Neoplasia

In these lectures you will understand the following: Etiology (causes) of neoplasia. What evidence is there that neoplasia is a genetic disorder? What is the role of the environment in carcinogenesis? Molecular Basis of neoplasia.Oncogenes and tumour suppressor genes. Multistep carcinogenesis or tumour progression environmental carcinogens and process of carcingenesis Mechanism of cancer spread. Types of cancer spread Tumour grading and staging Effects of tumours on host: local effects, cancer cachexia, paraneoplastic syndromes.

Neoplasia
Etiology genetic
Neoplasia is defined as: " an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli that evoked the change." Neoplasia has genetic and environmental causes. It is important to note that both play parts in causing neoplasia.

Genetic evidence of tumourigenesis 1. Introduction of genes (activated oncogenes) in normal Cells in culture make them transformed (they lose contact Inhibition Grow in suspension and divide uncontrollably) 2. Transgenic mice/knock-out mice (mice with new oncoGenes Introduced in cells at early embryological stages or Removing genes from them) have a higher incidence of cancer 3. Patients with familial cancers have siblings with relatively Higher risk of developing cancer. For example, mutation of BRCA-1 and BRCA-2 (Breast cancer )genes are linked to Familial breast and ovarian cancer. 4. Patients with well known inherited cancer syndromes In which inheritance of a single mutated gene have increased Risk of developing tumours. A well known example is Familial Polyposis coli. Patients who inherit mutations in the AdenomaPolyposis coli gene have innumerable polypoid adenomas of The colon and in 85% of cases are fated to develop colorectal Carcinoma by age 50 or so.

Neoplasia
Etiology environmental
The environment we live in is filled with cancer causing agents (See Table 1). Rremarkable difference in the incidence and death rates of specific forms of Cancer can be found around the world. This can either be explained by differences in the Genetic make up of different races or more likely that the environment different people live in Has different carcinogens. We know that Death from skin cancer (Melanoma) are 6 times more frequent in Australia and New Zealand (white settlers exposed to the sun) than in Iceland, which is probably attributed to exposure to the sun. Also, The death rates from stomach cancer in both men and women In Japan is seven to eight times more common than in Europe or the U.S.A. Why is that? Well It could be that the Japanese have some small different genetic make up that makes them more Susceptible to stomach cancer than the Americans but it is more likely that the Japanese are Exposed to some carcinogens that the Americans are not. So if one studies the incidence of Cancer in the Japanese Immigrants to the USA and their offspring's one can see that gastric cancer mortality rates of Japanese immigrants and their offsprings dropped dramatically and That these immigrants and their offsprings had increased rates of cancers common in the USA (FIGURE 1). This strongly suggests that environmental factors have a strong role in the neoplastic process

Neoplasia
Etiology environmental
Table 1: Carcinogenic agents and occupational cancer Agent Ionizing radiations radon X-rays, radium Radium Ultraviolet radiation Polycyclic hydrocarbons in soot 2-Naphthylamine; 1naph-thylamine Benzidine; 4aminobiphenyl Asbestos Arsenic Benzene Vinyl chloride Aflatoxin B1 Occupation certain underground miners radiologists, radiographers luminous dial painters farmers, sailors, etc. chimney sweepers,oil workers rubber workers chemical workers shipyard and insulation workers sheep dip manufacturers, gold miners workers with glues, varnishes, etc. PVC manufacturers Food storage. Due to growth of Aspergillus flavus (fungi) Smokers Cancer Site bronchus skin bone skin scrotum, skin, bronchus bladder bladder Mesothelioma lung skin and bronchus marrow (leukemia liver (angiosarcoma) Liver

