BASIC PATHOLOGY

Reversible Cell Injury

1. Cellular swelling (H20 accumulation in cytoplasm)

2. Fatty Change

Irreversible Cell Injury

1. Coagulation necrosis: preserves basic cell shape; nucleus is destroyed while cytoplasm
becomes brightly eosinophilic. Most common type of necrosis.

2. Liquefactive necrosis: everything dissolves, leaving a hole. Occurs in two situations; CNS
damage and abscess formation.

3. Fat necrosis: loss of cell structure through fat saponification: Occurs in high fat tissues.

4. Caseous necrosis: combines features of coagulation and liquefactive necrosis (curdled

cheese consistency). Characteristic of TB/histo granulomas.

Morphologic Features of Cell Death (common to early stages of most types of necrosis)

1. Cytoplasmic eosinophilia

2. Irregular cytoplasmic margins develop (cytoplasmic blebbing)

3. Increased cytoplasmic granularity due to H20 loss

4. Nuclear changes

a. chromatin clumping

b. chromatin shrinkage into dense, irregular ball (pyknosis)

c. nuclear fragmentation (karyorrhexis)

d. disappearance of nucleus (karyolysis)

INFLAMMATION

Cardinal Features of Inflammation

1. Redness (rubor)

2. Heat (calor)
3. Swelling (tumor)

4. Pain (dolor)

5. Loss of function

Stages of Inflammation

1. Vase dilatation

2. Exudation
a. fluid
b. cells

3. Demolition

4. Resolution or repair

Vasodilation

--begins with triple response (red line; flare’ wheal)

--flare medicated by axonal response; red line and wheal by chemical mediators which include:

a. vasocoactive amines (serotonin from platelets, histamine from st cells)

b. plasma proteases (kinin; complement (C3a, C5a); coagulation and fibrinolysis proteins)

c. arachidonic acid metabolites (prostaglandins, leukotrienes, chemotactic lipids)

Exudation

1. fluids
--vasoactive substances not only relax arteriolar muscle but increase venule
permeability to H20, ions and proteins

2. With severe injuries (implying some degree of cell necrosis), also get exudation of
inflammatory cells

a. When vessels become dilated and leaky, RBC clump in middle and WBC are
pushed to the outside.

b. If endothelium is altered and “sticky”, WBC will adhere to it.

c. Diapedesis then occurs under stimulation from chemotactic factors (substances that
attract leukocytes; released by dead bacteria, other inflammatory cells, etc.) In
 diapedisis, leukocytes squeeze between endothelial cells, break through basement
membrane and migrate out through vessel walls into tissue.

3. Demolition (applies to insults that cause at least some tissue necrosis)

The bodies “clean-up” cells (for example, macrophages) come in gobble up debris and take
it away.

4. Resolution or repair (again applies to injuries causing some degree of cell necrosis)

A. Resolution: appropriate cells regenerate and no scar results (examples: most cases of
pneumococcal pneumonia, acute tubular necrosis or kidney)

B. Repair = scar formation (fibrosis or gliosis)

Sequence of Repair

1. 24-48 hours after injury, fibroblasts and capillaries start to grow into necrotic areas under
the stimulation of substances released by macrophages.

2. When an extensive network of capillaries and fibroblasts have filled in an area, this is
called granulation tissue (no relationship to granulomas).

3. As fibroblasts produce collagen, granulation tissue matures into a fibrous scar. Eventually,
capillaries regress, leaving behind a relatively avascular, dense scar.

From the Surgical Literature

1. Wound healing by first intention: (e.g., response to scalpel cut) heals quickly, then leaves
scar.

2. Wound healing by second intention: lots of tissue necrosis (e.g., after wound infection);
wound slowly heals in with lots of granulation tissue which ends up as big scar.

Effectiveness of any type of wound healing is impaired by

1. Impaired blood supply (example: foot ulcers in person with severe atherosclerosis of leg
arteries).

2. Superimposed wound infection.

3. Foreign material in wound.

4. Deficiency of certain nutrients (example, scurvy)

5. Corticosteriods.
 TYPES OF INFLAMMATION

1. Acute: sudden onset; duration hours-days

chief cell type is the neutrophil

combination of acute inflammation and tissue destruction is abscess

2. Chronic: duration weeks-months-years

main cell types are lymphocytes, plasma cells and occasional histiocytes

may coexist with repair

3. Granulomatous: subtype of chronic inflammation

occurs in response to indigestible particles (TB bacilli, histoplasma yeast;

urate crystals; splinters, etc.)

characteristic cell is the epithelioid (or activated) macrophage (a big

macrophage with lots of cytoplasm). These cells may fuse to form
“Langerhans” or foreign body-type giant cells.

central caseation necrosis may or may not occur depending on the type of
particle (common with TB and histo)

Undesirable sequelae of inflammation may include

1. May get antigen-antibody complexes that get filtered out in kidney and other capillaries
leading to glomerulonephritis and vasculitis.

2. In some diseases like gout, neutrophils keep trying unsuccessfully to dissolve urate
crystals; die; release lytic enzymes and damage surrounding tissue without doing a thing to
the urate crystals.

3. Long term inflammation can lead to amyloidosis.

4. Sometimes inflammation is inappropriate (e.g., autoimmune diseases).

5. Repair can be excessive (e.g., keloid), or can cause adhesions.

Classification of immune responses that can lead to tissue damage

Type I hypersensitivity (anaphylactic types)

--mediated by IgE bound onto surface of mast cells. (Fc end is connected to cell membrane)
--when IgE recognizes and binds its corresponding antigen via the Fab end, there are presumable
conformational changes that end up by signaling the mast cell to degranulate and disgorge a
variety of vasoactive substances (histamine, serotonin, eosinophilic chemotactic factor of
anaphylaxis, SRS-A, etc.)

--examples: asthma; allergies such as hay fever; anaphylactic allergic responses to drugs, bee
stings, etc.

Type II hypersensitivity (cytotoxicity)

--an antibody (IgG or IgM) reacts with an antigen on the target cell surface. That cell is then
destroyed/damaged either by complement-mediated cell lysis or via attack from cell that have Fc
receptors (killer cells, macrophages, etc.)

--examples: mismatched transfusion reactions; Rh incompatibility (Rh-mother, Rh+baby);

autoimmune hemolytic anemia; Hashimotos thyroiditis; Goodpastures syndrome

Type III hypersensitivity (immune complex mediated)

--antigen-antibody complexes are formed in one location that get into the circulation and then
lodge in capillaries (glomerular or systemic). These complexes activate an inflammatory
response.

--examples: serum sickness, many types of glomerulonephritis and vasculitis (sometimes the
offending complex is know, e.g., streptococcal antigen-antibody complex in post-streptococcal
glomerulonephritis; or unknown, as in polyarteritis nodosa and idiopathic membranoproliferative
or membraneous glomerulonephritis)

Type IV hypersensitivity (cell mediated delayed hypersensitivity)

--mediated by sensitized T-cells; immunoglobulin, immune complexes are not involved.

--cell injury may be effected by cytotoxic T cells or by macrophages recruited by the sensitized T
cells.

--examples: TB/histo; poison ivy; some types of transplant rejection.

Type V hypersensitivity (anti-receptor disease)

--the antibody directed toward a receptor molecule may either activate the receptor (e.g., Graves
disease) or damage it and decrease its function (example, myasthenia gravis).
 AUTOIMMUNE DISEASES

May be humoral or cell-mediated.

4 theories as to why control mechanisms become deranged:

1. Sequestered antigen (body never had chance to develop tolerance)

2. Antigen modification—modified antigen no longer recognized as self, therefore attacked.

3. Cross-reactive antigen. An antibody made to a foreign invader (e.g., streptococcus)

4. Alteration in lymphoid system: balance between T helper and suppressor cells is impaired,
leading to out of control system.

SYSTEMIC TYPES OF AUTOIMMUNE DISEASE

Systemic Lupus Erythematosus (SLE)

--appears to be strongly associated with antinuclear antibodies (especially to native) double-

stranded) DNA.

--generally occurs in young females (age 20-40)

Features

articular pain
fever
skin rash (especially in butterfly facial distribution)
renal disease (glomerulonephritis: most common subtype is diffuse proliferative)
pleuritis and pleural effusion
pericarditis
neurological disease (seizures and/or psychosis)
lymphadenopathy and splenomegaly
hemolytic anemia (autoimmune)

--there is a “variant” called chronic discoid lupus erythematosus which s usually FANA negative
but has skin disease resembling SLE. Only a few cases of discoid lupus progress to SLE.

--a SLE-like syndrome (including +FANA) can be induced by drugs (especially the
antiarrhythmic procainamide and the antihypertensive drug hydralazine). Usually remits
after the drug is withdrawn.

Scleroderma (Progressive Systemic Sclerosis)

--associated with antinucleolar antibodies, other antibodies

--usually middle-aged women

--see fibrosis of multiple organs, especially the dermis of the skin; may also see submucosal
fibrosis of esophagus, GI tract; thickening of renal injury and hypertension; and pulmonary
fibrosis. May also be associated with joint pain.

Polyarteritis Nodosa

--necrotizing vasculitis affecting medium or small arteries in any part of the body.

--involvement most common in kidneys (85%), where it may be associated with focal
glomerulonephritis; heart (75%); liver (65%), GI tract (50%); but it can be seen almost
anywhere (although pulmonary circulation is usually spared).

--most common clinical presentation is fever and renal manifestations due to renal vessel
involvement (hypertension, renal failure). May cause infarcts elsewhere.

Sarcoidosis (not necessarily autoimmune disease, but where else to put it?)

--numerous non-caseating granulomas of unknown etiology which can occur anywhere in the
body.

--most common site of involvement is hilar lymph nodes (bilateral hilar adenopathy on CXR in
young women is often sarcoid).

--generally disease of young women. More common in blacks (10x incidence).

Goodpasture Syndrome

--antibodies to glomerular basement membrane

--damage to glomerular basement membrane leads to crescentic, rapidly progressive glomerulo-

nephritis and damage to alveolar basement membrane leads to hemoptysis, pulmonary
hemorrhage.

Wegeners Granulomatosis

--like polyarteritis nodosa, no specific antigen-antibody complex has been found.

--see acute necrotizing granulomas of upper and lower respiratory tracts (lung, nose, and sinuses,
generally in young to middle aged individuals.

--also see focal necrotizing vasculitis, also most common in upper airways and lungs

--associated renal disease in the form of focal or diffuse necrotizing glomerulonephritis.

Transplant Rejection

1. Hyperacute—organ turns purple as soon as the vascular supply is connected, resulting in

nearly immediate transplant loss.

--Due to preformed antibodies that bind to the endothelium of the transplanted organ and
damage vessels.

2. Acute (may be multiple episodes)

--see interstitial infiltration of lymphocytes plus damage to small vessel endothelium.

--T-cell mediated with additional humoral component if not treated within a few days.

3. Chronic rejection—slow, clinically silent damage to small vessels which ends up as

ischemic organ in 5-10 years.

EDEMA

Factors that lead to edema:

1. Increased hydrostatic pressure within vessels.

2. Decreased oncotic pressure due to decreased serum proteins.

3. Increased vascular permeability to proteins as seen in inflammation.

Localized edema may be due to:

1. Local increase in venous pressure due to local venous obstruction (e.g., leg edema distal to
deep vein thrombosis).

2. Local lymphatic obstruction (lymphedema due to lymphatic obstruction by tumor; filaria;

surgical ligation or radiation-induced fibrosis).

3. Pulmonary edema can be due to L pump failure.

4. Local inflammation with increased vascular permeability and exudation.

Systemic edema may be due to:

1. Decreased oncotic pressure due to protein loss (e.g., nephrotic syndrome, burns) or to
decreased protein synthesis (liver failure).

2. Anuric renal failure, with increased total body fluid that apportions between vessels and
interstitium.
3. Increased total body fluid due to secondary hyperaldosteronism (for example, renal artery
stenosis leads to low perfusions of kidneys and increased aldosterone levels; similar
process can occur in L cardiac pump failure with inadequate systemic perfusion).

4. Severe R sided cardiac pump failure leads to increased systemic venous pressure (often
there is associated forward failure leading to secondary hyperaldosteronism).

Distinction between transudates and exudates

Exudates by definition have high protein content (more than 2 gm/100ml) with or without cells;
and a high specific gravity (more than 1.018). They are commonly associated with inflammation
and with malignant effusions.

Transudates by definition have low protein contents (less than 2 gm/ml); few or no cells; and a
low specific gravity (less than 1.012). They are caused by increased capillary hydrostatic
pressure (as in pulmonary edema) or decreased oncotic pressure (as in nephrotic syndrome).

HEMOSTASIS AND THROMBOSIS

Participants: vessels and support structures

platelets
plasma coagulation factors
fibrinolytic system (plasminogen system)

Hemorrhagic problems related to weak vessels

1. Scurvy (impaired collagen synthesis)

2. Amyloidosis (vessel weakened by amyloid deposits in wall)

3. Steroid therapy/Cushings syndrome (fragile capillaries)

4. Ehlers Danlos syndrome (another weak collagen syndrome)

5. Hereditary telangestasia (weak, dilated capillaries)

Hemorrhagic problems related to platelets

1. Thrombocytopenia (ITP, acute leukemia, chemotherapy, DIC, etc.)

2. Impaired platelet function due to drugs—especially aspirin.

3. Impaired platelet function in uremia.

4. Von Willebrand’s disease (von Willebrands factor not only acts as the serum carrier for
Factor VIII, it is also involved in platelet admission).
Hemorrhagic problems related to the plasma coagulation cascade

1. Classical hemophilia A (decreased Factor VIII)

2. Hemophilia B (Christmas disease) decreased Factor IX

3. Von Willebrands disease (vWF required for full activity of Factor VIII).

4. Diminished Vitamin K dependent factors due to poor diet, coumadin therapy.

5. Severe liver failure (decreased clotting factor synthesis)

6. Consumption of factors (especially in DIC)

EXCESSIVE CLOTTING

Vessel Factors

1. Stasis (due to decreased blood flow, obstruction, etc. Example: cardiac mural thrombi)

2. Damage to vessel endothelium (example: thrombus forming over ulcerated atherosclerotic

plaque).

Platelet Factors

--very high platelet counts (over 1 million) may increase tendency to clot inappropriately.
Plasma Factors

--High levels of normal clotting factors don’t seem to be a common cause of hypercoagulability.

--Deficiencies in normal regulatory proteins such as antithrombin III, protein C may be

implicated in some case of multiple thrombi.

--Factors released by tumors, etc. may somehow activate the clotting system and increase the
tendency to thrombosis.

Disseminated Intravascular Coagulation

--Complex disorder.

--Initiated by variety of situations. For example, tumor products tend to promote coagulation;
gram negative endotoxin activates complement and damages endothelial cells, initiating the
clotting cascade.

--In addition to disseminated clotting, also get hemorrhage because inappropriate clotting has
consumed most platelets and coagulation factors, leaving patient vulnerable to bleeding.
On top of all this, the proteolytic system (plasmin) is activated by the clotting; it begins to
 degrade fibrin to fibrin split products while other clots are forming. Fibrin split products
tend to inhibit clotting, so have two reasons for hemorrhage (decrease coagulation factors
and platelets plus concurrent inhibition of clotting by fibrin split products).

INFARCTION

Defined as the death of cells secondary to deprivation of O2 by impairment of blood supply.

Two types of infarct

1. White (anemic) infarct

-- occurs if occlusion is in an end-arterial vessel system (a single vessel system with little
collateral circulation).

-- examples: heart, kidney

2. Red (hemorrhagic) infarct

--occurs if: a) Dual arterial system (examples: liver, lung)

b) Venous infarct. Venous infarcts are rare since most veins have good
collateral—but can occur in kidney after renal vein thrombosis since the
renal vein has no collateral. Since blood outflow is blocked, organ
swells; as pressure increases, arterial flow into the organ becomes
sluggish and O2 delivery is impaired.

c) Occasionally, if thrombus/emolus fragments after tissue becomes

necrotic.

Arterial infarcts generally result in coagulation necrosis, except in brain where liquefactive
necrosis is the rule.

EMBOLISM

1. Derived from venous source

--most common type

--generally arise in deep leg veins; occasionally in pelvic veins.

--embolus passes through R side of heart and impacts in lung. Not all pulmonary emboli
result in infarct because in some cases bronchial circulation can sustain tissue viability.

2. Emboli arising in heart

--May be due to valvular vegetations of endocarditis, or due to mural thrombi in dilated,

 akinetic cardiac chamber.
--R-sided thrombi/vegetations give rise to pulmonary emboli.

--L-sided thrombi/vegetations give rise to systemic emboli.

3. Derived from arterial source

--Usually from thrombus overlying ulcerated atherosclerotic plaque, or from mural

thrombus within atherosclerotic aneurysm.

--Emboli impact further distal in arterial system.

4. Fat embolism

--Complicates severe trauma with multiple fractures. Impacts in lungs.

NEOPLASIA AND CELL ALTERATIONS

1. Atrophy: loss of cells due to disuse, loss of nerve or blood supply, poor nutrition or
necessary endocrine stimulation.

