Lung cancer Tumour immunology Cancers are caused by the progressive growth of the progeny of a single transformed cell

. Immunosurvellance: 1. 2. 3. 4. It is the ability of the immune system to detect tumor cells and destroy them. It may be mediated by more than one component of the cellular immune responses (T cells and NK cells) It is believed that tumour cells continually arise in our body but they are rejected by immunocomptent cells activated by tumour associated transplantation antigen (TATA). Tumors express antigenic peptides that can become targets of a tumor-specific T-cell response. Tumour markers (antigens) • Tumour cells may be antigenically different from their normal precursors, they may gain or loss antigens, and so, will regarded as foreign antigen and attracted by immune system (Immunosurvellance) • • Tumour markers are helpful tool for early diagnosis and follow-up of tumour

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Types of tumour markers Tumour specific antigens: specific to one tumour in one site i. Tumour specific transplantation antigen, cell surface antigens ii. Antigens of viral origin (oncovirsus). • a. b. c. d. Tumour associated antigens Oncofoetal antigens: Alpha- fetoprotein (hepatic), CEA (breast and lung cancer) Proteins: casein (breast and GIT malignancy) and ferritin (leukemia and lymphoma) Enzyme: acid phosphatase (prostate) and alkaline phosphatase (lung, liver and bone malignancy) Hormones: increase in tumour of endocrine glands Immune response to tumour antigens: If the tumour is antigenically sufficiently different from normal tissue they will be regarded as foreign and attacked by the immune system. The major mechanisms of tumour cell destruction involve the following process: 1- Natural immunity to tumour a. Natural killer cells (kill tumour cells without prior antigenic stimulations) b. Macrophages (have major anti-tumour functions 2- Cell mediated immunity to tumour: a. T- Cells responses b. B-cell response (antibodies may be capable of lysing tumors of dispersed cells, B- cell act as APCs)

Lung cancer Failure of immune response to tumour = immunological escape: It means failure of the immune response to overcome the tumour growth. Factors that may contribute to immunological escape • Age a. In very young age the immune surveillance mechanism is still undergoing maturation b. In old age there is decrease in immune competence Immunodeficiency: Congenital Acquired Immunosuppression - Chemical Immunosuppression may be due to the release of immunosuppressive factors by tumour cells or from tumour associated macrophages. These factors include:  Prostaglandins  Alpha- fetoproteins  Phospholipids. - Infections e.g. AIDS - Malnutrition's - Immunosuppressive cytokines tumors might evade rejection is by making immunosuppressive cytokines, such as TGF-β, (suppress inflammatory T-cell responses and CMI, which are needed to control tumor growth), and IL-10(reduce dendritic cell development and activity) Tumour cell selection a. b. c. • lymphocytes • Antigen modulations: In the presence of the antibodies, some The tumour may not express sufficient marker to induce an immune response until it has reach a size that can not controlled by the host. As lack they either distinctive antigenic peptides or the adhesion or costimulatory molecules needed to elicit a primary T-cell response. Tumour cell kinetics: tumour cells grow faster than the immune system responses to its presence. Antigen masking : Certain molecules are frequently bound to the surface of tumour cells, and mask tumour antigens and so prevent adhesion of attacking

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• a. b.

antigen are modulated off the surface by (antigen shedding, endocytosis), this facilitates escape by removing the targets antigens that the immune system would recognize • lymphocytes in draining LN • form complex with:Blocking factors: When the tumour antigen are shed they may Lymphocytes trapping: by trapping of tumour specific

a. b. • •

Lung cancer 3 the host specific antibodies, these complex could block the cytotoxic of host T- cells by binding with them and so preventing T-cells from attacking tumour cells, Or by binding with T- helper cells and prevents them to recognize the tumour cells and deliver help to CTL. Privileged sites: in certain areas of the body the tumour may be

relatively protected from normal surveillance There are other mechanisms whereby tumors can avoid immune attack or evade it when it occurs. A. Tumors tend to be genetically unstable and can lose their antigens by mutation; this instability might generate mutants that can escape the immune response B. Some tumors, lose the expression of a particular MHC class I molecule (not attacked by CTLs), although it might become susceptible to NK cells. Tumour immunotherapy:  Cure may be suspected only if the tumour mass is small or is surgically excised  Curing cancer requires that all the malignant cells be removed or destroyed without killing the patient, through induction of an immune response against the tumor that would discriminate between the cells of the tumor and their normal cell counterparts.  -T cells are a critical mediator of tumor immunity. 1. Non- specific stimulation of immune system A. BCG - It is the most widely used immune therapy -It stimulates T-cells activity and activates macrophages - It may given systemically or injected directly to tumour mass B. Corynebacterium parvum, levamisole, and various mixed bacterial vaccines : less effective than BCG 2. specific immunotherapy A. Active immunization, May be effective after chemotherapy or surgery. Active immunization includes the following:i. Vaccinations with tumour cells or antigens, the results are unsatisfactory ii. Vaccines against oncogenic viruses. B. Passive immunization (immunopotentiation) C. Immuno-depletive therapy : This include the reduction of certain serum factors produced by tumour or related to it, which are immunosuppressive and inhibit optimal immunity to tumour and include ( prostaglandins, blocking factors, immune complexes, and suppressor cell activating tumour factors.

These onco-viral proteins are viral proteins that may be able to evoke a T-cell response. 1. a gene. or signals sent from the body to stop reproduction. Cancer cells rapidly reproduce despite restriction of space. makes a protein. 3. the drug or toxin is released in the endosomes and exerts its cytostatic or cytotoxic effect 4. the tumor cells are readily recognized and destroyed by the immune system. There are an estimated 30. Combinations of toxin-. After internalization. nutrients shared by other cells. Until recently. • • Cancers develop due to alterations (mutations) in genes. in human cell there are 46 (23 pairs) chromosomes (22 pairs of autosom & two sex chromosomes).Lung cancer 4 If tumors bear MHC molecules foreign to the host. Genes Definition: are the units of heredity that carry the information for specific character or specific structure. The most effective tumor vaccines so far are tumor cells that secrete GM-CSF (differentiation of hematopoietic precursors into dendritic cells and attracts these to the site) GM-CSF is also activating dendritic cells 5.000 to 35. so that host and tumor can be matched for their MHC type.000 different genes contained on these chromosomes. and linking the antibody molecule to chemotherapeutic drugs such as adriamycin or to radioisotopes (allow entry of antibody to tumor cells). ultimately. producing a reagent called an immunotoxin). Tumor rejection antigens are peptides of tumor-cell proteins that are presented to T cells by MHC molecules. So. 2. or a section of our DNA. Molecular Genetics of Lung Cancer Cancer is defined as abnormal growth of cells. DNA is made up of base pairs that provide the codes for making proteins. it needs to include a range of tumor antigens. also there is inefficient killing of cells after binding of the monoclonal antibody and inefficient penetration of the antibody into the tumor mass (overcome by linking the antibody to a toxin. But the tumor recur again in mutant form. Proteins encoded by viral oncogenes are a tumor rejection antigen. or radionuclide-linked monoclonal antibodies. might provide the most effective cancer immunotherapy. most cancer vaccines have used the individual patient's tumor removed at surgery as a source of vaccine antigens. together with vaccination strategies aimed at inducing CMI. The advent of monoclonal antibodies suggested the possibility of targeting and destroying tumors by making antibodies against tumor-specific antigens. Genes are segment on chromosomes. Tumour vaccine: To be effective. • . drug-. Genes are made of DNA. These peptides can become the targets of a tumor-specific T-cell response because they are not displayed on the surface of normal cells.

Cancer cells are often shaped differently from healthy cells. and are said to be "altered" or mutated. • a. These mutations occur at the cellular level after birth. and serotonin transporter genes . controlled cell growth. as a result of environmental exposures (such as smoking). not all DNA in our cells is used to make protein products. D2. “Acquired mutations: - • • Therefore. Genetic mutations: inherited mutations . The majority of cancers can be attributed to acquired mutations "Means that the tumor must be due to acquired somatic genetic alteration and are not passed to children. b. This gene is not identified yet. - Gene when working properly promotes normal. Cytochrome P450 subfamily polypeptide 6. in that they develop because of an accumulation of mutations in genes. • Cancers develop due to alterations (mutations) in genes.Lung cancer 5 - Some genes coding for certain characters which are not essential for growth or does not code for anything in particular. but simply serves as "spacer. and they can spread to many areas of the body. Mutations in a person's DNA accumulate over time. or chance alone. dopamine transporter. lifestyle behaviors (such as eating poorly or not exercising). but most are not inherited. Genes encountered in nicotine addiction are. all cancers are genetic. they may not work properly. they do not function properly." Therefore. dopamine receptors (D1.Only a small percentage of cancers involve inherited mutations due to germ line mutations or a cancer susceptibility gene that would result in a heritable cancer that are passed to children. D4). When these genes have an error in their DNA code.

and telophase (accompanied by cytokinesis). invasive cancer. G2 in which the mitotic apparatus is constructed. carcinoma in-situ. . The cell cycle • The cell cycle comprises 5 phases: • • 1. G0 or the resting phase ( cells carry on its usual metabolic activity to survive) Cells temporally stop dividing is said quiescence. ( continues its growth and metabolism. metaphase. a. CDK = catalytic subunit of cell division. anaphase. It is composed of 2 processes: Cytokinesis (cytoplasm physically divides) Mitosis: (chromosomes are divides between 2 daughter cells) . 5. • Cells enter the cell cycle when they pass the so-called restriction point in the G1 phase. and finally to metastatic cancer. Transition into the various phases of the cell cycle requires the formation of cyclin / cyclin-dependent kinase complex (cdk). but is still diploid) M in which nuclear and cytoplasmic division occur. Cells permanently stop dividing due to aging or accumulated DNA damage are calls senescent G1 in which RNA and protein synthesis take place (preparation). metaplasia. at which the determination is made to replicate or remain quiescent in response to the body requirements. 4. S in which DNA synthesis occurs (duplication). Cyclin = regulatory subunit.It is composed of 4 stages: prophase. 3. (2) histopathological changes and (3) morphological changes which progress from normal epithelium to hyperplasia (increase number and size). dysplasia (complete change or disorganization of cells). 2. b.• Lung cancer 6 The development of lung cancer is a multi-step process comprising a series of (1) genetic.

The checkpoint under influence of both +ve & -ve regulation. The most important checkpoint in G1 to S transition (restriction point) Checkpoints through cell cycle are: Restriction checkpoint:  1. These growth factors are: EGF. and hepatocyte growth factor. their regulation is critical to normal cell division. These DNA checkpoint regulated by p53 has been implicated in a large umber of cancers because its absence allow the cell to proceed into S phase with unrepaired DNA damage that leads to mutations when DNA replication machinery misinterprets the damaged region or uses lossy DNA repair mechanism. heregulin factor. there are check point at which the cell has the ability to assess itself & determine whether it is ready to progress to next phase of cell cycle or not. b. at G1-S transition. Negative Regulation • The cyclin are inactivated by degradation. or positive regulation is over-expressed. thus. 2. and one at entry of M phase. by determination of amino-acid sequence in protein). Progression through the cell cycle is regulated by transcription (protein synthesis). the cell may progress to next portion of cell cycle at an inappropriate time → uncontrolled cell growth may results. one at end of S phase. one at entry of S phase. • Certain growth factors induce gene expression of cyclin D (protein synthesis. transforming TGF. tyrosine kinase receptors. Mitotic assembly point: the chromosomes have migrated to cell poles (that the cell is ready to cytokinesis and exit from mitosis). and PDGF. IGF-1. Spindle checkpoint: between metaphase and anaphase. cell assess itself and determine if progress to next step or not. IGF-2. . Positive Regulation (cyclin proteins& growth factors) → transcription (protein synthesis) • The cyclin proteins are the rate limiters in the formation of cyclin/cdk complexes and therefore of initiation and transition through the cell cycle.Lung cancer Regulation of the Cell Cycle  7 At various point in the cell cycle. often referred to as positive regulation. If function of negative regulation is lost. one in G1.. with the G1 cyclins D and E exhibiting half-lives in the cell of only approximately 30 minutes. and protein degradation or inhibition so called negative regulation. thereby affecting the cell's replication and entrance into the cell cycle in the G1 phase. during which cells check that all between anaphase and telophase during which the cell ensures that chromosomes have successfully attached to mitotic spindle. Gastrin releasing peptide. 3.   a.  There are 4 DNA damage checkpoint regulated by p53.

The Ras family includes K-ras. Oncogenes are derived from normal cellular gene called proto.   Ras family • • Present on Inner surface of cell membrane The Ras oncogene leads to cancer through its important role in inappropriate signal transduction for cellular proliferation.specific cdk. Activation of this family in lung cancer occurs by gene amplification & overproduction of normal protein product which have been found in SCLC and less commonly.oncogenes &oncogenes are named with three letters (myc). chromosomal translocation. There are three main types of genes that can affect cell growth. The Ras genes are mutated in about 30% of all NSCLC. • Proto. or amplification → become unable to control the normal growth of cells and allowing abnormal cancer cells to begin to grow. The other family includes p15. C-myc is a positive regulator of G1. There are three families of related genes (c-myc. Bcl-2 human oncogenes): (1)Oncogenes • Oncogenes are genes that are believed make people more susceptible to cancer. respectively. tumor suppressor genes 1.oncogenes Proto-oncogenes are believed to turn into oncogenes when exposed to particular carcinogens. but rarely in SCLC . • These oncogenes can become activated by mutation. Mismatchrepair genes. which fall generally into two families. Clinically c-myc gene amplification has been related to more malignant course in SCLC. which prevent binding of cdk4 and cdk6 kinase to their regulatory cyclin D subunits. • . 2. and N-ras. p18. L-myc). particularly of cyclin E/CDK2 complexes. There are two classes of oncogenes: 1. RAS family) 2. H-ras. Recessive oncogenes . which can associate with and inactivate cyclin Ecdk2 and cyclin A-cdk2 complexes and prevent entrance into S phase or progression through S phase. RAS family) Myc family   MYC oncogenes are present in the nucleus. One family includes p21 and p53. and p19 . N-myc gene over-expression in SCLC has been related to a poor response to chemotherapy & more aggressive malignant course in SCLC. It encodes nuclear products. p16. in NSCLC. and are altered (mutated) in certain types of cancers. Dominant oncogenes (MYC family. is unknown. 1. including the following (Oncogenes.• Lung cancer 8 Negative regulation of the cell cycle also occurs through the inhibition of cdks by cyclindependent kinase inhibitors. (K-ras in adenocarcinoma and in cigarette smoke exposure). N-myc. Dominant oncogenes (MYC family.

A. cyclin D1 kinase activity. • K-ras mutations are relatively common in NSCLC. (So considered a pre-malignant marker) and is associated with poor prognosis. Retinoblastoma gene • Normal mechanism of action: The p16INK4a-cyclin D1-CDK4-RB pathway is central to controlling the G1 to S phase transition of the cell cycle. activated by Cytochrome P450 in human lung especially in vascularised area → more carcinogenic effect which react with DNA forming methylated bases→ mutation on codon 12 & development of activated proto –oncogene K-Ras • • K-Ras mutations are closely associated with cigarette smoke exposure. Mechanism of action in lung tumor : RB protein isolated from tumors is often mutated. a check point in the cell cycle regulation. resulting in a functionally inactive protein unable to bind to E2F or to be regulated by phosphorylation. So. RB protein is the key regulator of passage through the G1 phase. and can interrupt their reproduction until the defect is corrected . If the tumor suppressor genes are mutated. Recessive oncogenes . P16INK4a and RB binds and controls a number of other cellular proteins including: the transcription factors E2F1. 3.• Lung cancer 9 NNK pro-carcinogen.or tumor suppressor genes These genes are able to recognize abnormal growth and reproduction of damaged cells. hypophosphorylated RB is the active growth-suppressing form. and they do not function properly. but return to an unphosphorylated state just before G0. P53 gene • • Normal function of p53: it maintains the integrity of the human genome. especially adenocarcinoma developing in ex.  B. Thus cellular proliferation becomes unregulated. 1. E2F2 and E2F3 which are essential for progression through the G1/S phase transition block of S phase entry→ stop cell division.smokers so damage seems irreversible. RB. P16 regulates the activity of RB by inhibition of CDK4. P16INK4a arrest cells in G1 phase by leading to phosphorylation of a nuclear protein. 2. RB is Hypophosphotylated in early G1 phase & heavily phosphorylated in late G1 just before S phase. however. RB regulates the G1/S boundary. A K-ras mutation have been found in bronchial biopsies from smokers with no evidence of lung cancer one year before the clinical diagnosis. tumor growth may occur. or cancer cells. So absence of p16 allows uncontrolled CDK4 phosphorylation and transcription factor activation. Mechanism of action: . [   Successive phosphorylation inactivates its ability to suppress cell proliferation. 2.

thus giving the cell a chance to repair the DNA before its errors are duplicated & passed to daughter cells. there are 3 forms (latent. If the DNA does not "match" perfectly. a human oncogene. this allows mutations to accumulate in other genes and leads to more than 50% of all human cancers.normally present in cell cycle which can't be detected. it extends the survival of cells that normally would die. causing them to be damaged. Unlike other oncogenes. G1 arrest. instead. If these genes are not working properly. as. p53 act as a transcription factor inducing expression of suppressor genes such as p21. Latent forms: . extended cell survival is also carcinogenic. b. Mutant form. errors in DNA can be transmitted to new cells." . wild. Bcl-2 does not promote the growth of cells. (3) Bcl-2(enhance apoptosis) • Bcl-2. & mutant form) 1.Lung cancer 10 In response to DNA damage induced by carcinogens.  Previously it was believed that p53 is oncogene because mutant form has long life span than wild form. 2.  MDM2 is an oncoprotein that inhibits the p53 tumor suppressor protein. however.is formed when latent form of P53 is under stimulation (UV. it blocks cell suicide. smoking. it loses its protective function. Abnormalities in MDM2 protein are common in patients with adenocarcinoma. so it is frequently found in association with tumors. “So Bcl-2 constitutes the first member of a new category of oncogenes: regulators of cell death. BAX and GADD45. risk factors) → wild form is the active form which  Arrest • mitosis late in G1 phase whenever it senses that a cell's DNA is damaged. allowing DNA repair. Wild form: .  Interact with gene responsible for DNA repair apoptosis  Promote 3. • "Thus. Apoptotic cell death. It is important in cell growth differentiation & protect against malignancy. these genes repair the mismatch and correct the error. theses genes regulate the cellcycle checkpoint signal that causes the cell to undergo either: a.  How mutation of p53 result in lung cancer: Abrogation (‫)أبطال‬of p53 function by tumor cell can results in inappropriate progression through the dysregulated cell-cycle checkpoints and allows the inappropriate survival of genetically damaged cells. (2) Mismatch-repair genes These genes help recognize errors when DNA is copied to make a new cell. And when Bcl-2 is deregulated.

TGF & her2/neu) are expressed by cancer cells. "It promotes death. Evading apoptosis. There are several isoform of VEGF encountered in angiogenesis. Proto-oncogenes and tumour suppressor genes play an important role in the multistage model of carcinogenesis: • .’ an initiated cell undergoes clonal expansion to form a preneoplastic lesion. thus producing autocrine and paracrine growth stimulation loops. 6. mainly VEGF 189 mRNA has a good correlation with angiogenesis. • • The first step is when carcinogenic agents mutate DNA to give altered gene expression (initiation). Carcinogenic agents affect DNA by several molecular mechanisms. A number of growth factors and their receptors (EGFR. The altered gene expression leads to ‘promotion.• Lung cancer 11 A second form of Bcl-2 that "looks like its evil twin brother. yielding the following hallmarks of cancers: 1. generally they form electrophilic intermediates that bind to DNA causing mispairing or base substitutions during DNA synthesis. Bad seems to release Bax and allow it to kill cells. consistent with the multistep model of carcinogenesis. Limitless replicative potential. 3. Abnormalities in self-sufficiency of growth signals. • The changes that lead to tumour formation occur in the genetic material that is responsible for regulating cell growth and differentiation. It appears that genetic damage continues to accumulate in bronchial epithelial cells in line with traditional indices of increasing preneoplastic morphology. lung cancer engender angiogenesis with expression of large number of blood vessels (poor prognosis). • Tissue invasion and metastasis. "And there is also another one that promotes death which is called Bad. Insensitivity to anti-growth signals. Laminins and integrins are being intensively studied as a key markers of tissue invasion through the basement membrane Tumors arise via a process of carcinogenesis. Sustained angiogenesis. 4. 5." is the Bax. IGF-2. IGF-1." Tumour Formation  It is likely that lung cancer cells start to harbors genetic damage after prolonged exposure to tobacco smoke or other carcinogens. 2. The genetic and cellular targets of the carcinogenic process are notably diverse. Ultimately multiple clonal lesions are detectable in overt invasive lung cancers and perhaps more in metastatic lesions. Should this lesion undergo further genetic change (conversion) a malignant tumour develops.

