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

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-, (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

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.

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

Lung cancer

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." Therefore, not all DNA in our cells is used to make protein products.

Gene when working properly promotes normal, controlled cell growth. When these genes have an error in their DNA code, they may not work properly, and are said to be "altered" or mutated.

Cancers develop due to alterations (mutations) in genes. Cancer cells are often shaped differently from healthy cells, they do not function properly, and they can spread to many areas of the body.

a.

Genetic mutations:
inherited mutations

- 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. b.

This gene is not identified yet. 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. These mutations occur at the cellular level after birth, as a result of environmental exposures (such as smoking), lifestyle behaviors (such as eating poorly or not exercising), or chance alone. Mutations in a person's DNA accumulate over time.

Acquired mutations:

Therefore, all cancers are genetic, in that they develop because of an accumulation of mutations in genes, but most are not inherited. Genes encountered in nicotine addiction are, Cytochrome P450 subfamily polypeptide 6, dopamine receptors (D1, D2, D4), dopamine transporter, and serotonin transporter genes

Lung cancer 6 The development of lung cancer is a multi-step process comprising a series of (1) genetic, (2)
histopathological changes and (3) morphological changes which progress from normal

epithelium to hyperplasia (increase number and size), metaplasia, dysplasia (complete change or disorganization of cells), carcinoma in-situ, invasive cancer, and finally to metastatic cancer.
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. Cells permanently stop dividing due to aging or accumulated DNA damage are calls senescent G1 in which RNA and protein synthesis take place (preparation). S in which DNA synthesis occurs (duplication).

2. 3. 4. 5. a. b.

G2 in which the mitotic apparatus is constructed. ( continues its growth and metabolism, but is still diploid) M in which nuclear and cytoplasmic division occur. It is composed of 2 processes: Cytokinesis (cytoplasm physically divides) Mitosis: (chromosomes are divides between 2 daughter cells) .It is composed of 4 stages: prophase, metaphase, anaphase, and telophase (accompanied by cytokinesis).

Cells enter the cell cycle when they pass the so-called restriction point in the G1 phase, at which the determination is made to replicate or remain quiescent in response to the body requirements. Transition into the various phases of the cell cycle requires the formation of cyclin / cyclin-dependent kinase complex (cdk). Cyclin = regulatory subunit, CDK = catalytic subunit of cell division.

Lung cancer
Regulation of the Cell Cycle

At various point in the cell cycle, 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. The most important checkpoint in G1 to S transition (restriction point)
Checkpoints through cell cycle are:
Restriction checkpoint:

1. 2. 3.

at G1-S transition, cell assess itself and determine if progress to next

step or not.
Spindle checkpoint:

between metaphase and anaphase, during which cells check that all between anaphase and telophase during which the cell ensures that

chromosomes have successfully attached to mitotic spindle.

Mitotic assembly point:

the chromosomes have migrated to cell poles (that the cell is ready to cytokinesis and exit from mitosis).

There are 4 DNA damage checkpoint regulated by p53, one in G1, one at entry of S phase, one at end of S phase, and one at entry of M phase. 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. Progression through the cell cycle is regulated by transcription (protein synthesis), often referred to as positive regulation, and protein degradation or inhibition so called negative regulation. The checkpoint under influence of both +ve & -ve regulation. If function of negative regulation is lost, or positive regulation is over-expressed, the cell may progress to next portion of cell cycle at an inappropriate time uncontrolled cell growth may results.

a. 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; thus, their regulation is critical to normal cell division.

Certain growth factors induce gene expression of cyclin D (protein synthesis, by determination of amino-acid sequence in protein), thereby affecting the cell's replication and entrance into the cell cycle in the G1 phase. These growth factors are: EGF,. IGF-1. IGF-2, heregulin factor, transforming TGF, Gastrin releasing peptide, tyrosine kinase receptors, and PDGF, and hepatocyte growth factor.

b. Negative Regulation

The cyclin are inactivated by degradation, with the G1 cyclins D and E exhibiting half-lives in the cell of only approximately 30 minutes.

Lung cancer 8 Negative regulation of the cell cycle also occurs through the inhibition of cdks by cyclindependent kinase inhibitors, which fall generally into two families. 1. One family includes p21 and p53, which can associate with and inactivate cyclin Ecdk2 and cyclin A-cdk2 complexes and prevent entrance into S phase or progression

through S phase, respectively. 2. The other family includes p15, p16, p18, and p19 , which prevent binding of cdk4
and cdk6 kinase to their regulatory cyclin D subunits.

There are three main types of genes that can affect cell growth, and are altered (mutated) in certain types of cancers, including the following (Oncogenes, Mismatchrepair genes, Bcl-2 human oncogenes):

(1)Oncogenes

Oncogenes are genes that are believed make people more susceptible to cancer. Oncogenes are derived from normal cellular gene called proto- oncogenes Proto-oncogenes are believed to turn into oncogenes when exposed to particular carcinogens.

These oncogenes can become activated by mutation, chromosomal translocation, or amplification become unable to control the normal growth of cells and allowing abnormal cancer cells to begin to grow, is unknown.

Proto- oncogenes &oncogenes are named with three letters (myc). There are two classes of oncogenes: 1. Dominant oncogenes (MYC family, RAS family) 2. Recessive oncogenes , tumor suppressor genes

1. Dominant oncogenes (MYC family, RAS family) Myc family

MYC oncogenes are present in the nucleus. It encodes nuclear products. There are three families of related genes (c-myc, N-myc, L-myc). 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, in NSCLC. C-myc is a positive regulator of G1- specific cdk, particularly of cyclin E/CDK2 complexes. Clinically c-myc gene amplification has been related to more malignant course in SCLC. N-myc gene over-expression in SCLC has been related to a poor response to chemotherapy & more aggressive malignant course in SCLC.

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. The Ras family includes K-ras, H-ras, and N-ras. The Ras genes are mutated in about 30% of all NSCLC, but rarely in SCLC . (K-ras in adenocarcinoma and in cigarette smoke exposure).

Lung cancer 9 NNK pro-carcinogen, 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. A K-ras mutation have been found in bronchial biopsies from smokers with no evidence of lung cancer one year before the clinical diagnosis, (So considered a pre-malignant marker) and is associated with poor prognosis.

K-ras mutations are relatively common in NSCLC, especially adenocarcinoma developing in ex- smokers so damage seems irreversible.

2. Recessive oncogenes ,or tumor suppressor genes These genes are able to recognize abnormal growth and reproduction of damaged cells, or cancer cells, and can interrupt their reproduction until the defect is corrected . If the tumor suppressor genes are mutated, however, and they do not function properly, tumor growth may occur. A. 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. 1. P16INK4a arrest cells in G1 phase by leading to phosphorylation of a nuclear protein. 2. RB protein is the key regulator of passage through the G1 phase. RB is Hypophosphotylated in early G1 phase & heavily phosphorylated in late G1 just before S phase, but return to an unphosphorylated state just before G0. So, RB regulates the G1/S boundary, a check point in the cell cycle regulation. RB, hypophosphorylated RB is the active growth-suppressing form. 3. P16INK4a and RB binds and controls a number of other cellular proteins including: the transcription factors E2F1, E2F2 and E2F3 which are essential for progression through the G1/S phase transition block of S phase entry stop cell division.

Successive phosphorylation inactivates its ability to suppress cell proliferation. Mechanism of action in lung tumor : RB protein isolated from tumors is often mutated, resulting in a functionally inactive protein unable to bind to E2F or to be regulated by phosphorylation. Thus cellular proliferation becomes unregulated. P16 regulates the activity of RB by inhibition of CDK4, cyclin D1 kinase activity. So absence of p16 allows uncontrolled CDK4 phosphorylation and transcription factor activation.

B. P53 gene

Normal function of p53: it maintains the integrity of the human genome. Mechanism of action:

Lung cancer 10 In response to DNA damage induced by carcinogens, p53 act as a transcription factor inducing expression of suppressor genes such as p21, BAX and GADD45, theses genes regulate the cellcycle checkpoint signal that causes the cell to undergo either: a. G1 arrest, allowing DNA repair. b. Apoptotic cell death. It is important in cell growth differentiation & protect against malignancy, there are 3 forms (latent, wild, & mutant form) 1. Latent forms: - normally present in cell cycle which can't be detected. 2. Wild form: - is formed when latent form of P53 is under stimulation (UV, smoking, 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, thus

giving the cell a chance to repair the DNA before its errors are duplicated & passed to daughter cells.
Interact

with gene responsible for DNA repair apoptosis

Promote

3. Mutant form, it loses its protective function; this allows mutations to accumulate in other genes and leads to more than 50% of all human cancers. Previously it was believed that p53 is oncogene because mutant form has long life span than wild form, so it is frequently found in association with tumors. MDM2 is an oncoprotein that inhibits the p53 tumor suppressor protein. Abnormalities in MDM2 protein are common in patients with adenocarcinoma. How mutation of p53 result in lung cancer: Abrogation ()of 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. If the DNA does not "match" perfectly, these genes repair the mismatch and correct the error. If these genes are not working properly, however, errors in DNA can be transmitted to new cells, causing them to be damaged.