Benzo(a)pyrene

Lung

Dont forget the role of viruses and bacteria in Cancer

Neoplasia
Molecular basis of neoplasia Basic principles
Basic Principles: Cancer arises from nonlethal genetic damage which can be transmitted to cell progeny. Most tumors initially develop as monoclonal, arising from a single mutated cell. Three kinds of genes are targets for carcinogenic transformation: 1) proto-oncogenes promote cell growth and require the alteration of only one allele ?to create out of control cellular growth (dominant gene) 2) tumor suppressor genes inhibit cell growth and require the alteration of both alleles to affect cell growth (recessive oncogenes), DNA repair genes are similar 3) genes that regulate apoptosis may be dominant or recessive but influence the ability of the cell to target itself for destruction following cell damage Tumor progression refers to the ability of transformed cells to acquire further abnormal characteristics over time, independent of tumor size. These include ability to invade, metastatic spread, further anaplasia. It is believed that these characteristics are acquired through mutations within the tumor leading to subgroups of cells with varying characteristics. At the time of diagnosis, most tumors are heterogenous and have multiple cell lines present. The absence of p53 in many human tumors may contribute to the increased instability of DNA in tumorus.

Neoplasia
Molecular basis of neoplasia Oncogenes
ONCOGENES Proto-oncogenes are normal cellular genes that regulate cell growth, division, and differentiation. Oncogenes are cancer-causing genes derived from proto-oncogenes by mutation, retroviral transduction, gene amplification, or dislocations. Oncogenes occur as transformations of genes that normally regulate expression of growth factors and receptors, signal transducing proteins, nuclear transcriptions factors, and cyclins and their associated proteins. Classes of Oncogenes: Growth Factors: Genes that encode growth factors may become oncogenic. For example, cells that produce PDGF may also develop receptors for it and become permanently turned on via autocrine stimulation. Usually, the PDGF gene (sis) is normal, but oncogenes such as ras cause PDGF to be overexpressed. Excess growth factor itself cannot completely transform a cell, but in conditions of excessive growth and cell division, other mutations become more likely. Growth Factor Receptors: most are transmembrane proteins that cause phosphorylation of proteins on the cytoplasmic side when activated. Normally, the cytoplasmic side gets transiently turned "on" and then rapidly deactivated. Oncogenic receptors exist in a prolonged "on" state, even in the absence of bound growth factor. Point mutations in the ret protooncogene (codes for receptor associated with glial cells) are associated with MEN and familial medullary thyroid carcinoma. Growth factor receptors may also be overexpressed. c-erb1 codes for an EGF receptor overexpressed in many squamous cell cas, and HER-2in the adenoca of the breast, ovary and others. Signal Transducing Proteins: these proteins exist on the inner plasma membrane and following activation work to phosphorylate cytoplasmic proteins. Ras, a GTP cleaving protein receptor associated transducing protein, is the prototype and mutated versions of the ras proteins are present in 10-20% of human cancers. The normal GTPase activity of ras protein is accelerated when in association with GAPs (GTPase-activating proteins). Ras normally works to activate MAP (mitogen activated protein) kinase that increase nuclear transcription factors. Mutated forms of ras bind GAP normally, but the GTPase activity of GAP fails to occur. Translocation of the signal transducing protein (non-receptor associated) c-abl on chromosome 9 to the bcr region of chromosome 22 activates it to increase cell growth. This translocation is associated with CML. Nuclear Transcription Proteins: these proteins influence DNA synthesis in the nucleus. C-myc, forms a heterodimer with max protein, and the myc-max combination activates transcription. Mad, a similar protein to myc, may also combine with max to turn off transcription and is therefore a tumor-suppressor gene. Cyclins and CDKs: CDKs are present within the cell at all times and help the cell through the cell cycle. Cyclins are synthesized and then rapidly degraded and work to activate the CDKs. CDKIs regulate the activity of CDKs. CDK4 mutation seems to be implicated in melanomas and other cancers.

Neoplasia
Molecular basis of neoplasia Oncogenes
Methods of Activation of Oncogenes: 1. Point mutations: typical of ras proteins 2. Chromosomal rearrangements: translocation may associate a growth factor or receptor with an actively transcribed area, or result in the formation of an active hybrid protein. For example Philadelphia chromosome c-abl-bcr has hybrid activity 3. Gene Amplification: duplication, multiplication of DNA sequences in the genome. Associated with N-myc In neuroblastoma and c-erb 2 in breast cancer.

