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New page: {{review}} {{toplink |linkpage =General Pathology |linktext =General Pathology |maplink = General Pathology (Content Map) |pagetype =Pathology |sublink1=Disorders of Cell Growth - Patholo...
{{review}}
{{toplink
|linkpage =General Pathology
|linktext =General Pathology
|maplink = General Pathology (Content Map)
|pagetype =Pathology
|sublink1=Disorders of Cell Growth - Pathology
|subtext1=DISORDERS OF CELL GROWTH
}}
<br>
==Neoplasia==
* Neoplasia is a serious disturbance of growth of tissues.
** Results in malfunction of organ systems.
** Often culminates in death unless treated.
* Neoplasia is a multifactorial disease.
* Neoplasia in the veterinary species.
** The tumours that occur in the veterinary species are spontaneous, naturally-occurring states.
** Naturally-occurring neoplasia is most common in mature/ geriatric animals.
** Companion animals have the highest tumour occurrence, especially dogs and cats.
** There are some species differences in the incidence of some types of tumour.
*** FeLV-induced neoplasia in cats.
*** Testicular tumours in dogs.
*** Alimentary tumours in cattle and sheep.
==Classification==
* Neoplasms are classified so that one can:
** Deduce a prognosis
** Investigate the cause
*** Perhaps with a view to prevention
** Assess the results of treatment.
* It must be remembered that there are several types of proliferative change, and neoplasia must be distinguised from these.
** In addition to neoplasia, [[Disorders of Cell Growth - Pathology#Hyperplasia|hyperplasia]] and [[Disorders of Cell Growth - Pathology#Dysplasia|dysplasia]] are also proliferative changes.
* Inflammatory, repair and granuloma lesions may also masquerade as neoplasms.
** However, destructive or necrotic tumours may have inflammation present.
* Unlike inflammation, hyperplasia or dysplasia, neoplastic cells show uncontrolled proliferation in the absence of a triggering stimulus.
===Categories of Classifiaction===
* Tumours are classified by:
** '''Histogenesis'''
*** Identification of the cells/ tissue of origin.
** '''Anatomical origin'''
*** Site of anatomical growth.
** '''State of differentiation'''
*** Relative development or maturity of the cell type involved.
** '''Behaviour'''
*** Host-tumour growth patterns.
**** I.e. '''benign''' or '''malignant'''.
===Behaviour===
* The terms "benign" and "malignant" represent two ends of a spectrum of behaviour patterns in tumours.
* Certain features exhibited by the neoplastic cells allows tumours to be labelled as benign or malignant.
{| style="width:75%; height:200px" border="1"
!'''Feature'''
!'''Benign'''
!'''Malignant'''
|-
| '''Cell size'''
| Uniform
| Pleiomorphic
|-
| '''Nucleoli'''
| Normal
| Large; usually multiple
|-
| '''Chromatin, DNA'''
| Usually a normal amount
| Hyperchromatic; often polyploid
|-
| '''Mitoses'''
| Few
| Usually mulitple, including pathologic ones
|-
| '''Mitotic rate'''
| Slow
| Rapid
|-
| '''Nuclear:cytoplasmic ratio'''
| Rather low
| Rather high
|-
| '''Structure'''
| Well differentiated
| Imperfectly differentiated to anaplastic
|-
| '''Mode of growth'''
| Usually expansive and encapsulated
| Infiltrative as well as expansive. Not encapsulated
|-
| '''Rate of growth'''
| Usually slow
| May be rapid
|-
| '''Course of growth'''
| May come to a standstill or regress
| Rarely cease growing
|-
| '''Effect on host'''
| Not usually dangerous. There is no metastatis, but problems may arise to due tumour location or hormone production.
| Dangerous, because of destructive infiltrative growth. Prone to recurrence and metastasis.
|-
|}
* Some malignant tumours, such as adenocarcinoma, can provoke substantial fibrous tissue within and around them.
** This is thought to be an attempt at walling off the tumour.
*** Unsuccessful, since these tumours are capable of producing substances can break down the fibrous tissue.
* Malignant tumours can also provoke an intense inflammatory response through their damage to nearby tissue and their own internal necrosis.
==Nomenclature==
===Tumours of Epithelial Tissue===
* '''Sheet epithelium'''
** Benign = papilloma
*** A nipple-shaped projection
** Malignant = carcinoma
* '''Glandular epithelium'''
** Benign = adenoma
** Malignant = adenocarcinoma
===Tumours of Mesodermal (Connective) Tissue===
* E.g. fibrous tissue, bone, muscle, cartilage, lymphoid tissue.
* Benign - use the prefix of the tissue and the suffix "-oma" suffix.
** E.g. fibroma
* Malignant - use the prefix of the tissue and the suffix "-sarcoma".
** E.g. fibrosarcoma.
* Also state the region of origin.
===Others===
====Melanotic Tumours====
* These may be benign or malignant.
* Arise from melanin-producing cells in epithelial or mesodermal tissues.
====Embryonic Tumours====
* Arise from blast or embryonic cells with the potential to form more than one cell type.
* To namme, refer to the organ of origin and use the suffix "-blastoma".
** E.g. nephroblastoma, retinoblastoma.
====Mixed Tumours====
* Have more than one cell type.
* Contain neoplastic cells of more than one histogenic cell type.
* Known as teratomas.
==Causes of Neoplasia==
* The causes of neoplasia are complex.
* The risk of an animal developing a tumour is often related to a combination of events:
** Exposure to a carcinogen.
*** A carcinogen is any agent causing normal cells to become neoplastic.
** Environmental co-carcinogens;
** Predisposing host factors.
* In a few cases there is a known aetiological agent.
** For example, the Feline Leukaemia virus.
* In the majority of neoplasias the cause is unknown or only partially explained.
* There appear to be extrinsic and intrinsic causal factors involved.
===Extrinsic Causes===
* '''Physical agents'''
** UV light
** Ionising radiation
* '''Tumour viruses'''
** DNA viruses
** RNA viruses
* '''Chemical carcinogens'''
** Aromatic hydrocarbons
** Nitrosamines
** Benzidines
** Mycotoxins
===Intrinsic Causes===
====Diet====
* Unlikely to be a direct effect.
* Excess fat may be important.
* Components may act to initiate cell changes or modulate organ susceptibility.
** Examples:
*** Bracken in ox and sheep.
*** Aflatoxin in pigs/mice.
====Hormones====
* Neoplasia can result from prolonged hormonal stimulation of a tissue.
** For example, the mammary gland, uterus and testes.
====Genetic====
* Genetic susceptibility and hereditary predisposition is well- recognised for certain types of tumour.
** For example:
*** Chemoreceptor tumours in brachycephalic dogs (e.g. boxers and bulldogs).
*** Squamous cell carcinoma in the skin of white cats.
*** Melanotic tumours in black dogs (e.g. Scottish Terriers) and Arabian horses.
** Lymphoma clusters in dogs, pigs and cattle.
====Age====
* Most neoplasia occurs in older animals.
** There are important exceptions, notably the embryonic tumours.
* The effect of age is related to factors such as:
** Duration of exposure to a carcinogen.
** Changes in the tissues, promoting abnormal cells to grow.
*** Less efficient apoptosis.
*** Increased mitotic errors.
** Chromosomal deletions.
===Other factors===
====Host-dependent Factors====
* '''Species'''
** Companion animals are kept for longer than production species and so are more likely to develop neoplasia in their lifetime.
* '''Breed'''
** There are breed susceptibilities to some tumours.
*** This is probably related to genetic and familial factors.
* '''Sex'''
** The effect of castration/ spaying is important.
====Environmental Factors====
* Environmental factors contribute to the cause of neoplasia, but are rather difficult to assess.
* '''Climatic/ geographical'''
** The type of habitation.
* '''Diet and general nutritional plane'''.
** Any dietary imbalance may result in a high level of carcinogen.
** Poorly nourished groups tend to develop more neoplasms.
*** May be related to apoptosis and chromosomal aberrations.
* '''Management systems'''
** Especially reproductive and lactational patterns.
*** Stress-related regimes may be a contributory factor.
==Tumour Assessment==
* When assessing a tumour, it is best to assess the whole tumour (in situ or excised) wherever possible.
