Pathology I

Cellular Pathology (I-II):

Pathology includes study of etiology (what initiates a process), pathogenesis (mechanism),
morphology (how its recognized) and functional consequences (how it produces disease).
The three fundamental processes of cellular pathology are cell injury, cell death and cellular
adaptation. In response to stressors, cells may adapt or die!e injured.
The etiology of cell injury may !e e"trinsic or intrinsic, including hypo"ia, physicalchemical
agents, drugs, infection, immunologic reactions, genetic, or nutritional pro!lems.
#ypo"ia is the reduction or a!sence of normal o"ygen supply. It may !e a result of ischemia,
which is the reduction or a!sence of !lood supply. They most often go together, !ut ischemia
alone can !e damaging from a lac$ of trophic su!stances or accumulation of to"ins, and
hypo"ia alone can still !e damaging (e"% anemia, pulmonary disease, cyanide poisoning).
Infarction is the process in which a portion of a tissue dies as a result of ischemia. &n infarct
is the end result of this process. They may !e white or red (still some !lood supply to the
dead tissue), !ut !oth result from the same underlying mechanism.
The mechanisms !y which ischemia causes cell death are inter'dependent and synergistic.
To"ins often influence one of these mechanisms. They include%
o (ecreases in &TP ) o"idati*e phosphorylation shuts down first in ischemia. Pumps stop
running and cellsorganelles swell and ha*e !le!s, glycolysis lowers p# and chromatin
clumps, protein synthesis decreases and lipids accumulate since proteins arent a*aila!le
to e"port lipids as lipoproteins. These early changes are re*ersi!le.
o Increased intracellular +a, which is critical to homeostasis. ,any enzymes only function
within a *ery narrow range of -+a.. Ischemia inacti*ates calcium pumps, resulting in
calcium acti*ation of enzymes and increased mem!rane !rea$down along with decreased
mem!rane synthesis.
o ,em!rane damage (considered the point of no return)
o /eacti*e o"ygen species ) endogenous or e"ogenous free radicals. /eperfusion of an
ischemic area can add to ischemic damage, li$ely !y sudden calcium influ" or e"posure
to free radicals from an influ" of inflammatory cells. 0e ha*e some le*el of antio"idant
defense from *itamins + and 1, glutathione pero"idase, catalase and supero"ide
dismutase. 2ut o"idati*e stress can result from im!alance !etween /34 and
antio"idants. 3"idati*e stress is associated with aging, dia!etes, atherosclerosis,
&lzheimer, etc.
+ell injury !ecomes irre*ersi!le most quic$ly in neurons, followed !y myocardium and
hepatocytes, and most slowly in s$eletal muscle.
/e*ersi!le cell injury is characterized !y cell swelling, *acuolar degeneration, and lipid
deposition (especially in the myocardium and li*er).
Irre*ersi!le injury% necrosis ) the morphological changes in the nucleus and cytoplasm
occurring after death in a li*ing tissue, regardless of the cause of injury. 2y the time necrosis
is o!ser*ed, the cell is dead. This need not occur at the tissue le*el.
o 5eatures of necrosis include% eosinophilia due to loss of /6&ri!osomes and denatured
protein, nuclear changes (small'py$nosis, !ro$en apart'$aryorrhe"is, or dissol*ed'
$aryolysis), I657&,,&TI36. The inflammation is the !ig distinguishing feature, and
it usually occurs a!out 8 hours after cell death. Thus, it wont occur if the cell dies and
organism also dies at the same time.
Types of 6ecrosis%
o +oagulati*e% /esults from ischemic cell death, and is seen in most tissues e"cept for the
!rain. In this type of necrosis, the tissue architecture is retained. 9ou typically see
:tom!stones of hyper'eosinophilic cells. It typically resol*es !y scar formation.
o 7iquefacti*e% +haracterized !y complete hydrolysis of dead cells, resulting in a loss of
tissue architecture and usually resulting in a cyst or ca*ity. This is the usual response to
infarction in the !rain.
o &!scess% 7iquefacti*e necrosis resulting from localized !acterialfungalparasitic
infections. It usually has lots of neutrophils within the a!scess (pus;dead neutrophils and
de!ris) which are the source of hydrolytic enzymes. It often requires surgical drainage,
since *asculature is commonly damaged and anti!iotics wont !e deli*ered effecti*ely.
o +aseous (cheese'li$e)% +haracteristic of T2 and fungal infections. It has a center of
cheese'li$e necrosis surrounded !y a rim of inflammatory cells (all together called a
granuloma).
o 5at% +ommon in the pancreas (from release of pancreatic enzymes) and !reast (from
minor trauma). ,em!rane lipids are digested into 55&s, and com!ine with calcium
(saponification) to form chal$y white deposits. ,ay mimic a carcinoma clinically.
+ellular adaptations include hyperplasis, hypertrophy, atrophy, and metaplasia.