It is thought that K-ras activation is particularly important in the development of adenocarcinoma of the lung. High intake of green. particularly those over the age of 40.Lung cancer 12 2. Proto-oncogenes are important to the regulatory mechanisms of growth. 70% of all cigarettes Japan are charcoal. High age onset of smoking 2. Epidemiology of lung cancer     Lung cancer is the most common cancer worldwide: 2. green tea may inhibit tumergenesis due to anti oxidative effects of polyphenols in tea. Death increased 150% bet. and in the UK for 90%.000 case per year 5. More death from lung cancer than breast. Lung cancer has always been more common in men. Tumour suppressor genes code for products that enhance neoplastic activity when mutated. 3. Incidence & mortality rates higher for African American than white Americans due to difference in metabolism of tobacco nicotine smoke carcinogens. programmed cell death and terminal differentiation. It is found to be mutated in 90% of SCLC and 50% of NSCLC.yellow vegetables & fruits 4. Tea preparations esp. cell-cycle control. In biomarker study the urinary metabolites of NNK was much higher in white smokers than in African American. the number of women developing lung cancer has gone up considerably.  [  Lung cancer remain far lower in Japan than US or UK which may be due to:- 1.containing filter. Low fat diet (fat content of diet may play key role in the risk of developing lung cancer in cigarette smoker) 3. ovarian. smoking is estimated to account for 87% of lung cancer cases (90% in ♂ & 79% in ♀). & uterine cancer combined 3. Women are more susceptible to tobacco effects 1. as more women have started smoking.000. The most commonly altered tumour suppressor gene is the p53 gene found on chromosome 17. 2.years survival is less than 15% & has only shown minimal improvement over the past 30 years One third of all cancer deaths due to lung cancer. angiogenesis and metastasis. In the US. Death rate peaked in 1990 The biggest causal factor in lung cancer is smoking. 5. However.9 times more likely to develop lung cancer than men with same smoking habits .  Effect of gender (lung cancer in women) 1. 1974 & 1994. as more men used to smoke than women. It has been demonstrated that activation of the ras proto-oncogenes leads to tumour formation. it codes for a phosphoprotein involved in the control of cell proliferation and loss of function can be caused by single base substitutions.

Lung cancer 13 4. Hormonal factors may play a role in causing lung cancer 6. I. 1st degree relative b. c.000 different chemicals. education. b. and diet has been suggested as a cause of lung cancer but this is difficult to prove.g. or constitutional characteristics of the individual. The incidence of adenocarcinoma is higher among female (50-80%) higher than male especially in non smoking females 5. cigarettes smoke contains more than 4. . nicotine appears to depress the immune response to malignant growths in exposed tissue. Risk of lung cancer higher in pt. immediately causes cumulative changes to the (bronchial mucous membrane) and more tissue gets damaged until a tumour develops.  There is no one single cause for cancer. polonium. Pulmonary fibrosis (scar carcinoma). non radical oxidants [radioactive substance e. C14. Lung cancer takes many years to develop. more than 19 substance known carcinogens including free radical oxidants. o Cigarette smoking cause lung cancer due to: a. 4. The role of smoking o 87% of lung cancers are related to smoking. income.  The major causes of lung cancer (and cancer in general) are: 1. K40 & radon nitrosamine. Air pollution & socioeconomic stander measured by occupation. But changes in the lung can begin almost as soon as a person is exposed to cancer-causing substances. 2. There is a strong dose response relationship . 3. The factors involved may be genetic. with COPD. 5. such as those present in tobacco smoke. Scientists believe that it is the interaction of many factors together that produces cancer. Additionally. 3. phenol derivative and benzopyrene]. Exposure to carcinogens. Smoking Radiation exposure Occupational exposure Genetic susceptibility Viral infection Other risk factors a. 2. Estrogen replacement therapy significantly increased the risk of developing adenocarcinoma Causes of lung cancer 1. environmental. 6.

7% of smokers compared to 0. Black tobacco is slightly alkaline. filters) Depth of inhalation (personal smoking behaviors) Gender & dietary factors Smoking cannabis may also increase the risk of lung cancer. so higher levels of free nicotine are released. Atypical cells are present in sputum of 96. K-ras activation due smoking • K-ras mutations are closely associated with cigarette smoke exposure. 2. In women the number of adenocarcinoma increased faster. 4. either free radical or non radical oxidants can damage DNA.9% in non smokers o Risk of lung cancer related to 1. 4. Adenocarcinoma increased due to deeper inhalation of low light nicotine. SI) Age of smoking onset Product smoked (tar/ nicotine content. as smoking tobacco. protein & lipid d. . Cannabis Amount smoked (pack /y. o Consequently. filtered cigarette. so deep inhalation is unnecessary. elevated levels of carcinogens are found in the blood & urin of those passively exposed to cigarette smoke o Lung cancer attributed to Environmental Tobacco Smoke (ETS) has been estimated to be about 20-30% in western countries. o Main stream smoke: smoke directly inhaled by smoker o Side stream smoke: inhalation of smoke released from burning tobacco bet.Lung cancer 14 c. they are at a much greater risk than non smokers. 3. Smoking & histology of lung cancer 1. Oxidants. 3. Chronic inflammation due to smoking lead to genetic alteration in bronchial cells. Recent investigation of sidestream smoke suggests that it contain 100 times the weight of carcinogens of main stream smoke. it is believed to cause similar damage to the cells in the lungs. the number of adenocarcinoma absolutely increased while the frequency of squamous carcinoma remained stable 2. Although less is known about the harmful effects of smoking cannabis. 5. Puffs do not pass through filter of cigarettes. Pipes and cigars Although pipe and cigar smokers have a lower risk of lung cancer than cigarette smokers.

stroke.000 lung cancer deaths each year in the US Radon is a colorless and odorless radioactive gas generated by the breakdown of radioactive radium. emphysema and chronic bronchitis. c. so most radon disintegrates safely while still underground Some radon gases diffuse through the soil under a home or building and enter through gaps and cracks in the foundation or insulation. nickel. Radon causes between 15. the risk of lung cancer decreases each year as normal cells replace abnormal cells. . • K-ras mutations are relatively common in NSCLC. Radon '' half. chromates. the risk drops to 1/3 to 1/2 of the risk for people who continue to smoke. that person’s chances of developing the disease are similar to that of a non-smoker. arsenic. a. found in the earth's crust. • III. as well as through pipes. exposure to radon is an even greater health risk. too. Radon can be a problem in schools and workplaces. polycyclic aromatic hydrocarbons. walls or other openings. After 10 years. • • • • • Exposure to radon in combination with cigarette smoking greatly increases the risk of lung cancer. II.smokers so damage seems irreversible. mustard gas. 12 % of all lung cancer deaths are linked to radon.000 and 22.• Lung cancer 15 K-ras mutations have been found in bronchial biopsies from smokers with no evidence of lung cancer one year before the clinical diagnosis. passive smoke. asbestos dust. After about 15 years. silica dust Asbestos . such as heart disease. b. Radon causes lung cancer because it causes arbitrary damage to the chromosomes and DNA molecules contained in the nucleus of the cell. especially adenocarcinoma developing in ex. Occupational exposure  Exposure to carcinogens in the work place have been implicated in several industrial situations. drains. (So considered a pre-malignant marker) and are associated with poor prognosis.life'' only 4 days from when it forms. Stopping smoking If a person stops smoking. radioactive materials. cessation of smoking greatly reduces the risk of developing other smokingrelated diseases. That means for smokers. Radiation exposure Radon gas • Radon exposure is the second major cause of lung cancer after smoking. which in turn is the decay product of uranium. In addition.

the relative contribution of individual genetic factors in lung cancer susceptibility is unknown.  GSTu detoxifies PAH epoxides in tobacco smoke. pleural plaque & IPF(asbestosis). This area requires further study before application in such areas as screening. Asbestos can cause a variety of lung diseases i.  GSTu null individuals have reduced ability to detoxify benzo pyrene diol epoxide (BPDE) with high susceptibility to lung cancer. no single genetic factor is sufficiently predictive to be of diagnostic use. but for most patients exogenous factor are more imp. smokers may be more likely to develop lung cancer due to an inherited faulty gene. while heavy exposure may result in a much higher risk of lung cancer. Low-level exposure increases the risk of lung cancer only slightly. between two alleles does not usually lead to changes in function of coded protein. and in the context of complex extrinsic factors such as smoking. Many people have been in contact with asbestos during their working lives. • • • IV. There is a synergistic effect between tobacco smoking and asbestos in the formation of lung cancer. It increases the risk of developing lung cancer. Than the combination of exogenous & endogenous effect. Genetic polymorphisms of carcinogen metabolizing enzyme.• Lung cancer 16 The most important malignancy related to asbestos is malignant mesothelioma of pleura & peritoneum. . • There is a familial tendency to develop lung cancer that cannot be explained by shared environment. • There may be small subgroup with a genetic predisposition to develop lung cancer. we do not know what this gene is. compared to the risk from smoking. which could potentially have a large impact on how lung cancer is tackled. prevention or treatment. Altered DNA base sequence in gene. Though associations have been made between various metabolic polymorphisms and markers of mutagenic susceptibility. In some families. Genetic susceptibility • Less than 20% of heavy smoker develops lung cancer. At present.  Gene locus for GSTu is polymorphic in man & lacking in 50% of Caucasians. • Individual variations in metabolic activation of tobacco smoke carcinogen & DNA repair reflect the acquired & inherited host factors that may affect the risk for smoker in developing lung cancer.e.

but they may influence pathogenesis. 1. LUNG CANCER  Refers to a group of neoplastic growth arising from the epithelium of the air passages or lung. However this requires examination with E/M. This classification although based on simple pathomorphological criteria has very important implications for clinical management and prognosis of the disease. . mesothelium and soft tissue. lipomas etc may be found in the lung. which can arise from any type of tissue in the lung neurofibromas. Lung Tumors Pathology: processes and classification BENIGN LUNG TUMOURS  Only 3% of lung tumors are benign. Proto-oncogenes are believed to turn into oncogenes when exposed to particular carcinogens. Viruses are also suspected of causing cancer in humans. They often present late. when local invasion and metastases are already present  Can arise from the different tissues present such as epithelium. Genetics and viruses Oncogenes are genes that are believed make people more susceptible to cancer. these are often classified according to the most predominant cell type found. Individuals with 2 mutant NAT2 alleles exhibit '' slow acetylator phenotype'' with reduced detoxification of aromatic amines & an association of bladder cancer. and diagnosis is based on the histological findings of biopsy seen by L/M. Non-small cell lung cancer (NSCLC) (80%).  There are two main types of lung cancer categorized by the size and appearance of the malignant cells seen by a histopathologist under a microscope: non-small cell (80%) and smallcell (roughly 20%) lung cancer. Small cell lung cancer (SCLC) (roughly 20%)  Oat cell carcinoma  Intermediate cell type  Combined oat cell carcinoma 2. Types of Lung Cancer Epithelial tumors consist of two major types of lung cancer:. lymphatic.Lung cancer 17  N.SCLC & NSCLC. but the most common are pulmonary hamartomas or carcinoid tumors and other forms are very rare. as this link has already been proven in animals.Acetyltransferases (NATs) play a role in detoxifying aromatic amines in tobacco smoke. Genetic susceptibility and viral infection are not of major importance in lung cancer.  Commonly affect the upper lobes more frequently than lower and the RT lung more than the LT.

bone. Papillary Adenocarcinoma: 3. Well differentiated 2. 4. and bone. Undifferentiated  Adenocarcinoma: 1.  The most important site for metastasis are liver. also prostate carcinoma  The oncogene most commonly involved is L-myc. breast. Acinar Adenocarcinoma: 2. . bone. Small cell carcinoma (SCLC. 3. Giant cell carcinoma 2. These usually present as round shadows of about 1. the adrenal glands. Moderately differentiated 3. Sometimes.25% of all lung cancers  It tends to start in the large. GIT. grows rapidly & metastasized early. usually affecting the parenchyma 2. they can present in asymptomatic patient. Clear cell carcinoma 3. Solid carcinoma with mucous formation  Large-cell (mixed small cell) undifferentiated carcinoma: 1. central airway. LN. and the 1ry found later on CT scans or other investigations  Common sites for metastasis from lung. Brain . liver. kidney. brain. also called "oat cell carcinoma")  Other names for SCLC are oat cell carcinoma and small cell undifferentiated carcinoma. Often arise from 1ry tumors in.5-3 cm diameter on CXR.Lung cancer 18  Squamous cell carcinoma 1.  SCLC (Oat) cell carcinoma accounts for about 20. Other types • • • • Carcinoid (the main representatives in this group) Adenoid cystic carcinoma Cylindroma Mucoepidermoid carcinoma SECONDARY TUMOURS  Common sites give metastasis to lung: The lung is a common place for metastasis: 1. Bronchoalveolar carcinoma 4. prostate cervix or ovary.

 It is more sensitive to chemotherapy.  L/M: . characterized by high nuclear/ cytoplasmic ratio. Intermediate cell-carcinomas.  WHO classify SCLC into 3 types: 1. 3.30% of all lung cancers. contain some large cells and so more resistant to chemotherapy.  SCLC tends to spread widely through the body. tend to behave aggressively & extra thoracic metastasis being . hilar.  SCLC is almost always caused by smoking.they form sheets of darkly staining cells with prominent nuclei and little cytoplasm. 2. Squamous cell carcinoma (epidermoid carcinoma): 25% . It is very rare for someone who has never smoked to have SCLC. and chemical make-up.Lung cancer 19  The "oat" cell contains dense neurosecretory granules which secrete a large amount of polypeptide hormones. or around major bronchi. A combined subgroup< and SCLC containing areas of squamous carcinomas or adenocarcinoma.carcinomas. shape.  The non-small cell lung cancers (NSCLC) are grouped together because their prognosis and management is roughly identical. Moderately differentiated more frequent  Widespread Metastases occur relatively late.87% of all lung cancers  There are three sub-types of NSCLC. 2. mediastinal LN. less likely to give extra-thoracic metastasis. thought to be as a result of their development from cells of the APUD system give this endocrine /paraneoplastic syndrome association. their secretory activity can be seen as the presence of neurosecretory granules in the cytoplasm seen by EM.  WHO classifications divided it into 1. Well differentiated grow more slowly & confined to lung.  Sensitive to radiotherapy. Small or oat. • • Common in smoker→ squamous metaplasia Tend to be found centrally. Undifferentiated type. The cells in these sub-types differ in size. 3. but carries a worse prognosis and is often metastatic at presentation. ’’’ Non-small Cell Lung Cancer  NSCLC accounts for about 80.

the characteristic histological features are cell keratinization & intracellular bridge.  Adenocarcinomas arise peripherally from mucous glands near the gas-exchanging surface of the lung.  Adenocarcinoma commonly arises around scar tissue and is also associated with asbestos exposure.  Most cases of the adenocarcinoma are associated with smoking. it is the most common form of lung cancer . the tumors are truly bronchogenic.  5% arise at the extreme periphery of the lung & disseminate over pleural surface as mesothelioma  Brain and bones frequent site of metastasis. Adenocarcinoma: 1.  As a tumor grows: a. Keratinous mass which appears cheesy on dissection.Lung cancer 20  They grow in a stratified or pseudoductal arrangement. Some work into the treatment of various cancers has looked at the possibility of suppressing or counteracting the effect of TAF in the hope that restricting the flow of blood to a tumor will restrict growth and spread.  Regional & more distant metastasis occur less commonly than in case of other lung cancer. Papillary Adenocarcinoma: 3. among non-smokers and in particular female non-smokers. they die. Acinar Adenocarcinoma: 2. Bronchoalveolar carcinoma 4.  It is usually found peripherally. c. If the tumor grows too large for its blood supply then the central areas can become deprived of oxygen and nutrients and will undergo necrosis. acinar or papillary differentiation and mucus production. Well differentiated tumors deposit keratin pearl formation. This allows tumors to grow more rapidly and increase in size. and show the greatest tendency to cavitate . However. This is the process by which squamous cell carcinomas frequently develop into necrotic masses. b.  The cells retain some of the tubular.  Few cases. It secretes substances called tumor angiogenesis factors (TAF) which cause blood vessels to grow into the mass of tumor cells. In US it is the most frequently diagnosed histological type. Solid carcinoma with mucous formation  This type accounts for about 40% of lung cancers. arising from mucus gland in proximal bronchi.

15% of lung cancers. They behave like other lung tumor tending to involve local lymphatic & extra thoracic metastasis being more frequent f. these characteristically have well differentiated ‘bland’ cells which grow along alveolar ducts. Tend to have a better prognosis than those with other types of lung cancer. Clear cell carcinoma  This type of cancer accounts for about 10% . Clara cells. bronchiolar & mucosal cells. Giant cell carcinoma 3.Lung cancer 21  N/E discrete peripheral tumor mass may be found with or without scar tissue particularly in upper lobe  Broncho-alveolar carcinoma a. It is peripheral lung tumor arising from any epithelial cells within or distal to terminal bronchioles. e. Other Types of Lung Cancer . resulting in a poor prognosis  N/E: large. More common in female non-smokers and may have different responses to treatment. b.  E/M: may show feature of squamous or adenocarcinoma & may be undifferentiated  It is primarily a diagnosis of exclusion. sometimes produce ill defined fluffy infiltration resulting from its tendency to spread in contiguous ''lepidic'' manner along airways at bronchiolar levels. ciliated. The tumor is multicentric or lobar in location. oval cell with abundant cytoplasm. bulky & appear unrelated to bronchi. and when more investigation is done. It produce copous watery secretion ''bronchorrhoea'' g. CXR: can't be differentiated from other type of carcinoma. L/M: can't differentiated from metastatic adenocarcinoma Large-cell undifferentiated carcinoma: 2. it is usually reclassified to squamous cell carcinoma or adenocarcinoma. i. N/E: there margin less well differentiated & often appears as multiple pulmonary nodules or as area of peripheral '' pneumonic consolidation'' → refractory pneumonia. h. but the majority arise at periphery of lung  it tends to grow and spread early. having large.  It may appear in any part of the lung. c. Bronchiolo-alveolar carcinoma.  L/M: anaplastic carcinomas. These include type I pneumocyte. d. highly aggressive with predilection for metastasis to intestine. showing no feature of maturation. less well differentiated spindle shaped.

 Though not strictly tumors. even more rare.  Most are slow-growing tumors that are called typical carcinoid tumors.  They are very slow growing and generally asymptomatic but may cause obstruction if arising from a major bronchus. but due to the similarity in appearance on CXR → need to differentiate between them and lung cancers.Lung cancer 22 Carcinoid tumors of the lung  Account for fewer than 5% of lung tumors. They rarely give rise to the carcinoid syndrome. occasionally may arise in peripheral lung. with secretory granules. Squamous cell carcinoma. they grow slowly and eventually cause lobar collapse by blocking the bronchus. hamartomas. Carcinoid tumour) Spread to mediastinal structures → mediastinal syndrome . derived from primitive gut and so it secretes substance responsible for paraneoplastic syndrome. lymphomas. Spread of lung cancer 1. There are other. lung tumors such as adenoid cystic carcinomas. Pulmonary hamartomas  Small well-defined non-neoplastic areas of disorganized tissue overgrowth that commonly arise in the periphery of the lung parenchyma. Since these tumors are treated differently from the more common lung cancers. Cancers intermediate between the benign carcinoid and SCLC are known as atypical carcinoid tumors.  Atypical carcinoid tumors: a. Adenomas may form in the bronchial mucous gland and can obstruct the bronchioles as they grow.  Carcinoid tumors may be divided into typical & atypical carcinoid tumors can spread. accounting 11-24% of all carcinoid tumors b. they usually have a better prognosis than SCLC or NSCLC.  Seen bronchoscopically as intraluminal tumors.  It is neoplasm of bronchial endocrine or APUD cells.  Are very low grade malignant tumors arising in larger bronchi (main or segmental bronchi).  Site. and sarcomas. They are generally cured by surgery. and resembles intestinal carcinoid. Direct spread  Central type: (SCLC. having more malignant histological &clinical features c. The tumour has a typical endocrine packeted appearance. mainly in main or segmental bronchi.