* Parameters for assessment are listed below.
===Macroscopic===
* '''Size'''
** Large tumours are not necessarily aggressive or malignant.
** Rate and duration of growth are probably more important.
* '''Shape '''
** Shape may depend on the site of the tumour and the constraints placed on it by the surrounding tissue.
** Within the category of shape, the following must be considered.
*** The mode of growth of the tumour, i.e. by expansion or infiltration.
*** If the tumour is diffuse or solitary.
*** Superficial tumours may be plaque, nodular or pedunculate.
*** Tumours in spherical or tubular organisms may be papillary, stenosing or infiltrating.
* '''Consistency'''
** Relative cellular and stromal content.
** Tumours containing many less-differentiaed/anaplastic cells are more friable, as these cells are more fragile.
** The presence of necrosis reflects the speed of growth or outgrowth of the blood supply.
** Benign, slow-growing tumours may calcify.
*** Others may exhibit metaplasia with cartilage or bone formation.
* '''Colour'''
** Colour gives a reflection of vascularity and necrosis.
** Pigment may be present in e.g. melanomas and adrenal tissues.
===Microscopic===
* '''General architecture'''
** Consider:
*** The degree of organisation.
*** The relative content of cells and stroma.
*** The degree of encapsulation or infiltration.
*** The nature of the cell content - well or poorly differentiated.
*** Mimicry of the normal tissue or a bizarre formation.
* '''Cytology'''
** Cytology helps elucidate:
*** The Degree of cellular/ stromal abnormality.
*** Cell morphology (nuclear and cytoplasmic).
*** The mitotic index.
* '''Blood/ lymphatic/ nerve supplies'''
** Look for:
*** Pressure on vascular or lymphatic drainage or supply
*** Infiltration of vessels by tumour cells
*** Infiltration of nerves
==Phases of Tumour Development==
* The development of a tumour is a complex phenomenon, and can be unpredictable.
** However, there are three phases that are recognised in many tumours.
*** '''Mutation'''
*** '''Promotion'''
*** '''Irreversible tumour growth'''
===Mutation===
* The mutation stage refers to the damage of nuclear DNA.
** Results in a stable heritable mutation.
* The mutation is not always expressed.
** It may be said to be "latent".
===Promotion===
* Promotion can be brought about by a variety of factors; certain:
** Irritants
** Drugs
** Viruses
** Hormones.
* Factors promote the replication of mutated cells.
** The mutated part of the genome is expressed, causing the mutated cells to become cancerous.
* The cell is clearly abnormal.
* In the promotion stage, abnormal cells are present in small numbers.
** Can be eliminated by the immune system.
*** I.e. it is a '''reversible stage'''.
===Irreversible Tumour Growth===
* Intrinsic factors in the cell genoma can contribute to malignant transfomation.
* In particular, oncogenes ( genes involved in regulation of cell replication ) can become altered .
** Produce gene products that lead to abnormal cell replication, resulting in the tumour.
==Growth of Tumours==
* There are several features and factors associated with growth of primary tumours:
** '''Mode of growth'''
** '''Rate of growth'''
** '''Degree of differentiation'''
** '''Vascularity'''
===Mode of Growth===
* Benign tumours
** Remain localised
** Grow by expansion into available space or by compression of tissues.
*** Cause adverse effects if near vital structures.
* Malignant tumours
** Do not remain localised
** Local growth is by infiltration and super-population of adjacent tissues.
** Invasion causes destruction of local normal tissue.
===Rate of Growth===
* Rate of growth is based on:
** Proportion of cells in cell cycle in comparison to those that have differentiated and entered G<sub>0</sub>.
** Death rate of cells in the tumour.
*** Where proliferation exceeds cell death then the primary tumour increases rapidly in size.
*** A high rate of apoptosis is often seen in tumours.
*** This is often independent of tumour blood supply.
** Adequacy of supply of oxygen and nutrients to tumour cells.
*** This often depends on the neoplastic cells inducing a supporting stroma, containing capillaries, in and around the tumour.
* Doubling time of tumours is an important measure.
** 30 doubling cycles can yield 109 cells i.e. 1g of tissue.
===Degree of Differentiation===
* Benign tumours are usually well-differentiated; malignant ones are not.
* Degree of differentiation is inversely proportional to growth.
* Well-differentiated tumours induce adequate supporting stroma which supports tumour cell growth.
* Malignant tumours often outgrow stromal development and consequently necrose.
===Vascularity===
* Secretion of angiogenesis factors allow tumours to develop a vascular stromal support.
** These angiogenesis factors are often growth factors.
*** E.g. fibroblast growth factor (FGF).
* Failure to maintain adequate oxygen and nutrient supply results in either
** Necrosis, or
** Slower degeneration with dystrophic calcification.
==Dissemination of Malignant Neoplasia==
* A key feature of malignant tumours is their propensity to spread from the primary site to other locations.
** When this involves spread of the tumour to distant sites, the process is known as '''metastasis'''.
===Methods of Spread===
* Carcinomas disseminate initially via lymphatics and then later via bloodstream.
* Sarcomas tend to spread via the blood.
====Invasion/ Infiltration====
* This is local spread through fascial planes, around nerves and into adjacent tissues/organs.
* Invasion involves a combination of:
** Pressure
** Cell motility
*** Loss of contact inhibition and adhesiveness.
** Release of enzymes
*** E.g. collagenase, hyaluronidase.
====Lymphatic Spread====
* Tumour cells permeate lymph vessels.
** Proceed to spread to local or regional lymph nodes.
*** Grow here as secondary tumours.
====Vascular Spread====
* Tumour cells permeate drainage veins.
** Consequently spread to vascular organs.
*** E.g the lungs, [[Liver - Anatomy & Physiology|liver]] , [[Spleen - Anatomy & Physiology|spleen]], kidney and brain.
*** Form secondary tumours in these organs.
* Neoplastic [[Thrombosis - Pathology#Thromboembolism|thromboembolism]] is often involved.
====Transcoelomic Spread====
* Transcoelomic spread describes the "seeding" or shedding of cells directly into peritoneal or pleural cavities.
** Cells then migrate onto the surface of adjacent organs.
* Alternatively, this can occur via lymphatic vessel involvement with blockage and rupture.
===The Process of Metastasis===
* In order to spread from the primary mass, malignant cells have to "escape" from the primary environment and penetrate either the lymphatics or blood vessels.
* The trigger for developing migratory activities is unknown but several features are important:
*# '''Cells must become mobile'''
*#* This is probably enabled by the secretion of proteases and blocking antiprotease secretions from stromal cells.
*# '''Cells must adhere to the basement membrane'''
*#* Mediated by the expression of adhesion molecules (integrins).
*# '''Cells must destroy the basement membrane'''
*#* Occurs by secretion of proteases which lyse the type IV collagen.
* Cell movement into the vessel is the result of secretion of motility factors by the cells themselves.
* In blood vessel involvement, the breaching of the basement membrane predisposes to thrombosis.
** Further tumour cell dissemination is probably via embolism.
* The determining factors for where the tumour cells leave the vessels are unknown.
** Complementary cell adhesion molecules are probably involved, together with growth factor secretion.
** Where emboli are formed, mechanical blockage in capillary beds is important.
*** Reversed diapedesis ensues.
===Secondary deposits===
* A variety of fates awaits secondary deposits.
** Some secondary deposits are abortive.
** Some remain dormant.
** Some establish and grow.
** The reasons are not known.
*** There is probably involvement of growth factors and angiogenesis factors.
**** E.g. EGF, FGF, TGF.
* Tissues vary in their abilities to "grow" secondary deposits.
