INTRODUCTION TO INTRODUCTION TO NEOPLASIANEOPLASIA

DEFINITION DEFINITION

An abnormal tissue mass whose An abnormal tissue mass whose growth exceeds and is growth exceeds and is uncoordinated with that of adjacent uncoordinated with that of adjacent normal tissue and persists after normal tissue and persists after cessation of the stimuli that cessation of the stimuli that provoked it.provoked it.

CLASSIFICATIONCLASSIFICATION

Classification according to their tissue of origin :- 1) epithelial (neoplasia of lining tissues),2) mesenchymal (neoplasia of connective tissue derivatives),3) germ cell (neoplasia of undifferentiated stem cells ,sperm, ovarian egg etc).

Benign NeoplasmBenign Neoplasm

A neoplasm that grows without A neoplasm that grows without invading adjacent tissue or invading adjacent tissue or spreading to distant sites. It is spreading to distant sites. It is usually fairly well-circumscribed due usually fairly well-circumscribed due to the lack of invasion of to the lack of invasion of surrounding tissuessurrounding tissues Malignant NeoplasmMalignant Neoplasm

A neoplasm that invades the A neoplasm that invades the surrounding normal tissue and surrounding normal tissue and usually spreads to distant sites given usually spreads to distant sites given sufficient time. sufficient time.

NomenclatureNomenclature NeoplasmsNeoplasms have two components have two components

1.1. Parenchyma= neoplastic cellsParenchyma= neoplastic cells decides behavior & Pathologic consequencesdecides behavior & Pathologic consequences

2.2. StromaStroma= Supportive ( connective tissue & = Supportive ( connective tissue & Vessels)Vessels) Determines Growth & EvolutionDetermines Growth & Evolution Soft & fleshy neoplasmSoft & fleshy neoplasm Scant stroma Scant stroma

Neoplasia- Neoplasia- NomenclatureNomenclature BenignBenign

MesenchymalMesenchymal

Easy =Cell origin + omaEasy =Cell origin + oma Chondro + Oma = Chondro + Oma =

ChondromaChondroma

{Cartilage}{Cartilage} Fibro + Oma = Fibroma Fibro + Oma = Fibroma

{Fibroblast}{Fibroblast} Lipo + Oma = LipomaLipo + Oma = Lipoma

{Fat/ lipocyte / {Fat/ lipocyte / adipocyte}adipocyte}

EpithelialEpithelial Not easyNot easy

• AdenomaAdenoma benign epithelial tumor benign epithelial tumor derived from or present with glandular derived from or present with glandular

patternpattern• Papilloma Papilloma finger-likefinger-like or warty or warty

projections from the projections from the epithelialepithelial surfaces (MC - skin)surfaces (MC - skin)

• Polyp Polyp fist-likefist-like projection from projection from mucosal epithelialmucosal epithelial surfaces( MC - surfaces( MC -

colon)colon)• CystadenomasCystadenomas: forms large cystic : forms large cystic

mass (ovaries)mass (ovaries)• Papillary cystadenomaPapillary cystadenoma: papillary : papillary

patterns that protrude into the cystic patterns that protrude into the cystic spaces (ovaries)spaces (ovaries)

Neoplasia- Neoplasia- NomenclatureNomenclature MalignantMalignant

Mesenchymal

Sarcoma

Greek = “fleshy” ( little stroma)

Chondro + sarcoma = Chondrosarcoma

{Cartilage} Fibro + sarcoma =

Fibrosarcoma {Fibroblast}

Lipo + sarcoma = Liposarcoma

{Fat/ lipocyte / adipocyte}

Rhabdomyo +sarcoma = Rhabdomyosarcoma

{striated muscle}

Epithelial

carcinoma (any germ layer) Adenocarcinoma glandular growth

pattern Squamous cell carcinoma squamous

cell differentiation specify organ of origin Renal cell

adenocarcinoma, Bronchogenic Undifferentiated/ poorly differentiated

Can’t determine tissue of origin Mixed tumors Pleomorphic adenoma

Divergent differentiation of a single germ line of parenchymal cells

(salivary gland) Teratoma From Totipotential cells

(gonads), > one germ layer { Dermoid cyst ovary}

Malignant neoplasias with benign Malignant neoplasias with benign suffixessuffixes

LymphomaLymphoma

MesotheliomaMesothelioma

MyelomaMyeloma

AstrocytomaAstrocytoma

GliomaGlioma

Benign -EpithelialBenign -Epithelial

BA

MesenchymalMesenchymalLeiomyomaLeiomyoma

Benign

EpithelialAdenoma = thyroid

Pleomorphic adenoma - Salivary glandPleomorphic adenoma - Salivary gland

cartilage

Epithelial components

TeratomaTeratoma

DysplasiaDysplasia

Atypical proliferation of cells Atypical proliferation of cells characterized by nuclear characterized by nuclear enlargement and failure of enlargement and failure of maturation and differentiation, short maturation and differentiation, short of malignancy.of malignancy.