Signs and symptoms of lung cancer Symptoms that suggest lung cancer include: Dyspnoea (shortness of breath) Hemoptysis (coughing up blood) Chronic cough or change in regular coughing pattern Wheezing Chest pain or pain in the abdomen Cachexia (weight loss). ulceration. the release of pyrogens causes fever in the absence of infection. Hematogenous spread commonly to liver. clubbing and anemia found in some cases. these include serine proteases. and dysphagia. Scalene LN → supraclavicular LN 3. Obstruction of any nearby structure can occur (either by pressure from contained tumour or invasion) and often include SVC obstruction. 3.  Paraneoplastic disorders are found in lung cancers with ectopic ACTH production. dyspnoea due to lobar collapse. Lymphatic spread (embolization or permeation) 1. These may lead to a new approach in the management of lung cancer.  MMPs have also been suggested as having a part in the control of growth and apoptosis of cells. cachexia.  Occasionally central necrosis occurs in the middle of a tumour (particularly in squamous carcinoma) when it outgrows its blood supply. Mediastinal (subcarinal. The hilar (peribronchial LN. invasion and systemic effects due to central necrosis and paramalignant disorders. Broncho pulmonary LN 2. sup tracheo bronchial.). As well as metastases. SIADH.Lung cancer 23  Peripheral type → spread to pleura → malignant pleural effusion → If apical→ thoracic inlet syndrome  Direct spread may occur by penetration through the basement membrane to the extracellular matrix (ECM). brain & adrenal glands 4. Clinical trials of synthetic inhibitors of MMPs (batimastat. Cathepsin and the matrix metalloproteinases (MMPs). bones. 2. vocal cord paralysis due to damage to recurrent laryngeal nerve. Penetration of the basement layer that distinguishes benign from invasive tumors. para tracheal LN) 4. Trans-bronchial spread rare in bronchiolo-alveolar carcinoma  Lung cancers often cause local complications of obstruction. fatigue and loss of appetite Dysphonia (hoarse voice) . Enzymes from the malignant tumour cells are capable of degrading the ECM. LN. marimastat) are being carried out.

Patients with lung cancer may be present in 4 ways: I. causing C. 2. Partial or complete collapse of distal segment of lung. . The surface of the cancer may be fragile. D. Central tumors: • patients). but may be due to involvement of peribronchial or perivascular nerves. 4. either alone or in combination. Chest pain: − Poorly localized chest discomfort occurs in 1/3 of patients at diagnosis − The exact cause is unknown. 3. Haemoptysis. A small percentage has no symptoms and the diagnosis made by the chance of finding of opacity on PCX-ray done for some other reasons. leading to bleeding from the cancer into the airway. Fourth group may present as a results of metastatic. This can lead to accumulation of secretions behind the blockage. Cough is the most common symptoms at presentation. • The commonest symptoms are cough. Any new cough that persists more than 2 weeks especially in patients over 40 years who is smoker is suspicious. This blood may subsequently be coughed up   Mainly squamous and small cell carcinoma (about 1/3 of It may be minimal blood streaked in mucoid sputum. Clubbing of the fingernails (uncommon) Difficulty swallowing The majority of patients present as a result of investigation of some new respiratory symptoms or because their pre-existing respiratory conditions become worse. dyspnoea and chest pain. predisposing the patient to pneumonia. many lung cancers have a rich blood supply. II. Central airway narrowing. B. Peripheral tumors: Commonly Adenocarcinoma or large cell type. If the cancer grows into the lumen it may obstruct the airway.Lung cancer 24 1. Dyspnoea may be due to: • • • breathing difficulties. anorexia. A. A third group may present with non-specific symptoms such as malaise. and weight loss. haemoptysis. Copious haemoptysis is uncommon.

location. Weakness or paralysis that is limited to a specific area of the body may indicate a tumor in the area of the brain that controls the affected part Cerebral metastasis. Dyspnoea :   if large enough c. b. Skeletal metastasis (common in SCLC and in large cell-carcinoma. . a. (Because a tumor has eroded away the involved bone. or are associated with a minor impact that would not normally cause a bone to break. o o Pain is the most common symptom associated with bone metastases from lung cancer. 1. and seizures. uncontrollable vomiting. and pleural effusion also causes dyspnoea . Present with progressive neurological symptoms and common in patients with wide spread disease. If present it is due to pleural involvement or blockage of lymphatic in lymphangitis carcinomatosis.Present with Bone pain and even pathological fractures. The symptoms vary depending on the size.Sites: Any bone in the body can be involved in lung cancer spread . • • number of tumors present. • i. 2. Distant metastasis: About 1/3 of patients with lung cancer present with metastasis spread outside thorax.Lung cancer 25 They may cause no respiratory symptoms at diagnosis. − Bronchorrhoea is described in bronchoalveolar (but unusual). These fractures typically occur without any history of a fall or an impact. • • of the body. The pain can range from mild to severe. Cough and haemoptysis: − Are less common than central tumor. Pathological bone fracture. and Is less common. Focal neurological deficits: Changes in vision Symptoms of increased intracranial tension: Severe headaches. Chest pain: Spread beyond pleura to chest wall produce dull aching continuous pain that interfere III.

. • The most common symptom associated with adrenal metastases is pain caused by tumor growth or sudden bleeding into the gland. Determine the most appropriate sequence of investigation. to the right or left of the spine. 5. around waist-level. iv. 4. 2. Bovine cough: When the patient is asking to cough they produce ineffectual expiratory noise.Lung cancer 26 ii. Preliminary assessment of the extent of disease. Common clinical findings at presentation: 1. Cervical lymph node and adrenal involvement (not produce symptoms). a. The pain is typically located in the back. Involvement of right recurrent laryngeal nerve indicates a thoracic inlet tumor or invasion of the cervical lymph node (it loops around the right subclavian artery in the root of the neck). loss of balance or coordination. Vocal cord paralysis: only seen in irresectable tumor. there can be many other symptoms. Hepatic metastasis: • • • Rarely produce symptoms. If the tumors interfere with the function of the liver. physical examination may reveal sign that are important in: • • • • difficulty speaking swallowing. Stretch of liver capsule leads to pain. o o o Hoarse voice of vocal cord paralysis is easily detectable. Physical examination of the chest in case of lung cancer is frequently normal. However. The left recurrent laryngeal nerve is the most commonly involved as it loops around aortic arch where it passes over left main bronchus. It is produced by juxtaposition of the two fully adducted vocal cords. It may determine treatment in individual cases. • not produce symptoms. disease. iii. Confusion associated with metastatic brain Adrenal gland metastasis: Adrenal metastases from primary lung cancer are often Reaching a diagnosis of lung cancer. 3.

5-10% of cases show sign of SVC obstruction: Symptoms: swollen of face and neck with tightness around the collar which may progress to gross edema. Secondary to complicating infection process or other some process. PCX-ray or U/S show paradoxical movement). • With distal obstruction by tumor give rise to localized wheezes which may be heard without stethoscope. VI. (Tidal percussion. h. Lung collapse. Paraneoplastic syndromes: . Pleural effusion.a. f. Lymphatic spread is common. i. -  Sign of pleural effusion which may be due to: Neoplastic pleural involvement (more common). Pleura: • • d. Paralyzed hemi diaphragm due to invasion of phrenic nerve by wide spread mediastinal tumour. j. Atelectasis of the obstructed area of the lung if treatment is delayed. Airway obstruction: Narrowing of trachea or lesion in either main bronchus at the level of carina may cause stridor (inspiration). Clinical picture of superior sulcus (Pancoast) tumors. Sign and symptoms of raised intra-cranial pressure. e. The scalene and supraclavicular lymph glands are the first to be enlarged. Axillary lymph glands are rarely involved (indicate invasion of chest wall). b. c. • Lung cancer 27 Clubbing of finger and toes and may be associated with HPOA. A central obstructing tumour may cause a decrease in intensity of breath sound over lobe or entire lung.  Pleural friction rub may b heard over area of pleuritic pain. The enlarged lymph nodes provide readily access for histological sampling and positive histological confirmations indicate inoperability. Clinical picture of paraneoplastic syndromes. Palpable liver due to hepatic involvement (unusual). Sign. the earliest and commonest sign is bilateral jugular venous engorgement and superficial varicosities over are drained by SVC. Dullness to percussion at lung bases: g.

Definitions: it means a variety of non-metastatic or neuromuscular manifestations of lung cancer. (Because it arises from A PUD system). o years.Melanocyte stimulating hormone Adrenocorticotrophic hormone β. it most commonly associated with SCLC. Although it can occur with all types of lung cancer.endorphin β-lipotropin pro-opiomelanocortin Vasopressin Oxytocin VP-HNP OT-HNP Bombesin Neurotensin Glucagon Calcitonin Normal site of production Hypothalamus Anterior pituitary gland Posterior pituitary gland Gut-brain C-cells (thyroid) o obscure. o arise from: The mechanisms for arising of these syndromes remain in most parts These syndromes may ante-date discovery of tumor by months or even Approximately 10-20% of patients with lung caner exhibit para-neoplastic It dose not results from the physical effects of tumor. o syndromes. Neurosecretory granules: Source: in neural tissue. b.o o o Lung cancer 28 Depending on the type of tumor. But its believed to . o a. including hypothalamus and pituitary and in gut-derived tissue. A number of metabolic para-neoplastic syndromes are well recognized clinically Hormone Thyrotropin releasing hormone Somatostatin Thyrotropin Growth hormone β. so-called paraneoplastic phenomena may initially attract attention to the disease. which commonly elaborates ectopic hormones from neurosecretory granules.

5. Neurovascular reflexes. Neurological disorders: including Lambert-Eaton syndrome. 2. Endocrine disorders: including. hypercalcemia. psychosis. Cushing's syndrome. binocular visual loss. 9.Lung cancer 29 a. leucocytosis. erythema multiform. Excessive production of hormones and other polypeptides. b.. and SIADH. B. and dementia. Excessive release of cellular products by tumors. encephalomyelopathy. acanthosis nigrigans. and hemorrhagic diathesis. It is common in squamous cell carcinoma. A. extremely rare. thrombotic diseases. limbic encephalitis. subacute peripheral neuropathy. o The spectrum of clinical conditions includes the following: 1. 3. 4. It may also results from production of abnormal circulating factors by the tumor. True ectopic para-thyroid production of hormone is incidence of malignant hypercalcemia: Malignant diseases responsible for most cases of hypercalcemia . Rheumatologic disorders: as polymyositis. c. 8. Lung cancer especially squamous-cell carcinoma can produce para-thyroid like hormones that cause calcium mobilization from bones and by increased renal tubular absorption. 2. cerebellar degeneration. and SLE. 6. eosinophilia. 8% of patients with lung cancer have hypercalcemia.dermatomyositis. Hypercalcemia : 1. C. Cutaneous and musculoskeletal disorders: including Urticaria. fever. 60%. and malaise. Causes of malignant hypercalcemia: Destruction of bone by osteolytic metastatic disease. a. Renal disorders: such as membranous glomerulo-nephritis and nephrotic syndrome. digital clubbing and PHOA. D. Miscellaneous disorders: consisting of non-bacterial thrombotic endocarditis. Systemic disorders: such as anorexia. Hematological disorders: such as anemia. and lactic acidosis. Symptoms of hypercalcemia: may develop insidiously or rapidly. thrombocytosis. c. 3. 7. necrotizing myelopathy. b. polycythemia.

Lung cancer 30 Kidney: Polyuria. by: A. drowsiness and finally coma. it occur in Correction of dehydration with IV saline. Loop diuretics as furosemide. GIT: anorexia. Syndrome of inappropriate ADH secretion (SIADH_: Mild hypercalcemia (<3 mmol/L): Cornerstone of treatment is correction of dehydration 1. 4.a. vomiting and constipation.  with IV saline. nausea. treatment of malignant hypercalcemia: in terminal cases if it is felt that the patients quality of life would benefit from lowering serum calcium patient can be treated by: if no bone metastasis it is assuming that the tumor is producing para-thyroid hormone like substance: So treatment of tumor (radiotherapy. resection) will result in improvement of the condition. and renal failure. most common paraneoplastic form present in SCLC. Incidence: a. and thirst if these symptoms persist it lead to dehydration. Renal function should be monitored. Adequate K supplementation. c. 5-22% It is common in SCLC. hypovolemia. b. First correcting the biochemical disturbance by medical treatment. If hypercalcemia persists: Agents which prevent calcium absorption from bone can be used.   B. It manifested by significant hyponatremia (serum sodium <120 mmol/L). b. o o o o  2. IV and oral bisphosphonates have a role in treatment of malignancy associated hypercalcemia. d. Cytotoxic antibiotic mithramycin is rarely used (not effective. . Adequate K supplementation. weakness. Renal function should be monitored. nocturia. General: malaise. side effects) Oral steroids are unreliable but it can be used. Severe hypercalcemia or hypercalcemia not responding to simple rehydration:     C. CNS: Mental slowing confusion.

and headache As hyponatremia worsened. 7. resulting in low plasma osmolaity (<260 mosmol/ kg of water) There is continued loss of sodium in urine at a level inappropriate for plasma sodium concentration so that the urine osmolaity is high (twice to that of plasma). Causes: A. Diagnosis is by: measurement of urine and plasma osmolaity. vomiting. 4. b. b. Clinical picture: a. It may cause photosensitivity. clinical syndrome of ectopic ACTH secretion is found in only 5% of patients with SCLC and is less common in other cell types. Treatment of primary tumor (chemotherapy)  a. It carries a poor prognosis. Antibiotic Demeclocycline Given orally if: compliance is difficult. Biochemical characteristics: Raised concentrations of immunoreactive adrenocorticotrophic hormone. If plasma level of NA less than 115 mmol/ L seizures and coma. 2. 6. Many of agent used for treatment of SCLC ( as cyclophosphamide. . Cornerstone of treatment is water depletion. B. Uncontrolled secretion of ADH by the tumor. Asymptomatic. Vincristine and cisplatin) can lead to SIADH. This drug competes for ADH binding site in renal tubules. Treatment: A. 5. Incidence: It is found in about 50% of patients with SCLC. C. No response to water deprivation. However. Biochemical characteristics: dilutional hyponatremia (low plasma sodium in presence of water retention). impaired concentration with forgetfulness and confusion. It is given in a maintenance dose of 600-900 mg daily. Loss of diurnal variation. It best avoided in patients with renal impairment or hepatic disease. Ectopic adrenocorticotrophic hormone secretion: 1.Lung cancer 31 3. 500-750 ml of fluid given daily + addition to the losses in previous 24 hr. Or may complain of: Anorexia. c. nausea. B.

and ulna). . . b.Edema. . Diagnosis: a. • Other authors show equal distribution among major cell types with exception of SCLC. Patients not usually develop the sign associated with Cushing's syndrome (moon face. 3. Inhibition of adrenal steroid synthesis with antifungal agent ketoconazole may be effective. The most common physical findings are: . Incidence: • Lung cancer is by far the most common cause of HPOA.Proximal myopathy. Symptoms: a. 2. ankle and Bony pain in the involved area. Symptoms: such as: anorexia. • Some authors believe that it is more common with Adenocarcinoma. Clubbing of digits is found in over 90% of cases. tibia. It is a syndrome characterized by periostitis of the distal end of long bone at (common. central obesity. Treatment:: • • Most effective treatment is that of tumor itself (chemotherapy).  Hypertrophic pulmonary osteoarthropathy: fibula. c. d. which are often hot and tender to 1. There may be associated pain and tenderness in wrist.Lung cancer 32 Failure of cortisol to suppress following dexamethasone injection. radius. 3. touch. ACTH assays also shows elevated levels. knee joints. c. b. this may be profound and associated with hypokalaemic alkalosis (due to urinary loss of K). and cutaneous striae) mostly due to short history of SCLC.Melanocyte stimulating hormone production). Confirmation of diagnosis is by finding an: • • 4. Elevated cortisol levels that fail to fall following dexamethasone administration. mental slowing Muscle weakness.Progressive cutaneous pigmentation (result from associated β.

Other endocrine and metabolic complications: It occurs most frequently with large-cell and Adenocarcinoma types. Most other cases respond to NSAID. • Treatment of primary condition produces dramatic response. 2. treatment: Successful resection of tumor deals with this complication. resulting in loosely packed new bone being laid outside the original cortex and this produce the characteristics bony change in plain-X-ray 5. 3. Site: Lower end of radius. B. ulna. Characteristics radiographic findings: 1-2 mm line shadow running parallel to the cortex starting few centimeters beyond the wrist or ankle joint and running for a variable distance along the shaft of the bone. Mechanisms of HPOA in lung cancer:. involve the production of human chorionic gonadotrophin by tumor cells. Plain X-ray: a. c. Pathogenesis: A.     1. Treatment:  Vagotomy is invasive procedures and not indicated except thoracotomy is done in attempt to cure tumor.Lung cancer 33 4. . Remains obscure. active deposition of new bone can be demonstrated by the avid (‫ )النهم‬uptake of technetium in affected area. If the knee is painful proximal part of tibia and fibula with distal part of femoral shaft. 4. this substance results in overproduction of testicular estrogen. • Vagally mediated afferent neural output from the tumor-bearing lung (vagotomy produce symptomatic relief) 6. fibula and hands (if no pain). Bone scan. tibia. 7. The increased vascularity of subcutaneous tissue and periosteum leads to periostitis. Mechanism. b. Corticosteroids may produce similar relief. Drug-induced gynaecomastia should be excluded first. It has been shown that blood flow to the calf and forearm is increased in HPOA and this hyperemia is directed particularly towards connective tissue and bone.Gynaecomastia: . • Remains obscure.

Poliomyelitis / dermatomyositis: Characterized by:    Proximal muscle weakness. An autonomic neuropathy may result in postural hypotension or disturbance of GIT motility. The pathogenesis of neural injury is unknown. including intestinal pseudoobstruction (Ogilvies syndrome). Eaton-Lambert myasthenic syndrome:   . 2. in lung cancer. C.Eosinophilia 1. c. . hypoesthesia. Neuromuscular junction and muscle syndromes: a. Patients with sensory neuropathy usually have SCLC and often have high titer of antibody to the nuclear associated HUD protein. pain and tenderness A variety of systemic symptoms Characteristic facial heliotrope rash.Non-metastatic neuromuscular syndrome: Incidence: a. as well as eosinophilia. B. It is associated with advanced and rapidly progressive disease. It is characterized by high total white cell count. .• Lung cancer 34 If resection is not possible. D. A variety of neuromuscular syndromes are described: 1. sensory or mixed it accompanied by muscle weakness and wasting with loss of tendon reflexes and stock and glove Associated with SCLC Often precede the discovery of underlying tumor. 3. in neural tissues. Motor. It occurs in 6% of patients with SCLC. It may result from increased bone marrow production of an eosinophilic chemotactic factor. Peripheral neuropathy: A. In contrast to myasthenia gravis the muscle weakness improves with repeated efforts. b. 2. Para neoplastic neurological syndromes have long been described Causes: It thought to result from cross-reaction to anti-tumor antibodies with antigens also present b. then anti-estrogen such as Tamoxifen may be effective in reliving symptoms.

