Disease

What is it?

Renal Agenesis

Completely missing
renal tissue

Horseshoe
Kidney

Kidneys don't separate Developmental issue

at lower poles during
dev, so ascension is
stopped by inferior
mesenteric artery.
Located in the pelvis
Developmental issue

Ectopic Kidney

What causes it?

(Pathogenesis)
Developmental issue

Intrinsic/Acquire Morphology/Pathology
d?
Intrinsic
Unilateral (usually
asympomatic) or Bilateral

Intrinsic

???

Intrinsic

Uni or Bilat;

Autosomal
Bilaterally enlarged
Dominant
multicystic kidneys
(adult)
with renal failure
Polycystic
happening in adult
Kidney Disease life
(ADPKD)

- cilia-centrosome complex Intrinsic

of tubular epi cells
(Congenital)
Autosomal Dominant
- 85% muts in polycystic kidney
disease gene PKD1, 15% in
PKD2
- Gene products polycystin-1
and polycystin-2 are in
primary cilia of tubular epi cells
- Cysts show up in segments or
tubules but are disconnected in
tubules

Autosomal
Cystic
Recessive
transformation of
(childhood)
collecting ducts in
Polycystic
infants; renal failure
Kidney Disease in infancy (75% die
(ARPKD)
in perinatal period
due to pulm
hypoplasia caused
by oligohydramnios
(low in amniotic
fluid)

mutation in PKHD1 gene

leading to its product,
fibrocystin, to be defective.
Mutation also leads to
pancreatic cysts, hepatic
biliary dysgenesis, fibrosis
- cilia-centrosome complex
of tubular epi cells
Autosomal Recessive

Intrinsic
(Congenital)

Glomeruloneph Inflammation due to

ritis
deposition of
immune complexes
or antibodies
reacting in situ
within glomeruli

Acute
Ex. of Proliferative Occurs after infection with Extrinsic
Poststreptococ glomerulonephritis, group A (B-hemolytic) strep.
cal
nephritic syndrome. Latent period 9-14 days
Glomeruloneph Acute Proliferative after infection. Immune
ritis
glomneph Caused by complexes depo'd from
deposition of
circulation or form in situ as
immune complexes bacterial Ag trapped in
in glomeruli
glom blind circulating
antibodies. Initiate inf by
activating complement, recruit
of leukocytes, other humoral
and cellular inf mediators

Ex. of
Glomerulonephritis
with Necrosis.
Clinical entity with
features of nephritic
syndrome, rapid
loss of renal
function.
Severe glom injury
w/ necrosis, inf, GBM
break, prolif of
parietal epi
(crescents of
bowman's capsule)
AntiExample of RPGN.
- autoantibody against
Intrinsic
Glomerular
Aggressive form of component of GBM within
Basement
glomneph occurs as globular noncollagenous
Membrane
rate-limited disease domain of a-3 type of
(Type I)
or combined with
collagen IV
Crescentic
pulm hemorrhage
- reacts with both GBM and
Glomeruloneph (Goodpasture
pulm alv cap basement
ritis
syndrome)
membrane
- 1/2 pts - pulm
hemorr/hemoptysis
- Goodpasture Syndrome both lungs and kidneys
affected
-Injury may be mediated by
anti-GBM antibodies, anti-GBM
T cells, or both
-Genetic susceptibility to antiGBM diseases assoc w/ HLADR2 genes

Clinical
Misc.
Significance/Features
Uni - 1 in 800 live births,
opposite kidney is large
(compense hypertroph)
bilat - lethal, 1 in 5000
(Potter Syndr)
Might compress vena cava or
aorta and cause Urinary tract
obstruction
Prone to infection or
obstruction

-Each weighs 1000 g, up to - asymptomatic til 4th

4500 g (normal is 100-170 decade
g)
- Renal failure in
-Bilat enlargement (super
adulthood (4th decade)
large), lots of fluid filled
- Flank pain
cysts)
- Bilateral flank and
- surfaces irregular,
abdominal mass
covered with cysts of
Sense of heaviness in loins
varying sizes, up to 3-4 Intermittent gross hematuria
cm in dia, scant normal -Hypertension (75% pts)
parenchyma between
-UTI
cysts
- Azotemia (^ blood urea N2)
- cyst fluid is clear,
-> uremia (clinical renal
turbid, or hemorrhagic
failure) - 1/2 pts over several
- intervening
years
parenchyma subjected
to ischemic atrophy due
to cyst pressure
- asymptomatic liver
cysts = 1/3 of pts
-Bilateral
Serious manifestations
-External surface is
present at birth, may die
smooth
quickly from hepatic or renal
-Numerous small cysts in failure, pts who survive
cortex/medulla
infancy develop liver
-cysts are fusiform
cirrhosis (congenital
dilations of cortical and hepatic fibrosis)
medullary collecting
ducts, radial
arrangement, lined by
cuboidal epi cells
-interstitial fibrosis,
tubular atrophy common
-Liver affected by
congenital hepatic
fibrosis
Proliferation of endothelial, Nephritic Syndrome
mesangial and epithelial
- Hematuria (acute onset,
cells, glomerular necrosis
may be grossly visible),
proteinuria (mild to
moderate), Decreased glom
filtraton rate
-Elevated blood urea N2,
serum creatinine, oliguria
(scanty), salt and water
retention, hypoalbuminemia,
edema, hypertension
-Acute diffuse proliferative -90% kids recover with no
glomerulonephritis
complications
-Diffuse glomeruli
- Still one of most common
enlargement and
childhood renal diseases
hypercellularity
-Short lived Nephritic
-Proliferation of
syndrome begins abruptly
endothelial, mesangial
with oliguria, azotemia,
and parietal cells
hematuria, hypertension,
-Infiltration of
facial edema and proteinuria
neutr/monocytes
may persist for several
-Subepithelial dense
months. Eventually deposits
immune complex
clear over period of 2 months
deposits (isolated
humps, between outer
surface of the GBM and
the podocytes)
-Subendothelial deposits
in the mesangium,
between the endothelial
cells and the GBM
Early: coarsely, granular
deposits of IgG and C3
(immunofluorescence)
Later: deposits of C3

-1 in 400 to 1000
births
10% of cases of
CKD

-1 in 20000 live
births

Rapid
progressive
(Crescentic)
glomeruloneph
ritis

Acute Tubular
Necrosis
(Acute Renal
Injury)

Ex. of Diseases of
Renal Tubules

Ischemic Acute
Tubular Necrosis

Urinary Tract
Infection

-Ischemia
Acquired
-Toxic Injuries (Ethylene
glycol aka antifreeze,
mercuric chloride,
therapeutic drugs such as
gentamicin, chems such as
CCl4)
-Slough/necro of epi cells ->
cast form -> obstruction, ^
intraluminal pressure ->
reduced glom filtration. Afferent
arteriolar vasoconstriction.
Caused by tubuloglomerular
feedback -> decreased glom
cap filtratio pressure. Tubular
injury and ^ intraluminal
pressure cause fluid back
leakage from lumen into
interstitium
Reduced renal perfusion, assoc acquired
w/ hypoperf in pts w/
hypovolemic or endotoxemia
shock or circulatory collapse
owing to pump failure (e.g. MI)

-diagnosed clinically
and confirmed by
urinalysis showing
bac colonies in
excess of100K/mL,
presence of WBCs
-infection route
hematogenous or
ascending

- conditions predispose
acquired
ascending UTI: urinary
stones, congenital
megaureter, strictures,
pregnancy, tumors,
vesicoureteral sphincter
incompetence, chronic
cystitis, BPH, short urethra
in females, insertion of
catheter, instrumentationResults from bacteremic
spread. Most common is
ascending infection, combo
of urinary bladder infect,
vesicouretal reflux,
intrarenal reflux

Acute
Manifestation of UTI
Pyelonephritis Common suppurative
inflammation of
kidney, renal pelvis,
caused by bac infect

-Gram neg bacteria, E. coli, Acquired

Klebsiella, Enterobacter,
Proteus, Pseudomonas, and
Serratia etc
-Predisposing conditions. In
absence of instrumentation,
UTI most commonly affects
females, outflow obstruct,
bladder dysfunc, genetic
factors, vesicoureteral
reflux, intrarenal reflux, see
above

Kidney Stones

Urinary Tract Calculi

-risk factors: concentrated

Both possible
urine, hereditary, diet, assoc
diseases (sarcoidosis, inf bowl
disease, cancer)
Wilms Tumor
Malignant neoplasm -90% cases
Probs mostly
(Nephroblasto made of embryonal sporadic/unilateral
intrinsic
ma)
elements w/ mix of -10% cases assoc w/ defects
blastemal, stromal, of WT1, Wilms tumor gene
epi tissue.
located on chrom 11
(11p13)
- WT1 tumor suppressor
gene that regs transcription
of several other genes

Renal Cell
carcinoma

Most common
primary cancer of
kidney
- Malignant
neoplasm of renal
tubular or ductal epi
cells
-typically seen in
men btwn age 50
and 70

Tumors of
Urinary Bladder

Urinary Bladder - most

common site of urinary
tract tumors. Most
occur in older pts
(median age 65), rare
in ppl under 50s. More
in men than women
3:1. Most
microscopically
classified as urothelial
(transitional cell)
neoplasms).
Rare: squamcc,
adenocarcs, neuroendo
carcs, sarcomas
-Cancer ranges from -Cig smoking is most
Acquired
superficial papillary important risk factor
to deply invasive
- Industrial exposure to azo
-Can be anywhere
dyes
that has transitional -schistosomiasis
epithelium, often
-Drugs
multifocal
-Radiation therapy

Urothelial
Carcinoma
(Transitional
Cell
Carcinoma)

-most sporadic, all sporadic Both possible

cases assoc w/ loss of
heterozygosity of tumor
suppressor gene VHL on
chrom 3p
- Mut in VHL found >1/2 of
sporadic RCC tumors
-hereditory forms of RCC:
autosomal dom and VHL
disease assoc w/ chrom
transloc involving 3p, VHL
disease has mut in VHL
gene itself. Hereditary
papillary RCC has no assoc
w/ VHL gene

-kidneys enlarged, pale,

often petechial hemorrages
on cortical surface
- segmental necrosis,
GBM breaks
- prolif of parietal epi
cells, migrate
monocytes/macrophages
form crescents, fill
bowman's
- Strong diffuse linear
staining of GBM for IgG
and C3 with
immfluorescence. Depos
not seen under EM.
Distinct ruptures in GBM
- Crescents eventually
obliterate Bowman's
space, compress glom
-Fibrin strands
prominent btwn cell
layers in crescent
- In time crescents undergo
scarring,
glomeruloschlerosis devs

-10-20% of RPGN
- Presents with rapid
progressive renal fail,
nephritic signs/symptoms
-If untreated, pt dies from
renal fail within period of
weeks to months
- treatments include
immsuppressive therapy and
plasmapheresis (removes
pathogenic antibodies from
circ)
-renal transplant

-decreased GFR

Related to Acute
Kidney injury:
Various inj ->
direct damage
tubs, ->
decrease GFR by
multiple
mechanisms,
promotes
vasoconstriction.
Some injs that
cause tub injury
also directly dec
GFR by
decreasing renal
flow

-Tub inj is most prominent in -ATN, whether due to isch

straight portion of proximal or toxicity is leading cause
tubs and thick limbs of loop of acute renal failure
of Henle in outer medulla
-rapid rising serum creatinine
- prox tubs display focal
level, decreased urine output
flattening of epi, dilation of (oliguria)
lumen, loss of brush
-Oliguria reversible, tubules
bordern
regenerate
-proteinaceous casts in -Urinalysis shows degen
distal tubs, collecting
epi cells, 'dirty brown'
ducts (made of Tammgranular casts (tub prots
Horsfall protein normally and hemoglobin)
secrete in tub epi, along - Renal function can
w/ hemoglobin and other recover within weeks or
plasma prots
months if cause of injury
-Short segment necrosis.
removed
Absence of widespread
necrosis of tubular epi cells
-Indiv necro cells shed into
lumen, areas of denudation
of tubular basement
membrane
-Vasarecta of outer medulla
congested, freq contain
mononuclear leukocytes
- tub cells can regen