Anaplasia

Loss of differentiation

Carcinoma Carcinoma in situin situ (cis) (cis)

Full-thickness dysplasia extending Full-thickness dysplasia extending from the basement membrane to the from the basement membrane to the surface of the epithelium. Applicable surface of the epithelium. Applicable only to epithelial neoplasms. If the only to epithelial neoplasms. If the entire lesion is no more advanced than entire lesion is no more advanced than CIS, then the risk of metastasis is zero. CIS, then the risk of metastasis is zero. This is because there are no blood This is because there are no blood vessels or lymphatics within the vessels or lymphatics within the epithelium above the basement epithelium above the basement membrane.membrane.

CarcinomaCarcinoma

Squamous cell carcinomaCarcinoma in-situ

The tissue type represented by the tumor.Well-differentiated tumors resemble identifiable tissue types, while poorly differentiated tumors may only be identifiable by the expression of cell markers or by extremely focal and subtle histologic and/or cytologic findings.

Differentiation

MetastasisMetastasis

Spread of tumor to distant sites by Spread of tumor to distant sites by lymphatic, hematogenous routes, or lymphatic, hematogenous routes, or seeding of body cavities.seeding of body cavities.

Local Invasion

Growth into the surrounding tissue by direct expansion.

DIFFERENCESDIFFERENCES

FeaturesFeaturesBenign Benign MalignantMalignant

BoundariesBoundariesEncapsulatedEncapsulatedIrregularIrregular

Surrounding Surrounding tissuestissues

Often Often compressedcompressed

Usually invadedUsually invaded

Size Size Usually smallUsually small Often largeOften large

GrowthGrowthSlow & Slow & expandingexpanding

Rapid & Rapid & infiltratinginfiltrating

CapsuleCapsulePresentPresentAbsentAbsent

DegenerationDegenerationRare Rare CommonCommon

RecurrenceRecurrenceNot commonNot commonCommonCommon

Fixity Fixity AbsentAbsentPresentPresent

Secondary Secondary changeschanges

Less oftenLess oftenMore offenMore offen

DIFFERENCESDIFFERENCES

FeaturesFeaturesBenignBenign MalignantMalignant

PatternPattern Usually Usually resembleresemble

Poor Poor resemblenceresemblence

Basal polarityBasal polarityRetainedRetainedLostLost

PleomorphisPleomorphismm

Not presentNot presentOften presentOften present

N/C ratioN/C ratioNormalNormalIncreasedIncreased

AnisonucleosiAnisonucleosiss

AbsentAbsentPresentPresent

HyperchromaHyperchromatismtism

AbsentAbsentPresentPresent

MitosisMitosis Typical Typical mitosismitosis

Atypical & Atypical & abnormalabnormal

DIFFERENCESDIFFERENCES

FeaturesFeaturesBenignBenign MalignantMalignant

Tumour Tumour giant cellsgiant cells

Without Without nuclear atypianuclear atypia

With nuclear With nuclear atypiaatypia

CytoplasmCytoplasmNormal Normal constituentsconstituents

Decreased or Decreased or lostlost

FunctionFunctionWell Well maintainedmaintained

Lost or Lost or abnormalabnormal

Growth rateGrowth rateSlowSlowRapidRapid

Local Local invasioninvasion

Compreses the Compreses the surrounding surrounding

tissuetissue..