It dose not respond to cytotoxic chemotherapy. 3. 1. Treatment: a. b. b. Common early findings are slight prominence of a hilar shadow (central tumor) or a small pulmonary nodule (peripheral tumor). Mass: .Lambert myasthenic syndrome. The complexity of investigation should correlate with the patient's suitability for active treatment. To asses the extent of disease. impaired coordination and dysarthria described in patients with SCLC. Some imaging studies can provide information that can help determine if a lung tumor is likely to be benign or malignant. Hilar shadow: By the time. Including if possible the histological type. when there is symptoms PCX-ray show obvious unilateral hilar or perihilar enlargement (primary carcinoma or L. Cerebellar ataxia. b. o Investigations: The purpose of any investigation performed is to: Confirm diagnosis. • Chest X-Rays • PCX-ray is always abnormal in patient with lung cancer at presentation: 1. To determine the most appropriate treatment. c. with nystagmus. which could indicate cancerous spread. 3. c. even in patients with detectable anti-neural antibodies. e. Lung cancer 35 It thought to result from auto-antibody-mediated functional blockade of the voltage-gated calcium channels involved in release of acetylcholine at nerve terminals. Diagnosis of lung cancer I. To determine operability. N). Radiological investigations: Imaging tests are performed to determine if a lung tumor is present. 2. A part from patients with Eaton. Imaging tests are useful to look for enlargement of regional lymph nodes. o a. d. a. immunosuppression including plasmapheresis has not been shown to be beneficial.

this tumor may sometimes produce diffuse ill-defined fluffy infiltrates (due to its tendency to spread along the airways at bronchiolar levels. cavitation may be present • Common in squamous cell carcinoma • It is not a feature of SCLC. Partial or complete collapse of segment. Atelectasis or consolidation ay suggest central lung tumor. and more lucent. True lung abscess.D pleural thickening). it may produce only thin rim of shadowing at lung apex (D. In few cases lymphatic spread from mediastinal or hilar lymph nodes to pulmonary lymphatics. 10. In advanced disease. Pancoast tumor: (thoracic inlet or superior sulcus syndrome): Early stage. The most striking PCX-ray findings are that produced due to mechanical effect of the tunor: bronchial obstruction may cause: 7. Elevation of one or other hemi diaphragm may indicate phrenic nerve paralysis.Lung cancer 36 i. lace-like shadows that may involve one or both lung fields (lymphangitis carcinomatosis) Is often not radiologically seen on PCX-ray. ii. Characteristics displacement of interlobar fissures. Ipsilateral unaffected lobe tend to be hyper inflated. Mediastinal lymph node: A. C. . mediastinum is seen. Peripheral lung cancer produces a homogenous mass shadow Its margin is poorly defined (mistaken for inflammatory diseases) The diameter of rounded lesion is about 3-4 cm at presentation (lesion less than 1 cm is missed on PCX-ray). Cavitation: • When central necrosis occurs in the tumor. 6. 5. lobe or lung. B.D of lung abscess). c. producing fine. b. it is due to bronchial obstruction by tumor and distal stagnation of secretion which lead to secondary infection (consolidation without cavitation is more common). iii. However. widening of superior 9. • The inner lining of the cavity I soften irregular (D. Confirmed by Fluoroscopy or US which show paradoxical movement on sniffing. 4. 8. Bronchoalveolar carcinoma: a. Are frequently indistinguishable from other histological type. Radiologically it resemble pneumonia. but it not respond to antibiotic.

shape. 2. chest x-rays can detect a pleural effusion.11. It collects the image of the chest with a computerized detector instead of on a piece of film as is done with a conventional chest x-ray. New types of chest x-ray: Digital chest x-ray. b. • Common X-ray Appearance Of Bronchial Carcinomas  Abnormal mediastinum  Lymphatic invasion  Lobar or Lung collapse  Unilateral hilar enlargement  Peripheral solid tumour mass  Peripheral cavitating tumour mass  Pleural effusion • 1. For example. Early research indicates the combination of digital chest x-rays and CAD has the potential to greatly improve the efficiency and accuracy of chest x-rays in detecting lung tumors. clearer images. Chest x-rays can be useful for detecting abnormalities other than tumors that may be related to lung cancer. and exact location of a tumor because they collect information in three dimensions instead of two. Computer-assisted diagnosis (CAD). they may erode and destroy adjacent ribs and infiltrate nerves of brachial plexus. A lung tumor can be missed on chest x-ray if it is small or hidden behind a rib. Normal PCX-ray: it may be found if the tumor is small and central. They are also better able to determine the size. The use of the detector instead of film allows for sharper. 3.  Even if the diagnosis of lung cancer is already clear. . Researchers are also testing the use of computers to aid the reading of chest x-rays in an effort to pick up more lung tumors. Following chest x-rays over time can help monitor the course of disease. a chest x-ray may be taken to compare with previous and future chest x-rays. CT Scans CT scans are able to detect smaller tumors than chest x-rays. collar bone. • Lung cancer 37 If enlarged. CT scans are better able to detect enlarged regional lymph nodes. For the same reasons. a.  0. or the breastbone.

PET scans are particular useful for finding cancerous spread to regional lymph nodes and detecting distant metastatic tumors. They are sometimes used after chest x-rays or CT scans to differentiate between benign and cancerous tumors. c.  MRI Scans MRI scans use a large magnet instead of x MRI is not often used in the routine workIn special circumstances. and metastatic tumors all appear as bright spots on a PET scan. PET scans are not generally used as first-line diagnostic tests   a. Primary tumors. Disadvantage of PEF: There are conditions other than cancer that cause positive findings on PET scans (lung infections). •  rays to produce three-dimensional images. However.  up of suspected lung cancer. lymph nodes containing cancer cells. areas of the body with cancer cells show up brighter on the scan than normal tissues. for lung cancer. Substances other than radiolabeled sugar are sometimes used for PET Cancer cells take up more sugar than normal cells because they are growing and dividing rapidly.4. d. b. Indication in lung cancer: a. scans. Lung cancer 38 The continuous nature of data collection by the computer and the reduced effects of movement make CT scans performed with helical/spiral machines clearer and better able to detect small tumors than conventional CT. •   a. CT is superior to MRI for imaging the structures in the chest. Sugar molecules that have a radioactive component are injected into the body and then a scan is taken. . Therefore. MRI may be used to study a particular area that may be difficult to interpret on a CT scan such as lung tumor near diaphragm or the uppermost part of the lung. c. b. in most instances. Principle of PEF: PET Scans PET (positron emission tomography) scanning is a relatively new technology.

b. Samples may be collected on three consecutive days to increase the chances of finding cancer cells.   . this does not rule out the possibility of lung cancer because sputum cytology is positive in only 5-20% of people with lung cancer. Large size tumor. vi. Lesion situated in lower lobes. It provides information about histological typing (biopsy) and extent of disease. First sputum in the morning or one produced after bronchoscope tends to produce a higher positive yield. It gives better results if: ii. Sputum cytology:  Examination of expectorated sputum from patients suspected of having lung cancer is a simple and valuable diagnostic aid. One sample gives positive yield in 40% of cases. as not all malignancies are positive on PET scan (such as bronchoalveolar carcinoma). iii. Squamous cells carcinoma and NSCLC give higher positive yield. Multiple samples. II.  Tumor is centrally located.  Collection of adequate samples is extremely important: a.   A definitive diagnosis of lung cancer may be made in 60-70% of cases. v. Positive yield increased with multiple samples. if cancer cells are not detected.b. Invasive procedures and tissue diagnosis: • • The only way to make a certain diagnosis of lung cancer and determine the type of lung cancer present is to examine a sample of the tumor under the microscope. Tumor that situated centrally on PCX-ray is visible bronchoscopy as an intraluminal mass. However.. Bronchoscopy  Bronchoscopy is the most common technique used to biopsy a suspected lung cancer. III. c. iv. The method used to obtain a biopsy depends on the size and location of the tumor or lymph node being tested. Lung cancer 39 PET is not useful as screening.

node). c. Any evidence of mediastinal involvement. but imaging studies failed to show a lung tumor. suggested by: vocal cord paralysis. Tumors and other abnormal cells naturally glow when exposed to specific types of fluorescent light. A modified bronchoscopy procedure that uses fluorescent light to detect potentially cancerous areas of the airways. Intraluminal mass. node involvement). TBNA). Bronchoscopy is particularly useful for: i. C. c. Blind brushing and washing Transthoracic needle biopsies. Lung cancer 40 The presence of tumor is indicated bronchoscopy by: a. Advantages: • This technique helps to identify suspicious areas in the airways to sample. • It is also better than standard bronchoscopy for detecting lesions that may be progressing to lung cancer (premalignant). • It is particularly useful for people whose sputum cytology test showed cancer cells. Tumors that are not visible via bronchoscope. b. usually in the central part of the lung. biopsy is obtained by: iii. Or external compression (tumor mass or lymph   Tissue samples from lymph nodes in and around the lungs can also be obtained with a bronchoscope. External compression of lateral wall lower end of trachea by enlarged Para tracheal lymph node. Trans-bronchial technique (TBNX. Endobronchial site of tumor. LIFE Lung Bronchoscopy:  . Obtaining tissue samples from tumors growing in the larger airways. Widening of main carina (subcarinal lymph Bronchial stenosis. B. Bronchoscopic evidence for inoperability is provided by: A. ii. b. positive results have been made in about 60% when the tumor  mass is greater than 2 cm in diameter  Auto fluorescence bronchoscopy is: a.

• Lung cancer 41 This is a special blue light bronchoscope which can see cancerous changes in the lung airways earlier than they would appear This allows cancer to be detected earlier in the screening process. . B. stomach. Technical problems: . pancreas & colorectal carcinoma. • Selection of therapeutic modality of ELC. recurrences after previous treatment. • Nodal staging.Endoscopic ultrasound (EUS) .Assessment of peribronchial (PB) pathology.Air in the lumen & lung parenchyma.Catheter-based miniature transducers. II. • Guiding bronchoscopic procedures in endosmotically invisible lesions. with a normal bronchoscope. . Inefficiency of conventional methods • Tumor staging: . . . .Displacement of US probe by respiratory movements & cough. and it is also an excellent way to monitor for lung cancer Endobronchial ultrasound (EBUS): EBUS a new method for assessment of lung cancer • Are the available methods inefficient? • What will it add beyond the available methods? I. . IV. Lung cancer? III. Indications 1. Tomographic images of the tracheobronchial wall and adjacent peribronchial areas through advancing an US probe inside the bronchi. • Application: .Infiltration of mediastinal structures. Esophageal.Ggenitourinary tract followed by GIT. Endoluminal ultrasound Basis: .US probes originally designed for intravascular application.Estimating the exact depth of tumor invasion to bronchial wall and extent of early lung cancer (ELC). .A. .Complex unusual mediastinal planes.

Lung cancer 42 2. Inhalation (4%). Atropine sulphate. . . VII. ELC. Extra-luminal lesions & Lymph nodes: . Nodal & Vascular Anatomy of Mediastinum . . . .Combined rigid & FOB.Lidocaine: . Qualitative diagnosis???. Assists in TBNA.Nodal (N): additional LN & assist TBNA. • Clinical applications in Lung cancer: . Indications & clinical applications Indications: .Therapeutic bronchoscopy. • Topical anesthesia: . VIII.Tumor (T): depth. mediastinal & peripheral lesions. Positional relationships of the lesion to bronchial lumen & mediastinal structures. ± Salbutamol + Ipratropium bromide solution. .Assisting bronchoscopic procedures of extra-luminal. General or topical anesthesia General anesthesia: . impression Vs invasion of mediastinal structures & vessel. Prednisolone (COPD). Oxygen supplement and Pulse-oxymetric monitoring.Peripheral lesions: . . V. Titrated midazolam sedation. Identifies. . .Premedication:. . Pethidine. Identifies & localize lesion. localize lesion & assists TBX. . Instillation (2%).Therapeutic bronchoscopy. 3. Determining the depth of invasion of intramural tracheobronchial tumors. . .

g. selecting proper stent size.Lung cancer 43 IX. X. guiding tumor debridement. EBUS . 7 desaturation & 1tachycardia).  No more fatal Haemoptysis during thermal ablation. .Partially tolerated 22% (14 Cough. Side effects & tolerability Topical anesthesia: N = 81 .Not tolerated 1 %( 1severe cough) • General anesthesia: .assisted therapeutic bronchoscopic procedures  EBUS guided or changed management in 43% e.Completely tolerated 77% .

• interventions. Mediastinoscopy is usually performed as a diagnostic test in people who have centrally located lung tumors that can be reached from the mediastinum. A. or fluoroscopy. Concerns • Operator dependent. Saving expenses of further invasive diagnostic procedures or unneeded surgical XI. 4. • Its addition can improve the diagnosis and assessment of lung cancer. • Initial instrument handling difficulties. . 3. • Providing valuable beneficial additional information beyond bronchoscopy and CT alone. but reducible with acquisition of experience. • Acceptable prolongation in examination time.Lung cancer 44 . It is usually reserved for people who have tumors near the surface of the lung that would be difficult to reach by bronchoscopy. Conclusions EBUS application under topical anaesthesia: • Well tolerated. X. Mediastinoscopy is often used for both diagnosis and staging. • Prolongation of examination time ~ 6-12 min. Mediastinoscopy is a surgical procedure in which a rigid instrument called an endoscope is inserted through a small incision at the base of the neck or near the breastbone into the mediastinum. • Sampling is assisted not guided.Published reports made no reference to possible complication of GA. 2. taken during the procedure. • Mild infrequent side effects. Mediastinoscopy is performed under general anesthesia. Biopsies of the primary tumor and mediastinal lymph nodes are Transthoracic Needle Biopsy= fine needle aspiration (FNA) biopsy. • Depth of invasion: experimental Vs clinical studies. This procedure is performed using either CT . • Further expected technical improvements will allow EBUS to play a more important role in diagnostic and interventional bronchoscopy in the near future.Rare desaturation & tachycardia. B. Mediastinoscopy 1.

the surgeon will sample regional lymph nodes to determine if a surgical cure is possible. Thoracoscopy 1. Is surgical procedure in which an endoscope is inserted into the chest. and a mild sedative is used to relax the patient. the lymph nodes are examined while the patient is still in the operating room. 3. Advantages: a. 2. Blood tests and lung function testing are also necessary to assess whether the V. 2. Lung cancer 45 Local anesthesia is used to numb the skin where the needle is inserted. 3. Detection of hepatic involvement. b. 2. Laboratory investigations and PFT: Routine laboratory investigations have no diagnostic role in lung cancer except: 1. a potentially curative operation will be performed. doctors are unable to biopsy a suspicious lung tumor using IV. but is sometimes used to biopsy a suspicious tumor and regional lymph nodes . Thoracoscopy has limited use in lung cancer diagnosis. a tiny video camera is inserted into the chest by a small incision separate from the incision used for the thoracoscopy. Detection of paraneoplastic syndromes patient is well enough to be operated on. VATS is technique in which: E. In rare instances. 3. VATS and routine thoracoscopy procedures are performed under general anesthesia Pictures of the chest cavity are projected onto a screen 4. Again. Tumour markers= Biomarkers= Oncofoetal:  Definitions: . Thoracoscopy allowing the surface of the lung to be examined Permitting sampling of any pleural effusion that may be present. Thoracotomy 1.C. If surgical cure is possible. G. A thoracotomy is major surgery A biopsy of the tumor is performed and the tissue is examined under the microscope while the patient is still in the operating room. F. during the procedure. other methods. If cancer is found.

8.than. 3. 4. Serum 3. Classification of certain tumors (differential diagnosis of lung cancer). 6. and molecular alterations by which a normal. Clinical management. Plasma 4. 7. Any proteins or chemical has the potential to be a tumor marker.  Disadvantages = limitations in routine use of tumor markers: Measurements of most tumor marker levels alone are often insufficient to diagnose cancer for the following reasons: 1. Tumor marker levels not elevated in every person with cancer. biochemical. abnormal or simply a biological process can be monitored. especially in the early stages of the disease. Buccal cell isolate serve as viable sources of biomarkers 5. Proteins are sometimes measured in urine.2.  Nature of tumor markers: Tumor markers are cellular. 6. they are either produced by tumor cells (tumor-derived) or by the body in response to tumor cells (tumorassociated).normal amounts in the tissue or cells of an organ site. Follow-up of tumor and detection of early recurrence. 5. Specimens used for detection of tumor markers: tumor marker levels can be elevated in people with benign . 3.  2. Lung cancer 46 Are measurable biochemical's that are associated with malignancy. Some tumor markers provide prognostic information (response to treatment) 9. Some tumor marker is elevated in patients with renal failure. Many tumor markers are not specific to a particular type of cancer. Aid in diagnosis of cancer.  Uses of tumor markers: 5. these proteins are present at very low level (undetectable). 4. 6. Tissue-bound receptors that must be measured in a biopsy from solid tumor. conditions 2. for example serum calcium is elevated in some cancer. It is sometimes called Oncofoetal. they are typically released into the circulation and thus measured in the blood. Tumor markers are substance that can often be detected in higher. because it present not only in tumor but also expressed in fetal tissue during normal development In normal individuals. The level of a tumor marker can be elevated by more than one type of cancer.

Some tumor markers for specific cancer: .Lung cancer 47 10. Has limited value in tumors screening.

diagnosis including: ii. It may be used in differential diagnosis of NSCLS (in combination with CYFRA 211). ii. For detection of recurrent disease of SCLC after primary It used to aid the diagnosis of SCLC: High serum levels of NSE (>100 µg/L) in patients with suspicious of malignancy suggest the presence of SCLC with the differentia i. and platelets. Neuron Specific Enolase (NSE): 1. C. Carcinoembryonic Antigen (CEA): A. . Moderate elevation of NSE is found in: . . Hepatoma. . Have considerable potential for the monitoring of treatment of SCLC. .Patients with benign lung conditions. . • Several studies have demonstrated the presence of significantly higher concentrations of circulating DNA in plasma/ serum in patients with different types of lung cancer.Pancreatic cancer. Dose not has the sensitivity or specificity necessary for use in screening.Lung cancer 48 • • Currently available markers for lung cancer: Many molecular changes are present in lung cancers and involve dominant oncogenes and recessive growth regulatory genes including p53 and K-RAS mutations. However.Colorectal cancer. Uses: i. therapy 3. serum or plasma must be separated from RBCs within minutes to avoid false high results. including primary or recurrent lung cancer. Neuroendocrine tumors of other localizations. plasma cells.Gastric cancer.Breast cancer. 2. Lymphoma. Seminoma. B. 2. • Thus. Its concentration is particularly high in adenocarcinoma and large cell carcinoma. ii. its use in screening and diagnosis is limited due to it is elevated in various benign pathologies and other malignancies. quantification of plasma DNA and characterization of specific molecular changes could represent useful biomarkers of lung cancer: 1. Because it present in RBCs.

ProGRP is a reliable marker for SCLC with good sensitivity and specificity.Lung cancer 49 D. It also may detect recurrent disease of adenocarcinoma. 3. a. It may be used for monitoring of SCLC and for detecting recurrent disease after primary therapy G. Cytokeratin-19 Fragments (CYFRA 21-1): CYFRA 20-1 is the most sensitive tumor marker for NSCLC particularly squamous cell carcinoma. it is also elevated in: urological tumor. E. Its value may be significantly influenced by renal failure (high results). CYRFA 20-1 has potential for monitoring treatment of NSCLC in advanced disease. Disadvantage (limit its use in screening and diagnostic c. Gynecological tumors. Recent studies demonstrated CYRFA 21-1 to be independent prognostic factor in both early and late stages of NSCLC. Progastrin-Releasing Peptide (ProGRP): A. It can be used to provide prognostic information in NCSLC (adenocarcinoma). Levels > 300ng /L for SCLC if renal function is not impaired. ProGRP concentration: Levels >200 ng /L are highly suspicious for lung cancer. Disadvantage: it is elevated in patients with renal failure (up to 300ng/ L. It also has a role for detection of recurrent disease of NSCLC after primary therapy particularly in squamous cell carcinoma. b. tests): • Due to its presence in low concentration in various benign diseases its use as a screening and diagnostic test is limited But. GIT tumor. It may be helpful in the differential diagnosis of suspicious lung mass particularly if biopsy is not possible. e. E. B. Other reports have suggested CYRFA 21-1 may also have prognostic value in SCLC. It has shown to be helpful in differential diagnosis of SCLC from other lung cancers. 5. It is rarely elevated in other malignancies and if so. It may have a role in monitoring therapy in advanced stages. f. D. Squamous Cell Carcinoma Antigen (SCCA): . C. Only one report supports the use of ProGRP in prognosis F. d.). • • • 4. F. its levels are only mildly elevated.

i. Renal failure. or adenocarcinoma) B. of SCLC. Epigenetic Changes: . RB is mutation (inactivation) is: The preferential mechanism in SCLC 90%. Alteration of p53 is observed in 75-100% Meta-analysis found p53 alteration in 47% of patients with NSCLC (squamous. It may be used in differential diagnosis of NSCLC (squamous Potential prognostic utility of SCCA has been reported 6. Oligonucleotide array for p53 mutation appear to be a rabid test of detecting p53 missense mutation in primary lung cancers. Squamous tumors of head and neck. Clinical meta-analysis study suggest that the p53 alteration (by immunohistochemical. Lung cancer 50 Less sensitive than CYRFA 21-1 in NSCLC it has superior specificity for squamous cell carcinoma. 8. b. iii. Squamous tumors of oesophagus. Preanalytical contamination with skin or saliva. 2. large cell. Mutations (inactivation) of p16INK4a have been observed in 30-70% of NSCLC. Disadvantages: It is elevated in: 1. 6. p53: A. It can be used for histological subtyping of NSCLC. or molecular) may be a significant marker for poor prognosis in patients with pulmonary adenocarcinoma. cell carcinoma). Dermatological diseases. 4. ii. P16INK4a: • The two tumor suppressor genes affected in lung cancers are a. D. iv. Squamous tumors of cervix. 7. 5. It is unclear whether the absence of RB expression is associated with poor prognosis in NSCLC. C. v. 3. But mutation of RB may occur in 15-30% of NSCLC.

it causes chemical processes inside the cell that make it grow and divide more quickly than it should.  Epidermal growth factor receptor (EGFR): Role: On the surface of many types of cancer cells. a. Receptors tyrosine kinases are major components in positive signaling cascades. (e. are structures known as epidermal growth factor receptors (EGFRs). (Adenocarcinoma). 10. Overexpression of EGFR is seen: Frequently in NSCLC (squamous cell carcinoma) Rarely in SCLC.  Hregulin receptor (HER2/neu): Is highly expressed in 30% of NSCLC. When the epidermal growth factor (EGF) attaches to the receptor. . - Lung cancer 51 Abnormal DNA hypermethylation is associated with the silencing (suppression) of certain genes including putative or known It can be used in screening test due to: Many of these methylated genes can be detected in histologically uninvolved lung tissue from patients with lung cancer It can be detected in sputum from persons at high risk for the development of lung cancer 9. RAS: b.Drugs known as EGFR antagonists Erlotinib (Tarceva®).15-20 % of all NSCLC. The receptors allow epidermal growth factor (a particular protein present in the body) to attach to them. Its mutations are detected in: .g. d. TSG in human cancer. c. heregulin receptor. epidermal growth factor. some of which are over-expressed in lung cancer. b. C.20-30% of lung adenocarcinoma. HER2/neu over expression is associated with: . and tyrosine kinase receptor-oncogene KIT {CD117}).B. . Receptors Tyrosine Kinase: i. It is unclear whether K-RAS mutations are associated with an adverse prognosis in NSCLC The activated RAS proteins or their downstream components are attractive target for new therapeutic agents such as farnesyl-transferase and geranyl-greanyl-transferase 1 inhibitors. .

