepts. . . • Most common cause of chronic renal failure • Glomerular nephritis/glomerulopathy/glomerular disease are all the same thing • “Glomerularnephritis” is a misnomer: you don’t always see inflammatory cells o Glomerulopathy is a better term • Primary vs. Secondary Glomerular disease o Primary: a glomerular problem o Secondary: systemic disease and one of the manifestations is a problem in the glomerulus  Ex: diabetes, SLE • Clinical manifestations of glomerular disease are different combos of nephritic or nephrotic, maybe some renal failure o Clinically, we decide if they’re primarily nephritic or nephrotic Histological alterations seen in a diseased glomerulus: • Proliferation of cells: particularly mesangial, but also endothelial, and visceral/parietal epithelial o You’ll see too many nuclei o Mesangial cells lay down mesangium (you’ll see lots of pink stuff) o This is proliferative glomerular nephritis • Inflammatory infiltrate: particularly neutrophils • Thickening of the glomerular basement membrane: (membranous nephritis) • Scarring/sclerosis/hyalinization
  5. 5. 5/16 More adjectives to further describe where the damage is histologically: • Diffuse: most of the glomeruli are involved • Focal: only some of the glomeruli are involved • Generalized (global) involvement vs. segmental (local) within a glomerulus Now you just combine the adjectives to classify the diseases. Immune pathophysiology of the major glomerular diseases: • Immune complex deposition is the most common (Type III Hypersensitivity) o Ag/Ab immune complex form in the circulation and are trapped by the glomerular capillary net → activates complement cascade and chemotactic factors→ mesangial cells release oxidants → damage of glomerulus o Immune complexes can be detected by electron microscopy (EM) o Immunoflourescence shows a granular pattern of deposition o These complexes can reside in three places in the glomerulus:  Subendothelial: between endothelial cells and the basement membrane  Intramembranous: within the basement membrane itself  Subepithelial: between the membrane and epithelial cells o Ags that form immune complexes are either exogenous or endogenous:  Exogenous antigens: Streptococcus or HBV, HCV  Autoimmune/endogenous antigens: as in SLE, where you have Ag to ds-DNA • Type II hypersensitivity reaction: Ab directed against the basement membrane o Goodpasture syndrome: the only example of this in the kidney. o Immunofluorescence has a linear pattern. • ANCA mediated glomerular disease: o ANCA: anti-neutrophil cytoplasm antibody o Ex: Wegener’s granulomatosis: vascular disease causing glomerular nephritis • Each of these three immune-mediated mechanisms involve humoral as well as cell-mediated immunity. (Clinically there are no lab tests to order for the cell-mediated immunity) Renal biopsies are always analyzed by 3 types of microscopy for disease classification: • H&E stain (light microscopy, or LM) • Immunoflouresence microscopy (IF) • Electron microscopy (EM) SPECIFIC GLOMERULAR DISEASES: *** Important point: the histologic changes seen in primary glomerular nephritis can also be seen in secondary glomerular nephritis. Therefore, you must look at the total clinical picture in order to be able to differentiate between diseases (Ex: primary membranous glomerular nephritis will look like membranous disease due to SLE)*** Primary glomerular nephritis: • Acute diffuse proliferative glomerulonephritis: o Post-streptococcal or Non-streptococcal  Post-strep: • Follows strep throat or skin infection (group A β- hemolytic strep) by a few weeks • More common in kids • Good prognosis  Non-streptococcal: due to other antigens, like HBV o LM: Proliferative means you’ll have hypercellularity (mesangial cells and because it’s due to an