2. Hypertrophy: increase in cell size (no increase in cell number). May translate into organ
enlargement. May be physiologic (e.g., increase in muscle mass in manual
laborer) or pathologic (e.g., chronic hypertension causing left ventricular
hypertrophy). Hypertrophy generally occurs in muscular tissues (skeletal,
cardiac, or smooth muscle).

3. Metaplasia: reversible change in which one type of adult tissue is replaced by another.
Example: squamous metaplasia in smokers’ bronchi—squamous epithelium
replaces normal ciliated respiratory epithelium.

4. Hyperplasia: increase in number of cells in an organ or tissue with resulting increase in

organ size. May be physiologic or pathologic: pathologic hyperplasia may
be precursor to cancer (example: adenomatous endometrial hyperplasia).

5. Dysplasia:

A. Non-neoplastic (example: congenital malformations, as in cystic dysplasia of kidney).

B. Pre-neoplastic: can occur in cervix; skin; lung; esophagus; colon and stomach. Best
example of progression is seen in cervix: normal cells: dysplastic cells: carcinoma in
situ: invasive carcinoma.

6. Neoplasia (means new growth) may be benign or malignant

Malignant neoplasms (cancer) have characteristic features:

 A. They arise from a single cell (monoclonality).

B. Chromosomes are often abnormal and very unstable.

C. They have lost ability to regulate growth (example: loss of contact inhibition).

D. Have ability to metastasize.

Subtypes of Malignancies

1. Carcinoma (epithelial cells) main subtypes are squamous cell carcinoma (produce keratin)
and adenocarcinoma (produce mucin and/or grow in glands).

2. Sarcoma (mesenchymal cell origin) Many types of differentiation; rhabdomyosarcoma

(skeletal muscle); leiomyosarcoma (smooth muscle); angiosarcoma (vessels); liposarcoma
(fat); chondrosarcoma (cartilage); osteosarcoma (bone); fibrosarcoma (fibroblasts);
malignant fibrous histiocytoma (MFH); mixed fibrohistiocytic differentiation).

3. Lymphoma (lymphocytes)

4. Gliomas (glial cells; include astrocytomas, glioblastomas, etc.)

5. Germ Cell tumors (Seminoma, embryonal carcinoma, teratomas, etc.)

6. Melanoma (melanocytes)

7. Leukemia (white blood cells; distinction from lymphoma to be discussed later)

Current two hit theory: need initiator (carcinogen) and promoter (example: hormonal mileau).

Carcinogenic events may include radiation damage, chemical carcinogen and viral carcinogens.

Individual virus which may be implicated in some malignancies in humans include:

Hepatitis B (hepatocellular carcinoma)
Epstein Barr virus (EBV) (Burkitts lymphoma; nasopharyngeal carcinoma)
HTLV I (an unusual type of T cell leukemia-lymphoma)
?papilloma virus (cervical carcinoma)
?herpes simplex (cervical carcinoma)

Best predicator of prognosis in cancer: stage

 NUTRITIONAL DEFICIENCIES

Marasmus: deficient calories and protein

Kwashiorkor: adequate calories; deficient protein

Vitamin Deficiencies

A = night blindness, skin and mucous membrane problems

B1 = (thiamine): beriberi: cardiomyopathy, spinal cord and nerve degeneration

B2 = (riboflavin): dermatitis, glossitis, cheilosis

B6 = (pyridoxine): folate: megaloblastic anemia

Niacin = pellagra (dermatitis, diarrhea, dementia)

C = scurvy (impaired collagen synthesis; easy bleeding, soft bones due to inadequate
osteoid formation, weakened tooth sockets.

D = rickets/osteomalacia: soft, deformable bones due to inadequate mineralization.

INBORN ERRORS OF METABOLISM

Almost all are autosomal recessive: most have onset in childhood.

Phenyketonuria: inability to convert phenylalanine to tyrosine. Effects: musty odor; fair

complexion due to inability to synthesize melanin; seizure and mental retardation unless
phenylalanine-restricted diet begun near birth.

Lysosomal storage diseases (mucopolysaccharidoses) (includes Hurler’s, Hunter’s, etc.) caused

by inability to Metabolize a given mucopolysaccharide. Most types have enlarged liver, spleen.
Often associated retardation.

Glycogen storage diseases (deficiencies of glycogen synthesis or metabolism enzymes) some

affect only muscle, others are systemic.

Alpha-1-antitrypsin deficiency—leads to cirrhosis, emphysema.

DIABETES MELLITUS

Type I: juvenile onset Type II: adult onset

insulin dependent not always insulin dependent
brittle fairly stable
ketosis-prone ketosis-resistant
10% cases of diabetes 90% cases of diabetes
generally not obese generally obese
Type I diabetics present acutely in childhood with polyuria, polydipsia, polyphagia; and possibly
in ketosis. Have markedly low serum insulin levels.

Type II diabetics have insidious onset in adulthood; rarely become ketotic. They have normal to
increased serum insulin levels. Weight loss may improve diabetic control.

Long-Term Sequelae of Diabetes Mellitus

Prolonged hyperglycemia leads to thickening of basement membranes as small blood vessels

throughout the body, which is the underlying cause of much of the long term morbidity and
mortality.

Clinical Manifestations of Long-standing diabetes mellitus

1. Nephropathy:

--6 months to 1 year: see GBM thickening by EM and increased mesangial matrix
material.

--Changes visible by light microscopy after 10-12 years; these include diffuse glomerular
capillary basement membrane thickening in almost all cases; approximately 25% develop
Kimmelsteil Wilson lesions nodular glomerulosclerosis.

--A leading cause of renal failure in the US.

2. Retinopathy

--The leading cause of blindness in the U.S.

--See first “background retinopathy” with small hemorrhages and aneurysms.

--Proliferative retinopathy refers to proliferation of capillaries, fibrous tissue in the retina—

associated with visual impairment.

3. Cardiovascular disease: diabetics have a higher rate and faster progression of

atherosclerosis.

4. Neuropathy: often in a stocking-glove distribution: sensory most affected.

5. Increased susceptibility to infection: hyperglycemia may impair neutrophil function.

6. Gangrene of the extremities/foot ulcers.

7. Renal papillary necrosis: combination of pyelonephritis in papilla with impaired blood

supply.
Causes of death: #1. MI #2. renal failure #3. Cerebrovascular Disease. Death
from ketosis/hyperglycemic coma is now rare.

AMYLOIDOSIS

A multisystem disease.

Gross: organomegaly.

Micro: eosinophilic amorphous-looking material deposited around blood vessels; expands later
into the interstitium of organs. Amyloid stains salmon-pink with Congo-Red stain under
normal light; polarization yields apple-green birefringence.

Ultrastructure: amyloid is composed of relatively uniform protein fibrils arranged into a beta-
pleated sheet.

Two main types of amyloid:

1. AL: (breakdown products of immunoglobulin light chains. Also called “primary”

amyloid) seen in multiple myeloma; Waldenstroms macroglobulinemia; also in cases of
“idiopathic amyloid” without demonstrable myeloma.

2. AA: (breakdown product of serum amyloid associated protein, an acute phase reactant
elevated in chronic inflammatory states). This type of amyloid (also called secondary
amyloid) complicates chronic inflammatory states like chronic osteomyelitis, TB leprosy,
rheumatoid arthritis, etc.

Almost any organ can be involved. GI tract, heart, respiratory tract most common in AL type;
spleen, kidney, liver in AA type; but there is much overlap. Death usually occurs because of
heart or kidney failure.

Other types of (localized) amyloidosis:

1. Calcitonin derived amyloid in medullary carcinoma of the thyroid within the tumor itself
(not usually systemic).

2. Solitary cardiac involvement in elderly persons is usually related to a breakdown product of

prealbumin.

3. Amyloid within Alzheimer’s plaques: biochemistry uncertain.

HEMOCHROMATOSIS

Triad of Findings

Diabetes mellitus (“bronze diabetes”)

Cirrhosis of the liver (pigment cirrhosis)
Atypical skin pigmentation

There is massive overload of iron within hepatocytes, Kupfer cells, cardiac myocytes, pancreatic
acinar cells, etc.

Idiopathic: due to inborn error of iron metabolism (autosomal recessive; exact biochemical
defect is unclear.

Secondary: due to need for recurrent transfusion (for example, in thalassemia major); also
seems to occasionally occur in alcoholics, possibly due to alcohol increasing iron absorption
from the GI tract.

SKIN: Inflammatory Conditions

1. Acne vulgaris (adolescent misery) see acute inflammation around plugged hair follicles.

2. Psoriasis: occurs in 1-2% of American adults.

Gross: scaly white plaques on extensor surfaces (especially elbows and knees)
scaly areas may bleed easily (Asupitz sign).

Micro: chronic inflammatory and neutrophilic infiltrate within dermis;

thickened epidermis with hyperkeratosis.

Biology: increased epidermal cell turnover (3-4 days versus 28 days). Cause
unknown.

3. Bullous lesions include pemphigus, pemphigoid, Stevens-Johnson syndrome, dermatitis

herpetiformis.

4. Warts (verruca vulgaris): raised lesion associated with papilloma virus. Microscopically,
see acanthosis, papillomatosis, hyperkeratosis and parakeratosis.

EPIDERMAL PROLIFERATIVE LESIONS

1. Seborrheic keratosis: benign proliferation of squamous epidermis in non-sun-exposed

areas of older individuals.

2. Actinic keratosis: preneoplastic, dysplastic keratosis that occurs in sun-exposed areas. See
dysplasia of basal layer; hyper and parakeratosis.

3. Malignant melanoma.

Superficial spreading (approx. 70-80% of cases)

Nodular (approximately 10-20% of cases)
Lentigo maligna melanoma (approx. 5% of cases)
 Some people add acral lentiginous melanoma (rare; looks like lentigo maligna melanoma
but arises in extremities, especially hands and feet.)

Gross features that help to separate melanoma from benign mole:

Irregular borders
Variegated colors or deep blue black color versus shades of brown-black.’
History of growth or color change.
Bleeding without being traumatized. (see ulceration microscopically)

Melanoma represents 1-3% of all cancers. It is associated with previous heavy sun exposure
and/or severe sunburn in fair-skinned person. It may metastasize either to regional lymph nodes
or distantly by hematogenous spread.

Major prognostic factor is stage: known metastatic disease is hopeless, if still thought to be
confined to skin, then depth of invasion is crucial. Deeper into dermis does worse.

DERMIS

1. Dermatofibroma (fibrous histiocytoma) of fibrohistiocytic lineage. Most common benign

dermal tumor.

2. Kaposi’s sarcoma:

--Grossly appears as purplish papule/nodule

--Microscopically, see spindled cells surrounding slit-like vascular spaces; located initially
in dermis.

--May occur in legs of elderly men of Mediterranean descent (where has very indolent
course) or in association with AIDS (fulminant course).

--Believed to be of vascular or lymphatic origin.

3. Mycosis fungoides: special type of T-cell lymphoma that chiefly affects skin; forms raised
skin plaques progressing to nodules. Malignant lymphocytes are chiefly in sheets in the
dermis with some invasion upward into the epidermis. Generally occurs in middle-aged or
elderly.

HYPERTENSION

May affect systemic circulation (systemic hypertension) or pulmonary circulation (pulmonary

hypertension).
Systemic hypertension is due to increase in systemic resistance: it is defined as a pressure of
greater than 140/90 over a prolonged period of time.

Essential Hypertension (90-95% or cases)

No known cause.

More common in blacks; slightly more common in females; may affect up to 50% of the
population over 50.

Secondary Hypertension (5-10% of all cases) May be due to:

A) Chronic renal disease (diabetes, glomerulonephritis, polycystic kidneys, etc.).

B) Renal artery stenosis (“Goldblatt Kidney”) leads to increased release of rennin from the
kidney, hyperaldosteronism, and peripheral vasoconstriction. The obstruction may be
due to fibromuscular dysplasia or atherosclerosis of the renal artery or its origin from
the aorta.
C) Coarctation of the aorta (increased blood pressure proximal to coarct; diminished blood
pressure distal to the coarct.
D) Pheochromobytoma
E) Aldosterone—secreting adrenal cortical tumor

“Benign” Hypertension: induces slow changes in vessels including arteriolar and arterial
muscular hypertrophy followed by fibrosal thickening of arteries.

“Malignant” Hypertension (less than 5% or cases of hypertension) characterized by fibrinoid

necrosis +/- inflammation in arteriolar walls, accompanied by proliferation of smooth muscle
cells. May lead to rapid cardiac decompensation, rapid renal failure or intracerebral hemorrhage
acutely.

Long term complications of “benign” hypertension include increased risk of cerebral

hemorrhage; nephrosclerosis which may lead to renal failure; and acceleration of atherosclerosis
throughout the body.

AORTIC LESIONS

1. Atherosclerotic Abdominal aortic Aneurysm

Usually in the abdominal aorta.

Atherosclerotic plaque deposition weakens aortic wall, leading dilatation.

Many have mural thrombi within the aneurysms, with possible embolic complications.

Large aneurysm may rupture = catastrophe.

 Clinical presentation is variable; may be detected due to embolic phenomena, abdominal
discomfort, as an asymptomatic, pulsatile mass; or at rupture.

2. Dissecting Aortic Aneurysm

Generally starts in thoracic aorta.

Blood exists through intimal tear into the arterial wall and then dissects between muscle
planes.

Associated with hypertension in 90% of cases.

Also associated with Marfan’s syndrome and with isolated cystic medial necrosis of the
aortic wall (loss of elastic fibers and replacement with mucopolysaccharide ground
substance).

May extend up to aortic valve ring, causing aortic valvular incompetence.

May cause obstruction at the mouths of arteries taking off in that area.

Commonly present with excruciating pain in anterior chest radiating to back.

3. Syphilitic Aortic Aneurysm

Occurs in thoracic aorta; generally involves arch.

Occurs during the tertiary phase of syphilis.

A chronic inflammatory infiltrate is seen surrounding the vasa vasorum; resulting vessel
damage causes ischemia of the muscle layers of the aorta and weakening of aortic wall.

May involve aortic ring (causing valvular incompetence because of ring dilation).

May involve mouths of coronary arteries and intercostals, with resultant ischemia.

May rupture.

OTHER ARTERIAL LESIONS

1. Polyarteritis nodosa (see autoimmune diseases) Widespread necrotizing inflammation of

middle sized muscular arteries.

2. Temporal arteritis: Most commonly affects cranial vessels, especially temporal arteries.

--Most common type of vasculitits.

--Generally occurs in individuals older than 50.

 --Presents with headache, tenderness of artery; increased sed rate; the syndrome of
polymyalgia rheumatica (diffuse muscle aching and stiffness); and visual disturbance.

--May lead to blindness if untreated (drug of choice is corticosteriods).

--Histology: giant cell inflammation of arterial wall.

3. Thromboangitis obliterans: seen in young male cigarette smokers: obliterative acute and
chronic inflammation of intermediate and small arteries. Disease often remits if smoking
ceases.

ATHEROSCLEROTIC CORONARY ARTERY DISEASE

700,000 people each year die from ASCVD. Risk factors include family history, diabetes,
hypercholesterolemia, and hypertension.

A bout of coronary ischemia may be precipitated by:

1. Atherosclerosis itself coupled with increased demand; stenosis must be greater than 50%.

2. Intramural hemorrhage into atherosclerotic plaque.

3. Thrombosis on top of an ulcerated plaque.

Ischemia may lead to:

1. Cardiac ischemia without infarction (angina pectoris).

2. Fatal arrhythmia.

3. Myocardial infarct.

MI SEQUENCE

12-24 hours: develop classical coagulation necrosis.

24-48 hours: invasion of neutrophils
3 days-1week: macrophages resorb dead cell debris (maximum wall weakness at this time)
1-6 weeks: ingrowth of capillaries; formation of granulation tissue that later matures to a
dense fibrous scar (non-contractile).

MI Site by site of coronary artery lesion

LAD: supplies anterior 2/3 or septum, and anterior LV wall.

Circumflex: supplies lateral wall of left ventricle.

RCA: supplies posterior wall of left ventricle, posterior 1/3 of septum, and right ventricle
(thinner right ventricle rarely infarcts).

MIs may be subendocardial or transmural.

Complications of Myocardial Infarcts

1. Sudden death due to arrhythmia arising in ischemic area.

2. Fibrinous peridcarditis (complication of transmural MI; get pain, pericardial friction rub 4-
6 days after MI. Resolves spontaneously.)

3. Rupture of heart structure (most common 4-7 days post infarct).

A) LV free wall rupture - causes hemopericardium and near-instant death due to

tamponade).

B) Ventricular septum rupture - get loud systolic murmur; sudden L to R shunt with
increased pulmonic circulation flow, leading to pulmonary edema.

C) Papillary muscle rupture: if complete, rapidly fatal due to massive regurgitation into
LA and resultant pulmonary edema; if partial, get pulmonary edema and systolic
regurgitation murmur.

4. May also get papillary muscle dysfunction/mitral regurgitation without rupture; infracted
papillary muscle doesn't contract properly.

5. Aneurysm formation: thinned, fibrotic, akinetic old infarct may bulge outward during
systole. Aneurysms often have mural thrombi (embolic complications) and also promote
CHF (outward bulging seems to increase cardiac workload).