-Small white abscesses

on subcap surface and
cut surfaces
- Pelvic/calyceal urothelium
hyperemic, purulent
exudate
- lesions are often focal,
much of kidney appears
normal
-parenchyma, esp cortex
extensive focal
destruction by inf
process, vessels and
glomeruli preferentially
spared
- inf infilitrates - neutrs, fill
tubs and esp collecting
ducts
- severe cases - necrosis of
papillary tips may occur or
perinephric abscess may
form
-Obstruction -> pus filling
renal pelvis, calyces ad
ureter - pyonephrosis
Stones blcoking flow
everywhere

-Fever, Chills, sweats,

malaise, frequency,
dysuria, bacteriuria, flank
pain, leukocytosis and
neutrophilia common,
presence of leukocyte
casts in urine
(pathognomonic)

-Large tumor when

Presents btwn 1 and 3 yrs Most freq abdom
detected, bulging, pale age
solid tumor in
tan, cut surface enclosed -98% before age 10
kids, 1 in 10000
in thin rim of renal
-Palpable abdominal mass,
cortex and capsule
pain, intestinal
- contains stuff
obstruction, hypertension,
resembling normal fetal hematuria
tissue including
-Combine surgical, chemo,
metanephric blastema, radiation to favorable
immature stroma
prognosis
(mesenchymal tissue),
immature epi elements
-RCC has several variants
-Triad of presenting
-80% of all renal
-Clear cell RCC most
features: Hematuria
cancers, >30000
common type, arises
(single most common
cases in US
from proximal tubular
presenting sign), Flank
epi cells
Pain, Palpable Mass
-Yellow-orange mass,
- Freq source of ectopic
shows conspicuous focal hormone production,
hemorrhage and
assoc w/ fever and
necrosis
paraneoplastic symptoms
-tumors solid or focally -early hematogenous
cystic
dissemination freq
-clear cytoplasm of
-Tumor stage most
neoplastic cells reflects important prog factor
removal of abundant
-5 yr survival is 90% if
cytoplasmic lipids and
tumor has not extended
glycogen during tissue
beyond renal capusle
processing
-5 yr survival rate is 30%
-Tumor cells arranged in or less if distant
round or elongated
metastasis (most freq
collections demarcated lungs and bones)
by network of delicate
vessels
-little cellular or nuclear
pleomorphism
-most tumors malignant,
aggressive, prognosis varies,
dpending on clinical stage,
microscopic grade. Tumors
often multifocal and occur in
any part of urinary tract lined
by transitional epithelium.
Surgical treatment often
followed by recurrence

-staged according to
TNM class
-Varies from small,
delicate, low grade
papillary lesions limited
to mucosal surface or
larger, highergrade solid
invasive masses, often
ulcerated.
-Papillary and exophytic
cancers tend to be
better differentiated;
infiltrating tumors
usually more anaplastic

-Sudden hematuria
-Dysuria
- initial presentation - 85%
confined in urinary
bladder, 15% already
metastasized
-Papillary lesions limited
to mucosa or lamina
propria commonly treated
by transurethral resection
-Radical cystectomy done
with tumors showing
muscle invasion and
occasionally for advanced

Disease

What is it?

What causes it?

Intrinsic/Acquire Morphology/Pathology
(Pathogenesis)
d?
Hyperthyroidis Thyrotoxicosis - Hyperfunction of thyroid
Intrinsic
Clinical Features 1
m in general
hypermetabolic gland. Alternatively,
-skin - soft, warm, flush; heat
state due to
excessive release of
intolerance/excess sweating
too much T3/T4 preformed thyroid
common
hormones or extra-thyroid
- weight loss even though
source
more hungry
- GI - hypermobility,
malabsorption, diarrhea
-Cardiac - Palpitations, tachy
- Elderly may -> CHF because
of aggravating preexisting
heart cond
- Neuromusc - nervous,
tremor, irritable. 50% dev
proximal muscle weakness
(thyroid myopathy)

Hypothyroidism Not enough

in general
thyroid
hormone

Any structural or
functional problem that
interferes with production
of adequate thyroid
hormone levels
- Defective thyroid
hormone synth (goitrous
hypothyroidism)
- Inadequate thyroid
parenchyma function
(thyroiditis)
- Inadequate secretion of
TSH by pituitary or TRH by
hypothalamus
dietary iodine deficiency
Acquired
(endemic in such areas)

Cretinism

Hypothyroidism
developing in
infancy or early
childhood

Myxedema

Hypothyroidism
developing in
older children
and adults

Chronic
Lymphocytic
Thyroiditis
(Hashimoto
Thyroiditis)

Example of
Autoimmune disease with
Hypothyroidism gradual destruction,
- most common failure of thyroid gland.
cause of
Sensitized CD4+ helper T
goitrous
cells to thyroid Ag ->
hypothyroidism delayed type
in areas of
hypersensitivity reaction
world where
(tissue destruction from
iodine levels
toxic products of inf cells,
sufficient
T-cell mediated cell death)
or stimulates cytotoxic Tcell responses , helper B
cells -> auto antibody
secreting plasma cells

Intrinsic - occurs
with increased
freq in 1st degree
relatives, but
more prevalent in
regions with
greatest intake of
iodine

Diffuse and
Multinodular
Goiter

Hypothyroidism Dietary iodine deficiency. Acquired

without
Low TH levels lead to
inflammation
compensatory rise in
not caused by serum TSH -> hypertrophy
neoplasm and hyperplasia of thyroid
inadequate
folicular cells and
synthesis of
enlargement of gland
thyroid
Pts mostly normal thyroid
hormone.
function, some hypothyroid.
Endemic goiter - affects >10%
pop, low iodine (areas of
glaciation)
sporadic goiter - most causes
unknown
- toxic goiter - hormonally
active, causes thyrotoxicosis
Graves Disease Most common Autoimmune disease
Acquired
form of
mediated by antibodies to
hyperthyroidis thyroid stimulating hormone
m. 1)
(TSH) receptors. Antibodies
thyrotoxicosis bound to TSH receptors
2)
stimulate thyroid cells to
ophthalmopath synth T4, thyroxine
y
-Smoking increases risk
3) dermopathy

Thyroid Adenoma -Solitary, benign

clonal neoplasm
showing follicular
differentiation.
Most
nonfunctional,
some toxic
adenomas that
cause
thyrotoxicosis.

Carcinomas of the Derived from

Thyroid
Thyroid Follicular
Epi
- Papillary carcs
(>85%)
-Follicular carcs
(5-15%)
-Anaplastic carc
(<5%)
Derived from
parafollicular C
cells
-Medullary carc
(5%)
Papillary
Ex. of Thyroid
Thyroid
Cancer
Carcinoma
Most common
thyroid cancer
and accounts
for up to 90%
of sporadic
cases of
thyroid cancer
in US

Hyperparathyro
idism

-Activation of MAP kinase

pathway feat of most papillary
carcs
- somatic muts rearrangement of RET protooncogene on chrom 10
(10q11.2) common
-Iodine excess
-Radiation
-Genetic factors - 4 to 10 fold
higher in first degree relatives
of pts

Primary
hyperparathyroidism
char'd by spontaneous
hypersecretion of
parathyroid hormone
(PTH)
- Solid parathyroid
adenoma in 85% of cases
-Primary hyperplasia of all
four parathyroid glands in
5-10% of cases
- Parathyroid carcinoma
seen in 1% of caes, char'd
by invasive growth and
metastases

Hypercortisolis Example of
- exogenous m (Cushing
Adrenocortical administration of
Syndrome)
Hyperfunction exogenous steroids
- Endogenous - primary
adrenocortical
hyperplasia,
adrenocortical neoplasia,
Adrenocorticotropic
hormone (ACTH)-secreting
pituitary adenomas
(Cushing disease), Ectopic
ACTH-secreting nonendocrine neoplasms (e.g.
small cell carcinoma of
lungs)

Chronic
Adrenocortical
Insufficiency
(Addison
Disease)

Example of
adrenal
hypofunction
- Deficient
production of
adrenal cortical
hormone
- Fatal wasting
disorder

can result from 1) adrenal Acquired

gland destruction, 2)
pituitary or hypothalamic
dysfunction w/ decreased
ACTH production, 3)
chronic corticosteroid
therapy
-Failure of adrenals to
produce glucocorticoids,
mineralocorticoids,
androgens.
- >90% due to four
disorders - autoimmune
adrenalitis, Tuberculosis,
AIDS, metastatic canc

Pheochromocyt Neoplastic
-most sporadic
Most acquired,
oma
disorder of
- small amount inherited
some intrinsic
adrenal
alone or part of hereditary
medulla
syndromes suchas MEN
types 2A and 2B, VHL
Catecholamine disease, neurofibromatosis
secreting
type 1 (NF1), RET, etc.
tumors of
- Can be part of multiple
chromaffin cells endocrine neoplasia
of adrenal
syndrome (MEN)
medulla
- Presenting
symptoms
reflect
sustained or
episodic
hypertension
-Pallor, anxiety,
cardiac
arrhytmias
Hyperpituitaris Excessive
-Most common cause is
m
secretion of
adenoma arising in
trophic
anterior lobe.
hormones
Pituitary
Class'd on basis - Most single cell type, one
Adenomas
of hormones
predom hormone
produced in
- most common adenoma
neoplastic cells secretes more than one
-Can be
hormone, one secretes
functional,
both growth hormone,
assoc w/
prolactin
hormonal
excess, clinical
manifest
-can be silent,
w/o clinical
manifest of
hormonal
excess (30%)

Prolactinomas

-Most common
type of
hyperfunctionin
g pituitary
adenomas (50%
of cases)

Growth
HormoneProducing
Adenomas

Somatotroph
-Persistent hypersecretion of
adenomas - incl GH stimulates hepatic
those that
secretion of insulin-like growth
produce mix of factor I (somatomedin C)
growth
hormone and
other hormones
(e.g. prolactin)
- 2nd most
common type
of functional
pituitary
adenoma)

Adrenocorticotr
opic HormoneProducing
Adenomas

Most
microadenomas
. Accumulation
of ACTHcontaining
granules in
cells

Hypopituitarism Not enough

secretion of
one or more

-Pituitary tumors (>1/2

hypopituitarism in adults),
may be functional or

-Gland diffusely enlarged, firm

(60-200 g)
- Cut surface pale tan, flashy,
vaguely nodular pattern
- Capsule intact
-Parathyroid not affected
Conspicuous mononuclear
infiltration of lymphocytes,
plasma cells
-Destroyed, atrophy of follicles
-Acidophilic metaplasia of
follicular epi cells (Hurthle or
oxyphil cells)
-Lymphoid follicles, often
germinal centers, present)

Clinical Significance/Features Misc.