  6. 6. 6/16 infection, neutrophils) o IF: granular staining of immune complexes and complement  Deposition will be mesangial and associated with the BM o EM: subepithelial deposits o Diffuse means it is in most of the glomeruli • Rapidly progressive/Crescentic glomerular nephritis: o Proliferation of parietal and visceral epithelial cells obliterate Bowman’s space, forming a crescent o Not really a specific type of glomerular nephritis; you can see it related to various different types of glomerular nephritis o Poor prognosis: patient will probably go on to develop renal failure and require dialysis Primary nephrotic diseases: • Membranuous glomerular nephritis o Most common cause of nephrotic syndrome in adults o Thickened basement membrane o Granular deposition of immune complexes and complement within membrane o Spikes: result of immune complexes pushing up against BM (subepithelial on EM) o We don’t know if the antigen is exogenous or endogenous o Bad prognosis: 70-90% progression to renal failure • Minimal Change Disease (aka lipoid nephrosis): o Most common cause of nephrotic syndrome in kids o Deposition of lipid in tubular epithelial cells o Good prognosis; responds well to steroids o LM and IF: don’t see anything o EM: see fusion (loss) of podocyte foot processes (visceral epithelial cells) o No immune complexes! • Focal Segmental Glomerulosclerosis: o 10-15% of all nephrotic syndromes o Variable clinical course o Steroid-resistant o may slowly progress to renal failure o IF: immune complex deposition of complement and IgM o EM: loss of foot processes o LM: some of the glomeruli will be involved, and parts of the glomerulus (focal segmental).  Sclerosis/scarring • Membranoproliferative glomerulonephritis: o Primarily nephrotic, but kind of a combo of nephritic and nephrotic o Slowly progressive o Overall poor prognosis o Proliferation of cells, increase in mesangium o Thickening of basement membranes o Tram track appearance: immune complex deposition splits the BM o 2 subtypes:  Type I: 2/3 of cases • Subendothelial deposits of immune complexes • Poor prognosis, but cured by kidney transplant
  7. 7. 7/16  Type II: 1/3 of cases • Deposits are denser and bigger within BM • Complement-mediated involving alternate pathway (no immunoglobulins) • Poor prognosis and recurs with a kidney transplant • Focal glomerulonephritis (Mesangioproliferative glomerulonephritis): o Main type: Berger’s Disease (IgA Nephropathy) o Occurs in young people after a respiratory infection o Good prognosis o IF: Mesangial deposition of IgA • Chronic glomerulonephritis: o Dr. K doesn’t think this deserves its own category because you’ll see scarring (chronic glomerulonephritis) at the end stage of any the above diseases o Clinical progression to dialysis and ultimately renal transplant SYSTEMIC DISEASES (SECONDARY GLOMERULAR DISEASE): • Systemic Lupus Erythematosus: o Usually nephrotic o Anti-dsDNA immune complexes o Subendothelial deposits of immunoglobulin and complement o Classic wire loop appearance: thickened BM o WHO classification system for glomerular findings in SLE  Type I: normal  Type II: mesangial  Type III: focal proliferative  Type IV: diffuse proliferative  Type V: membranous  Type VI: chronic glomerulonephritis • Goodpasture Syndrome: o Antibodies directed against basement membrane in the kidney and lung o Patients present with hemopytsis and renal failure  If you have a patient that presents with hemoptysis and renal failure, your differential is Goodpasture syndrome and Wegener granulomatosis o IF: linear deposition of immunoglobulin (not complexes) o EM: no deposits o Primarily nephritic • Wegener granulomatosis: o Vascular disease: associated with c-ANCA o Primarily nephritic o Cresentic glomerulonephritis • Henoch-Schonlein Purpura (HSP): read on your own • Diabetes mellitus: o Most frequent systemic disease that will give rise to kidney disease o Usually nephrotic o Most frequent glomerular manifestation of diabetes: diffuse glomerulosclerosis (all the