Neoplasia
Molecular basis of neoplasia Tumour suppressor genes
Tumor Suppressor Genes Tumor suppressor genes are normal cell genes that "brake" cell division and cycling at various point in the cell cycle. They work through similar mechanisms to proto-oncogenes, through signal transduction, through cell surface receptors and nuclear transcription regulators. Suppressor genes are "recessive" and require loss of both copies of the normal before cancer becomes likely, the "two-hit" model of carcinogenesis. Retinoblastoma models this behavior and exists as 60% sporadic and 40% familial, but occurs much earlier if familial. The theory is that both alleles of Rb must be ineffective before tumor suppression is lost. In the familial forms, all somatic cells have inherited one defective allele, and only one cell must lose its other allele to become predisposed to produce tumors. pRb works to prevent cells in G1 from advancing to S phase. This is an extremely sensitive transition since no further growth factors are required to complete mitosis following progression into S phase. pRb normally exists in an active, hypophosphorylated state and when phosphorylated, it releases the brakes and allows cell division to progress. Most likely, Rb forms tumors in the retina and osteosarcoma because deletion of both active alleles should trigger apoptosis. But, for reasons not fully understood, retinoblasts fail to die following transformation. p53, a protein exclusive to the nucleus, is the most common transformed gene in human cancer, presenting in over 50% of human tumors. p53, designated "guardian of the genome," acts in the nucleus to stop replication of damaged cells. Following damage, p53 gets rapidly up regulated and its accumulation triggers increased transcription of DNA repair proteins and those that stop the cell cycle. If repair occurs, the cell cycle resumes. If not, p53 plays a role in triggering apoptosis. Loss of both normal alleles of p53 causes the cell cycle to continue with the mistakes in DNA transcription intact. p73 has recently been discovered and appears to work by similar mechanisms. Other tumor suppressor genes include NF-1, NF-2, VHL, and WT-1. Suppressors of apoptosis involved in carcinomas include bcl-2 , which inhibits apoptosis and is transformed in most B cell lymphomas. Growth arises from decreased cell death rather than increased cell proliferation. The bax and bad gene accelerates cell death and opposes bcl-2. Defective DNA repair genes are implicated in the development of cancers as they may allow cell division despite mutated DNA. HNPCC (hereditary nonpolyposis colon cancer) illustrates a cancer associated with defects in DNA repair.

Neoplasia
Molecular basis of neoplasia Tumour progression/Multistep process of carcinogenesis
Tumour progression implies the gradual transition of a localised, slow growing tumour to an invasive, metastatic cancer. In the past epidemiologists suggested that the age related increase in cancer could be best explained by postulating that several independent steps were required for tumourigenesis. It was Vogelstein et al who put a firm a firm molecular footing for the concept of multistep carcinogenesis. Since colorectal cancer arise in preneoplastic lesions called adenomas (small polyps), they have used colorectal cancer as a model to answer the question: Do tumours accumulate genetic mutations (aberrations) as they progress to cancers? Thus Vogelstein et al (1988). analysed the patterns and frequencies of four different genetic abnormalities (losses in 5q, 17p, 18q and mutations of ras genes). In this study, adenomas with different sizes and forms (class I-III) were compared with carcinomas from different patients in an attempt to delineate genetic alterations associated with progression of adenomas to carcinomas. Deletions involving 5q chromosome were found in 29% of class II adenomas and 35% of carcinomas, indicating early involvement of genes on this chromosome arm in tumour progression. A specific region of chromosome 18q was found to be deleted in 47% of late adenomas (class III) and 73% of carcinomas, indicating that this genetic aberration occurred late in the progression sequence. In addition, deletions involving 17p were most frequent in carcinomas (75%) and were rarely found in early adenomas. Mutant ras genes were found in 12% of class I adenomas, 42%-57% of class II-III adenomas respectively and in 47% of carcinomas, indicating that ras mutation occurs early in the progression sequence. The authors concluded that the four molecular alterations accumulated in a fashion that paralleled the clinical progression of tumours and that there appears to be a preferred sequence of genetic changes that leads to progression in colorectal cancer (Figure 2). The authors also concluded that it is not the sequential genetic aberration of particular genes in any given order that is of prime importance, rather it is the overall accumulation of genetic aberrations (Fearon and Vogelstein, 1990). Thus, while only 9% of class I adenomas accumulated more than two of the four genetic aberrations, 40% of carcinomas have accumulated more than two genetic aberrations. Therefore, as trumours progress to cancer they accumulate more

genetic abnormalities.