Clinical Features 2
-Ocular - wide, staring gaze,
lid lag present b/c of
sympathetic overstimulation
of levator palpebrae
superioris muscle
- Thyroid storm - abrupt onset
of severe hyperthyroidism,
probs due to acute elevation
in catecholamine levels,
might be encountered during
stress. MEDICAL EMERGENCY.
can die of cardiac arrhythmia
- Diagnosis based on clinical
feats, lab data. TSH levels
most useful single screening
test bc TSH levels decreased
in earliest stage when
diseases is subclinical
- Diagnosis - Measurement of
serum TSH. TSH increased in
primary hypothyroidism, not
increased in persons with
condition caused by primary
hypothalamic or pituitary
disease. Serum T4 decreased
in individuals with
hypothyroidism of any origin

Impaired skeletal +CNS dev,

severe mental retardation, short
stature, coarse facial features,
protruding tongue, umbilical
hernia
-generalized apathy and mental
sluggishness
-listless, cold intolerant, often
obese
-mucopolysaccharide rich edema
builds up in skin, subcut. Tissue,
visceral areas, so broader,
coarser facial features, larger
tongue, deeper voice
- Constipation from decreased
bowel motility
- pericardial effusions common,
later stages, heart enlarged,
heart failure supervenes
- painless enlargement of thyroid
assoc w/ hypothyroidism, devs
slow
- sometimes preceded by
transient thyrotoxicosis
caused by disruption of
follicles w/ 2ndry release of
thyroid hormones. Free T3/T4
elevated, TSH diminished,
radioactive iodine uptake
decr.
-progressing hypothyroidism
-> T3 T4 progressively falls,
TSH rises
- often other autoimm diseases,
^ risk of dev of B-cell nonHodgkin lymphoma
- Thyroid hormone given to
alleviate hypothyroidism,
decrease gland size

'salary'

- common manifestations with

thyrotoxicosis
-diffuse hyperplasia of thyroid,
ophthalmopathy, dermopathy
-Diffuse enlargement of gland
- Sympathetic overactivity ->
wide, staring gaze, lid lag
- skin lesions slightly pigmented
papules or nodules, orange-peel
texture
-Elevated serum free T4/T3,
decrease TSH
- Radioactive iodine uptake
increased, diffused uptake image

Women affected
7 times more
often than men.
Peak incidence
20-40 yrs. Seen
in 1.5-2% of
women in US.

-Most take up radioactive iodine

less avidly than normal thyroid
parenc, 'cold nodules', but toxic
ones (active) are 'warm' or 'hot'
-10% 'cold' eventually malignant.
Most 'hot' practically never

- definitive diag
only after careful
histologic exam
of resected spec
-excellent
prognosis, no
recurrence or
metastasizing

most prevalent
btwn 45 & 54 yrs
old.
Women
predominant
over men 10:1
Found in older
women, major
cause of
nonenedemic
goiter in kids

Diffuse - diffuse, symmetric,

enlargement of gland. Follicles
lined by crowded columnar cells,
pile up and form projections.
If dietary iodine increased or
demands for hormone decreased,
follicular epi involutes to form an
enlarged colloid rich gland
(colloid goiter)
Multinodular - recurrent episodes
of hyperplasia, involution
combine to produce irrelgular
enlargement of gland

-Thyroid enlarged symmetrically,

35-100g
-Hyperplastic folicular epi, highly
vasc
-Epi cells tall, columnar, arranged
as papillae that project into
lumen of follicles. No fibrous
cores.
- Colloid appears scalloped
- lymphoid infiltrates, most T,
some B & plasma, germinal
centers common
-Exophthalamos caused by
enlargement of orbital
extraocular muscles swollen by
mucinous edema, accumulation
of fibroblasts, lymphocyte
infiltration. Proptosis - increased
orbital contents displace eye
forward
- Dermopathy - dermis thickening
due to glycosaminoglycans,
lymphocyte infiltrate
-Usually solitary, circumscribed
nodule 1-3 cm in dia, protrudes
from surface of thyroid,
surrounded completely by welldefined, fibrous capsule,
compresses adjacent nonneoplastic thyroid
-Hemorrhage, fibrosis, cystic
changes common
-neoplastic cells demarcated from
adjacent parenc by well-defined
capsule
-neo cells arranged in uniform
follicles that contain colloid
-Follicular growth pattern in
adenoma distinct from adjacent
non-neoplastic thyroid
-neo cells uniform, well-defined
borders
-papillary changes not typical of
adenoma
- Hurthle cell adenoma w/
oxyphils behaves like adenoma
-Hallmark - presence of intact
well-formed caps around tumor

- May present solitary or

(Pathology Continued)
Most freq btwn
multifocal lesion in thyroid
-Invagination of cytoplasm -> ages 20 and 50
-Can be well circumscribed,
looks like intranuclear
yrs, fem to male
encapsulated or can infiltrate inclusions in cross sections,
ratio 3:1
adjacent parench w/ ill'pseudo-inclusions'
defined margins
- Papillary architecture
-May contain areas of fibrosis, present in many cases
calcification, and cystic
- neoplastic papillae do have
-Diag of papillary carc based dense fibrovasc cores
on nuclear features even in
-Psammoma bodies
absence of papillary
concentricalkly calcified
architecture
structs often present within
-Nuclei of papillary carc cells papillae
contain very finely dispersed -Metastases to adjacent
chromatin, imparts optically cervical lymph nodes
clear appearance, designation estimated to occur in about
'ground glass' or 'Orphan
half cases
Annie eye' nuclei
-Survival rate ~85% at 20 yrs
-Secondary hyperparathyroidism Most common manifestation
- Diffuse enlargement of all four of primary
glands in response to
hyperparathyroidism increase
hypocalcemia such as seen in
in serum ionized Ca
end-stage renal disease,
-Primary hyperthyroidism
malabsorption syndromes, Vit D most common cause of
deficiency
clinically silent hypercalcemia
-Tertiary hyperparathyroidism
-PTH elevated
-Diffuse enlargement of all four
-Hypophosphatemia
glands. Autonomous
- Demineralization of bone
hypersecretion of PTH follows
results in bone softening,
secondary hyperparathyroidsm, painful fractures (osteitis
persists even after cause of
cystica fibrosa in primary,
hyperplasia eliminated
renal osteodystrophy in 2ndry
hyperparathyr)
- Hypercalciuria predisposes
to urinary calculi
- Constibation, peptic ulcers,
pancreatitis, biliary stones
sources of abd pain
-Mental symptoms - lethargy,
depression
- Cardiac Arrhythmias may be
present
- Yellow, thickened, multinodular - Obesity - gradual onset of
due to hypertrophy, hyperplasia obesity of face (moon face),
of lipid-rich zona fasciculata and neck (buffalo hump), trunk,
reticularis.
abdomen. Extremities not
affected or even wasted
-Skin - atrophic, subcut. Fat
decreased, stretched with
striae
- Musc-skel system osteoporosis, proximal musc
wasting, weakness
-Cardiovasc - hypertension,
possible congestive heart
failure
-2ndry sex chars - virilization
acne, oligomenorrhea in
women, erectile dysfunct in
men, decrease libido in both
sexes
-Glucose intolerance and
hyperinsulinemia, diabetes
mellitus devs in 15% of pts
-Psycho changes - irritability,
emotional lability,
depression, paranoia
(Autoimmune)
- weakness, weightloss, GI
-Autoimmune adrenalitis
symptoms, hypotension,
accounts for 60-70% of cases
electrolyte imbalance,
- autoimm destruction of steroid hyperpigmentation
producing cells, autoantibodies to
several key steroidogenic
(Infections)
enzymes
- Particularly TB and
-1/2 of cases, autoimm reaction produced by fungi, also
restricted to adrenals (isolated
primary chronic
autoimm Addison disease)
adrenocortical insufficiency
-rest of pts, other imm diseases -Tuberculous adrenalitis assoc
coexist -autoimm
w/ infection in other sites
polyendocrinopathy syndrome
- AIDS pts at risk for dev'ing
adrenal insufficiencies from
infections
-Metastatic neoplasms
sometimes destroy sufficient
adrenal cortex to produce
degree of adrenal
insufficiency
-sporadic? - 80% uni, 10% bilat, - Bouts of paroxysmal
-If arise in extra10% in extraadrenal locations
hypertension, headaches,
adrenal sites,
-90% benign, 10% malignant
sweating, tachycardia,
called
-Histology highly variable.
nervousness
paragangliomas
Typically circumscribed nests of ->90% pts show hypertension
neoplastic cells present
(2/3rd sustained, 1/3rd
(Zellballen)
episodic)
-Tumor cells range from
-Angina and MI in absence of
polyhedral to fusiform w/ granular coronary artery disease
amaphophilic or basophilic
(catecholamine
cytoplasm and vesicular nuclei.
cardiomyopathy)
Eosinophilic globules usually seen -Diagnosis - increased urinary
in cytoplasm
levels of catecholamine
metabolites, particularly
Vanillylmandelic acid

-Macroadenoma: >1cm in dia

-Microadenoma - <1cm in dia
-well circumscribed soft
lesion, may be confined by
sella turcica, larger lesions
extend superiorly through
sellar diaphragm into
suprasellar region, often
compress optic chiasm,
adjacent structs
- Invasive adenomas - 30% of
cases, adenomas grossly
nonencapsulated and
infiltrate adjacent bone, dura,
uncommonly brain

-Bitemporal Hemianopsia,
reduction of field of vision
(Histopathology)
- Composed of relatively uniform,
polygonal cells arrayed in sheets,
cords, papillae
- Supporting CT (reticulin) is
sparse
- Nuclei uniform or pleomorphic
- Mitotic activity scanty
- cytoplasm of neoplastic cells
acidophilic, basophilic,
chromophobic
- functional status of adenoma
cannot be reliably predicted from
histo look
- cell monomorphism and
absence of significant reticulin
network distinguish pituitary
adenomas from non-neoplastic
anterior pituitary parenchyma
- Micro to macro adenomas
- Hyperprolactinemia - Prolactin-positive staining in neo Amenorrhea, galactorrhea,
cells
loss of libido, infertility in
women
- decreased libido and
impotency in men
- more symptomatic in younger
women
- Treatment included
bromocriptine (dopamine agonist)
to inhibit PRL secretion
- Large tumors require surgical
removal

(causes continued)
-Trauma - Head injury, surgery,
etc might damage hypothalamic

May be quite large by time of

discovery
-Gigantism happens if adenoma
occurs before epiphyses cloess
-Acromegaly if epiphyses
closed. Conspicuous growth in
soft tissues, skin, viscera, bones
of face, hands, feet. Enlarge jaw
results in protrusion
(prognathism), broader lower
face, separation of teeth.
- Most cases of gigantism are
accompanied by acromegaly
- Other manifests incl. abnorm
glucose tolerance, diabetes
mellitus, generalized muscle
weakness, hypertension,a rthritis,
osteoporosis, CHF
May be clinically silent
May cause hypercortisolism
(Cushing disease)
Nelson syndrome - large clinically
aggressive corticotroph cell
adenomas develop after surgical
removal of adrenal glands for
treatment of Cushign syndrome
(w/o adrenals, hypercortisolism
does not develop)
Hyperpigmentation - ACTH
cleaved from POMC
(Proopiomelanocortin)
- depends on extent of loss,
specific hormones, pt's age
-Major ones - Pituitary

Disease

What is it?

Anemia -Classified Normocyticbased on

normochromic RBC
morphology of RBC - Blood loss,
hemolytic anemia,
aplastic anemia,
anemia of chronic
disease (most cases)

Hemolytic
Anemias

assoc w/
accelerated
destruction

What causes it?

(Pathogenesis)
Microcytic-hypochromic RBC
-Iron deficiency anemia
(anisocytosis), thalassemia
(target cells), anemia of chronic
disease (20-30% of cases)

Intracorpuscular defects
(intrinsic)- membrane
abnormalities, enzyme
deficiencies, defective
hemoglobin synthesis
Extracorpuscular defect
(extrinsic)-Antibody mediated,
mechanical trauma to red
cells, infections

Intrinsic/Acquired? Morphology/Pathology

Clinical Significance/Features

Macrocytichyperchromic RBC
-large, lack central
pallor, Vitamin B12
or folate deficiency,
alcoholism

-depends on severity, speed of

onset, underlying pathologic
conditions
-Acute - SOB, organ fail, shock
-Pallor, fatigue, lassitude
-hemolytic anemias hyperbilirubinemia, jaundice,
pigment
- Ineffective hematopoiesis - iron
overload, heart and endocrin
failure
-Congenital abnormalities, cachexia

- Compensatory mechanisms
- Hyperplasia of erythroid
precursors in bone marrow,
extramedullary hematopoiesis in
secondary hematopoietic organs
(liver, spleen, lymph nodes)

Misc.

