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DR.

JOHN BARONE KAPLAN


LECTURES POST-MINI 1
Monday, March 17, 2014
LIVER
o Free Radicals/Fenton reaction:
H2O2 via catalase O2 + H2O
If high levels of iron/copper? H2O2 OH Leads to Hemochromatosis/Wilsons disease
o Cirrhosis: macro vs micronodular
Alcoholic cirrhosis = most common cause of micronodular cirrhosis in
US
GGT increases w alcohol and biliary obstruction
Micro: <3mm nodules:
Biliary tract obstruction: PBC or PSC
Metabolic: alcoholic liver cirrhosis; Wilsons disease;
Hemochromatosis; A1-AT def
Macro: >3mm nodules:
Virus: Hepatitis
Toxin: acetaminophen; drycleaner [carbon tetrachloride, CCL4
via CYP450 CCL3]; halothane
o Eval of Liver Disease:
Markers for hepatocyte injury: AST, ALT, LDH [nonspecific]
Almost all Liver diseases: ALT > AST
Markers for hepatocyte function: serum albumin*, prothrombin time
[PT]*, serum ammonia [green top tube]
[[Hematology/purple tubes: chem panel [red] & cbc [purple]
Need VitK for gamma carboxylation of factors 2,7,9,10 & protein
C & S need Ca2+ to work!]] Gamma carboxylation creates
Ca2+ binding site
When liver doesnt work [[INCREASED PT d/t liver failure
TRANSPLANT]]
Markers of biliary function/injury: serum bilirubin, ALP [[specific
marker for biliary]], GGT [U.S], 5-nucleosidase [Europe]
Bone diseases also increases ALP: ALP increased therefore DDX:
BONE & BILIARY
If GGT normal, Bone; if GGT increased: Biliary
Liver biopsy [gold standard]
o Jaundice: INCREASED total bilirubin!! [Unconjugated or Conjugated?]
Conjugated: [Most d/o]
Unconjugated:
Hemolytic anemias
o Increased RBC turnover increased bilirubin
o i.e. Sickle cell; Spherocytosis
o Increased risk of pigmented bilirubinate stones
Physiologic [newborn] jaundice: UGT not ready!!
o Transient mild increases in unconjugated bilirubin d/t
immaturity of liver

Jaundice occurs 24-48 hrs after birth


Prematurity and hemolytic anemias will exacerbate
High levels of unconjugated bilirubin may cross
immature BBB
o Kernicterus: Basal ganglia turns yellow Tx:
phototherapy!! Mech: Photoisomerization!! Making
bilirubin water soluble [unconjugated]
Hereditary hyperbilirubinemias: child/adult stress
jaundice
o UNCONJUGATED:
Gilbert [[PROMOTER region]]
~7% of US pop
AR; mut in promoter region of UDP
glucuronyltransferase [UGT] gene
Crigler-Najjar [[CODING region]]
Mut of UDP glucoronyltransferase [UGT] gene
Type 1: AR NO UGT activity FATAL d/t
kernicterus
o Phenobarbital does NOT work!
Type 2: AD reduced UGT activity less
severe
o Phenobarbital works!!
o CONJUGATED:
Dubin-Johnson:
AR mut in hepatocyte bilirubin glucoronide
transport protein
Decreased bilirubin excretion
Gross: BLACK liver [d/t catecholamine
metabolites]
Rotor syndrome:
AR mut in uptake and storage? Defective
excretion?
NO liver pigmentation
Biliary obstruction: Most common cause = stones in bile duct [4
Fs]; Cancer; C. senensis Asian liver fluke; stricture from fibrosis
scleroderma; PBC; PSC
Sx: jaundice [conjug bilirubin]; itching d/t bile salts; xanthomas
d/t cholesterol; abdom pain; DARK urine d/t decreased or NO
urobilinogen bc of high/increased conjug bilirubin; Pale stool d/t
decreased stercobilinogen
INCREASED: conjug bilirubin
INCREASED [sky high] ALP
INCREASED GGT/5-nucleosidase
PBC: chronic progressive cholestatic disease characterized by
intrahepatic bile ducts, inflammation and scarring d/t
granulomas blocking bile duct!!
o Autoimmune disease affects women in reproductive
years
o Initially asx, discovered by elevated ALP progression to
obstructive jaundice, pruritis
o
o
o

Assoc w other autoimmune diseases [sjogren,


scleroderma]
o Dx: Anti-mitochondrial Abs***; biopsy showing florid
duct lesion = duct destruction by lymphoplasmacytic
inflammation with granulomas
o Tx: oral ursodeoxycholic acid improves disease course
and slows progression; Liver transplant
PSC: chronic cholestatic disease characterized by fibrosis and
destruction of intra and extrahepatic bile ducts
o 20-30yo; M>F
o Initially asx, and discovered by elevated ALP; later,
obstructive jaundice
o Increased risk of acute cholangitis
o assoc with ULCERATIVE COLITIS [70%]
o Dx: cholangiogram: beaded appearance; biopsy
showing concentric onion skin fibrosis around bile
ducts; p-ANCA Abs
o Prognosis: increased risk of cirrhosis and
cholangiocarcinoma [d/t PSC or thorotrast] [10-15%]
UC: p-ANCA abs
Crohns: ASCA [Anti-saccharomyces cerevisiae Abs]
Hashimotoss: anti-microsomal abs
Cirrhosis: chronic end-stage liver disease characterized by diffuse
destruction of normal architectuture by bands of bridging fibrosis
and nodules of regeneration hepatocytes
Causes: alcohol, viral hep [HBV, HCV];
Mech: hepatic stellate cell [ito cell] is stimulated by ROS.
Cytokines [il-1]tnf] and growth factors transforms into
myofibroblast; produces tgf-beta; synthesis of increased ECM
[collagen 1&3]
VitA def: [[toxicity vs def]] stored in ito [hepatic stellate] cells
o night blindness [rhodopsin rods]
o increased intracranial pressure; immunodeficiency
o hair follicles lined by specialized cuboidal cells
squamous metaplasia of hair follicles
o Bitot spots
o TGF-beta !!! Most powerful stimulator of fibrosis!!!
o TRICHROME = FIBROSIS!!!
Consequences of cirrhosis:
o Portal htn: ascites; portal caval shunts [hemorrhoids,
esoph varices - #1, caput medusae]; splenomegaly
hypersplenism
o Lack of detoxification: hepatic encephalopathy NH3;
hyperestrogenism: gynecomastia, hypogonadism males,
spider angioma, palmar erythema
o Lack of synthesis: coagulopathy; hypoalbuminemia;
hepatorenal syndrome = renal failure w.o primary
abnormalities of kidneys
o GIVE OCTREOTIDE TO LOWER PORTAL PRESSURE!! [[when
alcoholic comes in with blood in vomit d/t ruptured
varices]]
o

FECAL TRANSPLANT!! If all drugs fail for tx of c. difficile


pseudomembraneous colitis!! Helps to restore normal flora!!
[[also works for severe IBD]]
VIRAL HEPATITIS:
Clinical syndromes
Asx infection: HAV, HCV
o Found incidentally bc of elevated transaminases or ve Ab
serology
Acute viral hepatitis
o Incub period
o Sx preicteric phase
Malaise, fatigue, nausea, loss of appetite
Wt loss, low grade fever, headache, muscle and
joint aches
Mildly enlarged liver and elevated transaminases
o Sx icteric phase:
Conjug bilirubin
Dark urine
Pruritis [bile salts]
o Convalescence
Fulminant hep: uncommon; acute liver failure d/t massive
hepatic necrosis
Chronic hep:
o Sx/lab abnormalities >6mos
o Fatigue, malaise, loss of appetite, bouts of jaundice
o Hbv/hcv may form immune complexes prod vasculitis and
glomerulonephritis
Hbv = membranous glomerulonephritis
Hcv = membrano-proliferative glomerulonephritis
o Chronic carrier state: asx but harbor virus and may
transmit it
MOST COMMON [in US] to LEAST COMMON: A, B, C, D, E
o All RNA EXCEPT B
o Trans:
A & E = Fecal-Oral [[A&B via BOWELS]]
B,C,D = parenteral [[SEX & NEEDLES]]
o HCV = PRISON & POST-transfusion!!
o ALL = ACUTE Hepatitis! Therefore, need serology!!
Chronic: >6mos = only B, C, D! therefore all 3 at
risk for Cirrhosis & HCC
AUTOIMMUNE HEP: F>M
ANA+, SMA+
KIDNEY: CONGENITAL ANOMALIES:
o Bilateral renal agenesis [NO KIDNEYS]:
Oligohydramnios: Potters Sequence: Potters facies: Parrot beak
deformity, lord voldemort
Embryo: bilateral degeneration of ureteric buds leads to bilateral renal
agenesis
Die shortly after birth! Bc lungs do NOT mature [d/t pulm hypoplasia]
Unilateral renal agenesis: can live on 1!
o HORSESHOE KIDNEY: stuck in pelvis on IMA at L3!!

NORMAL renal fxn!! But predisposes for UTIs & Kidney stones bc of
torturous ureters
o Cystic diseases:
1 or 2 cysts = ANYONE can have! SIMPLE RETENTION CYSTS
Cysts in medulla = Medullary Sponge Kidney
SPONGEBOB IS GOOD = MEDULLARY SPONGE IS GOOD BENIGN
Polycystic kidney disease [PKD] AR
Usually infantile with aggressive and fatal renal failure
If dont die of renal failure, die of hepatic fibrosis
Cysts in BOTH liver & kidney
Gene: PKHD1 [polycystic Kidney & Hepatic disease 1]
Protein: fibrocystin protein [leads to fibrosis & cysts]
Whats affected? Proteins involved in cilia of renal tubule
Cysts = everywhere [cortex & medulla] and RADIATING CYSTS
PKD AD ****
Gene: PKD1; PKD2
Protein: polycystin 1; polycystin 2 [form complex together]
o Complex important for connective tissue adhesion if
w.o? asx until middle-aged & have problems everywhere!!
[[i.e. marfans]]
COMMON; 1 in 1000 affected [George Lopez]
Normal renal fxn till mid life when present with HTN,
HEMATURIA, RENAL INSUFFICIENCY [BUN/Creatinine
increase] and eventually need dialysis
100s of cysts bilaterally!! US/MRI/CT
Round, hemorrhagic, HUGE-ASS cysts!!
**WHATS WRONG EXTRA-RENALLY? **
o Circle of Willis: BERRY ANEURYSM!! When rupture,
SUBARACHNOID HEMORRHAGE worst headache
of my life
o Liver: more cysts
o Hear on auscultation of heart? MVP [mid systolic
click]
o Colon: diverticulosis [bright red blood coming out of
rectum]
Tuesday, March 18, 2014
High hepicidin anemia of chronic disease
Important labs:
o BUN [7-18] [~10]: excreted by kidney and reabsorbed
o Creatinine [Cr = ~1]: excreted by kidney but NOT reabsorbed
o BUN/Cr ratio [~10:1]
o Azotemia: increased BUN and Cr d/t decreased GFR [if increased & sticks
to 10:1 ratio, Prerenal; if one increases more than other; Renal]
o Prerenal Azotemia: hypoperfusion of kidney d/t decreased CO,
hypovolemia, renal artery stenosis, etc.
o Renal Azotemia: intrinsic renal disease
o Postrenal Azotemia: urine flow obstruction d/t stones [PAINFUL!], BPH,
tumors
o Uremia = Azotemia + Clinical sx
GLOMERULONEPHRITIS: Abs stuck in kidney

