Behaviour of tumours

The clinical effects of tumoursr are determined by the biological behaviour of the
neoplastic cells within them.Their most important property,in malignant tumours,is
the ability to invade and metastasise.
Invasion and metastasis
Invasion is the most important sole criterion for malignancy
Invasion is do to abnormal cell motility,reduced cellular cohesion,and
production of proteolytic enzymes
Metastasis is the process of formation of distant secondary tumours
Common routes of metastase include lymphatic channels,blood vessels,and
through body cavities
Invasion and metastasis merit detail consideration because they are responsible or
most of the lethal consequences of tumours.They also determine the most
appropriate treatment.There is no point in simply removing the tumours itself.In
most instances the tumours should be removed in continuity with a wide margin of
apparently normal tissue,to ensure that the plane of resection is clear of the often ill
defined invasive edge of the tumours;the regional lymph nodes may also be
resected.Incomplete local removal of a tumours may result in a local reccurence
because the original plane of resection transected the invasive edge of the lession.
Tumours should be manipulated with care during clinical examination or
surgical removal,to minimize the risk of pumping tumour cells in to blood and
lymphatic channels.A ligature is therefore often tied around the vascular pedicle at
an early stage in the surgical removal of a tumour.
Invasion
The invasiveness of malignant neoplasms is determined by the properties of the
neoplastic cells within them.Factors influencing tumour invasion are:

Abnormal or increased cellular motility

Secretion of proteolytic enzymes
Decreased celluler adhesion

Celluler motility is abnormal in that the cells are not only more motile than their
normal counterparts(which may not move at all),but also show loss of the normal
mechanism that arrest or reverses normal celluler migration:contact inhibition of
migration.
Proteinase and inhibitors

Matrix metalloproteinase are among the most important proteinases in neoplastic

invasion.These enzyme are secreted by malignat neoplastic cells,enabling them to
digest the sorruounding connective tisuue.There are three families:

Interstitial collageneses-degrade types I,II and III collagen

Gelatinases-degrade types IV collagen and gelatin
Stromelysins-degrade types IV collagen and proteoglicans

These
enzymes
are
countracted
by
tissue
inhibitors
of
metalloproteinases(TIMPs).The net effect is determined by the balance between
matalloproteinases and their inhibitors.It may be possible to limit the invasiveness
of tumour cells by artificilally increasing the level of inhibitory activity.
Invasion often occurs along tissue planes offering less resisntance to tumour
growth,such as perineural spaces and,of course,vascular lumina.Other tissue are
extremely resistant to neoplastic invasion,such as cartilage and the fibrocartilage of
intervertebral discs
Clinicopathological significance
Invasion is the single most important criterion of malignancy.Metastases are
consequence of invasion and,when detected clinically,are unequivocal markers of
malignancy.In epithelial tumours,invasion is relatively easy to recognize because the
basememnt membrane serves as a clear line of demarcation between the tissue
bound-aries.in connective tissue tumours,invasion is the less easy to recognize
unless there is clear evidence of vascular or lymphatic permeation;other histological
features,such as mitotic activity,are usually assessed for prognostic purposes.
Invasion within epithelium is known as pagetoid infiltration;it is named after pagets
diseased of the nipple,which is due to infiltration of the epidermis of the nipple by
tumour cells from a ductal carcinoma in the underlying breast.This pattern of
invasion can also occur with a few other epithelial malignancies.
Metastases
Metastases is the process where by malignant tumours spread from their site of
origin(the primary tumour)to form other tumours(secondary tumours)at distant
sites.The total tumour burden resulting from this process can be very great
indeed,and the total mass of the secondary tumours invariably exceeds that of the
primamry lesion;it is not uncommon at autopsy to find a liver weighing several
kilograms more than normal,laden with metastases.The word carcinomatosis is used
to denote extensive metastatic desease.
Sometimes,Metastases can be the presenting clinical feature.Bon pain or
fractures due to skeletal metastases can be the firs manifestation of a clinically
occult
internal
malignancy.palpable
lymph
nodes,due
to
metastatic
involvement,may appear before the sign and symptomps of the primary tumour.