Neoplasia
Molecular basis of neoplasia Tumour progression/Multistep process of carcinogenesis
Normal epithelium Loss of 5q Mutation and loss of Adenomatous Polyposis Coli (APC) gene.

figure2

Hyperproliferative epithelium

DNA hypomethylation

Early adenoma

Mutation of ras genes

Intermediate adenoma

Loss of 18q Loss of Deleted in Colorectal Carcinoma (DCC) gene

Dysplastic adenoma

Loss of 17p Mutation and loss ofTP53 gene

Carcinoma

Other alterations Metastases

Neoplasia
Carcinogens/process of carcinogenesis
Carcinogens are agents that have the ability to initiate the formation of cancer. They are divided into 4 groups: Chemical Carcinogens Physical Agents Ionizing Radiation Oncogenic Viruses It is useful to remember that 80 - 90% of all cancers may be related to environmental agents including diets, lifestyles, and viruses. Several environmental agents often act together (co-carcinogenesis). Chemical carcinogenesis It was Sir Percival Pott in 1775 who associated the increased incidence of scrotal skin cancer to chronic exposure to soot in chimney sweepers. Over the succeeding 2 centures hundreds of chemicals have been Shown to transform cells in culture and to cause tumours in experimental animals and in humans exposed to them (Table 1). These chemicals are known as carcinogens and the process by which they cause tumours Or cancer is called carcinogenesis. Nature has protected cells from these harmful agents (think of some of these protectors). Therefore, if one Or a group of agents are to produce a neoplasm they have to damage more than one gene. Thus, the Neoplastic transformation is a progressive process involving multiple hitsor genetic changes. Alterations in DNA cause changes in one or both of the following types of genes: Proto-oncogenes Tumor suppressor genes

Neoplasia
Carcinogens/process of carcinogenesis Chemical carcinogenesis
The multistep process involves 1. Initiation 2. Promotion These concepts have arisen from classical experiments performed on mouse skin. The researchers have shown that initiation results from the exposure of cells to a certain doze of a carcinogen (initiator). An initiated cell is altered making it more likely to give rise to a tumour (if exposed to another agent; group 2 and 3 in figure 3). Initiation alone is not sufficient for tumour formation (group 1). Initiation cause permanent DNA damage (Mutations). Thus it is rapid irreversible and inheritable (group 3). In this group tumours were produced even if the application of the promoting agent was delayed for a long period of time after a single application of the initiator. Initiators can themselves bind and change DNA(direct acting) or procarcinogens, which require metabolic conversion in vivo to produce ultimate carcinogen Promoters can induce tumours in initiated cells, but they are non-tumourigenic by themselves (group 5). Also, tumours do not result when the promoting agent is applied before the initiating agent (group 4). This indicates that unlike initiating agents, promoting agents do not affect DNA directly and are reversible (group 6).

Figure 3

Neoplasia
Carcinogens/process of carcinogenesis Chemical carcinogenesis
IN SUNNARY Initiation Results from interaction of chemical with DNA to activate a proto-oncogene or inactivate a tumor suppressor gene by formation of covalent adducts. Chemicals that can form adducts (direct acting) are usually electrophiles. Many chemical carcinogens require activation by metabolic pathways (pro-carcinogens or indirect acting carcinogens) an example of a metabolic pathway is the p-450 cytochrome mono-oxygenase. Initiation alone does not result in tumours. Promotion Promotors are usually irritants or substances that produce cell activation and proliferation. Effects of promotors are reversible. Promotors cannot induce neoplasia: i) alone, ii) if applied before initiator, iii) if applied in too small an amount for effect, or iv) if too much time elapses between applications.