6. Chronic congestive heart failure even without aneurysm, due to widespread damage to
contractile myocytes.

7. Infarction of bundle can lead to R to L bundle branch block, or complete heart block (may
require pacemaker).

CARDIOMYOPATHIES

Acute cardiomyopathy: a) infectious myocarditis, usually viral (especially ECHO, Coxsackie)

b) toxic (as in damage from diphtheria toxin)
c) as part of rheumatic fever pancarditis (see below)

Chronic cardiomyopathy: Dilated type: a) idiopathic

b) metabolic (example: hemochromatosis)
c) ischemic in origin
d) hypertensive in origin
 e) ?alcohol?

Obstructive (hypertrophic) type (also called idiopathic hypertrophic subarotic stenosis) get
asymmetric septal hypertrophy which obstructs LV outflow. Can lead to sudden death.

Restrictive cardiomyopathy: a) amyloid

b) sarcoid
c) many other rare and obscure causes

RHEUMATIC FEVER

An acute, recurrent inflammatory process which principally occurs in children and young adults.
Generally follows a pharyngeal infection with beta hemolytic, Group A streptococcus. Probably
due to cross reaction of antibodies to streptococcal antigens with normal tissues.

Cardinal Features of Acute Rheumatic Fever

1. Migratory Polyarthritis
2. Pancarditis
3. Erythema Marginatum of Skin
4. Subcutaneous Rheumatoid Nodules
5. Sydenhams Chorea (involuntary movements)
6. Also usually have fever, increased sed rate, etc.

Cardiac morphology during acute attack: Pancarditis

In myocardium, see a light infiltrate of chronic inflammatory cells (occasional lymphocytes,

plasma cells and histiocytes); fibrin deposition; and Aschoff bodies (interstitial nodules
composed of plump mesenchymal cells which are sometimes multinucleated).

Concurrently, see a fibrinous pericarditis and often rheumatic valvulitis (tiny fibrin clumps on
leaflets, different from the bulky vegetations of infectious endocarditis. Acute rheumatic
valvulitis rarely leads to embolic phenomena.)

Long Term Sequelae of Rheumatic Fever: Heart Disease

Get fibrocalcific deformities of cardiac valves developing over the years in some cases.

Most common involvement in mitral; then aortic; then tricuspid. Pulmonic rarely involved.

May have involvement of 1, 2 or 3 valves.

Fibrocalcific deformity may fail to open adequately (causing stenosis) or fail to completely close
(causing insufficiency).
 VALVULAR DISEASE BY VALVE

Mitral stenosis: (Rheumatic fever most common etiology)

Increased LA pressure, dilatation and hypertrophy.

Increase in pulmonary capillary pressure (pulmonary edema) accentuated by exercise diastolic

rumble.

Mitral Insufficiency: Common causes are RF; or myxoid degeneration (parachte valve) or
papillary muscle dysfunction/rupture from MI; or damage from infectious endocarditis)

--Results in LA dilation and increased LA and pulmonary capillary pressure (pulmonary edema).

--Decrescendo systolic murmur.

Aortic stenosis: may be due to RF (in this case, mitral valve almost always also involved) or to
calcification or a normal valve in elderly; or to calcification of a bicuspid valve in the middle
aged; or to a congenital lesion (rare).

Results in LV hypertrophy. When stenosis is getting critical, get onset of syncope, CHF angina.
At this stage the person is at high risk for sudden death.

Causes diamond-shaped systolic murmur.

Aortic insufficiency: may be due to valve problems (rheumatic damage; damage from
infectious endocarditis) or due to dilation of ring (occurs in syphilitic and dissecting aneurysms).

Causes LV dilation; may cause CHF; hear diastolic murmur.

Tricuspid valve lesions: stenosis usually due to RF. Leads to RA dilatation; increased systemic
venous pressures with ankle edema, hepatosplenomegaly, jugular venous distension, etc.

Tricuspid regurgitation may be due to either RF or infectious endocarditis (especially in IV drug

abusers). Also causes increased systemic venous pressures. Murmurs of tricuspid stenosis and
insufficiency resemble their mitral counterparts.

INFECTIOUS ENDOCARDITIS

Grossly, see valvular vegetations which are composed of fibrin, neutrophils and often organisms.
The inflammation associated with these vegetations may severely damage valves, leading to
valvular insufficiency (doesn't lead to stenosis).

1. Acute bacterial endocarditis

-Presents with high fever, chills, weakness; embolic phenomena.

-Rapidly changing murmurs with early cardiac decompensation.
 -Organisms are usually virulent: S. aureus; pneumococcus; gram negative rods, fungi,
gonococcus.
-Often occurs on normal valves or immediately after cardiac surgery (especially valve
replacement organisms are S. Aureus, candida, pneumococcus).

2. Subacute bacterial endocarditis

-Symptoms often have insidious onset: fever, weight loss, anemia.

-May see splinter hemorrhages under nails; tender subcutaneous fingertip nodules (Osler's
nodes) in addition to embolic phenomena.
-Spleen is often enlarged and painful.
-Generally occurs on previously damaged valves. Streptococcus viridans is most common
Organism, followed by enterococcus.

MARANTIC ENDOCARDITIS

See small fibrin masses (no organisms; few inflammatory cells) on valves of persons with
cancer, other chronic diseases. Like the similar lesions seen in acute RF, they rarely embolize.
Similar small fibrinoid clumps can be seen on valves in lupus.

CONGENITAL HEART DISEASE-NONCYANOTIC

1. Atrial septal defect L to R shunt

--Most are ostium escudo defects (region of fossa ovalis).

--If 1 cm or less in diameter, are well tolerated, since pressure gradient between atria is not
as high as between ventricles and thus shunt is less.

--Over many years, the increased flow through the pulmonic circulation may induce
pulmonary arterial muscular hypertrophy followed by pulmonary hypertension. When
pulmonary circulation pressures reach or exceed systemic pressures, the shunt reverses
to R to L, causing cyanosis in later adulthood, and CHF (Eisenmongers complex).

2. Ventricular septal defect L to R shunt

--Because of higher pressure gradient between ventricles, shunt is usually greater and
shunt reversal (Eisenmonger complex) occurs earlier, in childhood or young adulthood.
Often have loud holosystolic murmur; increased risk of infectious endocarditis at defect
site.

3. Patent ductus arteriosus L to R shunt

--Normally connects L pulmonary artery and aorta during fetal life; may fail to close.

--Acts as L to R shunt. Surgical closing is relatively safe procedure; if not treated, these
patients may also develop pulmonary hypertension/shunt reversal.
 CYANOTIC CONGENITAL HEART DISEASE

1. Tetralogy of Fallot: R to L shunt

Components: a) VSD
b) Obstruction to RV outflow (valvular or subvalvular stenosis)
c) RV hypertrophy
d) Overriding aorta--aorta originates opposite the VSD

Often survive into early childhood even without surgical intervention.

2. Transportation of the Great Vessels

--Aorta arises from RV; pulmonary artery from the LV.

--Prenatally, the circulations mix via the ductus arteriosus. After birth, neonates must have
some type of R-L connection to survive (PDA, ASD, VSD). Even so, death generally
occurs within a few weeks unless surgical correction is attempted.

OTHER CONGENITAL CARDIOVASCULAR LESIONS

1. Coarct of the Aorta

Most commonly occurs distal to the L subclavian artery takeoff. The patient has high
blood pressure in head, upper extremities and arterial insufficiency in lower extremities.
intercostals become enlarged; give some collateral circulation and cause rib notching.
Coarct is increased in frequency in females with Turners syndrome (45X).

PERICARDIAL DISEASE

1. Serofirbrinous pericarditis: may be due to rheumatic fever (part of pancarditis); viral

infection; uremia; lupus; post-MI; traumatic (including post-operative); or malignancy.

2. Purulent Pericarditis: derived from either contiguous or distant infection (usual organisms
that cause suppurative infection: bacteria or fungi).

3. Hemopericardium: may be due to ruptured MI; dissecting aortic aneurysm eroding into the
pericardium; or as a complication of serofibrinous pericarditis (especially with malignant
effusions).

4. Chronic changes of pericarditis: most cases of serofibrinous pericarditis spontaneously

resolve (excluding malignancy). Those that don't, and purulent/hemorrhagic pericarditis,
can lead either to simple adhesions or to a constrictive pericarditis (which impairs cardiac
function).
 PULMONARY INFECTIONS
Bacterial Pneumonia

1. Lobar pneumonia: widespread consolidation, often involving entire lobe. 4 stages:

a) Congestion (swollen capillaries, interstitial and intraalveolar edema).

b) Red Hepatization (alveoli filled with RBC, fluid, scattered neutrophils)
c) Gray Hepatization (RBC break up; alveoli filled with fibrin, neutrophils)
d. Resolution (macrophages clean up debris and are coughed up)

Etiology: usually pneumococcal pneumonia

2. Bronchopneumonia: (also called lobular pneumonia: patchy infiltrate surrounding

bronchi usually due to organisms other than pneumococcus; more likely to have one or
more complications.

Special problems following pneumonia

1. Organization rather than resolution: most common if there is airway obstruction (so
macrophages can't be coughed up) or if there is poor blood flow to the area (as in infected
pulmonary infarct). If macrophages don't clear out debris and then get coughed up,
fibroblasts move in and organize the exudate, leaving scarring.

2. Bacterial abscess: most common after aspiration (combination of aerobes and anaerobes)
also develop pneumonia caused by a virulent organism such as S. Aureus; in infected
infarcts; and distal to a bronchial obstruction (with trapped ups and organisms).

3. Empyema--occurs when bacterial infection breaks through into pleural space.

4. Bacteremia and seeding of other organs.

INTERSTITIAL PNEUMONIA

1. Mycoplasma pneumonia: see thickened, edematous septa infiltrated by lymphocytes and

histiocytes; alveoli generally clear.

2. Viral pneumonia (including RSV, influenza, rhinoviruses, CMV, varicella, etc.) also see
interstitial pneumonia (inclusions with CMV). May also see associated bronchiolitis
(lymphocytes and histiocytes within bronchiolar walls/lumens). Death from viral
pneumonia is most commonly due to bacterial superinfection.

3. Pneumocystitis carinii: interstitial pneumocystis associated with foamy material within

alveoli (silver stain reveals protozoan organisms, in alveoli).

4. Radiation/chemotherapy damage: also causes interstitial pneumonitis.

 NECROTIZING SEPTIC INFARCTS

1. Aspergillus and 2. Mucor. See fungal hyphae within blood vessels; associated thrombosis
results in infected infarcts (these organisms, like CMV and pneumocystitis, are
opportunistic).

GRANULOMATOUS DISEASES

1. T.B.

--Initial focus of infection is the Ghon complex: a parenchymal, subpleural lesion either
just above or below the interlobar fissure; + the draining lymph nodes with caseating
granulomatous inflammation. Rarely, primary infection with TB will go on to primary
progressive TB-but usually the area of caseous inflammation will be walled off.

--Most clinically detected TB cases are secondary: either due to reinfection with TB or
due to reactivation of walled off focus. Secondary TB generally occurs in apical area;
see confluent caseating granulomas. This may either scar off again or spread
throughout the lung as progressive pulmonary TB or have one of the below
complications.

--Possible complications of progressive TB (primary or secondary) include rupture into

bronchus (get tracheobronchial TB); rupture into pleura, with TB empyema; and escape
of TB meningitis; renal TB; TB epidydimitis; TB salphingitis; TB osteomyelitis; or
adrenal TB.

2. Histoplasma: mimics TB. Most cases present as walled off granulomas detected on a
CXR; but can cause progressive pulmonary disease or military disease.

3. Sarcoid: multiple non-caseating granulomas; most common in hilar lymph nodes but can
also involve lung diffusely.

ACUTE RESPIRATORY DISTRESS SYNDROME

May be caused by anything that can injure alveolar epithelium or endothelium; common causes
are neonatal hyaline membrane disease; shock; sepsis; uremia; viral infections; oxygen toxicity;
inhalation of toxic substances; chemotherapeutic drugs; radiation; etc.

Grossly, lungs are heavy and beefy red. Microscopically, see interstitial pneumonitis (septal
edema and infiltration by lymphocytes, plasma cells, histiocytes) plus alveolar lining hyaline
membranes. May resolve or go on to chronic fibrosis.

CHRONIC INTERSTITIAL LUNG DISEASE (AUTOIMMUNE/IDIOPATHIC)

1. Desquamative interstitial pneumonia: rare; idiopathic. See macrophages in alveoli;

associated interstitial pneumonia. Often responds to steroids.
2. Usual interstitial pneumonia (UIP): also called diffuse idiopathic pulmonary fibrosis;
(Hamman-Rich Syndrome). Histologically, see area of ongoing interstitial pneumonitis
resistant. Occasionally a similar histologic picture is seen in persons with collagen
vascular disease.

3. Hypersensitivity pneumonitis: example: farmers lung (due to spores of thermophilic

actinomycetes in hay). Hypersensitive person becomes dyspneic 4-8 hours after exposure
to allergen. Histologically, see bronchiolitis and interstitial pneumonitis.

Can progress to diffuse interstitial fibrosis with chronic exposure.

PNEUMONCONIOSES

Defined as the deposition of inorganic dust in the lung and subsequent tissue reaction.

1. Silicosis: seen in persons exposed to sandblasting, glass manufacturing, etc. silica is

inhaled; engulfed by macrophages which can't digest it, lyse and die; this cycle induces the
disorganized fibrous nodules characteristic of silicosis. If exposure is prolonged and at
high concentration, person may develop progressive massive fibrosis (confluence of
nodules to form masses greater than 1 cm in diameter).

2. Coal Miners Pneumonconiosis (Black Lung): Carbon dust is scattered throughout the lung,
giving black pigmentation. Associated nodule of progressive massive fibrosis generally
only occur when coal dust has a substantial silica component.

3. Asbestosis: seen in ship builders; brake liners; insulation technicians, etc. can include:
1) diffuse interstitial fibrosis
2) pleural fibrouse plaques
3) malignant mesothelioma

END STAGE HONEYCOMB LUNG

Can be end-stage of many different processes, including bad ARDS with extensive lung damage;
asbestosis; silicosis; UIP (idiopathic diffuse pulmonary fibrosis); collagen vascular disease;
hypersensitivity pneumonia (repeated exposures); sarcoid; radiation or chemotherapy damage;
and more.

COPD (CHRONIC OBSTRUCTIVE PULMONARY DISEASE)

Components: Chronic Bronchitis and Emphysema

1. Chronic Bronchitis: see squamous metaplasia of bronchial mucose and/or hyperplasia of

bronchial mucous glands; chronic inflammation of walls of bronchi.

2. Emphysema: overdistention of alveoli distal to terminal bronchioles, with eventual

destruction of alveolar walls.
Subtypes of emphysema: 1) contrilobular (95% of cases) caused by smoking
2) panacinar (5% or cases) associated with alpha 1 antitrypsin
deficiency

ASTHMA

Associated with IgE-mediated Type I hypersensitivity reaction in many cases. Functionally,

there is muscle spasm of the smooth muscle of the bronchial walls. Histologically, see mucous
plugging of bronchi; may see eosinophilic infiltrate into bronchial walls.

PULMONARY NEOPLASMS

1. "Bronchial ademona" (all are low-grade malignancies) 2-3% of all lung neoplasms.

Subtypes: 1) carcinoid tumor

2) mucoepidermoid carcinoma (a salivary-gland type neoplasm)
3) adenoid cystic carcinoma (a salivary-gland type neoplasm)

--Usually arise endobronchially--may obstruct bronchial lumen.

--With carcinoid tumors, see nests of uniform cells separated by a delicate vascular stroma
(identical to carcinoid tumors of the intestine). These contain neurosecretory granule by
EM and react with argyrophil stain; they are considered neuroendocrine tumors and part of
the "APUD" system.

--5 year survival is approximately 90%. These tumors can, however, metastasize to local lymph
nodes and occasionally distally.

2. Squamous cell carcinoma: 35% of all lung tumors

--Arise centrally; almost always in smokers.

--The type of bronchogenic carcinoma most likely to show central cavitation.

--Histologically, see nests/islands of large epithelial cells showing keratinization and intercellular
bridge formation (surrounded by fibrous stroma).

--Usually spread first by lympthatics/local invasion.

3. Adenocarcinoma: 30% of all lung tumors

--Generally arise peripherally; increased risk in smokers, but occasionally in non-smokers.

--May be associated with scars.

--Histologically, epithelial cells form glands or produce mucin.

--May spread either lymphatically or hematogenously.

Variant: Bronchoalveolar carcinoma (1-3% all lung cancers). Arises peripherally; may be
multiple; grossly resembles pneumonia. Histologically, see malignant columnar cells growing
along preexisting alveolar septa.

4. Small Cell Undifferentiated (Oat Cell) Carcinoma (25% of all lung tumors)

--Generally central; almost all are in smokers.

--Histologically, composed of sheets of small cells with scanty cytoplasm; high mitotic rate.

--Can see rare neurosecretory granules on EM; a few neoplasms produce hormones ectopically
such as ACTH.