The metastatic cascade

Neoplastic cells must successfully complete a cascade of events before forming a
metastatic tumour.Only a proportion of the neoplastic cells in a malignant tumour
may have the full repertoire of properties necesary for completion of the
cascade.many tumour studied experimentally in animal consist of metastatic and
non metastatic clones,and metastatic tumour in humans often appear histologically
less well differentiated than the primary lesion,suggesting that there is clonal
evolution of the metastatic phenotype.There is experimental evidence for the
inactivation of anti-metastaticgenes(metasto-genes)such as nm23, in neoplastic
cells capable of metastasis,but their precise role in the metastatic cascade is
uncertain.
The sequential steps involvd in the metastatic cascade are:
1. Detachment of tumour cells from their neighbours
2. Invasion of the surrounding connective tissue to reach conduits for
metastasis(blood and lymphatic vessels)
3. Intravasation into the lumen of vessels
4. Evasion of the host defence mechanisms,such as natural killer cells in the
blood
5. Adherence to endothelium at remote location
6. Extravasation of the cells from the vessels lumen into the surrounding tissue
On reaching the site of metastasis there is recapitulation of the events that were
required to form the primary tumour.The tumour cells must proliferate and,if they
are to grow to form a nodule larger than a few millimetress in diameter,the ingrowth
of blood vessels must be elicited by angiogenic factors.
Alterations in cell adhesion molecules are important at several point in the
metastatic cascade;these affect cell-cell and cell-substrate adhesion.studies on
experimental and human tumours show that reduced expression of cadherins,which are involved in adhesion between epithelial cells,correlates expression
of integrins apperars to be important for the invasive migration of neoplastic cells
into connectives tissues.
Routes of metastasis
The routes of metastasis are

Haematogenous,by the blood stream,to form secondary tumour in organs

perfused by blood which has drained from a tumour
Lymphatic,to form secondary tumour in the regional lymph nodes
Transcoelomic,in pleural,pericardial and peritoneal cavities where this
invariably results in a neoplastic effusion
Implantation,for wxample by accidental spillage of tumour cells during the
course of surgery.

Carcinomas tend to prefer lymphatic spread,at least initially,while sarcomas prefer

haematogenous spread.However,exceptions to these tendencies are coomon,and
carcinomas often generate blood-borne metastases
Haematogenous metastasis
Bone is a site favoured by haematogenous matastases from five carcinomaslung,breast,kidney,thyroid and prostate.Other organs commonly involved by
haematogenous metastases are lung,liver and brain the matastases are frequently
multiple,where as primary tumour arising in the affected organs are usually
solitary.Coriously,tumours rarely metastasis to skeletal muscle or to the
spleen,despite their lavish blood supply.
Metastases reaching the surface of the liver often have a central
depression(umbilication)as a consequence of necrosis within the tumour nodule.
Lymphatic metastasis
Tumour cell reach the lymph node through the afferent lymphatic channel.the
tumour cells settle and grow in the periphery of the node,gradually extending to
replace it.lymph nodes involved by metastatic tumour are usually firmer and larger
than normal groups of involved lymph node may be matted together by both
tumour tissue and connective tissue reaction to it lymph node metastases often
interrupt lymphatic flow,thus causing oedema in the territory that they drain.
Clinically,it is necessary to be cautious in interpreting the significance og enlarged
lymph nodes draining tumours because the enlargement could simply be due to
reactive changes.
Trancoelomic metastasis
The peritoneal,pleural and pericardial cavities are common sites of transcoelomic
metastasis.Which result in an effusion of fluid into the cavity.The fluid is rich in
protein(I,e,it is an exudate)and may contain fibrin.the fluid also contain the
neoplastic cells causing the effusion,and cytological examination of the aspirated
fluid is very im portant in diagnosing the cause of effusions into body cavities.The
tumour cells often grow as nodules on the mesothelial surface the cavity.
Peritonela effusion(ascites)may be due to involvement by any abdominal
tumour,but primaries within the ovaries are particularly common.Pleural and
pericardial effusions are common consequences of carcinomas of the breast and
lungs.
Clinical effect of tumours
Local effect due to compressions,invasion,ulceration or destruction of
adjacent structures