(3) Bcl-2(enhance apoptosis)

Bcl-2, a human oncogene. Unlike other oncogenes, Bcl-2 does not promote the growth of cells; instead, it blocks cell suicide. And when Bcl-2 is deregulated, as, it extends the survival of cells that normally would die.

"Thus, extended cell survival is also carcinogenic, So Bcl-2 constitutes the first member of a new category of oncogenes: regulators of cell death."

Lung cancer 11 A second form of Bcl-2 that "looks like its evil twin brother," is the Bax. "It promotes death. "And there is also another one that promotes death which is called Bad; Bad seems to release Bax and allow it to kill cells."

Tumour Formation It is likely that lung cancer cells start to harbors genetic damage after prolonged exposure to
tobacco smoke or other carcinogens. It appears that genetic damage continues to accumulate in bronchial epithelial cells in line with traditional indices of increasing preneoplastic morphology. Ultimately multiple clonal lesions are detectable in overt invasive lung cancers and perhaps more in metastatic lesions, consistent with the multistep model of carcinogenesis. The genetic and cellular targets of the carcinogenic process are notably diverse, yielding the following hallmarks of cancers: 1. Abnormalities in self-sufficiency of growth signals. A number of growth factors and their receptors (EGFR, IGF-1, IGF-2, TGF & her2/neu) are expressed by cancer cells, thus producing autocrine and paracrine growth stimulation loops. 2. 3. 4. 5. Evading apoptosis. Insensitivity to anti-growth signals. Limitless replicative potential. Sustained angiogenesis, lung cancer engender angiogenesis with expression of large number of blood vessels (poor prognosis). There are several isoform of VEGF encountered in angiogenesis, mainly VEGF 189 mRNA has a good correlation with angiogenesis. 6.

Tissue invasion and metastasis, 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. Carcinogenic agents affect DNA by several molecular mechanisms; generally they form electrophilic intermediates that bind to DNA causing mispairing or base substitutions during DNA synthesis.

The first step is when carcinogenic agents mutate DNA to give altered gene expression (initiation). The altered gene expression leads to promotion, an initiated cell undergoes clonal expansion to form a preneoplastic lesion. Should this lesion undergo further genetic change (conversion) a malignant tumour develops.

The changes that lead to tumour formation occur in the genetic material that is responsible for regulating cell growth and differentiation. Proto-oncogenes and tumour suppressor genes play an important role in the multistage model of carcinogenesis:

Lung cancer 12 2. Proto-oncogenes are important to the regulatory mechanisms of growth, cell-cycle control, programmed cell death and terminal differentiation. It has been demonstrated that activation of the ras proto-oncogenes leads to tumour formation, angiogenesis and metastasis. It is thought that K-ras activation is particularly important in the development of adenocarcinoma of the lung. 3. Tumour suppressor genes code for products that enhance neoplastic activity when mutated. The most commonly altered tumour suppressor gene is the p53 gene found on chromosome 17, it codes for a phosphoprotein involved in the control of cell proliferation and loss of function can be caused by single base substitutions. It is found to be mutated in 90% of SCLC and 50% of NSCLC. Epidemiology of lung cancer

Lung cancer is the most common cancer worldwide: 2.000.000 case per year 5- 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. Death rate peaked in 1990 The biggest causal factor in lung cancer is smoking. In the US, smoking is estimated to account for 87% of lung cancer cases (90% in & 79% in ), and in the UK for 90%. Incidence & mortality rates higher for African American than white Americans due to difference in metabolism of tobacco nicotine smoke carcinogens. In biomarker study the urinary metabolites of NNK was much higher in white smokers than in African American.

Lung cancer remain far lower in Japan than US or UK which may be due to:-

1. High age onset of smoking 2. Low fat diet (fat content of diet may play key role in the risk of developing lung cancer in cigarette smoker) 3. High intake of green- yellow vegetables & fruits 4. Tea preparations esp. green tea may inhibit tumergenesis due to anti oxidative effects of polyphenols in tea. 5. 70% of all cigarettes Japan are charcoal- containing filter.

Effect of gender (lung cancer in women)

1. Lung cancer has always been more common in men, particularly those over the age of 40, as more men used to smoke than women. However, as more women have started smoking, the number of women developing lung cancer has gone up considerably. 2. Death increased 150% bet. 1974 & 1994. More death from lung cancer than breast, ovarian, & uterine cancer combined 3. Women are more susceptible to tobacco effects 1.9 times more likely to develop lung cancer than men with same smoking habits

Lung cancer 13 4. The incidence of adenocarcinoma is higher among female (50-80%) higher than male especially in non smoking females 5. Hormonal factors may play a role in causing lung cancer 6. Estrogen replacement therapy significantly increased the risk of developing adenocarcinoma

Causes of lung cancer

1. Lung cancer takes many years to develop. 2. But changes in the lung can begin almost as soon as a person is exposed to cancer-causing substances. 3. Exposure to carcinogens, such as those present in tobacco smoke, 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. Scientists believe that it is the interaction of many factors together that produces cancer. The factors involved may be genetic, environmental, or constitutional characteristics of the individual.

The major causes of lung cancer (and cancer in general) are:

1. 2. 3. 4. 5. 6. Smoking Radiation exposure Occupational exposure Genetic susceptibility Viral infection Other risk factors a. 1st degree relative b. Pulmonary fibrosis (scar carcinoma). Risk of lung cancer higher in pt. with COPD. c. Air pollution & socioeconomic stander measured by occupation, income, education, and diet has been suggested as a cause of lung cancer but this is difficult to prove.

I. The role of smoking

o 87% of lung cancers are related to smoking. o Cigarette smoking cause lung cancer due to: a. cigarettes smoke contains more than 4,000 different chemicals, more than 19 substance known carcinogens including free radical oxidants, non radical oxidants [radioactive substance e.g. polonium, C14, K40 & radon nitrosamine, phenol derivative and benzopyrene]. b. Additionally, nicotine appears to depress the immune response to malignant growths in exposed tissue. There is a strong dose response relationship .

Lung cancer 14 c. Oxidants, either free radical or non radical oxidants can damage DNA, protein & lipid d. Chronic inflammation due to smoking lead to genetic alteration in bronchial cells. Atypical cells are present in sputum of 96.7% of smokers compared to 0.9% in non smokers o Risk of lung cancer related to 1. 2. 3. 4. 5. Cannabis Amount smoked (pack /y, SI) Age of smoking onset Product smoked (tar/ nicotine content, filters) Depth of inhalation (personal smoking behaviors) Gender & dietary factors

Smoking cannabis may also increase the risk of lung cancer. Although less is known about the harmful effects of smoking cannabis, it is believed to cause similar damage to the cells in the lungs, as smoking tobacco. Pipes and cigars Although pipe and cigar smokers have a lower risk of lung cancer than cigarette smokers, they are at a much greater risk than non smokers. o Main stream smoke: smoke directly inhaled by smoker o Side stream smoke: inhalation of smoke released from burning tobacco bet. Puffs do not pass through filter of cigarettes. Recent investigation of sidestream smoke suggests that it contain 100 times the weight of carcinogens of main stream smoke. o Consequently, 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. Smoking & histology of lung cancer 1. the number of adenocarcinoma absolutely increased while the frequency of squamous carcinoma remained stable 2. In women the number of adenocarcinoma increased faster. 3. Adenocarcinoma increased due to deeper inhalation of low light nicotine, filtered cigarette. 4. Black tobacco is slightly alkaline, so higher levels of free nicotine are released, so deep inhalation is unnecessary. K-ras activation due smoking

K-ras mutations are closely associated with cigarette smoke exposure.

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, (So considered a pre-malignant marker) and are associated with poor prognosis.

K-ras mutations are relatively common in NSCLC, especially adenocarcinoma developing in ex- smokers so damage seems irreversible.

Stopping smoking If a person stops smoking, the risk of lung cancer decreases each year as normal cells replace abnormal cells. a. After 10 years, the risk drops to 1/3 to 1/2 of the risk for people who continue to smoke. b. After about 15 years, that persons chances of developing the disease are similar to that of a non-smoker. c. In addition, cessation of smoking greatly reduces the risk of developing other smokingrelated diseases, such as heart disease, stroke, emphysema and chronic bronchitis.