Neoplasia
Carcinogens/process of carcinogenesis other carcinogenesis
Ultraviolet Light Strong epidemiologic relationship to squamous cell, basal cell, and melano-carcinoma in fair skinned people. Causes formation of pyrimidine dimers in the DNA leading to mutations. Activation of T-suppressor cells facilitates emergence of tumor clones. Individuals with defects in the enzymes that mediate DNA excision-repair are especially susceptible. Ionizing Radiation Ionizing radiation includes: X-rays, gamma rays, as well as particulate radiation; alpha, beta, positrons, protons, neutrons and primary cosmic radiation. All forms are carcinogenic with special sensitivity in: Bone Marrow: Acute leukemia occurs before other radiation-induced neoplasia (Seven year mean latent period in atomic bomb survivors). Thyroid: Carcinoma occurs in 9 % of those exposed during infancy or childhood. Lung: Increased frequency of lung cancer in miners exposed to Radon gas (an alpha particle emitter). Viral Carcinogenesis A large number of RNA and DNA viruses have been implicated in the causation of a variety of cancers in animals and humans some important ones are listed below. Human papiloma virus (HPV). There are more than 70 types of these DNA viruses. HPV types 16, 18 and 31 are associated with precancerous and invasive squamous cancer of the cervix. Epstein-Barr Virus (EBV) is a member of the Herpes family. It is associated with 4 types of human cancers: 1. African Burkitt lymphoma 2. B-cell Lymphoma (particularly in immunosuppressed individuals) 3. Hodgkin lymphoma 4. Nasopharyngeal carcinoma Hepatitis B virus is associated with increased risk of developing hepatocellular carcinoma RNA viruses like Human T-Cell Leukemia Virus Type 1 (HTLV) is associated with some forms Of T-Cell leukemia/Lymphoma.

Neoplasia
Cancer Invasion
What really distinguishes benign tumours from malignant cancers is the ability of cancer to invade and matastasise. Malignant Neoplasms grow by progressive infiltration, invasion, destruction, and penetration of the surrounding tissue Do not develop capsules This is why surgeons do Wide Excisions For a cancer cell to invade it has to: Detachment from other tumor cells. Adhesion to the extracellular matrix. Proteolytic degradation of the extracellular matrix. Motility and migration into the extracellular matrix. This process requires a number of genes to be activated. The extracellular matrix is a thick environment rich in collagen, glycoproteins and proteiglycans. Cells have to detach from the tumour mass and they can do that by reducing the cell-cell adhesion molecules on their surface (like E-Cadherins and others). They then have to adhere to proteins in the extracellular matrix by producing molecules on the surface called Integrins. Cells then can move towards rich sources of growth factors in a process called chemotaxis. But there are still a lot of tightly packed molecules and polymers in the Extracellular matrix so the cancer cell also secret proteolytic molecules called (matrix metallo-proteases, serine and cysteine proteases to degrade the extracellular matrix). This process also release some growth factors hidden in the extracellular matrix.

Cell-Extracellular matrix adhesion molecules involved in invasion and metastasis Integrins: A family comprising many heterodimeric cell-surface molecules that mediate cell adhesion to different extracellular matrix molecules. Laminin receptors CD44: Mediates tumor cell attachment to hyaluronate.