Lung cancer 52 i. Shorter survival time. ii. Intrinsic-multiple-drug resistance in NSCLC cells. Trastuzumab (Herceptin TM) a monoclonal antibody that recognizes

HER2/neu and thus blocks its activity (clinical trials of NSCLC).

Gastrin-releasing peptide (GRP). a. Is another important positive signaling pathway in lung cancer. b. It is expressed in 20-60% of SCLC. c. Less frequently in NSCLC. • v. Three myc- family (C-myc, N-myc, and L-myc): iv. Is another important positive growth-regulatory system for lung cancer. It is most frequently activated in SCLC (abnormality in N-myc and L-myc) and NSCLC.

11. Tissue Polypeptide Antigen (TPA):
A. It can be used for differential diagnosis of lung masses when biopsy is not available. B. It also used to assess prognosis of lung cancer, high preoperative levels predict adverse outcome in NSCLC. C. It can be used in combination with other markers to assist in following patients treated for lung, bladder and many other cancers (not specific for particular type of cancer).

12. Tissue Polypeptide Specific-Antigen (TPS):
a. Assessing diagnosis and prognosis, high levels predict adverse outcome in NSCLC. b. Used for monitoring therapy in advanced disease NSCLC and SCLC. c. Detection of recurrent disease, increasing kinetics indicates progressive disease in
NSCLC.

13. Tumor M2 Pyruvate kinase (TU M2-PK): DNA Fragments:
• • • Assessing diagnosis in NSCLC. Monitoring of therapy in NSCLC and SCLC. Detection of recurrent disease, increasing kinetics indicates progressive disease in NSCLC and SCLC.

14. DNA Fragments:
i. Assessing diagnosis (correlate with stage). ii. Assessing in prognosis, high levels predict adverse outcome.

Lung cancer 53 iii. Used for monitoring therapy in advanced NSCLC. iv. For early detection of therapy response in advanced NSCLC, increasing kinetics indicates progressive disease in NSCLC  • Role of tumor markers for early detection of lung cancer: Its role in Diagnosis of lung cancer: 1. There are no reports demonstrating the usefulness of single marker or combinations of markers for the early detection of lung cancer I asymptomatic population or in specific high risk group as smokers. 2. Tumor markers have considerable potential for differential diagnosis and histological subtyping, particularly in lung tumor of unknown origin. 3. Despite its overlap with healthy controls and patients with benign conditions, highly elevated concentrations of CEA, CYRFA 21-1, NSE, SCCA, and ProGRP are suggestive of malignancy. 4. Within the marker profile, the leading markers suggest the most probable
histologies, as follow:

-

Adenocarcinoma CEA. Squamous cell carcinoma CYFRA 21-1 and SCCA. Large cell carcinoma CYRFA 21-1 and NSE. Small cell lung cancer NSE and ProGRP.

5. Most tumor markers including CYRFA 21-1, CEA, NSE, and SCCA correlate with tumor burden. Only ProGRP can reach high levels even in limited SCLC. Normal or slightly increased marker concentrations never exclude any kind of tumor disease or its progression. • Its role in prognosis of lung cancer:

1.
a. b.

NSCLC:
CYRFA 21-1 appears to be the best prognostic markers both in patients with early operable disease and in late advanced disease. In addition LDH, albumin, NSE, CEA, CA 125, TPS, and DNA have shown independent prognostic value.

2.
A.

SCLC:
LDH, sodium, albumin and NSE has shown prognostic value.

B. in SCLC. 

Lung cancer 54 Recent work suggest that (CYRFA 21-1 and Chromogranin A) and (CYRFA 21-1 and NSE) may also be strong indicators for prognosis

Recommendations for use of markers in lung cancer:

VI. Determination of operability:
If the patient is candidate for surgical intervention, further evaluation id carried out to:

a. b. incurable

Assess whether he is fit for operation. Exclusion of metastatic disease, which could render the patient

1.
 •

Assessment for fitness for surgery:
Pulmonary function tests: It is common for PFT to be abnormal in patients with carcinoma of the bronchus due to: i. ii. • Total or partial collapse of large bronchus by a central lesion. Pre-existing COPD.

Careful considerations must be given to the effect of the removal of
functional lung tissue in the tumor bearing-lung to avoid: post-operative respiratory

failure and death, or at best extreme persistent dyspnoea A.
B.

Spirometry is reduced by about 10-15% as after lobectomy and by 20-30% after pneumonectomy.
FEV1 and FVC:

• • • • C. Involvement of mediastinal structures may be evident by: o History of dyspnoea. Other medical conditions: such as IHD and peripheral vascular disease. it may demonstrate that.  a. • • CT: The best non-invasive methods for mediastinal assessment in lung cancer being considered for resections Limitation of CT: . C. Some study suggest that the small and not contain malignant cells it dose not exclude operability (results of operation is poor in such condition). Patients whose exercise is limited by significant intermittent claudication are not suitable for surgical intervention. In general patients with pre-operative FEV1 > 2L tolerate surgery. in such condition operation may produce physiological improvement (by removing the major cause of ventilation/ perfusion mismatch). the patients may have undergone the physiological effect equivalent of pneumonectomy or lobectomy (tumor obstruct airway). assessment of mediastinum is essential in every patient presented by lung cancer by: 1. Pleural effusion: • • • Inoperable. 2. Assessment of local spread: A. Dysphagia. The results of operation correlate well with the extent of mediastinal lymph node involvement. B. o SVC obstruction. Diffusing capacity: post-operative complication is more common if Dlco is less than 40% of predicted before operation. D. b. It should be further evaluated by Aspiration and biopsy. dysphonia. Lung cancer 55 are most reliable measurements in evaluation of suitability for lung resection: Risk of post-operative chronic ventilatory insufficiency is high if the post-operative FEV1 is less than 1 L. Quantitative assessment of regional lung function. Patients who have controlled angina need to undergo exercise ECG. Patients who are considered marginal for surgery require further investigations.

not added advantage over CT.i. • 1.negative rates of about 10% are recorded due to inability to sample all mediastinal structures. irregular live (strong evidence of hepatic metastasis). Lung cancer 56 It can not distinguish between neoplastic and reactive Not detect whether the normal size lymph node contains microscopic deposits of tumor cells or not. lymph node. Abdominal US and Ct: . CT may also be useful for identifying tumor involvement of mediastinum and MRI may be useful in assessing Pancoast tumor and chest wall invasion. Patients who have specific symptoms or abnormal biochemical tests that may point to evidence of distant metastasis should have further evaluation: Liver metastasis: Examinations: • The finding of an enlarged. It leads to better selection of cases for surgery. Radioactive isotopes taken by tumor (gallium). 3. The a authors used 1 cm as the cut off value for normal lymph node size.5 cm as the upper limit of normal value There is a correlation between the nodal size and malignancy (fair). hard. to confirm or refute to presence of metastatic 4. b. some report suggest 1. spread. 3. False. 2. • Elevated value may be due to associated non-metastatic live disease. • Jaundice( unusual presentation) 2. so those with mesiastinal involvement are excluded. • Normal value does not exclude hepatic spread. ii. Assessment of distant spread: A. B. It is indicated for patients who show abnormal mediastinal examination on CT. • • • pleura. LFT: • Should be done routinely for patients with lung cancer (staging). 4. Spread of bronchial carcinoma outside chest makes the patients inoperable. mediastinoscopy: a. c.

Isotope Bone scans: • Is more sensitive than conventional radiograph. fine needle aspiration or liver biopsy may be done (under US or CT guided).Lung cancer 57 • Have the similar degree of accuracy for detecting liver metastasis. CT brain: • Is the investigation of choice when clinical features suggestive of cerebral metastasis are present. vomiting. fits. 3. Histological examination: if there is doubt about hepatic involvement. Symptoms: headache. • Routine CT brain in asymptomatic patients gives low yield and is not indicated as a screening procedure. • It is known that patients who is asymptomatic and have no abnormal biochemical tests have normal bone scan in 95% if cases. 4. but is reserved for those have clinical or biochemical abnormality suggest skeletal metastasis. Pain suggestive to bone metastasis should lead to 1. • There is no need for routine bone scanning in all patients with lung cancer. personality change. Occasionally intra-cranial metastasis may present when the primary tumor is neither symptomatic nor radiologically apparent. and the development of focal . 3. Brain metastasis is common in patients with SCLC. • Bone metastasis: radiography of the affected area 2. • It is better to include the liver and adrenal gland when CT chest is performed for patients with lung cancer. 1. • A false negative rate is less than 2 %. • False positive rates of 40-50% have been reported (increased uptake maybe due to benign bone disease). • Brain metastasis: neurological deficit. 5. 4. 4. 2. SCLC have a much higher incidence of bone metastasis. Symptoms: is usually symptomatic. Radiology: lytic lesions are usually seen. Sometimes biopsy is needed to confirm bone metastasis. in this situation bone scan may be need to determine both the extent of the disease and response to chemotherapy.

scans will be focused on that specific area. a. Determining Metastatic Status • The state of metastasis (M) is defined as follows. asymptomatic metastatic tumors. Generally. It helps to determine which treatments are likely to be most effective for tumor. metastatic disease is often asymptomatic at the time of diagnosis. 3. It also helps determine what the course of illness (prognosis) is likely to be. Definitions: Lung cancer staging is the process of classifying the extent of spread of the cancer from the original tumor to other parts of the body according to standard criteria. and brain • MRI scans . 0. The higher the stage. • M1: Distant metastasis is present. the less the cancer has spread. and local invasion N: regional lymph Node involvement M: Metastasis status. Lung cancer stage is the primary factor influencing the prognosis of the disease. Imaging tests commonly used to screen for metastatic disease are listed below. Under such circumstances. • However. . Aim of lung cancer staging: Staging is important for two reasons: 2. M0: No distant metastasis found.whole body . Lung cancer stages range from I through IV. In general: 7.Lung cancer 58 Lung cancer staging c. I. which necessitates a thorough search for distant. e.Any distant metastasis automatically moves a person to stage IV.Diagnosis of distant metastasis requires less invasive procedures than that required for N or T factors. location. The lower the stage. The three factors of the TNM system are as follows. d. Physical findings and presenting symptoms may raise suspicion of metastatic disease in a specific organ or area of the body.abdomen. doctors try to establish the M factor (a person’s metastasis status) as early as possible in the staging process. the more extensive is the spread of the disease Three factors are used to determine lung cancer stage. . pelvis.brain • PET scans . These factors are expressed using the TNM classification system. 8. T: Tumor characteristics including size. The reasons for this is that: . • CT scans .

the hilar lymph nodes. N0: No evidence of cancer in the regional lymph nodes N1: Cancer in the ipsilateral hilar lymph nodes N2: Cancer in the ipsilateral mediastinal lymph nodes N3: Cancer in the contra lateral lymph nodes or in the supraclavicular area. Tis: Carcinoma in situ. and local invasiveness of the primary tumor. Regional lymph nodes can be sampled and staged with the following procedures. the mediastinal lymph nodes.Lung cancer 59 • Ultrasonography –abdomen and liver. The categories for lung cancer tumor classification take into account the size. II. T1: Tumor that is: Less than 3 cm (1½ inches) in size Completely surrounded by lung tissue T2: Tumor that is: Larger than 3 cm (1½ inches) 3. 4. uses special frequency sound waves to visualize internal organs • Bone scans – whole body. The tumor categories and their descriptors are listed below. Determining Regional Lymph Node Status 1. Hot spots are areas in the skeleton with high uptake of the radiolabeled chemical that may indicate metastatic disease. Tumor characteristics are determined using the same methods used for diagnosis and evaluation of the regional lymph nodes. and the supraclavicular lymph nodes. location. Cancer in lymph nodes beyond the hilar. 3. Although tissue biopsy remains the gold standard for lymph node staging in lung cancer one imaging technology is the combined use of CT and PET scanning known as in-line CTPET scanning. The regional lymph nodes of the chest are divided into three major areas. a radioactively labeled substance that is taken up by actively growing and dividing cells is injected into the body. • Bronchoscopy • Mediastinoscopy • Thoracoscopy and VATS • Thoracotomy 5. . 2. mediastinal and supraclavicular lymph nodes is considered evidence of distant metastasis.    − −  − T0: No evidence of primary tumor. Regional lymph node status is divided into the following categories. 2. A scan is later taken of the entire body to look for ‘hot spots’ in the skeleton. Determining Tumor Characteristics 1. III.

body (a backbone). * T3 cancer is potentially respectable (surgically removable). ii.  The stage I TNM designations are:   Stage IA: T1N0M0 Stage IB: T2N0M0 • Stage II Stage II NSCLC is characterized by: . Tumors associated with a malignant pleural or a pericardial effusion are also T4 tumors. the tumor is 3 cm (1½ inches) or  Stage I NSCLC is local disease and is potentially curable with surgery.  less in size. as are separate tumor nodules in the same lung lobe. the tumor is larger than 3 cm (1½ inches) in size.  The difference between stage IA and stage IB disease is the size of the primary tumor. diaphragm.  .  i.Any size -Invades the chest wall. NSCLC is divided into four stages. NON-SMALL CELL LUNG CANCER STAGES Using the TNM classification system. Therefore. With stage IA disease.  There is no evidence of cancer in any lymph nodes. Generally cancer is divided into four stages: small and localized (stage one). or the pleura of the mediastinum or heart. tumors involving the carina are T4 tumors. • Stage I Stage I NSCLC is characterized by:  A cancerous tumor that has not spread. it may not be operable if the remaining airways cannot be sewn together.  With stage IB disease. or has spread to other parts of the body (stage four).Lung cancer 60 − − the mediastinum. has spread into surrounding structures (stages two or three). T4 tumors are generally inoperable. • • • Still surrounded by lung tissue Not invading the chest wall or any of the structures in T3: Tumor of: T4: A tumor of: Any size Invades the structures of the mediastinum or a vertebral If a tumor is close to the carina.

T2N3M0. or the pleura of the mediastinum or heart. diaphragm. T3N3M0. T4N1M0. T1N3M0. T4N3M0). with or without regional lymph node involvement (T4N0M0.  Stage IIIA disease includes a tumor that has: Invaded the chest wall. c. • • Stage II NSCLC is potentially curable with surgery. and there are significant differences in the treatment of stage IIIA versus stage IIIB disease. T4N2M0. b. spread of the disease beyond the regional lymph nodes. • Stage IV Stage IV NSCLC is assigned whenever there is distant metastasis. People with stage IIIB disease are generally not considered candidates for surgical cure The stage III TNM designations are: • T3N2M0T1N2M0 or T2N2M0 • Stage IIIB: T4N0M0. With stage IIA. Smaller tumors that involve the ipsilateral mediastinal lymph nodes are also stage IIIA (T1N2M0 or T2N2M0). 1. • • 3. or a vertebral body (T4 tumors).A tumor involving the chest wall without hilar lymph node involvement (T3. T4N1M0. although the chance of recurrence is higher.   2. and has ipsilateral hilar or mediastinal lymph node involvement (T3N1M0 or T3N2M0). the tumor is a T2 (greater than 3 cm). Stage IIIB disease includes: • Any size tumor that has invaded any of the vital structures of the mediastinum. A primary tumor that has spread to the ipsilateral hilar lymph nodes (the N1 area).Lung cancer 61 a. T4N3M0 Stage IIIA: T3N1M0. Lesser tumors (T1-3) that are associated with contra lateral lymph node involvement or any supraclavicular lymph node involvement are also stage IIIB. . The stage II TNM designations are: • • Stage IIA: T1N1M0 Stage IIB: T2N1M0 or T3N0M0 • Stage III Stage III is the most complex of the stages. N0) is also considered stage IIB disease. the carina. Stage IIIA is potentially operable. the tumor is a T1 (3 cm or less). that is. With stage IIB.

The TNM designation for carcinoma in situ is Tis. Table 1 gives the lung cancer TNM descriptors according to the International System for Staging Lung Cancer: 1. T2 Tumor with any of the following features of size or extent: b. Since there is currently no organized screening program for lung cancer. surrounded by lung or visceral pleura without bronchoscopic evidence of invasion more proximal than the lobar bronchus. chest wall (including superior sulcus tumors)diaphragm B. Carcinoma in situ is curable and incapable of spreading. The TNM designation for occult lung cancer is Tx. e. d. PRIMARY TUMOR (T)  Tx 1. examination with a bronchoscope. Primary tumor cannot be assessed 2. Special Cases Stage 0 (zero) represents carcinoma in situ. the percentage of people newly diagnosed with lung cancer who have stage 0 disease is very low. parietal pericardium  . mediastinal pleura C.Lung cancer 62 • 1. c.  greater than 3 cm in its greatest dimension may extend into the main bronchus if it remains more than 2 cm from the carina may invade the visceral pleura may be associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung T3 Tumor of any size that directly invades any of the following: A. No primary tumor can be seen on imaging studies or on direct 2. OR Tumor proven by the presence of malignant cell in sputum or bronchial washings but not visualized by imaging or bronchoscopy    T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor less than or equal to 3 cm in its greatest dimension. This unique situation refers to: • • • • The presence of an identifiable area of cancer cells that are confined to a local area and have not grown through the top lining of the lung. Occult lung cancer is another uncommon situation in which: • • Tumor cells are found in the sputum or bronchial washing.

Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1: Metastasis to the ipsilateral peribronchial and/or ipsilateral hilar lymph nodes N2 Metastasis to the ipsilateral mediastinal and/or subcarinal nodes N3 Metastasis to any of the following nodes: Contra lateral mediastinal Contra lateral hilar Ipsilateral or contra lateral scalene Supraclavicular DISTANT METASTASIS (M) 1. 2.Lung cancer 63 2. M1 Distant metastasis present * Separate metastatic tumor nodule(s) outside the lobe of the primary tumor are also classified as M1. most health care providers more commonly categorize SCLC as either limited or extensive stage disease. . M0 No distant metastasis 3. OR: Tumor with a malignant pleural or pericardial effusion 3. This classification system was created by the Veterans Administration Lung Cancer Study Group after it became clear that relatively small differences in the extent of tumor and/or lymph node involvement had little impact on response to therapy or prognosis among people with SCLC. OR: Tumor with a satellite tumor nodule(s) within the same lobe as the primary tumor. Tumor of any size that invades any of the following: Mediastinum Heart or great vessels Trachea Esophagus vertebral body Carina 2. While the TNM system is used for SCLC in some research settings. SMALL CELL LUNG CANCER STAGES 1. REGIONAL LYMPH NODES (N) o o o 1. Mx Presence of distant metastasis cannot be assessed 2. OR: Tumor in the main bronchus less than 2 cm from the carina but without involving the carina may be associated with atelectasis or obstructive pneumonitis of the entire lung  T4 1. OR Direct extension of the primary tumor into intrapulmonary nodes o o 2.

Extensive stage corresponds to stage IIIB with pleural Treatment of lung cancer • Treatment for lung cancer depends on: 3. A cancer is deemed to be resectable on the basis of its staging. 1. presence of metastases and position. Treatment of Non-small cell lung cancer 1. People whose disease is confined to one lung. The operability refers to the patients’ ability to cope with both the operation and the subsequent reduction of lung volume and function II. or is accompanied by distant metastasis. Approximately 70% of people with SCLC have extensive stage disease at the time of diagnosis. Limited stage corresponds to stages I through IIIB of the TNM staging system. . but the disease is operable only in small minority of cases: Prognosis is poor (5-years survival rate is less . 1. Cancer's specific cell type 4. 5. • Patient's performance status. Extensive stage SCLC: Has spread to the contra lateral lung. respectability and operability. There are two main issues to be taken into account when considering surgery for lung cancer. and regional lymph nodes are categorized with limited stage SCLC.Lung cancer 64 3. continued   1. taking into account invaded structures. Surgery: • • Indications: Is only option in NSCLC if the disease is limited to one lung and has not spread beyond its confines. the mediastinum. 3. is associated with a malignant pleural effusion. chemotherapy. effusion and stage IV of the TNM staging system. Table 1: TNM Descriptors. Common treatments include surgery. I. 30% of SCLC has limited stage disease at diagnosis. 2. Surgery is effective treatment for NSCLC. 2. and radiation therapy. People with SCLC are staged with limited or extensive disease based on the extent of the disease in the chest. How far it has spread. than 10%).