Infiltrates & Infiltrates & invades the invades the

tissuestissues

MetastasisMetastasis AbsentAbsentPresentPresent

Malignant tumorsMalignant tumors

FeatureFeatureSarcomaSarcomaCarcinomaCarcinoma

OriginOriginArise from Arise from mesenchymalmesenchymal

tissuetissueArise from Arise from epithelialepithelial

tissuetissue

Mass sizeMass sizeUsually Usually largerlarger since harder to since harder to

detect them in deep tissue.detect them in deep tissue.Usually Usually smallersmaller since since

easier to detect on easier to detect on surfacesurface

Time ofTime ofdiagnosisdiagnosis

Takes Takes longerlonger to diagnose to diagnoseTakes Takes shorter periodshorter period of of time to diagnose from time to diagnose from onsetonset

Route ofRoute ofMetastasisMetastasis

Goes directly to vascular Goes directly to vascular system/ Blood vessels (i.e. system/ Blood vessels (i.e. blood)blood)

Goes through Goes through lymphaticslymphatics first – longer route to first – longer route to vascular systemvascular system

PrognosisPrognosisWorse prognosisWorse prognosisGood/worseGood/worse

Malignant tumorsMalignant tumors

MesenchymalSarcoma

EpithelialAdenocarcinom

a

HamartomaHamartoma

May be mistaken for a true tumourMay be mistaken for a true tumour Focal , circumscribed overgrowth.Focal , circumscribed overgrowth. Improper proportions of tissue.Improper proportions of tissue. No continuous overgrowth.No continuous overgrowth. Tumour - like malformation.Tumour - like malformation. Tissues of which is composed are Tissues of which is composed are

present in that area. present in that area.

ChoristomaChoristoma

Similar to hamartoma.Similar to hamartoma. Tissues of which is composed are not Tissues of which is composed are not

normally present in that area.normally present in that area. Eg :-adrenal gland tissue in urinary Eg :-adrenal gland tissue in urinary

bladder.bladder.

MOLECULARMOLECULARBASISBASIS

OF OF NEOPLASMNEOPLASM

CarcinogenesisCarcinogenesis Induction of tumor is carcinogenesis & Induction of tumor is carcinogenesis &

agents which can induce tumor are agents which can induce tumor are carcinogens.carcinogens.

Carcinogens can be:-Carcinogens can be:-

1.1. Chemical carcinogens.Chemical carcinogens.

2.2. Physical carcinogens.Physical carcinogens.

3.3. Hormonal carcinogens.Hormonal carcinogens.

4.4. Biologic carcinogens.Biologic carcinogens.

Chemical carcinogens:Chemical carcinogens:

These can be:-These can be:- Direct acting-which require Direct acting-which require

no prior activation.no prior activation. Indirect acting- which Indirect acting- which

require prior activation.require prior activation.

Physical carcinogensPhysical carcinogens:-:-

It includesIt includes

1.1.RadiationRadiation

2.2. Non radiation carcinogens.Non radiation carcinogens.

For e.g. ultraviolet rays, For e.g. ultraviolet rays, ionizing rays, chronic ionizing rays, chronic irritation etc. irritation etc.

Hormonal carcinogens:-Hormonal carcinogens:-

Certain hormones e.g. oral Certain hormones e.g. oral contraceptives and anabolic steroids contraceptives and anabolic steroids increase the risk of developing increase the risk of developing benign and malignant tumors. benign and malignant tumors. Hormone sensitive tissues are Hormone sensitive tissues are breast, endometrium, myometrium, breast, endometrium, myometrium, thyroid, liver and prostate. thyroid, liver and prostate.

Biologic carcinogens:-Biologic carcinogens:-

It includes It includes

1.1.Viral carcinogens, e.g. HPV, Viral carcinogens, e.g. HPV, EBV, HBV etc.EBV, HBV etc.

2.2.Parasitic carcinogens, e.g. Parasitic carcinogens, e.g. schistosomiasis.schistosomiasis.

3.3.Bacterial carcinogens, e.g. Bacterial carcinogens, e.g. Helicobacter pylori.Helicobacter pylori.

Rate of growthRate of growth

The growth rate of tumors The growth rate of tumors correlates with their level of correlates with their level of differentiation, and thus malignant differentiation, and thus malignant tumors grow more rapidly than do tumors grow more rapidly than do the benign lesions, though the benign lesions, though examples of benign tumors with a examples of benign tumors with a higher growth rate also exist.higher growth rate also exist.

The rate of growth of benign The rate of growth of benign as well as malignant tumors is as well as malignant tumors is therefore not constant over therefore not constant over time.time.

Various factors govern the rate Various factors govern the rate of growth of tumors, e.g.:of growth of tumors, e.g.:

Hormone dependenceHormone dependence Adequacy of blood supplyAdequacy of blood supply Unknown influences.Unknown influences.