Intrinsic, usually
-all hemolytic anemias char'd
normal RBC life
inherited or extrinsic, by
span 120 days
usually acquired
1) ^ rate RBC destruct in
depending on defect spleen/liver
2) Reticulocytosis which
reflects compensatory increase
in erythropoiesis
3)retention by body of products
of red cell destruction
(including Fe)
leads to ->
4) Marked erythroid
hyperplasia in bone marrow
5) ^ reticulocyte count in
peripheral blood
6) Extramedullary
hematopoiesis devs in spleen,
liver, LN
Hereditary
Membrane
Transmitted most commonly intrinsic
Membrane stability affected, red
- splenectomy corrects anemic
Spherocytosis
abnormalities as an autosomal dominant
cells lose membrane fragments
condition without affecting
Hemolytic Anemia, trait: about 25& of cases as
until cells become spherical
hereditary defect and
Intracorpuscular - autonomal recessive and
(spherocytes)
spherocytosis. However, procedure
Anemia caused by more severe form of the
-Spherocytes have limited
increases risk for infections
increased RBC
disease - muts in structural
deformability; sequestered in
-Clinical Course
Destruction
proteins important in
spleen, destroyed by macrophages -Reduced life span of RBS from
maintaining spheroid cell
-muts affect integrity of
120d to 10-20d
RBCs become
shapes (e.g. spectrin,
membrane cytoskeleton,
-Anemia - usually mderate in
spheres
ankyrin, band 3 prot
erythrocyte loses membrane
severity, acute aplastic crisis
involved in vertical
fragments ->sphere. Less
may be triggered by parvovirus
interactions btwn membrane
deformable, so trapped in
infection which kills red cell
skeleton and intrinsic
splenic cords, phagocytosed by progenitor cells, reticulocytosis
membrane prots)
macrophages. GP, glycophorin -Splenomegaly - from
-Erythrostasis -> decrease glucose, congestion from RBC and
pH which leads to more membrane increased number of
loss
macrophages
-Blood smear shows anisocytosis,
-Jaundice, pigment stones,
dark-appearing (hyperchromatic)
systemic hemosiderosis - from
spherocytes, no central pallor.
degradation of excessive
Howell-Jolly bodies (small dark
amounts of hemoglobin
nuclear remnants) present
Sickle Cell
Structurally
Mutation in the gene coding (clinical course
-Upon deoxygenation, HbS
- Clinical Course
-~8% of African
Anemia
abnormal globin
for B-globin chain, single
continued 2)
molecules undrgo polymerization
Chronic hemolytic anemia and Americans are
synthesis amino acid substitution
2) Acute chest
(aka gelation, crystallation)
microvascular obstructions are heterozygous of
hemolytic anemia, (valine for glutamic acid at syndrome with
-RBCs distorted, assume an
the two major consequences
this
intracorpuscular - the 6th position), leads to
pulmonary
elongated crescentic, or sickle, - homozygous disease surfaces
hemoglobinopathy
anemia caused by formation of sickle
dysfunction,
shape
after the sixth month of life with
, about 1 in 600
increased RBC
hemoglobin (hemoglobin S, systemichypoxemi -Sickling of red cells initially
HbF being replaced by HbS.
have sickle cell
destruction
HbS)
a, sickling, vaso- reversible upon reoxygenation
Anemia severe, hematocrit 18-30% anemia
-Normal adult RBCS: 96^
occlusion
-Repeated sickling causes
(normal is 35-45%) - mean life
-Condition may
HbA, 3^HbA2, 1% fetal HbF 3) CNS stroke
membrane damage, eventually
span of RBC now 20 days (1/6 of
offer some degree
-Homozygotes sickle cell
- Conditions 2 and cells accumulate calcium, lose
normal) - Heterozygotes for
of protection in
anemia all HbA replaced by 3 are two leading potassium and water, become
Hemoglobin S (sickle cell trait) do Africa against
HbS
causes of ischemia irreversibly sickled, rapidly
not develop red cell sickling,
Malaria
-Heterozygotes sickle cell
related death
hemolyzed
clinically normal
anemia, about 40% replaced -Hypoxyurea can -Sickle cells, anisocytosis
-Reticulocytosis and
by HbS
reduce pain crises (considerable variation in size of
hyperbilirubinemia due to
and reduce anemia cells that are normally uniform),
chronic hemolysis
(Clinical Course continued 1) - increases level of Poikilocytosis (RBC of irregular
-Compensatory hyperplasia of
-hemosiderosis and
HbF, anti inf
shape), target cells
erythroid progenitor cells in
gallstone are common
effects, increases
bone marrow, vascular
-Vaso-occlusive or pain crisis mean cell volume, (Clinical course continued 3)
congestion, thrombosis and
(pl. crises)
produces NO, a
-Aplastic crisis - temporary
infarction can affect any organ
1) hypoxic injury and
potent vasodilator cessation of erythropoiesis
-avascular necrosis in bone
infarction in many sites
and inhibitor of
-pts prone to infections
-Autosplenectomy in adult
leading to pain, esp in the
platelet
starts as splenomegaly in the
bone marrow, can prog to
aggregation
young
infarction and necrosis
Glucose-6Enzyme defect
X-linked recessive disorder
G6PD helps recycle reduced
-drugs which can lead to
most prevalent in
Phosphate
(deficiency) with red cell sensitivity to
glutathione, deficiency renders
symptoms include
areas where
Dehydrogenase Hemolytic Anemia, oxidative stress manifested
RBCs susceptible to oxidative
antimalarials, some antibiotics malearia is
Deficiency
intracorpuscular - as hemolytic anemia - form
stress, conditions accentuated by (sulfonamides, nitrofurantoin), historically
anemia caused by of hereditary nonspherocytic
infections, some drugs.
some analgesics (phenacetin, endemic (Afircan
increased RBC
anemia
-Oxidation of hemoglobin caues aspirin in large doses), VitK
and parts of
destruction
precipitation in cytoplasm as
derivatives
Mediterranean)
Heinz bodies, increased cell
-Favism - fava bean ingestion appears to provide
regidity, ultimately hemolysis may lead to fatal hemolysis
some protection
-after passing through spleen, -Naphthalene sensitivity (moth against malaria
cells may have part of
balls)
- A- varient may be
membrane removed (bite cells) -Infections - phagocytosis w/
seen in 10-15% of
-Inert red cells precipitate
free radical production
American blacks,
denatured globin (Heinz
-Drug hemolysis acute, variable assoc with reduced
bodies), splenic macrophages severity, lage of 2-3 days
enzyme activity
pluck out inclusions, 'bite' cells -Avoid substances which may
(10% norm) due to
produced
trigger hemolytic reaction
decreased half-life
-Blood transfusion in acute phase of enzyme
of hemolysis
-Prompt treatment of infections
-Folic acid supplement
Thalassemia
Deficient globin
-Overall concentration of normal
Types of Thalassemia
-Hyperplasia of erythroid
- particularly
synthesis HbA reduced
-B-Thalassemia- most common,
progenitors with a shift toward common among
Hemolytic anemia - -Abnormal ratio of a chains
mutation of one or both genes that early forms
mediterranean,
intracorpuscular - to B chains results in
code B-globin. Red cell hemolysis
-Cachexia
african, asian
Anemia caused by intracellular deposits,
results from unbalanced rates of B- -Skeletal deformities due to
populations
increased
producing characteristic
globin and a-globin chain synth
marrow expansion (ex. in slide
destruction of RBC 'target cells' prone to
->unpaired a-globin chains form
is new bone formation
- Group of inherited hemolysis
aggregates that damage red cell
producing perpendicular
disorders caused by
precursors and impair
radiations resembling crewcut)
muts that decrease
erythropoiesis
-Splenomegaly, hepatomegaly,
rate of synthesis of a
--Thalassemia major (Cooley
lymphadenopathy
or B globin chains
anemia) - Homozygotes develop
-Iron overload can lead to
(normal is HbA a2b2
hemolysis, splenomegaly, bone
severe hemosiderosis
-Reduced hemoglobin
marrow, hyperplasia, bone
-B-Thalassemia major appears
synthesis, microcytic,
deformities
in children as HbF decreases,
hypochromic anemia
--Thalassemia minor (trait) - mild growth is retarded, repeated
anemia in heterozygotes
transfusion needed
-a-Thalassemia - deletion of one or -B-Thalassemia minor is used
more of the four a-globin genes.
only a mild microcytic
Sever or mild depends on number hypochromic anemia with
of genes deleted
normal life expectancy
-B-Thalassemia major - Failure
to thrive, repeated blood
transfusion helps, systemic
iron overload
Iron deficiency
Deficient Heme
-Chronic blood loss (most
-Microcytic-hypochromic
-Low bone marrow iron stores Iron def is most
Anemia
synthesis important cause in Western
anemia with anisocytosis (i.e. -Low serum iron
common form of
anemias of
world)
pencil or cigar-shaped cells)
-Low ferritin levels
nutritional
diminished
-Inadequate iron uptake;
-Hypochromic microcytic
-Low transferrin saturation
deficiency
erythropoiesis
dietary deficiency (most
aniemia of iron deficiency -High total iron binding
-most common
important in developing
small red cells containing
capacity (TIBC)
form of anemia
world)
narrow rim of peripheral
-No regulated
-Inadequate iron absorption;
hemoglobin.
pathway for iron
achlorhydria, celiac disease
excretion. Iron
-Excessive iron loss;
balance
menstruation, chronic GI
maintained by
bleeding
regulating
-Increased iron demand;
absorption of
pregnancy, lactation,
dietary iron
infancy
Anemia due to
Deficiencies in DNA Pernicious anemia - caused
-Pallor, easy fatigability
Vitamin B12 and synthesis - Anemia by vit b12 def (autoimm
-Macrocytic-hyperchromatic
Folate Deficiency due to decreased attack on gatric mucosa
RBCs
RBC production.
which secretes intrinsic
-Hypersegmented neutrophils
Synth of DNA in
factor - a substance critical
-Bone marrow with numerous
hematopoietic cells in absorption of vit B12
megaloblasts (ie immature RBC
affected, so is the -Malabsoprtion of Bit B12 in
precursors that are much
maturation of bone gastritis, Crohn disease, GI
larger than normoblasts)
marrow precursors parasitic infection
-Low platelet count
of blood cells
-Inadequate intake of folic acid,
-Serum vit B12 or folate levels
in malnutrition, alcoholism
low
-increased demand of folic acid
-atrophy of gastric fundic
in pregnancy
glands (PA)
-Drug therapy - interfere with
-CNS lesions with
absorption or act as foliate
demylelination of dorsal and
antagonist (e.g. methotrexate)
lateral tracts of the spinal cord
(PA), may not resolve even with
B12 supplementation
-Neurologic abnormalities do
NOT occur in folate deficiency
anemia
Aplastic Anemia
Disturbance of
- Multipotent myeloid stem cells
-Marked hypocellular marrow
- anemia, leukopenia,
proliferation and
suppressed -> marrow failure
contains mainly fat cells
thrombocytopenia
differentiation of
and pancytopenia
(hematopoietic cells in bone
-Hemorrhages, infections
stem cells. Anemia
- most times cause is unknown
marrow replaced by fat)
-repeated transfusions can lead to
due to deficiency in (idiopathic)
hemosiderosis
Red and White Cell
- Can be due to drug therapy,
production
toxins, radiation, viral infection
-Autoreactive T cells play
important role (genetically
altered stem cells produce new
antigens -> T-cell response) (immunosuppressive therapy
useful)
Polycythemia