  8. 8. 8/16 glomeruli have sclerosis) o Most specific glomerular manifestation: nodular glomerulosclerosis (Kimmelstiel-Wilson disease) o Tubular-interstitial manifestations: pyelonephritis, arteriolosclerosis • Amyloidosis: o Homogeneous eosinophilic material deposited in glomerulus and elsewhere in body o Congo Red stain and on IF: apple green birefringence o EM: β-pleated sheet TUBULAR/INTERSTITIAL DISEASE: • Acute tubular necrosis (ATN): o Most common cause of acute renal failure o Necrosis of tubular epithelial cells o Two causes:  Ischemic: due to hypotension or shock • Congestive heart failure: initially pt has prerenal azotemia, but if there’s enough ischemia to the kidneys, they’ll get ATN . . . now they have renal azotemia  Nephrotoxic: drugs (Ex. Gentamycin) o The only disease we’ll talk about that is strictly a tubular disease • Tubulointerstitial disease: o Second most common cause of chronic renal failure (glomerular disease is #1 cause) o 2 major types:  Acute interstitial nephritis: neutrophils in tubules and interstitium  Chronic interstitial nephritis: lymphocytes, plasma cells, eosinophils o Causes of interstitial nephritis (acute or chronic):  Pyelonephritis (infection of the kidney) • most common cause (know this one for sure!) • can be acute or chronic (more details below)  Drugs/Toxins: antibiotics (like methicillin), analgesics, NSAIDS, heavy metals (like Pb)  Metabolic diseases: urate nephropathy (gout) or pseudogout (calcium deposits)  Physical factors: radiation therapy  Tumors: infiltration by multiple myeloma is classic example  Immunologic reactions: transplant rejection, Sjogren’s syndrome (keratoconjunctivitis sicca: dry eyes and dry mouth because of lacrimal and salivary gland inflammation) • Acute Pyelonephritis o Major cause of tubulointerstitial nephritis o Acute, suppurative bacterial infection of kidney and renal pelvis usually associated with lower UTI that ascends from bladder up to kidney  Commonly caused by same bacteria that cause UTIs: gram negative bacilli (E. coli, Proteus, Klebsiella)  Rarely can be hematogenously spread leading to bacteremia and kidney infection o Clinical presentation: fever, malaise, dysuria, frequency (signs and symptoms of UTI) in addition to CVA pain o Lab tests to distinguish UTI alone from pyelonephritis:  Urine test: WBCs, protein in both  WBC casts specific for pyelonephritis
  9. 9. 9/16 An aside about casts . . . • Normally there is very little protein in the collecting ducts and urine o Some proteins are present (Tamm-Horschfall proteins) • An increase in proteins causes formation of a mold/cast of the tubular collecting duct called a hyaline cast → can traverse into ureter • If RBCs are around (as in glomerular disease) when these casts are being formed, they will stick to them → they traverse into ureter → RBC casts in urine o Diagnostic of glomerulonephritis • Pyelonephritis: WBCs adhere to hyaline cast → WBC casts in the urine o Diagnostic of pyelonephritis • Sometimes as the casts traverse into urine, they get broken up so that you cannot distinguish whether the casts were WBCs or RBCs → these are granular casts o Must correlate a finding of granular casts with clinical presentation to make a diagnosis • Waxy cast: Lipids in the urine • Chronic pyelonephritis: o Sequelae of acute pyelonephritis, or sometimes pt presents with chronic renal failure o Tubules/interstitium filled with chronic inflammatory cells; tubules are destroyed VASCULAR DISEASE: Hypertension is the #1 underlying disease causing renal vascular diseases • Benign arteriolar nephrosclerosis o Associated with hypertension o Thickening of vessel walls (too much pink in the walls) o Generally will not present with renal failure, nephritic/nephritic syndrome  Most frequent disease seen in patients with hypertension on autopsy • Malignant Nephrosclerosis o Associated