For e.g.:For e.g.:

Leiomyomas of uterus are benign Leiomyomas of uterus are benign smooth muscle tumors. These may smooth muscle tumors. These may show no significant increase in show no significant increase in size or may even undergo atrophy size or may even undergo atrophy post menopause, but, may enter a post menopause, but, may enter a rapid growth phase during rapid growth phase during pregnancy, under the influence of pregnancy, under the influence of circulating steroid hormones , circulating steroid hormones , particularly estrogen.particularly estrogen.

Clinical picture of leiomyoma Clinical picture of leiomyoma

uterusuterus

An abrupt increase in size An abrupt increase in size and disseminating behaviour and disseminating behaviour of malignant neoplasm is of malignant neoplasm is believed to be the result of believed to be the result of emergence of aggressive emergence of aggressive subclone of transformed subclone of transformed cells.cells.

Modes of spreadModes of spread

Neoplasia can spread by:-Neoplasia can spread by:-

1.1. Local invasionLocal invasion

2.2. Metastasis.Metastasis.

Local invasion:-Local invasion:-

Almost all benign tumorsAlmost all benign tumors

* grow as cohesive expansile * grow as cohesive expansile masses.masses.

* remaining localized to site of * remaining localized to site of origin.origin.

* do not have capacity to * do not have capacity to infiltrate, invade or infiltrate, invade or metastasize to distant sites.metastasize to distant sites.

As these expand and grow As these expand and grow slowly, they develop a rim of slowly, they develop a rim of compressed connective tissue compressed connective tissue called the called the fibrous capsulefibrous capsule.. Separates tumor from host tissue.Separates tumor from host tissue. Derived from native tissue.Derived from native tissue. Makes neoplasm discrete, readily Makes neoplasm discrete, readily

palpable & easily movable mass palpable & easily movable mass that can be surgically enucleated.that can be surgically enucleated.

Benign tumor of vertebral column.

There are There are exceptions for e.g. exceptions for e.g. hemangioma, hemangioma, which is a which is a neoplasm of neoplasm of tangled blood tangled blood vessels n are often vessels n are often unencapsulated & unencapsulated & may appear to may appear to permeate the site permeate the site of origin. of origin.

While benign tumors are non While benign tumors are non invasive, the growth of cancers invasive, the growth of cancers is accompanied by progressive is accompanied by progressive infiltration, invasion & infiltration, invasion & destruction of surrounding destruction of surrounding tissues. Sometimes the slowly tissues. Sometimes the slowly expanding malignant tumors expanding malignant tumors may develop an apparent may develop an apparent capsule. capsule.

Histology of this capsule Histology of this capsule shows tiny crab like feet shows tiny crab like feet penetrating the margins and penetrating the margins and infiltrating adjacent tissues.infiltrating adjacent tissues.

Thus, malignant tumors are Thus, malignant tumors are invasive, and recognize no invasive, and recognize no anatomical boundaries, anatomical boundaries, making surgical resection making surgical resection difficult.difficult.

Therefore, it is necessary to Therefore, it is necessary to remove a considerable margin remove a considerable margin of apparently normal tissue of apparently normal tissue around infiltrative neoplasm.around infiltrative neoplasm.

Invasiveness is one of the Invasiveness is one of the reliable factors differentiating reliable factors differentiating benign and malignant tumors.benign and malignant tumors.

Preinvasive stage of tumors Preinvasive stage of tumors in which they do not invade in which they do not invade the basement membrane is the basement membrane is termed as termed as carcinoma in carcinoma in situ.situ.

MetastasisMetastasis-:-:

Metastasis Metastasis are tumor are tumor implants implants discontinuoudiscontinuous with the s with the primary primary tumor.tumor.

Metastasis in progress

Metastasis alone mark s a Metastasis alone mark s a tumor as malignanttumor as malignant..

Almost all cancers Almost all cancers metastasizemetastasize ..

Exceptions are few for e.g.Exceptions are few for e.g.

1.1. Glioma, malignant Glioma, malignant neoplasm of glial cells of neoplasm of glial cells of CNS. CNS.

2. Basal cell 2. Basal cell carcinoma, carcinoma, locally invasive locally invasive neoplasm also neoplasm also known as rodent known as rodent ulcer but does ulcer but does not metastasizenot metastasize

In general, the more In general, the more aggressive, the more rapidly aggressive, the more rapidly growing & the larger the growing & the larger the primary neoplasm is the greater primary neoplasm is the greater are the chances of metastasis.are the chances of metastasis.