--Generally, there are widespread distant metastases by the time of diagnosis. Respond to
chemotherapy with regression but cure is not likely.

5. Large Cell Anaplastic Carcinoma (10% of all lung tumors)

--May be central or peripheral; most are in smokers; grab-bag category.

--Large cell tumors showing neither keratinization or mucin production/gland formation.

Only 25% of all lung cancers are resectable at the time of diagnosis. Overall 5 year survival is
8%.

PLEURAL TUMORS-PRIMARY

Malignant Mesothelioma: A malignant tumor of mesothelial cells.

--Tends to encase lungs; kill by respiratory failure.

--Generally not resectable.

--Strong association with asbestos exposure.

MEDIASTINAL NEOPLASMS

Mediastinal lymph nodes are commonly involved by Hodgkins, some non-Hodgkins lymphomas.
The most common non-hematologic tumor of the mediastinum is the thymoma, a neoplasm
derived from thymic epithelial cells. Well-encapsulated thymomas can be removed by surgery;
locally invasive ones kill by damage to adjacent structures. Up to 40% may have associated
syndrome such as myasthenia gravis.

MOUTH, TONGUE, LARYNX, PHARYNX

Most common malignancy is squamous cell carcinoma; strong association with
smoking/chewing tobacco. Tend to spread first lymphatically. Treatment: surgery, lymph node
dissection and radiation therapy.

NASOPHARYNX

Most common neoplasm is nasopharyngeal carcinoma (an undifferentiated large cell carcinoma
which often has a heavy lymphoid infiltrate). Very common in some parts of Asia, associated
with EBV infection. Very radiosensitive.

KIDNEY: GLOMERULAR LESIONS THAT CAUSE NEPHRITIC SYNDROME

Nephritic syndrome:includes hematuria, oliguria, hypertension and red cell casts.

I. Diffuse Proliferative Glomerulonephritis

A) Post-streptococcal glomerulonephritis

--Presents 7-10 days after an infection with B-hemolytic streptococcus Group A.

--Acute onset; generally in children
--Presumably mediated by circulating streptococcal antigen-antibody complexes, which
are filtered out and trapped in glomerular capillaries.
--Light: marked glomerular hypercellularity (capillary walls not significantly
thickened).
--EM: subepithelial "humps" (immune complex deposits).
--IF: IgA deposits in mesangium.
--Course: 50% go on to chronic renal failure within the next 20 years.

B) Focal proliferative glomerulonephritis is also seen sometimes as a manifestation of

systemic diseases (Heinloch-Schonlei purpura, lupus, Wegeners, Goodpastures, etc.)
(Also of above have IgG deposits, except for H-S purpura, which is also IgA).

III. Crescentic Glomerulonephritis (Rapidly Progressive Glomerulonephritis)

A) Goodpastures Syndrome

--Acute onset in young adults or full nephritic syndrome, hemoptysis.

--Mediated by glomerular membrane antibodies
--Light: hypercellular glomeruli (diffuse or focal proliferation) plus formation of
crescents by proliferating epithelial cells of Bowmans capsule.
--EM: Negative
--IF: Linear IgG.
--Course: renal failure within weeks unless aggressively treated early in course.

B) Anti-GBM disease restricted to kidney.

 C) Occasionally complicates post-streptococcal glomerulonephritis (these patients are
much less likely to regain renal function than other post-strep patients: occasionally in
other types of GN (membranoproliferative, Heinloch-Schonlein purpura); occasionally
idiopathically (EM, IF findings variable).

KIDNEY LESIONS THAT MAY CAUSE NEPHRITIC OR NEPHROTIC SYNDROME

I. Membranoproliferative glomerulonephritis (proliferation of cells and thickened walls)

A) Type I Idiopathic

--Clinical manifestations/patient population variable. Generally nephritic; occ. nephriti

--Cause: unknown
--Light: hypercellular glomeruli with thickened capillary walls.
--EM: subendothelial deposits
--IF: granular deposits of IgG and complement
--Course: most progress to chronic renal failure over several years.

B) Type II Idiopathic MPGN (Dense Deposit Disease)

--Clinical presentation variable/insidious onset.

--Light: hypercellular glomeruli; thickened capillary walls (can't distinguish on light
microscopy alone from Type I).
--EM: dense deposits run along the center of the glomerular capillary basement
membranes.
--IF: C3 deposits in tram-track distribution along outside of dense deposits. No
immunoglobulin in deposits.
--Course: usually progression to renal failure over several years.

C) Lupus

--Associated with antigen-antibody complexes of DNA/anti-DNA.

--Histologic appearance is variable. Among patients with lupus:

5-10% have no visible lesions by light or EM

5-10% have measangial cell proliferation
30-40% have focal proliferative glomerulonephritis
50% have diffuse proliferative or membranoproliferative glomerulonephritis
10% have membraneous disease.

In WHO Type IV (diffuse proliferative or membranoproliferative disease, see

subendothelial deposits by EM, granular staining for IgG, complement by IF.

Type IV has worst prognosis in terms of progression to chronic renal failure.

 D) Heinoch-Schonlein Purpura

--Occurs in children
--See purpura involving buttocks, extensor surfaces of arms and legs.
--Abdominal problems (pain, vomiting, bleeding).
--Renal manifestations in 1/3 patients.
--Arthralgias
--Light: may see either mesangioproliferative glomerulonephritis similar to that seen
in IgA nephropathy; diffuse proliferation; or crescentic glomerulonephritis.

KIDNEY DISEASES THAT CUASE NEPHROTIC SYNDROME/PROTEINURIA

Nephrotic Syndrome: proteinuria more than 3.5 gm/day; hypoalbuminemia secondary to

protein loss; peripheral edema secondary to low oncotic pressure; hyperlipidemia.

I. Minimal Change Disease (also called lipoid nephrosis, nil lesion)

--Most common cause of nephrotic syndrome in children (90% of cases; 10-30% of adult
cases.
--Light: glomeruli appear normal
--EM: fused podacytes (not specific for minimal change disease; occurs in most cases of
nephrotic syndrome--but in nephrotic syndrome is the only lesion)
--IF: negative
--Course: steroid-responsive; may also remit spontaneously. Rarely leads to renal failure.

II. Focal Glomerulosclerosis

--Causes 10-15% of nephrotic syndrome in children and adults.

--Light: see focal segmental sclerosis (scarring) of glomerulus.
--EM: podacyte fusion and areas of sclerosis.
--IF: may see occasional deposits of immunoglobulin in the scarred area; elsewhere
normal.
--Course: steroid resistant; 50% go on to renal failure in 10 years.

III. Kidney diseases that cause thickened capillary walls, including:

A) Membraneous Glomerulonephritis

--Occurs in wide spectrum of patients; 85% idiopathic, 15% associated with other
disease like lupus; serum sickness; syphilis; malaria; hepatitis B; drugs such as gold
and penacillamine, and more.
--Most common cause of true nephrotic syndrome in adults.
--10-15% will have hypertension +/- mild hematuria.
--Light: thickened glomerular capillary loops; no or minimal increase in cellularity.
--EM: subepithelial deposits; induce reactive thickening of glomerulular basement
membrane around them.
--IF: granular IgG, complement.
 --Course: most progress to renal failure over 2-20 years.

B) Diabetes Mellitus

--Proteinuria develops in 50% of diabetics (rarely so severe as to be nephrotic)

--Light: see hyalinosis of afferent and efferent arterioles; diffuse thickening of
glomerular capillary basement membranes; occasionally nodular
Glomerulosclerosis (Kimmelsteil-Wilson nodules).
--EM: thickening of lamina densa of GBM and blood vessels.
--Course; on average renal failure develops several years after onset of proteinuria.

C) Amyloidosis (see previous description under systemic diseases)

--Light: thickened capillary walls; occasional interstitial deposits. Amyloid stains

salmon pink with congo red; gives apple-green birefringence on polarization.
--EM: see amyloid fibrils.

CYSTIC DISORDERS OF THE KIDNEY

1. Congenital renal cystic dysplasia: may be unilateral or bilateral (if bilateral, renal
failure).

--90% are associated with congenital obstruction of the ureter. Not hereditary.
--Microscopically, see multiple cysts of varying sizes; primitive ducts surrounded by a
collarette of primitive mesenchyme; cartilage islands.

2. Polycystic Kidney Disease (Infantile, Autosomal Recessive Type)

--Bilateral, symmetrical diffuse enlargement of collecting tubules.

--Generally fatal within the first few months of life.
--Associated with congenital hepatic fibrosis.

3. Polycystic Kidney Disease (Adult, Autosomal Dominant Type)

--Cysts progressively enlarge during childhood and adulthood; bilateral

--Onset of symptoms in 30s and 40s, when develop palpable mass, hypertension, renal
failure.
--See numerous cysts that obliterate the shape of the kidney.
--Affects 1/500 adults.

4. Medullary Cystic Lesions: multiple types

Medullary sponge kidney results from dilated collecting ducts; generally asymptomatic.
Other types of medullary disease are rare, end in renal failure.

5. Simple Renal Cortical Cysts (may be single or several) Common in adults; no significance.
 TUBULAR LESIONS

1. Acute Tubular Necrosis: death of tubular epithelial cells, followed in most cases by
regeneration. There is a toxic form (exposure to such toxins as mercury, carbon tetrachloride,
etc.) which predominantly affects the epithelial cells of the proximal tubules; and an ischemic
type (following shock/severe hypotension) which predominantly affects the distal tubules.
Within 36 hours, the patient enters an anuric phase; after 1-2 weeks, enters a diuretic phase (high
output of water and ions which is not well-regulated, so that electrolyte imbalances may
develop); followed by regeneration most cases.

INTERSTITIAL DISORDERS

1. Acute pyelonephritis: acute infection of kidney parenchyma.

Bacterial organisms may reach kidney by two routes: hematogenous or ascending.

Ascending infection is the most common; occurs in setting of bacterial cystitis. Most cases
of cystitis remain restricted to bladder; however, pyelonephritis is encouraged by
vesicoureteral reflux (ureter is usually compressed by bladder muscle during urination, but
this mechanism is defective in some people).

The other main route of spread is hematogenous (sepsis, endocarditis, etc.).

Most common organisms are E. Coli, other coliforms, enterococci, staph, strep.

Since urinary tract obstruction impairs the ability of the kidney to rid itself of organisms,
obstruction increases the risk of both hematogenous and ascending infection.

Histology: patchy tubulointerstitial acute inflammation, often with microabscess formation.

Glomeruli are usually spared.

2. Acute Papillary Necrosis (necrotizing papillitis)

--Most common in the setting of acute pyelonephritis superimposed on diabetes (perhaps

because of the impaired blood supply characteristic of diabetes). Also see in sickle cell
anemia and as early consequence of analgesic nephropathy.

3. Chronic pyelonephritis:

--Generally develops in the setting of vesicoureteral reflux or chronic obstruction.

--Grossly, see broad-based cortical scars with underlying calyceal deformities.
--Microscopically, see tubular atrophy, interstitial chronic inflammatory infiltrate and focal
scarring of interstitium.
--Eventually, may develop focal Glomerulosclerosis and progress to chronic renal failure.

4. Acute Hypersensitivity Interstitial Nephritis

--Most commonly due to hypersensitivity to a synthetic penicillin (especially methicillin).

 --Microscopically, see interstitial infiltrate which includes numerous eosinophils.

5. Analgesic Abuse Nephropathy

--Caused by high doses of phenacetin, aspirin, other non-steroidal anti-inflammatory gents.

--First see papillary necrosis, followed by a nonspecific interstitial infiltrate in cortex.

BENIGN RENAL TUMORS

1. Adenoma: small lesions less than 2.5 cm in diameter; commonly found incidentally at
autopsy in cortex or medulla. May be multiple.

2. Mesoblastic Nephroma: congenital hamaroma of kidney; presents in first year of life;

composed of bundles of connective tissue, occasionally islands of cartilage.

MALIGNANT RENAL TUMORS

1. Renal Cell Carcinoma (also called hypernephroma)

--1-3% of all visceral cancers in adult.

--Most common onset is between 50 and 70.
--Classical triad of symptoms includes gross hematuria; flank pain and abdominal pain.
--May also present as fever of unknown origin (25% or RCC patients have chronic fever).
--Commonly also produces hormonal syndromes; RCC can produce erythopoitin, and 10%
of patients are found to be polycythemic (hematocrit 60-50%); it can also produce a
parathyroid hormone-like substance, inducing hypercalcemia.
--Gross: renal cortical lesion with yellow-brown cut surface; often partial cystic change.
--Micro: mixture of cells with clear cytoplasm (due to lipid and glycogen) and
eosinophilic cells with abundant mitochondria. (The prominent clear cell component in
many tumors led to synonym "clear cell carcinoma of the kidney.")
--Has unusual tendency to invade and grow along renal vein; may even grow up vena cava.
--May metastasize by either lymphatic or hematogenous route; most common metastatic
site is lung.
--5 year survival: 45% (again, stage at presentation is vital).

2. Wilms tumor

--Primarily presents in children between the age of 1 and 4 years.

--A minority of cases are associated with other anomalies such as aniridia or
hemihypertrophy.
--5-8% are bilateral.
--Gross: gray to tan in color.
--Micro: composed of sheets of undifferentiated small blue cells in which may be
embedded abortive glomerular/tubular structures or islands of metaplastic cartilage.
--May metastasize lymphatically or hematogenously.
--Many can be cured by combination of surgery, radiation t tumor bed, +/- chemotherapy.
3. Transitional Cell Carcinoma of Renal Pelvis: similar to those of bladder (see below).

URETERS, BLADDER, URETHRA

1. Urolithiasis: 0.1-6% of population have urinary track stones. 75-85% are calcium based
(calcium oxalate or calcium phosphate); other types include urate, cysteine, magnesium
ammonium phosphate. Present with hematuria, severe flank pain; can also develop
problems from urinary tract obstruction.

2. Bladder Exstrophy: congenital anomaly in which anterior wall of bladder is missing;

together with defect in abdominal wall. Increased risk of infection and carcinoma (chiefly
adenocarcinoma).

3. Cystitis: bacterial cystitis develops in up to 20% of women one or more times. Also
common in pregnant women; diabetics; men with enlarged prostates causing incomplete
emptying of bladder; persons with neurogenic bladders; persons with indwelling Foley
catheters. Elsewhere in world, schistosoma hematobium is common pathogen. Can also
see a sterile cystitis after cyclophosphamide administration.

4. Malaloplakia: rare inflammatory lesion of urinary tract associated with E. Coli infection.
Grossly, see multiple yellow nodules which microscopically are composed of macrophages
packed with bacteria, calcified Michaelis-Gutman bodies. Appears to occur in a few
people with localized defect in macrophage function.

5. Urethritis: Gonococcal or non-gonococcal (these often associated with Mycoplasma or

chlamydia).

6. Transitional Cell Carcinomas: (constitute more than 90% of all bladder cancers)

--May be papillary or flat; invasive or noninvasive. Noninvasive lesions generally Grade I

or II; invasive lesions Grade II, III, IV).
--Non-invasive papillary lesions can be excised through cystoscope; invasive require
cystectomy.,
--Survival related to stage; 90% 5 year survival with non-invasive, 10-30% if deeply
invasive.
--Persons with a history of any kind of TCC must be followed, since they are at much
higher risk of developing additional transitional cell carcinomas of ureters, renal pelvis,
bladder.

PROSTRATE

1. Prostatitis: generally produced by coliforms bacteria; may be acute or chronic. Presents

with urgency, frequency, dysuria.

2. Nodular Hyperplasia (Benign Prostatic Hypertrophy)

--Present in 50% of men over age 50; 80-90% of men over age 75.
 --Only 5-10% will require surgery to relieve obstruction (generally TRUP).
--Presenting complaints: frequency, urgency, nocturia.
--Gross: nodular enlarged prostate. Hyperplasia is usually central (median lobe).
--Micro: nodules of hyperplastic glands.

3. Prostatic Carcinoma

--2nd most common cause of cancer deaths in U.S. males. Generally occurs after age 50.
--May coexist with nodular hyperplasia, but not at higher frequency than expected.
--Occult foci also found at autopsy in 30% of males over 50.
--Gross: mass is peripheral (generally posterior lobe); so can be picked up by rectal
exam.
--Micro: small glands infiltrating throughout the prostate.
--Therapy: surgery; radiation; castration/antiandrogen therapy if metastatic (tumor growth
is often androgen dependent)
--Metastasizes both to lymph node and hematogenously; often to bone (osteoblastic mets).
--Can follow metastatic disease with serum acid phosphatase.
--Prognosis: combination of stage and grade.

CNS TRAUMA

Types of Infarct:

1. Ischemic (non-hemorrhagic)

2. Hemorrhagic (due either to breakup of occluding thrombus/embolus, more common in

embolic processes; or due to collateral circulation.

3. Lacunar: small infarcts, most common in the basal ganglia, thalamus, pons. Seen in
hypertension, diabetes. Generally due to arteriolar sclerosis in small vessels.

Causes of Infarction

1. Atherosclerosis (most common) may be due to thrombosis of artery due to stenosis or

ulceration of plaque; or embolism from extracranial vessel (e.g., carotids, vertebrals).