Increase in RBC mass Relative Absolute continued
Absolute continued
-hematocrit:
(Erythrocytosis) - abnormally high red hemoconcentration due to
-Secondary - High
-Blood viscous, cardiac
normal - 42-52%
blood cell count,
decreased plasma vol (e.g.
erythropoietin in system
function and peripheral blood M, 37-47% F
usually corresponding water deprivation
-Compensatory: lung disease, flow may be impaired. Skin and -Polycythemia:
increase in
dehydration, prolonged
high altitude living, cyanotic
mucosa appear dark red
52% M, >47%F
hemoglobin level
vomiting or diarrhea or
heart disease
Blood doping - autologous
excessive diuretic use w/
-Paraneo: erythropoietin
transfusion, homologous
'- Hemoglobin:
normal red cell mass
secreting tumors (renal cell
transfusion, EPO injections
normal
Absolute - actual increase in
carcinoma, hepatocellular
- 13.2-16.7g/dL M
total RCM split into primary
carcinoma, cerebral
- 11.9-15.0 g/dL in
or 2ndary
hemangioblastoma)
F
-Primary -Normal or Lower
- Hemoglobin mutations with
erythropoietin in system
high O2 affinity
-Polycythemia in
1) Polychtehmia vera, a
-inherited defects that increase
>18.5 M, >16.5 in
myeloproliferative disorder
stability of HIF-1a (hypoxia
F
w/ autonomous,
induced factor) leading to ^EP
erythropoietin independent
-Chuvash polychtemia
growth of red cell
(homozygous VHL muts)
progenitors
- Prolyl hydroxylase muts
2) Rare inherited
erythrpopoietin receptor
mutations with erythrpoietin
independent receptor
activation (primary familial
polycythemia)
Leukopenia:
Non neoplastic
-*decreased production:
(causes continued)
-Malaise, chills, fever, marked - Leukopenia Neutropenia/
disorder of WBC - irradiation, drug-induced,
-Marrow hypercellularity weakness, fatigability
decrease in WBC,
Agranulocytosis Neutropenia is
viral infects, congenital
increase in # of granulocytic
-ulcerating, necrotizing lesions mainly
absolute
-* ineffective production:
precursors b/c excess
on mucous membranes
granulocytes, total
neutrophil count
megaloblastic anemia,
destruction of mature
- infections sometimes with
WBC count <4300
<1600/uL
myelodysplastic syndrome
neutrophils, ineffective
massive growth of
uL
* generalized marrow failure
granulocytopoiesis
microorganisms
-absolute
- Increased destruction:
- Marrow hypocellularity w/
- control infection, treat with
neutrophil counte
autoimmune related,
decrease in maturing
granulocyte colony-stimulating <1000 /uL ->
idiopathic, infections
granulocytic precursors - seen factor
vulnerable to
when drugs which suppress
microbe infect
granulocytopoiesis are used
- absolute count
- with myelotoxic drugs, both
below 500/uL
RBC and WBC production are
(agranulocytosis)
affected
-> serious risk
infect
Leukopenia:
Non neoplastic
common reaction to variety
Neutrophils contain coarse purple (causes continued)
Reactive
disorder of WBC - of inf states. Depends on
cytoplasmic granules (toxic
Some causes
(inflammatory)
Increase in number size of myeloid and
granulations), blue cytoplasmic
-acute bacterial infects Proliferation
of white blood cells lymphoid precursor pools in
patches of dilated endoplasmic
neutrophilia
(non neoplastic
bone marrow, thymus,
reticulum
- Allergic disorders, parasitic
disorder of WBC
circulation, peripheral
infections (eosinophilia)
tissues, rate of release of
- chronic infects, bacterial
cells from storage pools into
endocarditis - monocytosis
circulation, marginal pool of
- Chronic imm stim such as TB,
cells adhering to vessel
epstein Barr, CMV etc walls, rate of extravasation
lymphocytosis (eg in infectious
of cells from blood into the
mononucleosis)
tissues
Lymphadentitis
Reactive
Infections, non-microbial inf
-swollen, grey-red, engorged.
-Acute nonspecific lymphadenitis
(inflammatory)
stimuli not only cause
- histopath nonspecific w/ large
may contain abscess in center of
proliferation of lymph leukocytosis, also act on lymph
germinal centers w/ numerous
follicles; neutrophilic infiltrates
nodes (nonnodes -> enlarged
mitotic figures
seen w/ pyogenic organisms
neoplastic disorder of (lymphadenopathy)
-Germ centers of follicles contain
- Chronic nonspecific lymphadenitis
WBC)
larger lymphocytes. More
-Follicular hyperplasia assoc w/
pronounced reactive change
infections or inf processes, activate
features larger follicle in lymph
B-cells, create follicular germ
node and germinal centers
center reaction (in rheumatoid
containing macrophages
arthritis, toxoplasmosis, early HIV
infect)
-Paracortical hyperplasia - reactive
changes in t-cell regions of node w/
large prolif immunoblasts (viral
infects (EBV), certain vaccinations
(e.g. small pox), certain drugs (e.g.
phenytoin/Dilantin for seizures))
Neoplastic
Leukemias - tumors Lymphomas - tumors produce
Lymphoid neos - non- Myeloid neoplasms - arise from
Histiocytic neoplasms
Proliferations of
primarily involve
masses in involved lymph
Hodgkin lymphomas, stem cells that normally give rise to (Leukemias)
White cells
bone marrow w/
nodes, spleen, extranodal
Hodgkin Lymphomas, formed elements of blood:
Leukemias - arise from muts that
spillage of neo cells tissues
lymphocytic
granulocytes, red cells, platelets.
block diff at early stages of white
into peripheral blood
leukemia, plasma
Monoclonal prolifs replace bone
cell dev, enhance self-renewal, inc
cell dyscrasias
marrow cells - Acute myeloblastic growth and survival. Important:
leukemia (AML), chronic
BCR-ABL (breakpoint chromosome
myeloproliferative disorders,
region-Abelson kinase fusion gene),
myelodysplastic syndromes
MLL (mixed lineage leukemia
gene), PML RARa, promyelocytic
leukemia retinoic acid receptor a
fusion gene
Acute Myelogenous Myeloid neoplasm - blocked at some early stage of
Blasts, which can exhibit evidence - Fatigue, pallor, fever, infections
Leukemia (AML)
clonal prolif of
myeloid cell dev ; no terminal
of granulocytic, erythroid,
(esp opportunistic organisms)
- accounts for 80%
immature myeloid
diff (commitment).
monocytic, or megakaryocytic diff common, abnormal bleeding
of acute leukemias
cells (blasts) in bone - may start de novo, or end
accumulate in marrow, replacing
(cutaneous bleed and serosal
in adults, median
marrow w/
stage of chronic myelkogenous
normal elements, freq circulate in hemorrhages over viscera)
age of 60 at onset
subsequent
leukemia and myelofibrosis
peripheral blood
- chemo leads to remission in
appearance in blood - assoc w/ acquired muts in tx
- prog accum in bone marrow of
>50% pts, overall 5 yr survival
& tissues
facs that inhibit normal myeloid
immature cells that lack potential <30%
diff (no terminal diff, no
for further diff and maturation ->
- bone marrow transplant common
commitment)
suppress normal hematopoiesis,
mode of treatment
granulocytopenia,
thrombocytopenia, anemia (bone
marrow failure)
Acute
example of AML
Mut in genes encoding Tx
- neo promyelocytes w/ abnormal
-treatment w/ all-trans retinoic acid
Promyelocytic
facs req'd for normal
coarse and numerous azurophilic
overcomes block, immature cells
Leukemia
myeloid cell diff. One mut
granules. Other findings ->
undergo terminal diff into neutros
involves t(15;17) transloc in
presence of several cells, bilobed
and die
acute promyelocyte
nuclei, cell in center of field
-retinoic acid + chemo -> excellent
leukemia -> formation of
contains multiple needle-like Auer prog
abnormal PML/RARA fusion
rods (lysosomes)
prot -> blocks myeloid diff
at promyelocytic stage. RARA
= retinoic acid receptor alpha
(gene on 17) PML (gene on 15).
- Assoc w/ radiation, cytotoxic
chemo, benzene exposure, and
in the case of cig smoking
doubles risk
Chronic
- Myeloid
Disorder assoc w/ activating
- philadelphia chrom (t(0:22)
- CML curable by allogenic bone
15-20% of all
Myelogenous
neoplasm, clonal
muts in tyrosine kinases,
(q34:q11)
marrow transplant early in dsease. leukemias. Mostly
Leukemia (CML) stem cell disorder. generate constitutive signals
- BCR (break point cluster region)
Drug imantinib mesylate (gleevec) adults 25-60 yrs
One of the
mimicking those normally
gene - chrom 22 fused to ABL gene blocks ATP-binding site on BCr/ABL age. Presence of
myeloproliferative produced in response to
on chrom 9 -> fusion prot p2190.
Tyr kin (inactivates). Untreated -> philadelphia
disorders. Char'd hematopoietic growth factors
Dimerized -> constitutive Tyr kin
blast criss resembling AML or
chrom (t(0:22)
by hyperprolif of
activity -> PO4's prots, activates
lymphoblastic leukemia
(q34:q11) by
neo myeloid
multiple downstream paths -> drive
conventional
progenitors that
growth factor independent prolif,
cytogenetics,
retain capacity for
survival of bone marrow
FISH, mol
terminal diff ->
progenitors. BCR-BCL does not
demonstration
increase one or
interfere w/ differentiation, so net ^
of BCR/ABL
more formed
in mature elements in peripheral
fusion gene
elements of
blood, esp granulocytes and
req'd for
peripheral blood.
platelets
diagnosis. 95% of
- Hypercellular bone marrow due to
CML cases
increase in granulocyte precursors,
mature granulocytes,
megakaryocytes. Numerous
granulocytes at various dev stages
B-Acute
Malignancy of
B-lymphoblastic leukemia (BMalignant lymphoblasts - 20% of
- tumor cells in marrow -> mass
Most common
Lymphoblastic
precursor
ALL) - precurosr B cell
bone marrow cellularity. Smalleffect w/ pain and arthralgias
childhood
Leukemia/Lymph Lymphocytes
malignancy involving primarily
medium size cells, increased nuc- - Childhood B-ALL treated w/
leukemia, 75%
oma (ALL/LBL)
- Immature
bone marrow, peripheral blood
cyto ratio, delicate chromatin,
chemo, excellent prognosis,
cases children
(precursor B
B-lymphoblastic lymphoma
inconspicuous nucleoli.
complete remission rate of >90% under age 6
lymphoblasts
(LBL) - precursor B-cell
- B-ALL feats numerous aberrations,
malignant cells in B- malignancy involving lymph
chromosomal translocs, incl,
ALL/LBL
nodes
Philadelphia chrom (w/ p190)
- Leukemic cells displace normal
marrow elements, -> anemia,
thrombocytopenia, neutropenia
-lymphoblasts w/ condensed nuc
chromatin, small nucleoli, scant
agranular cytoplasm
Mature
Neoplasm of
dervied from clonal proliferation
Most occur in 6th(peripheral) B
lymphoid cells
of peripheral B cells. Most
7th decades.
Cell Lymphomas -Lymphomas common B-cell lymphomas
Uncommon
tumors that
follicular lymphomas (22.1%),
inchildren except
produce masses in diffused large cell lymphomas
for Burkitt
involved lymph
(30.6%).
lymphoma, large
nodes, spleen,
cell B-cell
extranodal tissues.
lymphoma
Most common type
in western world
Diffuse Large B- Peripheral B-Cell
heterogeneous group of
-involves lymph nodes, extranodal - aggressive and rapidly fatal if
Cell Lymphoma Neoplasm. Most
aggressive, potentially curable
locations. Neo cells resemble
untreated. Good results w/
important type of B-cell neoplasms. All ages but
immunoblasts w/ nuclei, exhibit
intensive combo chemo, complete
lymphoma in
mostly 60-70 yrs age
prominent central nucleoli. Cells
remissino in 60-80% of pts, about