Approximately 30% of newly Approximately 30% of newly diagnosed patients of solid diagnosed patients of solid tumors present with metastasis.tumors present with metastasis.

Presence of metastasis reduces Presence of metastasis reduces the cure rate.the cure rate.

Pathways of Pathways of spreadspread

Dissemination of Dissemination of tumor cells occurs tumor cells occurs by:-by:-

Lymphatic spread.Lymphatic spread. Hematogenous Hematogenous

spread.spread. Direct seeding of Direct seeding of

body cavity/surfaces.body cavity/surfaces.

Direct transplantation of Direct transplantation of tumor cells, for e.g. by tumor cells, for e.g. by surgical instruments, may surgical instruments, may occur theoretically, but is occur theoretically, but is considered an artificial mode considered an artificial mode of dissemination .of dissemination .

Lymphatic spread:-Lymphatic spread:- It is the most common pathway It is the most common pathway

for initial dissemination of for initial dissemination of carcinomas.carcinomas.

Regional lymph nodes serve Regional lymph nodes serve as an effective barrier to further as an effective barrier to further dissemination of tumor cells, at dissemination of tumor cells, at least for sometime. The cells least for sometime. The cells may be destroyed by tumor may be destroyed by tumor specific immune response. specific immune response.

This drainage This drainage of tumor cell of tumor cell debris or debris or tumor antigens tumor antigens or both may or both may induce reactive induce reactive changes in the changes in the nodes.nodes.

The enlargement of nodes may The enlargement of nodes may be caused by:-be caused by:-

1.1. Spread and growth of cancer Spread and growth of cancer cellscells

2.2. Reactive hyperplasiaReactive hyperplasia

Thus, nodal enlargement in Thus, nodal enlargement in proximity to a cancer , does proximity to a cancer , does not necessarily mean not necessarily mean dissemination of primary lesiondissemination of primary lesion

The pattern The pattern of lymph of lymph node node involvement involvement follows the follows the natural natural routes of routes of drainage.drainage.

For e.g. For e.g. carcinomas carcinomas of lung of lung arising in arising in major major respiratory respiratory passage passage metastasize metastasize to prehilar to prehilar tracheobronctracheobronchial and hial and mediastinal mediastinal lymph nodes. lymph nodes.

Skip metastasis is also sometimes Skip metastasis is also sometimes seen i.e. bypassing of a lymph seen i.e. bypassing of a lymph node. This occurs due to:-node. This occurs due to:-

1.1.Venous lymphatic anastomoses in Venous lymphatic anastomoses in the area.the area.

2.2.Inflammation obliterated channels.Inflammation obliterated channels.

3.3.Radiation obliterated channels.Radiation obliterated channels.

Diagrammatic representation of lymphatic metastasisDiagrammatic representation of lymphatic metastasis..

Hematogenous Hematogenous spread:-spread:-

It is typical of It is typical of sarcomas but may sarcomas but may also be seen in also be seen in carcinomas.carcinomas.

It can spread by two It can spread by two ways:- ways:-

1.1.Arterial spread.Arterial spread.

2.2.Venous spread.Venous spread.

Arterial spread:-Arterial spread:-

Arteries have thicker walls than Arteries have thicker walls than veins, and thus are less readily veins, and thus are less readily penetrated.penetrated.

Arterial spread may however occur Arterial spread may however occur when tumor cells pass through the when tumor cells pass through the pulmonary capillary beds, pulmonary capillary beds, arteriovenous shunts or when arteriovenous shunts or when pulmonary metastasis themselves pulmonary metastasis themselves gives rise to additional tumor emboli.gives rise to additional tumor emboli.

Venous spread:-Venous spread:-

The cells follow the venous drainage. The cells follow the venous drainage. Liver &lungs are most commonly Liver &lungs are most commonly involved secondarily in such involved secondarily in such hematogenous dissemination. hematogenous dissemination.

All portal areas drainage flows to the All portal areas drainage flows to the liver, and all caval areas drainage flows liver, and all caval areas drainage flows to the lungs.to the lungs.