2. Emboli from cardiac source (endocarditis vegetation, mural thrombi).

3. Severe, prolonged hypotension (watershed infarcts). See infarction in borderzones

supplied by the terminal branches of two arteries; these terminal arteries are the most likely
to be poorly perfused with severe hypotension.

4. Arteriolar sclerosis (most common in hypertension); results in lacunar infarcts and in basal
ganglia hemorrhages.
 HEMORRHAGE-NONTRAUMATIC

1. Hypertension: vascular changes in hypertension often include focal necrosis or dilatation of

vessel wall, which may rupture. The lenticulate striate arteries are small arteries that take
off directly from the high pressure middle cerebral artery, and therefore are under higher
pressure than most cerebral arterioles. They are more likely to have arteriolarsclerosis and
also more likely to bleed.

The most common site of hypertensive hemorrhages is the basal ganglia (may secondarily
rupture into the ventricles). Hypertensive hemorrhages are also seen in the pons,
cerebellum, midbrain, thalamus, and occasionally the cerebral white matter.

2. Aneurysms

A) Saccular (berry) aneurysms: occur in Circle of Willis; due to congenital defects in the
media of arteries at the point of bifurcation. Rupture usually leads to subarachnoid
hemorrhage.

B) Fusiform (arteriosclerotic) aneurysms: generally due to combination of

atherosclerosis and hypertension. Less likely to rupture; may thrombose or embolize.

3. Vascular Malformations: Several Types

A) Arteriovenous malformations (AVMs). Direct shunt of blood from artery to vein at

high pressure; many eventually bleed.

B) Cavernous angioma--tangle of large veins. May bleed.

C) Capillary telangectasias (tangle of small capillaries). Rarely bleed.

DIFFUSE HYPOXIA

May be due to generalized cessation of blood flow (as in a cardiac arrest) or asphyxia (including
carbon monoxide poisoning). In general, neurons in the hippocampus, cerebral and cerebellar
cortices, corpus striatum and thalamus are relatively sensitive to anoxia; the hypothalamus, brain
stem and spinal cord are relatively resistant. If a person survives severe hypoxia, may get
generalized atrophy of the gray matter, and a vegetative or severely impaired mental state.

CNS INFECTIONS

1. Suppurative Meningitis

--Most common organisms are pneumococcus, H. influenzae, and meningococcus.

--In neonates, generally gram-negative rods, streptococcus, staphylococcus.
--In young children, H. influenzae.
--All ages: pneumococcus (esp. elderly); meningococcus.
 --CSF findings: pleocytosis with increased neutrophils; low sugar; high protein. May or
may not demonstrate organisms on gram stain.
--Pathology: grossly cloudy meninges; microscopically, neutrophils and fibrin filling
subarachnoid space.

Acute complications: septic shock; Waterhouse-Friedereckson syndrome with

meningococcus (intraadrenal hemorrhage and insufficiency); cerebral edema.

Chronic complications: leptomeningeal fibrosis leading to nerve palsies, hydrocephalus;

occasionally a seizure disorder.

2. Brain Abscess

--Source of infectious agent may be hematogenous (50%); direct from pericranial infection
(25-30%) otogenic; traumatic.
--Organisms: streptococcus, S. Aureus, gram negative rods; also nocardia.
--Pathology: pus-filled abscess surrounded by gliosis; may be surrounding localized
cerebral edema leading to increased intracranial pressure and risk of herniation.

3. Epidural Abscess

--Either from hematogenous of direct spread; may compress brain, spinal cord.

4. Subdural Abscess

--Often from adjacent chronic bacterial sinusitis.

5. Tuberculosis

A) TB meningitis is more common in young children; presumable disseminates from

pulmonary focus. CSF shows pleocytosis (mononuclear cells); increased protein;
decreased sugar.

--Pathology: often most severe inflammation at base of brain; see granulomatous

inflammation.
--May be complicated by meningeal fibrosis/hydrocephalus.

B) Rarely, see tuberculoma within cerebellum, elsewhere in CNS.

6. Tertiary Syphilis

A) Meningovascular - onset approximately ten years after exposure. See chronic

inflammation infiltrate (lymphocytes and plasma cells) in leptomeninges; often
inflammation of vessel walls as well. Can cause infarct due to vessel involvement; also
meningeal fibrosis, leading to CSF flow obstruction/hydrocephalus.
 B) Tabes dorsalis (most common type of tertiary syphilis). Onset twenty years after
exposure. See fiber loss and fibrosis of the dorsal spinal roots. There is loss of joint
position sense; absent deep tendon reflexes; occasional "lightening" pains accompanied
by diminished sensation.

C) General paresis: Onset 15-20 years after disease exposure. Caused by diffuse
parenchymal infection by spirochetes. Leads to cerebral cortical atrophy, gliosis,
dementia.

FUNGAL DISEASES

1. Cryptococcus: may occur either in normal or immunosuppressed host. May see minimal
inflammatory response, or may see a granulomatous response. Probably derived from an
occult primary pulmonary infection.

2. Coccidiomycosis: occasionally seen, especially in the southwestern U.S. causes a

granulomatous meningitis; may be complicated by hydrocephalus.

3. Histoplasmosis: syndrome like T.B.

4. Candida: see multiple microabscesses within the cerebral parenchyma or in the meninges
(usually in immunocompromised hosts).

5. Aspergillus: multiple hemorrhagic infarcts are induced by hyphae growing within blood
vessels and setting up thrombosis. Also in the immunosuppressed.

6. Mucor: growth pattern like aspergillus. Occurs in diabetics and the immunosuppressed.

VIRAL DISEASES

1. Acute Viral Meningitis:

--Many agents; include ECHO, coxsackie, mumps virus.

--See CSF pleocytosis (mononuclear cells); increased protein; normal sugar.

2. Acute encephalitis:

--May be due to arboviruses; herpes simplex; rabies.

--Microscopically, see mile meningeal and perivascular lymphocytic infiltrate; microglial
activation and nodule formation; neuron necrosis and neuronophagia; inclusions in
herpes simplex and rabies infections.
--CSF: like acute viral meningitis.

A. Arboviruses (include EEE; WEE; St. Louis; California)

--Morality rate ranges from 5-65% depending on type.

--Occur in epidemics
 B. Herpes simplex-sporadic. ? due to reactivation of virus in trigeminal ganglion?

--Has affinity for temporal lobes and cingulated gyrus.

--May see inclusions.
--High mortality rate; many survivors have sequelae.

C. Rabies - acquired from bite of rabid animal.

--Approximately 2 month incubation.

--Causes acute gray matter encephalitis; may see cytoplasmic Negri bodies (viral
inclusions with neurons).

3. Subacute/chronic encephalitis:

A. Subacute sclerosing panencephalitis (SSPE)

--Caused by measles virus or by closely related myxovirus.

--Most common in persons who contracted measles before age 2.
--Causes a meningoencephalitis similar to that seen in acute encephalitis.
--Survival: six months - two years.

B. Progressive multifocal leukodystrophy.

--Related to infection with papova virus; occurs in immunosuppressed.

--Predominantly attacks oligodendrocytes; causes patchy myelin destruction.
--Pathology: focal demyelination
--Generally fatal after 3-6 months.

4. Slow Virus Infection

--Cause Subacute spongioform degeneration of the CNS, with neuronal loss and gliosis.
--Creutzfeldt Jakob disease; most common in 60s, fatal after 6 months to 2 years.

5. Congenital Viral Infections: rubella, CMV

PARASITES

1. Toxoplasmosis: may occur as a congenital infection (leads to subacute meningo

encephalitis; hydrocephalus; chorioretinitis) or in immunocompromised adults.

2. Amebic Meninogoencephalitis (Analgesia fowleri); causes acute meningitis; probably

gains access through sinuses.
 CNS TUMORS

1. Gliomas (include glioblastoma multiforme; astrocytoma; oligodendroglioma;

ependymoma)

A. Glioblastoma Multiforme (most common glioma)

--Generally tumor of adults; age 40-60.

--Rapidly growing, aggressive neoplasm; most common in cerebral cortex.
--Often partially necrotic; may have distinct or indistinct border.
--Micro: see Anaplastic cells; geographic necrosis with palisading spongioblasts;
vascular proliferation.
--Only 10% 2 year survival due to local destructiveness.
--Rarely metastasize outside the CNS (if so, after surgery or shunt placement)

B. Astrocytoma (20-25% of all gliomas)

--Most common in children and young adults; in children, occur in the brainstem and
cerebellum; in adults, in the cerebral hemispheres.
--Slow growing tumor with ill-defined borders; generally not necrotic unless has been
operated on or irradiated.
--Composed in most cases of well-differentiated astrocytes.
--Average survival from 4 years (cerebral) to 13 years (cerebellar)

C. Oligodendroglioma (5% all gliomas)

--Generally arises in the 30s and 40s in the cerebral hemispheres.

--Slightly better circumscribed than astrocytomas.
--Composed of fairly well differentiate oligodendrocytes.
--Behavior/prognosis similar to astrocytomas.

D. Ependymoma (6% of all gliomas)

--Most common in children

--2/3 arise in 4th ventricle; obstruct of CSF flow by tumor leads to hydrocephalus.
--Prognosis: 5 year survival, 4th ventricle; 10 years if in spinal cord.

2. Medulloblastoma

--Composed of very primitive cells resembling external granular layer in developing

cerebellum.
--Occurs in the cerebellum in children (50% first decade; 33% second decade).
--Rapidly growing; highly malignant; can obstruct CSF flow leading to hydrocephalus, and
can also spread widely throughout meninges.

Metastasis outside the CNS is rare.

Prognosis: now 5-10 years with radiation therapy.
3. Leptomeningeal Tumors

A. Meningioma: 15% of all intracranial neoplasms; most common in middle age.

--Benign; encapsulated mass adherent to dura.

--Causes symptoms secondary to compression of brain/spinal cord.

B. Hemangioblastoma: benign, very vascular tumor arising in cerebellum. Some are

associated with von Hippel-Lindau disease (angiomatosis of the retina; multiple cysts of
the pancreas and kidney, renal cell carcinoma; hemangioblastoma of cerebellum).

4. Lymphomas: may be primary in CNS or systemic.

5. Metastatic Carcinoma/Melanoma

6. Peripheral Nervous System Tumors

A. Schwannoma: benign tumor of Schwann cells; may be along peripheral nerve, or nerve
root. Can occur intracranially along 8th nerve (acoustic neuroma).

B. Neurofibroma: also derived from Schwann cells. May be sporadic or part of von
Recklinghausens syndrome (up to 10% of those associated with neurofibromatosis can
undergo malignant change).

DEMYELINATING PROCESSES

1. Progressive Multifocal Leukoencephalopathy: see under viruses.

2. Multiple Sclerosis:

--Etiology unknown; most common in temperate zones.

--Average age at onset 20-40 years.
--Generally a protracted, waxing and waning course with variable, fluctuating symptoms.
--Pathology: demyelinating plaques anywhere in CNS (predilection for periventricular
areas)

3. Leukodystrophies:

--Genetics: x-linked or Autosomal recessive.

--Generally have onset in infancy or childhood.
--See abnormal or inadequate myelination (includes metachromatic leukodystrophy (aryl
sulfatase A deficiency); Krabbes disease (B galactosidase deficiency); adreno-
leukodystrophy (has associated adrenal gland atrophy with adrenal insufficiency).
 DEGENERATIVE DISEASE

1. Dementias (diseases affecting cerebral cortex)

A. Alzheimer's Disease

--Affects 7% of individuals over 65; 17% over 85.

--Clinical course: 5-10 years
--Gross: diffuse cortical atrophy with decreased weight of brain; widened sulci.
--Micro: see senile plaques (with or without amyloid; widespread intracytoplasmic
neurofibrillary tangles; and granulovaculoar degeneration of neurons. Also see
neuronal loss in the Basal Nucleus of Meynart.
--Occurs with increased frequency at early age in persons with Down's syndrome.

B. Pick's Disease: common in the 5th and 6th decades of life.

--2-10 year course.

--See predominantly frontal and temporal lobe atrophy.
--May see granulovacuolar degeneration; few or no tangles or plaques. Do see
intracytoplasmic inclusions in neurons (pick bodies).

2. Basal Ganglia and Brain Stem Disorders

A. Huntingdon's Chorea

--Autosomal dominant; develops from age 25-45.

--Features chorea with mental impairment; clinical course 15 years on average.
--See severe atrophy of the corpus striatum (caudate nucleus and putamen), with
neuronal loss and gliosis; also see diffuse cortical atrophy.

B. Parkinson's Disease

--onset 6th decade; usually sporadic disorder (occasionally complicate encephalitis).

--Clinical features: tremor; bradykinesia; mask-like facies; propulsive gait; stooped
posture.
--Pathology: loss of pigmented neurons in the substantia nigra and locus ceruleus
(dopaminergic neurons); may see intracytoplasmic Lewy body in remaining
neurons.

C. Various Spinocerebellar Ataxias

3. Motor Neuron Diseases

A. Amyotrophic Lateral Sclerosis

--Occurs in 6th and 7th decade; has 1-5 year course.

--Clinical features are weakness, hyperactive deep reflexes, atrophy of muscles.
 --Pathology: see loss of motor neurons in spinal cord and brainstem; also
degeneration of corticospinal tracts (upper motor neuron lesion).

B. Polio: attacks lower motor neurons of cranial nerve nuclei and anterior horn cells in
spinal cord.

C. Spinal Muscular Atrophy (e.g., Werdnig Hoffman disease)

--Disease of lower motor neurons; Autosomal recessive disorder.

CONGENITAL LESIONS

1. Cranioracischisis - no skull; underdeveloped, exposed brain; not compatible with life.

2. Encephaloceles/Meningoceles/Meningomyeloceles: due to defect in bone; get out

pouching of meninges +/- brain and spinal cord.

3. Spina Bifida Occulta: defect in bony spinal canal; no outpouching of spinal cord or
meninges but there can be a sinus from the meninges to the skin, making infection possible.

4. Porencephaly: connecting pore between lateral ventricle and outside, lined by ependyma;
caused by circulatory problem in utero.

5. Pachygyria: few, thickened gyri.

6. Micropolygyria: too many, small gyri.

7. Lissencephaly:smooth brain; no gyri

8. Heterotopias: neurons in wrong place (for example, in periventricular white matter0.

9. Arnold-Chiari Malformation: features:

A) Vermis extends down into cervical canal.

B) Slit like 4th ventricle extends into cervical area.

C) Medulla, pons, 4th ventricle elongate due to displacement.

D) Often associated lumbar spina bifida and meningomyelocele.

--Arnold-Chiari malformation often leads to hydrocephalus.

10. Dandy-Walker Syndrome: features:

A) Malformation of cerebellar vermis; large cyst in posterior fossa replaces vermis;

connects with 4th ventricle.
 B. Cyst may obstruct foramina of Luschka and Magendie.

C. Associated with hydrocephalus.

11. Syringomyelia: cavitation of central area of spinal cord and medulla. Progressive
disease; impairs temperature and sensation.

12. Hydrancephaly: perinatal destruction of CNS parenchyma; replaced by lots of cystic

spaces (liquefaction necrosis).

13. Hydrocephalus: may be either:

A) Communicating (due to meningeal fibrosis impairing secretion of CSF back into blood
via the arachnoid granulations.

B) Non-communicating: obstruction at level of 3rd, 4th ventricle or aqueduct or foramina.

Both cause ventricular dilatation.

PHAKOMATOSES-neuroectodermal dysplastic process

involving skin, nervous system, retina

1. Von Recklinhausens Neurofibromatosis: may have associated a variety of CNS tumors,

neurofibromas, neurofibrosarcomas, etc.

Also often have café-au-lait spots.

2. Tuberous Sclerosis

--Pathology: hard cortical glial nodules plus nodules in ventricular walls.

--Triad of symptoms: mental retardation; seizures; adenoma sebaceum (facial nodules)

3. Sturge-Weber Disease

--Facial port wine stain associate with seizures due to vascular malformations in meninges.

4. Von-Hippel Lindau Syndrome:

--Telangectasias of retina; hemangioblastoma of the cerebellum; renal cell carcinoma

multiple cysts.

PERINATAL LESIONS

1. Subependymal (periventricular) hemorrhage in infants with ARDS or respiratory distress.

May occur as a result of anoxia; venous congestion; stasis; and blood vessel necrosis.

2. Other types of hemorrhage due to birth trauma.

 THYROID; CAUSES OF HYPOTHYROIDISM

1. Congenital Defects (cretinism)

2. Iodine Deficiency (simple colloid goiter)

--Grossly, diffusely enlarged thyroid

--Micro - distended follicles with abundant colloid.

3. Thyroiditis

A. Hashimotos Thyroiditis

--An autoimmune disease; circulating autoantibodies directed against follicular

epithelial cell membrane proteins.
--F:M 10:1
--May be a transient hyperthyroidism followed generally by hypothyroidism.
--Gross: diffusely enlarged thyroid
--Micro: diffuse lymphocytic infiltrate, often with lymphoid follicle formation
Destruction of same follicles.
Hurthle cell change of epithelia lining residual follicles (eosinophilic cells
with increased numbers of mitochondria).