II. Radiation exposure

Radon gas

Radon exposure is the second major cause of lung cancer after smoking. 12 % of all lung cancer deaths are linked to radon. Radon causes between 15,000 and 22,000 lung cancer deaths each year in the US Radon is a colorless and odorless radioactive gas generated by the breakdown of radioactive radium, which in turn is the decay product of uranium, found in the earth's crust. Radon '' half- life'' only 4 days from when it forms, 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, as well as through pipes, drains, walls or other openings. Radon can be a problem in schools and workplaces, too.

Exposure to radon in combination with cigarette smoking greatly increases the risk of lung cancer. That means for smokers, exposure to radon is an even greater health risk. Radon causes lung cancer because it causes arbitrary damage to the chromosomes and DNA molecules contained in the nucleus of the cell.

III. Occupational exposure

Exposure to carcinogens in the work place have been implicated in several industrial situations;
asbestos dust, , radioactive materials, passive smoke, chromates, nickel, arsenic, polycyclic aromatic hydrocarbons, mustard gas, silica dust

Asbestos

Lung cancer 16 The most important malignancy related to asbestos is malignant mesothelioma of pleura & peritoneum. Asbestos can cause a variety of lung diseases i.e. pleural plaque & IPF(asbestosis), There is a synergistic effect between tobacco smoking and asbestos in the formation of lung cancer. It increases the risk of developing lung cancer. Many people have been in contact with asbestos during their working lives. Low-level exposure increases the risk of lung cancer only slightly, compared to the risk from smoking, while heavy exposure may result in a much higher risk of lung cancer.

IV. Genetic susceptibility

Less than 20% of heavy smoker develops lung cancer. In some families, smokers may be more likely to develop lung cancer due to an inherited faulty gene. At present, we do not know what this gene is.

There may be small subgroup with a genetic predisposition to develop lung cancer, but for most patients exogenous factor are more imp. Than the combination of exogenous & endogenous effect.

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.

There is a familial tendency to develop lung cancer that cannot be explained by shared environment. Though associations have been made between various metabolic polymorphisms and markers of mutagenic susceptibility, no single genetic factor is sufficiently predictive to be of diagnostic use, and in the context of complex extrinsic factors such as smoking, the relative contribution of individual genetic factors in lung cancer susceptibility is unknown. This area requires further study before application in such areas as screening, prevention or treatment, which could potentially have a large impact on how lung cancer is tackled.

Genetic polymorphisms of carcinogen metabolizing enzyme. Altered DNA base sequence in gene, between two alleles does not usually lead to changes in function of coded protein. Gene locus for GSTu is polymorphic in man & lacking in 50% of Caucasians. GSTu detoxifies PAH epoxides in tobacco smoke. GSTu null individuals have reduced ability to detoxify benzo pyrene diol epoxide (BPDE) with high susceptibility to lung cancer.

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

Types of Lung Cancer

Epithelial tumors consist of two major types of lung cancer:- SCLC & NSCLC. 1. Small cell lung cancer (SCLC) (roughly 20%) Oat cell carcinoma Intermediate cell type Combined oat cell carcinoma 2. Non-small cell lung cancer (NSCLC) (80%).

Lung cancer 18 Squamous cell carcinoma 1. Well differentiated 2. Moderately differentiated 3. Undifferentiated Adenocarcinoma: 1. Acinar Adenocarcinoma: 2. Papillary Adenocarcinoma: 3. Bronchoalveolar carcinoma 4. Solid carcinoma with mucous formation Large-cell (mixed small cell) undifferentiated carcinoma: 1. Giant cell carcinoma 2. Clear cell carcinoma 3. 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. usually affecting the parenchyma 2. Often arise from 1ry tumors in; breast, bone, GIT, kidney, prostate cervix or ovary. 3. These usually present as round shadows of about 1.5-3 cm diameter on CXR. 4. Sometimes, they can present in asymptomatic patient, and the 1ry found later on CT scans or other investigations Common sites for metastasis from lung, the adrenal glands, liver, brain, and bone.

Small cell carcinoma (SCLC, also called "oat cell carcinoma")

Other names for SCLC are oat cell carcinoma and small cell undifferentiated carcinoma. SCLC (Oat) cell carcinoma accounts for about 20- 25% of all lung cancers It tends to start in the large, central airway, grows rapidly & metastasized early. The most important site for metastasis are liver, LN, bone, Brain , also prostate carcinoma The oncogene most commonly involved is L-myc.

Lung cancer 19 The "oat" cell contains dense neurosecretory granules which secrete a large amount of polypeptide hormones, thought to be as a result of their development from cells of the APUD system give this endocrine /paraneoplastic syndrome association. SCLC tends to spread widely through the body. It is more sensitive to chemotherapy, but carries a worse prognosis and is often metastatic at presentation. SCLC is almost always caused by smoking. It is very rare for someone who has never smoked to have SCLC. L/M: - they form sheets of darkly staining cells with prominent nuclei and little cytoplasm; their secretory activity can be seen as the presence of neurosecretory granules in the cytoplasm seen by EM. WHO classify SCLC into 3 types: 1. Small or oat- carcinomas, characterized by high nuclear/ cytoplasmic ratio. 2. Intermediate cell-carcinomas, contain some large cells and so more resistant to chemotherapy. 3. A combined subgroup< and SCLC containing areas of squamous carcinomas or adenocarcinoma.

Non-small Cell Lung Cancer

NSCLC accounts for about 80- 87% of all lung cancers There are three sub-types of NSCLC. The cells in these sub-types differ in size, shape, and chemical make-up. The non-small cell lung cancers (NSCLC) are grouped together because their prognosis and management is roughly identical.

Squamous cell carcinoma (epidermoid carcinoma): 25% - 30% of all lung cancers.

Common in smoker squamous metaplasia Tend to be found centrally, or around major bronchi.

WHO classifications divided it into 1. Well differentiated grow more slowly & confined to lung, hilar, mediastinal LN, less likely to give extra-thoracic metastasis. 2. Moderately differentiated more frequent Widespread Metastases occur relatively late. Sensitive to radiotherapy. 3. Undifferentiated type, tend to behave aggressively & extra thoracic metastasis being

Lung cancer 20 They grow in a stratified or pseudoductal arrangement; the characteristic histological features are cell keratinization & intracellular bridge. Well differentiated tumors deposit keratin pearl formation, and show the greatest tendency to cavitate . Keratinous mass which appears cheesy on dissection. As a tumor grows: a. It secretes substances called tumor angiogenesis factors (TAF) which cause blood vessels to grow into the mass of tumor cells. This allows tumors to grow more rapidly and increase in size. b. 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, they die. This is the process by which squamous cell carcinomas frequently develop into necrotic masses. c. 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.

Adenocarcinoma:
1. Acinar Adenocarcinoma: 2. Papillary Adenocarcinoma: 3. Bronchoalveolar carcinoma 4. Solid carcinoma with mucous formation This type accounts for about 40% of lung cancers. It is usually found peripherally. In US it is the most frequently diagnosed histological type. Adenocarcinomas arise peripherally from mucous glands near the gas-exchanging surface of the lung. The cells retain some of the tubular, acinar or papillary differentiation and mucus production. Few cases, the tumors are truly bronchogenic, arising from mucus gland in proximal bronchi. Regional & more distant metastasis occur less commonly than in case of other lung cancer. 5% arise at the extreme periphery of the lung & disseminate over pleural surface as mesothelioma Brain and bones frequent site of metastasis. Adenocarcinoma commonly arises around scar tissue and is also associated with asbestos exposure. Most cases of the adenocarcinoma are associated with smoking. However, among non-smokers and in particular female non-smokers, it is the most common form of lung cancer

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. Tend to have a better prognosis than those with other types of lung cancer. b. Bronchiolo-alveolar carcinoma, these characteristically have well differentiated bland cells which grow along alveolar ducts. c. More common in female non-smokers and may have different responses to treatment. d. It is peripheral lung tumor arising from any epithelial cells within or distal to terminal bronchioles. These include type I pneumocyte, Clara cells, ciliated, bronchiolar & mucosal cells. e. They behave like other lung tumor tending to involve local lymphatic & extra thoracic metastasis being more frequent f. The tumor is multicentric or lobar in location. It produce copous watery secretion ''bronchorrhoea'' g. CXR: can't be differentiated from other type of carcinoma, sometimes produce ill defined fluffy infiltration resulting from its tendency to spread in contiguous ''lepidic'' manner along airways at bronchiolar levels. h. N/E: there margin less well differentiated & often appears as multiple pulmonary nodules or as area of peripheral '' pneumonic consolidation'' refractory pneumonia. i. L/M: can't differentiated from metastatic adenocarcinoma

Large-cell undifferentiated carcinoma:

2. Giant cell carcinoma 3. Clear cell carcinoma This type of cancer accounts for about 10% - 15% of lung cancers. It may appear in any part of the lung, but the majority arise at periphery of lung it tends to grow and spread early, highly aggressive with predilection for metastasis to intestine, resulting in a poor prognosis N/E: large, bulky & appear unrelated to bronchi. L/M: anaplastic carcinomas, showing no feature of maturation, having large, less well
differentiated spindle shaped, oval cell with abundant cytoplasm.