#yperplasia is an increase in the num!er of cells in a tissueorgan. In hyperplasia, you see
di*iding, mitotic cells. #yperplasia may !e physiologic, such as in lactating !reasts. 2ut is
can also !e pathologic, as in endometrial hyperplasia with unopposed estrogen stimulation
that results in prolonged cycles with menorrhagia (hea*y !leeding). &nother e"ample of
hyperplasia is in 2P#.
#ypertrophy is an increase in indi*idual cell mass, and is usually re*ersi!le. In !enign
prostatic hyperplasia, !ladder muscle hypertrophies as a results of needing to push the urine
out with more force. 3ther e"amples of pathologic hypertrophy may !e hypertrophy of the
heart in someone with aortic *al*e stenosis or chronic hypertension. #ypertrophy may
results from greater wor$load, as a!o*e, !ut also from increased le*els of hormones
(ana!olic or in pregnancy, etc). <enetic mutation in the myostatin gene has !een shown to
cause muscle hypertrophy in animals.
&trophy is cellular shrin$age due to a loss of su!stance, and may result from disuse,
dener*ation (polio), ischemia, star*ation (protein'calorie malnutrition, or marasmus), or
a!sence of endocrine stimulation. 1"% menopause can result in atrophy of cells ma$ing up
endometrial glands. 1"% cache"ia, a wasting associated with cancer, &I(4 and other chronic
inflammatory diseases.
o +ellular atrophy may culminate or !e accompanied !y progressi*e cell loss, and if
enough occurs an organ or tissue may shrin$. In these cases, atrophy descri!es !oth cell
shrin$age and cell loss.
,etaplasia is the re*ersi!le replacement of one differentiated cell type !y another
differentiated cell type. It can !e considered an adapti*e su!stitution !y cells that can !etter
withstand an ad*erse en*ironment. In smo$ers, you see squamous metaplasia where
respiratory epithelium is replaced !y stratified squamous cells. 4tem cells at the !asement
layer differentiate into squamous cells. ,etaplastic epithelium may undergo neoplastic
progression to dysplasia (not yet cancer, !ut cells lose normal architecture on the way there),
and ultimately to neoplasia (cancer w clonal cells ha*ing a genetic mutation). 6ot all
metplasias !ecome cancers, !ut if the stimulus persists, they may.
+ells may accumulate endogenous or e"ogenous su!stances (lipids, protein, glycogen, car!s,
minerals, pigments, etc).
o Pigment accumulations% anthracosis (accumulation of dar$ car!on pigment in city
dwellers) or lipofuscin (wear and tear pigment where you ha*e lots of cell turno*er) are
e"amples of !enign pigment accumulations.
o Intracellular lipid accumulation% 5atty change (steatosis) is potentially re*ersi!le. It
most commonly occurs in the li*er, and is caused most commonly !y o!esity or alcoholic
li*er disease. The li*er is typically enlarged and rather than red, it appears yellowwhite.
+ell death is not always pathologic= apoptosis is normal in em!ryogenesis, immune cell
differentiation, menstruation, etc. &poptosis may !e pathologic too, resulting from (6&
damage (w p>? as a principal mediator), *iral infection or +(8 T cell mediated injury.
o &poptosis is mediated !y caspases, cysteine protesases that require acti*ation. 2cl'@ is
an anti'apoptotic protein, and its family contains !oth pro and anti apoptotic factors. P>?
stops cell di*ision in response to (6& damage in order to facilitate reco*ery, and if
reco*er fails it initiates apoptosis.
o ,orphologically, apoptosis is characterized !y nuclei !rea$ing into apoptotic !odies.
This occurs in single cells with apoptosis, whereas necrosis tends to occur in large
regions of an organ. In apoptosis, (6& is systematically fragmented and shows as a
ladder on a gel, whereas necrotic cell death !rea$s it down at random, resulting in a
smear.
o 2asically, apoptosis is usually physiologic, occurs in single cells, fragments (6&
!etween nucleosomes, and produces apoptotic !odies 0IT#3AT inflammation.
6ecrosis is usually pathologic, occurs in groups of cells, randomly fragments (6& and
shows swelling, degeneration, and inflammation.
o Inhi!ition of apoptosis facilitates tumorigenesis. #PB !loc$s p>? and apoptosis, and can
result in squamous cell carcinoma of the cer*i". +onstituti*e acti*ation of 2cl'@ !loc$s
apoptosis and facilitates follicular lymphomas.
Inflammation (I-II):
Inflammation is a comple" response of *ascularized tissues to *arious stimuli, leading to
accumulation of fluids and leu$ocytes in the e"tra*ascular tissues.
1dema ) an e"cess of fluid in the interstitial space= either a transudate (low protein content
usually due to increased hydrostatic pressure) or e"udate (high protein content, often
containing !lood cells, and resulting from increased *ascular permea!ility).
1"udate (high protein) types% 4erous (lac$ing lots of inflammatory cells), serosanguinous
(containing erythrocytes), fi!rinous (lots of fi!rin after coagulation), purulent (lots of
inflammatory cells), or suppurati*e (purulent with significant liquefacti*e necrosis).