B. Subacute Granulomatous Thyroiditis (DeQuervains)

--Presents as acute febrile illness with swollen, painful thyroid.

--Possible viral etiology.
--Generally transient hypothyroidism; resolves in 6 months.
--Gross: diffusely enlarged thyroid
--Micro: granulomatous inflammation with giant cells (no caseation)

C. Riedels Thyroiditis (Riedels Struma)

--Pathogenesis unknown.
--Rare condition: females more often than males; age 40-70.
--Gross: see fibrotic thyroid; may extend into surrounding tissue raising question of
cancer.
--Micro: diffuse fibrosis

THYROID LESIONS THAT CAN CAUSE HYPERTHYROIDISM

1. Diffuse Toxic Hyperplasia (Graves Disease)

--Pathogenesis; autoimmune (antibodies that stimulate thyroid hormone production)

--F:M 5:1
--Clinical syndrome includes hyperthyroidism; diffusely enlarged thyroid; and
opthalmopathy (swollen orbital tissues cause bug eyed look).
 --Micro: tall epithelial cells with papillary infoldings; small amount of colloid in follicles
with scalloped colloid border.

2. Nodular Hyperplasia (multinodular goiter)

--May be toxic or nontoxic

--Possibly due to alternating cycles of hyperplasia and regression (stimulus unknown).
--Gross: enlarged nodular gland with scars; cysts, foci of hemorrhages; calcifications.
--Micro: various sizes and shapes of follicles; focal hemorrhages; clusters of
macrophages cleaning up colloid from ruptured follicles; scarring; calcifications.

3. Follicular Adenoma: may be functioning or nonfunctioning.

--Gross: solitary nodule, usually less than 4 cm. in diameter.

--Micro: follicular lesion (distinguish from follicular carcinoma by absence of capsule or
blood vessel invasion).

THYROID CARCINOMA

1. Papillary Carcinoma (70% of all cases of thyroid carcinoma)

--Most common in young females; may be induced in some cases by radiation.

--Gross: often encapsulated nodule.
--Micro: Papillary formations (with or without admixture of follicular areas); optically
clear nuclei in some cases; psammona bodies.
--Generally has indolent course; lymphatic metastases (to cervical lymph nodes).
--Has 70-80% 10 year survival.

2. Follicular Carcinoma (20% of all cases of thyroid carcinoma)

--Occurs at any age; female more than male.

--Composed of follicles (often has capsule/blood vessel invasion).
--Metastasizes hematogenously to lung, bone; only 25% 5 year survival.

3. Medullary Carcinoma of the Thyroid

--Derived from the calcitonin-secreting cells of the thyroid

--May be sporadic or part of an MEN syndrome (IIa or IIb).
--Age at onset: 20's if familial; 50's and 60's if sporadic.
--Micro: nests of cells separated by delicate vascular stroma; may have calcitonin-
derived amyloid in the stroma.
--EM - shows neurosecretory granules (part of APUD system).
--Survival: average 5-10 years.

4. Anaplastic Carcinoma of the Thyroid

--Terrible prognosis.
 --Only 10% survival at 1 year.
--Generally occurs in elderly.

PARATHYROID

1. Primary hyperparathyroidism: may be due to adenoma (j40-80%); or to diffuse

hyperplasia of all four glands. Parathyroid carcinomas are very rare.

2. Secondary hyperparathyroidism--usually related to renal disease.

Complications of hyperparathyroidism include:

1. Hypercalcemia with metastatic calcification of blood vessels, kidney.

2. Nephrocalcinosis and renal calculi.

3. Osteitis fibrosis cystica (brown tumor). There is focal demineralization due to osteoclast
resorption of bone. Replaced by vascular connective tissue.

4. High rate of peptic ulcer (gastrin levels are increased).

5. Pancreatitis; hypertension; mental disturbances.

Hypercalcemia can be due not only to hyperparathyroidism but also to bone malignancies; lab
error; excess Vitamin D., etc.

Hypoparathyroidism is rare; may be post surgical (due to parathyroidectomy or thyroidectomy)

familial; or idiopathic (often associated with other autoimmune diseases).

GALLBLADDER AND EXTRAHEPATIC BILE DUCTS

1. Cholelithiasis and cholecystitis

75% are mixed stones: cholesterol, calcium carbonate, calcium bilirubinate. These have
a laminated yellow friable interior. 10% are cholesterol stones (also have yellow friable
interior), and 15% are pigment stones (bilirubin)--have a faceted green-black surface, are
hard and solid. Pigment stones are seen in diseases with chronic hemolysis, such as sickle
cell anemia, hereditary spherocytosis, etc. Other types of stones are seen predominantly in
women (F:M = 3:1); much more common in the U.S. and Europe than in the third world.

Gallstones may cause 1) acute cholecystitis: when the cystic duct is blocked by a stone, a
chemical irritation ensues often followed by secondary bacterial infection. The bacteria
probably gain access to the gallbladder via lymphatics from the gut or the portal venous
system. Grossly, in acute cholecystitis the surface of the gallbladder is covered with fibrin,
and the wall is edematous. Microscopically, there is ulceration of the gallbladder mucosa
and an acute neutrophilic infiltrate within the gallbladder wall. Patients usually present
with acute RUO pain, fever, nausea, and vomiting. If not treated, it may resolve (usually if
 the stones pass through the duct); go on to chronic cholecystitis, or progress to gangrene of
the gallbladder and rupture (catastrophe) which leads to acute peritonitis. There are rare
cases of a calculous cholecystitis (no stones) usually in the setting of sepsis or toxic shock.

Chronic cholecystitis occurs in association with long standing gallstones. The gallbladder
walls become fibrotic and thickened; there is hypertrophy of the smooth muscle; usually a
chronic inflammatory infiltrate within the walls; and trapping of epithelium within the
inflamed areas ("Rokitansky-Aschoff sinuses"). End state is the "porcelain gallbladder"
which is a diffusely fibrotic gallbladder with calcified walls.

2. Gallbladder Carcinoma

Rare--one to three percent of all GI carcinomas. Usually occurs in the setting of chronic
cholecystitis and cholelithiasis. 90% + are adenocarcinomas. Prognosis is poor--usually
not diagnosed until too late; may invade directly into local organs (liver, intestines) and
eventually spread into lymphatics.

3. Sclerosing Cholangitis

Rare disorder of unknown etiology. Hallmark is diffuse fibrosis, chronic inflammation of

extrahepatic bile ducts (as opposed to the involvement of intrahepatic ducts in primary
biliary cirrhosis). May be associated with other idiopathic diseases like inflammatory
bowel disease (especially ulcerative colitis), retroperitoneal fibrosis, etc. Sclerosing
cholangitis may eventually cause a secondary biliary cirrhosis due to the bile duct
obstruction.

PANCREAS

1. Cystic Fibrosis

Autosomal recessive disorder most common in persons of Northern or Western European

descent. It is associated with sticky secretions and inspissation of secretions (plugging by
secretions) in ducts of multiple organs. Inspissation secretions in the pancreas leads to
chronic inflammation, fibrosis, atrophy of the exocrine pancreas; islets are preserved until
late. The obstruction to flow of the pancreatic secretions may impair intestinal absorption
due to lack of pancreatic enzymes. Diabetes rarely occurs even at terminal stages.
Inspissation of the obstruction; most common cause of death is pneumonia or respiratory
failure. May eventually lead to cirrhosis, duet to bile duct. Affected babies may also have
intestinal obstruction at birth due to meconium (sticky meconium forms solid plug in the
intestine).

2. Acute Pancreatitis

Associated with chronic alcohol abuse diseases of the biliary tract (especially if stone
impacts a the ampulla of Vater); neoplasms, postoperatively, post-trauma). Symptoms
include acute pain radiating to back, vomiting. Pathophysiologically, the initial insult leads
to injury of exocrine cells and release of lytic enzymes, with autodigestion of pancreatic
 tissue, adjacent fat. Microscopically and grossly, see foci of hemorrhage, necrosis of
pancreas and fat necrosis.

3. Chronic Pancreatitis

Presents as recurrent bouts of abdominal pain--usually caused by recurrent bouts of acute

Pancreatitis. Eventually, see a shrunken gland with fibrosis and atrophy of exocrine
pancreas (usually sparking of islets until late), also chronic inflammation. May lead to
malabsorption due to decreased output of pancreatic enzymes into small intestine.

4. Pancreatic Adenocarcinoma

Most pancreatic carcinomas are adenocarcinomas, arising from the epithelium of pancreatic
ducts. Generally occur in middle-aged or elderly individuals. If they arise in the head of
the pancreas, may cause jaundice due to obstruction of the ampulla of Vater. In the
tail/body of the pancreas, symptoms occur late--these include weight loss, abdominal pain
radiating to back; multiple thromboses (Trousseau's sign; due to hypercoagulable state
induced by tumor factors). Survival rate is up to 40% in those with tumors of the head of
the pancreas, at 5 years; due to earlier detection. 5 year survival in persons with carcinoma
arising in the tail or body of the pancreas is abysmal (les than 5%). Tends to kill via spread
to local organs.

5. Pancreatic Islet Cell Tumors

Insulinomas (90% being) produce insulin; induce hypoglycemia.

Gastrinomas (60-70% malignant) produce gastrin, may lead to Zollinger Ellison syndrome
(intractable peptic ulcers spurred by high serum gastrin levels).

VIPoma (most malignant); uncommon tumor that produces a factor that causes a watery
diarrhea syndrome (referred to as pancreatic cholera).

Glucagonoma (most are malignant)--very rare; causes hyperglycemia, and is associated

with necrotizing skin lesions.

Histologically, the islet cell tumors consist of clusters of uniform cells separated by a
delicate vascular stroma (may closely resemble carcinoid tumors). Islet cell tumors are
considered "neuroendocrine" and part of the "APUD system"; they have dense core
secretory granules containing hormone by EM. Up to 5% of islet cell tumors are associated
with MEN I syndrome (multiple endocrine neoplasia I; consists of pancreatic islet cell
tumors, pituitary adenomas, parathyroid lesions, adrenal cortical adenomas).

6. Diabetes Mellitus: see under systemic diseases in first handout.

 LIVER

1. Congenital Anomalies

A. Congenital Hepatic Fibrosis: associated with infantile polycystic kidney disease (Type
1). Microscopically, see diffuse periportal fibrosis, some dilated bile ducts.

B. Biliary Atresia: occurs in infants, who show progressive jaundice after the first week
of life. May affect either the intrahepatic or extrahepatic ducts, which fail to form
during fetal life. Leads to extreme cholestasis, portal fibrosis, bile duct proliferation,
and rapidly progressive cirrhosis. Most children die within the first year of life unless a
connection can be established surgically between patent intrahepatic ducts and an
extrahepatic drainage system. Only other alternative is liver transplant. Death may be
due to portal hypertension with varices formation, or to liver failure.

C. Congenital Defects in Bilirubin Metabolism

1. Gilberts Syndrome: has a benign course: (bilirubin usually less than 5mg/dl) the
increase is in unconjugated bilirubin, and is due to impaired ability of the
hepatocyte to take up unconjugated bilirubin from the bloodstream. The liver is
Histologically normal. The syndrome is Autosomal dominant.

2. Crigler-Najjar Syndrome: absence (Type I==Autosomal recessive) or diminished

amount (Type II--autosomal dominant with variable penetrance) of glucoronide
since this enzyme is essential for conjugation. Type I's usually die in childhood
while Type II's may do well, depending on the level of enzyme. Liver is both types
is Histologically normal.

3. Dubin-Johnson/Rotor Syndrome: defect in ability of hepatocyte to excrete

conjugated bilirubin into the bile canuliculi. See increases in serum of both direct
and indirect bilirubin. In Dubin-Johnson syndrome, liver is brown-black in color
due to pigment accumulation (?lipofuschein?) but otherwise is normal
Histologically. Rotor syndrome has the same biochemical abnormalities as Dubin-
Johnson syndrome but dues not accumulate pigment. Prognosis depends on extent
of impairment of ability to secrete bilirubin, but often is compatible with survival.

II. Parasitic Infections that can affect the liver (rare in U.S.)

A. Schistosomiasis: (see ova in liver parenchyma)

B. Echinococcus Cysts: (caused by larvae of dot tapeworm)

C. Amebic Cysts: (spread from large bowel in some cases of amebic dysentery)

III. Hepatitis and Acute Liver Disease

A. Viral
1. Hepatitis A: short incubation (15-40 days). Acquired from contaminated food
and water; may occur in epidemics. Does not spread through transfusion. Usually
causes a transient hepatitis (most are probably subclinical); rarely leads to acute
fulminant hepatitis with liver necrosis, and does not have the ability to establish a
chronic carrier state (so doesn't lead to chronic hepatitis).

2. Hepatitis B: longer incubation period (50-180 days). Generally transmitted either

through a blood exchange (transfusion of blood or clotting factors, shared needles,
accidental needle stick) or intimate contact (in this country, usually sexual contact).
Ranges in severity from a subclinical, anicteric infection to fulminant hepatitis.
Does establish a carrier state in 5-10% of all persons who contract it.

In acute Hepatitis B, the liver is grossly swollen (may see focal collapse of necrotic
liver in cases of fulminant hepatitis with massive hepatic necrosis). Histologically,
acute (nonfulminant) Hepatitis B is characterized by a periportal inflammatory
infiltrate (lymphocytes, plasma cells, histiocytes) with additional clusters of
mononuclear cells in lobules. There is disarray of the lobules, and necrosis of
individual hepatocytes (often see Councilman (acidophil) bodies, which are
hepatocytes with shrunken bright pink cytoplasm and absent nuclei (in other words,
hepatocytes which have undergone coagulation necrosis). Viable hepatocytes may
show ballooning (accumulation of water within the cell).

Some cases of acute Hepatitis B show bridging necrosis (band-like necrosis of

hepatocytes joining portal and/or central areas. 1% of cases of acute Hepatitis B go
on to fulminant hepatitis with massive hepatic necrosis (this has a 70% mortality
rate).

5-10% of persons who contract Hepatitis B go on to a chronic carrier state.

Majority are asymptomatic (but infectious) carriers. Others show chronic persistent
hepatitis (a portal lymphocytic infiltrate with intact limiting plate, no hepatocyte
necrosis; in general does not lead to cirrhosis). A few go on to chronic active
hepatitis, in which in addition to portal infiltration by lymphocytes there is necrosis
of hepatocytes a the edge of the portal tract (referred to as erosion of the limiting
plate or piecemeal necrosis). This has a significant risk of progressing to cirrhosis.

Ground glass cells may be seen in either CPH or CAH (reflects the accumulation of
Hepatitis B surface antigen in endoplasmic reticulum, giving the cytoplasm a pink
glassy appearance). They are not seen in acute Hepatitis B.

3. Hepatitis Delta

hepatitis delta is an RNA virus that can only superinfect persons with concurrent
Hepatitis B infection (it can't synthesize its own outer capsule, so it commandeers
Hepatitis B surface antigen being produced in the same cell to wrap itself in). In the
U.S., it is transmitted predominantly by blood produces/shared needles. In cases of
acute coinfection with both Hepatitis B and delta (for example, derived from the
blood of a combined Hepatitis B-delta carrier; there are no pure delta carriers since
 the virus can't survive alone) there is increased risk of fulminant hepatitis (10%
versus 1%). If the Hepatitis B is successfully eradicated by the body, then delta is
also eradicated. If this person is one of the 5-10% that go on to a carrier state, then
he or she is likely to develop a more severe disease and more likely to develop
cirrhosis as a combined carrier than would be the case with Hepatitis B alone.
Exposure of an established Hepatitis B carrier to a needle/transfusion infective for
hepatitis delta/B often results in delta superinfection and combined B/delta carrier
state with its higher risk for cirrhosis. Persons who are immune (by vaccine or
previous infection) to Hepatitis B are also de facto immune to delta (in other words,
delta won't be able to get a foothold if Hepatitis B infection can't be established).

(Note: The long discussion of hepatitis delta reflects the fact I had to give a grand
rounds on the topic and so of course I think you'll find it fascinating. Right now
hepatitis delta is pretty much confined in the U.S. to I.V. drug abusers on both
coasts; blood screened for HBV also theoretically should be adequately screened for
delta carriers must be coinfected with HBV. For some reason, delta hepatitis has
not (yet?) become a major problem in the gay community despite the high rate of
HBV infection in that group.)

4. Non-A, Non-B Hepatitis

The agent(s) is/are not yet isolated, but are transmitted through blood
transfusion/shared needle/needle stick. Incubation is 14-180 days. non-A, Non-B
Hepatitis causes disease states similar to those seen in HBV (from an anicteric
subclinical infection to severe acute hepatitis). Up to 40% may go on to a chronic
carrier state. Histology would be roughly similar to that seen in acute or chronic
Hepatitis B. Persons with chronic active hepatitis on this basis may go on to
cirrhosis.

B. Alcoholic Liver Disease - Acute

Fatty change occurs acutely after the ingestion of large quantities of alcohol or in the
setting of chronic excessive use. It is a reversible change with several days of
abstinence.