 Metabolic effect due to appropriate or unexpected neoplastic cell products

Effect due to metastases if tumour is malignant
The clinical effect of tumour are attributable to their location,their cell of origin and
their behaviour.The effect may be local,or occur at some distance from the tumour
Local effects
Tumour exert local effects through compression and displacement of adjacent
tissues and,if malignant,through their destruction by actual invasion.These effects
can be clinically inconsequential if the organ is large relative to the size of the
tumour or if no vital structure is threatened.However,even benign tumour can have
life-threatening effects on neighbouring stricter;for example,a functionally inactive
adenoma of the pituitary tissue,such is the confined space in which the gland
sits,resulting in hypopituitarism.
Malignant neoplasms obviously have more serious local effects because they
invade and destroy local structures.This may be fatal if a vital structure is eroded,for
example pulmonary artery by acarcinoma of the lung.In the case of basal cells
carcinoma of the skin(rodent ulcer)its local effect are sufficient to justify the
labelcarcinomabecause,although the tumou rarely metastasis,its invasiveness can
be very disfiguring.
Malignant tumour on mucosal surface are often ulcerated.Blood can ooze
from the lesions;this blood loss can be occult in the case of gastrointestinal tumour
and this is very important cause of anemia.Ulcerated surface also expose the
patient to the risk infection.
Metabolic effects
The metabolic effects of tumour can be subdivide into those spesifis to individual
tumours and those of a general nature.
Tumour-type specific effects
Well-differentiated andocreine tumours often retain the functional properties og the
parent tissue.Since such tumour are relatively autonomous and because the total
number of functioning cells often greatly exceeds that in the normal organ,clinical
effect are common.For example:

Thyrotoxicosis may result from a thyroid adenoma

Cushings syndrome may result from an adrenocortical adenoma
Hyperparathyroidism may result from a parathyroid adenoma

Sometime the metabolic consequences of a tumour are unexpected or

inappropriate,at least in the light of our current knowledge;for example oat

cell(small cell)carcinoma of the lung commonly secrete ACTH and ADH,although this
rarely gives rise to clinically significant consequences.
Other spesifis tumour associated phenomena have no metabolic consequences but
are nevertheless probably mediated by humoral factors.the most common example
is fingering-clubbing and hypertrophic osteoarthropathy in patients with carcinoma
of the lung.
Non specific metabolic effects
Disseminated malignant tumour are commonly associated with profound weight
loss despite apparently adequate nutrition.The catabolic clinical state of the cancer
patient with severe weight loss and debility is known as cachexia and is thought to
be mediated by tumour-derived humoral factor that interfere with protein
metabolism.Cachexia can also occur quaite early in the course of the
desease,notably in patients with carcinoma of the lung.Weight loss
Table 11.14 prognosis of some different type of solid malignant tumour based on
experience of responses to treathment in the UK
Prognostic category

Good(seminoma of testis basal cell carcinoma of skin)

Intermediate(carcinomas of breast,colon,rectum,larynx,uterus,bladder and
kidney malignant melanoma,teratoma og testis osteosarcoma
Poor(carcinomas
of
lung,pancreas,stomach,oesophagus
and
liver,mesothelioma

A good prognosis implies a greater than 80 % 5-year survival;poor prognosis implies

a less than 20%-5 year survival,prognosis in individual cases is,of course,influienced
by tumour grade and stage at presentation.
Can of course,also be due to interference with nutrition because
example,oesophageal obstruction,severe pain or depressive illness.