** Good "soils" :
*** [[Lymph Nodes - Anatomy & Physiology|Lymph nodes]]
*** [[Liver - Anatomy & Physiology|Liver]]
*** [[Bone Marrow - Anatomy & Physiology|Bone marrow]]
*** Adrenal medulla.
** Intermediate "soils":
*** Kidney
*** Lung
** Poor "soils":
*** Muscle
*** [[Spleen - Anatomy & Physiology|Spleen]]
*** Gut
===Examples in the Domestic Species===
* '''Mammary carcinoma'''
** Favours both lymphatic and vascular spead.
** Spreads commonly to the lung, [[Liver - Anatomy & Physiology|liver]], kidney, and adrenal glands.
** Spreads rarely to the brain and bone.
* '''Thyroid carcinoma'''
** Spead is primarily vascular.
** Commonly spreads to the lung, [[Liver - Anatomy & Physiology|liver]] and kidney.
* '''Pancreatic carcinoma'''
** Metasises by transcoelomic spread.
** Commonly spreads to the [[Liver - Anatomy & Physiology|liver]], spleen and peritoneum.
* '''Salivary gland carcinoma'''
** Spread via the lymphatics.
** Commonly spreads to the peripheral and deep lymph nodes, [[Liver - Anatomy & Physiology|liver]] and lungs.
* '''Osteosarcoma'''
** Spread is vascular and lymphatic.
** Commonly spreads to the regional lymph nodes, lungs and [[Liver - Anatomy & Physiology|liver]].
* '''Haemangiosarcoma'''
** Metastasis is vascular.
** Commonly spreads to the lungs, [[Liver - Anatomy & Physiology|liver]], kidneys and muscle.
* '''Lymphoid and melanotic tumours'''
** Are multicentric rather than metastatic.
==Tumour Grading and Staging==
===Grading===
* Tumour grading indicates the degree of differentiation and the growth pattern of the tumour.
* Grading depends on cellular morphology.
===Staging===
* Tumour staging indicates how far the tumour has spread.
* The '''TNM system''' is may be used.
** This is based on :
*** '''T''': Local '''tumour''' spread.
**** I.e. the size and fixation of the tumour.
*** '''N''': Regional lymph '''node''' involvement.
*** '''M''': Presence of distant '''metastases'''.
==Pathological Effects==
* The development of a tumour may cause a whole range of of pathological effects.
* For example:
** Tumours may put pressure on vital organs.
** Thromboses and infarction may result.
** Bones involved in neoplasia (either directly or indirectly) may be prone to pathological fractures.
** Ulcerated or necrotic tumours may become infected.
** Where tumours are large, there may be much necrotis tissue, which can ave a toxic effect.
** Secondary haemorrhagic syndromes and depression of bone marrow function may occur.
*** Result in with anaemia and [[Thrombosis - Pathology#Disseminated Intravascular Coagulation|disseminated intravascular coagulation]].
===Death===
* Death from malignancy is usually due to :
** Obliteration of a vital organ by primary or secondary tumours.
** Cachexia and nutritional failure because of multiple metastasis plus secondary infections.
===Para-Neoplastic Syndromes===
* Para-neoplastic syndromes are complications which are not directly due to the effects of malignancy.
*These syndromes can be related to:
*# [[Neoplasia - Pathology#Ectopic Hormone Production|Ectopic hormone secretion]].
*#* E.g. parahormone-like secretion in lung squamous cell carcinoma results in hypercalcaemia.
*# Neurological syndromes.
*#* E.g. neuropathies, cerebellar degeneration, encaphalitis.
*# Bone marrow malfunction.
*#* E.g. [[Haemorrhage - Pathology#Purpura|purpuric disease]], anaemia, [[Thrombosis - Pathology#Disseminated Intravascular Coagulation|disseminated intravascular coagulation]].
===Endocrine Aspects===
* Some tumours may secrete abnormal amounts of hormones.
** These tumours need not necessarily be of endocrine origin.
*** Where the tumour is not of endocrine origin this is referred to as ectopic production.
====Endocrine Tumours====
* Tumours of the adrenal cortex.
** May be benign or malignant (i.e. adenoma, carcinoma).
** Can result in excess cortisol production, causing Cushing's syndrome.
* tumours of the adrenal medulla.
** Phaeochromocytoma.
** Can result in excess adrenaline production, leading to hypertension.
*** Seen mainly in dogs but can also occur in cats and horses.
* Pancreatic islet cell tumours.
** Adenoma.
** Can result in excess insulin prodction, leading to hypglycaemia.
*** Seen mainly in dogs.
====Ectopic Hormone Production====
* E.g. in the lung,
** Squamous cell carcinoma.
*** Can produce parathyroid hormone, leading to hypercalcaemia.
** Oat cell carcinoma
** Can produce adrenocorticotropic hormone(ACTH), leading to Cushing's syndrome.
==Tumour Markers==
* Some tumours secrete products than can be detected in serum.
** For example, foetal proteins.
* These can be used to monitor the effects of therapy in man.
* For example:
** Alpha fetoprotein (AFP).
*** Secreted in hepatocellular carcinoma.
** Acid phosphatase.
*** Secreted in prostatic carcinoma.
** Carcinoembryonic antigen (CEA).
*** Secreted in colonic and gastric cancer, and lung carcinoma.
==Tumour Immunity==
* Immune responses to tumours are generally weak.
** They do not appear to contribute to the response to an established tumour.
* There is little support for they idea that immune surveillance is important in the prevention and regulation of tumout growth, except when there is a viral aetiology.
===Tumour Specific Transplantation Antigens (TSTAs)===
* When tumours are antigenic, they often express cell surface markers - TSTAs.
** Thses markers are recognised as foreign, inducing
*** T-cell-mediated cytotoxicity
*** Antibody plus complement-mediated killing.
* These are more common in virally-induced tumour.
** The viral proteins probably ellicit the response.
** E.g. FeLV, papillomas.
===Tumour-Associated Antigens===
* Tumour-associated antigens may be present on some normal cells as well as tumour cells.
* Many are differentiation markers in unusual sites or amounts .
** E.g. foetal antigens, stem cell markers.
===Tumour cell killing===
* NK cells, LAK (lymphokine-activated killer) cells and activated macrophages seem to be important.
* Tumour necrosis factors (TNF α and β) are produced by macrophages and bind to tumour cell membranes.
** Produce a cytostatic effect, allowing cytotoxic cell killing to take place.
* Interleukins promote cytotoxic tumour killing.
** Particularly lL-1 and lL-4.
* Interferons may be helpful in inhibiting tumour cells.
** IFN α is tumouricidal.
* Transforming growth factors may be important in tumour growth and spread.
** TGF α
*** Related to EGF.
*** May act as a growth and angiogenesis factor.
** TGF β
*** May control the breakdown of basement membranes by tumour cells and hence play a role in metastatic potential.
==Examples of Tumour Types==
* Tumours are often classified on architectural grounds into solid and non-solid types.
** "Non-solid" encompasses haematopoietic and related types.
===Solid Tumours===
* Many solid tumour types are well-recognised but their aetiology and behaviour in animals is often poorly understood.
* The following are good veterinary examples:
** Mammary tumours in dogs and cats.
** Adenocarcinoma in the [[Small Intestine - Anatomy & Physiology|small intestine]] of the sheep.
** Pulmonary adenomatosis in the sheep.
====Mammary Tumours in Dogs and Cats====
* Next to skin neoplasia, mammary tumours are the most common tumours in dogs and cats.
=====Dogs=====
* Affects bitches over 5 years of age.
** Entire females with a predisposition to pseudopregnancy are at particular risk.
** Rarer in spayed bitches.
* Often, more than one gland is involved.
* 50-60% of these tumours are benign.
* Many tumours are "mixed".
** I.e. there is epthelial neoplasia with cartilage or bone,
* Mammary caricnomas vary in their malignancy.
** May spead to the lymph nodes, lungs or elsewhere.
** Some of these tumours are hormone-dependent.
=====Cats=====
* Uncommon in cats in the U.K.
** This may be the effect of early spaying.
* 90% of tumours are aggressive carcinomas.
* Cause is currently unknown. L
** ikely to be multifactorial with major hormonal and genetic influences.
====Adenocarcinoma in the Small Intestine of the Sheep====
* Fairly common in Scotland.