Microalbuminuria = one of earliest signs of DM [DM: sugar make you lose neg
charge of basement membrane causing loss of albumin; dipstick will miss it!]
o Subendothelial immune complexes: very large or highly charged
o Immune complexes activate complement [C5a] causing neutrophils to come
in and cause inflammation
o Subpodocyte immune complexes
o Intramembranous immune complexes [into basement membrane]
o If just damage podocytes, get massive prOteinuria nephrOtic
syndrome
EVERY NEPHROTIC DISEASE MUST HAVE DAMAGE TO PODOCYTES!
o itis: if inflamed, blood leaks out HEMATURIA!
dark-colored smokey tea-colored coca-cola-colored urine
1st step: Dipstick [3 or 4+ = maximum]
Urinalysis under microscope
DDX of hematuria:
Bleed from uretha, bladder, prostate, ureter, kidney
If kidney bleeding, see red cell casts! [CASTS = KIDNEY]
If white cell casts, kidney! [polynephritis]
Eosinophil casts? Kidney!
If inflamed? DECREASED GFR! HTN, Oliguria
NEPHROTIC vs NEPHRITIC Syndromes! [[TABLE]]
o #1: Urinalysis
o #2: Biopsy of kidney
o NEPHROTIC: M&M FAN:
MEMBRANOUS
MINIMAL CHANGE
FOCAL SEGMENTAL GS
AMYLOIDOSIS
NODULAR GS
o Podocyte = epithelial cell
o Mesangial cell = supporting cell
Renal artery stenosis Vascular d/o:
o 20-30yof FIBROMUSCULAR DYSPLASIA in angiogram; BEADED
APPEARANCE
o >50yo m>f ATHEROSCLEROSIS on auscultation of abdom hear ABDOM
BRUIT
kidney releases renin!! HTN!!
GOLDBLATT KIDNEY: narrowing artery more and more get more
and more HTN
o Opposite kidney = hyperplasia/hypertrophy
HYALINE ARTERIOLOSCLEROSIS
o Renal vein renin level
o Do NOT give ACEI in this case bc kidney can infarct if drop BP too much!!
CHRONIC GLOMERULONEPHRITIS: ESRD:
o MCC = DM, HTN (d/t salt & water retention), & glomerular dz!
o Final end stage of all glomerular and tubular diseases
o C/F: anemia [NO KIDNEY, NO EPO from renal peritubular interstitial
cells!], anorexia, malaise, proteinuria, HTN, azotemia [normal ratio therefore
Renal azotemia]; urine shows BROAD, WAXY CASTS [tubules dilated;
atrophic]
HYPER-K+ with metabolic acidosis**
o

HYPO-Ca2+ d/t DEC 1-alpha-hydroxylation of vitD by PCT & HYPO-PO4


Osteitis fibrosa cystica
o Pathologic exam: kidneys grossly small and shrunken
o Micro: hyalinization of glomeruli, interstitial fibrosis, atrophy of tubules, and
lymphocytic infiltrate
o Tx: dialysis w renal transplant
Diseases of Tubules:
o ACUTE TUBULAR NECROSIS, ATN [ACUTE TUBULAR INJURY, ATI]
Acute renal failure - #1 most common cause in US POTENTIALLY
REVERSIBLE bc proximal tubule cells can regenerate if time
SUDDEN ONSET OF OLIGURIA & RENAL AZOTEMIA!! + Metabolic
acidosis, electrolyte imbalance [esp HYPERkalemia PT waves
leading to widening of QRS arrhythmias DEATH!]
Step 1: See hyperkalemia w EKG changes, IMMEDIATELY give
CA2+ [GLUCONATE] to stabilize/protect the heart!!!
Step 2, lower K+ [move from intracellular to extracellular] by:
insulin & dextrose; bicarb** [helps to shift K+ and metabolic
acidosis]; or Beta-2 agonist***
Step 3: remove K+ from body: [most effective] k+ [loop] wasting
diuretic like furosemide
EMERGENCY [if all else fails]: DIALYSIS!
Cause: [most common] ISCHEMIA: [hypoxia, hypotension, shock,
decreased CO]
Renal epithelial casts degenerate dirty/muddy brown granular
casts
Nephrotoxin ATN:
Drugs: All Sulfa drugs, aminoglycosides [esp gentamycin], Abx
[esp methicillin]
o Methicillin: Acute interstitial necrosis [AIN] fever, rash,
eosinophils
Drycleaners: Carbon tetrachloride [activated by CYP450 in liver
into free radical]
Ethylene glycol [antifreeze]
Suicide pts drinking antifreeze
o Ethylene glycol converted to oxalate [oxalic acid]
[envelope-shaped crystals]
o SUICIDE NOTE IN URINE
Myoglobin crush injury! Therefore give fluids!
ALL HEAVY METALS CAUSE ATN!
GOOD PROGNOSIS IF DO DIALYSIS & TX THE CAUSE!
o PYELONEPHRITIS:
Ascending infection from bladder, travels up ureters and into kidney
#1 bladder infection = Gm neg E. coli [via pili]
#2 E. faecalis
#3 - Klebsiella
Renal pelvis tubule interstitum
Most infections, glomeruli are spared!
INC risk with Vesico-ureteral reflux (VUR)*
F>>M bc of short urethra
R/F:
Obstruction

Reflux [urine flows wrong way (VUR)] children with pyelo!!


Pregnant women d/t hormones & uterus pushing up against
ureters [+everything else]
Diabetes [neurogenic bladder, neuropathy]
BPH
Stones
Tumors
High fever, chills, high WBC count [neutrophils and bands = LEFT
SHIFT therefore bacterial infection], unilateral [most] costovertebral
[CVA] tenderness [PAIN!! when tapping on kidneys]
Urine: bacteria, WBCs, WBC casts (WAXY)
HIGH FEVER, CHILLS, CVA TENDERNESS, WBC CASTS
Broad depressed scars [healing]: CHRONIC PYELO!! (d/t multiple
bouts of acute pyelo)
Dilated tubules filled with colloid-LIKE material (eosinophilc)
o THYROIDIZATION
Interstitial fibrosis and atrophy of tubules
Kidney Stones:
o Colicky pain with hematuria & UNILATERAL flank pain**
o Ca2+ oxalate [or Ca2+ phosphate] d/t supersaturation [MC= MEN]
High Ca2+: 1 hyperparathyroidism; metastatic tumor of bone; milkalkali syndrome: have peptic ulcer therefore take in antacids and milk
to coat build up of Ca2+ stones
1 tx: stop antacid/Ca2+ intake and prescribe PPI and check for
H. pylori
high oxalate: foods, IBD
stone seen on xray, ct; in urine, envelope-shaped crystals
MC stones TX with Hydrochlorothiazide Ca2+ sparing diuretic
o 2nd MC = Ammonium Mg2+ Phosphate: d/t UTI w urease + organism
[proteus, ureaplasma, etc.]
urea via urease NH3+ [ammonium] [urine smells like ammonium]
F>M
NH3+ will increase pH, therefore, Mg and Phosphate will supersaturate
with NH3+
STRUVITE STONE: Mg + Phosphate + NH3+
BIG!! Fill up pelvis!
STAGHORN CALCULUS [outline of renal calyces]
Seen on xray, ct
Tx: 1) stop growth of stone by acidifying urine [ascorbic acid]; 2) kill
proteus
Need to completely remove stone!! Bc big, need to do:
PERCUTANEOUS NEPHROLITHOTOMY then.Abx!
Proteus causes mummy coffin crystals and swarms plate
o Cysteine stones: hexagon-shaped
Pts with cysteinuria [AR]
Seen on xray, ct
KIDS!!
o Uric acid stones
CANNOT see on xray, but can see on CT
Pts with GOUT [Neg birefringement needles]
Pseudogout [pos polygons]

Seen with High grade leukemias [AML/ALL/Burkitts lymphoma]


TUMOR LYSIS SYNDROME [TLS]
Urate nephropathy
Pre-Tx BEFORE CHEMO: IV fluids and allopurinol bc will inhibit
xanthine oxidase [prevents prod of uric acid
RASBURICASE breaks down uric acid
Tumors of the kidney:
o BENIGN:
RENAL PAPILLARY CORTICAL ADENOMA
In cortex; <3mm [small]; papillary structure
Usually found at autopsy [incidental = common]
**RENAL ANGIOMYOLIPOMA**
proliferation of blood vessels, fat and muscle
not a tumor, but a HAMARTOMA!
Assoc w: TUBEROUS SCLEROSIS! AD
o TSC1 OR TSC2 gene make tuberin + hamartin proteins
= complex
o Composed of hamartomas throughout the body [[genetic
disease where you get hamartomasmost commonly in
brain]]
o In CNS: CORTICAL TUBER [neurons, oligodendrocytes]
proliferation of scrambled brain
Most common periventricular!!
can get benign proliferation of astrocytes:
astrocytoma [subependymal giant cell
astrocytoma] [[can become malignant]]
Get new onset seizures [~10-11yo; ~school age] by
about late childhood to adolescence
Devt of mental delays grades in school decline
o In kidney: Angiomyolipomas proliferation/tumor of
blood vessels, muscle, fat; like wilms but fatty
o in heart: rhabdomyoma striated muscle tumor can
give arrhythmias
o in lungs: hamartomas of lungs
o in skin: SHAGREEN PATCH [bumpy like orange peel]
ASH LEAF PATCH looks like leaf &
hypopigmentation
Anyone can get it!
DX: Woodslamp [UV-A light] lesion
fluoresces!
Angiofibromas of face looks like acne
o DX TRIAD: SEIZURES, RETARDATION, ACNE-LIKE
LESIONS OF FACE
ONCOCYTOMA: Benign tumor from INTERCALATED CELLS OF
COLLECTING DUCTS
o Gross: encapsulated, homogenous, TAN-MAHOGANY
BROWN MASS [d/t to mitochondrial pigments] w central
stellate scar
o Micro: large cells w abundant granular EOSINOPHILIC
CYTOPLASM [MITOCHONDRIA] w benign appearing nuclei
w prominent nucleoli

Wednesday, March 19, 2014


o RENAL CELL CARCINOMA (RCC) [HYPERNEPHROMA] [GRAWITZ TUMOR]
o Overall, M>F 50-70yo [females increasing incidence]
o Presentation:
[[not very classic 10% only]]: Classic Triad:
painless hematuria
palpable mass
flank pain
[[real life]]: just painless hematuria 60% cases
left varicocele of testes (rare association)
metastasis usually FATAL, BUT.
body can kill it!! Therefore, part of tx now is to stimulate immune
system to help fight off tumor
on exam: like Small cell carcinoma of lung: PARANEOPLASTIC
SYNDROME [[assoc w tumor but not caused by invasion nor metastasis]]
[[can look like anything]]
i.e. tumor makes EPO polycythemia
renin HTN
ACTH Cushings syndrome
ADH SIADH
Gonadotropin [HCG] feminization/masculinization
Eosinophilia; Amyloidosis; high white count [leukemoid rxn]
PTH-related peptide increased Ca2+ Stones
o R/F: #1 cause: SMOKING; NSAID abuse [esp phenactin]; cyclophosphamide;
acquired cystic disease [d/t long-term dialysis]; & von Hippul disease [AD;
germline mut in VHL gene on chr 3p knock out mut]
VHL [normally] inhibits hypoxia-inducible factor [HIF; that causes vessels
to grow] Heme angioblastoma [HAB; retina, cerebellum*, brainstem,
spinal cord]
HAB in cerebellum makes EPO polycythemia vera w mass in cerebellum
When see multiple bilateral renal cells
Elevated VMA in urine [[check adrenal medulla for pheochromocytoma]]
VHL HIF HAB EPO RCC VMA PHEO
**spreads hematogenously from kidney renal vein IVC into
right sided heart to lungs [[see HUGE, CANNONBALL-SIZED
METASTASES]]
once in lungs its everywhere = FATAL!
RCC & HCC = hematogenous spread
In men: from left renal vein can affect left testes VARICOCELE! [[bag of
worms]]
MICRO: CLEAR CELL CARCINOMA [CCC]! [[clear cytoplasm]]
Why is it clear??? Cytoplasm full of lipids and glycogen!! Why gross
tumor is yellow and looks like fat!
CCC = MC [65%]
Arise from proximal tubular epithelial cells
RCC
Loss of VHL gene [3p25]
Cells w clear cytoplasm d/t glycogen and
lipid
Sporadic
Papillary RCC = 15%
Hereditary
Arise from proximal tubular epithelial cells

- #1 R/F:
younger
smoking!