Alcoholic hepatitis may also be seen after an acute binge or with chronic excessive use.
In addition to fatty change, see a neutrophilic infiltrate in the portal tracts and small
clusters of neutrophils within the lobules, often around individual necrotic hepatocytes.
May, in the setting of chronic alcohol abuse, see Mallory bodies (Mallory hyaline)
within the cytoplasm of hepatocytes; these deep pink ropy aggregates of protein
probably represent aggregated prekeratin intermediate filaments.

C. Drug-induced Liver Disease

--Very variable in its morphology; many agents may cause it. May be due either to
dose-related toxicity (e.g., Tylenol) or to anidiosyncratic reaction to normal doses of a
drug. May give an acute picture resembling acute viral hepatitis (halothane, isoniazide,
 iproniazed, Salicylates, aldoment, oxyphenacetin); 6 mercaptopurine, sulfonamides)
granulomatous inflammation (non-caseating) (sulfonamides, phenylbutazone, aldomet);
submassive to massive hepatitic necrosis (Tylenol OD, holothane/isoniazid reaction),
etc. See Table 19-3 in Robbins for more details.

--A drug history should always be taken when evaluation hepatitis.

D. Reyes Syndrome

Usually follows influenza, chicken pox, other viral infections; has been linked to the
use of aspirin in that setting. Generally affects children/adolescents. Microscopically,
se microvesicular (very small droplet) fatty change in the liver, and an edematous
encephalopathy. 25-50% of cases are fatal, due usually to the cerebral edema and
herniation. Survivors have normal liver function; normal or impaired CNS.

E. Neonatal Hepatitis

Mixed bag of lesions--many cases caused by viruses, including CMV, rubella,

coxsackie, HBV; occasional cases not infectious but associated with alpha-1-antitrypsin
deficiency in the neonate.

IV. Cirrhosis

Often separated into macronodular (nodules greater than 3 cm in diameter) and

micronodular (nodules less than 3 cm in diameter) cirrhosis. Macronodular cirrhosis is
associated with post-necrotic (viral) cirrhosis; micronodular classically associated with
alcohol abuse, hemochromatosis, primary biliary cirrhosis. Wilson's disease and alpha-1-
antitrypsin deficiency can give rise to either.

Histology of cirrhosis involves: criss crossing fibrous bands surrounding regenerating

nodules of hepatocytes. There may also be proliferating small bile ducts within the
fibrotic, expanded portal tracts (in any type of cirrhosis, not just biliary).

Sequelae of cirrhosis include:

1) Portal hypertension (leads to esophageal varices, hemorrhoids, ascites)

2) Hepatocellular carcinoma (especially with Hepatitis B, hemochromatosis)

3) Liver dysfunction (impaired synthesis of clotting proteins, albumin, impaired

catabolism of bilirubin and other substances)

4) Hepatic encephalopathy (impaired liver can't handle large protein loads, for example
the protein load in the intestine caused by a massive upper GI bleed. Serum ammonia
levels rise; encephalopathy ensues due to this and other substances. Persons become
confused/comatose.
 CAUSES OF CIRRHOSIS IN THE U.S. ACCORDING TO ROBBINS

30-70% are due to alcohol.

10-50% are post necrotic (due to usually chronic viral infection).
10% are biliary cirrhosis (primary and secondary)
5% are due to hemochromatosis
Rare - Wilson's Disease
Rare - alpha-1-antitrypsin deficiency
10-60%: "cryptogenic": cause unknown

1. Alcohol: (#1 cause in the U.S.; generally micronodular)

2. Post-necrotic cirrhosis (post-viral): most common cause of cirrhosis world-wide;

generally macronodular. Especially high risk for hepatocellular carcinoma; HBV probably
has oncogenic potential.

3. Hemochromatosis: see previous notes under systemic disease. "Pigment" cirrhosis is

due to the widespread disposition of iron in various organs, including the liver, heart,
pancreas, and skin (hence the term "bronze diabetic", which has nothing to do with the
copper buildup in Wilson's disease but rather refers to the unusual skin color of persons
with hemochromatosis. May be primary (due to an inborn error of iron metabolism) or
secondary (due to repeated transfusions/high alcohol intake with increased absorption of
iron).

4. Wilson's Disease: autosomal recessive. Copper accumulates within organs of the body.
Associated with low ceruloplasmin levels (a serum copper-carrier); have high contents of
copper in the liver by biochemical assay (can't see the copper well rings in the corneas, and
copper accumulation in the lenticulate nuclei of the brain (hence the synonym
hepatolenticular degeneration) which leads to neurologic and psychiatric abnormalities.

5. Primary Biliary Cirrhosis: thought to be autoimmune in origin; it strikes middle-aged

women. Many have other autoimmune-type diseases (Hashimoto's disease, rheumatoid
arthritis, etc.) 90-100% have antimitochondrial antibodies. Microscopically, see intense
portal infiltration by lymphocytes, sometimes accompanied by small non-caseating
granulomas. Progresses to micronodular cirrhosis.

6. Secondary Biliary Cirrhosis: long-standing biliary tract obstruction due to impacted stone,
tumor, stricture, sclerosing cholangitis, or biliary Atresia in children can lead to bile stasis
in ducts, followed by periportal fibrosis and finally cirrhosis.

7. Alpha-1-antitrypsin Deficiency: normal persons have 2 M alleles at the A1AT locus

(PiMM); heterozygotes (PiMZ) are fairly normal; homozygotes (PiZZ) for the Z allele have
accumulation of an abnormal A1AT in the hepatocytes (seen as PAS-positive globules)
which can't be secreted into the blood stream. Sequelae: neonatal hepatitis; cirrhosis in
childhood/early adulthood (tends to be macronodular); and panacinar emphysema
(presumably due to lung damage occurring in the absence of this protease inhibitor).
V. Vascular Problems (Hepatic Congestion)

1. Budd-Chiari Syndrome: rare disorder affecting persons between the ages of 20 and
40. It refers to thrombosis of the hepatic vein for unknown causes, which give rise to
severe centrilobular congestion and progresses to cirrhosis. May be fatal.

2. Cardiac Decompensation (Right Sided): leads to increased pressures in the systemic

veins, including the hepatic vein. See congestion of the central veins and dilatation of
the centrilobular sinuses grossly (as a "nutmeg liver" with alternating tan and red
patches) and microscopically. May occasionally lead to cirrhosis.

VI. Benign Tumors and Tumor-Like Lesions

1. Hemangioma: most common benign tumor of the liver. Composed of large vascular
spaces lined by benign endothelium.

2. Peliosis Hepatitis: rare lesion. Not really a neoplasm, but rather a dilatation of
sinusoids to form blood-filled spaces. Associated with anabolic steroid use.

3. Hepatocellular Adenoma: rare lesion which is a benign tumor of bland hepatocytes.

Most cases occur in women on oral contraceptives. May present with mass;
occasionally adenomas may rupture and bleed into the abdominal cavity. No
premalignant potential.

4. Nodular Hyperplasia: see one or more nodules composed of benign hepatocytes; the
nodules often have a central scar. Etiology: undetermined; link to oral contraceptives is
disputed. No premalignant potential; rarely bleeds; no clinical sequelae in most cases.

VII. Malignant Neoplasms of the Liver

1. Hepatocellular Carcinoma: risk factors include chronic HBV infection (especially in

setting of chronic active hepatitis/cirrhosis; exposure to carcinogens (aflatoxin is
suspected as a carcinogen in Africa, while Thorotrast (a radioactive scanning agent
used in the 1940s) has been shown to increase the risk of angiosarcoma, hepatocellular
carcinoma and cholangiocarcinoma; and cirrhosis in general (with hepatitis-associated
cirrhosis and hemochromatosis having the highest risk, with a lower risk with alcoholic
cirrhosis and other types of cirrhosis having quite low rates of hepatocellular
carcinoma.

Gross exam shows one or more tumor nodules, usually in the background of a cirrhotic
liver. Microscopically, the cells resemble hepatocytes with abundant pink cytoplasm,
variable degrees of cytologic atypia/mitotic activity. Patients present with abdominal
pain, ascites, sudden deterioration of preexisting cirrhosis. Most are not surgically
resectable (due to inability to get through life without a liver). Hepatocellular
carcinomas have a tendency to grow into veins; may metastasize to local lymph nodes
but distant metastases are uncommon. Death is usually due to liver failure.
 An unusual variant (fibrolamellar hepatocellular carcinoma) arises in normal livers in a
younger age group (adolescents, young adults). Tends to be a solitary lesion and is
often resectable, with a better prognosis than standard hepatocellular carcinoma.

2. Cholangiocarcinoma: an adenocarcinoma that arises from intrahepatic bile ducts. Most

arise do novo in persons over 50; a few occur after Thorotrast administration or after
long-term infection of the liver (in the Far East) with the liver fluke Clonorchus
Sinensis. They commonly spread through the liver; may also metastasize distantly.

3. Hepatoblastoma: most occur in the first 2 years of life. These children present with an
enlarged abdomen, hepatomegaly, weight loss. Generally occur in a non-cirrhotic liver.
Microscopically, see sheets of small blue "embryonal" cells mixed with larger
"epithelial" or "fetal" cells with more abundant cytoplasm, resembling maturing liver.
May also see mesenchymal elements such as bone and cartilage within the tumor. Used
to be almost always fatal; prognosis now uncertain with new combinations of surgery
and chemotherapy.

4. Angiosarcoma of Liver: very rare; strongly associated with a history of Thorotrast

administration. Usually multifocal (arises at multiple sites). Consists of vascular
spaces lined by malignant endothelial cells.

DISORDERS OF WBC/LYMPH NODE/SPLEEN

I. Non-malignant Leukocytosis:

A. Neutrophilia: may be accompanied by a left shift (increased numbers of circulating

neutrophil precursors such as bands, metamyelocytes, mylocytes). Causes include
bacterial infection (viral infections don't usually cause neutrophilia), extensive tissue
damage/necrosis, and occasionally non-hematopoietic malignancies (cause unclear; in
some cases may be related to tumor necrosis, while some carcinomas may actually
secrete a factor that stimulates neutrophil production by the marrow.

Extreme reactive neutrophilia is termed a leukemoid reaction.

B. Eosinophilia (more than 500 eosinophils/mm3): causes include parasitic infections

(parasite must be invading tissue); allergic conditions (including drug allergies); and
skin diseases.

C. Basophilia: mild relative basophilia may be seen in renal failure, hypothyroidism.

Absolute basophilia is rare in benign conditions: is strongly associated with CML (see
below).

D. Lymphocytosis

1. Mature lymphocytosis: (increased numbers of small mature lymphocytes in

blood) is associated with whooping cough (Bordetella pertussis).
 2. Atypical lymphocytosis: (increased numbers of lymphocytes in blood with more
abundant cytoplasm; may have faint nucleolus). Associated with infectious
mononucleosis and CMV. In infectious mononucleosis due to the Epstein Barr
virus, lymphocytosis begins 1-2 weeks after the onset of symptoms and lasts 1-2
months. Should see more than 50% lymphs in the blood, and at least 10% of all
leukocytes should be atypical lymphocytes. Although EBV infects B cells, these
circulating atypical lymphocytes are T-cells. A heterophile antibody to sheep red
blood cells appears in the blood around the same time as the atypical lymphs and
also lasts 1-2 months (this heterophile antibody is the basis for the positive "mono
spot test").

A "heterophile-negative mononucleosis" (i.e., atypical lymphocytosis not caused by

EBV) can occur; it is most commonly the result of CMV infection, can also be
caused by toxoplasma and adenovirus.

II. Leukocytopenias

A. Neutropenia: causes include inadequate production (aplastic anemia); toxic and drug
related effects (chemotherapy; idiosyncratic reactions to drugs); hypersplenism (may
sequester/destroy WBC). Autoimmune granulocytopenia exists but is very rare. A
decrease in mature neutrophils is seen in acute leukemias (ALL and AML); and in the
pre-terminal stage of CLL (non in CML until blast crisis).

B. Lymphopenia: seen in steroid-treated patients.

III. Leukemias

Leukemias may be subclassified into acute leukemias (proliferation of immature or blast

cells) and chronic leukemias (proliferation of differentiating or mature cells). May be
further subtyped into myelogenous (also called myeloid or granulocytic) leukemias and
lymphocytic leukemias.

Etiologic factors in leukemia include:

1. Viruses: a rare adult T-cell leukemia/lymphoma (generally seen in Japan, the

Caribbean and the south-eastern U.S.) is associated with HTLV-1.

2. Radiation (high rate of leukemia among Hiroshima survivors)

3. Certain Genetic Syndromes (Down's syndrome in particular has a high rate of

leukemia)

4. Chemical Agents: benzene, insecticides, alkylating chemotherapeutic agents used in the

treatment of other forms of cancer.

Acute leukemias present with an acute onset; have evidence of bone marrow failure
(anemia, thrombocytopenia, Neutropenia,). Untreated, death occurs within months due to
 infection (related to Neutropenia) or hemorrhage (due to hrombocytopenia). Infection is
the most common cause of death. Marrow is packed with blasts.

A. ALL (Acute Lymphoblastic Leukemia): most common in children. The basic cell
type is the lymphoblast (high nucleus/cytoplasmic ratio; chromatin more finely
dispersed than in normal lymphs, may have convoluted nuclear outline; nucleoli
sometimes seen). 70-80% are pre-B in origin; 15-50% are T-cell; 2-3% are B cell. The
T-cell type of ALL is closely related to lymphoblastic lymphoma; the B cell type to
Burkett's lymphoma. No Auer rods should be visible. Currently, there is a 50% cure
rate for childhood ALL with chemotherapy.

B. AML (Acute Myelogenous Leukemia): occurs at any age; most cases are in adults.
The basic cell is the myeoblast (a large cell with a small amount of cytoplasm (more
than the lymphoblast), finely dispersed chromatin and 1-5 nucleoli). Cytoplasmic
granules and/or Auer Rods may be seen. (The Auer rod is diagnostic of AML or
evolving AML). Acute myleomonocytic leukemia and acute monocytic leukemia are
considered as variants of AML in the FAB classification, and may have Auer rods.
AML may go into remission with chemotherapy, but most relapse within 1-3 years.

Chronic Leukemias: generally run a more prolonged course.

A. CLL (Chronic Lymphocytic Leukemia): a disease of older adults (usually older than
60). Patients present with splenomegaly, adenopathy, and a high white count with most
cells having the appearance of mature lymphocytes. Marrow contains increased
numbers of lymphocytes, often has a fair number of residual hematopoietic precursors.
Anemia, thrombocytopenia occur late in the course. Generally has an indolent course
(average survival 5-10 years). Very closely related to well differentiated lymphocytic
lymphoma (see below). Almost all are B-cell.

B. CML (Chronic Myelogenous Leukemia): 98-99% of persons with CML have the
Philadelphia Chromosome (a translocation of chromosomes 9 and 22, that results in the
translocation of the abl oncogene). A disease of the middle-aged. Patients have a
hypercellular marrow that contains large numbers of maturing neutrophils and
precursors (blast count usually less than 3% of marrow cells); megakaryocytes are
normal to increased in number; red cells are also usually fairly well preserved. These
patients have a high white count (usually greater than 50,000), consisting of segmented
neutrophils, bands, metamyelocytes, myelocytes, and a rare circulating blast; they
usually also have thrombocytosis. Anemia if present is usually mild. Basophilia is
characteristic. CML usually terminates in a blast crisis after 3-5 years; (70% transform
to AML, 30% to ALL). Auer rods are not seen except in AML blast crisis. Blast crisis
is usually rapidly fatal.

CML must be separated from a leukemoid reaction (an exaggerated neutrophilia with
left shift, which is reactive in origin). CML has a low LAP score, basophilia, and the
Philadelphia chromosome. Leukemoid reactions (neutrophilia) have a high LAP score,
no basophilia, and no Philadelphia chromosome.
III. Reactive Lymphadenopathy

3 major patterns: paracortical hyperplasia (infectious mononucleosis, CMV); follicular

hyperplasia (syphilis, AIDs-related complex, autoimmune-related Lymphadenopathy which
occasionally is noted in rheumatoid arthritis; toxoplasmosis; and reactions to local bacterial
infections, such as seen in cervical lymph nodes with strep throat or tooth abscess) and
granulomatous reactions (sarcoid; small granulomas may also be seen in toxoplasmosis
along with follicular hyperplasia). Hypersensitivity reactions to drugs and vaccinations
may have either a paracortical or follicular hyperplasia. Dermatopathic lymphadenitis
(seen in lymph nodes draining chronically inflamed, abrade skin) is a mixture of follicular
hyperplasia with an infiltrate of normal histiocytes within the sinuses. Cat scratch Fever--
usually see microabscesses in association with follicular hyperplasia.