E/M: may show feature of squamous or adenocarcinoma & may be undifferentiated It is primarily a diagnosis of exclusion, and when more investigation is done, it is usually reclassified to squamous cell carcinoma or adenocarcinoma.

Other Types of Lung Cancer

Lung cancer 22

Carcinoid tumors of the lung

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

1. Direct spread
Central type: (SCLC, Squamous cell carcinoma, Carcinoid tumour) Spread to mediastinal structures mediastinal syndrome

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). Penetration of the basement layer that distinguishes benign from invasive tumors. Enzymes from the malignant tumour cells are capable of degrading the ECM; these include serine proteases, Cathepsin and the matrix metalloproteinases (MMPs). MMPs have also been suggested as having a part in the control of growth and apoptosis of cells. Clinical trials of synthetic inhibitors of MMPs (batimastat, marimastat) are being
carried out. These may lead to a new approach in the management of lung cancer. As well as metastases,

2. Lymphatic spread (embolization or permeation)

1. Broncho pulmonary LN 2. The hilar (peribronchial LN,), 3. Mediastinal (subcarinal, sup tracheo bronchial, para tracheal LN) 4. Scalene LN supraclavicular LN

3. Hematogenous spread commonly to liver, LN, bones, brain & adrenal glands 4. Trans-bronchial spread rare in bronchiolo-alveolar carcinoma
Lung cancers often cause local complications of obstruction, ulceration, invasion and systemic effects due to central necrosis and paramalignant disorders. Obstruction of any nearby structure can occur (either by pressure from contained tumour or invasion) and often include SVC obstruction, vocal cord paralysis due to damage to recurrent laryngeal nerve, dyspnoea due to lobar collapse, and dysphagia. Occasionally central necrosis occurs in the middle of a tumour (particularly in squamous carcinoma) when it outgrows its blood supply, the release of pyrogens causes fever in the absence of infection. Paraneoplastic disorders are found in lung cancers with ectopic ACTH production, SIADH, cachexia, clubbing and anemia found in some cases. 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), fatigue and loss of appetite Dysphonia (hoarse voice)

Lung cancer 24 1. 2. 3. 4. 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. 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. A third group may present with non-specific symptoms such as malaise, anorexia, and weight loss. Fourth group may present as a results of metastatic.

Patients with lung cancer may be present in 4 ways:

I. Central tumors: patients). The commonest symptoms are cough, haemoptysis, dyspnoea and chest pain, either alone or in combination. A. Cough is the most common symptoms at presentation. Any new cough that persists more than 2 weeks especially in patients over 40 years who is smoker is suspicious. B. Haemoptysis, many lung cancers have a rich blood supply. The surface of the cancer may be fragile, leading to bleeding from the cancer into the airway. 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. Copious haemoptysis is uncommon. Central airway narrowing. Partial or complete collapse of distal segment of lung. If the cancer grows into the lumen it may obstruct the airway, causing

C. Dyspnoea may be due to:

breathing difficulties. This can lead to accumulation of secretions behind the blockage, predisposing the patient to pneumonia. D. Chest pain: Poorly localized chest discomfort occurs in 1/3 of patients at diagnosis The exact cause is unknown, but may be due to involvement of peribronchial or perivascular nerves. II. Peripheral tumors: Commonly Adenocarcinoma or large cell type.

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

Lung cancer 26 ii. iii. iv. disease. 3. 4. Cervical lymph node and adrenal involvement (not produce symptoms). Hepatic metastasis: Rarely produce symptoms. Stretch of liver capsule leads to pain. If the tumors interfere with the function of the liver, there can be many other symptoms. 5. not produce symptoms. The most common symptom associated with adrenal metastases is pain caused by tumor growth or sudden bleeding into the gland. The pain is typically located in the back, around waist-level, to the right or left of the spine. Common clinical findings at presentation: 1. Physical examination of the chest in case of lung cancer is frequently normal. 2. However, physical examination may reveal sign that are important in:

difficulty speaking swallowing, loss of balance or coordination, Confusion associated with metastatic brain

Adrenal gland metastasis: Adrenal metastases from primary lung cancer are often

Reaching a diagnosis of lung cancer. Preliminary assessment of the extent of disease. Determine the most appropriate sequence of investigation. It may determine treatment in individual cases. Vocal cord paralysis: only seen in irresectable tumor.

a. o o o

Hoarse voice of vocal cord paralysis is easily detectable. Bovine cough: When the patient is asking to cough they produce ineffectual expiratory noise. It is produced by juxtaposition of the two fully adducted vocal cords. The left recurrent laryngeal nerve is the most commonly involved as it loops around aortic arch where it passes over left main bronchus. 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).

a. b. c.

Lung cancer 27 Clubbing of finger and toes and may be associated with HPOA. Lymphatic spread is common. The scalene and supraclavicular lymph glands are the first to be enlarged. Axillary lymph glands are rarely involved (indicate invasion of chest wall). The enlarged lymph nodes provide readily access for histological sampling and positive histological confirmations indicate inoperability. Airway obstruction: Narrowing of trachea or lesion in either main bronchus at the level of carina may cause stridor (inspiration).

With distal obstruction by tumor give rise to localized wheezes which may be heard without stethoscope. A central obstructing tumour may cause a decrease in intensity of breath sound over lobe or entire lung. Atelectasis of the obstructed area of the lung if treatment is delayed. Pleura:

d. -

Sign of pleural effusion which may be due to: Neoplastic pleural involvement (more common). Secondary to complicating infection process or other some process.

Pleural friction rub may b heard over area of pleuritic pain. e. f. Lung collapse. Pleural effusion. Paralyzed hemi diaphragm due to invasion of phrenic nerve by wide spread mediastinal tumour. (Tidal percussion, PCX-ray or U/S show paradoxical movement). Palpable liver due to hepatic involvement (unusual). Sign and symptoms of raised intra-cranial pressure. Clinical picture of superior sulcus (Pancoast) tumors. Clinical picture of paraneoplastic syndromes. 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. 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. h. i. j. VI. Paraneoplastic syndromes:

o o o

Lung cancer 28 Depending on the type of tumor, so-called paraneoplastic phenomena may initially attract attention to the disease. Definitions: it means a variety of non-metastatic or neuromuscular manifestations of lung cancer. Although it can occur with all types of lung cancer, it most commonly associated with SCLC, which commonly elaborates ectopic hormones from neurosecretory granules. (Because it arises from A PUD system).

o a. b.

Neurosecretory granules: Source: in neural tissue, 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 - Melanocyte stimulating hormone Adrenocorticotrophic hormone - endorphin -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 years. o syndromes. 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. But its believed to

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

a. b. c. d. 4.

Lung cancer 30 Kidney: Polyuria, nocturia, and thirst if these symptoms persist it lead to dehydration, hypovolemia, and renal failure. General: malaise, weakness. GIT: anorexia, nausea, vomiting and constipation. CNS: Mental slowing confusion, drowsiness and finally coma. 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. First correcting the biochemical disturbance by medical treatment, by: A. with IV saline. B. Renal function should be monitored. Adequate K supplementation. Severe hypercalcemia or hypercalcemia not responding to simple rehydration: C. o o o o 2. Incidence: a. b. 5-22% It is common in SCLC. most common paraneoplastic form present in SCLC, it occur in Correction of dehydration with IV saline. Renal function should be monitored. Adequate K supplementation. Loop diuretics as furosemide. If hypercalcemia persists: Agents which prevent calcium absorption from bone can be used. IV and oral bisphosphonates have a role in treatment of malignancy associated hypercalcemia. Cytotoxic antibiotic mithramycin is rarely used (not effective, side effects) Oral steroids are unreliable but it can be used. Syndrome of inappropriate ADH secretion (SIADH_: Mild hypercalcemia (<3 mmol/L): Cornerstone of treatment is correction of dehydration

1. It manifested by significant hyponatremia (serum sodium <120 mmol/L).

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

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

Lung cancer 33 4. Pathogenesis: A. B. Remains obscure. 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. The increased vascularity of subcutaneous tissue and periosteum leads to periostitis, resulting in loosely packed new bone being laid outside the original cortex and this produce the characteristics bony change in plain-X-ray 5. Mechanisms of HPOA in lung cancer:. Remains obscure. Vagally mediated afferent neural output from the tumor-bearing lung (vagotomy produce symptomatic relief) 6. Plain X-ray: a. Site: Lower end of radius, ulna, tibia, fibula and hands (if no pain). If the knee is painful proximal part of tibia and fibula with distal part of femoral shaft. b. 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. c. Bone scan, active deposition of new bone can be demonstrated by the avid ( )uptake of technetium in affected area. 7. Treatment: Vagotomy is invasive procedures and not indicated except thoracotomy is done in attempt to cure tumor. 1. 2. 3. 4. Treatment of primary condition produces dramatic response. Most other cases respond to NSAID. Corticosteroids may produce similar relief.