10

Papillary growth pattern


Often multifocal and bilateral
Mut in MET gene = hepatocyte growth factor
Chromophobe RCC = 5%
Arise from intercalated cells of collecting ducts
Grossly brown tan
Extreme hypoploidy
Good prognosis
Sarcomatoid changes = indicate a poor prognosis
Sarcomatoid = BAD!! Dont respond to anything BUT surgery!!!
BABY BORN W ANIRIDIA?? WILMS TUMOR!!! [[NEPHROBLASTOMA]] Tumor of
metanephric nephros
o WT1 & WT2 [TSGs] on chr 11 right next to gene for devt of iris [PAX6; PAired
HomeoboX gene]
**WAGR syndrome: Wilms, ANIRIDIA, Genitals, Retardation [mental
& motor]
Delete JUST PAX6, Aniridia
Since WT1 and PAX6 next to each other BOTH deleted can get
wilms tumor + aniridia
Denys-Drash syndrome [DDS]
HIGH RISK [90%] for Wilms tumor + Renal anomalies + gonadal
dysgenesis
DOMINANT NEG INACTIVATION MUT OF WT1
o Dominant disease where mut protein knocks out wildtype
effect [[like Marfans, osteogenesis imperfect]]
Beckwith-Weidemann syndrome [BWS] = WT2 mut!!
Enlargement of organs or body parts [hemihypertrophy]
o HALF of body gets HUGE!! Therefore, Risk of Wilms tumor of
kidney on HUGE half of body!
Gross: white tan tumor
Micro: adrenal cytomegaly = enlarged adrenal cortical cells
Loss of imprinting of maternal allele overexpression of IGF-2
o Get massive growth of one side of body & Neonatal
HYPOglycemia [[used by babies]]
o IGF-1: causes growth like acromegaly & HYPERglycemia
[[used by adults]]
C/F: MC = age 2-5yo; unilateral palpable abdom mass; fever,
hematuria, intestinal obstruction
o Other blastoma palpable mass could be: NEUROBLASTOMA
can DDX via byproduct; both malignant, but NEUROblastoma
can cross midline and calcify
Micro: triphasic tumor
1. Blastema [small round blue cells]
2. Epithelial [tubules and glomerular structures]
3. Stroma
o Important for prognosis = BAD = Anaplasia = hyperchromatic
pleomorphic nuclei w abnormal mitosis
Correlates w p53 mut and resistance to chemotx
o Prognosis WITHOUT Anaplasia = GOOD! 90% 5yr cure rate!
o Neurogenic rests [[?Precursor?]]
TX with surgery, radiation

11

o
o

Sterile Pyuria:
o Pyuria with NEGATIVE urine culture suggests urethritis d/t C. trachomatis or
N. gonorrheae
CYSTITIS: inflammation of bladder d/t:
o #1: infectious cystitis: F>>>M d/t shorter urethra [[d/t E. coli]]
urgency, burning, suprapubic pain/tenderness [[NO fever, shaking chills; if
so? In kidney]]
o #2: Radiation to bladder
o #3: chemo Rx: esp Cyclophosphamide [[Hemorrhagic cystitis]]
CHEMO via CYP450 in liver Nitrogen mustard + Acrolein
CYP450 activates cyclophosphamide [[active metabolite = nitrogen
mustard alkylating agent; damages DNA] + bydproduct [Acrolein]
with cyclophosphamide, give MESNA to bind Acrolein to prevent
hemorrhagic cystitis
o Bladder cancer:
#1 MCC: TRANSITIONAL CELL CARCINOMA (TCC) [AKA UROTHELIAL
CARCINOMA]
involves bladder & renal pelvis*
2 ways can look: either like papillary or flat
o papillary: multifocal & tends to recur therefore tx:
transurethral resection & if keeps recurring, +
immunotherapy [inject BCG into bladder [intravesicular BCG]
inflammation/granulomas kills tumor]
o once tumor invades muscle of bladder = Cystectomy
KEY MGMT DECISION: has it invaded muscle of bladder
yet?
R/F: #1: SMOKING!!
o Working with dyes/rubbers [beta-naphylamine]
Moth balls = pure beta-naphylamine
#2 = SCC
Swimming in the Nile Schistosomiasis [hematobium or mansoni]
o Intermediate host = fresh water snail
o Leaves snail, and penetrates intact skin
o Mansoni intestines and liver and lays eggs [LATERAL
spine]
Liver: PIPE STEM fibrosis
Intestines: gastroenteritis, etc.
o Hematobium to bladder and lays eggs [terminal toenail spine]
o Major basic protein [[like complement for parasites]]
therefore always see eosinophilia
Squamous metaplasia Squamous Cell Carcinoma [~5%]
chronic inflammation
o S. hematobium
o Infections
o Stones
Transitional cells squamous metaplasia dysplasia SCC
presents as painless hematuria
#3: [[RARE!!]] ADENOCARCINOMA OF BLADDER
DOME of bladder

12

arising from remnant of URACHUS (lined by glandular cells; duct


that connects fetal bladder with yolk sac; allows bladder to drain
waste into yolk sac)
o if patent urachus? Pee out of belly button
o if meconium out of belly button? Patent vitelline duct fistula
o if vitelline duct obliterates, but little bit left? Meckels
diverticulum
o mass next to umbilicus? Sister mary joseph nodule [[periumbilical nodule]]
GENITAL SYSTEM:
o FEMALE GENITAL SYSTEM (FGT):
VULVA:
VULVITIS: inflammation of vulva
o Causes:
Contact IRRITANT dermatitis
Rxn to irritants in urine, soaps,
detergents, deodorants
Erythematous weeping and crusting
papules and plaques
Contact ALLERGIC dermatitis
Rxn to Ags in perfumes, creams,
lotions
Erythematous weeping and crusting
papules and plaques
Infectious
STDs
HPV, HSV, gonorrhea, etc
o BARTHOLIN CYST: (usually d/t previous infx;
common)
Complic of vulvitis
Inflammation causes obstruction of excretory
ducts of Bartholin glands
Cystic mass in posterior lateral aspect of
vestibule; 3-5cm in diameter; lined by
squamous or metaplastic squamous epithelium
Painful, large cyst requires marsupialization
(or excision)
o Discomfort during sex and during
insertion of tampon
o BEHCETS DISEASE:
Ophthalmic inflammation, genital ulcers, oral
ulcers
CANT SEE! CANT PEE! CANT EAT SPICY!
CONYLOMA:
CONYLOMA ACUMINATA: BENIGN exophytic lesion of vulva;
warty lesions in anogenital region (VERRUCOUS)
o HPV types 6 & 11 (STD)
o HPV viral effect = Koilocytosis = perinuclear
cytoplasmic vacuolization and wrinkled nuclear
contours
o Low risk of malignant transformation

13

Tx:

Podophyllin, trichloroacetic acid [TCA]


Imiquinod [Aldara] activates immune
system
CO2 laser/Cryotherapy
Prevent? Gardasil HPV vaccine types 6, 11, 16,
18
Prob? Doesnt cover all types!!
o HIGH RISK TYPES of HPV: 16, 18, 31, 33 [[all #s over
sweet 16]]
Insert themselves into DNA and become latent
& start making viral oncogenes [E6, E7]
E6 binds and inhibits p53
E7 binds and inhibits Rb
Before cancer, get dysplasia: (PREMALIGNANT):
In cervix: CERVICAL INTRAEPITHELIAL
NEOPLASIA [CIN]
o NOT cancer yet, misnomer!!
In vulva: VULVAR INTRAEPITHELIAL
NEOPLASIA [VIN]
Squamous metaplastic lesion
Old name: bowers dz/Ca-in-situ
Nuclear atypia
INC mitoses
NO maturation of cells
Reproductive age grp
(same R/F as cervical CA)
HPV 16+**
Differentiated VIN: HPV
NEGATIVE; chronic epithelial
irritation in Lichen sclerosis (R/F)
In vagina: VAGINAL INTRAEPITHELIAL
NEOPLASIA [VAIN]
If untxd? Can progress to SCC!!
o LOW RISK TYPES of HPV:
6 & 11 [go to heaven]: genital warts
1-4 [get from the floor]: plantar warts
42 & 44
o condyloma around the anus?? Pt engaging in anal
intercourse and at risk for HIV
CONDYLOMATA LATA:
o 2 syphilis [+ VDRL; +RPR; +FTA]
o Flat, moist, minimally elevated lesions
LEUKOPLAKIA: = white patches, opaque, white, mucosal
thickening, pruritus, scaling
o (LICHENOID LESIONS: APPEARS as leukoplakia)
Major DDX: NEED TO BIOPSY TO R/O CANCER!!
o Lichen sclerosis
Smooth white plaques [leukoplakia]
MC in postmenopausal females

14

Possible autoimmune etiology


May progress to SCC in 1-5%
Micro: thin epidermis, loss of rete pegs,
hydropic degeneration, dermal fibrosis, scant
perivascular inflammation
o Lichen simplex chronicus (aka squamous cell
hyperplasia)
Smooth white plaques [leukoplakia]
d/t chronic irritation from scratching
NO increased rsk of cancr but often found next
to SCC
Micro: thick epidermis [esp stratum
granulosum], hyperkeratosis, no atypia, dermal
inflammation
o VIN
o Vulvar SCC
Carcinoma of Vulva: (NON-HPV-related keratinizing SCC):
o SCC: Women >60yo; preceded by lichen sclerosis;
well-differentiated and keratinizing
o Avg age = 76yo
o HPV NEGATIVE
o Invasive nests of tumor cells with keratin pearls
HPV-related SCC: less common form
o assoc w hgh risk HPV 16 & 18, &31
o middle-ages; smokers and immunodeficiency
o precursor: VIN
o GROSS: begins as discrete, white, flesh-colored or
pigmented, slightly raised lesions (VIN)
o BASALOID:
Immature cells; resemble basal cells of
epithelium
HPV+
WARTY:
Exophytic; papillary with koilocytic atypia
HPV+
BASALOID & WARTY:
Carcinoma
Begins as CLASSIC VIN*
C/F:
o VIN & carcinoma may present as leukoplakia,
exophytic tumors, or ulcerative endophytic tumors
o Most commonly located on labia majora; also labia
minora & clitoris
o May remain localized for long period before eventually
spreading
o Risk of metastasis correlates w size and depth of
invasion
o Metastasis to regional LNs:
LABIA SUPERFICIAL inguinal nodes
CLITORIS DEEP inguinal nodes
o EXTRAMAMMARY PAGET DISEASE: MALIGNANT!