3. segmental level. v. b. 15-15% of cases are rejected because of mediastinal spread at mediastinoscopy. Lung cancer 65 2/3 of cases are inoperable due to. 2. Resection of tumor extending from the right upper lobe bronchus into the right main and intermediate bronchi. the remaining lobe or lobes. ii. Lobectomy: it involves: i. other medical condition. ii. in order to stabilize the mediastinum. Sleeve resection is the most common procedures. bronchial stump at the level of carina. Suturing or stapling of the . iii. advanced age. left side. ii. poor respiratory function.a. 2. Removal of tumor and yet conserve part of the lung subtended by the involved bronchus. Hilar and accessible mediastinal lymph node should be removed and labeled according to their site of origin in order to enable more accurate pathological staging. and evidence of tumor spread. iii. Division of pulmonary artery. 3. Hilar and accessible mediastinal lymph node should be removed and labeled according to their site of origin in order to Ligation of pulmonary veins. Only about 12-15% of all patients presented with NSCLC have a potentially of being curable by operation. c. III. iv. Types of operations: 1. Anatomical considerations make it difficult on Underwater seal drainage is mandatory to prevent the accumulation of fluid an due to allow full expansion of Ligation of lobar vessels at the Serosanguineous fluid is allowed to accumulate in the empty hemi thorax. Bronchoplastic procedures: i. enable more accurate pathological staging. Pneumonectomy: it involves: i.

4.

Lung cancer 66 When it carried out, facilities for frozen section are required at operation, to sure that both side of sleeve are clear of tumor.

4. Segmentectomy: i. broncho-pulmonary segment ii. 5. Sublobar resection (extended wedge resection): a. b. Survival rate appears to be equivalent to that of lobectomy; the local recurrence rate has been high. Accordingly, sublobar resection used as a "compromise resection" approach for the management of small (less than 3 centimeters diameter) stage I peripheral NSCLC identified in patients with impaired cardiopulmonary reserve. c. recurrence can be reduced. IV. Complications: • Use of intraoperative radioactive iodine brachytherapy implants at the margins of sublobar resection suggests that local May be done by thoracoscopy. Is indicated for peripheral lung opacity, which is small (less than 2 centimeter diameter) stage I NSC , and confined to

General complications: as any surgical operation.

• Specific complications:

Infections: • Lower respiratory tract infection in residual lung tissue is common. Require antibiotic therapy and physiotherapy. • Postoperative infection of the resected space (empyema), particularly difficult problem especially in upper lobectomy Nerve injury: • Phrenic nerve, it must be scarified in resection of central tumor abutted the pericardium. • Left recurrent laryngeal nerve may be damaged during left pneumonectomy.


ii. iii. V. Results:

Mortality :
Operative mortality has been fallen over the years and it is the reflection of better surgical technique, and selection of cases. Surgery in old age is associated with high mortality rate.

Lung cancer 67 1. Survival for NSCLC after surgery is closely related to the staging of disease and pathological:    Stage 1 tumors carry a 5-years survival rate of 40-60%. Stage 2, 5-years survival rate fallen to 20-50% depending on histology. Stage IIIA 5-years survival rate is 9-13%.

2. Patients with squamous cell carcinoma have survival rate after surgery better than adenocarcinoma at all stages. 2. Radiotherapy: VI. VII. 1. 2. as possible. 3. Radiation or radiotherapy uses high-energy rays to kill lung cancer cells, shrink tumors, and prevent cancer cells from dividing and spreading. Radiation is directed to the area where the tumor is located and injures or destroys the cells by damaging the cells’ genetic material. This kills the cells or makes it impossible for them to grow. 4. Tissue absorption of radiation is measured in grays (Gy). 1 Gy being equivalent to 1Joule of energy absorbed /kg of tissue. 1 Joule/ kg 1 Gy VIII. A. 1cGy (centigray) Indications of radiotherapy: = = = 1 Gy 100 Rad (old units) 1 Rad Treatments are usually administered by means of megavoltage limner accelerator mode of action: Some centers use cobalt-60 as a source for palliative treatment. The collimated beams of ionizing radiation are positioned to produce a tumoricidal dose in an area where the beams cross, with sparing of normal tissue as much

Is the most frequently employed treatment in patients with NSCLC. Palliative radiotherapy is used to achieve symptomatic relief when given in low palliative doses to patients who are inoperable and have appropriate symptoms due to their disease. B. Radical radiotherapy: may offer the chance of cure in a small proportion of patients with NSCLC who are unsuitable for surgery on medical ground, and have operable disease. IX. Mode of administration of radiotherapy: There are two ways in which radiation can be given: 1. cancer. External beam radiation is the most common type of radiation used in lung

Lung cancer 68 The radiation only lasts for a few minutes at each session, and is usually given once daily for 5 days a week for up to 6 - 8 weeks. You will probably not receive radiation on the weekend, which allows the normal cells time to recover.

Another type of external beam radiation is called hyper fractionated radiation. During hyper-fractionated radiation, the daily dose of radiation is given as smaller doses but more than once a day separated by 4 to 6 hours.

2. X. 1.

Type of internal radiation called brachytherapy Radical radiotherapy: this type of treatment is prolonged and requires the good patient performance.

Types of radiotherapy:

A. Indications: it means delivery of large dose of treatment in order to increase patient's survival of even to achieve cure: • 1. conditions. 2. 3. • thorax. B. Methods: • o Planning field of radiation. Patients lie under a large machine called a simulator, which takes x-rays of the area to be treated. Sometimes, a CT scanner or bronchoscopic findings can be used for the same purpose. o o CT of chest gives much more precise location of the tumor (especially tumor in anterolateral plan where lateral film is difficult to interpret. Treatment field should include the primary tumor mass, ipsilateral and contralateral hilar lymph nodes, and the mediastinal lymph nodes. Ipsilateral supraclavicular lymph node may also be included (especially in upper lobe tumor). • Dose of radiation. It is important to determine: a. Total dose of radiation. b. The number of fraction in which it is given. c. Duration of treatment. Provided that the patient general condition is good. Sufficient ventilatory capacity to survive the loss of functioning lung tissue that results from radiation. Stage IIIB NSCLC (inoperable). Provided that the disease is limited to hemi Stage I and II NSCLC: If a patient is unsuitable for surgical intervention due to some medical

ii.Year survival rarely exceeds 20%. Give chance of further assessment of extra-thoracic spread before second course of treatment. Radiotherapy itself may because radiographic changes in normal lung that makes the detection of local recurrence difficult. course. Survival rates are better with in patients with stage I NSCLC. according to site of . • Small numbers of large fraction are less effective than large numbers of small fractions (even the total dose is fixed). Indications: it is indicated in patients with extrathoracic metastasis to relive symptoms by reducing tumor growth and not cure. Many authors report good 1.Lung cancer 69 1. iii. 3. Disadvantage: Cell kinetic studies have demonstrated that tumors may repopulate in the standard intervals between treatments. Results: 2. Split-course therapy: i. Palliative radiotherapy: • • a. Extra-thoracic radiotherapy. Advantage: It added the advantage of initial palliation due to tumor shrinkage with the same side effect.year survival of 30-40%. Regimen: the same total dose is given in two half-dose courses with a rest period of about 4 weeks. while 5.   2. • • metastasis. regular continuous regimen: In general doses of 50-60 Gy over a period of 4-6 weeks are used: • Survival related to the dose of radiotherapy. have the same results of continues  Survival results of radical radiotherapy in inoperable patients are generally disappointing. Methods: Planning field of treatment: Chest irradiation as in radical radiotherapy. Continuous Hyper fractionated Accelerated radiotherapy (CHART) regimen: treatment is given three times daily at intervals of 4-6 hour for 12 consecutive days (to avoid growth of tumor cells in standard intervals between treatment) C.

Dyspnoea due lymphangitis carcinomatosis.  Unfit patients: one treatment of 10 Gy are effective as two treatment of 8. C. Haemoptysis (80%) Thoracic symptoms that relived by B. Improvement is small and dense neurological deficit rarely respond.    b. Dysphagia due to esophageal compression by lymph node responds in (60-86%) E. SVC obstruction responds in (60-86%). Chest pain. spinal cord compression due to tumor:    Corticosteroids should be given Neurosurgery If neurosurgery id not advised palliative radiotherapy is indicated. c.5 Gy. Total dose is usually small (20-30 Gy) given Fit patients: two treatments of 8. G. D. is unrelieved F. Ares of atelectasis. • palliative radiotherapy: A. Bone metastasis: pain is responding to palliative radiotherapy in most cases.5 Gy 7 days apart are equal efficacy to 3 Gy 10 days apart. brain metastasis:  Extra-thoracic symptoms that relived by palliative radiotherapy: brain metastasis: spinal cord Total brain irradiation using 30 Gy dose given as 10 fractions over 2 weeks. in up to 10 fractions:  Lung cancer 70 Dose.b. Distressing cough (60%). . partially re-expand (>25%). more diffuse discomfort is not responding. • compression: a. Dexamethasone is given initially in dose of 16mg/ day may produce temporary relief by decrease intra-cranial pressure. Median survival for untreated patients with brain metastasis is about 3 months. which is due to chest wall or rib involvement (70%).

although occasionally the hair loss is permanent. its margin is characteristically straight. 2. Pale skin may become red and sore or itchy Darker skin may develop a blue or black tinge. 3. Feeling sick Nausea Dysphagia: 2. g. 1. • Radiological changes becoming evident 2-6 months after the completion of treatment. so it is more common in patients 1. Systemic symptoms is not responding to palliative radiotherapy f. Time of start: Towards the end of the course of treatment.  All the side effects should disappear gradually once your course of treatment is over. or head hair if you are given prophylactic cranial radiotherapy. B. • PCX-ray show non-specific hazy infiltrate. local side effects: • Occur following radical radiotherapy. 5. Cervical lymph node enlargement. The hair usually grows back. Paraneoplastic syndromes. hair will fall out within the treatment area. its response is variable and unpredictable. These side effects can be can usually be effectively treated by anti-emetics. matching the shielding around field of treatment. XI. depending on the strength of the radiotherapy dose. Symptoms: difficulty in swallowing. such as chest hair for men. 2. Hair loss: With external radiotherapy. for a few days..Lung cancer 71 d.    Some people develop a skin reaction similar to sunburn. Skin care: 6. 1. 3. 4. 2. general side effects: General side effects. 7. Tiredness. Since the aim in palliative radiotherapy is to relief symptoms and not cure tumor any side effects should be kept to a minimum. undergoing radical radiotherapy. mild or more troublesome. or chest pain. 4. Side effects of radiotherapy Dose related. Radiation pneumonitis: . heartburn and indigestion. Flu-like symptoms such as feeling sick (nausea) and tiredness. Causes: This happens because the radiotherapy can narrow oesophagus. Recurrent laryngeal or frank nerve palsy is not respond. but it is important to tell your doctor if they continue. is not responding to radiotherapy e.

• • • Types: Laser therapy: Definitions of laser: Laser is an electrical device for producing an extremely powerful and narrow beam of light. • Treatment: Symptoms may respond to steroids if in early stage (inflammation). and critical obstruction of airways. Transient and self limiting. Causes: It is due to spinal cord vascular damage and Most serious side effects. • Types: 1. Radiation pericarditis: o Occur 3-6 months after radiotherapy in about 4% of cases. D. except in 10% of cases who complain from gradual onset of dyspnoea and dry cough. • • demyelination. Various types of laser are available but.CO2 lasers can remove a very thin layer of tissue from the surface of the skin without removing deeper layers. A. dyspnoea and ECG changes. Radiation myelitis: • • • radiotherapy. • Symptoms: It is usually not associated with symptoms. o The condition is self-limiting and treatment is symptomatic. B. progression to complete paraplegia with loss of sphincter control may occur. Symptoms: Pain and paraesthesia occur 3 months after Indications: it is used to palliate symptoms such as hemoptysis. radiation. Rarely. Nd-Yag laser is the most commonly used type in respiratory work: Carbon dioxide (CO2) lasers .Lung cancer 72 • Causes: initially inflammation and later fibrosis. • Endobronchial radiotherapy treatments: Course: disappear gradually over a few weeks. C. o It is associated with. The term laser stands for light amplification by the stimulated emission of Laser light can be delivered either continuously or intermittently and can be used with fiber optics to treat areas of the body that are often difficult to reach. sternal discomfort. . The CO 2 laser may be used to remove skin cancers and some precancer cells. XII.

LITT uses lasers to heat areas of the body between organs (interstitial areas) that are near a tumor. D. Techniques deliver high-dose via catheter: a. The heat from the laser increases the temperature of the tumor. or destroying the cancer cells. The initial equipment cost is substantial. 2. thereby shrinking. Its energy evaporates moisture and coagulates blood vessels to a depth of about 5mm. A. at bronchoscopy. The laser light can be carried through optical fibers to reach less accessible internal parts of the body. o Also in symptomatic relief of hemoptysis by coagulation of blood vessels. Method: Photodynamic therapy: .Argon lasers pass only through superficial layers of tissue. • C. • Laser-induced interstitial thermotherapy (LITT) . • such as skin. 3.irradiation to the tumor via a catheter positioned next to tumor b. and special training and certification is necessary. Indications: relief symptoms due to bronchial obstruction caused by tumor or extra-luminal pressure caused by lymph nodes. E. Cannot effectively treat extrinsic compression.Nd-Yag lasers can penetrate deeper into tissue and can cause blood to clot quickly. Mode of action: The beam is transmitted via bronchoscope. Duration of treatment: about 10 minutes. Complications: secondary hemorrhage.• Lung cancer 73 Neodymium: yttrium-aluminum-garnet (Nd-Yag) lasers . damaging. Disadvantages: used only as palliative treatment as most lesions is out of reach of FOB and so out of reach of laser. The fiber can be passed down the suction channel of FOB and the beam is directed against tissue. Uses: o Symptomatic relief of dyspnoea by de bulking proximal endobronchial or tracheal tumor. 1. 3. c.PDT uses argon laser light to activate chemicals in the cancer cells. 2. Photodynamic therapy (PDT) . Argon lasers . d. Method: it delivers high dose.

This drug is activated by laser light delivered at. 5. At the right time (After 24 to 48 hours. destroyed tumor tissue is removed during a second bronchoscopy procedure. Indications: PDT can be used to: help open up a blocked airway.). there is a requirement for multiple bronchoscopies for debridement and possibly retreatment. E. Its results are delayed. Advantages: • • • • It is performed on an outpatient basis It is relatively pain free It requires minimum sedation It has minimal side effects D. patients may experience other temporary side effects.g. Cells throughout the body absorb the chemicals. when the healthy cells surrounding the tumor are relatively free of the chemicals. 3. 3. The light activates the drug which produces a toxic form of oxygen that destroys tumor tissue. The side effects of photodynamic therapy are relatively mild and may include: 1. 6. a patient’s skin and eyes are sensitive to light for 6 weeks or more after treatment is completed.1. 2. and can use for retreating cancers and also for treating very early (in-situ) lung cancers. B. Disadvantages. 4. the red light of an argon laser can be focused directly (bronchoscopy)on the tumor. haemtoporphyrin derivative (has affinity for malignant tissue) which makes tumors respond to the cold red laser light (that react to argon light). Also. Side effects of photodynamic therapy. 2. the direct application of a radioactive isotope into the tumor bed . delivers a high dose to the tumor as compared to the surrounding normal tissue . C. Depending on the area that is treated. via necrosis and sluggish. which last longer in cancer cells than in healthy cells. 4. Lung Brachytherapy: • Brachytherapy. A small amount of damage to healthy tissue. Lung cancer 74 It involves intravenous administration of a light sensitive drug e. One to two days after the laser treatment.

Once the bronchoscope is removed. Forms of Brachytherapy techniques: Endobronchial Interstitial brachytherapy. 3. 1. Duration of brachytherapy: These . can be used intraoperative to deliver a large dose of radiation to a determined target area. To help open an almost-blocked lung airway To help stop bleeding To retreat a previously irradiated lung cancer To use in addition to regular external beam irradiation to increase the radiation dose and chance of cure To use alone for the treatment of in-situ (very early) lung cancers • B. such as malignant pleural mesothelioma and malignant thymoma. • • Method: During bronchoscopy. Other intrathoracic malignancies. B. the placement of the isotope into a tumor bed where no lumen exists. a thin plastic tube is placed down the nose. Temporary interstitial or endoluminal implants (where radioactive sources irradiate a tumor bed over a certain length of time and then are removed). • This effectively treats the cancer from the inside-out. into the diseased bronchus. have been treated with brachytherapy. NSCLC (Brachytherapy can treat submucosal and peribronchial lesions) • • • • 2. and down into the airways of the lung. Permanent interstitial volume or planar implants (radioactive sources permanently imbedded into the tumor or tumor bed). can be in the form of:  brachytherapy. a thin tube remains in place for about 45 minutes.• Lung cancer 75 Lung brachytherapy can be used almost any time a tumor can be seen in an airway on bronchoscopy. delivering a high radioactive dose directly to that site through the segment of the tube which is lying against the cancer. the placement of the source within the airway lumen  A. 4. treatments can be delivered:  Over a short interval (high-dose rate [HDR]). Lung brachytherapy can be used in the following situations:: A.

the results are delayed. radiation delivery is not affected by respiratory movements or by cardiac movements. • • and experience. 6. because the hemorrhage is from larger blood vessels. Advantages: brachytherapy is of value in selected situations and offers the clinician and the patient an innovative method of delivering conformal high-dose radiation to a defined target with preferential sparing of normal surrounding structures. After marking and calculation of the treatment plan. 2. Over a more protracted time (low-dose rate). As the dose is administered from inside the lesion. Prior application of CT-guided bronchoscopic barium marking facilitates the performance of brachytherapy and effectively shortens the procedure time. limited. B. brachytherapy can be performed under fluoroscopic guidance. • a. Disadvantages: it is technical difficulty. . and doses are medical condition is less than ideal to permit other therapeutic modalities. CT-guided percutaneous brachytherapy: Can feasibly be performed with good results. • There are no contraindications to the procedure other than those that would contraindicate basic bronchoscopy.Lung cancer 76  5. Delivering an appropriate radiation dose from inside the lesions while minimizing damage to surrounding normal tissue. Small lesions are difficult to approach even under CT guidance and require a certain level of skill Complication: Hemorrhage from ordinary endobronchial brachytherapy for cancers located in the central bronchi or the trachea is sometimes fatal than those originating from peripheral cancer. Method: A. • Advantages: 1. • • • CT-assisted transbronchial brachytherapy: Indications: is indicated for small peripheral lung cancers in patients whose Disadvantages: complications such as fistula formation and pulmonary artery erosion can occur.

Tomotherapy allows delivering precise and powerful doses of radiation from 360-degrees.b. In both of these conditions there is a need for systemic treatment that is most commonly o Survival: . Lung cancer 77 However. based on individual tumor size. • Method: 1. cytotoxic drugs. c. Chemotherapy : o 2. Use a PET/CT scan to find all the active cancer. Failure of treatment due to occurrence of disease at distant site. Patients have metastatic disease at time of presentation. a radioprotectant drug. shape and IMRT directs radiation at the tumor and modulates the intensity of radiation with laser accuracy 3. Iatrogenic infection and pneumothorax are not significant concerns with a transbronchial approach. Indications: 1. • Advantages: Traditional radiation therapies project radiation on a tumor from a few directions. We add amifostine. the transbronchial approach allows the use of thicker catheters than those permitted by a transthoracic approach. to reduce the damage that radiation can cause to healthy lung tissue. advanced computer program to plan a precise dose of radiation in three dimensions. Tomotherapy : • Tomotherapy is one of the most advanced and targeted forms of radiation available today. and then use tomotherapy to target it. • This new form of therapy combines an advanced form of Intensity Modulated Radiation Therapy (IMRT) with CT scanning technology to deliver radiation with unprecedented accuracy to hard-to-reach areas. in contrast to a transthoracic approach. 3. 5. • Tomotherapy technology enables to re-treat previously treated areas that have a recurrence of cancer. 2. • Two ways that IMRT differs from conventional radiation are: o location o IMRT employs a powerful.