Certain cancers have the Certain cancers have the propensity for invasion of propensity for invasion of veins. For e.g. renal cell veins. For e.g. renal cell carcinoma invades carcinoma invades branches of renal vein & branches of renal vein & renal vein itself grows in renal vein itself grows in snake like fashion to IVC & snake like fashion to IVC & may reach right heart.may reach right heart.

Hematogenous spreadHematogenous spread..

Direct seeding of body Direct seeding of body cavities & surfaces:-cavities & surfaces:-

Seeding occurs whenever a Seeding occurs whenever a neoplasm penetrates into neoplasm penetrates into natural natural OPEN FIELDS. OPEN FIELDS. Mostly it is the peritoneal Mostly it is the peritoneal cavity but any cavity may cavity but any cavity may be involved.be involved.

Direct seeding of body cavity Direct seeding of body cavity is common in carcinomas is common in carcinomas arising in the ovaries, where arising in the ovaries, where the peritoneal surface gets the peritoneal surface gets coated with a heavy layer of coated with a heavy layer of cancerous glaze.cancerous glaze.

METASTATIC CASCADEMETASTATIC CASCADE

Invasion of Invasion of ECM & ECM & vascular vascular disseminatiodissemination.n.

Homing of Homing of tumor cells.tumor cells.

INVASION OF ECMINVASION OF ECM

Detachment of tumor cells from each Detachment of tumor cells from each other.other.

Local degradation of the basement Local degradation of the basement membrane & interstitial connective membrane & interstitial connective tissue.tissue.

Changes in attachment of tumor cells Changes in attachment of tumor cells to ECM proteins.to ECM proteins.

Migration of tumor cells.Migration of tumor cells.

Detachment of tumor Detachment of tumor cells from each othercells from each other

Loosening of tumor Loosening of tumor cells due to loss of cells due to loss of function of function of E-cadherins & E-cadherins & beta catenin.beta catenin.

Local degradation of the basement Local degradation of the basement membrane & interstitial membrane & interstitial

connective tissueconnective tissue

Tumor cells secrete Tumor cells secrete proteolytic enzymes proteolytic enzymes or induce stromal or induce stromal cells to eloborate cells to eloborate proteases (MMPs, proteases (MMPs, cathepsin D, cathepsin D, urokinase urokinase plasminogen plasminogen activator). activator).

Changes in attachment of Changes in attachment of tumor cells to ECM tumor cells to ECM

proteinsproteins

Tumor cells are Tumor cells are resistant to resistant to apoptosis.apoptosis.

Matrix itself is Matrix itself is modified in ways modified in ways that promote that promote invasion & invasion & metastasis.metastasis.

Migration of tumor cellsMigration of tumor cells

Tumor cells are Tumor cells are propelled through the propelled through the degraded basement degraded basement membrane & zones membrane & zones of matrix proteolysis.of matrix proteolysis.

Such movement is Such movement is potentiated by: potentiated by: tumor cell-derived tumor cell-derived cytokines (AMF) & cytokines (AMF) & stromal cells derived stromal cells derived paracrine effectors. paracrine effectors.

VASCULAR VASCULAR DISSEMINATION & DISSEMINATION &

HOMING OF TUMOR HOMING OF TUMOR CELLSCELLS In the bloodstream, some tumor cells In the bloodstream, some tumor cells

form emboli by aggregating & adhering form emboli by aggregating & adhering to circulating leukocytes, particularly to circulating leukocytes, particularly platelets.platelets.

Extravasation of free tumor cells or tumor Extravasation of free tumor cells or tumor emboli involves adhesion to the vascular emboli involves adhesion to the vascular endothelium, followed by egress through endothelium, followed by egress through the basement membrane into the organ the basement membrane into the organ parenchyma by mechanisms similar to parenchyma by mechanisms similar to those involved in invasion.those involved in invasion.

The site of extravasation & organ The site of extravasation & organ distribution of metastasis generally can be distribution of metastasis generally can be predicted by the location of the 1predicted by the location of the 1o o tumor & tumor & its vascular or lymphatic drainage.its vascular or lymphatic drainage.

After extravasation, tumor cells are After extravasation, tumor cells are dependent on a receptive stroma for dependent on a receptive stroma for growth. Thus, tumors may fail to growth. Thus, tumors may fail to metastasize to certain target tissues metastasize to certain target tissues because they present a non- permissive because they present a non- permissive growth environment.growth environment.