The goal of inflammation is to deli*er effector cells and molecules to the site of injury. It
also see$s to pro*ide a physical !arrier *ia micro*ascular coagulation to pre*ent the spread
of the insulting agent, and promotes the repair of the injured tissue. 4o fundamentally, its
good. 2ut it can !e harmful.
The > cardinal signs are% calor, ru!or, tumor, dolor (+elsus), and loss of function (Birchow).
+onheim noted the associated *asodilatation, edema, and leu$ocyte emigration. ,etchni$off
and 1hrlich got the CDE8 6o!el for noting the cells and anti!odies role in immunity.
&cute inflammation is an immediate, early response to injury that lasts minutes to days. Its
characterized !y edema and emigration of leu$ocytes (mainly neutrophils).
Inflammation may !e triggered !y trauma, ischemia, neoplasm, infection, foreign matter, or
immune reactions to endogenous stuff.
&cute inflammation has three $ey e*ents% +hanges in *ascular cali!er and flow, Increased
*ascular permea!ility, and +ellular e*ents (e"tra*asation and phagocytosis).
The continuity equation% flow ; (*elocity)F("'sectional area).
Poiseuilles 7aw% flow ; GPressureFradius
H
8FlengthF*iscocity
2ernoulli principle% GP I *elocity ; constantJ.so as fluid *elocity increases, its pressure
decreases and *ice *ersa.
0ith acute inflammation, for the first few seconds there is *asoconstriction of arterioles.
This is followed !y *asodilatation, which increases flow (Poiseuilles, gi*ing heat and
redness), decreases *elocity (continuity eqn, leading to stasis of !lood at site of injury), and
increases hydrostatic pressure (2ernoulli, leading to outflow of things from the *essels).
&cute inflammation is also characterized !y increased *ascular permea!ility. The mo*ement
of protein into the tissues alters oncotic pressure to fa*or fluid mo*ement to the interstitium.
&lso, the increased hydrostatic pressure from the changes in *essel cali!erflow forces fluid
out. 6ormally, the fluid lost on the arteriolar side is ta$en !ac$ up on the *enular side !y
oncotic pressure, !ut in inflammation protein loss pre*ents this re'upta$e and leads to edema.
o The mechanisms of this include contraction of endothelial cells (re*ersi!le, short li*ed),
reorganization of their cytos$eletons, transcytosis, and direct endothelial injury. 0hen
endothelial cells contract, only a !asement mem!rane remains. +ells ma$e proteases that
!rea$ it down, and stuff lea$s out.
The triple response of 7ewis sums up the *ascular response% first you get *asoconstriction
and an injury is white, second you get fluid lea$age (wheal), and third you get *asodilation
(flare).
+ellular e*ents% Inflammation seems to deli*er leu$ocytes to $ill micro!es and degrade
necrotic tissue. The process of leu$ocyte mo*ement from the !lood to tissue is e"tra*asation.
o <ranulocytes% 6eutrophils (acute inflammation), 1osinophils (allergies, parasitic
infections), and 2asophils,ast +ells (allergic hypersensiti*ity).
o ,ononuclear phagocytes% ,onocytes and ,acrophages (phagocytic, antigen
presentation, secrete cyto$ines).
o 7ymphocytes and plasma cells% not a !ig part of acute inflammation, they are in*ol*ed
with immune response acti*ation. T (helper, $iller, natural $iller) and 2 (plasma) cells.
6K cells produce proinflammatory cyto$ines and lyse target cells.
o Platelets% Important for *ascular integrity and maintenance of flow.
The type of leu$ocytes *aries with age of the inflammatory lesion. 6eutrophils predominate
for the first L@H hours, then monocytesmacrophages come from @H'H8 hours, and finally
lymphocytes populate the lesions and remain common in lots of chronic inflammation.
The process of e"tra*asation includes margination, rolling and adhesion in the lumen,
diapedesis (passage across the endothelium) and chemota"is along a chemical gradient.
6ormally, leu$ocytes tra*el along the wall of *essels and erythrocytes are in the middle, !ut
with inflammation, leu$ocytes are pushed further outward (margination). In rolling,
leu$ocytes tum!le across the endothelium, halting at some points. 1*entually they firmly
attach to the endothelial surface (mediated !y +&,s on acti*ated leu$ocytes and acti*ated
endothelial cells).
&dhesion molecules come in three families%
o Integrins% ,ost a!undant. #eterodimers of an M and N su!unit. Their su!families are
defined !y the !eta su!units. OC integrins (B7&s) mediate !inding to the 1+,. B7&'H
is only on leu$ocytes, and mediates attachment to endothelial cells B+&,'C. & N@
integrin, 75&'C, mediates attachment to endothelial cells I+&,C. 75&'CI+&,C
!inding is regulated !y magnesium dependent conformational changes to increase
!inding affinity and calcium dependent multimerization of 75&'C to increase a*idity.