** Also recorded in Iceland, Norway, New Zealand and Australia.
* Affects mature sheep up to 6 years of age.
* Animals are cachectic and show [[Oedema - Pathology#Introduction|ascites]].
* Tumours are ususally found in the [[Small Intestine - Anatomy & Physiology|small intestine]].
** Are annular, causing stenosis.
*** There is proximal dilation.
* Tumours thicken the gut.
* Spread as small plaques/ nodules the on bowel serosa, and to the mesenteric lymph nodes.
* Peritoneal fibrous plaques with small nests of carcinoma cells often from.
* The cause is unknown.
** There may be an association with bracken fern grazing.
====Pulmonary Adenomatosis in the Sheep====
* Can affect sheep from 6 months to 6 years of age.
* Affected sheep may not show signs for up to 2 years.
** Signs include respiratory distress and fluid production via nose if the sheep is elevated.
* Lesions may be
** Discrete nodules, or
** Extensive solid grey consolidation of the dependant parts of all lobes, often on both sides.
*** More common.
* Lungs are heavy with frothy fluid.
* The main cell type affected are the alveolar (type 2) cells.
** Form adenomatous or papillary growths.
** The bronchiolar Clara are also affected.
* The neoplasia is transmissible.
** Caused by a retrovirus, possibly in association with a herpes virus.
===Haematopoietic Tumours===
* Any cell of the haematopoietic and related tissues can undergo neoplastic transformation.
** The transformed cell produces a tumour having a distribution pattern and growth rate characteristic of the normal counterpart.
* The nomenclature is confusing because of the heterogeneity of the cell populations which have the potential to be involved.
** E.g.
*** Leukaemia is malignant transformation of cells derived from haematopoietic tissues in the blood.
*** Myeloma is malignant transformation of an antibody secreting plasma cell normally found in organised lymphoid tissue and bone marrow.
====Acute Undifferentiated Leukaemia====
* Rare in animals.
* Composed of immature cells.
* Malignancy affects the stem cell phenotype.
** Primary lymphoid organs and other organs with lymphohaematopoietic function are predominantly involved rather than lymph nodes.
*** I.e. bone marrow, spleen, [[Liver - Anatomy & Physiology|liver]].
====Lymphoid Neoplasms====
* '''Lymphoma''', '''malignant lymphoma''' and '''lymphosarcoma''' are different terms for the same condition.
===== Classification=====
* '''Cytological classification'''.
** Well differentiaed (lymphocytic)
*** The malignant cells represent normal lymphocytes, although in excessive numbers.
** Poorly differentiated (lymphoblastic).
*** The malignant cells represent atypical lymphocytic cells with lymphoblastic characteristics.
* '''Tumour distribution'''
** Nodular/ follicular.
*** A well organised pattern of slow growth.
*** No metastasis.
*** Are of the B-lymphocyte type.
** Diffuse.
*** Result in effacement of normal lymphoid architecture by a very homogeneous population of lymphoid cells.
* '''Anatomical classification'''
** Thymic.
** Only the [[Thymus - Anatomy & Physiology|thymus]].
** Alimentary.
*** Gut and associated lymphoid tissue.
** Multicentric.
*** Widespread involvement of lymph nodes.
** Cutaneous lymphoma.
*** Usually presents as generalised skin disease, but is a malignant transformation of T cells with a propensity for pithelial sites
* '''Type of lymphocyte'''
** T-cell.
** B-cell.
** NK-cell.
* '''Time scale'''
** Acute.
** Chronic.
=====Prevalence=====
* Order of prevalence in UK: cats, dogs, cattle, pigs and sheep.
** In the cat and ox, viral agents have been identified as the causal agents.
* Lymphoma is one of the prevalent neoplasms in the dog.
** 80% of cases affect the 5 to 11 year old age group.
** The incidence is about 28 per 100,000 dogs.
** Blood of affected dogs shows neither a relative nor absolute increase in the number of lymphocytes until the late stages of the disease.
*** When this stage is reached, poorly differentiated cells may appear in the blood.
* FeLV is an important cause of lymphoma in the cat.
** 70% of cats with lymphoma will test positive for FeLV.
** FeLV also causes a number of non-neoplastic diseases.
*** Anaemia.
*** Leukopaenia.
*** Thymic atrophy.
* Cattle suffer both lymphosarcoma and leukosis in a variety of cytological forms.
** Bovine lymphoma is caused by Bovine Leukaemia Virus (BLV).
*** A retrovirus.
*** There is a juvenile form of bovine lymphoma seen in young cattle which is not associated with BLV.
=====Species Differences=====
* The form of the disease may differe between species.
* '''Feline'''
** Alimentary.
*** Affects the mesenteric lymph nodes, intestine, [[Liver - Anatomy & Physiology|liver]], spleen , and potentially the kidney.
** Thymic
*** Presents as a thymis mass, also in the mediastinal lymph nodes.
*** The pleural lymph nodes and the [[Liver - Anatomy & Physiology|liver]] may potentially be affected.
** Multicentric
*** Found in the peripheral and deep lymph nodes, [[Liver - Anatomy & Physiology|liver]] and spleen.
**** The kidney may sometimes be affected.
** Renal
*** The kidney and other abdominal organs are affected.
** Leukaemic
*** Affects the bone marrow alone.
*** This form is rare.
* '''Canine'''
** Alimentary.
*** Affects the mesenteric lymph nodes, pancreatic lymph nodes, intestine, and potentially the [[Liver - Anatomy & Physiology|liver]].
** Thymic.
*** Thymic and mediastinal masses.
** Multicentric.
*** Affects the peripheral and deep lymph nodes, [[Liver - Anatomy & Physiology|liver]], spleen and kidney.
* '''Bovine'''
** Thymic.
*** Mainly affects adults.
*** Thymic and mediastinal masses.
*** Some lymph nodes are also affected.
** Multicentric.
*** Mainly affects yopung adults.
*** Affects the peripheral and deep lymph nodes, spleen, [[Liver - Anatomy & Physiology|liver]] and kidney.
* '''Equine'''
** Takes mainly an alimentary form.
** Can rarely be cutaneous.
* '''Porcine'''
** Mainly multicentric.
*** Lymph nodes, [[Liver - Anatomy & Physiology|liver]], spleen.
* '''Ovine'''
** Uncommon.
** May be multicentric or thymic.
====Lymphocytic Leukaemia====
* A leukaemic manifestation arises when neoplastic cells retain the migratory patterns of their counterparts, when these are bone marrow, T- or B- cells.
* Lymphoid tissue may or may not be involved.
** This depends on the biological properties of the lymphocyte undergoing neoplastic transformation.
*** Lymphoid tissue is invplved when the cell has the capacity to recirculate and enter this.
* '''Acute lymphocytic leukaemia'''.
** Predominantly a T-cell tumour in man and dog.
* '''Chronic lymphocytic leukaemia'''.
** A B-cell tumour in dog and man.
* '''Plasma cell tumours'''.
** Also known as multiple myeloma or plasmacytoma.
** Rare in domestic animals.
*** When is does arrive, it is associated with abnormally high levels of immunoglobulins.
====Myeloproliferative Disorders====
* Myeloproliferative disorders are characterised by the malignant proliferation of one, several or all of the non-lymphoid bone marrow cells.
** I.e. the granulocytic, monocytic, erythromytic and megakaryocytic cells.
* May be acute or chronic.
* May gove rise to granulocytic or monocytic leukaemias.
====Mast Cell Proliferation Disorders====
* '''Cutaneous mastocytoma'''.
** Common in certain breeds of dogs, e.g. Boxers.
** Occur rarely in the cat and ox.
* '''Cutaneous mast cell sarcomas'''.
** Rapid growth with spread to drainage lymph nodes and involvement of other organs.
* '''Generalised mast cell sarcoma'''.
** Widespread lesions.
====Histiocytomas====
* Common in young dogs.
* Usually present as solitary cutaneous nodules.
** Do not metastasise.
** May regress spontaneously.
====Vasoformative Neoplasms====
* Include haemangioma of the spleen.