2 tumors similar to those seen


in breast:
1. Extramammary Pagets
2. Papillary Hidradenoma:

BENIGN

Glandular

Arises from modified


apocrine sweat glands

Sharply circumscribed nodule

On labia majora or interlabial


folds

Tends to ulcerate!! (confused


w/ carcinoma)

Micro: papillary tumor lined


by double layer of cells

15

Key features: Intraepidermal spread of malignant epithelial cells in skin


of vulva; Majority of classes have NO UNDERLYING TUMOR (adenoCA)*

MELANOMA:
o
o

PAGET [[red lesion]]

Cytokerati
n
+

PAS+

S100

HMB45
-

MELANOMA [[black
lesion]]

Poor prognosis;
6th-7th decade
DDX Pagets dz (in
INITIAL phase
when confined to
epithelium)

Origin:

Most cases thought to arise from epidermal


progenitor cells
Small # of cases from sweat glands
Micro: epidermis infiltrated by large epitheloid cells w abundant
cytoplasm which occur as single cells and clusters; cells contain
mucin PAS+; may resemble melanoma [[**melanoma is PAS-]]
C/F: red, scaly crusted or oozing plaque that may resemble an
inflammatory dermatitis; confined to epidermis, good prognosis but
may recur; invasion of dermis may lead to metastasis
VAGINA:
Gardners duct cyst: 1-2cm, fluid filled cysts o Giardia Lamblia: falling leaf
motility from streams
o In lateral vaginal walls
beaver fever
o Remnant of wolfian duct [mesonephric duct]
o Listeria monocytogenes:
o Non-mucus secreting
tumbling motility; from soft
cheeses or birth canal; see
Vaginitis:
Tcells bc intracellular; avoids
o Vaginal discharge [leucorrhea]
Mullerian [[FEMALES]]:
o Normal commensal organisms may become pathogenic w:
1. Fallopian tube
Diabetes
2. Uterus
System Abx therapy
3. Cervix
Wolfian [[MALES]]: testes
4. Upper 1/3 of vagina [[lower
Immunodeficiency
make Mullerian inhibitory
2/3 from urogenital sinus]]
Pregnancy
factor [MIF] from Sertoli cells
o MULLERIAN AGENESIS [aka
Recent abortion
& Males need to make
ROKITANSKY-KUSTERTESTOSTERONE to make
o Trichomonas vaginalis [[motile;
HAUSER Syndrome]: NO
Wolfian structures:
FUCU Structures!!
corkscrew motility]] protozoa
1. Epididymis
o Usually presents
Found in 10% of Asx women
2. Vas [ductus] deferens
~13yo [NO
3. Seminal vesicle
Sx infection d/t R/F or
MENSES]
4. Ejaculatory duct
nd
superinfection w new more
o 2 MCC of 1
o Need 5-alpha-reductase to
st
Amenorrhea [1
aggressive strain
make DHT which makes
MCC is Turners]
WATERY, COPIOUS GRAY
genitalia male and gets
o DES, given for threatened
rid of Urogenital sinus
GREEN
DISCHARGE
abortion BUT messes up
o
FINESTERIDE: inhibits 5
STRAWBERRY
CERVIX
mullarian ducts [causes
alpha-reductase; tx for
cervical stenosis]
o Candidal [Monilal] vaginitis:
BPH; S/E of menopause;
infertility of baby [T-shaped
yeast
need to be on for 6mosuterine cavity] & get glands
Part of normal flora in 5% or
in upper 1/3 of vagina
females
Sx infection d/t R/F or superinfection w new more
aggressive strain
CURDY WHITE DISCHARGE
Dx: PAP smear; KOH prep

TUMORS of VAGINA:

16

o
o

SCC [RARE (1%)]: Primary Vag CA


d/t HPV 16 & 18 VAIN = precursor
cervical SCC extending down to vagina
MC MALIGNANT TUMOR OF VAG = METS CA FROM CERVIX!!**
CLEAR CELL ADENOCARCINOMA:
DES exposure Adenosis adenocarcinoma
Teens/young adults
Red granular foci that dont stain with Lugols
iodine soln = vaginal adenosis and clear cell
adenocarcinona
EMBRYONAL RHABDOMYOSARCOMA:
Aka SARCOMA BOITRYOIDES
Boitryoides [greek: grapes]
Malignant striated muscle tumor
Polypoid, rounded, bulky masses that fill and project
from vagina
From muscle of vagina as well as muscle of
bladder, and head & neck region
Infants to 1 yr ((*<5yo))
Grape-like lesions/tumors coming out of vagina
CAMBIUM LAYER: layer under mucosa where all tumor
cells growing
strap tadpole
some cells have cross striations [trying to be
muscle]
o tennis racket-like cytoplasm
malignant rhabdomyoblasts
marker for muscle cells:
o Actin+
o **Desmin+
o MyoD1+
o Myogenin+
DDX: inflammatory polyps!

CERVIX:
Inflammatory conditions
CERVICITIS: inflammation of cervix; BENIGN!
o Purulent vaginal discharge
o ACUTE or CHRONIC
At menarche, estrogen maturation of cervical/vag
squamous epithelium with intracellular glycogen
vacuoles in squamous cells
PAP SMEAR**
Infectious: STDs
o esp chlamydia & gonorrhea [[tx together]]
Pelvic Inflammatory Disease [PID]
o DX:
1. PAP Smear
2. Gram stain/culture
3. Blood: INC ESR/CRP
o When infection ascends
(from vulva/vag) involves most structures of FGT

17

causative organisms:
N. gonorrheae (Gonococcus) infx may begin with
bartholin glands
marked acute inflammation 2-7days after
inoculation
MC site of initial involvement endocervical
mucosa
Endometrium usually spared
Spreads to tubo-ovarian regions from any of
above locations (retrograde)
NON-Gonococcal Infx spread via lymphatics or venous
channels**
C. trachomatis
Polymicrobial infx staph, strep, coliform bact, C.
perfringens
o Puss In Dere
o PID Endometritis midline abdom pain Fallopian
Tubes [Salpingitis] Peritoneal cavity [guarding, rigidity,
rebound tenderness] Peritonitis Perihepatitis
[abscesses next to liver]; RUQ pain Adhesions [violin
strings; Fitz-Hughs-Curtis Syndrome (form of PID)]
o Tubo-Ovarian Abscess: abscess btwn fallopian tube &
ovary
o Complic: #1: Infertility; [if do get pregnant] ectopic tubule
pregnancy [[#1 cause for ectopic pregnancy is scarring
from prior PID; #1 location in ampulla]]
CANCERS of Lower Female Genital System:
o Incidence: [top 3]
#1: Endometrial cancer [[most common]]
#2: Ovarian cancer
#3: Cervical cancer
o Mortality:
#1: Ovarian Cancer***
#2: Endometrial Cancer
#3: Cervical Cancer [[in US, #3; rest of world, #1]]
Metastasis:
o Direct spread: uremia = most freq cause of death in stage IV
o Local & distant LNs
o Distant metastasis: to LIVER, LUNGS, and BONE MARROW! =
cervical CA**
bc we do yearly Pap Smears!!
o NORMAL pap smear: Small round nuclei; lots of cytoplasm
o Papanicolaou [PAP] smear:
Most successful screening test ever developed
Micro exam of scraped cells from transformation zone
o CERVICAL CANCER:
R/F: HPV [Human Papilloma Virus] 16,18* = #1 Most Imp R/F in
cervical oncogenesis*
HPV has tropism for immature squamous metaplasia of
transformation zone
Endocervical: columnar glandular cells
o

18

What makes pap smear adequate? Have both squamous and


columnar cells on smear
Other R/F:
o Early age of intercourse
o Multiple sex partners
o AIDS (immunosuppressed)
o Multiple STD exposure
o Certain HLA subtypes
o OCPs; Nicotine
R/F: Smoking!
CIN: precursor lesion
Peak incidence of CIN: ~30yo
Peak incidence of invasive SCC: ~45yo
CIN I: Low-grade squamous intraepithelial lesion [mild dysplasia]
o Koilocytic atypia
o Most regress spontaneously
o Atypical, immature cell layer confined to LOWER 1/3 of
epithelium*
o Tx: observe and re do pap smear
CIN II: moderate dysplasia [high grade squamous intraepithelial
lesion]
o Atypical, immature cells occupy 2/3 of epithelium
o Progression deregulates cell cycle
**CIN III: severe dysplasia [high grade squamous intraepithelial
lesion]
o atypical, dysplastic cells in >2/3 (or entire thickness)
C/F:
Vaginal bleeding from intercourse; leucorrhea; dyspareunia; dysuria
MC in women who have not been screened with PAP smear
If truly invasive, recommend hysterectomy!
If micro invasive (infiltrates stoma just below basement membrane), in
situ, or dysplasia: LOCAL THERAPY coat it, freeze it, etc. [[anything to get
it out!!]]
Can proliferate anteriorly impacting ureters at trigone causing dilation of
ureters [hydroureters], backing up to kidney, causing HYDRONEPHROSIS
COMPLIC: KIDNEY FAILURE!!
PELVIC EXONERATION
DX:
HPV DNA detection via Hybridization
Immuno stain with Ki-67 (prolif marker) & p16 (cell cycle inhibitor)
POLYPS:
ENDOCERVICAL POLYPS: tx = surgical excision
Benign polypoid mass arising from endocervical mucosa
Gross: soft smooth glistening surface with underlying cystic spaces
containing mucous
Micro: mucin-secreting lining with edematous stroma
C/F: may bleed (spotting), protrudes through vagina
NO MALIGNANT POTENTIAL!!
ENDOMETRIAL POLYPS: sessile, occasionally pedunculated
MALIGNANT POTENTIAL

19

Composed of endometrial glands and stroma


Estrogen effect: hyperplastic polyps

UTERUS:
(BIFID) Bicornuate Uterus:
abnormal Y-shaped uterine cavity (RARE)
can cause habitual abortions freq d/t Leiomyomas
o results in defective placental implantation with spontaneous
abortion, usually in 2nd trimester
Abnormal uterine bleeding (AUB):
MENORRHAGIA: profuse or prolonged bleeding at regular intervals
METROHHAGIA: irregular bleeding btwn periods
OLIGOMENORRHEA: bleeding at intervals >3-5 days
AMENORRHEA: NO uterine bleeding >6mos
o 1: Turner Syndrome; Mullerian agenesis
o 2: Pregnancy
POSTMENOPAUSAL BLEEDING: uterine bleeding after
menopause
o Tx: dilation + biopsy/curettage
Common causes:
o Endometrial polyps
o Endometritis
o Leiomyomas [fibroids]
o Endometrial
hyperplasia**
o Endometrial
carcinoma**
Dysfxnal Uterine bleeding (DUB):
Abnormal bleeding from uterus without a structural or organic
uterine pathology
o R/O causes of Abnormal uterine bleeding
DX of exclusion
1. Anovulatory cycle: failure of ovulation [MCC in ~90% cases]
2. Inadeq luteal phase
3. OCPs
4. Menopausal and postmenopausal changes
ASHERMAN SYNDROME
ENDOMETRITIS:
Fever, midline abdom pain, menstrual irregularities
Tx: Abx!! Prevents sequelae like salpingitis*
ACUTE:
o Neutrophilic infiltrates and microabscesses
o Post delivery or miscarriage
CHRONIC:
o Always secondary to underlying cause:
IUCD
Chronic PID
Postpartum or postabortal states
TB military spread or from tuberculous salpingiitis
o Presence of ***PLASMA CELLS*** in endometrium
o Consequence of PID
o Intrauterine device [IUD]: take out, send for culture of
Actinomyces [sulfur granules]

20

ADENOMYOSIS:
Growth of basal layer of endometrium down into myometrium
o + of endometrial tissue DEEP within uterine wall
(myometrium)
Micro:
o Benign appearing endometrial glands and stroma
within myometrium
o Since composed of stratum basalis the gland DO NOT
UNDERGO CYCLIC BLEEDING
o Reactive HYPERTROPHY OF MUSCLE enlarged
globular uterus w thickened TRABECULATED UTERINE
WALL
C/F: Menorrhagia; Dysmenorrhea (colicky); Pelvic pain prior to onset
of menses
*****ENDOMETRIOSIS*****:
o Presence of endometrial glands and stroma OUTSIDE
UTERUS
o Definitive Dx (2 of 3):
Endometrial glands in ectopic lesion
Stroma in ectopic lesion
Hemosiderin pigment in ectopic lesion
o Hypotheses:
Regurgitation theory retrograde menstruation
through fallopian tubes even in normal female
Metaplastic theory endometrium could arise directly
from coelic epithelium
Vascular/lymphatic disseminated theory
dissemination through pelvic veins and lymphatics
would explain endometriotic lesions in lungs or LNs
o Mech of ability for endometrial tissues to survive:
PGE2, ILs, TNF, etc. d/t profound stimulation of
inflammation
COX-2 inhibitors good to tx pelvic pain in these
pts
aromatase estrogen production
NOT in normal endometrium*
Can tx with Aromatase inhibitors
o Fxning endometrium undergoes cyclic bleeding
o Micro: endometrial glands; stroma; hemosiderin pigment
o Locations:
MC site: OVARY: Chocolate cyst [endometrioma]
Large, 3-5cm with brown fluid
Uterine ligaments and fallopian tubes
Pouch of douglas
Peritoneal cavity: red-brown areas [powder burns]
Rectovaginal septum and cul-de-sac;
bowels/appendix/etc.
o C/F:
Can develop malignancy, but UNcommon!
Common
~10% women of reproductive age