of,for

Neuropathies and myopathies are associated with the presence of malignant

neoplasms,particularly with carcinoma of the lung.A tendency to venous thrombosis
is associated with mucus producing adenocarcinomas,notably of the
pancreas.Glomerular injury can result from deposition of immune complexes in
which one of the ingredients is tumour antigen(Ch.9).
Prognosis.
Malignant tumour have a variable prognosis.this is determined partly by the innate
characteristics of the tumour cells(e.g.growth rate,invasiveness of modern cancer
theraphy for individual types of tumour.

Prognostic indices
One of the major efforts in histopathology continues to be the search for feautures
that more accurately predict the likely behaviour of individual tumors.It is
insufficient merely to diagnose a tumour as malignant and to identift its origin.The
patients treathment is guided by the most accurate determination of:

Tumour type(e.g.melanoma,squamosh cell carcinoma,leiomyosarcoma)

Grade or degree of differentiation
Stage or extent of spread

It is also important to determine whether the presenting lesion is primary tumour or

a metastasis.this can be difficult.There may be little point in performing radical
surgry for a tumour if it si a metastaseis,and the primary tumour and perhaps other
metastases are left unattended
Tumour type
The tumour type is usually determined from the growth pattern of the tumour and
its relationship to the surrounding structures from which an origin may be
evident.Thus,a glans-forming neoplasm in the breast is most likely to be a primary
adenocarcinoma of the breast,particularly if carcinoma cell are also presnt within
the original breast duct near the tumour(intraduct carcinoma).A squamous cell
carcinoma is often recognizable from the production of keratin,and it may be in
continuity with adjacent squamosh epithelium that may show carcinoma in situ.
Some types of tumour need to be subclassified because variants with
differing behaviour exist.Malignant lymphomas,for example,are subclassified into
hodgkins and non-hodgkins lymphoma,each of which is then further subclassified
by detailed appraisal of the histology(Ch.22)
Electron microscopy or immunohistology may be necessary to type tumours
that do not have obvious differentiated features detectable on rountine light
microscopy.
Tumour grade
The grade of tumour is an assessment of its degree of malignancy or
aggressiveness.This can be inferred from its histology.The most important features
contributing to the assessment of tumour grade are :

Mitotic activity
Nuclear size and pleomorphism
Degree of resemblance to the normal tissue(i.e.differentiation)

Tumour stage

The stage of a tumour is the extent of spread.This is determined by

histopathological examination of the resected tumour and by clinical assessment of
the patient,often involving imaging techniques.Perhaps the best known staging
system is that devised by Cuthbert dukes for colorectal carcinomas(see Ch.15)

DukesA:Invasion into,but not through,the bowel wall

DukesB:invasion through the bowel wall but without lymph node metastases
DukesC:involvement of the local lymph nodes
DukesDa stage added by some surgeon): hepatic metastases present.

The most generally applicable staging system is the TNM system:

T refers to the primary tumour and is suffixed by a number that denotes

tumour size or local anatomical extent.The number varies according to the
organ harbouring the tumour.
N refers to lymph node status and is suffixed by a number denoting the
number of lymph nodes or groups of lymph nodes containing metastases.
M refers to the anatomical extent of distant metastases.