In metastatic lung cancer. It also indicated if residual from tumor is left in chest. Some authors have claimed prolonged survival for patients who respond compared with non-responder. Lung cancer 78 NSCLC are relatively resistant to the drugs currently available. b. The average increase in survival is only 6 weeks Drug regimen: Cisplatin or Carboplatin. The exception to this is Pancoast tumor. the addition of Bevacizumab when added to Carboplatin and Paclitaxel was found to improve survival. surgery and radiotherapy: a. Docetaxel. such as the trinuclear platinum agent BBR3464 . adjuvant chemotherapy may be recommended if lymph nodes within the lung tissues resected (stage 2) or the mediastinum (lymph nodes in the peri-tracheal region -stage 3) are found to be positive for cancer spread . Preoperative radiotherapy: Some tumor may initially inoperable but after radiotherapy and shrinkage of tumor mass become resectable. Paclitaxel. + Gemcitabine. These compounds could be developed in combination with agents such as Paclitaxel. ii. Cisplatin and Carboplatin use is limited by toxicity and inherent resistance. Gemcitabine or Vinorelbine in patients with advanced and/or refractory NSCLC solid tumors 4. it shown to improve local control to chest in stage I and II. It is proved that the rate of recurrence after surgery alone is 70% outside the chest that may be due to occult distant metastasis present at time of surgical intervention. No change in survival.• • • o o o Etoposide or Vinorelbine. b. B. surgery and chemotherapy: • indications: a. Postoperative radiotherapy: i. the platinum complex ZD0473 and Oxaliplatin. These considerations have prompted research into new platinum agents. Combined modality treatment: A.

from gefitinib • Erlotinib (Tarceva) : In recent years.g. inhibitor for EGF). 4. • • K-RAS oncogene is found to be a significant prognostic marker in resected specimens (responders). b. C. possibly due to its role in prevention of micro metastasis. various molecular targeted therapies have been developed for the treatment of advanced lung cancer. radiotherapy and chemotherapy: • Aim: is to optimize local control and to control distant metastasis. 2. Cisplatin and Vinorelbine). although females.• Lung cancer 79 This led to the interest in combining good local control (surgery) with systemic treatment (chemotherapy). it is standard practice to offer patients with resected stage 2-3A NSCLC adjuvant 3rd generation Platinum based chemotherapy (e. which is EGFR antagonist (competitive Indication: typically given to patients with advanced NSCLC that have previously received chemotherapy Gefitinib (Iressa): It targets the epidermal growth factor receptor (EGF-R) which is expressed in many cases of NSCLC.based chemotherapy before chemotherapy gives the modest survival. • Platinum. Targeted therapy 1. nonsmokers and those with the adenocarcinoma cell type appear to be deriving most benefit . Recently: Better results obtained from given it before operation. • a. • 3. Asians. it was not shown to increase survival. • The optimal sequence of chemotherapy before or during radiotherapy is not known. if chemotherapy is given with surgery there is good response and some cases may show increased respectability. The results of surgical treatment on stage IIIA is poor. At present. • There was definite for combined therapy compared with radiation alone. Time of chemotherapy: In the Past give postoperatively (adjunct therapy). 5.

an instrument. to treat people with NSCLC whose: Lung cancer 80 Increase survival in lung cancer patients and has recently been approved by the FDA for second-line treatment of Benefits: It appeared to work best in females. and include diarrhea.Not responded to at least one course of chemotherapy. Asians. . vi. Materials used: Current systems utilize nitrous oxide. v. help to stop the cancer cells from growing so quickly iv. • • • The introduction and availability of small. non-smokers and those with the adenocarcinoma. Liquid nitrogen is then circulated through the probe to freeze the tumor. Mechanism of action: it attaches them to the EGFR inside the cell. Side effects are generally mild 6. Other methods of treating lung cancer: 1. a rash. and prevents the receptor from being activated. this can Indications: It is sometimes used -Cancer has come back after initial treatment . iii. Using a bronchoscope. Endobronchial cryotherapy • Cryotherapy uses extreme cold to freeze and destroy cancer cells. ii.i. called a cryoprobe put. nausea and tiredness. advanced NSCLC. Advantages: -Safe -With no danger of bronchial wall perforation - No radiation danger .No risk of electrical accidents or fires . flexible cryoprobes that can be passed through FOB make it easier to perform. Route of administration: tablet.Does not require laser training and certification. close to the tumor.

obstruction. Benign lesions such as granulation tissue and papillomas may be treated with cryotherapy. which is put inside the airway to hold it open. There appears to be evidence of a favorable impact on subsequent radiation response when cryotherapy is used initially to debulk the lesion being treated. 3. 4. . Airway stents • Sometimes an airway can become blocked by pressure on it from the outside. Indications for cryotherapy: Malignant lesions. The stent can stay in lung permanently and should not cause any problems. 2. It can be useful in helping extract foreign bodies. called a stent. It is inserted through a bronchoscope in a folded up position and as it comes out of the end of the bronchoscope it opens up. Lung cancer 81 Disadvantages: include delayed results and the requirement for multiple endoscopies to remove debris or to retreat. and mucus plugs. ( inappropriate for management of acute airway obstruction). This pushes the walls of the narrowed airway open. which makes it close. 2. Cryotherapy may be effective in treating airway strictures due to granulation tissue after lung transplantation as well as tracheo-bronchial • Combined modalities: Cryotherapy may be combined with other modalities such as radiation therapy and chemotherapy. • • Stents are usually put in under a general anesthetic. that local therapy resulting in destruction of the bronchial mucosa alone may not be curative in early cases since regeneration of the mucosa proceeds from sub mucosal glands that may harbor neoplastic cells. This can sometimes be relieved using a small device.• • 1. clots. like an umbrella. • Use of cryotherapy with curative intent in early lesions (carcinoma in situ). usually squamous cell or adenocarcinoma of the lung. Treatment is usually palliative for hemoptysis and dyspnoea but the effect is delayed. • The most commonly used stent is a little wire frame. 5. But there is evidence. Lesions such as suspected carcinoid tumors might be frozen first to reduce the risk of hemorrhage during biopsy.

to destroy cancer cells. Tumors in the superior sulcus: 1. Guidelines for treatment of NSCLC The following recommendations for treatment are based on guidelines produced by the National Cancer Institute: Stage 0: 1. Surgery is the treatment of choice 2. Inoperable patients may be given radiotherapy in an attempt to cure. radiotherapy with curative intent. . The stent can usually be put in under local anesthetic. Local therapy for such tumors is therefore more likely to achieve cure. 3. uses an electrical current passed through a needle. Alternatively with endoscopic phototherapy in some patients. Diathermy Diathermy. Stage IIA and IIB NSCLC should be treated similarly to Stage IA and IB NSCLC with surgery. Surgical resection 2. Surgery alone is indicated in a very select number of cases. 3. . Prognosis is poor. or by putting a stent in the blood vessel to keep it open. Stage IIIA 1. however there is a long term survival benefit in 5% to 10% of patients with radiotherapy.• Lung cancer 82 Stents may also be used if SVC has become blocked by the cancer. The stent is inserted through a small cut in the groin and passed up through the blood vessels to the chest. with postoperative radiotherapy likely to improve local control. Stage IA and IB 1. which is sometimes known as electrocautery. Again careful pre-operative assessment of the patient must be undertaken before surgery. 2. This can usually be relieved by radiotherapy. Stage IIA and IIB 1. 2. Patients who have undergone resection should be considered for trial chemotherapy to combat the occurrence of metastases. 3. 2. Such trials examining: Fractionation schedules Endobronchial laser therapy Brachytherapy Combinations of treatment modalities may improve survival in this category. Often cause problems due to local invasion and have a reduced tendency for distant metastases. Patients who require a thoracotomy to prove the presence of non-resectable disease and those with excellent performance status should be considered for clinical trials.

When agents are combined together the results are better. 4. but if used singly their duration of action is brief with minimal effect on survival.3. Stage IV 1. Tumors directly invading the chest wall can often be cured with surgery alone. Cyclophosphamide 2. Without treatment the median survival for patients with limited disease is 6-8 weeks.Cisplatin + Gemcitabine . Treatment of Small cell lung cancer • • • • 1. 3. Stage IIIB: Stage IIIB is best managed with chemotherapy and radiotherapy alone or in combinations. At presentation 70% have extensive disease. Doxorubicin. Chemother apy: o o o SCLC is sensitive to chemotherapy. Ifosfamide. there are many combination regimens associated with a similar outcome: . Response in range of 10-40% (if used alone) is seen with: 1. and patients with extensive disease have worse survival.Cisplatin + Vinblastine + Mitomycin . Stage IV patients are suitable for palliative relief of local symptoms by radiotherapy. 2. o . The disease expressed in terms of limited and extensive disease. Many drugs are effective against this tumor. Chemotherapy can be offered to patients. Patients usually present with short history and evidence of metastasis. Vincristine 4.Cisplatin + Vinorelbine .Cisplatin +P . Lung cancer 83 Surgery and radiotherapy separately or in various combinations may be curative in some patients. so this now is considered the accepted modality for most patients presented with SCLC. Cisplatin. 5.Carboplatin +Paclitaxel II.

For example:  spindle formation. iv.o Lung cancer 84 The cytotoxic substances used in chemotherapy act on different stages in the process of cell division. + Etoposide or Ifosfamide. combinations with Gemcitabine. o o • • • • Disease may show objective response (partial or complete). . Cisplatin or Carboplatin. iii. Cyclophosphamide+ Doxorubicin+ Etoposide. they are affected more than normal cells. usually lasts a few days. 3. injection or sometimes as tablets. the addition of Bevacizumab when added to Carboplatin and Paclitaxel was found to improve survival. • Route of administration: i. Topotecan and Irinotecan are being studied In metastatic lung cancer. After having chemotherapy there is a rest period of a few weeks (3-4 weeks). Paclitaxel. which allows the body to recover from any side A session of chemotherapy The drugs are given by IV • Treatment with platinum requires hydration and anti-emetic therapy. As cancers are rapidly dividing. Vincristine inhibits the formation of microtubules preventing o  Doxorubicin inhibits DNA and RNA synthesis. targeting the process of cell division. The number of sessions will depend on the type of cancer and how well it is responding to the drugs. These drugs. Cisplatin + Etoposide.8-10 months in extensive disease. effects of the treatment. o Median survival rate is: . . Vinorelbine. recently: 1. Drug regimens that used are and give predictable results are: Cyclophosphamide + Doxorubicin + Vincristine. ii. thus have a greater effect on cells that are rapidly dividing than those that are not. 2.14-16 months in limited disease. This activity also accounts for side effects such as alopecia and myelosuppression caused by such drugs.

The main problem with increasing drugs is that the side effects also increased. Unless the disease is progressive or patient cannot tolerate the • • • • a. scanning or bronchoscopy. The principle drug-related toxicity that threatens life is myelosuppression. diameter. treatment. B.Lung cancer 85 • Assessments: A. Response: measured in response rate (oncologist): Partial Response: Shrinkage of tumor by at least 50% in a measurable Duration: patients should be assessed for response to treatment after a minimum of 2-3 cycles. it is not often known whether the changes in radiographic opacity are due to tumor or perhaps to atelectasis or consolidation around tumor. Replacement of patients own bone marrow. Which can be overcome by: Autologous bone marrow transplantation: • chemotherapy. Give high dose chemotherapy that normally cause complete bone marrow failure and eradication of disease. Attempts to overcome this by cleansing the bone Bone marrow taken from patient before starting . • • • • marrow after harvesting. and 25% with extensive disease.  i. Measuring a shadow on PCX-ray gives definite data but.  • • Complete response: Total removal of all tumors as evaluated by physical examination. ii. Disadvantage: Malignant cells may be harvested as well as normal bone marrow cells (patient received untreated cancer cells). Seen in approximately 50% of patients with limited disease. High-dose chemotherapy: Combination of 2 or 3 drugs give better results than single drug (dose-response relation ship). radiology.

Course: Blood cells will then increase steadily and will usually have returned to normal before next course of chemotherapy.Suddenly feel unwell (even with a normal temperature). 3. .g. it will grow back over a period of 3–6 months.b. Sign of infections: . Granulocytes colony stimulating factor. 4. It is important to allow yourself plenty of time to rest. Feeling sick vomiting. Duration: This effect can begin seven days after treatment and resistance to infection usually reaches its lowest point 10–14 days after chemotherapy. 6. Anemia chemotherapy can also reduce the production of platelets. Sore mouth Some chemotherapy drugs can make your mouth sore and cause mouth ulcers. Regular mouthwashes can help to keep your mouth clean and relieve any soreness. Lung cancer 86 Other strategy involves the use of hematopoietic growth factors that can stimulate normal haematopiosis e. Bruising or bleeding. Although they may be hard to bear at the time. Maintenance therapy is of no value but retreatment on relapse is worth while. 7.  1. There are now very effective IV anti-emetics (metoclopromide and ordansetron) to prevent or reduce nausea and vomiting. However. and E. many people have few side effects: Lowered resistance to infection: • • • • Causes: the chemotherapy can reduce the production of WBCs by the bone marrow. Tiredness You may feel tired and have a general feeling of weakness. • • • 2. these side effects will gradually disappear once your treatment is over. Precautions: a blood test before having more chemotherapy. Side effects of chemotherapy: Chemotherapy can cause unpleasant side effects.broad spectrum antibiotic. Aeruginosa. 5. Some people prefer to use hats or scarves rather than a wig (‫)باروكة‬. Organisms: staph.Temperature goes above 38ºC (100. Aureus. This may make you feel tired and breathless. If fall out.coli Treatment of infection: immediate .  Scheduling: patients receive chemotherapy for SCLC should receive. Hair loss Unfortunately. Ps. hair loss is another common side effect of some – but not all – chemotherapy drugs.5ºF) . if possible no less than 4 courses and no more than 6 courses of induction therapy. It is also due to bone marrow Some of the drugs used to treat lung cancer may cause nausea and suppression.

Lung cancer 87 • • • • Palliative chemotherapy: Reason for use of palliative chemotherapy: In general the results of chemotherapy in terms of long term survival are poor and associated with many side effects. oral Etoposide form the bases of this regimen. Distressing symptoms (haemoptysis. intractable cough). Recently. and so it is to be expected that the combining radiotherapy with chemotherapy might improve survival. Other authors believe that if patients are fit to have chemotherapy it should not be withheld since good control of disease and good palliation go together.. and SVC obstruction. the use of simple more gentle chemotherapy regimens that have minor side effect and good palliation of symptoms is tried. 2. 2. • • Radiotherapy: SCLC is more radiosensitive than NSCLC. localized pain. Dose: At least 40 Gy are required for a clinical response. A more difficult problem can be whether to treat patients with extensive disease who have poor performance status? No chemotherapy is given to these patients as there is no realistic prospect of useful palliation or improvement in quality of life. 2. Some authors believe that patients who have no symptoms should be left until they develop symptoms and then palliated. • • • 1. Indications: The precise role of radiotherapy in SCLC remain undefined. Symptoms arising from CNS metastasis. • Dose of palliative chemotherapy: Etoposide capsule were administrated for 5 days to a total dose of 800mg /m2. it may fulfill a useful role in palliation of: 1. • 1. but this dose is associated with . 2. Primary tumor control: The primary site is by far the most common location for disease to relapse after failure of chemotherapy. bone metastasis. Palliative chemotherapy means less than 4 courses chemotherapy. Advantages: The majority of patients under going palliative chemotherapy reported disappearance of local symptoms and decrease of systemic problems such as anorexia. • toxicity. a feature not seen with radiotherapy.

Or have local symptoms attributable to the disease.• • • • • 3. Indications:   Not advised as a routine treatment in SCLC. Cytotoxic drug in general do not cross blood brain . Accelerated fractionation allow for frequent treatment to be given in shorter time. Indications: in order to submit patients with SCLC to chest radiotherapy as an adjunct to chemotherapy they should have: • • • Limited disease at presentation. 4. The reasons for its use are: • • barrier. Should only be given to patients with limited stage SCLC. • Prophylactic cranial irradiation: 1. confusion and additional neurological deficits. The theory behind hyper fractionation and accelerated schedule is to optimize the effects of radiotherapy and allowing normal cells to recover. with memory loss. Lung cancer 88 Scheduling effect is also important (therapeutic ratio of radiotherapy increased with division of total dose into fractions). 2. The use of prophylactic cranial irradiation is controversial. 5. • The incidence of brain metastasis increase as survival prolonged by chemotherapy. Disadvantages: • Acute organic syndrome. who are in complete remission after chemotherapy. 3. A large than standard dose 2 Gy produces a large kills of tumor cells.  Palliative cranial irradiation is often helpful in relieving symptoms due to cerebral metastasis. Seen 6-8 weeks after treatment. Irradiation of the brain dose not of course prevents new metastasis in relapsed patients (so term prophylactic is inappropriate). Dividing the total daily dose into smaller fractions (hyper fractionation) improve therapeutic index. Show complete regression with chemotherapy. but it may also affect normal cells. Brain is the common site for spread of SCLC.

 efficiency compared to Paclitaxel. High incidence of mixed histology or a conversion to NSCLC histology following chemotherapy. Newer drugs in the treatment of small cell lung cancer  fail. combined modality therapy is possible in SCLC. High local control rate. 4.  SCLC. 2.  SCLC. 6. o Surgery: Patients with limited SCLC treated with chemotherapy and chest radiotherapy have high incidence of local recurrence. These drugs are mostly used when the initial chemotherapy with Cisplatin and Etoposide It is to be noted that new study from Japan has shown that combination of Irinotecan plus Cisplatin may be superior to combination of Cisplatin and line treatment (when the cancer recurs after treatment with Cisplatin and Etoposide) and is approved by FDA for this indication.  Etoposide.Lung cancer 89 • Late neurological toxicity. Irinotecan: This is a promising drug in the treatment of Guidelines for treatment of SCLC The following recommendations for treatment are based on guidelines produced by the National Cancer Institute: . 3.  Topotecan: This drug has proven efficiency in the second DEcetaxel: This drug appears to have slightly lower Paclitaxel: This drug may be effective in the treatment of These drugs have limited role in the initial treatment of SCLC. So they conclude that. Dexamethasone is also useful in patients with cranial metastasis from SCLC. o Studies done on group of patients with limited disease treated with preoperative chemotherapy followed by surgical resection show that: 1. and this led investigator to re-explore role of surgery in combination with other treatment in limited stage SCLC.

CAV: Cyclophosphamide + Adriamycin + Vincristine CAE: Cyclophosphamide + Adriamycin + Etoposide EP or EC: Etoposide + Cisplatin or carboplatin ICE: Ifosfamide + Carboplatin + Etoposide Radiotherapy to sites of metastatic disease unlikely to be immediately palliated by chemotherapy. Surgical resection followed by chemotherapy or chemotherapy plus chest irradiation (with or without PCI) for patients in highly selected cases. (NSCLC).Lung cancer 90 Limited Stage SCLC: • • • irradiation: o o • EC: Etoposide +Cisplatin + 4000-4500 cGy chest radiation therapy ECV: etoposide + Cisplatin + Vincristine + 4500cGy chest radiation therapy Patients who achieve complete remission may also be given prophylactic Chemotherapy is the mainstay of treatment for limited stage SCLC. Treatment Options: Combination chemotherapy with one of the following regimens and chest cranial irradiation (PCI) in an attempt to prevent CNS metastases. 1. EGFR antagonist: EGFR is transmembrane receptors which constitute a potential growth signals. especially brain. 2. . Monoclonal antibodies against EGFR (C225. (NSCLC). ZD1839. 2. ImClone) are under trial in combination with chemotherapy. thoracic irradiation is seldom used because of the presence of Treatment Options: Combination chemotherapy with one of the following regimens with or without PCI is well reported and has been shown to have similar survival benefits. Tyrosine kinase inhibitors (CP35774. Extensive stage SCLC: • metastatic disease. • New therapeutics agent under trials in treatment of lung cancers: 1. • Second line therapy can achieve a survival benefit in patients with recurrences. epidural and bone metastases. Combination Chemotherapy (with or without PCI) especially in patients with impaired PFT or poor performance status.Iressa) are tried with advantage of being orally active. • • • • • • Chemotherapy regimens similar to those used in limited disease are used in extensive disease.

Treatment can often be given that will not completely get rid of the tumor. as well as GRP antagonist referred as Bombesin. but it may lead to unexpected bleeding from large necrotic lung tumor masses. Lung cancer 91 Clinical trials investigating chemotherapy combined with Trastuzumab (monoclonal antibody to Her2/ neu) are in progress. In-vitro re-introduction of p16 into tumor cells of a wild RB suppresses SCLC growth. Among the anti-apoptosis strategies in preclinical trials are studies of antisense BCL2 in SCLC (down-regulate BCL2 protein expression). but will help to relieve symptoms by. The necessity for RAS protein to undergo farnesylation to become active has led to the development of specific inhibitors of farensyltransferase enzyme.3.MYC expression and decrease N-MYC expression. (NSCLC).trans-retinoic acid appears to e associated with increased L. Flavopiridol is a compound which inhibits CDK is being tested in clinical trials. Antisense therapy strategies directed at down-regulating MYC expression are under trials. Targeting VEGF with humanized monoclonal anti-VEGF. 5. Adenoviral mediated p53 gene transfer delivered by direct tumor injection appear feasible when given in conjunction with radiation therapy. and specific BCL2BCL-xL antisense to target both SCLC and NSCLC. Also trials of vaccination with mutant K-RAS peptides are under trials. Other potential also to block RAS include antisense treatment. Preclinical studies showed that resorting of p53 function resulted in apoptosis of cancer cells. 8. 4. Gastrin releasing peptide inhibitors with neutralizing monoclonal antibody. Treatment of advanced lung cancer If the lung cancer is advanced it can sometimes cause problems such as breathlessness and a hoarse voice. 7. • • • • • Laser therapy Airway stents Cryosurgery Diathermy PDT . 6. Vaccine trials with mutant p53 peptides are also being performed. BCL. Therapeutics manipulation of MYC expression for instance the growth inhibition of SCLC cell line by all.XL antisense in NSCLC. 9. 11. and inhibition of protein expression. 10.