Disease

What is it?

Congenital
Anormalities

Malformation of
urethral groove
and urethral canal
-> abnormal
openings

Phimosis

Opening of
Congenital anomaly or
prepuce too small results from scarring of
to permit normal prepuce as result of
retraction
previous inf
-Balanitis - glans
penis
-Balanoposthitis glans penis and
prepuce
-Bacteria, fungi
-Benign sexually -HPV assoc w/ type 6,
transmitted
less w/ type 11
tumor (genital -may occur on any moist
warts)
mucocutaneous surface
of external genitals in
either sex
-in male, most often
about coronal sulcus
and inner surface of
prepuce

Inflammation

Condyloma
acuminatum

Cancer of the originates

Penis
mostly from
squam mucosa
of glans and
contiguous
urethral meatus
or prepuce and
skin covering
penile shaft
Bowen
Carcinoma in
Disease
situ of the Penis

Bowenoid
papulosis

What causes it?

(Pathogenesis)

Intrinsic/Acquir Morphology/Pathology
Clinical
Misc.
ed?
Significance/Features
-hypospadias - ventral surface, -Opening may be constricted,
more common, 1 in 250 live
trac obstruction, increased
births
risk of ascending infections
'epispadias- urethral orifice on -May affect fertility
dorsal surface
(hypospadias)
-May be assoc w/ bladder
exstrophy (epispadias)
Interferes with cleanliness,
increased risks of infection,
possibly cancer

- Single/multiple sessile or -Gardasil vaccine, preventive

pedunculated, red
must be inoculated before
papillary outgrowth, 1mm start of sexual life
to several mm in dia
-Branching, villous, papillary
connective stroma covered by
epi that may have
considerable superficial
hyperkeratosis and thickening
of underlying epidermis
(acanthosis)
-orderly maturation of epi is
preserved
-koilocytosis, cytoplasmic
vacuolization of squam cells
char of HPV infect, noted in
lesions
- lesions tend to recur,
rarely progress into in situ
or invasive cancer
Penile carcinoma occurs ni
a preinvasive form
(carcinoma in situ) and an
invasive variety

-most pts uncircumsized

and older than 40 yrs
-Prolonged contact btwn
smegma and penile epi
may play role
-HPV 16/18 may play a role

strong assoc w/ HPV,

esp type 16

Carcinoma in situ strong assoc w/ HPV, esp

of the Penis
type 16, occurs in young,
sexually active males

Squamous
-usually
Cell
involves glans
Carcinoma of or prepuce
the Penis

Cryptorchidis -Undescended
m
Testis
- unilateral or
bilateral

-Congenital abnormality

Testicular
Neoplasms

Most important
cause of firm,
painless
enlargement of
testis

in Adults, 95% arise from

germ cells, all of these
malignant. Cryptorchidism
assoc w/ 3-5 fold increase
in risk of cancer

Seminoma

Ex. of Germ cell

tumor of testis.
Most common
testicular
cancer, 40% of
all germ cell
tumors.

Prostatitis

Inflammation of Can be Bacterial or

Prostate
chronic.

Intrinsic

Acquired

Nodular
BPH, benign
Most hyperplastic lesions
Hyperplasia of Prostatic
arise from transitional and
the Prostate Hyperplasia,
central zone
nodular
hyperplasia.
Begins to
appear in men
after age 40,
prog inc w/ age,
90% in eighth
decade

Cancer of the Common cancer

Prostate
of older men btwn
65 and 75 yrs of
age.

PSA and
-PSA - Serine
- If elevated, means
Should everybody
Prostate Cancer: protease made by Prostatitis, BPH, Prostate Ca over 50 get a PSA
To Test or not to prostatic epi cells
test?
Test?
-race, age,family
history, recs from
prof organizations

-not common in
US (<0.5%),
more common
in Africa and
Asia (>10%) of
all cancers in
men

-genital region, usu >35 yr

old
- skin of shaft of penis and
scrotum
-solitary, thickened, graywhite opaque plaque
- Epidermis shows
proliferation w/ numerous
mitosis, some atypical
-Cells markedly dysplastic
w/ large hyperchromatic
nuclei, lack orderly
maturation
- Dermal-epidermal border
sharply delineated by
intact BM
- may transform into SCC in
10% or more
-Erythroplasia of Queyrat presents as erythematous
patch on glans penis
Multiple lesions, reddish brown
papule
-Histologically identical to
Bowen disease
-Virtually never develops into
invasive carc and many caes
spontaneously regress
-Gray, crusted papular
lesion
-infiltrates underlying
connective tissue to
produce indurated,
ulcerated lesion w/
irregular margins
-Histological appearance keratinizing SCC w/
infiltrating margins
-Indolent, locally
infiltrative lesions
-Regional metastasis in
inguinal nodes ~25% of
cases at time of diag
- Estensive destruction of
penile tissue in neglected
cases
-Overall 5yr survival is 70%
-May be arrested at any
-Assoc w/ 3-5 fold higher
point from abd cavity to
risk of testicular cancer,
upper scrotum
even after surgical
-Arrested dev of germ cells correction
assoc w/ marked
hyalinzation/thickening of
BM of semin. Tubs
- Leydig cells appear
prominent
-Progressive atrophy,
cryptorchid testis small in
size, firm from fibrosis
Germ cell tumors include:
Self exam
seminoma, embryonal
important for
carcinoma, yok sac tumor,
early detection.
choriocarcinoma, teratoma
Seen in 5 per
-non-germ cell tumors include:
100,000 males.
Leydig Cell tumors, Sertoli Cell
Peak incidence
tumors
20-35 yrs
-presents as solid,
- Grows as progressive
Peak incidence
rubbery-firm, lumpy
scrotal mass
30-40 years
masses
-Diag'd while can be cured
-Cut surface shows
by orchiectomy w/ or w/o
lobulation, homogeneously abdominal lymph node
tan or grayish-yellow
dissection
-single population of
- highly radiosensitive
uniform polygonal cells w/ -Those in advanced stages
centrally located vesicular of dissemination are
nuclei
treated w/ additional
-Cytoplasm contains large chemo
amount of glycogen &
-Cure rate is >90%
lipid, pale and eosinophilic
or clear in sections
-Tumor cells arranged as
nests or sheets w/
intervening fibrous septa
-Lymphocytic infiltrate
usually present.
-25% of cases - cell stain
positive for hCG
Acute Bacteria Prostatitis
-Dysuria, Urinary
-UTI bacteria, e.g. E. coli etc. frequency, lower back
-Acute neutr inf infiltrate,
pain, poorly localized
congestion, stromal edema,
suprapubic or pelvic pain,
-Neutrophils first in glands,
prostate may be enlarged
then into stroma ->
and tender, esp. in acute
microabscesses
prostatitis, chronic cases
Chronic Prostatitis
may be symptomatic or
- Varia amount of lymphoid
silent. Important cause of
infiltrate, evidence of gland inj recurrent UTI in males.
-Concomitant acute/chronic inf PSA may be elevated
- evidence of tissue destruct,
fibroblast prolif, presence of
other inf cells req'd for histo
diag
- older individuals, abacterial
prostatitis: negaative culture,
>10WBC per high field
-Prolif of epi and stromal
elements.
- Gland enlarged, may
cause urinary obstruction
-Cut surface contains many
fairly well-circumscribed
nodules that bulge from
cut surface.
-Cystic spaces represent
dilated glandular elements
-Urethra usually
compressed
-Nodules composed of
proliferating glandular
elements, fibro musc stroma
- Hyperplastic glands lined by
tall, columnar epi cells,
peripheral basal cells
-Prolif of stromal elements
-Areas of infarc fairly
common in adv cases, freq
accom by foci of squam
metaplasia in adjacent
glands
-Arises from peripheral
- Most local cancers are
Blacks>Caucasi
zone, may be palpable via clinically silent, detected ans>orientals
digital rectal exam
by routinely monitoring
- adenoarc w/ variable
PSA in older men
differentiation and
- advanced cancers
anaplasia
present w/ metastasis,
- Neoplastic glands lined
freq to bones
by single layer of cells.
- Serum PSA levels under 4
Basal reserve cells not
ng/mL considered normal.
present
Values over 10 ng/mL
- Grading of prostate
suggestive of cancer
cancer by Gleason system - Anatomical staging of
correlates w/ anatomical
extent of disease has
stage and prognosis
important role in
evaluation and treatment
- Prostate canc is staged
by clinical exam, surgical
exploration, radiographic
imaging techs, and in
some systems, histologic
grade of tumor and levels
of tumor markers
-Treat w/ surgery,
radiation, hormones
why the controversy?
Best use of PSA?
What is 'wait
-Over diagnosis, unpredictable -Monitor tumor recurrence
and see'
cancer biology, serious
after treatment
approach to
complications assoc w/ some 'Biggest challenge for
prostate
untreatment modalities
prostate cancer diagnosis?
cancer?
- No good way to tell if cancer 0Pt may die of
(seen in biopsy) going to be other causes in
slow growing or aggressive
spite of having
prostate cancer

Disease
Vulvitis

What is it?

What causes it?

(Pathogenesis)
moist hair-bearing most important STD in North
skin and delicate
America:
membrane of vulva -Chlamydia, most common
are vulnerable to
-human papillomavirus (HPV),
many nonspecific
producing condyloma
microbe-induced inf acuminata and vulvar
and dermatologic
intraepithelial neoplasia
disorders
-herpes genitalis (herpes
simplex (HSV-1 or 2), causing
vesicular eruption
-gonococcal suppurative
infection of the vulvovaginal
glands
-syphillis, with its primary
chance at the site of
inoculation
-candidal vulvitis

Intrinsic/Acquired Morphology/Pathology
?
Acquired

Clinical Significance/Features Misc.