For example,a T1 breast carcinoma is equal to,or less than,20 mm in diameter;large

numbers denote large tumours,N0 denotes no nodal metastases, N1 one or few
nodal metastases,and N2many nodal metastases. M0 denotes an absence of
metastases,and M1 and greater denotes increasing number of metastases.
Commonly confused condition and entities realting to carcinogenesis and neoplasia

Commonly confused

Distinction and explanation

Protooncogenes,celluler
oncogenes
and
oncogene

Proto-oncogenes and celluler oncogenes are normal

unmutated
genes
with
important
functions
in
morphogenesis and in the growth and differentiation of
normal cells.when these genes become mutated or
abnormally expressed as part of the neoplastic
process,they are referred to as oncogenes

Gatekeepers
caretakers

and

These are two categoreies of tumour suppressor

genes.gatekeeper genes stop cells with mutated or
damaged DNA from proceeding through the cell cycle and
replicating the error caretaker genes repair damaged DNA

Grade and stage

The grade of tumour is its degree of histopatological

resemblance to the parents tissue the stage of a tumour is
its anatomical extent of spread

Histogenesis
differentiated

and

Sarcoma
carcinoma

and

In-situ carcinoma and

intraepithelial
neoplasia

Histogenesis indicates the cell type from which neoplasms

has arisen;this can be often deduced from the
morphological
features
of
the
neoplastic
cell.Differentiation is the extent to which the neoplastic
cell resemble the normal cell lineage from which they are
assumed to have arisen
Both are malignant neoplasms.A sarcoma is of connective
tissue(mesenchymak)origin.A carcinoma is of epithelial
origin.
An in-situ carcinoma has all the cytological features of a
malignant epithelial neoplasms,but has not yet invaded
through the basement membrane and therefore,cannot
have metastasized.Because epithelial dysplasia(disordered
differentiation)may progress to in situ carcinoma and
histopatologist may be unable reliably to distinguish the
entities,they are marged together as intraepithelial
neoplasia and for example in the cervix catagorised
according to the severity of the abnormality(CIN 1,CIN
2,CIN 3)

Tumour dormancy
After surgical removal,radiotherapy and/or chemotherapy there maya be no
clinically detectable tumour remaining in a patient.This does not mean that the
tumour has been completely eradicated,however,as minute deposits can evade
detection by even the most sophisticated imaging techniques.These occult tumour
foci can remain clinically dormant for perhaps several years before their regrowth
cause sign and symptoms.For this reason,it is virtually impossible to speak of a

cancer patient as beingcuredand prognosis can be given only in terms of the

probability of survival or the length of the desese-free interval.The prognostic
information derived from tumour type,grade and stage is used to predict the
patients chances of surviving,say,,5 years.
Early detection of cancer
Its should be evident from the above description of the pathology,biology and
clinical aspects of tumour that their prevention and early diagnosis are just as
important as treatment in determining the outcome of the disease.Preventive
measures can be planned from the result of epidemiological studies that identify
specific risks.the success of early diagnosis relies upon finding tumours at a curable
stage before they have had a chance to spread from their site of origin.Thi is best
achieved by screening asymptomatic people,concentrating on those at greatest
risks,in the hope of detecting very early lesions.In many contries there are active
screening programmes for cervical and breast cancer.
Cervical intraepithelial neoplasia(CIN)can be detected by exfoliative cytology
of the cervix.Cells are scraped from the cervix,smeared on the glass
slides,stained,and then examined by a cytologist trained to detect
abnormalities.Breast cancer can be detected at an early stage by regular screening
by mammography(X-ray imaging og the breast).followed by diagnosis by fineneedle aspiration cytology or biopsy.
While these approaches work in theory in practice the benefit may be less
than anticipated.This is partl;y because some people are reluctant to be
screened;those that do volunteer may not be from the socio-economic groups most
at risks, particularly in the case of cancer of the cervix. furthermore, early detection
may not significantly affect the overall mortality from the screened cancer ,but
merely cause individual premature anxiety abiut a desease that would not have
become symptomatic for a few more years.Finally,it is not certain that all of the
early abnormalities detected by screening would have progressed to more serious
lesions within the otherwise natural lifetime of the individual concerned.
However,despite these doubt,screening for early cancers and precursor
lesions is likely to be a major area of progress in the next few decades.the
successful prevention and early detection of cancer are highly dependent on public
education targeted at those groups most at risks an on public education targeted at
those groups most at risk and on adequate financial investment.