with very high blood pressure of 200/100 o Histology  Acute: fibrinoid necrosis of arterioles  Chronic: “onion skin”: intimal fibrosis and smooth muscle proliferation o Main problem you’re worried about is that they could have an intra-cerebral bleed! • Renal artery stenosis: o Due to atherosclerosis of one of the renal arteries o Activates the renin-angiotensin system so you’ll see those manifestations • Microangiopathic disorders (thrombotic) o Thrombosis in small blood vessels can lead to DIC  Hemolytic Uremic Syndrome (HUS): seen in kids  Thrombotic Thrombocytopenic Purpura (TTP): seen in adults • Embolic renal disease: o Atherosclerosis: underlying disease process o Emboli from heart (mural thrombus): usual source of emboli to kidneys UROLITHIASIS (kidney stones) • Increased concentration of urinary constituents that exceed their solubility o Most kidney stones show up on plain film because 75% are made of Ca+ (calcium oxalate or
  10. 10. 10/16 calcium phosphate)  Most gall stones cannot be seen on films o 15% are “triple stones”: Magnesium ammonium phosphate  Mostly due to Proteus infection b/c it converts urea to ammonium o 6% are uric acid stones  occurs when you have a rapid nucleic acid turnover such as in gout or leukemia o Cystine stones: very rare TUMORS: Benign tumors in tubules: • Adenoma (Renal Cortical Adenoma): o Most frequently seen o Usually occurs in cortex Malignant • Adenocarcinoma/renal cell carcinoma: most common type • Wilms tumor (nephroblastoma): most common tumor of kids • Transitional cell carcinoma: seen in renal pelvis or ureter Now on to the ladies . . . FEMALE GENITAL TRACT • Lower genital tract: vulva, vagina and cervix • Upper: uterus, tubes, ovaries • Adenexa: tubes and ovaries together FEMALE GENITAL INFECTIONS: Lower genital tract infections: • Herpes o HSV 2: involves the vulva, vagina and cervix o Sexually transmitted disease o Lesions occur 3-7 days after sex: papules, vesicles or ulcers  Lesions heal within a couple weeks o Can be transmitted to the neonate especially if infection is active (lesions present) in the birth canal • Yeast infections: o Candida, particularly o White patches o The lucky Ob/gyne will make this diagnosis by looking at a wet mount slide under microscope o Seen on pap smear • Trichomonas vaginalis: (a protozoa) o Also seen by wet mount in the ob/gyn’s office • Mycoplasma: one of the more common causes of spontaneous abortions • Gardnerella vaginalis: small gram (-) bacillus often seen on pap smears, can be treated Infections involving the upper and lower genital tract: PID (pelvic inflammatory disease): • Present with pelvic pain, adenexal tenderness, fever, vaginal discharge o Acute salpingitis or oophoritis o Abscess may form (tubo-ovarian abscess) o Significant scarring may form → infertility
  11. 11. 11/16 • Gonococcal (N. gonorrhea): o Vagina resistant to infection • Non-gonnococcal (Chlamydia or enteric gram (-) bacilli) o Can occur post-abortion, post-partum, post D&C (usually E. Coli, or other enterics) • Complications: o Peritonitis o Intestinal obstruction o Bacteremia o Infertility due to scarring of tubes • Treatment: antibiotics, surgery occasionally to remove tube and/or ovary VULVA: • Inflammatory diseases of the skin like Psoriasis and Eczema • Bartholin cyst: secondary to obstruction of the Bartholin duct → stasis of secretions → cystic dilatation • Vulvar vestibulitis: sweat glands can get inflamed → vulvar pain Non-neoplastic epithelial disorders of vulva: • Leukoplakia: non-specific white patch of squamous epithelial proliferation on vulva (benign, premalignant, or malignant) o Squamous hyperplasia: make sure there’s no dysplasia • Lichen sclerosus: atrophy of epidermis, dense sclerosis of underlying dermis o Usually seen in post-menopausal women Tumors and neoplasms of vulva • Benign o Papillary hydradinoma: tumor sweat glands o Condyloma