o 4electins% Three +'type lectins are e"pressed e"clusi*ely !y endothelial cells and !one'
marrow'deri*ed cells. They are calcium dependent, and use a conser*ed car!ohydrate
recognition domain (+/(). They mediate adhesion, !ut also ha*e signaling functions to
acti*ate leu$ocytes. 1'selectin is e"pressed on inflamed endothelium, !inds to
leu$ocytes P4<7'C and is the hallmar$ of cyto$ine induced inflammation.
o &ddressins% more molecules e"pressed on endothelial cells that !ind to lymphocyte
receptors.
o &dhesions molecules to $now%
Endothelial
molecule
Leukocyte
receptor
Major role
B+&,'C HC integrin &dhesion
I+&,'C 75&'C &dhesion,
diapedesis
P'selectin P4<7'C /olling
1'selectin P4<7'C /olling
<ly+am'C 7'selectin #oming to #1B
7eu$ocyte recruitment process% non'acti*ated leu$ocytes ha*e low affinity +&,s. (ilated
*essels slow them down, and they rolltether along cyto$ine'acti*ated endothelial cells *ia
selectins. In reponse to chemo$ines, the leu$ocytes are acti*ated too, and their integrins
!ecome high affinity. They adhere and mo*e up chemo$ine gradients to migrate through the
*essel walls. 1ndothelial cells sequentially e"press different adhesion molecules that
preferentially !ind different leu$ocytes.
(iapedesis (transmigration) occurs through intercellular junctions. It mostly happens in the
*enules, which ha*e *ery little smooth muscle. 7eu$ocytes secrete collagenases to penetrate
the !asement mem!rane. 3nce through, they follow chemotactic gradients of e"ogenous and
endogenous (complement, chemo$ine) su!stances.
+hemo$ines may !e quite specific for the cell types they direct%
o I56'P from the host Q +R+7 D, CE, CC Q monocyte, macrophage recruitment.
Phagocytosis% opsonic phagocytosis occurs when a pathogen is co*ered !y 5c receptors or
complement receptors that enhance its phagocytosis. 6on'opsonic phagocytosis occurs *ia
P&,Ps that T7/s and other receptors recognize. In phagocytosis, engagement of surface
receptors acti*ates internalization, and the phagosome fuses with lysosomes.
6eutrophils produce micro!icidal free radicals, which occur within phagocytic *acuoles.
6&P(# o"idase con*erts o"ygen to supero"ide, which is con*erted to hydrogen pero"ide.
,yelopero"idase con*erts hydrogen pero"ide into #3+l, which destroys !acteria. People
with +hronic <ranulomatous (isease ha*e defects in 6&P(# o"idase and are suscepti!le to
infection, especially !y micro!es that produce catalase, and enzyme that degrades hydrogen
pero"ide.
+hemical mediators of inflammation include%
o Basoacti*e amines% histamine and serotonin, which are ready to !e released from mast
cells in seconds.
o Plasma proteases% complement proteins, $inin system (pain, *ascular permea!ility),
clotting system.
o &rachidonic acid meta!olites% prostaglandins and leu$otrienes, which aspirin !loc$s.
o +yto$ines.
&cute inflammation is characterized !y *asodilation and lea$age, and cellular e"tra*asation
and phagocytosis. Its H outcomes include complete resolution and restoration of normal
anatomy, healing !y +T replacement (,34T +3,,36, includes granulation
tissueorganisation or fi!rosis), a!scess formation or chronic inflammation.
<ranulation tissue and 3rganisation occur when there is su!stantial tissue destruction and
lots of fi!rin e"uded. The +T at the site of injury will transform into granulation tissue,
which includes neo*ascularization, macrophage and myofi!ro!last migrationproliferation,
and production of collagen fi!ers that can lead to fi!rosis.
The granulation tissue is pac$ed with cells, though it still appears edematouspale. There,
capillaries, fi!ro!lasts, myofi!ro!lasts, and macrophages proliferate and a lot of collagen is
deposited. The fi!ro!lasts produce a lot of it, as do the contractile myofi!ro!lasts.
Keloids form when there is a propensity toward e"cessi*e collagen deposition in granulation
tissue, which forms a raised scar. They are characterized !y !road !ands of collagen that
replace normal dermal structures. 1"cessi*e collagen can !e deposited after inflammation, as
in cirrhosis of the li*er.
3rganisation is the process in which granulation tissue replaces necrotic tissue or a
throm!usclot. It can occur with inflammation, wound healing, infarct or throm!us.
o 1"% 7ung inflammation leads to fi!rin e"udate in pleural space. Its not easily remo*ed,
and organization occurs (neo*ascularization, fi!rous tissue and adhesions).
&n a!scess is a localized collection of pus in a newly formed ca*ity. &n empyema is when
pus collects in an e"isting ca*ity. Pus is neutrophils, necrotic de!ris and edematous fluid.
Its typically caused !y 4taph infections.
o &n a!scess has a central region of necrotic de!ris. &round this is a zone of preser*ed
neutrophils. The outermost region is of *ascular dilation and fi!ro!lastic proliferation
that may wall off the a!scess with +T. &n a!scess may empty its contents *ia a fistula
into an internal ca*ity or out of the !ody.