IV. Metastatic Carcinoma: to be considered in the differential of Lymphadenopathy always.

V. Lymphoma

A. Hodgkins Disease: the neoplastic cell is believed to be the Reed-Sternberg cell.

Other cells within the infiltrate are believed to be reactive (benign). The derivation of
the Reed-Sternberg cell (from B cells, T cells or histiocytes) is hotly disputed.
Hodgkins Disease is most common in adults -- ages 25-55. Four subtypes:

1. Nodular Sclerosing Hodgkins Disease: accounts for 60-70% of all cased os

Hodgkins. This is the only variant which is more common in females. Tends to
occur in lower cervical, supraclavicular and mediastinal lymph node chains.
Histologically, see broad bands of fibrosis criss-crossing the node. Classical Reed-
Sternberg cells are rare; lacunar variants of Reed-Sternberg cells are common (large
cells with cleared cytoplasm, a single often crumples-appearing nucleus). In the
background, see mostly lymphocytes, histiocytes, a few plasma cells and
eosinophils.

2. Mixed Cellularity Hodgkins Disease: accounts for 20-40% of all cases of Hodgkins
Disease. There is diffuse obliteration of lymph node architecture (or paracortical
infiltration in the early stages) by a polymorphous infiltrate containing eosinophils,
lymphocytes, histiocytes, plasma cells, and numerous classical bi-lobed Reed-
Sternberg cells (which has a bi-lobed nucleus, each with a prominent central
eosinophilic nucleolus). Mixed cellularity may affect any lymph node chain; male
predominance.

3. Lymphocyte Predominance Hodgkins Disease: 5-15% of all cases of Hodgkins.

Also has a male predominance. there is diffuse obliteration of the lymph node
architecture by an infiltrate of small, well-differentiated lymphocytes in which are
embedded occasional diagnostic Reed-Sternberg cells. Has the best prognosis.

4. Lymphocyte Depletion Hodgkins Disease: occurs in an older age group (is 5-10%
of all cases of Hodgkins). Tends to have disseminated disease. the lymph node is
 replaced by sheets of cells composed predominantly of Reed-Sternberg cells and
atypical mononuclear variants. Has the worst prognosis.

Prognosis in Hodgkins depends on 3 things. 1) Stage 2) Histologic subtype:

lymphocyte predominant does best, nodular sclerosis and mixed cellularity are
intermediate, lymphocyte depleted does worst and 3) age (younger persons do
better). Current overall cure rates for Hodgkins disease with radiation therapy and
chemotherapy are 80-90%.

B. Non-Hodgkins Lymphoma

A very complex group of disorders; numerous classifications. Most lymphomas are of

B cell origin. Below are Rappaports initial classification (which mostly covers well
differentiated and follicular center cell lymphomas) with their international formulation
equivalent. In the international formulation, the term "histiocytic" was dropped since
most of the lymphomas so described by Rappaport turned out to be of large B cell
origin; and "follicular" replaced "nodular".

Rappaport International Formulation

1. Well differentiated lymphocytic (always 1. Small lymphocytic (always diffuse)

diffuse)

2. Poorly differentiated lymphocytic 2. Small cleaved cell (follicular or

(nodular or diffuse) diffuse)

3. Mixed lymphocytic/histiocytic (nodular 3. Mixed small cleaved cell and large

or diffuse) cell (follicular or diffuse)

4. Histiocytic (nodular or diffuse) 4. Large cell (follicular or diffuse); also

includes immunoblastic

Basically: 4 general groups to know:

1. Well differentiated lymphocytic (small lymphocytic lymphoma): occurs in older adults as

does CLL, to which it is closely related. there is diffuse replacement of normal lymph node
architecture by a population of small lymphocytes with round, regular nuclei (no nodular
variant). this is a B-cell lymphoma in almost all cases. It is separated from CLL only by
whether or not the blood is involved; lymph nodes involved by CLL have an identical
appearance to those involved by WDL. WDL generally has a very indolent course.

2. Follicular center dell lymphomas: most common type of lymphoma in adults (usually
middle-aged at onset). These may be nodular (recapitulating the normal lymphoid follicle,
from which cells these lymphomas derive) or diffuse in pattern. Includes most small
cleaved cell, mixed, and large cell lymphomas. These are all B cell lymphomas. In
general, nodular lymphomas have a more indolent course than diffuse follicular center cell
lymphomas, and small cleaved cell types are more indolent than the large cell ones (with
 mixed lymphoma having an intermediate prognosis). Survival for nodular small-cleaved
cell lymphoma (PDL) is up to 10 years; survival with diffuse large cell lymphoma is
usually only a few years.

3. Burkitts Lymphoma: (also called diffuse small non-cleaved cell lymphoma in the
international formulation). May result from a small transformed follicular center cell - but
has a very different clinical presentation/course. These are all B cell lymphomas. Lymph
node architecture is effaced by a monotonous population of immature-appearing cells with
a high mititoc rate. Burkitts lymphoma is strongly associated with Epstein Barr infection
(not true of other follicular center cell lymphomas). Tends to occur in children (high
incidence in Africa), and often presents in extranodal sites (jaw, ovary, GI tract). Fairly
uncommon in the U.S. Occasionally it may be present in a disseminated form as ALL
(accounts for the 2-3% of ALLs that are true B cell in origin). Has a very aggressive
course, may show some response to therapy.

4. Lymphoblastic Lymphoma: most common lymphoma in children. Tends to present as a

mediastinal mass in teenage males. These are almost always composed of T lymphoblasts,
and are closely related to the 15-20% of ALLs that are T-cell in nature. Since the cells are
identical, the two entities are separated by the extent of blood and bone marrow
involvement. T-lymphoblastic lymphoma may disseminate and behave like a T-ALL.
Lymphoblastic lymphoma has an aggressive course if untreated (in the nodes, see sheets of
lymphoblasts with convoluted nuclei and a high mitotic rate). It may respond to ALL-type
chemotherapy, although prognosis is not as good as in standard childhood pre-B cell ALL.

5. Other lymphomas of mature (rather than lymphoblastic) T cell phenotype: probably not
much more than 10% of all lymphomas. Include mycosis fungoides (t T-cell lymphoma
that usually involves the skin); the adult T-cell leukemia/lymphoma mostly commonly seen
in the Caribbean and Japan which is associated with HTLV-1; and other less well defined
entities, which tend to look like a diffuse mixed large and small cell lymphoma.

SPLEEN DISORDERS

1. Hyposplenism: may be due to congenital absence; autoinfarction (for example, in sickle

cell anemia); or splenectomy. Predisposes to serious sepsis. There are a variety of red cell
abnormalities also (Howell-Jolly bodies, nucleated RBC's, target cells, etc.) but these don't
have much clinical significance.

2. Hypersplenism: huge number of causes including (1) portal hypertension, (2) right-sided
cardiac insufficiency, (3) hereditary sphrocytosis (all of these first 3 have increased red
pulp, with vascular congestion prominent in the first 2), (4) Gauchers disease (also a red
pulp disease, due to lack of glucocerebrosidase which allows glucocereboside to
accumulated in the reticuloendothelial cells of the spleen). See clusters of large cells with
abundant pink cytoplasm filling the red pulp (Gauchers cells). Presents with splenomegaly;
usually no CNS involvement and may be compatible with long life. Splenectomy may be
necessary if cytopenia ensues. (5) White pulp follicular hyperplasia (occurs in infections,
autoimmune disease), and (6) involvement of the spleen by Hodgkins or non-Hodgkins
 lymphoma. Spleen is rarely involved by metastatic carcinoma; reasons for its resistance
not clear.

Sequelae of hypersplenism include cytopenia due to trapping of blood cells; if very severe,
may have to resort to splenectomy despite the increased risk of sepsis.

ADRENAL INSUFFICIENCY

Symptoms of adrenal insufficiency: range from fulminant vascular collapse (acute deficiency
to malaise, weight loss, hypotension, abnormal pigmentation, menstrual abnormalities in chronic
deficiency (Addison's disease).

Primary Causes

1. Idiopathic (autoimmune) 50% have circulating antibodies to adrenal cortex; many have
other autoimmune processes (e.g., thyroiditis).

2. Tuberculosis

3. Bacterial sepsis (acute insufficiency); Waterhouse-Friederichson syndrome, especially with

meningococcus.

4. Other (metastatic tumor fungus, amyloid--must destroy 90% of adrenals to get

insufficiency).

Secondary Causes

1. Pituitary: due to infarct, adenoma.

2. Exogenous steroids which are too rapidly withdrawn

3. Hypothalamic disease

HYPERADRENALISM

A. Glucocorticoid excess - Cushing's syndrome.

B. Minerallocortocoid excess - Conn's syndrome

C. Androgen excess - virilization; congenital adrenal hyperplasia.

Cushing's Syndrome (truncal obesity; striae; moon facies; buffalo hump; hypertension, diabetes
mellitus; osteoporosis may be due to:

1. Iatrogenic (steroid administration). Pathology: atrophic adrenals.

2. ACTH-secreting pituitary edenema (60% of cases - Cushing's disease. Pathology: bilateral
diffuse cortical hyperplasia.

3. Functioning cortical adrenal tumor: carcinoma or adenoma (20% due to carcinoma; 5% to

adenomas.

4. ACTH produced ectopically by neoplasm (especially oat cell/small cell undifferentiated of

lung) (15% of cases) Pathology: diffuse adrenal cortical hyperplasia.

Isolated minerallocorticoid excess (Conns syndrome) may be due to:

1. Cortical adrenal adenoma (carcinomas rarely produce Conns syndrome).

Increased androgens may be due to:

1. Cortical carcinoma--functioning

2. Cortical adenoma--functioning

3. Congenital adrenal hyperplasia

Lack of an enzyme necessary for glucocorticoid synthesis removes feedback inhibition of earlier
steps in the pathway because of low cortisol levels. Androgenic precursors are produced in
excess, leading to pseudohermaphroditism in girls and virilization in boys. 21 hydroxylase
deficiency leads to salt wasting, since block is before mineralo corticoids; 11 hydroxylase
deficiency leads to hypertension, since block is after minerallocorticoids but before
glucocorticoids. Pathology: diffuse bilateral cortical adrenal hyperplasia.

Adrenal adenomas: are benign; most are non-functional (up to 5% of persons have one or more
adenomas at autopsy). Grossly, they are bright yellow cortical nodules; microscopically they are
composted of lipid-laden cells resembling normal adrenal cortex.

Adrenal cortical carcinoma: 90% function; most commonly secrete glucocorticoids; also
androgens and minerallocorticoids. They are generally larger than adenomas, and may have
invaded adjacent tissue; degree of pleomorphism histologically varies.

TUMORS OF THE ADRENAL MEDULLA

1. Phenochromocytoma: derived from adrenal medulla cells. Generally occur in adults. 10%
are bilateral; 10% associated with MEN IIa or IIb.

Gross: fleshy gray mass in medulla

Micro: large cells with abundant eosinophilic to amphophilic cytoplasm in a nested pattern
separated by a delicate vascular stroma. Varying degrees of nuclear anaplasia.

EM: neurosecretory granules

 Biochemistry: produce epinephrine; lesser amount of norepinephrine.

Presentation: hypertension (intermittent or sustained); palpitations; headache.

Diagnosis: urine has catecholamine metabolites normetanephrine and/or vanillylmandelic

acid (VMA).

Pheochromocytomas can also sometimes arise elsewhere in sympathetic ganglia.

2. Neuroblastoma

Common childhood malignancy; 80% less than 5 years old.

Most commonly arise in the adrenal medulla; can also arise in sympathetic ganglia. 80%
of patients also have elevated VMA/netanephrines; some may have diarrhea, flushing
diaphoresis.

Histology: small blue cell tumor; may form rosettes by light microscopy. By EM, see
neural processes and neurosecretory granules.

Prognosis: better in young children; low stage; those also showing ganglionic
differentiation.

PITUITARY ADENOMAS

A. Acidophilic

1. Lactotroph: produces prolactin; may see galactorrhea; gynecomastia; amenorrhea.

2. Somatotroph: produces growth hormone. Leads to gigantism in children; acromegaly

in adults, with increased hand and foot size, increased circumference of head, coarse facial
features, enlarged viscera, and high frequency of diabetes mellitus.

B. Pasophil

1. ACTH-cell adenoma: produces Cushing's disease with bilateral adrenal hyperplasia. If

no adenoma can be found and so adrenalectomy is performed, may get Nelson's syndrome:
rapid enlargement of previously occult microadenoa of pituitary, presumable from removal
of feedback inhibition.

2. Gonadotroph adenoma - relatively uncommon.

3. Thyrotroph adenoma - exceedingly rare.

C. Chromophobe adenoma: composed of pale cells with few granules on EM often non-
functioning; occasionally may produce any of above syndromes. May give rise to
problems by compressing normal pituitary.
 CAUSES OF HYPOPITUITARISM

1. Pituitary adenoma (usually chromophobe, occasionally acidophil; rarely basophil) which

ahs compressed/ destroyed normal pituitary tissue.

2. Sheehan's syndrome; during pregnancy, pituitary enlarges; in this setting, shock (for
example, from a OB catastrophe) can lead to infarct of pituitary.

3. Craniopharyngioma: a suprasellar tumor derived from Rathkes pouch. Most common in

children; often calcify so can be seen on x-ray. Histologically, see cords of epithelial cells.
Complications include visual difficulties due to compression of optic chiasm; posterior
pituitary damage leading to diabetes insipidus; and anterior pituitary
compression/destruction.

Causes of diabetes insipidus include craniopharyngioma; head trauma; metastatic tumor;

histiocytosis X; intracerebral hemorrhage; inflammation/infection.

MEN SYNDROMES: FAMILIAL AND AUTOSOMAL DOMINANT

I. MEN I (Wermers syndrome) pituitary adenomas; islet cell tumors of pancreas; adrenal
cortical adenomas; parathyroid hyperplasia or adenomas.

II. MEN IIA (Sipple syndrome) medullary carcinoma of the thyroid; pheochromocytoma;
parathyroid hyperplasia or adenoma.

III. MEN IIB: as above (parathyroid involvement less common) plus multiple mucosal and
gastrointestinal neurons.

TESTIS

1. Cryptorchidism: affects 0.2% of males--failure of one or more testicles to descend into

scrotum. May be located anywhere along path of descent; often inguinal; occasionally
retroperitoneal. Morphology: atrophic, hyalinized tubules with decreased
spermatogenesis; interstitial fibrosis; often Eliding cell hypertrophy. Complications
include sterility and a 20X increase in risk for germ cell neoplasia; testosterone production
is often quite adequate. Treatment of choice is orchiopexy in first year of life.

2. Epidydimitis/Orchitis

A) Infections which begin in epidydimus; may spread to testes include gonorrhea;

chlamydia; and organisms associated with UTIs in general (E. Coli, other gram
negative rods). These probably reach the epidydimus via the vas deferens or the
spermatic cord lymphatics. TB may also reach the epidydimus via the bloodstream
from a primary pulmonary focus, and then reach the testis.
 B) Infections which generally cause orchititis without epidydimitis include syphilis in the
tertiary phase (see gummas: plasma cell/lymphocytic endarteritis with central
necrosis). Also, mumps orchititis may complicate up to 30% of cases of mumps in
males over 10 (see a chronic inflammatory infiltrate in the interstitium).

C) Granulomatous (?autoimmune?) orchititis: see non-caseating granulomas in

epidydimus/testis; often there is a history of trauma/vasectomy.

TESTICULAR NEOPLASMS

Germ Cell Neoplasms: most common cause of cancer death in males age 15-34.

1. Seminoma: most common type of germ cell tumor (40%). Peak incidence in 20's - 40's.
Grossly, appears as a solid, fleshy white mass.

Micro: classical type has relatively uniform cells with clear cells, separated into lobules by
fibrous septa which are infiltrated by lymphocytes.

Spermatocytic type (less than 5% of total) has admixture of smaller cells which resemble
maturing spermatocytes. This type is almost always in elderly men.

Classical type: tends to spread first via lymphatics to periaortic chain. Rarely invades
through testis capsule into scrotum. Very radiosensitive and chemotherapy sensitive.

2. Embryonal Carcinoma: 15-15% of testis neoplasm. Generally occurs in teens and 20's.
Grossly, fleshy tumor, often with some foci of necrosis/hemorrhage.

Microscopically: cells have abundant eosinophilic cytoplas; form sheets, tubules papillae.
Also tend to spread via lymphatics; less radio and chemo sensitive, but may respond to
aggressive chemotherapy.

3. Teratoma: 30% of adult tumors, more common in children.

May be mature: all components resemble mature, normal tissue (these generally occur
only in children, and behave in benign fashion) or may be immature: with mixture of
mature and fetal-type tissues: these are seen most commonly in older children and adults,
and are malignant: can metastasize. Immature teratomas behave like embryonal
carcinoma.

4. Yolk sac tumor (also called endodermal sinus tumor, infantile embryonal carcinoma). The
most common germ cell tumor in infants/toddlers. Has a complex pattern; hallmark is the
Schiller-Duvall body (tumor cells growing I a ring around small blood vessels). When it
occurs in adults, it is usually a component in a mixed germ cell tumor.

5. Choriocarcinoma: in testis, this is usually a component of a mixed germ cell tumor. A

similar pure tumor arises in the placenta.
 Grossly, this is often a relatively small nodules, very hemorrhagic and necrotic.

Microscopic feature is a biphasic pattern, with syncytiotrophoblast growing in a cap-like

layer over cytotrophoblast.

These tumors metastasize early hematogenously; produce high levels of HCG.

6. Mixed germ cell tumors: 40% of all germ cell tumors.