** Gives rise to extensive endothelial lined vascular channels.
** Haemorrhage and necrosis are common.
{{toplink
|linkpage =General Pathology
|linktext =General Pathology
|maplink = General Pathology (Content Map)
|pagetype =Pathology
|sublink1=Disorders of Cell Growth - Pathology
|subtext1=DISORDERS OF CELL GROWTH
}}
<br>
==Neoplasia==
* Neoplasia is a serious disturbance of growth of tissues.
** Results in malfunction of organ systems.
** Often culminates in death unless treated.
* Neoplasia is a multifactorial disease.
* Neoplasia in the veterinary species.
** The tumours that occur in the veterinary species are spontaneous, naturally-occurring states.
** Naturally-occurring neoplasia is most common in mature/ geriatric animals.
** Companion animals have the highest tumour occurrence, especially dogs and cats.
** There are some species differences in the incidence of some types of tumour.
*** FeLV-induced neoplasia in cats.
*** Testicular tumours in dogs.
*** Alimentary tumours in cattle and sheep.
==Classification==
* Neoplasms are classified so that one can:
** Deduce a prognosis
** Investigate the cause
*** Perhaps with a view to prevention
** Assess the results of treatment.
* It must be remembered that there are several types of proliferative change, and neoplasia must be distinguised from these.
** In addition to neoplasia, [[Disorders of Cell Growth - Pathology#Hyperplasia|hyperplasia]] and [[Disorders of Cell Growth - Pathology#Dysplasia|dysplasia]] are also proliferative changes.
* Inflammatory, repair and granuloma lesions may also masquerade as neoplasms.
** However, destructive or necrotic tumours may have inflammation present.
* Unlike inflammation, hyperplasia or dysplasia, neoplastic cells show uncontrolled proliferation in the absence of a triggering stimulus.
===Categories of Classifiaction===
* Tumours are classified by:
** '''Histogenesis'''
*** Identification of the cells/ tissue of origin.
** '''Anatomical origin'''
*** Site of anatomical growth.
** '''State of differentiation'''
*** Relative development or maturity of the cell type involved.
** '''Behaviour'''
*** Host-tumour growth patterns.
**** I.e. '''benign''' or '''malignant'''.
===Behaviour===
* The terms "benign" and "malignant" represent two ends of a spectrum of behaviour patterns in tumours.
* Certain features exhibited by the neoplastic cells allows tumours to be labelled as benign or malignant.
{| style="width:75%; height:200px" border="1"
!'''Feature'''
!'''Benign'''
!'''Malignant'''
|-
| '''Cell size'''
| Uniform
| Pleiomorphic
|-
| '''Nucleoli'''
| Normal
| Large; usually multiple
|-
| '''Chromatin, DNA'''
| Usually a normal amount
| Hyperchromatic; often polyploid
|-
| '''Mitoses'''
| Few
| Usually mulitple, including pathologic ones
|-
| '''Mitotic rate'''
| Slow
| Rapid
|-
| '''Nuclear:cytoplasmic ratio'''
| Rather low
| Rather high
|-
| '''Structure'''
| Well differentiated
| Imperfectly differentiated to anaplastic
|-
| '''Mode of growth'''
| Usually expansive and encapsulated
| Infiltrative as well as expansive. Not encapsulated
|-
| '''Rate of growth'''
| Usually slow
| May be rapid
|-
| '''Course of growth'''
| May come to a standstill or regress
| Rarely cease growing
|-
| '''Effect on host'''
| Not usually dangerous. There is no metastatis, but problems may arise to due tumour location or hormone production.
| Dangerous, because of destructive infiltrative growth. Prone to recurrence and metastasis.
|-
|}
* Some malignant tumours, such as adenocarcinoma, can provoke substantial fibrous tissue within and around them.
** This is thought to be an attempt at walling off the tumour.
*** Unsuccessful, since these tumours are capable of producing substances can break down the fibrous tissue.
* Malignant tumours can also provoke an intense inflammatory response through their damage to nearby tissue and their own internal necrosis.
==Nomenclature==
===Tumours of Epithelial Tissue===
* '''Sheet epithelium'''
** Benign = papilloma
*** A nipple-shaped projection
** Malignant = carcinoma
* '''Glandular epithelium'''
** Benign = adenoma
** Malignant = adenocarcinoma
===Tumours of Mesodermal (Connective) Tissue===
* E.g. fibrous tissue, bone, muscle, cartilage, lymphoid tissue.
* Benign - use the prefix of the tissue and the suffix "-oma" suffix.
** E.g. fibroma
* Malignant - use the prefix of the tissue and the suffix "-sarcoma".
** E.g. fibrosarcoma.
* Also state the region of origin.
===Others===
====Melanotic Tumours====
* These may be benign or malignant.
* Arise from melanin-producing cells in epithelial or mesodermal tissues.
====Embryonic Tumours====
* Arise from blast or embryonic cells with the potential to form more than one cell type.
* To namme, refer to the organ of origin and use the suffix "-blastoma".
** E.g. nephroblastoma, retinoblastoma.
====Mixed Tumours====
* Have more than one cell type.
* Contain neoplastic cells of more than one histogenic cell type.
* Known as teratomas.
==Causes of Neoplasia==
* The causes of neoplasia are complex.
* The risk of an animal developing a tumour is often related to a combination of events:
** Exposure to a carcinogen.
*** A carcinogen is any agent causing normal cells to become neoplastic.
** Environmental co-carcinogens;
** Predisposing host factors.
* In a few cases there is a known aetiological agent.
** For example, the Feline Leukaemia virus.
* In the majority of neoplasias the cause is unknown or only partially explained.
* There appear to be extrinsic and intrinsic causal factors involved.
===Extrinsic Causes===
* '''Physical agents'''
** UV light
** Ionising radiation
* '''Tumour viruses'''
** DNA viruses
** RNA viruses
* '''Chemical carcinogens'''
** Aromatic hydrocarbons
** Nitrosamines
** Benzidines
** Mycotoxins
===Intrinsic Causes===
====Diet====
* Unlikely to be a direct effect.
* Excess fat may be important.
* Components may act to initiate cell changes or modulate organ susceptibility.
** Examples:
*** Bracken in ox and sheep.
*** Aflatoxin in pigs/mice.
====Hormones====
* Neoplasia can result from prolonged hormonal stimulation of a tissue.
** For example, the mammary gland, uterus and testes.
====Genetic====
* Genetic susceptibility and hereditary predisposition is well- recognised for certain types of tumour.
** For example:
*** Chemoreceptor tumours in brachycephalic dogs (e.g. boxers and bulldogs).
*** Squamous cell carcinoma in the skin of white cats.
*** Melanotic tumours in black dogs (e.g. Scottish Terriers) and Arabian horses.
** Lymphoma clusters in dogs, pigs and cattle.
====Age====
* Most neoplasia occurs in older animals.
** There are important exceptions, notably the embryonic tumours.
* The effect of age is related to factors such as:
** Duration of exposure to a carcinogen.
** Changes in the tissues, promoting abnormal cells to grow.
*** Less efficient apoptosis.
*** Increased mitotic errors.
** Chromosomal deletions.
===Other factors===
====Host-dependent Factors====
* '''Species'''
** Companion animals are kept for longer than production species and so are more likely to develop neoplasia in their lifetime.
* '''Breed'''
** There are breed susceptibilities to some tumours.
*** This is probably related to genetic and familial factors.
* '''Sex'''
** The effect of castration/ spaying is important.
====Environmental Factors====
* Environmental factors contribute to the cause of neoplasia, but are rather difficult to assess.
* '''Climatic/ geographical'''
** The type of habitation.
* '''Diet and general nutritional plane'''.
** Any dietary imbalance may result in a high level of carcinogen.
** Poorly nourished groups tend to develop more neoplasms.
*** May be related to apoptosis and chromosomal aberrations.
* '''Management systems'''
** Especially reproductive and lactational patterns.
*** Stress-related regimes may be a contributory factor.
==Tumour Assessment==
* When assessing a tumour, it is best to assess the whole tumour (in situ or excised) wherever possible.