& phlegmon (a$a cellulitis) is an acute infection that spreads along the s$in and su!cutaneous
tissue !efore it can !e walled off (unli$e an a!scess). +ommon causes include 4. aureus and
some 4trep.
+hronic inflammation is a prolonged process where acute inflammation and destruction
occur concurrently with attempts at healing or immune responses. It may !e primary with no
acute e*ent that precipitates it (typical of autoimmunity), or it may !e secondary to an acute
inflammatory episode.
+hronic inflammation may !e caused !y the same things that cause acute inflammation if
they persist (microorganisms, autoimmunity, foreign material).
+hronic inflammation may !e classified as%
o ,acrophagic (diffuse or granulomatous)
o 7ymphocytic (diffuse or follicular)
o 4uppurati*e (uncommon, characterized !y neutrophils and a!scess formation)
,acrophages (a$a histiocytes) circulate as monocytes then migrate into *arious tissues.
They are the !odys main phagocytic cells, and also induce immune reactions *ia antigen
presentation and release of many cyto$ines. ,acrophages, particularly when acti*ated,
release a lot of su!stances and are central in chronic inflammation. They are a !ig part of the
!odys defense, !ut can induce a lot of tissue damage.
o 4tuff released !y macrophages% 63, /34, proteases, cyto$ines, growth factors,
enzymes, complement components, coagulation factors, eicosanoids, etc.
o Types of macophagic inflammation%
(iffuse (non'granulomatous)% macrophages interspersed among other
inflammatory cells.
<ranulomatous% macrophages arrange into compact follicles and assume an
epithelioid appearance (columnar, large, pale, granular, indistinct !oundaries).
<ranulomatous inflammation (macrophages)% a type of chronic inflammation in which the
predominant cell type is an acti*ated macrophage with an epithelioid appearance.
& granuloma is a focal area of granulomatous inflammation, usually a cluster of epithelioid
macrophages surrounded !y lymphocytes. It may include a caseation center (cheesy, pus,
necrotic de!ris, or !acteria). It also has <I&6T +1774, which are epithelioid cells fused
togetherJa classical feature of a granuloma. There are other epithelioid cells, surrounded !y
lymphocytes and possi!ly en*eloped in a fi!rous capsule.
The insulting agent determines if a granuloma will form.
,ultinucleated giant cells may contain @E or so nuclei and !e up to >E microns. 6uclei may
!e arranged peripherally li$e a horseshoe (7anghans cells) indicating T2 or sarcoidosis. 3r,
nuclei may !e arranged haphazardly, indicating ingestion of insolu!le material.
& granuloma may !e a foreign !ody granuloma or an immune granuloma (triggers cell
mediated immunity).
o 5oreign !ody granuloma% induced !y an inert foreign !ody too large to !e phagocytosed
!y a single macrophage. 1pithelioid cells encircle the foreign !ody.
o Immune granuloma% caused !y particles that induce a cell'mediated immune response.
,acrophages engulf the material, process it and present it to T cells. T cells ma$e
cyto$ines that transform macrophages into epithelioid and giant cells. These are
commonly caused !y T2, *arious infections, and some autoimmune disorders.
o & tu!ercle is an immune granuloma in response to myo!acterium tu!erculosis.
7ymphocytic chronic inflammation includes lots of the diffuse inflammation in response to
autoimmunity seen in the A4&. 7ymphocytes may also form follicles that loo$ li$e lymph
nodes.
Neoplaia: Introduction and !"er"ie# $%&:
& neoplasia is a clonal proliferation of cells with somatic alterations and a!errant regulation
of growth. 6on'threatening ones are !enign. ,alignant neoplasias are characterized !y the
a!ilities to in*ade adjacent tissue or metastasize to distant tissue.
& tumor is just a mass formed !y a neoplasia. Pre'in*asi*e (in situ) neoplasms dont form
tumors.
Though they share se*eral $ey features, cancers are *ery heterogeneous. Their common
properties include dysregulated population growth, the a!ilities to in*ade and metastasize,
the a!ility to modify the host en*ironment, an e"tended dou!ling potential, and genomic
insta!ility.
(ysregulated population growth% +ancer cells typically ignore e"ternal signals regulating
when to replicate, resulting in inappropriate replication. ,any $nown genetic defects (p>?,
cyclin (C, /2, &$t) in cancer affect genes related to growth factors and cell cycle regulation.
(espite this, not all cancers are completely autonomous to cell'growth regulation. Asually,
!ut not always, cancers ha*e increased fractions of cells undergoing mitoses compared to
normal cells.
&nother contri!uting factor may !e reduced cell death, often *ia resistance to apoptotic
signals. +ommon mutations in cancer also affect apoptosis genes (p>?, &$t, 2a", 2cl@). 4o,
in many cases, stopping cells from di*iding inappropriately may fail to stop tumor growth.
In some cases, called, oncogene addiction, a cancer is highly dependent on one mutation, !ut
this isnt *ery common. <rowth factor (1<5/, #er@) signaling may also !e altered.