Contact is intrinsic

Contact Dermatitis
-Irritant dermatitis, reactive
inf to exogenous stimulus
-Allergic dermatitis, reactive
inf to allergen
Bartholin Cyst
and Abscess

Lichen
Schlerosus of
the Vulva

Paired Bartholin's
glands (greater
vestibular glands)
produce clear
mucoid secretion
that continuously
lubricates vestibular
surface - Ducts
prone to obstruction
and consequent
cyst formation
non-neoplastic
Autoimmune
epi disorder
-inf disease assoc
w/ autoimm
disorders (e.g.
vilitigo,
pernicious
anemia,
thyroiditis)
characterizied by
atrophic epi,
usually w/ dermal
fibrosis

Condyloma
Acuminatum

Benign lesion benign sexually

transmitted
tumor, anogenital
warts

Vulvar
Intraepithelial
Neoplasm and
Vulvar
Carcinoma

Carcinoma of the
vulva represents
3% of all genital
tract cancers in
women, 2/3 in
women older than
60
-90% of vulva
carcinomas are
squamous cell
carcinomas
-10% are
adenocarcinomas,
melanomas, or
basal cell
carcinomas
-Associated with HPV 16, 18 assoc vulvar
HPV
cancer, 30% of scc cases
-Develop from
precancerous in situ lesion
called vulvar
intraepithelial neoplasia
(VIN)
-Includes 'carcinoma in
situ' and Bowen disease

Basaloid and
Warty
Carcinomas

Keratinizing
-Not associated
Squamous Cell with HPV
Carcinomas of
the Vulva

-Caused by HPV, assoc w/

type 6, less freq w/ type
11
-May occur on any moist
mucocutaneous surface of
the external genitals in
either sex
-on the vulva they range
from few mm to many cm
in dia

Arise in individual with

long standing lichen
schlerosus or squamous
cell hyperplasia

Cervical
Intraepithelial
neoplasia (CIN)
and Squamous
Cell Carcinoma

Most tumors of
Nearly all invasive cervical
cervix are of epi SCCs arise from precursor
origin, assoc w/
epi changes referred to as
oncogenic strains CIN
of HPV
However, not all cases of
Cervical cancer
CIN progress to invasive
ranked 13th in
cancer
cancer death in
US, low ranking
CIN, dysplasia, SIL
mainly due to pap (squamous intraepithelial
smear
lesion) used
Conversely,
interchangeably
incidence of
precursor CIN
increased, mainly
due to Pap smear

Low-grade
Squamous
Intraepithelial
Lesions (LSIL),
CIN I
High-Grade
Squamous
intraepithelial
Lesion, HSIL,
CIN II and III

CIN, low-grade
dysplasia - assoc
w/ productive
HPV infection

Carcinomas of
the Cervix

CIN, moderate,
-80% HSIL dev from LSIL, 20%
severe,
of HSIL dev de novo
carcinoma in situ
-Progressive
deregulation of
cell cycle by HPV
75% cervical
HSIL is immediate precursor
cancers SCC, 20%
adenocarcs, mixed
adenosquamous
carcs, 5% misc. All
assoc w/ high risk
HPV

Endometriosis Presence of
benign
endometrial
glands and
stroma outside
the uterus
-Seen in 5-10% of
women in repro
age
-Regresses after
natural or
artificial
menopause
(tissue hormone
responsive)

Endometrial
Carcinoma

-Regurgitation Theory Menstrual endometrium

fragments refluxed through
the fallopian tubes to ectopic
sites
-Metaplastic Theory Endometrial tissue arising
directly from coelomic epi
(mesothelium of pelvis or
abdomen)
-Vascular/Lymphatic
Dissemination Theory
-Theories are not mutually
exclusive

4th most
frequent type of
cancer in
American women
and most freq
cancer occuring
in female genital
tract

Endometrial
Assoc w/
-Major form of
Adenocarcinom endometrial
endometrial cancer, 80%
a (Type I)
intraepi neoplasia of cases
(EIN) precursors, -Linked to prolonged
prior exposrure
estrogen stimulation of
to estrogens,
the endometrium
slow clinical
-Obesity, hypertension,
course
diabetes
-Mutation in the mismatch
repair genes and the PTEN
tumor suppressor gene
found in 30-80% of cases
Precursor is complex
endometrial hyperplasia
with atypia

Nonendometroid
Adenocarcinom
a (Type II)

Not assoc w/
estrogen, emerge
without warning,
have higher
fatality rates

Less common, generally

occur in women a decade
later than type I
carcinoma, usually arise in
the setting of endometrial
atrophy, not associated
with estrogen exposure,
poorly differentiated

Serous
Non-endometroid
Carcinoma of the endometrial
Endometrium
Adenocarcinoma
(Type II)

Leiomyoma

Benign tumor
that arises from
smooth muscle
cells in
myometrium.
Colloquially
known as
"myoma" or
"fibroid"

Leiomyosarcom Malignant tumor

a
of the
myometrium
which arises de
novo from the
mesenchymal
cells of the
myometrium, not
from preexisting
leiomyomas
-Much, much less
freq than
leiomyomas
-Malignant
tumors solitary
and usually larger
(10-15 cm vs 3-5
cm)

Estrogen promotes their

growth, although it does not
initiate them.
-Postmenopausal shrinkage
-Although often multiple, each
tumor is monoclonal
-Nonrandom chromosomal
abnormalities seen in 40% of
tumors

-Cyst infection leads to abscess -Bartholin duct

formation
cysts relatively
-acute inf within gland (adenitis) common, occur
and may result in abscess
at all ages
-Gonorrhea, Staphylococci,
Chlamydia, anaerobes frequently
involved
-Treatments include incision,
drainage, marsupialization,
antibiotics
intrinsic

-White plaques (leukoplakia),

atrophic skin, parchment-like
or crinkled appearance
-thinning of epidermis and
disappearance of rete pegs,
hydropic degeneration of the
basal cells, superficial
hyperkeratosis, dermal
fibrosis
-Scant perivascular,
mononuclear inf cell infiltrate
(including activated T cells) bandlike

Features
-occurs in all age groups but
most common in
postmenopausal women
-Pruritis/Itching is the most
common symptom
-Dyspareunia (pain during
intercourse)
Implications
-Women w/ symptomatic
lichen sclerosus, 1%-5%
develop SCC of vulva
-Biopsy to differentiate from
other lesions with white
plaques

-Branching, villous, papillary

connective stroma covered
by epi that may have
considerable superficial
hyperkeratosis and
thickening of the underlying
epidermis (acanthosis)
-The orderly maturation of
the epi cells preserved
-Koilocytosis, perinuclear
cytoplasmic vacuolization of
the squamous cells,
characteristic HPV infection
noted in these lesions
-Lesions tend to recur
-May co-exist w/ low-grade
vulvar intraepithelial
neoplasia (VIN) but only
rarely progress into in situ or
invasive cancers
Two Forms: Basaloid and
Warty Carcinomas and
Keratinizing Squamous Cell
carcinomas of the vulva

-VIN shows nuclear atypia,

increased mitosis, lack of
cellular maturation, nuclear
crowding
-Precursor: VIN. Progresses
to:
-Squamous Cell Carcinoma
--Infiltrating tumor
characterized by nests and
cords of small, tightly packed
malignant squamous cells
lacking maturation that
resemble immature cells
from the basal layer of the
normal epithelium
--The tumor may have foci of
central necrosis
-Warty carcinoma
characterized by exophytic
papillary architecture and
prominent koilocytic atypia
-Immediate premature lesion is
called differentiated vulvar
intraepielial neoplasia
(differentiated VIN)
-Marked atypia of the basal layer
of the squamous epithelium
-Normal epithelial maturation
and differentiation in the
superficial layers
-Hyperkeratosis
-Etiology unknown
Progress to:
Keratinizing squamous cell
carcinoma of the vulva infiltrating tumor characterized
by nests and tongues of
malignant squamous epithelium
with prominent central keratin
pearls

-Pruritis/itching of long
-mean age is 76
duration is commonly the
yrs
first symptom
-Ulceration, bleeding,
secondary infection may
develop
-Tumors grow slowly and
then extend to the
contiguous skin, vagina,
rectum
-Metastaize to superficial
inguinal then deep inguinal
femoral and pelvic lymph
nodes
-Lympho-hematogenous
dissemination to the lungs,
liver and other internal
organs may occur
-Pts w/ lesions <2cm in dia
have 60-80% 5-yr survival
after treatment with
vulvectomy and
lymphadenectomy
-Pts with larger lesions with
lymph node involvement
have 5-yr survival rate of
<10%
-Diagnosis based on ID of
->80% LSIL and 100% HSIL
nuclear atypia with nuclear
assoc w/ oncogenic risk HPVs
enlargement,
(HSIL occurs: 80% LSIL, 20%
hyperchromasia, presence of de novo)-HPV 16 single most
coarse chromatin granules,
common HPV type detected
variation of nuclear sizes and in both
shapes
-risk dev'ing precancer and
-Koilocytic atypia
cancer conferred only in part
Grading into low or high SIL by HPV type and depends
based on expansion of the
also on immune status and
immature cell layer from its environmental factors.
normal, basal location
Infection with a high risk
-LSIL: immature squamous
HPV type itself is not
cells confined to lower 1/3 of sufficient to cause cancer, as
epi
vast majority of women w/
-HSIL: immature squamous
HPV infections do not nave
cells expand to 2/3 of epi
cancer
thickness
-Vaccines presently being
used are effective against 4
types of HPV (6,11,16,18)
and do not afford same
degree of protection for
black women as for white
women (inclusion of
33,35,58,68 subtye will give
broader range of protection)
-Progression into invasive
carcinoma when it happens
may take place in a few
months to more than a
decade, thus screening and
early detection are
important
-may regress spontaneously
-do not progress directly to
invasive carcinoma
-Often followed conservatively
-Increased cellular prolif,
decreased/arrested epi
maturation, lower rate of viral
replication
-1/10th as common as LSIL

10% will progress to carcinoma,

usually within 2-10 yrs
-Treated according to extent of
disease

Squamous Cell Carcinoma - Nests -Electrocautery, conization,

and tongues of malignant
cryosurgery, hysterectomy,
squamous epi, either keratinizing lymph node dissection,
or non-keratinizing, invading the irradiation
underlying cervical stroma
-Prognosis and survival for
-Nest breaking through basement invasive cancer depends largely
membrane of HSIL for
on the stage at which the cancer
microinvasion
is first detected and to some
-Adenocarc/Endocervical
degree on the cell type
adenocarc
-15% of cervical cancer, devs
from adenocarc in situ
-Assoc w/ high oncogenic risk
HPVs
-Proliferation of glandular epi
composed of malignant
endocervical cells with large,
hyperchromatic nuclei and
relatively mucin-depleted
cytoplasm, resulting in dark
appearance of glands
-Variable in color. Yellow-red -Severe dysmenorrhea
stains reflect breakdown of
-Dyspareunia (pain with
blood products
intercourse)
-Red lesions reflect early
-Pelvic pain due to
form of disease
intrapelvic bleeding
-With repeat cycles of
-Malignancy occurs in about
hemorrhage and onset of
1-2% of cases
fibrosis, affected surface may -Complications include
show scarring and take on
adhesions, infertility (30grossly brown discoloration 40% of pts), ectopic
("powder burns")
pregnancy
-In extensive disease, may be -Sites include ovaries
extensive fibrous adhesions (>60%), other uterine
-Chocolate cysts in ovary
adnexa (uterine ligaments,
from repeated hemorrhage
rectovaginal septum, pouch
-Ectopic endometrial glands of douglas), and the pelvic
and stroma, with or without peritoneum covering the
the presence of hemosiderin uterus, fallopian tubes,
-The endometriotic tissue is rectosigmoid colon, and the
not just misplaced but is also bladder and even lymph
abnormal
nodes, lungs, heart, skeletal
-Tissue exhibits a number of muscle or bones
changes which enhance
survival and persistence of
the tissue within a foreign
location
Two types: Type I Endometrial
-Abnormal uterine bleeding
adenocarcinoma and Type II Non- -May spread directly to paraendometroid adenocarcinoma
aortic lymph nodes
-Prognosis depends heavily
on the clinical stage of the
disease when it is discovered
-High levels of estrogen and
progesterone receptors in
the tumor and low levels of
proliferative activity
correlate with a better
diagnosis
-Endometroid carcinoma
have better prognosis than
non-endometroid carcinoma
such as serous carcinoma
-Localized polyploid tumor or See Endometrial adenocarc
diffuse tumor involving the
endometrial surface
-Gland patterns resemble
normal endometrium
epithelium
-Varies from well
differentiated (Grade 1), with
easily recognizable glandular
patterns;
-to moderately differentiated
(Grade 2), showing wellformed glands mixed with
solid sheets of malignant
cells
-to poorly differentiated
(Grade 3), characterized by
solid sheets of cells with
barely recognizable glands
and a greta degree of nuclear
atypia and mitotic activity
See Endometrial adenocarc

-All non-endometroid adenocarcs See Endometrial adenocarc

classified as Grade 3 irrespective
of histologic pattern, cells with
marked cytologic atypia,
mutatino in p53 tumor
suppressor gene seen in 90% of
serous endometrial
adenocarcinoma
-Firm, pale-gray, sharply
-Can be clinically silent
Most common
circumscribed, whorled masses -Menorrhagia is the most
benign tumor in
without encapsulation
frequent manifestation, with
females, found in
-Sizes range from 1mm to
excessively prolonged or profuse 30-50% of
>30cm in dia
menses
women during
-Some intramural, others directly -Metrorhagia may be present,
repro life
beneath the endometrium
irregular, acyclic bleeding btwn
(submucosal), or directly beneath periods
the serosa (subserosal)
-Rarely transforms into sarcomas
-Whorling bundles of smooth
muscle cells
-Foci of fibrosis, calcification,
ischemic necrosis, cystic
degeneration, hemorrhage may
be present
-Appearance variable from bulky -Recurrence after removal
-Accounts for
mass to polypoid lesions
common
~2% of uterin
projecting into the uterine cavity -Many metastasize to lungs
malignancies
or structure that resembles
-5 yr survival rate is about 40% -Age of
benign leiomyoma
appearance on
-Soft, hemorrhagic, necrotic
average more
-Wide range of differentiation
than a decade
from those that closely resemble
(age above 50
leiomyoma to wildly anaplastic
yrs) than those
tumors
with leiomyomas
-Mitosis activity, cellular atypia,
and geographical necrosis are
the best diagnostic criteria

Disease

What is it?