* Parameters for assessment are listed below.
===Macroscopic===
* '''Size'''
** Large tumours are not necessarily aggressive or malignant.
** Rate and duration of growth are probably more important.
* '''Shape '''
** Shape may depend on the site of the tumour and the constraints placed on it by the surrounding tissue.
** Within the category of shape, the following must be considered.
*** The mode of growth of the tumour, i.e. by expansion or infiltration.
*** If the tumour is diffuse or solitary.
*** Superficial tumours may be plaque, nodular or pedunculate.
*** Tumours in spherical or tubular organisms may be papillary, stenosing or infiltrating.
* '''Consistency'''
** Relative cellular and stromal content.
** Tumours containing many less-differentiaed/anaplastic cells are more friable, as these cells are more fragile.
** The presence of necrosis reflects the speed of growth or outgrowth of the blood supply.
** Benign, slow-growing tumours may calcify.
*** Others may exhibit metaplasia with cartilage or bone formation.
* '''Colour'''
** Colour gives a reflection of vascularity and necrosis.
** Pigment may be present in e.g. melanomas and adrenal tissues.
===Microscopic===
* '''General architecture'''
** Consider:
*** The degree of organisation.
*** The relative content of cells and stroma.
*** The degree of encapsulation or infiltration.
*** The nature of the cell content - well or poorly differentiated.
*** Mimicry of the normal tissue or a bizarre formation.
* '''Cytology'''
** Cytology helps elucidate:
*** The Degree of cellular/ stromal abnormality.
*** Cell morphology (nuclear and cytoplasmic).
*** The mitotic index.
* '''Blood/ lymphatic/ nerve supplies'''
** Look for:
*** Pressure on vascular or lymphatic drainage or supply
*** Infiltration of vessels by tumour cells
*** Infiltration of nerves
==Phases of Tumour Development==
* The development of a tumour is a complex phenomenon, and can be unpredictable.
** However, there are three phases that are recognised in many tumours.
*** '''Mutation'''
*** '''Promotion'''
*** '''Irreversible tumour growth'''
===Mutation===
* The mutation stage refers to the damage of nuclear DNA.
** Results in a stable heritable mutation.
* The mutation is not always expressed.
** It may be said to be "latent".
===Promotion===
* Promotion can be brought about by a variety of factors; certain:
** Irritants
** Drugs
** Viruses
** Hormones.
* Factors promote the replication of mutated cells.
** The mutated part of the genome is expressed, causing the mutated cells to become cancerous.
* The cell is clearly abnormal.
* In the promotion stage, abnormal cells are present in small numbers.
** Can be eliminated by the immune system.
*** I.e. it is a '''reversible stage'''.
===Irreversible Tumour Growth===
* Intrinsic factors in the cell genoma can contribute to malignant transfomation.
* In particular, oncogenes ( genes involved in regulation of cell replication ) can become altered .
** Produce gene products that lead to abnormal cell replication, resulting in the tumour.
==Growth of Tumours==
* There are several features and factors associated with growth of primary tumours:
** '''Mode of growth'''
** '''Rate of growth'''
** '''Degree of differentiation'''
** '''Vascularity'''
===Mode of Growth===
* Benign tumours
** Remain localised
** Grow by expansion into available space or by compression of tissues.
*** Cause adverse effects if near vital structures.
* Malignant tumours
** Do not remain localised
** Local growth is by infiltration and super-population of adjacent tissues.
** Invasion causes destruction of local normal tissue.
===Rate of Growth===
* Rate of growth is based on:
** Proportion of cells in cell cycle in comparison to those that have differentiated and entered G<sub>0</sub>.
** Death rate of cells in the tumour.
*** Where proliferation exceeds cell death then the primary tumour increases rapidly in size.
*** A high rate of apoptosis is often seen in tumours.
*** This is often independent of tumour blood supply.
** Adequacy of supply of oxygen and nutrients to tumour cells.
*** This often depends on the neoplastic cells inducing a supporting stroma, containing capillaries, in and around the tumour.
* Doubling time of tumours is an important measure.
** 30 doubling cycles can yield 109 cells i.e. 1g of tissue.
===Degree of Differentiation===
* Benign tumours are usually well-differentiated; malignant ones are not.
* Degree of differentiation is inversely proportional to growth.
* Well-differentiated tumours induce adequate supporting stroma which supports tumour cell growth.
* Malignant tumours often outgrow stromal development and consequently necrose.
===Vascularity===
* Secretion of angiogenesis factors allow tumours to develop a vascular stromal support.
** These angiogenesis factors are often growth factors.
*** E.g. fibroblast growth factor (FGF).
* Failure to maintain adequate oxygen and nutrient supply results in either
** Necrosis, or
** Slower degeneration with dystrophic calcification.
==Dissemination of Malignant Neoplasia==
* A key feature of malignant tumours is their propensity to spread from the primary site to other locations.
** When this involves spread of the tumour to distant sites, the process is known as '''metastasis'''.
===Methods of Spread===
* Carcinomas disseminate initially via lymphatics and then later via bloodstream.
* Sarcomas tend to spread via the blood.
====Invasion/ Infiltration====
* This is local spread through fascial planes, around nerves and into adjacent tissues/organs.
* Invasion involves a combination of:
** Pressure
** Cell motility
*** Loss of contact inhibition and adhesiveness.
** Release of enzymes
*** E.g. collagenase, hyaluronidase.
====Lymphatic Spread====
* Tumour cells permeate lymph vessels.
** Proceed to spread to local or regional lymph nodes.
*** Grow here as secondary tumours.
====Vascular Spread====
* Tumour cells permeate drainage veins.
** Consequently spread to vascular organs.
*** E.g the lungs, [[Liver - Anatomy & Physiology|liver]] , [[Spleen - Anatomy & Physiology|spleen]], kidney and brain.
*** Form secondary tumours in these organs.
* Neoplastic [[Thrombosis - Pathology#Thromboembolism|thromboembolism]] is often involved.
====Transcoelomic Spread====
* Transcoelomic spread describes the "seeding" or shedding of cells directly into peritoneal or pleural cavities.
** Cells then migrate onto the surface of adjacent organs.
* Alternatively, this can occur via lymphatic vessel involvement with blockage and rupture.
===The Process of Metastasis===
* In order to spread from the primary mass, malignant cells have to "escape" from the primary environment and penetrate either the lymphatics or blood vessels.
* The trigger for developing migratory activities is unknown but several features are important:
*# '''Cells must become mobile'''
*#* This is probably enabled by the secretion of proteases and blocking antiprotease secretions from stromal cells.
*# '''Cells must adhere to the basement membrane'''
*#* Mediated by the expression of adhesion molecules (integrins).
*# '''Cells must destroy the basement membrane'''
*#* Occurs by secretion of proteases which lyse the type IV collagen.
* Cell movement into the vessel is the result of secretion of motility factors by the cells themselves.
* In blood vessel involvement, the breaching of the basement membrane predisposes to thrombosis.
** Further tumour cell dissemination is probably via embolism.
* The determining factors for where the tumour cells leave the vessels are unknown.
** Complementary cell adhesion molecules are probably involved, together with growth factor secretion.
** Where emboli are formed, mechanical blockage in capillary beds is important.
*** Reversed diapedesis ensues.
===Secondary deposits===
* A variety of fates awaits secondary deposits.
** Some secondary deposits are abortive.
** Some remain dormant.
** Some establish and grow.
** The reasons are not known.
*** There is probably involvement of growth factors and angiogenesis factors.
**** E.g. EGF, FGF, TGF.
* Tissues vary in their abilities to "grow" secondary deposits.