Other endocrine and metabolic complications: It occurs most frequently with large-cell and Adenocarcinoma types. Mechanism, involve the production of human chorionic gonadotrophin by tumor cells, this substance results in overproduction of testicular estrogen. Drug-induced gynaecomastia should be excluded first. treatment: Successful resection of tumor deals with this complication.

- Gynaecomastia:

Lung cancer 34 If resection is not possible, then anti-estrogen such as Tamoxifen may be effective in reliving symptoms.

- Eosinophilia 1. It may result from increased bone marrow production of an eosinophilic chemotactic factor. 2. It is characterized by high total white cell count, as well as eosinophilia. 3. It is associated with advanced and rapidly progressive disease. - Non-metastatic neuromuscular syndrome: Incidence: a. in lung cancer. b. c. in neural tissues. A variety of neuromuscular syndromes are described: 1. Peripheral neuropathy: A. hypoesthesia. B. An autonomic neuropathy may result in postural hypotension or disturbance of GIT motility, including intestinal pseudoobstruction (Ogilvies syndrome). C. D. Patients with sensory neuropathy usually have SCLC and often have high titer of antibody to the nuclear associated HUD protein. The pathogenesis of neural injury is unknown. 2. Neuromuscular junction and muscle syndromes: a. Poliomyelitis / dermatomyositis: Characterized by: Proximal muscle weakness, pain and tenderness A variety of systemic symptoms Characteristic facial heliotrope rash. It occurs in 6% of patients with SCLC. In contrast to myasthenia gravis the muscle weakness improves with repeated efforts. Motor, 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. 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. Eaton-Lambert myasthenic syndrome:

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.

3. Cerebellar ataxia, with nystagmus, impaired coordination and dysarthria described in patients with SCLC. Treatment: a. A part from patients with Eaton- Lambert myasthenic syndrome, immunosuppression including plasmapheresis has not been shown to be beneficial, even in patients with detectable anti-neural antibodies. b. It dose not respond to cytotoxic chemotherapy. Diagnosis of lung cancer I. o a. b. c. d. e. o Investigations: The purpose of any investigation performed is to: Confirm diagnosis. Including if possible the histological type. To asses the extent of disease. To determine operability. To determine the most appropriate treatment. The complexity of investigation should correlate with the patient's

suitability for active treatment.

1.
a.

Radiological investigations:
Imaging tests are performed to determine if a lung tumor is present. Some imaging studies can provide information that can help determine if a lung tumor is likely to be benign or malignant. Imaging tests are useful to look for enlargement of regional lymph nodes, which could indicate cancerous spread.

b. c.

Chest X-Rays PCX-ray is always abnormal in patient with lung cancer at presentation:
1. 2. 3. Common early findings are slight prominence of a hilar shadow (central tumor) or a small pulmonary nodule (peripheral tumor). Hilar shadow: By the time, when there is symptoms PCX-ray show obvious unilateral hilar or perihilar enlargement (primary carcinoma or L. N). Mass:

Lung cancer 36 i. ii. iii. 4. Cavitation: When central necrosis occurs in the tumor, cavitation may be present Common in squamous cell carcinoma It is not a feature of SCLC. The inner lining of the cavity I soften irregular (D.D of lung abscess). 5. 6. True lung abscess, it is due to bronchial obstruction by tumor and distal stagnation of secretion which lead to secondary infection (consolidation without cavitation is more common). The most striking PCX-ray findings are that produced due to mechanical effect of the tunor: bronchial obstruction may cause: 7. 8. Partial or complete collapse of segment, lobe or lung. Ipsilateral unaffected lobe tend to be hyper inflated, and more lucent. Characteristics displacement of interlobar fissures. Atelectasis or consolidation ay suggest central lung tumor. 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).

Elevation of one or other hemi diaphragm may indicate phrenic nerve paralysis. Confirmed by Fluoroscopy or US which show paradoxical movement on sniffing. Mediastinal lymph node: A. B. mediastinum is seen. C. In few cases lymphatic spread from mediastinal or hilar lymph nodes to pulmonary lymphatics, producing fine, lace-like shadows that may involve one or both lung fields (lymphangitis carcinomatosis) Is often not radiologically seen on PCX-ray. In advanced disease, widening of superior

9.

Bronchoalveolar carcinoma: a. b. c. Are frequently indistinguishable from other histological type. However, this tumor may sometimes produce diffuse ill-defined fluffy infiltrates (due to its tendency to spread along the airways at bronchiolar levels. Radiologically it resemble pneumonia, but it not respond to antibiotic.

10.

Pancoast tumor: (thoracic inlet or superior sulcus syndrome): Early stage, it may produce only thin rim of shadowing at lung apex (D.D pleural thickening).

11.

Lung cancer 37 If enlarged, they may erode and destroy adjacent ribs and infiltrate nerves of brachial plexus.

Chest x-rays can be useful for detecting abnormalities other than tumors that may be related to lung cancer. For example, chest x-rays can detect a pleural effusion.

Normal PCX-ray: it may be found if the tumor is small and central. A lung
tumor can be missed on chest x-ray if it is small or hidden behind a rib, collar bone, or the breastbone.

Even if the diagnosis of lung cancer is already clear, a chest x-ray may be taken to compare with previous and future chest x-rays. Following chest x-rays over time can help monitor the course of disease.

0.

New types of chest x-ray:

Digital chest x-ray. 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. The use of the detector instead of film allows for sharper, clearer images. a. b. Computer-assisted diagnosis (CAD). 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. 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. 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. 2. 3.

CT Scans
CT scans are able to detect smaller tumors than chest x-rays. They are also better able to determine the size, shape, and exact location of a tumor because they collect information in three dimensions instead of two. For the same reasons, CT scans are better able to detect enlarged regional lymph
nodes.

4.

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.

rays to produce three-dimensional images. up of suspected lung cancer.

MRI Scans
MRI scans use a large magnet instead of x MRI is not often used in the routine workIn special circumstances, 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. However, in most instances, CT is superior to MRI for imaging the structures in the chest.

a. scans. b. c. d. Principle of PEF:

PET Scans
PET (positron emission tomography) scanning is a relatively new technology.

Sugar molecules that have a radioactive component are injected into the body and then a scan is taken. 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. Therefore, areas of the body with cancer cells show up brighter on the scan than normal tissues. Primary tumors, lymph nodes containing cancer cells, and metastatic tumors all appear as bright spots on a PET scan. Indication in lung cancer: a. for lung cancer. b. c. They are sometimes used after chest x-rays or CT scans to differentiate between benign and cancerous tumors. PET scans are particular useful for finding cancerous spread to regional lymph nodes and detecting distant metastatic tumors. Disadvantage of PEF: There are conditions other than cancer that cause positive findings on PET scans (lung infections). PET scans are not generally used as first-line diagnostic tests

a.

b.

Lung cancer 39 PET is not useful as screening, as not all malignancies are positive on PET scan (such as bronchoalveolar carcinoma).

II. Sputum cytology:

Examination of expectorated sputum from patients suspected of having lung cancer is a simple and valuable diagnostic aid. Collection of adequate samples is extremely important: a. b. c. First sputum in the morning or one produced after bronchoscope tends to produce a higher positive yield. One sample gives positive yield in 40% of cases. Positive yield increased with multiple samples. Samples may be collected on three consecutive days to increase the chances of finding cancer cells.. A definitive diagnosis of lung cancer may be made in 60-70% of cases. It gives better results if: ii. iii. iv. v. vi. Tumor is centrally located. Large size tumor. Lesion situated in lower lobes. Squamous cells carcinoma and NSCLC give higher positive yield. Multiple samples.

However, if cancer cells are not detected, this does not rule out the possibility of lung cancer because sputum cytology is positive in only 5-20% of people with lung cancer.

III. 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. The method used to obtain a biopsy depends on the size and location of the tumor or lymph node being tested. Bronchoscopy

Bronchoscopy is the most common technique used to biopsy a suspected lung cancer. It provides information about histological typing (biopsy) and extent of disease. Tumor that situated centrally on PCX-ray is visible bronchoscopy as an intraluminal mass.