Neoplasia
Cancer Invasion Cancer Invasion

Neoplasia
Cancer metastasis
Metastasis is defined as the development of secondary implants discontinuous with the primary Malignant neoplasm and possibly in remote tissues. Once metastases are detected a cure becomes difficult if not impossible. Also, patients survival dramatically drops if metastases are present. Cancers spread by three ways: 1. Direct spread into natural cavities. Such as peritoneum, pleura, etc 2. Lymphatic spread (via lymphatic vessels) 3. Haematogenous spread (via veins) Why not arteries?? Metastasis is a multi-step process (Figure 4). A selected clone of cells growing in the primary tumour has to detach from the tumour mass and invade through a thick layer of connective tissue known as the basement membrane (BM). This process involves the production of a collection of proteolytic enzymes capable of destroying collagen type IV and other proteins and carbohydrate polymers, which are the main constituents of the BM. This process was discussed in invasion section. The metastatic cells then reach blood or lymphatic vessels by which they are transported to distant sites. The tumour cells then extravasate from the vessels to colonize distant organs as micrometastases. Metastasis is therefore a complex process involving multiple steps and requiring the expression of multiple unrelated genes. Metastasis is an inefficient process. Metastatic tumour cells are typically cleared from the host biphasically. The initial phase (6-24 hours), represents an exponential decline of cell numbers due to mechanical trauma, oxygen toxicity and clearance by the immune system. The second more gradual decline phase represents cell death at colonized sites (Weiss, 1990). However, recent evidence from intravital videomicroscopy, have strongly proposed that the major cause of metastasis inefficiency is failure of cells to grow in distant sites post-extravasation (Chambers et al., 1995; Koop et al., 1996). Metastasis is therefore a complex process involving multiple steps and requiring the expression of multiple unrelated genes. Metastasis is an inefficient process. Metastatic tumour cells are typically cleared from the host biphasically. The initial phase (6-24 hours), represents an exponential decline of cell numbers due to mechanical trauma, oxygen toxicity and clearance by the immune system. The second more gradual decline phase represents cell death at colonized sites (Weiss, 1990). The liver represents the major site for metastasis in gastrointestinal cancers. However, metastasis to the lung, brain and bone is not uncommon. Haemodynamic considerations could explain the involvement of the liver in the majority of metastases, since the liver represents the first capillary bed encountered by metastatic gastrointestinal cancer cells. Similarly, tumours in the lower rectum are more likely to metastasize to the lung since the lower rectum principally drains into the systemic circulation via the inferior vena cava. Although haemodynamic distribution contributes to the formation of metastases by mechanical trapping, it fails to account for liver, instead of the expected lung, colonization after intravenous injections of tumour cells in mice. The preference to metastasize to specific organs is well documented. Indeed, this 'soil phenomenon' was first described by Pagets as far as a century ago.

Neoplasia
Cancer metastasis
Figure 4

Adhesion to endothelial cells Tumour cells express E-Selectins Molecules that bind to Sialyl-Lewis X on endothelial cells

Neoplasia
Cancer metastasis
Facts about metastasis Direct spread Cancer of the Ovary is another big peritoneal spreader

Multiple Liver Metastases

Cancer of the Colon invades the peri-colonic fat and breaks free into the peritoneal cavity

Cancer involvement of cavities tends to produce haemorrhagic effusion, adhesions Lymphatic Spread More typical of carcinomas rather than sarcomas (hematogenous)e.g Breast, stomach, Papillary thyroid carcinoma Cancer cells travel in lymphatics and reach regional lymph nodes. They get arrested, die or grow or travel to other nodes Regional Lymph nodes draining the cancer area are first involved It is the rationale for lymph node dissection in many Carcinomas. The lymph nodes in the specimen are enlarged and firm. Hematogenous Spread Sarcomas predominate but Carcinomas also use this rout Arteries are rarely invaded Veins are the route of hematogenous spread Liver and Lungs are the usual endpoints of hematogenous spread, but remember that metastases can also metastasise. Portal flow to liver and vena caval flow to lungs Renal Cell Ca has a propensity to invade the renal vein and hepatocellular cancer has a tendency to penetrate portal and hepatic radicles. The distribution of metastases follow the anatomical distribution. Thus, breast cancer in the upper-outer quadrant is likely to metastasise to the axillary lymph nodes, while a upperinner breast cancer (medial) tends to metastasise to supraclavicular lymphnodes. Colon cancer tends to metastasise to Liver while cancers of the lower rectum tends to metastasise to the lung as described earlier. Prostate cancer prefer to metastasise to bone Bronchogenic cancer tends to involve adrenals and brain Neuroblastoma spread to liver and bones. Why do some cancers metastasise to certain organs and other organs such as Skeletal muscle and spleen are rarely involved???

Neoplasia
Cancer grading and staging
Grading and staging tumours are important because of their clinical relevance and so that different clinicians know how to standardise, plan and organise patients treatment. Grading is based on the degree of differentiation and the number of mitosis within a tumour. Cancers are classified as grades I to IV with increasing metaplasia. In general, Higher-grade tumours are more aggressive than lower grade tumours. It is important to note that within the same tumour Some cells have different grades and this is because of tumour progression. Thus tumour grade could change as the tumour grows. Staging is based on the anatomic extent of the tumour. In 1932 Cuthbert Dukes described a system for staging rectal cancer. The staging system associated the clinical-pathological behaviour of rectal tumours with prognosis (Figure 5). When the tumour is confined entirely within the wall of the bowel (Dukes A) more than 90 % of patients can be cured by surgery alone. Penetration through the muscularis propria (Dukes B) worsens the prognosis, and when there is metastasis to the lymph nodes (Dukes C) the outlook deteriorates further so that twothirds of the affected patients die of the disease within five years. When distant metastases to the liver are present (Dukes' D) most patients will die by the end of the first year (Dukes, 1932). Currently, two of staging are used: the TNM (Tumour, Node, Metastases) and the American Joint Committee (AJC) systems. Both systems use the primary tumour size, extent of invasion and number of Lymph nods involved with the tumour and the presence or absence of distant metastases as factors relevant to prognosis.
5-Years survival % >90 85-75 70 65-35 <5