** Good "soils" :
*** [[Lymph Nodes - Anatomy & Physiology|Lymph nodes]]
*** [[Liver - Anatomy & Physiology|Liver]]
*** [[Bone Marrow - Anatomy & Physiology|Bone marrow]]
*** Adrenal medulla.
** Intermediate "soils":
*** Kidney
*** Lung
** Poor "soils":
*** Muscle
*** [[Spleen - Anatomy & Physiology|Spleen]]
*** Gut
===Examples in the Domestic Species===
* '''Mammary carcinoma'''
** Favours both lymphatic and vascular spead.
** Spreads commonly to the lung, [[Liver - Anatomy & Physiology|liver]], kidney, and adrenal glands.
** Spreads rarely to the brain and bone.
* '''Thyroid carcinoma'''
** Spead is primarily vascular.
** Commonly spreads to the lung, [[Liver - Anatomy & Physiology|liver]] and kidney.
* '''Pancreatic carcinoma'''
** Metasises by transcoelomic spread.
** Commonly spreads to the [[Liver - Anatomy & Physiology|liver]], spleen and peritoneum.
* '''Salivary gland carcinoma'''
** Spread via the lymphatics.
** Commonly spreads to the peripheral and deep lymph nodes, [[Liver - Anatomy & Physiology|liver]] and lungs.
* '''Osteosarcoma'''
** Spread is vascular and lymphatic.
** Commonly spreads to the regional lymph nodes, lungs and [[Liver - Anatomy & Physiology|liver]].
* '''Haemangiosarcoma'''
** Metastasis is vascular.
** Commonly spreads to the lungs, [[Liver - Anatomy & Physiology|liver]], kidneys and muscle.
* '''Lymphoid and melanotic tumours'''
** Are multicentric rather than metastatic.
==Tumour Grading and Staging==
===Grading===
* Tumour grading indicates the degree of differentiation and the growth pattern of the tumour.
* Grading depends on cellular morphology.
===Staging===
* Tumour staging indicates how far the tumour has spread.
* The '''TNM system''' is may be used.
** This is based on :
*** '''T''': Local '''tumour''' spread.
**** I.e. the size and fixation of the tumour.
*** '''N''': Regional lymph '''node''' involvement.
*** '''M''': Presence of distant '''metastases'''.
==Pathological Effects==
* The development of a tumour may cause a whole range of of pathological effects.
* For example:
** Tumours may put pressure on vital organs.
** Thromboses and infarction may result.
** Bones involved in neoplasia (either directly or indirectly) may be prone to pathological fractures.
** Ulcerated or necrotic tumours may become infected.
** Where tumours are large, there may be much necrotis tissue, which can ave a toxic effect.
** Secondary haemorrhagic syndromes and depression of bone marrow function may occur.
*** Result in with anaemia and [[Thrombosis - Pathology#Disseminated Intravascular Coagulation|disseminated intravascular coagulation]].
===Death===
* Death from malignancy is usually due to :
** Obliteration of a vital organ by primary or secondary tumours.
** Cachexia and nutritional failure because of multiple metastasis plus secondary infections.
===Para-Neoplastic Syndromes===
* Para-neoplastic syndromes are complications which are not directly due to the effects of malignancy.
*These syndromes can be related to:
*# [[Neoplasia - Pathology#Ectopic Hormone Production|Ectopic hormone secretion]].
*#* E.g. parahormone-like secretion in lung squamous cell carcinoma results in hypercalcaemia.
*# Neurological syndromes.
*#* E.g. neuropathies, cerebellar degeneration, encaphalitis.
*# Bone marrow malfunction.
*#* E.g. [[Haemorrhage - Pathology#Purpura|purpuric disease]], anaemia, [[Thrombosis - Pathology#Disseminated Intravascular Coagulation|disseminated intravascular coagulation]].
===Endocrine Aspects===
* Some tumours may secrete abnormal amounts of hormones.
** These tumours need not necessarily be of endocrine origin.
*** Where the tumour is not of endocrine origin this is referred to as ectopic production.
====Endocrine Tumours====
* Tumours of the adrenal cortex.
** May be benign or malignant (i.e. adenoma, carcinoma).
** Can result in excess cortisol production, causing Cushing's syndrome.
* tumours of the adrenal medulla.
** Phaeochromocytoma.
** Can result in excess adrenaline production, leading to hypertension.
*** Seen mainly in dogs but can also occur in cats and horses.
* Pancreatic islet cell tumours.
** Adenoma.
** Can result in excess insulin prodction, leading to hypglycaemia.
*** Seen mainly in dogs.
====Ectopic Hormone Production====
* E.g. in the lung,
** Squamous cell carcinoma.
*** Can produce parathyroid hormone, leading to hypercalcaemia.
** Oat cell carcinoma
** Can produce adrenocorticotropic hormone(ACTH), leading to Cushing's syndrome.
==Tumour Markers==
* Some tumours secrete products than can be detected in serum.
** For example, foetal proteins.
* These can be used to monitor the effects of therapy in man.
* For example:
** Alpha fetoprotein (AFP).
*** Secreted in hepatocellular carcinoma.
** Acid phosphatase.
*** Secreted in prostatic carcinoma.
** Carcinoembryonic antigen (CEA).
*** Secreted in colonic and gastric cancer, and lung carcinoma.
==Tumour Immunity==
* Immune responses to tumours are generally weak.
** They do not appear to contribute to the response to an established tumour.
* There is little support for they idea that immune surveillance is important in the prevention and regulation of tumout growth, except when there is a viral aetiology.
===Tumour Specific Transplantation Antigens (TSTAs)===
* When tumours are antigenic, they often express cell surface markers - TSTAs.
** Thses markers are recognised as foreign, inducing
*** T-cell-mediated cytotoxicity
*** Antibody plus complement-mediated killing.
* These are more common in virally-induced tumour.
** The viral proteins probably ellicit the response.
** E.g. FeLV, papillomas.
===Tumour-Associated Antigens===
* Tumour-associated antigens may be present on some normal cells as well as tumour cells.
* Many are differentiation markers in unusual sites or amounts .
** E.g. foetal antigens, stem cell markers.
===Tumour cell killing===
* NK cells, LAK (lymphokine-activated killer) cells and activated macrophages seem to be important.
* Tumour necrosis factors (TNF α and β) are produced by macrophages and bind to tumour cell membranes.
** Produce a cytostatic effect, allowing cytotoxic cell killing to take place.
* Interleukins promote cytotoxic tumour killing.
** Particularly lL-1 and lL-4.
* Interferons may be helpful in inhibiting tumour cells.
** IFN α is tumouricidal.
* Transforming growth factors may be important in tumour growth and spread.
** TGF α
*** Related to EGF.
*** May act as a growth and angiogenesis factor.
** TGF β
*** May control the breakdown of basement membranes by tumour cells and hence play a role in metastatic potential.
==Examples of Tumour Types==
* Tumours are often classified on architectural grounds into solid and non-solid types.
** "Non-solid" encompasses haematopoietic and related types.
===Solid Tumours===
* Many solid tumour types are well-recognised but their aetiology and behaviour in animals is often poorly understood.
* The following are good veterinary examples:
** Mammary tumours in dogs and cats.
** Adenocarcinoma in the [[Small Intestine - Anatomy & Physiology|small intestine]] of the sheep.
** Pulmonary adenomatosis in the sheep.
====Mammary Tumours in Dogs and Cats====
* Next to skin neoplasia, mammary tumours are the most common tumours in dogs and cats.
=====Dogs=====
* Affects bitches over 5 years of age.
** Entire females with a predisposition to pseudopregnancy are at particular risk.
** Rarer in spayed bitches.
* Often, more than one gland is involved.
* 50-60% of these tumours are benign.
* Many tumours are "mixed".
** I.e. there is epthelial neoplasia with cartilage or bone,
* Mammary caricnomas vary in their malignancy.
** May spead to the lymph nodes, lungs or elsewhere.
** Some of these tumours are hormone-dependent.
=====Cats=====
* Uncommon in cats in the U.K.
** This may be the effect of early spaying.
* 90% of tumours are aggressive carcinomas.
* Cause is currently unknown. L
** ikely to be multifactorial with major hormonal and genetic influences.
====Adenocarcinoma in the Small Intestine of the Sheep====
* Fairly common in Scotland.
** Also recorded in Iceland, Norway, New Zealand and Australia.
* Affects mature sheep up to 6 years of age.