Lung cancer 40 The presence of tumor is indicated bronchoscopy by: a. b. node). c. Intraluminal mass. Bronchoscopic evidence for inoperability is provided by: A. B. node involvement). C. External compression of lateral wall lower end of trachea by enlarged Para tracheal lymph node. Bronchoscopy is particularly useful for: i. ii. Obtaining tissue samples from tumors growing in the larger airways, usually in the central part of the lung. Tumors that are not visible via bronchoscope, biopsy is obtained by: iii. Trans-bronchial technique (TBNX, TBNA). Blind brushing and washing Transthoracic needle biopsies. Endobronchial site of tumor. Any evidence of mediastinal involvement, suggested by: vocal cord paralysis. Widening of main carina (subcarinal lymph Bronchial stenosis. Or external compression (tumor mass or lymph

Tissue samples from lymph nodes in and around the lungs can also be obtained with a bronchoscope. positive results have been made in about 60% when the tumor

mass is greater than 2 cm in diameter

Auto fluorescence bronchoscopy is:

a. b. c.

A modified bronchoscopy procedure that uses fluorescent light to detect potentially cancerous areas of the airways. Tumors and other abnormal cells naturally glow when exposed to specific types of fluorescent light. Advantages: This technique helps to identify suspicious areas in the airways to sample. It is particularly useful for people whose sputum cytology test showed cancer cells, but imaging studies failed to show a lung tumor. It is also better than standard bronchoscopy for detecting lesions that may be progressing to lung cancer (premalignant).
LIFE Lung Bronchoscopy:

A. with a normal bronchoscope. B. recurrences after previous treatment.

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, 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. Inefficiency of conventional methods

Tumor staging: - Estimating the exact depth of tumor invasion to bronchial wall and extent of early lung cancer (ELC). - Assessment of peribronchial (PB) pathology. - Infiltration of mediastinal structures.

Nodal staging. Selection of therapeutic modality of ELC. Guiding bronchoscopic procedures in endosmotically invisible lesions.
II. Endoluminal ultrasound

Basis: - Catheter-based miniature transducers. - US probes originally designed for intravascular application. Application: - Ggenitourinary tract followed by GIT. - Endoscopic ultrasound (EUS) . Esophageal, stomach, pancreas & colorectal carcinoma. . Lung cancer?
III. Technical problems:

- Air in the lumen & lung parenchyma. - Displacement of US probe by respiratory movements & cough. - Complex unusual mediastinal planes.
IV. Indications

1. Tomographic images of the tracheobronchial wall and adjacent peribronchial areas through advancing an US probe inside the bronchi.

Lung cancer 42 2. Determining the depth of invasion of intramural tracheobronchial tumors. 3. Extra-luminal lesions & Lymph nodes: . Identifies & localize lesion. . Positional relationships of the lesion to bronchial lumen & mediastinal structures. . Assists in TBNA.
V. Indications & clinical applications

Indications: - Peripheral lesions: . Identifies, localize lesion & assists TBX. . Qualitative diagnosis???. - Therapeutic bronchoscopy. Clinical applications in Lung cancer: - Nodal (N): additional LN & assist TBNA. - Tumor (T): depth, ELC, impression Vs invasion of mediastinal structures & vessel. - Assisting bronchoscopic procedures of extra-luminal, mediastinal & peripheral lesions. - Therapeutic bronchoscopy.
VII. General or topical anesthesia

General anesthesia: - Combined rigid & FOB. Topical anesthesia: - Premedication:. . Atropine sulphate. . Pethidine. . Titrated midazolam sedation. . Prednisolone (COPD). - Lidocaine: . Inhalation (4%). . Instillation (2%). Salbutamol + Ipratropium bromide solution. Oxygen supplement and Pulse-oxymetric monitoring.
VIII. Nodal & Vascular Anatomy of Mediastinum

Lung cancer 43

IX. EBUS - assisted therapeutic bronchoscopic procedures

EBUS guided or changed management in 43% e.g. selecting proper stent size, guiding tumor debridement. No more fatal Haemoptysis during thermal ablation.
X. Side effects & tolerability

Topical anesthesia: N = 81 - Completely tolerated 77% - Partially tolerated 22% (14 Cough, 7 desaturation & 1tachycardia). - Not tolerated 1 %( 1severe cough) General anesthesia:

Lung cancer 44 - Rare desaturation & tachycardia. - Published reports made no reference to possible complication of GA.
X. Concerns

Operator dependent. Prolongation of examination time ~ 6-12 min. Depth of invasion: experimental Vs clinical studies. Sampling is assisted not guided. Initial instrument handling difficulties. interventions. Saving expenses of further invasive diagnostic procedures or unneeded surgical

XI. Conclusions EBUS application under topical anaesthesia: Well tolerated. Mild infrequent side effects. Acceptable prolongation in examination time, but reducible with acquisition of experience. Providing valuable beneficial additional information beyond bronchoscopy and CT alone. Its addition can improve the diagnosis and assessment of lung cancer. Further expected technical improvements will allow EBUS to play a more important role in diagnostic and interventional bronchoscopy in the near future. Mediastinoscopy 1. 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. 2. taken during the procedure. 3. 4. Mediastinoscopy is usually performed as a diagnostic test in people who have centrally located lung tumors that can be reached from the mediastinum. Mediastinoscopy is performed under general anesthesia. Mediastinoscopy is often used for both diagnosis and
staging. Biopsies of the primary tumor and mediastinal lymph nodes are

Transthoracic Needle Biopsy= fine needle aspiration (FNA) biopsy. A. B. or fluoroscopy. It is usually reserved for people who have
tumors near the surface of the lung that would be difficult to reach by bronchoscopy.

This procedure is performed using either CT

C.

Lung cancer 45 Local anesthesia is used to numb the skin where the needle is inserted, and a mild sedative is used to relax the patient.

Thoracoscopy 1. 2. 3. Is surgical procedure in which an endoscope is inserted into the chest. Thoracoscopy has limited use in lung cancer diagnosis, but is sometimes used to
biopsy a suspicious tumor and regional lymph nodes .

Advantages: a. b. Thoracoscopy allowing the surface of the lung to be examined Permitting sampling of any pleural effusion that may be present. a tiny video camera is inserted into the chest by a small incision separate from the incision used for the thoracoscopy. F. during the procedure. G. VATS and routine thoracoscopy procedures are performed under general anesthesia Pictures of the chest cavity are projected onto a screen

4.

VATS is technique in which: E.

Thoracotomy 1. other methods. 2. 3. 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. If cancer is found, the surgeon will sample regional lymph nodes to determine if a surgical cure is possible. Again, the lymph nodes are examined while the patient is still in the operating room. If surgical cure is possible, a potentially curative operation will be performed. In rare instances, doctors are unable to biopsy a suspicious lung tumor using

IV. Laboratory investigations and PFT:

Routine laboratory investigations have no diagnostic role in lung cancer except: 1. Detection of hepatic involvement. 2. Detection of paraneoplastic syndromes patient is well enough to be operated on. 3. Blood tests and lung function testing are also necessary to assess whether the

V. Tumour markers= Biomarkers= Oncofoetal:

Definitions:

2.

Lung cancer 46 Are measurable biochemical's that are associated with malignancy, they are either produced by tumor cells (tumor-derived) or by the body in response to tumor cells (tumorassociated), they are typically released into the circulation and thus measured in the blood.

3. 4. 5. 6.

Tumor markers are substance that can often be detected in higher- than- normal
amounts in the tissue or cells of an organ site.

It is sometimes called Oncofoetal, because it present not only in tumor but also expressed in fetal tissue during normal development In normal individuals, these proteins are present at very low level (undetectable). Any proteins or chemical has the potential to be a tumor marker, for example serum calcium is elevated in some cancer.

Nature of tumor markers:

Tumor markers are cellular, biochemical, and molecular alterations by which a normal, abnormal or simply a biological process can be monitored. 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. conditions 2. 3. 4. 2. Serum 3. Plasma 4. Buccal cell isolate serve as viable sources of biomarkers 5. Tissue-bound receptors that must be measured in a biopsy from solid tumor. 6. Proteins are sometimes measured in urine. Uses of tumor markers: 5. Aid in diagnosis of cancer. 6. Classification of certain tumors (differential diagnosis of lung cancer). 7. Clinical management. 8. Some tumor markers provide prognostic information (response to treatment) 9. Follow-up of tumor and detection of early recurrence. Tumor marker levels not elevated in every person with cancer, especially in the early stages of the disease. Many tumor markers are not specific to a particular type of cancer. The level of a tumor marker can be elevated by more than one type of cancer. Some tumor marker is elevated in patients with renal failure. Specimens used for detection of tumor markers: tumor marker levels can be elevated in people with benign

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

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.

Several studies have demonstrated the presence of significantly higher concentrations of

circulating DNA in plasma/ serum in patients with different types of lung cancer,

including primary or recurrent lung cancer.