21

causes ~50% infertility bc of scarring


lower abdom discomfort; pelvic pain; severe
dysmenorrhea [pain during cycle]
uterine serosa dyspareunia [pain during intercourse]
bladder serosa dysuria [pain on urination]
rectal wall pain on defecation
o Morph:
Red-blue to yellow-brown nodules
Fibrous adhesions
LEIOMYOMA: aka FIBROIDS:
MC tumor in females!
Smooth muscle tumor (tumor of myometrium)
Can lead to infertility and if numerous chronic pelvic pain (if intrude
uterine cavity)
BENIGN!!
Common in African American Females
Most have normal karyotypes
40% = simple chromosomal abnormality like balanced translocation
btwn 12;14
ESTROGEN-RESPONSIVE***
Locations within uterus:
Submucosal
Intramural
Subserosal
Well-circumscribed, whorled, trabeculated, spindle-shaped
smooth muscle cells!
What causes these to grow? ESTROGEN-dependent tumors!
Grow most during reproductive ages & typically multiple
Old African American woman Xray multiple calcified abscesses
GROW RAPIDLY during pregnancy and can cause spontaneous abortion!
SX:
Abnormal bleeding
Compression of bladder urinary freq
Sudden pain (disruption of blood supply)
Infertility
LEIOMYOSARCOMA: UNcommon!
ALMOST NEVER FROM LEIOMYOMAS!!
Peak age = 40-60yo
HIGH recurrence rate!
MALIGNANT; arises POSTMENOPAUSALLY; SINGLE
De novo from myometrium OR from endometrial stromal precursor
cells
Hemorrhagic; bulky, fleshy masses that invade uterine wall; polypoid
masses that project into uterine ligament
Micro: wide range of ATYPIA; extremely well-differentiated; anaplastic
lesions
Much more cellular; more mitoses
How do all sarcomas spread? Hematogenously! Therefore where does this
go 1st? LUNGS!!
3 ways tumor can spread:
1. thick wall artery

22

2. thin wall vein


a. portal veins: in GI Liver
b. vena cava veins: in rest of body IVC/SVC
Lungs
3. thin wall lymphatic channel [MOST TUMORS spread to
regional LNs]
o EXCEPTIONS:
ALL SARCOMAS SPREAD HEMATOGENOUSLY
(1&2)
RCC/HCC
Follicular thyroid cancer
Malignant germ cell tumor [CHORIOCARCINOMA]
Ovarian tumors seed belly
Appendiceal adenocarcinoma seeds belly fills
belly w mucus [PSEUDOMYXOMA PERITONIAE]
Gallbladder cancer seed belly
ENDOMETRIAL HYPERPLASIA: precursor of endometrial carcinoma
INC prolif of glands INC gland:stroma ratio
Imp cause of DUB
Mech: excessive estrogen
R/F: [[d/t excessive estrogen]]
failure to ovulation
unopposed estrogens
obesity
Polycystic ovarian syndrome (PCOS)
Estrogen-prod ovarian tumors [granulosa-thecal cell tumor]
Pts with COMPLEX HYPERPLASIA WITH ATYPIA have 25% chance of
eventually developing endometrial carcinoma d/t HIGH mitotic activity,
disorganization, and nuclear atypia
Pts with COMPLEX HYPERPLASIA WITHOUT ATYPIA have 5% chance of
developing endometrial carcinoma
Micro: severity of hyperplasia corresponds to amount and duration
Architectural crowding simple vs complex
Presence or absence of ATYPIA: presence of atypia increases risk of
cancer
Genetics: INACTIVATION OF PTEN TSG
PTEN is brake on PI-3 kinase/ATK signaling pathway
On chr 10
Leads to prostate tumors and endometrial cancers
Cowden Syndrome AD mut in PTEN
o HAMARTOMAS around body

Simple Hyperplasia: irregularity or cystic dilation of glands; swiss cheese appearance


WITHOUT Atypia irregular, cystic glands; stromal hyperplasia
WITH Atypia UNcommon; progression to CA is HIGHLY Unlikely!!

Complex Hyperplasia: crowding or budding of glands


[[mut in MLH1 & MSH2 [DNA mismatch repair genes]
HNPCC Colon, Endometrial, Ovarian cancer]]

23

Complex Atypical Hyperplasia: cell stratification, tufting, loss of nuclear polarity,


enlarged nuclei, mitosis; 23-48% have hysterectomy
[[KRAS mut; PTEN mut]]

Invasive [endometroid] carcinoma: beta-catenin & PIK3CA mut


Thursday, March 20, 2014
ENDOMETRIAL CANCER:
o MC cancer of FGT!!**
o C/F:
MC in postmenopausal women 55-65yo, usually in nulliparous!
Leucorrhea or postmenopausal bleeding*
Invades local structures
Late in course metastasis to regional LNs and distant sites
TX: surgery/radiation; prognosis depends on stage, grade, and type
o 2 forms: Type I & II:
ENDOMETROID [80%] Type I indolent behavior
R/F:
o Obesity
o Diabetes
o HTN
o Infertility
o Unopposed estrogens [ERT/tamoxifen [breast cancer
Rx] use]
o Endometrial hyperplasia
Genetics:
o Mut in mismatch repair genes [hMLH1, hMSH2
(microsatellite instability)]
o Mut in PTEN, beta-catenin, KRAS
Gross: localized, polypoid mass or diffuse mass
Micro: resembles normal endometrium
Spread:
o Via myometrial invasion and then to peri-uterine
structures
o Into broad ligament (palpable mass)
o Mets to regional LNs then to lungs, liver, bones
DX: curettage or biopsy and histopathology
Course:
o NO screening tests available!
o Asx!

**3 step grading system**


well-differentiated = grade 1 = well-defined glands
moderately-differentiated = grade 2 = glands mixed with solid sheets
of malignant cells
poorly-differentiated = grade 3 = solid sheets; barely recognizable
glands

SEROUS [15%] Type II (grade 3)

24

R/F:
o
o
o
o
o
o
o

Older age, postmenopausal


Arise from atrophic endometrium
Mut in p53
Form small tufts and papillae
More cytologic atypia
More aggressive
May spread via fallopian tube into peritoneal cavity
Seeds belly like ovarian cancer
MMMT Malignant Mixed Mullerian Tumor
Endometrial adenoca with malignant changes in stroma
carcinocarcinoma
HIGHLY aggressive!!
In elderly, postmenopausal women
POOR prognosis!!
Ashermans syndrome: adhesions in endometrium after rigorous D&C
Chronic endometritis: plasma cells+ in endometrium
Actinomyces growing on IUD
Adenomyosis: basal layer growth of endometrium down into myometrium
Endometriosis: endometrial glands+ and stroma outside uterus
Chocolate cyst: appearance of ovary in endometriosis
Complex endometrial hyperplasia: increased #s of endometrial glands w crowding
or budding of glands
POLYCYSTIC OVARIAN SYNDROME [PCOS]: aka Stein-Levinthal
o String of Pearls
o cystic follicles that aborted ovulation
numerous within cortex
o young, reproductive age [avg teen]
o commonly present w: OHIO
Oligouria
Hirsutism
Infertility
Obesity [have aromatase: peripheral conversion of androgens to
estrogen]
o Other c/f:
Oligomenorrhea
Anovolutary cycles
Virulism (rare)
o LH +thecal cells to start developing follicles [then gets aborted d/t
androgens] +androstenedione [often presents w hirsutism (need for laser
hair removal); acne] estrogen
o gross: ovaries 2x the normal size; smooth gray-white outer cortex studded
with cysts 0.5-1.5cm in diameter
OYSTER OVARIES
o micro: thickened cortex; multiple subcortical follicular cysts with follicular
hyperthecosis = hyperplasia of theca interna
o LINK to INSULIN RESISTANCE sometimes tx of PCOS leads to resumption of
ovulation
These pts at INC risk for DM!
o Variety of enzymes involved in androgen synthesis are poorly regulated in
PCOS

25

LH / FSH

+Theca cells

NEG
FEEDBACK

+Androgens
(Androstenedione)

Estrogen
(Estrone)

MOST COMMON ENDOCRINE D/O!


FSH [<2]
Give pt Clomiphene for ovulation [prob? Ovulate multiple eggs and get
multiple births]
o How to control LH? Give OCs!
OVARIAN TUMORS:
o 3 categories:
1. Benign 80% - 20-45yo
2. Borderline slightly older pts
3. Malignant 45-65yo
o Some bilateral, some non-fxnal, others are hormonally active
o Sx: abdom pain, progressive distention, urinary and GIT sx, vaginal bleeding
o Epithelium, stroma, and germ cells can all turn malignant
o EPITHELIAL surface tumors = MC & MC MALIGNANT
Aka mullerian epithelial tumors
d/t inflammation of surface irritation can get trapped in cyst
[trapped epithelial inclusion within ovary] can turn malignant
present as big cystic ovaries; VAGUE SIGNS/SX!
[[CYSTADENOMAS]]
1. SEROUS TYPE: MC & MOST LETHAL!
Papillary
Clear fluid prod cells (cystic)
25% bilateral
borderline = tumor of low malignant potential
o more intricate papillae; NO stromal invasion!
malignant = cystadenocarcinoma = has to invade stroma!!
o More solid than cystic, fleshy, numerous, irregular
papillae, fixation, nodularity of capsule
o if lined by serous cells = Serous Cystadenocarcinoma =
most common
SEROUS PAPILLARY CYSTADENOCARCINOMA
line papillaries
layered whirled calcification = Psammoma bodies
Marker: CA-125 to follow these tumors
o lined by mucinous cells = mucinous cystadenocarcinoma
o R/F:
Nulliparity
Gonadal dysgenesis in kids
Fam Hx
Mut in BRCA1/2, KRAS, BRAF, p53
o
o
o

26

2.

3.