accumlatum (venereal warts): most common benign tumor associated with HPV 6 and 11 Malignancies and pre-malignant conditions • Premalignant: o Vulvar Intraepithelial Neoplasia: (Associated with HPV 16 and 18)  VIN I: mild dysplasia, lower 1/3 of thickness vulvar epithelial cells  VIN II: moderate dysplasia, 2/3 of thickness of vulvar epithelial cells  VIN III: severe dysplasia, full thickness of vulvar epithelial cells. • Synonymous with carcinoma in situ • Invasive squamous carcinoma: if it penetrates the basement membrane Extramammary Paget’s Disease of the vulva • Malignant cells in the overlying skin, and occasionally you have an underlying cancer. • Usually only involves the overlying epidermis o Paget’s disease of the breast: most of the time you have an underlying infiltrating ductal carcinoma VAGINAL DISEASES: Congenital anomalies: • Atresia, double septate vagina, congenital cysts Premalignant Neoplasms: • Vaginal Intraepithelial Neoplasia- analogous to VIN and CIN o VAIN I: mild dysplasia
  12. 12. 12/16 o VAIN II: moderate dysplasia o VAIN III: severe dysplasia/carcinoma in situ o If untreated, it will progress into invasive squamous cell carcinoma Malignant Neoplasms: • Types of Carcinoma: o Adenocarcinoma: tends to be clear cells  Occurs in young women whose mothers were treated with DES during pregnancy for threatened abortion o Embryonal Rhabdomyosarcoma (Sarcoma Botryoides)  Tumor of malignant skeletal muscle  Occurs in infants (<5 yo)  Histo: looks like skeletal muscle (strap cells or racket cells), desmin and actin markers CERVICAL DISEASE • Cervicitis: o Infections: kind of covered them as they related to female genital infections in general o Most frequent of these categories that you’ll see Neoplasms: • Endocervical polyp: Benign proliferation of glands and stroma that gives rise to something protruding from the cervix o Presents with vaginal bleeding • Cervical Intraepithelial and Invasive Squamous Neoplasia (CIN) o Incidence of invasive CIN has decreased over last 40 years due to screening with pap smear o Risk factors for CIN:  Genital infections with HPV: most important! • HPV 16, 18: associated with cervical dysplasias and carcinoma  Vaccine developed against HPV 16 for men and women • HPV 6,11: low risk  Multiple sexual partners  Early age of intercourse  Oral contraceptives  Smoking  Family history o Pap Smear terminology: Low grade vs. High Grade Squamous Intraepithelial Lesion (SIL)  Low grade SIL: corresponds to CIN I and HPV changes  High grade SIL: corresponds to CIN II, CIN III (carcinoma in situ)  Biopsy (colposcopy) is next step after abnormal pap smear o Look for areas where the blood vessels are particularly prominent: “mosaic pattern” which corresponds to areas that probably have dysplasia o Send it to the pathologist who diagnoses CIN I, II, or III  Most important area to sample in pap smear is transformation zone (squamocolumnar junction) o Classification of CIN (biopsy terminology):  CIN I: mild dysplasia  CIN II: moderate dysplasia  CIN III: severe dysplasia = carcinoma in situ o Treat CIN III with a cone biopsy (LEEP- loop electrosurgical excision procedure) and send again to pathologist who will look at the cone biopsy to see if the dysplasia involves
  13. 13. 13/16 the margins of the biopsy.  If margins are not involved, patient is cured. If they are, then you’d need to treat further.  