Salpingitis

Inflammation of
the fallopian
tubes

Ovarian
Neoplasms

Second most
freqwuent
gynecological
malignancy after
endometrial
cancer. Carries
higher mortality
rate than all
other female
genital cancers
combined

Surface
EpithelialStromal Cell
Tumors

What causes it?

Intrinsic/Acquire Morphology/Pathology
(Pathogenesis)
d?
typically due to infection Acquired
-Acute inf phase - marked
ascending from the lower
infiltration by polys,
genital tract
pronounced edema,
-E.coli, Chlamydia,
congestion of mucosal folds
Mycoplasma, Neisseria
-chronic salpingitis gonorrhea
infiltrate consists of
lymphocytes, plasma cells.
Edema and congestion tend
to be minimal
-Late stages, tubes may be
sealed and become
distended with pus
(pyosalpinx) or a transudate
(hydrosalpinx)
-Tubes allow access to the
peritoneal cavity by
microorganisms, leading to
peritonitis and PID
-Infiltration with numerous
neutrophils

Two of the most important

risk factors are nulliparity
(para 0) [never having
given birth] and family
history
-5--10% of ovarian
cancers familial. Majority
of cases of hereditary
ovarian cancers has muts
in BRCA gene with
lifetime risk of 3% in
BRCA1 carriers and
somewhat lower in BRCA2
carriers
-Muts in BRCA genes only
about 10% in sporadic
cancers
-Overexpression of
HER2/NEU assoc w/ poor
prognosis

Serous Tumors Surface

of the Ovary
Epithelial-stromal
Cell Tumor Most freq of
ovarian tumors
(60-70%)
-Benign lesions
usually cistic
encountered
btwn ages 30-40;
cystadenoma
-Malignant
lesions more
commonly seen
btwn 45-65 yrs of
age cystadenocarcino
ma
-Combined,
borderline and
malignant serous
tumors most
common
malignant
ovarian tumors,
account for about
60^ of all ovarian
cancers
Serous Ovarian Surface
Tumors
Epithelial-stromal
Cell Tumor
-usually large,
spherical to
ovoid cystic
structures and
can reach 3040cm in dia
-25% of benign
forms bilateral

Malignant
EpithelialStromal Tumors
of the Ovary

Cancer of the
Breast

Cancer of the
Breast Hereditary

Cancer of the
Breast - NonHereditary

Ductal
Carcinoma in
situ

Clinical
Misc.
Significance/Features
-Acute episode, esp. w/
Chlamydia, may be
asymptomatic
-Reinfections common
-Usually component of pelvic
inf disease
-Adhesion may develop;
formation of tuboovarian
abscess
-Damage caused by chronic
salpingitis may impair tubal
motility and the passage of
sperm, leading to infertility
-Chronic salpingitis common
cause of ectopic pregnancy

Most common
-Poorly understood process
malignancy of
and risk factors are complex
women in the US -Cancers exhibit diverse
- mortality rate
histopathology, molecular
from this disease features, overall pt outcomes
second only to
-Thus, can be viewed as a
that of lung
multifaced and complex epi
cancer
malignancy
-1 in 8 American
women may be
expected to
develop breast
cancer, 1/4 of
whom will die of
the disease
-4-5x more freq
in Western
industrialized
countries than in
dev'ing countries
Strongest assoc Breast Cancer Genes
w/ increased risk -BRCA1 (breast cancer 1)
for breast cancer -Tumor suppressor gene
is fam history,
on chroms 17 (17q21)
specifically
-Implicated in pathogenesis
breasat cancer in of hereditary breast and
first degree
ovarian cancers, may be
relatives (mother, prostate and colon ca too
sister, daughter) -Mutations thought to be
-Risk is greater
present in 1in 200 to 400 ppl
when relative
in US
devs disease at -Germline point muts and
young age or w/ dels in BRCA1 confer 60% to
bilateral breast 85% lifetime risk for breast
cancer
cancer, with more than half
of the tumors developing
before 50 yrs of age
-Mutated BRCA1 is propbs
responsible for 20% of all
inherited breast cancer,
responsible for about 3% of
all breast cancers
-somatic muts in BRCA1
infreq detected in sporadic
breast cancers
Make up the
Risk Factors:
Majority of the
-Hormones: strong link
cases
btwn breast cancer and
-Most breast
hormonal status of
cancers not assoc woman
w/ hereditary
-Nulliparous women or
factors
those w/ 1st pregnancy
after age 35 have a 2x
higher risk for breast
cancer than those whose
first pregnancy occurred
before age 25
-Radiation - therapeutic
doses increase risk
-Previous cancer of the
breast - 10x increased
risk of developing a
second primary breast in
the same or in the
contralateral breast
-Fibrocystic change women with proliferative
fibrocystic change (esp.
with atypical hyperplasia
are at an increased risk
for cancer
Most common
form of in situ
breast carcinoma
-Arose from
terminal duct
lobular unit
-Malignant epi
cells have not
penetrated the
BM

Comedo DCIS

High grade
subtype of DCIS

Lobular
Carcinoma in
situ

Second most
common form of
in situ breast
carcinoma
-Arose within
terminal ductal
lobular nits
-Malignant epi
cells have not
penetrated BM

-Single layer of tall columnar

epi that lines cyst or cysts
-frank carcs - lining cells
display anaplasia nad
invasion of stroma
-subtype intermediate btwn
benign and invasive cancer
('borderline'), the 'tumors of
low malignant potential' can reach great size (100+
kg)
-Spread to regional lymph
node but distant metastasis
is infreq for this type of
tumor
CA-125, antibody to cancer
antigen in serum detects half of
epi tumors confined to ovary,
90% that have already spread
-Ovarian masses rarely cause
symptoms until already large
-Mass effects - pain, pelvic
pressure, or compression of
regional organs
-By the time of diagnosis, may
have metastasized (implanted)
to the surface of the pelvis,
abdominal organs, bladder,
diaphragm, paracolic gutter, or
omentum
-Survival w/ malignant ovarian
cancer generally poor - 5 yr rate
is 35% due to late detection
Chief forms of carcinomas in - "Lumpiness" or other
the breast
symptoms (1% of these pts
A. Noninvasive
have cancer)
1. From the terminal duct lobular -Pain (5% of these pts have
unit
cancer)
2. Ductal carcinoma in situ
- Nipple discharge (7% of pts
(DCIS; intraductal carcinoma)
have cancer)
3. Lobular carcinoma in situ
-Palpable mass (12% of these
(LCIS)
pts have cancer)
B. Invasive (Infiltrating)
1. Invasive ductal carcinoma
("not otherwise
specified")/scirrhous carcinoma,
most common
2. Invasive lobular carcinoma
3. Medullary carcinoma
4. Colloid carcinoma (mucinous
carcinoma)
5. Tubular Carcinoma
6. Other types
More Breast Cancer Genes
-BRCA2 (Breast cancer 2)
-Gene is located on chrom
13q12
-Implicated in about 20% of
hereditary breast cancers
-Carrier of one copy of BRCA2
gene has 30-40% lifetime
chance of dev'ing breast cancer
and increased risk for ovarian
cancer
-Mut esp. common in Ashkenazi
Jewish women
-Men with this mutation are at
increased risk of breast cancer
-P53
-Mutated in Li-Fraumeni
syndrome. Breast cancer will
dev in almost all young
women with this disease
-Germline (inherited muts in p53
account for 1% of breast cancer
among women under age of 40
yrs
-Genetic changes
-Mutations affecting protooncogenes and tumor
suppressor genes in breast
epi contribute to the
oncogenic transformation
process
-Overexpression of
HER2/NEU proto-oncogene
has been found in up to 30%
of invasive breast cancers
-Gene is member of
epidermal growth factor
receptor family and its over
expression is assoc w/ poor
prognosis
-Environmental Factors

-Tends to fill, distort, unfold -W/ early screening, DCIS

involved lobules, thus
only rarely presents as a
appears to involve ductlike palpable or radiologically
spaces
detectable mass
-Histologic appearance
-If detection is delayed, a
varies and are often mixed, palpable mass or nipple
including solid, comedo,
discharge may develop
cribiform, papillary,
-Prognosis for DCIs is
micropapillary types etc.
excellent with over 97% long
-Nuc appearance usually
term survival after simple
uniform in a given case and mastectomy
ranges from bland and
-At least 1/3 of women with
monotonous (low grade) to small areas of untreated
pleomorphic (high grade)
low-nuclear-grade DCIS will
-Necrosis is minimal
eventually develop invasive
-Calcifications are freq assoc carcinoma
w/ DCIS and important in
-When invasive cancer does
detection of these lesions
develop, it is usually in the
during screening
same breast and quadrant
-Cells in better diff'd DCIS
as teh earlier DCIs
express estrogen and, less
-Surgery, radiation, antioften, progesterone
estrogens
receptors
-Non-comedo subtype less
likely to incite desmoplastic
response
-Solid pattern w/ neo cells
filled and expand duct
lumina, still within ducts and
have not broken through BM
into adjacent stroma.
-Composed of very large,
pleomorphic epi cells w/
abundant cytoplasm,
irregular nuclei, often
prominent heterogenous
nucleoli
-Cancer cells grow rapidly
within ducts and freq show
intraductal necrosis
-Gross: lesion often shows
distended duct-like
structures containing white,
necrotic material resembling
comedos, which often
undergoes dystrophic
calcification; this results in
multiple, microscopic
calcified bodies visible on a
mammogram (see necrotic
materials w/ calcification)
-May incite chronic innf,
neovascularization,
desmoplastic response
(fibroblast proliferation and
subsequent fibrosis) in a
peritubular distribution
-Cells tend to be smaller and -Virtually always an
more monotonous than DCIS, incidental finding
round, regular nuclei and
-Does not form masses and
minute nucleoli
is only rarely assoc w/
-Malignant cells appear as
calcifications
solid clusters that pack and -1/3 of women with LCIS will
distend terminal ducts but
eventually dev invasive
not to the extent of DCIS
carcinoma
-Intracellular mucin vacuoles -With this lesion,
(signet ring cells) common
subsequent invasive
carcinomas arise in either
breast at significant
frequency
-LCIS is both a marker of
increased chance of
developing breast cancer in
either breast and a direct
precursor of some cancers