* Animals are cachectic and show [[Oedema - Pathology#Introduction|ascites]].
* Tumours are ususally found in the [[Small Intestine - Anatomy & Physiology|small intestine]].
** Are annular, causing stenosis.
*** There is proximal dilation.
* Tumours thicken the gut.
* Spread as small plaques/ nodules the on bowel serosa, and to the mesenteric lymph nodes.
* Peritoneal fibrous plaques with small nests of carcinoma cells often from.
* The cause is unknown.
** There may be an association with bracken fern grazing.
====Pulmonary Adenomatosis in the Sheep====
* Can affect sheep from 6 months to 6 years of age.
* Affected sheep may not show signs for up to 2 years.
** Signs include respiratory distress and fluid production via nose if the sheep is elevated.
* Lesions may be
** Discrete nodules, or
** Extensive solid grey consolidation of the dependant parts of all lobes, often on both sides.
*** More common.
* Lungs are heavy with frothy fluid.
* The main cell type affected are the alveolar (type 2) cells.
** Form adenomatous or papillary growths.
** The bronchiolar Clara are also affected.
* The neoplasia is transmissible.
** Caused by a retrovirus, possibly in association with a herpes virus.
===Haematopoietic Tumours===
* Any cell of the haematopoietic and related tissues can undergo neoplastic transformation.
** The transformed cell produces a tumour having a distribution pattern and growth rate characteristic of the normal counterpart.
* The nomenclature is confusing because of the heterogeneity of the cell populations which have the potential to be involved.
** E.g.
*** Leukaemia is malignant transformation of cells derived from haematopoietic tissues in the blood.
*** Myeloma is malignant transformation of an antibody secreting plasma cell normally found in organised lymphoid tissue and bone marrow.
====Acute Undifferentiated Leukaemia====
* Rare in animals.
* Composed of immature cells.
* Malignancy affects the stem cell phenotype.
** Primary lymphoid organs and other organs with lymphohaematopoietic function are predominantly involved rather than lymph nodes.
*** I.e. bone marrow, spleen, [[Liver - Anatomy & Physiology|liver]].
====Lymphoid Neoplasms====
* '''Lymphoma''', '''malignant lymphoma''' and '''lymphosarcoma''' are different terms for the same condition.
===== Classification=====
* '''Cytological classification'''.
** Well differentiaed (lymphocytic)
*** The malignant cells represent normal lymphocytes, although in excessive numbers.
** Poorly differentiated (lymphoblastic).
*** The malignant cells represent atypical lymphocytic cells with lymphoblastic characteristics.
* '''Tumour distribution'''
** Nodular/ follicular.
*** A well organised pattern of slow growth.
*** No metastasis.
*** Are of the B-lymphocyte type.
** Diffuse.
*** Result in effacement of normal lymphoid architecture by a very homogeneous population of lymphoid cells.
* '''Anatomical classification'''
** Thymic.
** Only the [[Thymus - Anatomy & Physiology|thymus]].
** Alimentary.
*** Gut and associated lymphoid tissue.
** Multicentric.
*** Widespread involvement of lymph nodes.
** Cutaneous lymphoma.
*** Usually presents as generalised skin disease, but is a malignant transformation of T cells with a propensity for pithelial sites
* '''Type of lymphocyte'''
** T-cell.
** B-cell.
** NK-cell.
* '''Time scale'''
** Acute.
** Chronic.
=====Prevalence=====
* Order of prevalence in UK: cats, dogs, cattle, pigs and sheep.
** In the cat and ox, viral agents have been identified as the causal agents.
* Lymphoma is one of the prevalent neoplasms in the dog.
** 80% of cases affect the 5 to 11 year old age group.
** The incidence is about 28 per 100,000 dogs.
** Blood of affected dogs shows neither a relative nor absolute increase in the number of lymphocytes until the late stages of the disease.
*** When this stage is reached, poorly differentiated cells may appear in the blood.
* FeLV is an important cause of lymphoma in the cat.
** 70% of cats with lymphoma will test positive for FeLV.
** FeLV also causes a number of non-neoplastic diseases.
*** Anaemia.
*** Leukopaenia.
*** Thymic atrophy.
* Cattle suffer both lymphosarcoma and leukosis in a variety of cytological forms.
** Bovine lymphoma is caused by Bovine Leukaemia Virus (BLV).
*** A retrovirus.
*** There is a juvenile form of bovine lymphoma seen in young cattle which is not associated with BLV.
=====Species Differences=====
* The form of the disease may differe between species.
* '''Feline'''
** Alimentary.
*** Affects the mesenteric lymph nodes, intestine, [[Liver - Anatomy & Physiology|liver]], spleen , and potentially the kidney.
** Thymic
*** Presents as a thymis mass, also in the mediastinal lymph nodes.
*** The pleural lymph nodes and the [[Liver - Anatomy & Physiology|liver]] may potentially be affected.
** Multicentric
*** Found in the peripheral and deep lymph nodes, [[Liver - Anatomy & Physiology|liver]] and spleen.
**** The kidney may sometimes be affected.
** Renal
*** The kidney and other abdominal organs are affected.
** Leukaemic
*** Affects the bone marrow alone.
*** This form is rare.
* '''Canine'''
** Alimentary.
*** Affects the mesenteric lymph nodes, pancreatic lymph nodes, intestine, and potentially the [[Liver - Anatomy & Physiology|liver]].
** Thymic.
*** Thymic and mediastinal masses.
** Multicentric.
*** Affects the peripheral and deep lymph nodes, [[Liver - Anatomy & Physiology|liver]], spleen and kidney.
* '''Bovine'''
** Thymic.
*** Mainly affects adults.
*** Thymic and mediastinal masses.
*** Some lymph nodes are also affected.
** Multicentric.
*** Mainly affects yopung adults.
*** Affects the peripheral and deep lymph nodes, spleen, [[Liver - Anatomy & Physiology|liver]] and kidney.
* '''Equine'''
** Takes mainly an alimentary form.
** Can rarely be cutaneous.
* '''Porcine'''
** Mainly multicentric.
*** Lymph nodes, [[Liver - Anatomy & Physiology|liver]], spleen.
* '''Ovine'''
** Uncommon.
** May be multicentric or thymic.
====Lymphocytic Leukaemia====
* A leukaemic manifestation arises when neoplastic cells retain the migratory patterns of their counterparts, when these are bone marrow, T- or B- cells.
* Lymphoid tissue may or may not be involved.
** This depends on the biological properties of the lymphocyte undergoing neoplastic transformation.
*** Lymphoid tissue is invplved when the cell has the capacity to recirculate and enter this.
* '''Acute lymphocytic leukaemia'''.
** Predominantly a T-cell tumour in man and dog.
* '''Chronic lymphocytic leukaemia'''.
** A B-cell tumour in dog and man.
* '''Plasma cell tumours'''.
** Also known as multiple myeloma or plasmacytoma.
** Rare in domestic animals.
*** When is does arrive, it is associated with abnormally high levels of immunoglobulins.
====Myeloproliferative Disorders====
* Myeloproliferative disorders are characterised by the malignant proliferation of one, several or all of the non-lymphoid bone marrow cells.
** I.e. the granulocytic, monocytic, erythromytic and megakaryocytic cells.
* May be acute or chronic.
* May gove rise to granulocytic or monocytic leukaemias.
====Mast Cell Proliferation Disorders====
* '''Cutaneous mastocytoma'''.
** Common in certain breeds of dogs, e.g. Boxers.
** Occur rarely in the cat and ox.
* '''Cutaneous mast cell sarcomas'''.
** Rapid growth with spread to drainage lymph nodes and involvement of other organs.
* '''Generalised mast cell sarcoma'''.
** Widespread lesions.
====Histiocytomas====
* Common in young dogs.
* Usually present as solitary cutaneous nodules.
** Do not metastasise.
** May regress spontaneously.
====Vasoformative Neoplasms====
* Include haemangioma of the spleen.
** Gives rise to extensive endothelial lined vascular channels.
** Haemorrhage and necrosis are common.