&!ility to in*ade and metastasize% ,alignant neoplastic cells (cancer cells) can in*ade
adjacent normal tissues and metastasize to distant sites. 6ormal cells are confined to specific
compartments, and require intercellular signals that indicate this for their sur*i*al.
0ith in*asion, cell surface receptors for the nati*e en*ironment may !e lost. 1'cadherin
(signaling, adhesion molecule) is commonly lost. ,any cancer cells also e"press new cell
surface receptors allowing them to !ind 1+, components. The tissue of origin loses some
order and !egins to remodel. 4ome malignant cells then secrete proteolytic enzymes (matri"
metalloproteinases, cathepsin (). (ue to a lac$ of !asement mem!rane, lymphatics are
prone to in*asion. Benules are li$ewise more frequently in*aded, as they ha*e less structure
than arterioles. (ense collagen and cartilage are quite resistant to in*asion.
,etastasis occurs !y lymphatics or !lood. +ells must in*ade and sur*i*e the *ascular
en*ironment, particularly its shear stress and anoi$is, apoptosis from the lac$ of solid matri".
4ome cancer cells ha*e Sstem li$eT properties such as small size that help them sur*i*e.
,alignant cells must also !e a!le to adhere to and e"tra*asate through the *ascular walls.
The location is often determined !y the drainage pattern, and lymph nodes are common sites
of metastasis. 5or tumor growth in a secondary site, the en*ironment of a tissue must !e
somewhat suita!le for that cancer cells properties (seed and soil hypothesis). 3ne important
factor influencing this may !e the chemo$ines present, $ind of li$e how leu$ocytes figure out
where to lea*e the !loodstream.
,odification of host en*ironment% Tumors consist of stroma, inflammatory cells and *essels
in addition to the cancer cells.
,any cancers produce angiogenic su!stances (B1<5, 5<5), while others produce anti'
angiogenic factors (endostatin, angiostatin). &n anti'B1<5 anti!ody (!e*acizuma!a*astin)
has !een used to treat some cancers.
+ancers are often sufficiently altered to elicit a cell'mediated immune response, and
many ha*e strategies to e*ade immune sur*eillance. These include cyto$ines (T<5 !eta) or
prostaglandin (P<1@) release, release of proteins that inhi!it immune cells (I(3, &/<C),
e"pression of decoy receptors, and secretion of decoy antigens.
,any cancers also secrete humoral factors li$e ectopic hormones (&+T#, PT# related
protein) and cache"ins (T65). They contri!ute to mor!idity and mortality, !ut are poorly
understood. They can result in paraneoplastic syndromes or cancer cache"ia (wasting).
1"tending dou!ling potential of tumor cells% #ayflic$ showed there to !e limits to how long
cells can replicate, which we now $now is related to telomere length. ,ost cancer cells
e"press increased telomerase to maintain telomeres indefinitely= its normally only e"pressed
in renewing cell populations. +ancer cells still ha*e shortened telomeres, li$ely !ecause
telomerase wasnt acti*ated until after telomeres had !een shortened. Telomerase deficiency
seems to lend itself toward chromosomal insta!ility. &ssessing le*els of telomerase could !e
useful in cancer diagnosisdetection, or e*en therapy though there is some acti*ity in normal
cells.
<enomic insta!ility% ,ost cancer cells ha*e a!normal chromosome num!er and structure,
suggesting that they are continuously rearranged as tumor cells di*ide. 4hortened telomeres
contri!ute to this, ma$ing chromosomes prone to !rea$s and rearrangements. Inadequate
mitotic spindle chec$points , (6& damage chec$points in*ol*ing p>?2/+& that lead to
translocations, and mismatch repair (increases mutation rate) also contri!ute. ,icrosatellites
are particularly prone to mismatch repair errors, called microsatellite insta!ility (,4I).
<enomic insta!ility is li$ely part of the carcinogenesis process, or else its unli$ely any
one cell would accumulate so many mutations. These changes also result in the
morphologically a!normal nuclei we see in la! (hyperchomatism, a!normalirregular nuclei).
,itosis also loo$s a!normal in these cells. This also allows cancers to rapidly mutate and
acquire new properties li$e drug resistance.
Carcinogenei' Cancer (e"elopment' and )ro#th of Cancer $%&:
+ancers arise from clonal e*olution, meaning that sequential genetic changes are
accompanied !y clonal e"pansion of cells with a selecti*e ad*antage for growth or sur*i*al.
This increases the changes of multiple mutations accumulating in any single cell. The
e"pansion is a non'genetic component of carcinogenesis. 0hen these altered cells di*ide
(for e"trinsic or intrinsic reasons), its called tumor promotion.
The steps of carcinogenesis are initiation (irre*ersi!le (6& alteration), promotion
(stimulation of clonal e"pansion of that cell), and con*ersion to malignancy. & genoto"in is
something that induces mutation, !oth initiation and con*ersion. #uman cancers require
more than two mutations.