Above categories determined by looking at a biopsy (H&E stain) o Main histologic feature: koilocytes: nucleus is atypical with a clearing around it (cytoplasmic halo)  CIN almost never progresses to invasive carcinoma if treated early and properly  Age distribution: o CIN I-II seen in 30’s o CIN III about 45 UTERUS/ENDOMETRIUM: What we’ll cover: • Functional Endometerial disorders • Inflammation • Endometriosis • Endometrial Hyperplasia • Neoplasms Endometrial histology in the menstrual cycle: • First half of cycle: proliferative endometrium o Proliferation of glands o Under effect of estrogen • Second half of cycle: secretory o Changes of stroma and glands o Under effect of progesterone produced by corpus luteum • Basal endometrium doesn’t change with the menstrual cycle • Pituitary involvement in menstrual cycle: o First controlled by FSH until midpoint of cycle when you get an LH kick Functional endometrial disorders (Dysfunctional uterine bleeding): • Abnormal bleeding secondary to a functional hormonal problem rather than a physical lesion like an endometrial polyp or carcinoma • Terminology: o Menorrhagia: heavy menses o Metrorrahagia: bleeding in between menses o Metromenorrhagia: bleeding in between menses and heavy menses • Anovulatory cycle: prolonged estrogen without a progesterone phase (no corpus luteum) • Inadequate luteal phase: you have a corpus luteum, but there’s decrease in progesterone o More glands than stroma • Hormonal contraceptives: Alter normal estrogen/progesterone balance o Difference between the date that the glands and stroma look like in the cycle Endometritis/Inflammation: In general, endometrium is relatively resistant to infection • Acute endometritis: rare, but generally seen postpartum or after a miscarriage o Generally caused by bacteria (Staph A and GABS) o Treatment: Antibiotics • Chronic endometritis: associated with PID or IUD use o **Plasma cells must be seen to make this diagnosis**
  14. 14. 14/16 Adenomyosis: endometrial glands in the myometrium • Can give rise to an enlarged uterus • Also can give rise to menorrhagia or metorraghia Endometriosis: Endometrial glands or stroma outside of uterus • Most frequent site: ovaries o Can be other places such a uterine ligaments, pelvic peritoneum, pretty much anywhere • Clinically presents with infertility, dysmenorrhea, pelvic pain, can cause enlargement of the ovary • Endometrioma (chocolate cysts): massive cyst of the ovary due to ednometriosis o Treatment: hormones to shrink lesion or surgery to remove cyst • Diagnosis of endometriosis requires 2 out of 3 histological findings: o Endometrial glands, stroma or blood Endometrial polyps: • Benign proliferation of glands or stroma that project into endometrial cavity • Probably related to too much estrogen and not enough progesterone • Present with uterine bleeding • Treatment: surgically remove Endometrial hyperplasia: • Increase in endometrial glands to stroma • Four types: simple or complex, with or without atypia o Obviously complex with atypia is the worst kind to have which can lead to endometrial adenocarcinoma Malignant Tumors: • Endometrium: o Glands:  Adenocarcinoma: most common invasive tumor of female genital tract  Can arise from glands or stroma  Generally seen in post-menopausal women  Pap smears are not good for screening for endometrial cancers  Risk factors: obesity, diabetes, HTN, nulliparous or infertile (unopposed estrogen)  Review from 5 sec. ago: complex hyperplasia with atypia can lead to adenocarcinoma o Endometrial stroma:  Endometrial stromal nodule: benign proliferation of stromal cells • Presents as a mass, gives rise to bleeding  Endometrial stromal sarcoma: malignant • Low grade or high grade • Spindle shaped cells o Malignant Mixed Mullerian Tumor (MMMT)  Malignant combination of stroma and glands of the endometrium  Sometimes the stroma differentiates: • Heterologous MMMT: stromal cells differentiate into muscle, cartilage, or bone • Homologous MMMT: stromal cells are undifferentiated • Myometrium: o Leiomyoma:  One of the most frequent benign tumors  Generally occurs in 3rd–4th decade  Estrogen responsive (can grow during pregnancy)  Can be submucosal, intramural, subserosal  Blacks > whites  Clinically can be asymptomatic, or can present with uterine bleeding