• There are several cancer screening programs in US. In the absence of lung cancer screening and early detection. • There is no screening program for lung cancer ? The reasons are complex and There are two major problems: 1. 2. • Clinical researches of lung cancer screening and early detection suggest such a program should have the following components. • • A Program Model There are two known facts 1. • Given these two known facts. washings or sputum samples are both - X-rays are not a useful screening tool as tumors are not generally visible until they reach an advanced stage.Lung cancer 92 Lung cancer screening and early detection Cancer screening • Definition: Is testing performed on apparently healthy people to detect unrecognized cancer. Most lung cancers are present for many years before symptoms of the disease appear. There is a lack of understanding of premalignant conditions and the natural history of lung cancers. It is also difficult to easily obtain a representative sample: biopsy is too invasive bronchial unreliable. • The purpose of cancer screening is to identify people with the disease so that measures can be taken improve their prognosis. the outcome is dramatically better when the disease is detected at an early stage and surgically treated. most people with lung cancer cannot be cured because the disease is already too advanced at the time of diagnosis. . • Breast cancer – mammograms and monthly self-breast exams • Cervical cancer – Pap smears • Colon cancer – sigmoidoscopy and occult blood tests • Prostate cancer – prostate specific antigen (PSA) tests and physical examinations • controversial. 2.

helical/spiral CT scans. crack cocaine).g. although we do not yet have such a test. EGFR antagonists: •   On the surface of many types of cancer cells. or family history about appropriate testing. a questionnaire or interview to get information about lung cancer risk factors such as smoking history (tobacco. Computed tomography (CT) scanning is now being actively evaluated as a screening tool for lung cancer. Primary prevention  Smoking cessation is the most important preventative tool in this process. An assessment of risk i.e.  Policy interventions to decrease passive smoking (e. Screening and secondary prevention Because prognosis depends heavily on early detection there have been several attempts at secondary prevention:  Regular chest radiography and sputum examination programs were not effective in early detection of this cancer and did not result in a reduction of mortality. possible tests that might be used include standard chest x-rays. When the EGF attaches to the receptor. 2. An educational component to inform the general public especially those at risk of lung cancer due to smoking history. such testing could identify people at risk who may need close monitoring  Smoking cessation counseling and treatment to help those addicted to nicotine overcome their habit Prevention 1. and family history of lung and other epithelial cancers . and it is showing promising results. digital chest x-rays. occupation. tumor markers. 3. exposure to lung carcinogens.Lung cancer 93 1. sputum-based tests. The receptors allow epidermal growth factor (a particular protein present in the body) to attach to them. are structures known as epidermal growth factor receptors (EGFRs). in restaurants and workplaces)  Test your home for radon by radon detector 2. it causes chemical processes inside the cell that make it grow and divide more quickly than it should. marijuana. A testing program which could have several components :  Imaging studies of the lungs and other early detection test. this is an active area of research. or other tests that are currently being developed  Tests to determine genetic susceptibility to cancer. .

iv. iii. ii. or has not responded to at least one course of chemotherapy. Is an EGFR (epidermal growth factor receptor) antagonist. mesothelioma. Erlotinib is given as a tablet. testicular CA. right main bronchus). whose cancer has come back after initial treatment. mechanism: • • • The tumor usually compresses vessels from without Occasionally invades its wall. thymic tumors. • Erlotinib (Tarceva®). Side effects are generally mild and include diarrhea.• Lung cancer 94 Drugs known as EGFR antagonists attach themselves to the EGF receptor inside the cell. Over 80% of SVC obstruction is caused by malignant disease (lung cancer 60% {SCLC}. Superior vena cava obstruction: • Causes: 1. 20% by lymphoma. Pathophysiology • SVC particularly prone to obstruction because of its thin walls. SPECIAL PROBLEMS IN LUNG CANCERS 1. This can help to stop the cancer cells from growing so quickly. . and metastatic from mediastinal adenopathy). 2. It is sometimes used to treat people with NSCLC. a rash. Intra-luminal thrombosis may occur (failure of treatment) 20% by benign conditions: Granulomatous diseases Cryptogenic mediastinal fibrosis (11%) Intra-thoracic goiter. sternum. nausea and tiredness. i. breast CA. or aneurysm As a complications of central venous catheterization Thrombosis Inflammatory lymphadenopathy Radiation fibrosis Idiopathic. low pressure and the fact that it is surrounded by relatively firm nondistensible neighboring structures (eg trachea. and prevent the receptor from being activated.

Distention of veins and venules across the chest. If not the collaterals must flow inferiorly to drain into the IVC • symptoms are due to poor venous return. upper arms and neck. 4. If radiotherapy is given first it may make the subsequent histological diagnosis difficult or impossible. Radiotherapy may be administrated to patients with benign conditions. collateral development and underlying disease process Diagnosis: A. Symptoms sing: • • • • • • • • • • • • • • symptoms may be increase in prone position Swelling of face. Slow processes allow time for the development of collaterals while rapidly growing tumors may produce more dramatic symptoms • Location of block relative to the opening of the azygos vein into the SVC is important in determining clinical features. B. prominent venous pattern over chest ± upper abdomen chemosis "full" supraclavicular fossae Histological diagnosis is usually obtained by bronchoscopy (central tumor evident) if endobronchial lesions do mediastinoscopy (exploration of mediastinum) more tissue biopsy. increased intravenous pressure.• Lung cancer 95 Symptoms depend to some extent on speed of progression of obstruction. Vertigo. neck and upper limbs. • Next step is to obtain histological confirmation: . • some hold the view that it is more important to initiate immediate treatment with radiotherapy and then search for confirmation but this have certain disadvantages: 3. Orthopnoea common Headaches and nightmares which are lessened by sleeping upright. drowsiness. If the block allows the azygos to function as a bypass system most of the signs and symptoms are in the super-epigastric region. Due to increased cerebral venous pressure change in voice due to laryngeal oedema dysphagia due to esophageal oedema or invasion Syncope visual disturbance Congested non-pulsating neck veins. dry eyes or teary eyes. Collar compression.

also been tried: • SCLC: Chemotherapy is given. chemotherapy has no role. Venography is used to determine the field of treatment. The high initial dose of radiotherapy is followed by a lower daily dose to a total dose of 20 Gy spread over 2 weeks. SVC obstruction is not usually leading to mortality but primary cause may do. adjunct radiotherapy has no benefit. CT with contrast Venography: • May be helpful in determine extent of disease. However. localizes mass gives clues to other impending complications Treatment of lung cancer if it is the underling Treatment: a. 6. Symptoms usually begin to improve rapidly with sign diminishing more gradually (90% of patients are free from symptoms after 3 weeks) Endovascular treatment of SVC obstruction has Initial attempts use simple balloon angioplasty effective in benign conditions while recurrence rate is high in malignant disease (inability of central veins to resist external compression). Superior mediastinal mass can be seen C.Lung cancer 96 5. Corticosteroids may be used but have not been convincingly shown to be of benefit. • Intravascular Stents: . This procedures is also required if stenting of the SVC is contemplated. If the cause of obstruction is SCLC (respond to chemotherapy) so radiotherapy is not required. Abnormal in 80%. patients who relapse with obstruction of SVC following primary chemotherapy should be treated with radiotherapy (relieve symptoms and sign) NSCLC: Radiotherapy is given. • • in 70% of patients CXR. cause : • • b. so it is important to determine primary cause as early and accurate as possible. Allows visualization of collateral system.

miosis. thick line over apex of lung (DD pleural thickening). It re-present less than 5% of all bronchogenic carcinoma. There is no clear consensus on the need for thrombolysis or anticoagulant following stent insertion.- Lung cancer 97 Its use appears to be confined to patients with SVC obstruction due to malignant disease how have not responding to conventional treatment or who require urgent relive of symptoms. B. Disadvantages of stent: few complications have been reported. • • • • Eighths cervical nerve (ulnar nerve) First and second thoracic nerve trunks. and stellate ganglion. A further neurological component is involvement of the lower sympathetic ganglia (stellate ganglion) at or above T1 level to produce Horner's syndrome (ipsilateral partial ptosis. At presentation it is usually at advanced stage. parietal pleura. Pain in the lower part of the shoulder and inner aspect of the arm (C8. Clinical picture of Pancoast tumor: this clinical manifestation is due to invasion of: 1. E. anhidrosis. Definition: it s a carcinoma situated at the extreme apex of the lung. Migration of stent to right ventricle from SVC has not bee reported. enophthalmos. and hypohidrosis of face). F. It may accompanied by sensory loss in the same distribution. C. and enophathalmous. Thrombosis in SVC is not a contraindication to stenting as this can be dealt with by local thrombolysis or dispersed with mechanical device. 2. apical ribs. - Results of this procedure are impressive (90% success rate). T1 and T12 distribution). Radiological findings: • Early. miosis. and finger flexors. D. 3. subclavian vessels. vertebral bodies. Inferior sympathetic ganglia. Horner syndrome: ptosis. wrist. 2. Causes: it is caused by a benign or malignant condition invading lower part of the brachial plexus. Superior sulcus tumor= superior sulcus pulmonary tumor: A. There is no evidence that anticoagulant is required in patients in whom there is a good blood flow through the stent at the end of the procedure. It is expensive.. . G. There may be weakness and wasting of small muscle of the hand and of the medial forearm. of this tumor 90-95% are NSCLC. that may be severe and unremitting.

Usually incomplete forms of this syndrome are present. Any histological types of lung cancer can occur in this situation. I. We must exclude other causes of thoracic outlet syndrome. 4. If tetracycline is used for pleurodesis it may be mixed with local anaesthetic in order to reduce pleural pain. sign. If re-accumulation is rapid or if repeated aspiration is required. Presence of malignant pleural effusion (cytology or biopsy) indicates inoperability and short life span. However. H. They rare difficult to diagnose with bronchoscopy. . Treatment: • If intracranial metastasis become clinically evident in patients who is clearly dying of advanced metastasis. surgery should proceed directly. mass at lung apex with local evidence of bone destruction (first and second ribs).• Lung cancer 98 Later. Once diagnosis is certain aspiration is necessary only if the effusion is of sufficient amount to cause dyspnoea. 3. adequate narcotic analgesia is the most appropriate treatment. L. Malignant pleural effusion: 1. 2. but if it is unrespectable. Symptoms. J. requiring percutaneous needle biopsy. Treatment: according to histological type of tumour. B. K. Diagnosis: Is usually obvious where all components of the syndrome are present. Intracranial metastasis: A. or of vertebral body or transverse process. Management: • • This tumor was originally regarded as uniformly inoperable. In this situation bronchoscopy should be carried out with submission of washing for cytology and microbiology. 4. and investigation as discussed before. radiotherapy should be given as a single course. Encouraging results were reported for radiotherapy followed by lobectomy. • Some authors take the view that if the tumor appears resectable after staging. then a chemical pleurodesis can be performed. 3. with the completion of radiotherapy after surgical healing or placement of radioactive implants if the tumor is found to be unrespectable at thoracotomy. other diseases such as TB may occasionally produce confluent apical shadow.

Symptoms: • • • • Tracheal malignancy may occur at any age and may be mistaken as asthma. in few cases. or rarely may be the site of primary malignancy. Tracheal tumor: A. improvement is often obtained with oral high dose corticosteroids (dexamethasone 16 mg/ day). The increasing stridor of a few weeks duration in young or middle aged adult should raise the possibility of tracheal malignancy. Confirmation of diagnosis is made by bronchoscopy (FOB may occlude the a narrowed opening. c. occult in the chest. Treatment: . Origin: Trachea may be involved by direct extension of adjacent tumor. the slow. Investigations: D. PCX-ray: is frequently normal CT: may demonstrate mass in the trachea. B. when the disease can be shown to take the form of a solitary deposit that has arisen following an otherwise successful surgical resection for primary NSCLC lung cancer b. Surgical treatment has small role in the management of intracranial or brain metastasis a. If it is the primary site. C. Biopsy. Or when the primary tumor remains After exclusion of other metastatic diseases) as intracranial metastasis may be the only extra-thoracic site of disease 5. Radiotherapy may be administrated either externally or endotracheally. and then reduced according to response. Ideal treatment is by complete surgical excision of the tumor (may be impossible due to involvement of surrounding mediastinal structure). However. if the tumor is confined to trachea complete excision using tracheobronchoplastic procedures. • • Cranial irradiation produces symptomatic relief in 80% of cases. Hemoptysis may occur.• Lung cancer 99 Sometimes the general condition of the patient requires more active supportive treatment.growing adenoid cystic carcinoma is the most common type.

Inheritance • Sporadic-LAM – – • • Tumor-suppressor syndromes like TSC are caused by Loss-of-function mutations in genes that control cell growth • Molecular Basis . England.5 per million women. Sporadic Lymphangioliomyoma • Epidemiology • – – • – – • – – • – – – – – – • Sex: Almost exclusively young women Never in men without TSC Age Range: Usually between menarche and occasionally after the menopause Mean age : Early to middle 30s (always of child-bearing period) Race Most of the reports are from the United States. 25.000 to 50.000 patients LAM Foundation Registry (1028 patients) National Institutes of Health Registry (237 patients). and Korea ?? countries with the greatest access to health care resources are overrepresented Prevalence of TSC-LAM Incidence of TSC is 1 in 6000 births Occurs equally in both sexes Prevalence of TSC is 1. Japan. France.- Lung cancer100 ND-YAG laser radiotherapy may be used to relieve asphyxia and allowing time for further diagnostic evaluation and planning of treatment.000 LAM occurs in males but is quite rare (Only 3 men with biopsy-proven LAM in the literature) Sporadic-LAM global prevalence – – 1 .5 million people TSC-LAM in 30% of women Prevalence of 250.

growth. • Onset in pregnancy: • No systematic studies • Onset of symptoms during pregnancy in 20% • Exacerbation of LAM in 14% • o o Other manifestation of systemic diseases: lymphoedema Liomyomas of kidneys or uterus. proliferation. Angiomyolipomas – Hamartomas composed of • Fat • Smooth muscle • Abnormal blood vessels. – Location • Abdomen (commonly kidney) • Chest. Symptoms related to reflux of chyle The peritoneum (Chylous ascitis) Pericardium (chylopericardium) Airways (chyloptysis) Urinary tract (chyluria) Genital tract (Chylous metrorrhea). which regulate signaling through the Akt pathway that controls cell size.Lung cancer101 • TSC1 and TSC2 encode hamartin and tuberin proteins. and survival • • Clinical features: • • – – – – • – – – – – • It Only Affects Women Other symptoms Cough Hemoptysis Chest pain Progressive dyspnoea over about 10 years. • Physical examination: .

bullae. Complications – Pneumothorax – Chylous pleural effusion High-resolution CT Chest • More sensitive than CXR • Characteristic abnormalities • – – – – – – – – – – • Cysts In 100% Diffuse Bilateral From 1 to 45 mm Round Thin walled May be irregular May be without walls May not be diffuse Air trapping at expiratory CT is uncommon Lung tissue between cysts • Typically normal • Nodules • Reticulation .Lung cancer102 • • • • • • • Crackles in 15% to 20% Rhonchi in less than 15% Clubbing in 4% Pleural effusion Ascitis Pneumothorax Imaging PCX-ray 1. • Septal line • Bilateral • Symmetrical • Basal predominance (summation effect) 4. or a "honeycombing" 5. Later – Hyperinflation or frank emphysema. Nonspecific 2. Early – Normal – Hyperinflation 3. Characteristic feature Preservation of lung volumes despite increased interstitial markings 6. Later stages Cysts. – Reticulonodular infiltrates • Summation of numerous cysts • Diffuse • Seldom profuse.

it is the most sensitive functional abnormality. DLCO. than total lung capacity (helium dilution).97% Exercise-induced hypoxemia even with normal resting FEV1 and DLCO Pathology • Grossly. This represents air trapping in cysts by peribronchial muscle hypertrophy. Higher thoracic gas volume (pleothysmoraphy).Lung cancer103 • Ground-glass Characteristics features: • Linear densities (29%) • Ground-glass opacities (12%) • Nodules (11%) • Hilar or mediastinal lymphadenopathy (9%) • Pleural effusion o Hemothorax o Unilateral or bilateral o Large o Recurrent • Pneumothorax Abdominal Imaging • Renal Angiomyolipomas: Fat density within a renal mass is pathognomonic • Pulmonary Function Testing • • • • • PFT show an obstructive pattern and hyperinflation.0 cm • Microscopic: – Focal smooth muscle cell infiltration • lung parenchyma • Airways • lymphatic • blood vessels . and abnormal in 82% . enlarged lungs with diffuse cysts up to 2.

leading to air trapping and thin walled cyst formation. Lung cancer104 There is proliferation of spindle. c.With or without visible walls Pneumatoceles • Usually with acute pneumonia • Transient • Clinical presentation makes the diagnosis clear Pulmonary Fibrosis • Honeycomb cysts .Areas of low attenuation . 3. Rupture of theses cysts causes' pneumothorax. • Diagnosis: 1.shaped primitive smooth muscle cells around lymphatic through out the lungs or pleura.Centrilobular . b.Upper lobes . 2. If differential diagnosis specific to each clinical setting is considered Differential diagnosis of cystic lung – – – Emphysema Langerhans cell histiocytosis lymphocytic interstitial pneumonitis Skin nodules Lung cysts Renal masses – Birt-Hogg-Dubé syndrome a. Diagnosis of LAM may be established based on radiographic findings 2.Smokers . In smoking patients • Langerhans cell histiocytosis • Emphysema Emphysema .1. The airways obstruction is probably related to smooth muscle proliferation around bronchioles. Also there is perivenular muscle hypertrophy leads to capillary congestion which lead to hemoptysis.

• Prognosis • Slowly progressive: The Rate of decline in FEV1 is about 100 ml/year. – ovarian irradiation – Immunosuppression – Anti-inflammatory therapies • Pleurodesis – On the first pneumothorax – Increases perioperative bleeding in transplant patients but – Does NOT affect candidacy or survival. • Chylous effusions – Small: No intervention – Large: Drainage.. Norethindrone acetate 10 mg PO daily or twice a day • Intramuscular e. • In postmenopausal women it is more slowly progressive (hormonal dependent). • Renal Angiomyolipomas – Embolization if bleeding occurs – Resections for very large tumors • Experimental: Rapamycine. Medroxyprogesterone acetate 400 mg IM each month • No convincing evidence supports – Oophorectomy.g. Progesterone and estrogen receptors have been demonstrated on lung biopsy material. • Progressive increasing dyspnoea over about 10 years which may lead to death from respiratory failure.Lung cancer105 – – – Subpleural Basal Volume loss Lung biopsy – If there is any doubt – Surgical lung biopsy is better – TBLB is rarely helpful • Treatment • No well-designed studies • No consensus • Progestins • Oral (preferred) e. • Lung transplantation.. .g. if failed pleurodesis • Transplantation – 100 transplantations in the USA – Survival 50% at 5 years.

e. • patchy depigmentation • Angiofibromas (face) • Periungual fibromas and Subungual fibromas • Shagreen patch: patches of elevated rough yellowish skin on the back. Pathology: This lesion is multiple liomyomas. It affects male and females equally. but can also be found occasionally on the extremities and face. These macules are often the first cutaneous sign of tuberous sclerosis. d. ash leaf macules are subtle and can only be detected with a Wood's light (ultraviolet light with 365nm wavelength). Ash Leaf Macule . This inherited disorder usually presented with: . • • Hypopigmented macules Confetti configuration. • Ash leaf macules: a. oval at one end and pointed at the opposite end. Are usually present at birth b. Tuberous Sclerosis complex Lymphangioliomyoma • • Epilepsy • Mental sub normality • Adenoma sebceum: Hypopigmented macules warty elevations on the face.A 1-3 cm hypo pigmented macules that are ash-leaf shaped. f. Commonly located on the trunk. though probably based on blood vessels rather than lymphatic. Oftentimes. Also known as an ash leaf spot. PCX-ray: it shows nodular infiltration that may lead to cystic changes. Because of this hormonal dependence it has been suggested that the use of oral contraceptive may be an etiological factor. and this diagnosis should be strongly suspected in patients with three or more ash leaf macules.Lung cancer106 • The condition was deteriorated in response to oral contraceptive and remit after oophorectomy or treatment with progesterone. c. CNS abnormalities • Common in TSC – Cortical or subependymal tubers – Astrocytomas • Not found in S-LAM • • • a.

Reduced diffusing capacity. Complication: Recurrent pneumothorax. • c.b. Treatment: hormonal therapy gives limited results . • f. • Lung cancer107 Similar smooth muscle tumors are found in other organs. d. Airflow obstruction. Pulmonary function test: e. Pleural effusion.