4.
5.

o DEC risk with OCPs; tubal ligation!!**


gross: complex, multilocular cysts w nodules and solid area
micro:
o tall, columnar epithelial cells (ciliated and non-ciliated)
often forming papillary structures
o psammoma bodies
low grade: KRAS, BRAF or ERBB2 mut
high grade: p53
MUCINOUS TYPE (less common than serous)
Can be benign, borderline, or invasive
o Malignant in 15%
Usually affects in middle adult life
R/F: Smoking! Very few molecular alterations IDd but 1
consistent finding = KRAS mut
With signet ring cells
Mucinous lining thats invading = CYSTADENOCARCINOMA
Compared to serous:
o Less likely to be benign; bilateral [usually unilateral]
o Usually larger and multicystic [therefore more easily
noticed]
o Better prognosis
Rarely cause pseudomyxoma peritonei [[jelly belly MC:
adenocarcinoma of appendix]]
o Extensive mucinous ascites, cystic epithelial implants on
peritoneal surfaces, adhesions if extensive, leads to
intestinal obstruction and death
o 2ary to:
appendiceal mucinous tumor with 2ary ovarian and
peritoneal spread
ovarian mucinous tumors
o micro: mucin producing epithelium and glands; free
mucin+
Must be DDX from metastatic stomach cancer KRUCKENBERG
tumor [usually bilateral]
ENDOMETROID CARCINOMA
d/t metaplasia
mostly malignant
bilateral in 30%; 15% coexist with endometriosis
may be solid or cystic; glands resemble endometrial glands (low
grade)
15-30% also have endometrial carcinoma!!
Mut in PTEN, KRAS, beta-catenin, microsatellite instability, p53
(poorly diff)
CLEAR CELL TUMOR
BRENNER TUMOR: adenofibromas
Mostly benign
can be seen with mucinous cystadenoma or with teratoma
cystic or Solid unilateral ovarian tumor; yellowish color; <1cm to
massive (20-30cm)
Abundant stroma with nests of transitional-type
endothelium

27

o coffee-bean nuclei
Arise from surface epithelium or urogenital epithelium trapped
within the germinal ridge
Ovarian mass + ascites = BAD!
Tx: multiple resections!
Can develop multiple adhesions from multiple surgeries or even
bowel obstruction which ultimately causes death
R/F: [[Lots of OVULATIONS]]
o NO PREGNANCY
o BRCA1/2
o Lynch Syndrome [[CEO]]
GERM CELL TUMORS = 2nd MC [Also in men germ cells of tests]
In men: SEMINOMA // in women: DYSGERMINOMA (malignant)
Occurs in 2nd and 3rd decade of life [15-35yo]
Assoc with gonadal dysgenesis
o DYSGERMINOMA = assoc w Turners Syndrome
o SEMINOMA = assoc w Kleinfelters
Micro:
o large clear cells bc lots of glycogen [[CLEAR CELL
CARCINOMA]]
o Stroma w lymphocytes and granulomas
Syncytial trophoblasts can make beta-HCG
Radiosensitive [[3 ways to kill it: chemo, radiation, and
resection = GOOD PROGNOSIS]]
Malignant [80% cured]
CHORIOCARCINOMA
YOLK SAC
EMBRYONAL CARCINOMA
TERATOMA [scrambled baby]: aka Dermoid Cyst
Dx: ultrasound of ovary bc dont want to radiate gonads
In women, ~90% BENIGN; in men ALMOST ALL MALIGNANT
[until proven otherwise]
Occur in young women [1st 2 decades of life]
MC germ cell tumor
BENIGN [MATURE] CYSTIC TERATOMAS
o Presence of mature tissue from all 3 germ layers:
ectoderm, endoderm, mesoderm
o Gross: Cysts containing sebaceous secretions, hair,
and teeth
o C/F: infertility; ovarian torsion,
LIMBIC ENCEPHALITIS: paraneoplastic syndrome
w teratormas containing mature neural tissue
Inflamm of limbic system
Subacute onset [<12wks] of seizures, short
term memory loss, confusion, and psychiatric
Anti-NMDAR = teratomas containing
mature neural tissue
Anti-Ma2 = germ cell tumors of testes
Anti-Hu = small cell carcinoma of lung
SPECIALIZED TERATOMA: STRUMA OVARII

28

o Composed almost completely of mature thyroid tissue


o May cause hyperthyroidism [[w NO goiter]]
o Unilateral solid brown mass
MALIGNANT [IMMATURE] TERATOMA
o HIGHER RISK OF CANCERS!!
o Gross: bulky solid mass w areas of necrosis
o Micro: presence of immature elements; foci of
neuroepithelial differentiation [may be aggressive
and metastasize widely]
SEX CORD STROMAL TUMORS:
FIBROMA
THECOMA-FIBROMA:
o Unilateral
o Firm gray white mass
o Meigs syndrome:
Ovarian fibroma
Ascites
Right sided hydrothorax
o Benign
o Chief complaint: mass in anexa with ascites [[mimics
death sentence of seeding]]
GRANULOSA CELL TUMOR
Often prod large amounts of estrogen
C/F: depends on age
o Prepubertal: precocious puberty
o Reproductive life: irregular cycles
o Postmenopausal: postmenopausal bleeding
Gross: unilateral solid gray yellow ovarian mass
Micro: composed of granulosa cells in cords or sheets; CallExner Bodies [granulosa cells prod small follicle-like structures
filled w eosinophilic material]
May cause endometrial and breast hyperplasia and cancers
[[tumor causing tumors]]
SERTOLI-LEYDIG CELL TUMOR: ovaries making androgens!!
Same gross appearance!!
o Hirsutism, deep voice, etc
o If pregnant? Pseudo-hermaphroditism if female baby
CONNECTIVE TISSUE TUMORS
METASTASIS: Classic:
GASTRIC CANCER: Signet ring cells: KRUKENBERG TUMOR
BREAST CANCER [esp LOBULAR CANCER]
5-10% breast cancer = hereditary
BRCA1 chr 17 most common for breast and ovary cancer; &
prostate cancer
o Esp serous AND mucinous epithelial tumors
BRCA2 chr 13 breast cancer in MEN AND WOMEN in 1 family
DNA Break ATM BRCA1/2 OR p53 tells Rb to stop cell
cycle at G1/S
o mut ATM? Ataxia, telangiectasia, malignancy & microbial
infections bc immune system cannot repair itself
o mut p53? All cancers

29

mut Rb? Mostly retinoblastoma & osteoblastoma

CANCER AGS:
o CA 15-3: for FOLLOWING [NOT DX] Breast cancer
o CA 19-9: pancreatic cancer
o CA 125: ovarian cancer

D/O of Pregnancy:
o ASCENDING INFECTIONS
Assoc w premature rupture of membranes
Acute chorioamnionitis: neutrophils, edema, congestion
Funisitis: acute vasculitis of cord
Mycoplasma, candida, vaginal flora
o HEMATOGENOUS INFECTION
Villitis: inflammation of placental villi
Syphilis, TB, Listeriosis, TORCH
o TRANSPLACENTAL INFECTION OF FETUS
TORCH Complex:
Toxoplasmosis
Other
Rubella
CMV
Herpes
ECTOPIC PREGNANCY: implanted fertilized ovum in any site OUTSIDE uterine
cavity
o ~1% of pregnancies
o Sites:
Oviducts: tubal pregnancy
MC ~90% cases
MC site: ampulla
Ovary
Abdom cavity
o R/F: delayed passage of ovum
Chronic salpingitis and scarring
Endometriosis
have NO IDable cause
o micro: placental villi and fetal tissues
o tubal pregnancies invade wall leading to intratubal hemorrhage
[hematosalpinx] and intraperitoneal hemorrhage
o rupture = med emergency: acute abdom shock exsanguination
MCC OF FETAL LOSS IN 1ST TRIMESTER = Chromosomal Abnormalities [i.e.
trisomies] therefore, always look for translocations
GESTATIONAL TROPHOBLASTIC DISEASES = tumors of placenta
o Complete Mole [100% DAD] = Completely tumor
o Partial Mole = Part Baby + Part Tumor

Partial mole
Karyotyp
e
Villous
edema

Triploid [69, xxy]


Some villi

Complete mole
Diploid [46, xy]
[all paternal]
All villi
30

Trophobl
ast
prolifera
tion
Serum
and
tissue
hCG
Fetal
tissue
o

Focal; slight

Diffuse; marked

Present

absent

Types:
HYDATIDIFORM MOLE: [Aka Molar Pregnancy]
Incidence:
o In US: ~1-1.5 per 2000 pregnancies
o More common in Asia
o MC in ages <20 and >40
o risk of having another in future
C/F: beta-HCG +Pregnancy Test Ultrasound NO viable
fetus, NO Heartbeat; see swollen chorionic villi [look like grapes]
= Snowstorm
o Before ultrasound: Size of uterus >> Date of conception &
blood + grapes
Micro:
o hydropic swollen chronic villi [grapes]
o Virtual absence of vascularization of villi
o Proliferation of cytotrophoblasts and syncytiotrophoblasts
[b-hCG]
TX: dilatation and curettage [D&C]; Monitor hCG; chemo
[methotrexate] if hCG doesnt go down
INVASIVE MOLE: have grapes!
~10% of complete moles are invasive
hydropic villi invade myometrium
may lead to uterine rupture and life-threatening hemorrhage
atypical changes in cytotrophoblasts and syncytiotrophoblasts
does not metastasize but may embolize
CHORIOCARCINOMA***: NO grapes!
Most malignant germ cell tumor [highly] of JUST trophoblasts
[NO VILLI]
o NO uterine enlargement, NO grapes
o See hemorrhage and necrosis
Early spread by hematogenous routes therefore goes to lungs,
liver, bone, brain, skin, etc.
B-hCG is typically INC
2 forms:
o Gestational:
most of time after complete mole
after spontaneous abortion

31

after normal preg [rare]


~100% cure rate with chemo!!
Highly responsive to Chemo
Tumor is mom, dad foreign Ags
therefore immune system kicks in to fight
dads foreign Ags
GOOD PROGNOSIS!
o Gonadal:
from germ cells of ovary/testes
POOR PROGNOSIS
Responsive to chemo
NO immune response be NO foreign Ags
Testes: good dx test = +preg test
o All prod elevations of human chorionic gonadotropin [hCG] [therefore
+pregnancy test]
o Response to therapy is critical
PLACENTAL SITE TROPHOBLASTIC TUMOR
o Derived from placental site intermediate trophoblast
o Arise a few months after a pregnancy
o karyotype: diploid [46, XX]
o prod human placental lactogen
o not as sensitive to chemo as other trophoblastic tumors
o prognosis:
confined to uterus: favorable
spread beyond uterus: poor
PREECLAMPSIA/ECLAMPSIA: aka toxemia of pregnancy
o In 5-10% of pregnancies
o MC w 1st pregnancies in women >35yo
o Preeclampsia:
HTN
Proteinuria
Edema
o Preeclampsia in 1st trimester morning sickness = tumor, NO baby!
[[usually in 2nd-3rd trimester]]
o Eclampsia = Preeclampsia + Seizures
o HELLP Syndrome: [[on the way to DIC]]
In ~10% [severe preeclampsia]
Hemolysis
liver enzynes
Low platelets
o Mech: insufficient maternal blood flow to the placenta 2 to
inadequate remodeling of spiral arteries
o d/t altered placentation decreased perfusion to placenta STOP making
OGI2, PGE2, increased renin/ATII, increased TXA2, endothelial dysfxn
arterial vasoconstriction, endothelial injury, + of intravascular coagulation
systemic HTN, DIC
o Path:
Placental infections
HTN d/t reduced vasodilators; increase vasoconstrictors
Hypercoagulability: endothelial dysfxn and release of tissue factor
[+Factor 7] to start clotting from ischemic purpura

32

End organ mircroangiopath and failure of kidney, liver


o Tx: delivery is ONLY cure!!
o B-hCG responsible for morning sickness!
BREAST:
o [[pic in robbins]]
o ***ALL BREAST LESIONS MUST BE DDX FROM CANCER!!!*****
o age: >50yo favor malignant
o palpable mass or not?
In situ lesions usually do not have a palpable mass while an invasive
one may
o Causes of breast lumps:
1. Fibrocystic change [[MCC for lump in breast]]
2. Normal breast
3. Other benign
4. Cancer
o Pattern of calcification
Favor benign
Course or popcorn-like MACROcalcifications benign
fibroadenoma
Egg-shell or rim-like fat necrosis or cysts
More worrisome
Amorphous coarse heterogenous
Fine pleomorphic clustered MICROcalcifications
Fine linear branching calcified ducts
Pattern of calcifications may be suggestive but only biopsy is definitive
o Presence of myoepithelial layer
Presence = critical for determining invasion
an intact myoepithelial cell [MEC] layer is seen in both benign and in
situ lesions, whereas loss of MEC layer is considered the gold
standard for the dx of invasive cancer
o normal anatomy:
2 cell layers for ducts & lobules!!
Surface = epithelial [luminal] cell
o Cells that make milk [[respond to Prolactin]]
Myoepithelial [basal] cell
o Muscle: eject the milk to baby [[respond to Oxytocin]]
o BENIGN breast lesions
Supernumery [multiple] nipples or breast tissue
May occur anywhere along the embryonic ridge [milk line]
May develop breast pathology
Congenital inversion of nipple
Nipple is pulled inward by fibrous bands
May mimic breast cancer and interfere with nursing
Galactocele
In lactating women
Obstructed duct develops cystic dilation
Painful lump
Rupture prod inflammation and results in a scar mimicking
breast cancer
Acute mastitis