T1N0M0

T2-3N0M0 T4N0M0 T2N1M0 T3-4N1M0

TXNXM1

Mucosa Submucosa Muscularis Propria Serosa Lymph nodes A B1 B2 C1 B3 C2

Duke s D Metastasis Liver Lung Brain Bone

Primary tumor (T) T0 T1 T2

No evidence of primary tumor Tumor <5 cm Tumor >5 cm

Lymph nodes (N) N0 N1

No regional metastasis Regional node metastasis

Distant metastasis (M) M0 M1

No distinct metastasis Distant metastasis

Histopathalogic grading (G) G1 G2 G3 G4

Well differentiated (low grade) Moderately differentiated (intermediate grade) Poorly differentiated (high grade) Undifferentiated

American Joint Committee on Cancer AJCC of soft tissue sarcomas classification Stage IA IB IIA IIB IIIA IIIB IVA IVB

G1 G1 G2 G2 G3 G4 G3 G4 Any G Any G

T1 T2 T1 T2 T1 T1 T2 T2 Any T Any T

N0 N0 N0 N0 N0 N0 N0 N0 N1 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Neoplasia
Tumour effects on Host
Tumours can effect the host in the following ways: Local Effects Cancer Cachexia Paraneoplastic Syndromes Endocrinopathies Neuromyopathies Osteochondral Disorders Vascular Phenomena Fever Nephrotic Syndrome Finger Clubbing

Local Effects
Tumor Impingement on nearby structures Pituitary adenoma on normal gland, Pancreatic carcinoma on bile duct, Esophageal carcinoma on lumen Ulceration/bleeding Colon, Gastric, and Renal cell carcinomas. Patient presents with anaemia. Infection (often due to obstruction) Pulmonary infections due to blocked bronchi (lung carcinoma), Urinary infections due to blocked ureters (cervical carcinoma) Rupture or Infarction Ovarian, Hepatocellular, and Adrenal cortical carcinomas; Melano-carcinoma metastases

Neoplasia
Tumour effects on Host

Cachexia
Cachexia is seen in advanced ca and includes body wasting, weakness, anorexia, and anemia. It is *not* caused by the tumor's nutritional needs, although the larger the tumor, the worse it is. Both fat and protein are consumed equally. Cause unknown, but some relation to Tumour necrosis factor alpha (TNF-alpha) and perhaps to a newly isolated protein-mobilizing factor, which, when injected into healthy mice causes rapid weight loss despite maintenance of caloric intake.

Paraneoplastic Syndromes
Cushings Syndrome Adrenal carcinoma (cortisol) more common with benign adrenal processes. Small cell undifferentiated lung cancer (ACTH) released through cleavage of pro-opiomelanocortin gene product. Inappropriate ADH syndrome (Hyponatremia) Small cell undifferentiated lung cancer (vassopressin-like hormone. Hypothalamic tumors (vasopressin) Hypercalcemia Hypercalcemia arises from either osteolysis by primary tumors or production of PTHrP that may act as PTH at various sites. Hypercalcemia is especially associated with carcinomas of breast, kidney, ovary, and squamous cell ca of the lung. -Squamous cell lung cancer (PTH-like peptide) Renal cell carcinoma (prostaglandins) Parathyroid carcinoma (PTH) Multiple myeloma and T-cell lymphoma (IL-1 and perhaps TNF-a) Breast carcinoma, usually by bone metastasis

Disseminated intravascular coagulation , migratory thrombophlebitis, neuromyopathies are also associated with various forms of advanced cancer.