9ou can get chromosomal injury and pathologically atypical cells without in*asion. These in
situ cells may e*entually !ecome in*asi*e and result in in*asi*emetastatic tumors. 5rom the
first mutation to the clinical presentation, it may ta$e C>'>E years to accumulate the
mutations. 4o theres a long latency period !etween the cellulargenetic injury and
de*elopment of the cancer to clinical significance.
7esions with more nuclear atypia are called carcinoma in situ, whereas those with less
nuclear atypia are called hyperplasias (technically a misuse of the term, since this is clonal).
Intermediate le*els of atypia are called dysplasias.
6ot all early neoplasms result in in*asi*e cancers, !ut some are more li$ely than others (esp.
higher grade ones).
Though cancers are :clonal in origin, they still ha*e quite a !it or heterogeneity. They all
arise from a single precursor cell with some genetic changes common to all cancer cells. 2ut
due to genetic insta!ility, they de*elop more genetic changes o*er time, resulting in
heterogeneity. &s the tumor e*ol*es, one cell type generally predominates.
,ost !enign tumors dont ma$e it all the way to cancer.
Pathology of Neoplaia $%&:
6omenclature of neoplasia recognizes the pattern of differentiation (usually tissue or origin)
and whether the tumor is !enign or malignant.
The suffi" )oma usually indicates a !enign tumor. 1"ceptions% melanoma, astrocytoma,
lymphoma, hepatoma.
The suffi"es )carcinoma (epithelial origin) and )sarcoma (mesenchymestroma) always refer
to malignant tumors.
There are > major patterns of differentiation (some tumors may ha*e multiple patterns)%
o #ematopoietic% may !e leu$emia (!lood) or lymphoma (lymph nodes), !oth are
malignant.
o 1pithelial% may !e squamous (squamous papilloma'!enign, squamous cell
carcinomaepidermoid carcinoma'malignant), glandular (adenoma'!enign,
adenocarcinoma'malignant), !asal (!asaloid), transitional (e"% urothelial), or
undifferentiated. 7i*er;hepatic adenoma'!enign, hepatomahepatocellular carcinoma'
malignant.
o ,esenchymal% smooth muscle (leiomyoma'!enign, leiomyosarcoma'malignant),
adipocyte (lipoma'!enign, liposarcoma'malignant), cartilage (chondroma'!enign,
chondrosarcoma'malignant), !one (osteoma'!enign, osteosarcoma'malignant),
endothelial (hemangioma'!enign, hemangiosarcoma'malignant).
o ,elanocytic% melanocytic ne*us'!enign, melanoma'malignant.
o <lial% may !e astrocytoma, ependymoma, or oligodendroglioma, all of which are
malignant.
o ,i"ed epithelialmesenchymal% fi!roadenoma'!enign, carcinosarcoma'malignant.
o ,ore than C germ cell layer from pleuripotent stem cells% Teratoma
(escripti*e terms li$e papillary (some stroma, cauliflower'li$e), cystic, polypoid (lots of
stroma), mucinous, annular, or schirrhous may also !e applied.
4ome not'yet'metastatic cancers are not completely !enign, and they ha*e intermediate
malignant potential. They may !e termed Slow malignant potentialT or S!orderline,T and one
important e"ample of this is a carcinoid tumor (neuroendocrine differentiation), which may
occur in the respiratory or digesti*e systems.
,ost neoplasms of solid tissues form *isi!le tumors. In situ neoplasm may !e much harder
to recognize with the na$ed eye.
2enign tumors are generally well circumscri!ed and often encapsulated. ,alignant tumors
can !e identified !y local in*asion into adjacent normal tissue, or metastatic spread.
+ytologically, !enign cells ha*e a low nucleus%cytoplasm ratio, a round nucleus with e*en
chromatin and inconspicuous nucleoli, cell polarity and differentiation, uncommon mitoses in
the appropriate locations. +ytologically, malignant cells ha*e a larger nucleus with irregular
shape, irregular distri!ution of chromatin, and prominent nucleoli, loss of polarity and
*aria!le loss of differentiation, common mitoses with atypical appearances.
In addition to histopathology and cytopathology, the clinical situation is also important in
considering the diagnosis of malignancy. 4ome sites may !e more li$ely (colon) than others
(uterus) to !e malignant. +ertain cancers ha*e different malignancy rates !etween genders
(e"% gonadal teratomas in males are much more aggressi*e). &ge also plays an important
factor for some tumors, with teratomas in !oys testes !eing much more !enign than in men.
The grade of a cancer refers to the degree of malignant features cells ha*e (low has less than
high). & well differentiated neoplasm closely resem!les normal tissue, whereas a poorly
differentiated one doesnt. Poor differentiation and high grade tend to go together. There are
standard criteria for grading, !ased on nuclear and tissue le*el features. <rade isnt always
predicti*e of how malignant something will !e.
The stage of a cancer is used to designate the e"tent of the cancers spread. This is more
influential in predicting clinical !eha*ior than grade. There is a T6, system of grading.
o T (size and e"tent of spread of tumor) ranges from TE (a!sent)TC (small, no in*asion) to
TH (*ery large, e"tensi*e in*asion)
o 6 (spread to lymph nodes) ranges from 6E (none)6C (single or ipsilateral node), to 6?