Thus, quantification of plasma DNA and characterization of specific molecular

changes could represent useful biomarkers of lung cancer:

1.

Neuron Specific Enolase (NSE):

1. Dose not has the sensitivity or specificity necessary for use in screening. 2. Uses: i. ii. diagnosis including: ii. Neuroendocrine tumors of other localizations. Hepatoma. Lymphoma. Seminoma. Moderate elevation of NSE is found in: - Patients with benign lung conditions. - Gastric cancer. - Pancreatic cancer. - Colorectal cancer. - Breast cancer. Have considerable potential for the monitoring of treatment of SCLC. ii. therapy 3. Because it present in RBCs, plasma cells, and platelets, serum or plasma must be separated from RBCs within minutes to avoid false high results. For detection of recurrent disease of SCLC after primary It used to aid the diagnosis of SCLC: High serum levels of NSE (>100 g/L) in patients with suspicious of malignancy suggest the presence of SCLC with the differentia

i.

2.

Carcinoembryonic Antigen (CEA):

A. Its concentration is particularly high in adenocarcinoma and large cell carcinoma. B. However, its use in screening and diagnosis is limited due to it is elevated in various benign pathologies and other malignancies. C. It may be used in differential diagnosis of NSCLS (in combination with CYFRA 211).

Lung cancer 49 D. It can be used to provide prognostic information in NCSLC (adenocarcinoma). E. It may have a role in monitoring therapy in advanced stages. F. It also may detect recurrent disease of adenocarcinoma.

3.
a. b.

Cytokeratin-19 Fragments (CYFRA 21-1):

CYFRA 20-1 is the most sensitive tumor marker for
NSCLC particularly squamous cell carcinoma.

CYRFA 20-1 has potential for monitoring treatment of NSCLC in advanced disease. It also has a role for detection of recurrent disease of NSCLC after primary therapy particularly in squamous cell carcinoma. It may be helpful in the differential diagnosis of suspicious lung mass particularly if biopsy is not possible. Recent studies demonstrated CYRFA 21-1 to be independent prognostic factor in both early and late stages of NSCLC.
Disadvantage (limit its use in screening and diagnostic

c. d. e. f. tests):

Due to its presence in low concentration in various benign diseases its use as a screening and diagnostic test is limited But, it is also elevated in: urological tumor. GIT tumor. Gynecological tumors. Its value may be significantly influenced by renal failure (high results). Other reports have suggested CYRFA 21-1 may also have prognostic value in
SCLC.

4.

Progastrin-Releasing Peptide (ProGRP):

A. ProGRP is a reliable marker for SCLC with good sensitivity and specificity. B. It is rarely elevated in other malignancies and if so, its levels are only mildly elevated. C. ProGRP concentration: Levels >200 ng /L are highly suspicious for lung cancer. Levels > 300ng /L for SCLC if renal function is not impaired.

D. It has shown to be helpful in differential diagnosis of SCLC from other lung cancers. E. Only one report supports the use of ProGRP in prognosis F. It may be used for monitoring of SCLC and for detecting recurrent disease after primary therapy G. Disadvantage: it is elevated in patients with renal failure (up to 300ng/ L.).

5.

Squamous Cell Carcinoma Antigen (SCCA):

i. ii. iii.

Lung cancer 50 Less sensitive than CYRFA 21-1 in NSCLC it has superior specificity for squamous cell carcinoma. It can be used for histological subtyping of NSCLC. Disadvantages: It is elevated in: 1. Squamous tumors of cervix. 2. Squamous tumors of oesophagus. 3. Squamous tumors of head and neck. 4. Dermatological diseases. 5. Preanalytical contamination with skin or saliva. 6. Renal failure.

iv. cell carcinoma). v.

It may be used in differential diagnosis of NSCLC (squamous Potential prognostic utility of SCCA has been reported

6. p53:
A.
of SCLC.

Alteration of p53 is observed in 75-100% Meta-analysis found p53 alteration in 47%

of patients with NSCLC (squamous, large cell, or adenocarcinoma)

B. C.

Clinical meta-analysis study suggest that the p53 alteration (by immunohistochemical, or molecular) may be a significant marker for poor prognosis in patients with pulmonary adenocarcinoma.

D.

Oligonucleotide array for p53 mutation appear to be a rabid test of detecting p53 missense mutation in primary lung cancers.

7. P16INK4a:

The two tumor suppressor genes affected in lung cancers are a. b. Mutations (inactivation) of p16INK4a have been observed in 30-70% of NSCLC. RB is mutation (inactivation) is: The preferential mechanism in SCLC 90%. But mutation of RB may occur in 15-30% of NSCLC. It is unclear whether the absence of RB expression is associated with poor prognosis in NSCLC.

8. Epigenetic Changes:

B. TSG in human cancer. C. -

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. Its mutations are detected in:
- 20-30% of lung adenocarcinoma. - 15-20 % of all NSCLC.

c. d.

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.

10. Receptors Tyrosine Kinase:

i. Receptors tyrosine kinases are major components in positive signaling cascades, some of which are over-expressed in lung cancer. (e.g. epidermal growth factor, heregulin receptor, and tyrosine kinase receptor-oncogene KIT {CD117}).

Epidermal growth factor receptor (EGFR): Role: On the surface of many types of cancer cells, are structures known as epidermal growth factor receptors (EGFRs). The receptors allow epidermal growth factor (a particular protein present in the body) to attach to them. When the epidermal growth factor (EGF) attaches to the receptor, it causes chemical processes inside the cell that make it grow and divide more quickly than it should. a. b. Overexpression of EGFR is seen: Frequently in NSCLC (squamous cell carcinoma) Rarely in SCLC.

- Drugs known as EGFR antagonists Erlotinib (Tarceva), .

Hregulin receptor (HER2/neu): Is highly expressed in 30% of NSCLC. (Adenocarcinoma). HER2/neu over expression is associated with:

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.

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. In general patients with pre-operative FEV1 > 2L tolerate surgery. Patients who are considered marginal for surgery require further investigations. Quantitative assessment of regional lung function,

it may demonstrate that, the patients may have undergone the physiological effect equivalent of pneumonectomy or lobectomy (tumor obstruct airway), in such condition operation may produce physiological improvement (by removing the major cause of ventilation/ perfusion mismatch). D.
Diffusing capacity: post-operative complication is

more common if Dlco is less than 40% of predicted before operation. a. b. Other medical conditions: such as IHD and peripheral vascular disease. Patients who have controlled angina need to undergo exercise ECG. Patients whose exercise is limited by significant intermittent claudication are not suitable for surgical intervention.

2.

Assessment of local spread:

A. Involvement of mediastinal structures may be evident by: o History of dyspnoea. Dysphagia, dysphonia. o SVC obstruction. B. Pleural effusion: Inoperable, It should be further evaluated by Aspiration and biopsy. Some study suggest that the small and not contain malignant cells it dose not exclude operability (results of operation is poor in such condition). C. The results of operation correlate well with the extent of mediastinal lymph node involvement, assessment of mediastinum is essential in every patient presented by lung cancer by:

1.

CT: The best non-invasive methods for mediastinal assessment in lung cancer being considered for resections Limitation of CT:

i. lymph node. ii. pleura. 2. 3. 4.

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. The a authors used 1 cm as the cut off value for normal lymph node size, some

report suggest 1.5 cm as the upper limit of normal value There is a correlation between the nodal size and malignancy (fair). CT may also be useful for identifying tumor involvement of mediastinum and

MRI may be useful in assessing Pancoast tumor and chest wall invasion. Radioactive isotopes taken by tumor (gallium), not added advantage over CT. mediastinoscopy: a. spread. b. c. It leads to better selection of cases for surgery, so those with mesiastinal involvement are excluded. False- negative rates of about 10% are recorded due to inability to sample all mediastinal structures. It is indicated for patients who show abnormal mediastinal examination on CT, to confirm or refute to presence of metastatic

4. Assessment of distant spread:

A. B. 1. Spread of bronchial carcinoma outside chest makes the patients inoperable. 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, hard, irregular live (strong evidence of hepatic metastasis). Jaundice( unusual presentation) 2. LFT: Should be done routinely for patients with lung cancer (staging). Normal value does not exclude hepatic spread. Elevated value may be due to associated non-metastatic live disease. 3. Abdominal US and Ct:

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

1. Symptoms: is usually symptomatic. Pain suggestive to bone metastasis should lead to

1. Symptoms: headache, vomiting, personality change, fits, and the development of focal

Lung cancer 58

Lung cancer staging c. d. 3. e. 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. Aim of lung cancer staging: Staging is important for two reasons: 2. It helps to determine which treatments are likely to be most effective for tumor. It also helps determine what the course of illness (prognosis) is likely to be. Lung cancer stage is the primary factor influencing the prognosis of the disease. Lung cancer stages range from I through IV. In general: 7. 0. The lower the stage, the less the cancer has spread. 8. The higher the stage, the more extensive is the spread of the disease Three factors are used to determine lung cancer stage. These factors are expressed using the TNM classification system. The three factors of the TNM system are as follows. T: Tumor characteristics including size, location, and local invasion N: regional lymph Node involvement M: Metastasis status. a. . Generally, doctors try to establish the M factor (a persons metastasis status) as early as possible in the staging process. The reasons for this is that: - 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. I. Determining Metastatic Status The state of metastasis (M) is defined as follows. M0: No distant metastasis found. M1: Distant metastasis is present. Physical findings and presenting symptoms may raise suspicion of metastatic disease in

a specific organ or area of the body. Under such circumstances, scans will be focused on that specific area. However, metastatic disease is often asymptomatic at the time of diagnosis, which

necessitates a thorough search for distant, asymptomatic metastatic tumors. Imaging tests commonly used to screen for metastatic disease are listed below.