  15. 15. 15/16 o Leiomyosarcoma:  Malignant proliferation of smooth muscle  Distinguish from leiomyoma by: o Cellular atypia (increased N:C ratio, hyperchromatic nuclei, nuclear pleomorphism) o Number of mitoses per 10 high power field • Benign: 0-5 • Malignant: >10 • Borderline: 5-10  Distinguish from endometrial stromal sarcoma with markers for smooth muscle cells FALLOPIAN TUBES: Fallopian tube can be affected by: • Ectopic pregnancy • Salpingitis: inflammation o Gonococcal vs. Non-gonococcal (see PID above) • Endometriosis • Benign peritubal cysts • Tumors (both benign and malignant) are very rare OVARY Inflammation of the ovary not common, occasionally occurs with PID Cysts: • Serous cysts: invagination of surface epithelium • Follicular cysts: o Granulosa or theca cell cysts o Corpus leuteum cysts • Polycystic ovarian disease (PCOD, or Stein-Leventhal syndrome): o Multiple follicular cysts and hirsutism, oligomenorrhea, obesity (due to androgen production) o Thickening/fibrosis of tunica (capsule) of ovary o Hyperplasia of the theca lining the follicular cysts which tend to produce the androgens Ovarian Tumors General: • Ovarian tumors are mostly benign (~ 80%) o Benign ones generally occur in the young (20-45 yo) o Malignant ones generally occur in the old (40-65 yo) • Risk factors: o Nulliparous o Family history o BRCA1 and BRCA2, especially for serous cystadenoma (also breast cancer) o Her2-nu oncogenes o p53 mutation (lose apoptosis protection) • Types of ovarian tumors (benign and malignant): o Surface epithelial: ~ 2/3 of all ovarian tumors o Germ cell:15-20% o Sex chord stromal tumors: 5-10%  What is the sex chord anyway?!! It’s what lines the follicle: granulosa/theca cells o Metastasis from other sites-5% o Primary tumors are more frequent than mets
  16. 16. 16/16 • Frequency of malignant ovarian tumors o 90% are surface epithelium o ~ 3-4% each germ cell, sex chord stromal • Ages of presentation of ovarian tumors o Surface epithelial: adults >20 o Germ cell: children <25 years old o Sex chord stromal: all ages Surface Epithelial Tumors: • Serous: neoplastic epithelium resembles fallopian tube. o Most frequent (~30% of all ovarian tumors)  Benign: 75% of serous tumors are benign or borderline • Grossly: lined by smooth, glistening surface  Malignant: Serous Cystadenocarcinoma • 2/3 are bilateral (contrast to mucinous) • Main criteria for malignancy: demonstration of invasion of cells into underlying stroma; also stratification of nuclei • Grossly: irregular, papillary and granular lining • Women will be slightly older than those with benign serous tumors  Borderline o Filled with serous fluid: clear nonviscous fluid • Mucinous: neoplastic epithelium resembles cervix o Approx 20% of ovarian tumors o Mostly benign (~80%) o Fluid is thick and viscous o More often unilateral o Pseudomyxoma peritonei: have implants of mucin and maybe a few glands on peritoneal surface; doesn’t necessarily mean it’s malignant • Endometriod: resembles endometrium o Mostly malignant o ~15% associated with endometriosis o ~15-30% associated with endometrial cancer o Clear cell adenocarcinoma variant associated with worse prognosis • Brenner: transitional epithelium o Most benign • Special types Clinical course of surface epithelial tumors: • Patients won’t present until tumors are very big and have broken through ovary into peritoneum o Why it’s important to have a good screening test for ovarian tumors (there isn’t one) o CA-125: not sensitive or specific enough  Used to follow patient after diagnosis of ovarian tumor (we want to see CA-125 levels go down) • Prognosis for malignant surface epithelial tumors: bad, because they present at an advanced stage Germ cell and Sex Chord tumors: start here on Thursday Coop submitted by: Merrie Warden mwarde1@uic.edu Prof Sig: No, no no Reviewer #1: _______________________________________ Date: ______________ Reviewer #2: _______________________________________ Date: ______________