(distant, contralateral nodes affected)
o , (metastasis to distant organs) includes ,E (a!sent) and ,C (present)
&n alternati*e staging strategy com!ines these, and ran$s them as stages% E, I&, I2, II&, II2,
III&, III2, or IB (if ,;C). The higher the stage, the !igger and more spread the cancer.
Immunohistochemistry can !e used to e"amine neoplasms. 5or e"ample, you can stain
prostate cancer for a mar$er of the !asal layer, which no longer e"ists in in*asi*e cancers.
&,&+/ is an enzyme that is o*ere"pressed in most prostate cancers, and can also !e stained
for. Its not a great technique for telling !enign from malignant, !ut can !e useful for
determining the tumors phenotypeline of differentiationtissue of origin. 1"% +(@E
indicates an origin in the colon, +KU the !reast.
+ancer can !e detected with molecular mar$ers, li$e P4& or (6& with #'ras mutations (in
colorectal cancer). There are !ig limits to this though.
0hat we can outline so far doesnt really tell us much a!out how a cancer will respond to
treatment, in most cases. #opefully they can find more predicti*e mar$ers and molecular
classifications that are rele*ant to therapies. 1"% measure estrogen receptors in !reast cancer
(more has a !etter prognosis).
Molecular )enetic $%*:
There are lots of social controls (adhesion signals, cyto$ines) on cells and tissues needed for
growth and sur*i*al. The normal mutational load that occurs is handled !y limiting the
num!er of di*isions in germ cells (normally theres a quite high rate of mutation) and innate
resistance mechanisms to tumorigenesis. ,ost malignancy requires multiple mutations.
3*er generations su!clones may accumulate mutations and compete. Those with a
reproducti*e or sur*i*al ad*antage can dominate o*er time. Initial mutations often dont do
much, !ut as they accumulate the effects can !e !ig, especially when a mutation increases the
rate of su!sequent mutations.
+lonal selection theory% neoplasia requires multiple steps. 4ome mutations lead to a
selecti*e ad*antage, and clonal changes reflect the $ey selected e*ents. 4o tumors are
homogeneous for early changes, !ut may !e heterogeneous for later changes.
Types of mutations include oncogenes (gain of function, usually dominant), tumor suppressor
genes (loss of function, usually recessi*e), genome maintenance genes (loss of function,
usually recessi*e), and genes that affect telomeres. There are also lots of passenger
mutations, which are *ery common and dont ha*e an effect on the neoplasm. They may
predate the neoplastic changes and ma$e identifying causal genes difficult.
To test if a cancer is caused !y an oncogene or tumor suppressor, fuse a neoplastic cell with a
normal cell. If oncogenic, the result will !e neoplastic. If tumor suppressor, itll !e normal.
,utation types include translocation, amplification (creates dou!le minutes of e"tra (6&
representing the amplified region), point mutations, and deletions.
Telomeres are shorter than normal in neoplasia, !ut they sur*i*e. 4o the senescence
mechanism is somehow turned off.
0hen two chromosomes fuse, you can get multiple centromeres that result in a!normal
mitoses and !rea$s in chromosomes or changes in chromosomal num!er.
To find oncogenes, they added transforming (6& to cells, implanted them in mice and got
tumors. 4o, the mutated genes must ha*e !een oncogenes. 3ncogene functions include
growth factor receptors, signal transduction mutations, changes in nuclear oncoproteins that
affect gene e"pression, anti'apoptotic factors and tumor'suppressor antagonists.
Tumor suppressor gene functions include adhesion molecules, cytos$eletal components,
signal transduction or cell cycle regulators, apoptotic factors, and chromatin structural
molecules. ,any *iral proteins inhi!it the same regulatory proteins to promote replication,
in an e"ample of con*ergent e*olution.
9ou may ha*e cascades of tumor suppressor and oncogene products that inhi!it influence one
another.
(ominant oncogenes are rarely inherited since they usually result in de*elopmental defects.
<enome maintenance genes are commonly inherited, as are tumor suppressor genes.
4yndromes resulting from inheritance of one mutant copy of a tumor suppressor gene show
autosomal dominant pedigree patterns, though their histology loo$s recessi*e with only a few
neoplastic cells. 4yndromes li$e this include retino!lastoma, 7i'5raumeni syndrome,
&denomatous polyposis coli, *on #ippel'7indau, and neurofi!romatosis.
4yndromes resulting from defecti*e genome maintenance genes include "eroderma
pigmentosa (need to !e homozygous), #6P++'7ynch syndrome (shows up if heterozygous),
and for one mutation fanconi anemia (homozygous) or !reasto*arypancreatic cancer
(heterozygous).
/ational therapy for cancer may see$ to $ill cells !ased on a cancer'cell specific
!iochemistry, or alter gene functione"pression or immune response to a specific target.
,utation !ased drug resistance can occur, in which changes alter the drug !inding poc$et so
the drug no longer wor$s.