33

MC organism: S. aureus
In women breastfeeding d/t cracks or fissures in nipple
Erythematous, warm breast w purulent nipple discharge
May progress to abscess formation and fistula tract to areola
Clinically may resemble inflammatory carcinoma
Tx: Abx and continued expression of milk from breast
o If does NOT get better w Abx, BIOPSY!!
Mammary duct ectasia [plasma cell mastitis]
Non bacterial chronic inflammation of breast w inspissated
secretions
Assoc w lactation [occurs few yrs after cessation]
Dilated ducts
Duct rupture leads to reactive inflammatory changes mimicking
breast cancer
Firm periareolar mass w nipple discharge and retraction
Traumatic fat necrosis
Seen in young females
May or may not have hx of antecedent trauma to breast
Early lesions are sharply localized w central fat necrosis
surrounded by neutrophils and macrophages
Late lesions are composed of calcified scars
May mimic breast cancer
Galactorrhea
Milky nipple discharge in non-lactating woman
Causes:
o Excessive nipple stimulation
o **Prolactinoma of anterior pituitary
o Drugs [**antipsychotic meds antidopaminergic effects]
Friday, March 21, 2014
[[contd]] THE BREAST
o FIBROCYSTIC CHANGES [FC]: BENIGN
Old name: Fibrocystic disease
MC in reproductive ages
Typically multifocal and often bilateral lumps & bumps
Almost every woman has a little bit
FC vs Cancer
FC: multiple, bilateral, changes w menses, calcification [diffuse,
large]
Cancer: single, unilateral, doesnt change w menses [slowly
enlarges], calcification [local, micro]
Normal breast tissue = yellow and fatty Change: white fibrosis; blue
dome cysts
FC is made of:
NON-PROLIFERATIVE component = NO risk of breast cancer!
o Calcifications
o Fibrosis
o Cysts [blue brown cysts w watery turbid fluid]
o Apocrine metaplasia [big, juicy cells = big & pink] large
polygonal cells
PROLIFERATIVE component = risk of breast cancer!

34

Epithelial hyperplasia: >2 cell layers


**ATYPICAL Hyperplasia
Atypical Ductal Hyperplasia: some spaces are
round and regular; others more slit-shaped
Atypical Lobular Hyperplasia: monomorphic
round loosely cohesive cells fill some of lobules
Lobular Carcinoma in situ ALL ROUND! [All
lobules filled with cells; NO more slit-shaped]
o Ductal Papillomatosis - small papillary projections in ducts
o SCLEROSING ADENOSIS [[lots of gland proliferating in
very dense fibrous stroma]]
Mimics breast cancer
Firm consistency
Micro:
Sclerosing: fibrosis distorts the proliferating
epthelium
Adenosis: proliferation of small ductules
and acini; lined by epithelial and
myoepithelial cells
To DDX from invasive cancer, do muscle stain
bc still contains myoepithelial layer
o Present? Sclerosing adenosis
o Not present? cancer
MC site: upper outer quadrant of breast [[MC site for almost all lesions
of breast]]
Bc contains MOST amount of breast tissue & bc of TAIL OF
SPENCE goes all the way into axilla
NO risk of breast cancer
[[non-proife changes]]
Slight risk [1.5-2x]
Mod to florid hyperplasia w.o atypia
Ductal papillimatosis
Sclerosing adenosis
SIGNIF risk [5x]
ATYPICAL ductal or lobular hyperplasia
RADIAL SCAR: COMPLEX SCLEROSING LESION
in center, looks like cancer!!
XRAY: irregular density
Gross: firm fibrotic scar
Micro: [[can DDX from cancer]]
Central nidus of small tubules trapped in densely fibrotic
stroma
Surrounded by radiating arms of epithelium w cysts and
hyperplasia
FIBROADENOMA:
MC BENIGN TUMOR IN BREAST IN WOMEN <30YO!
estrogen may play role in devt
Enlarge late in menstrual cycle and during pregnancy
Regress and calcify after menopause
SOLITARY, FIRM, RUBBERY, MOBILE MASS [[breast mouse]]
XRAY: heavy coarse calcifications [[POPCORN]]
o
o

35

Micro: well-circumscribed; proliferation of fibrosis and ducts [[more so


fibrosis therefore more of a stromal tumor than ductal tumor]]
Benign biphasic tumor
Epithelial component
Neoplastic fibroplastic stroma
Fibroadenomatosis: multifocal disease is assoc w CYCLOSPORIN A
used for kidney transplants
Malignant version: PHYLLODES TUMOR [[aka Cystosarcoma
Phyllodes]]
o Technically malignant but usually behaves in Benign
fashion
o Arise de novo rather from fibroadenomas
o Usually benign biphasic tumor
Epithelial component
Abundant cellular neoplastic fibroblastic
stroma form leaf-like structures [[phyllodes =
leaf-like in Greek]]
o Sign of malignany:
Inc stromal cellularity
Anaplasia
High mitotic count
Infiltrative margins
May recur and rarely mestastasize
o Affects mostly older, peri- or postmenopausal women
o Similar to leiomyosarcoma
INTRADUCTAL PAPILLOMA:
BENIGN BUT SCARY papillary growth INSIDE ducts!
Unilateral bloody nipple discharge
Usually occurs in lactiferous ducts or sinuses under nipple
C/F: serous or bloody nipple discharge; small subareolar tumor
Micro: papillae w a fibrovascular stalks within large ducts; lined by
myoepithelial and epithelial cells
Tends to occur in younger, premenopausal women [[30-40s]]
If >50yo, Invasive ductal cancer causing bloody nipple
discharge!!
**BREAST CANCER**:
MC cancer in women [lifetime risk: 1 in 8 women]
2nd MC cause of cancer of deaths in women [[LUNG is #1 for men and
women]]
R/F:
Female gender [[#1 R/F!!]]
Age: risk w age
Family hx of breast cancer in 1st degree relative
US >> Asia or Africa
MC in white women, but early and more aggressive in blacks and
Hispanics
Prolonged exposure to estrogen
o Hormone replacement therapy
o Early age of menarche
o Late menopause
o Nulliparity

36

Obesity
Estrogen prod ovarian tumors [[i.e. granulosa cell
tumors]]
Ionizing radiation
Genetics:
**Overexpression of HER2-neu** [[Her 2 new]
o Human Epidermal growth factor receptor 2 neuronal
Tyrosine-kinase receptor!!
Gene Erb-B2 AMPLIFICATION!!!
Amplification of RAS and MYC genes
Mut in RB and p53
Hereditary breast cancer genes BRCA1/BRCA2 [[5-10% of
cases]]
SERM: selective estrogen receptor modulators block
estrogen receptors if cancer d/t overexpression of these
HERCEPTIN: monoclonal Ab intercepts HER2-neu
o On exam: TRASTUZUMAB [[generic name]] [[2 Tits]]
C/F:
o MC in upper outer quadrant
o Small lesions [~1cm] detected my mammography [15%
LN metastasis]
o Larger lesions [2-3cm] prod firm palpable painless mass
[50% LN metastasis]
o Nipple retraction and dimpling of skin
o Adherent to pectoral muscles or chest wall
o Involvement of dermal lymphatics: inflammatory breast
cancer
Peau dorange [orange peel appearance]
Poor prognosis
o Lymphatic spread:
upper outer quadrant axillary LN
medial quadrants internal mammary artery LN
o Distant spread to lungs, bone, liver, adrenal, brain
o Prognosis:
Tumor invasion and size
Extent of LN involvement
Distant metastasis
Histo grade
Histo type
Receptor status: ER/PR, HER2-neu
NONINVASIVE IN SITU CARCINOMA:
Ductal carcinoma in situ [DCIS]
o Usually detected by calcifications on mammography
o Rarely prod a palpable mass or mass on radiography
o Excellent prognosis: 97% long term survival
o **Comedo subtype**: high grade nuclei w central
necrosis
o TX:
Eradication w surgery and radiation
Antiestrogenic agents [tamoxifen and aromatase]
may risk of recurrence
o
o

37

Lobular carcinoma in situ [LCIS]


Usually detected incidentally
Rarely prod calcifications, palpable mass, or mass on
radiography
o Risk of invasive carcinoma may occur in EITHER
breast!!
Progesterone
Her2-neu
Estrogen receptor
receptor
overexpression
o
o
o

Molecular subtypes
Luminal A [[GOOD]]

Luminal B Triple +

Her2-neu

Basal-like Triple
[BRCA1/2] [[BAD
cant do SHIT!]]

- [tamoxifen]
+ [tamoxifen

+ tratuzumab]

[tratuzumab]

[N/A]

Uniform monomorphic appearance w loosely


cohesive cells w the lobules

INVASIVE CARCINOMA: NO MYOEPITHELIAL LAYER!!


Invasive Ductal Carcinoma:
o White color bc lots of desmoplasia/fibrosis good bc can
feel it!
o Desmoplastic response firm mass
o MC type [70-80%]
o Infiltrating glands w varying degrees of differentiation
**Invasive Lobular Carcinoma**:
o Accounts for ~20% of breast cancer
o May prod palpable mass or calcification
o May be clinically occult
o More freq BILATERAL & MULTIFOCAL
o Mut in E-cadherin loss of cellular cohesion [[why dont
stick together]]
o LCIS
o Micro:
Assoc w adjacent LCIS in 2/3 cases
Cells identical to LCIS
Tumor cells invade stroma in single-file
pattern
See some signet ring cells, too!
o Receptor status:
Most are ERPR positive
HER2-neu overexpression is rare
o Pattern of spread:

38

More freq spread to CSF, serosal surface, GIT,


ovary, uterus, bone marrow
Medullary carcinoma:
o Accounts for ~1% of breast cancer
o May be confused w fibroadenoma bc of being wellcircumscribed
o Occur w INC freq w BRCA1 mut
o Micro:
Sheets of large anaplastic cells w wellcircumscribed pushing borders
Surrounded by a dense lymphoplasmacytic
infiltrate
o Receptor status: Triple Negative
Most are ER/PR negative
Her2-neu overexpression is rare
Colloid [Mucinous] carcinoma:
o May be confused w fibroadenoma of being wellcircumscribed
o Soft gelatinous mass
o Micro: cluster of tumor cells within pools of
extracellular mucin
o Receptor status:
Most ER/PR+
Her2-neu overexpression rare
Tubular carcinoma:
o Small tumors found on mammographic screening
o Infiltrating well-formed glands w low grade nuclei
o ER/PR +; HER2-neu overexpression rare
o LN metastasis rare EXCELLENT prognosis
Inflammatory carcinoma:
o Involvement of dermal lymphatics therefore also in
axillary nodes
o Nipple retraction and dimpling of skin
o Peau dorange appearance: small pin size holes are
attachment sites for Kuper-suspensory ligaments [[sp?]]
o Poor prognosis
Pagets disease [of the nipple]:
o Inflamed red oozing crusted nipple that does NOT get
better w Abx!
o Assoc w underlying DCIS or invasive tumor in almost
all cases
o C/F: fissuring, ulcerated oozing skin; resembles eczema
o Micro:
In situ carcinoma
Intraepidermal spread
May be + for mucin [PAS]
Cytokeratin CK7+; S100+; HMB45+
Just s100+ & HMB45+ = Melanoma
o Prognosis: depends on underlying tumor

MALE REPRO:
o MALE BREAST:

39

GYNECOMASTIA: enlargement of male breast d/t relative excess of


estrogens
d/t:
o cirrhosis: inability to metabolize estrogen
o klinefelters syndrome
o anabolic steroids
o physiologic: puberty and extreme old age
o paraneoplastic: lung, kidney, choriocarcinoma, leydig cell
tumor
C/F: unilateral or bilateral button or disc like subareolar
swelling
o In 13yof normal puberty; the breast bud
Micro:
o INC connective tissue
o Epithelial hyperplasia of ducts
o Proliferation of ducts w.o lobules
CARCINOMA:
Rare in men <1%
Rapidly invades overlying skin and underlying thoracic wall
Most have spread to regional LNs or distal sites at dx
INC risk in familial mut of BRCA2 & Klinefelters
Congenital malformations:
Epi-, hypospadias
Inflammatory conditions
Balanitis = inflamm of glans penis
Balanoposthitis = inflamm of prepuce
R/F: poor hygiene in uncircumscribed males leads to
accumulation of smegna = desquamated epithelial cells, sweat,
debris
Common organisms: candida, anaerobic bacteria, garnerella
Complic: scarring may lead to Phimosis = prepuce cannot be
retracted easily over the glans penis
Peyronies disease:
Fibrosis of penis leading to painful curved erections
May be assoc w fibrosis in other areas such as foot or hand
[Dupuytrens contracture]
Assoc w phenytoin [Dylantin] seizure Rx
Condylomata acuminata:
Warty lesion occurring on anogenital region
HPV types 6&11
HPV viral effect = koilocytosis = perinuclear cytoplasmic
vacuolization and wrinkled nuclear contours
Low risk of malignant transformation
Tumors!!
Penile cancer:
Much MC in developing countries
MC in UNcircumsized males >40yo
R/F: poor hygiene [carcinogens in smegma]; smoking; HPV
16&18
Precursor: SCC in situ

o
o

40

White plaque on shaft of penis or scrotum [Bowmens


disease]
o Red plaques on glans or foreskin [Erythroplasia of
Queyrat]
o Malignant cells w.o invasion
o Progression to invasion in 10%
Invasive SCC:
MC on glans penis or prepuce
Often ulcerated, indurated mass
Metastasis to inguinal nodes prognosis
Verrous carcinoma:
Variant of SCC
Scrotum:
Scrotal Cancer:
o SCC
o 1st human malignancy assoc w environmental exposure
o Sir Percival Pott noted SCC in English chimney sweeps
Scrotal Enlargement:
o 1st thing to do, shine light through it if transilluminates?
Benign!
o Hydrocele:
MCC of scrotal enlargement
Accumulation of serous fluid in tunica vaginalis
d/t patent process vaginalis
Will transilluminate
o Varicocele:
Dilated veins of pampiniform venous plexus of
scrotum
Feels like bag of worms
Dragging sensation, feeling of heaviness,
infertility
Will NOT transilluminate, therefore do Ultrasound!
o Spermatocele:
Painless cystic mass at head of epididymis that
contains spermatozoa
Will transilluminate
o Elephantiasis:
Filariasis d/t lymphatic obstruction
Epididymitis:
Pain in upper back of testes w scrotal redness and warmth
Cremasteric reflex present
d/t:
o <35yo and sexually active: chlamydia, Neisseria
o >35yo: e. coli
micro: neutrophil infiltrate
may 2ly involve testes [orchitis]
other:
o TB may also cause epididymitis and orchitis
o Granulomatous inflamm w caseous necrosis
Mumps orchitis:
o

41

Adult males ~20% develop orchitis


Micro: edematous testes w lymphoplasmacytc infiltrate
Severe cases may cause sterility [unusual bc usually
unilateral]
Testicular torsion:
Twisting of spermatic cord casues venous compression
Intense engorgement of testes leading to infarction
Risk: bell clapper abnormality testicular mobility
C/F:
o MC in adolescents
o Sudden onset of testicular pain
o Firm swollen elevated testicle
o **Loss of cremasteric reflex** [on P/E]
Duplex ultrasound
Tx:
o Urological emergency: must be untwisted within 6hrs to
maintain viability
o How? Manual detorsion open book technique medial
to lateral
o If manual detorsion fails Surgical exploration [gold
standard]
o Once untwisted tie it down [orchiopexy: surgery to
move an undescended testicle into the scrotum and
permanently fix it there]
Cryptorchidism:
Failure of testicular descent into the scrotum
Affects 1% of males
~10% bilateral
undescended testes become atrophic leading to sterility
Micro:
o Tubular atrophy proceeding to hyalinization
o Foci of intratubular germ cell neoplasia may be present
INC risk [3-5x] of testicular cancer in either testes
Orchiopexy before puberty likelihood of atrophy, sterility and
cancer
TESTICULAR TUMORS:
MC ages 15-35yo
Whites > blacks
~10% bilateral
R/F:
o Cryptorchidism
o Intersex syndromes [androgen insensitivity syndrome,
testicular dysgenesis]
o Family hx of testicular cancer
Precursor: intratubular germ cell neoplasia
ALL TESTICULAR GERM CELL TUMORS HAVE AN
ISOCHROMOSOME OF SHORT ARM OF CHR 12!!
C/F:
o MCC of painless testicular enlargement [[large bulky
masses]]
o
o
o

42

Painful enlarging testes = infection


o Will NOT transilluminate bc SOLID mass in testes, then to
dx do Ultrasound
**NEVER BIOPSY TESTES IF WORRIED ABOUT CANCER!! Bc
will cause spread of cancer!**
Tumor marker assays
o LDH [nonspecific marker of cell death] correlates w tumor
burden
Higher it is, the more tumor present
Measure BEFORE & AFTER surgery
o *Seminoma: placental alkaline phosphatase
[PLALP]
~10% have beta-hCG
o *Choriocarcinoma: Beta-hCG
Can get gynecomastia!!
o *Yolk sac carcinoma: alpha-fetoprotein
o Teratoma: [[NO MARKER]] In women, benign//in men,
can be malignant
TX: radical orchiectomy
**SEMINOMA**:
o MC germ cell tumor [[15-35yo]]
o Gross:
Large bulky mass
Well-circumscribed
Areas of necrosis may be seen
o Micro:
Large uniform cells w clear glycogen-rich
cytoplasm
CLEAR CELL CARCINOMA [CCC]
Round nuclei and nucleoli
Lymphocytic infiltrate
May have granulomatous rxn and
syncytiotrophoblasts [in ~10% - beta-hCG]
o Radiosensitive/chemo-sensitive
o Often stays confined to the testes for long periods of time
o Excellent prognosis
o Spermatocytic seminomas:
Older men >65yo
Same just in older guys
EMBRYONAL CARCINOMA:
o WORSE!!! More aggressive!!
o Gross:
Ill-defined invasive mass w hemorrhage and
necrosis
Micro:
Large primitive cells w basophilic cytoplasm
Large nuclei and prominent nucleoli
May form sheets or primitive glands
May have other components mixed in
o Markers: AFP or b-hCG

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**YOLK SAC TUMOR**: [aka ENDODERMAL SINUS TUMOR]


o MC germ cell tumor in kids <3yo [[YOLK SAC = YOUNG]]
Kids do well
Adults often have other components mixed w it
o Gross: large well demarcated mass
o Micro:
Low cuboidal to columnar epithelial cells
Forms microcysts, reticular patterns, sheets,
glands, and papillae
**Schiller-Duvall bodies**: resemble primitive
glomeruli
Eosinophilic hyaline globules composed of AFP or
A1-AT may be seen
o Serum tumor marker = AFP+
CHORIOCARCINOMA***: NO grapes!
o Most malignant germ cell tumor [highly] of JUST
trophoblasts [NO VILLI]
NO uterine enlargement, NO grapes
See hemorrhage and necrosis
o Early spread by hematogenous routes therefore goes to
lungs, liver, bone, brain, skin, etc.
o B-hCG is typically
o 2 forms:
Gestational:
most of time after complete mole
after spontaneous abortion
after normal preg [rare]
~100% cure rate with chemo!!
o Highly responsive to Chemo
o Tumor is mom, dad foreign Ags
therefore immune system kicks in to
fight dads foreign Ags
o GOOD PROGNOSIS!
Gonadal:
from germ cells of ovary/testes
POOR PROGNOSIS
o Responsive to chemo
o NO immune response be NO foreign
Ags
Testes: good dx test = +preg test
TERATOMAS [scrambled baby]: aka Dermoid Cyst
o Dx: ultrasound of ovary bc dont want to radiate gonads
o In women, ~90% BENIGN; in men ALMOST ALL
MALIGNANT [until proven otherwise]
o Occur in young women [1st 2 decades of life]
o MC germ cell tumor
o BENIGN [MATURE] CYSTIC TERATOMAS
Presence of mature tissue from all 3 germ layers:
ectoderm, endoderm, mesoderm
Gross: Cysts containing sebaceous secretions,
hair, and teeth

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C/F: infertility; ovarian torsion,


LIMBIC ENCEPHALITIS: paraneoplastic
syndrome w teratormas containing mature
neural tissue
o Inflamm of limbic system
o Subacute onset [<12wks] of seizures,
short term memory loss, confusion,
and psychiatric
o Anti-NMDAR = teratomas
containing mature neural tissue
o Anti-Ma2 = germ cell tumors of
testes
o Anti-Hu = small cell carcinoma of
lung
o SPECIALIZED TERATOMA: STRUMA OVARII
Composed almost completely of mature thyroid
tissue
May cause hyperthyroidism [[w NO goiter]]
Unilateral solid brown mass
o MALIGNANT [IMMATURE] TERATOMA
HIGHER RISK OF CANCERS!!
Gross: bulky solid mass w areas of necrosis
Micro: presence of immature elements; foci of
neuroepithelial differentiation [may be
aggressive and metastasize widely]
PROSTATE:
o BPH: BENIGN PROSTATIC HYPERPLASIA
Gross:
Enlarged prostate w many well circumscribed
nodules
Typically occurs in inner transitional zone
Urethra may be compressed into a slit-shape
If see nodule in peripheral zone = cancer
DHT is R/F for enlarged prostate
C/F:
Freq urination
Feeling of never fully emptying bladder
Micro:
Hyperplastic nodules containing proliferation
glands and fibromuscular stroma
Glands are dilated and have papillary
infolding
Glands are lined by tall columnar
epithelial cells w basal cell layer
Corpora amylacea: inspissated proteinaceous
material within gland lumens
Tx:
5-alpha-reductase inhibitors: Finesteride
inhibit DHT formation
alpha-adrenergic receptor blockers [relax
smooth muscle]

45

surgery transurethral resection of prostate


[TURP]
PROSTATE CANCER:
MC form of cancer in Men >50yo
GENE: PTEN mut
Hard to see, but easy to feel
Comes form peripheral zone usually posterior
peripheral zone
Precursor: high grade prostatic intraepithelial
neoplasia [PIN]
Micro:
Smaller crowded glands
Lack branching and papillary infolding
Lined by single layer
Lack basal cell layer!!
Enlarged nuclei and nucleoli
GLEASON GRADING SYSTEM:
Grade 1-5 based on differentiation
o 1 = good // 5 = bad
Add 2 most dominant patterns together to
get Gleason score
Will be # btwn 2-10
o Higher the #, the worst prognosis!!
Grows around nerves
C/F:
Often Asx: detected as firm ndule on DRE &
elevated PSA
May present as lower back pain:
osteoblastic metastasis can be seen on
radionucleotide bone scans; elevated ALP
Prostatic specific Ag [PSA]:
Organ specific but not cancer specific
May be elevated with BPH, prostatitis,
prostate infarcts, instrumentation and
ejaculation
Product of prostatic epithelium secreted in
semen
Local invasion
Advanced cancers may invade seminal
vesicles or thru capsule into bladder/rectum
Periurethral zone involvement may prod
urinary obstruction
TX:
Local: prostatectomy or radiation or active
surveillance
Metastatic: androgen deprivation [palliative,
not curative]
o Orchiectomy or luteinzing hormone
[LH]
o LUPRON + Flutamide

46

When first give Lupron, LH first


INC then DEC
To block initial INC, block it with
Flutamide

47