Neoplasia - Pathology

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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.
  • 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 Classification

  • 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.


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 G0.
    • 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 , spleen, kidney and brain.
      • Form secondary tumours in these organs.
  • Neoplastic 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:
    1. Cells must become mobile
      • This is probably enabled by the secretion of proteases and blocking antiprotease secretions from stromal cells.
    2. Cells must adhere to the basement membrane
      • Mediated by the expression of adhesion molecules (integrins).
    3. 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.

Examples in the Domestic Species

  • Mammary carcinoma
    • Favours both lymphatic and vascular spead.
    • Spreads commonly to the lung, liver, kidney, and adrenal glands.
    • Spreads rarely to the brain and bone.
  • Thyroid carcinoma
    • Spead is primarily vascular.
    • Commonly spreads to the lung, liver and kidney.
  • Pancreatic carcinoma
    • Metasises by transcoelomic spread.
    • Commonly spreads to the liver, spleen and peritoneum.
  • Salivary gland carcinoma
    • Spread via the lymphatics.
    • Commonly spreads to the peripheral and deep lymph nodes, liver and lungs.
  • Osteosarcoma
    • Spread is vascular and lymphatic.
    • Commonly spreads to the regional lymph nodes, lungs and liver.
  • Haemangiosarcoma
    • Metastasis is vascular.
    • Commonly spreads to the lungs, 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.

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:
    1. Ectopic hormone secretion.
      • E.g. parahormone-like secretion in lung squamous cell carcinoma results in hypercalcaemia.
    2. Neurological syndromes.
      • E.g. neuropathies, cerebellar degeneration, encaphalitis.
    3. Bone marrow malfunction.

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 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 ascites.
  • Tumours are ususally found in the 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.

Lymphoid Neoplasms

See Lymphoma

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.