CT scans - abdomen, pelvis, and brain

MRI scans - brain PET scans - whole body

Lung cancer 59 Ultrasonography abdomen and liver, uses special frequency sound waves to visualize internal organs Bone scans whole body, a radioactively labeled substance that is taken up by actively growing and dividing cells is injected into the body. A scan is later taken of the entire body to look for hot spots in the skeleton. Hot spots are areas in the skeleton with high uptake of the radiolabeled chemical that may indicate metastatic disease. II. Determining Regional Lymph Node Status

1. The regional lymph nodes of the chest are divided into three major areas, the hilar lymph nodes, the mediastinal lymph nodes, and the supraclavicular lymph nodes. 2. Cancer in lymph nodes beyond the hilar, mediastinal and supraclavicular lymph nodes is considered evidence of distant metastasis. 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. 4. Regional lymph nodes can be sampled and staged with the following procedures. Bronchoscopy Mediastinoscopy Thoracoscopy and VATS Thoracotomy 5. 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 categories for lung cancer tumor classification take into account the size, location, and local invasiveness of the primary tumor. Tumor characteristics are determined using the same methods used for diagnosis and evaluation of the regional lymph nodes. The tumor categories and their descriptors are listed below. T0: No evidence of primary tumor. Tis: Carcinoma in situ. T1: Tumor that is: Less than 3 cm (1 inches) in size Completely surrounded by lung tissue T2: Tumor that is: Larger than 3 cm (1 inches)

3. Regional lymph node status is divided into the following categories.

III. Determining Tumor Characteristics 1. 2. 3.

Lung cancer 60 the mediastinum. - Any size -Invades the chest wall, diaphragm, or the pleura of the mediastinum or heart. * T3 cancer is potentially respectable (surgically removable). i. ii. body (a backbone).

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, it may not be operable if the remaining airways cannot be sewn together. Therefore, tumors involving the carina are T4 tumors. Tumors associated with a malignant pleural or a pericardial effusion are also T4 tumors, as are separate tumor nodules in the same lung lobe.
T4 tumors are generally inoperable.

NON-SMALL CELL LUNG CANCER STAGES Using the TNM classification system, NSCLC is divided into four stages. Generally cancer is divided into four stages: small and localized (stage one); has spread into surrounding structures (stages two or three); or has spread to other parts of the body (stage four).

Stage I
Stage I NSCLC is characterized by: A cancerous tumor that has not spread. There is no evidence of cancer in any lymph nodes. The difference between stage IA and stage IB disease is the size of the primary tumor. less in size. With stage IB disease, the tumor is larger than 3 cm (1 inches) in size. With stage IA disease, the tumor is 3 cm (1 inches) or

Stage I NSCLC is local disease and is potentially curable with surgery. The stage I TNM designations are: Stage IA: T1N0M0 Stage IB: T2N0M0

Stage II

Stage II NSCLC is characterized by:

Lung cancer 61 a. b. c. A primary tumor that has spread to the ipsilateral hilar lymph
nodes (the N1 area).

With stage IIA, the tumor is a T1 (3 cm or less). With stage IIB, the tumor is a T2 (greater than 3 cm).A tumor involving the chest wall without hilar lymph node involvement (T3, N0) is also considered stage IIB disease.

Stage II NSCLC is potentially curable with surgery, although the chance of recurrence is higher. 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, and there are significant differences in the treatment of stage IIIA versus stage IIIB disease. 1. Stage IIIA disease includes a tumor that has: Invaded the chest wall, diaphragm, or the pleura of the mediastinum or heart, and has ipsilateral hilar or mediastinal lymph node involvement (T3N1M0 or T3N2M0). Smaller tumors that involve the ipsilateral mediastinal lymph nodes are also stage IIIA (T1N2M0 or T2N2M0). Stage IIIA is potentially operable. Stage IIIB disease includes: Any size tumor that has invaded any of the vital structures of the mediastinum, the carina, or a vertebral body (T4 tumors), with or without regional lymph node involvement (T4N0M0, T4N1M0, T4N3M0). Lesser tumors (T1-3) that are associated with contra lateral lymph node involvement or any supraclavicular lymph node involvement are also stage IIIB. 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, T4N1M0, T4N2M0, T1N3M0, T2N3M0, T3N3M0, T4N3M0 Stage IIIA: T3N1M0,

2.

3.

Stage IV

Stage IV NSCLC is assigned whenever there is distant metastasis, that is, spread of the disease beyond the regional lymph nodes.

Lung cancer 62

1.

Special Cases
Stage 0 (zero) represents carcinoma in situ. 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. Carcinoma in situ is curable and incapable of spreading. The TNM designation for carcinoma in situ is Tis. Since there is currently no organized screening program for lung cancer, the percentage of people newly diagnosed with lung cancer who have stage 0 disease is very low. Occult lung cancer is another uncommon situation in which:
Tumor cells are found in the sputum or bronchial washing, No primary tumor can be seen on imaging studies or on direct

2.

examination with a bronchoscope. The TNM designation for occult lung cancer is Tx.
Table 1 gives the lung cancer TNM descriptors according to the International System for Staging Lung Cancer:

1. PRIMARY TUMOR (T) Tx 1. Primary tumor cannot be assessed 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, surrounded by lung or visceral pleura without bronchoscopic evidence of invasion more proximal than the lobar bronchus. T2 Tumor with any of the following features of size or extent: b. c. d. e. 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. chest wall (including superior sulcus tumors)diaphragm B. mediastinal pleura C. parietal pericardium

Lung cancer 63 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. Tumor of any size that invades any of the following: Mediastinum Heart or great vessels Trachea Esophagus vertebral body Carina 2. OR: Tumor with a malignant pleural or pericardial effusion 3. OR: Tumor with a satellite tumor nodule(s) within the same lobe as the primary tumor. REGIONAL LYMPH NODES (N) o o o 1. 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. Mx Presence of distant metastasis cannot be assessed 2. M0 No distant metastasis 3. M1 Distant metastasis present * Separate metastatic tumor nodule(s) outside the lobe of the primary tumor are also classified as M1. SMALL CELL LUNG CANCER STAGES 1. While the TNM system is used for SCLC in some research settings, most health care providers more commonly categorize SCLC as either limited or extensive stage disease. 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.

2. OR Direct extension of the primary tumor into intrapulmonary nodes o o

2.

Lung cancer 64 3. . People with SCLC are staged with limited or extensive disease based on the extent of the disease in the chest. People whose disease is confined to one lung, the mediastinum, and regional lymph nodes are categorized with limited stage SCLC. Table 1: TNM Descriptors, continued 1. 2. 3. 30% of SCLC has limited stage disease at diagnosis. Limited stage corresponds to stages I through IIIB of the TNM staging system. Extensive stage SCLC: Has spread to the contra lateral lung, is associated with a malignant pleural effusion, or is accompanied by distant metastasis. Approximately 70% of people with SCLC have extensive stage disease at the time of diagnosis.
effusion and stage IV of the TNM staging system.

Extensive stage corresponds to stage IIIB with pleural

Treatment of lung cancer Treatment for lung cancer depends on: 3. Cancer's specific cell type 4. How far it has spread, 5. Patient's performance status. Common treatments include surgery, chemotherapy, and radiation therapy.

I. Treatment of Non-small cell lung cancer

1. than 10%). 1. Surgery: Indications: Is only option in NSCLC if the disease is limited to one lung and has not spread beyond its confines. There are two main issues to be taken into account when considering surgery for lung cancer; respectability and operability. 1. A cancer is deemed to be resectable on the basis of its staging, taking into account invaded structures, presence of metastases and position. 2. The operability refers to the patients ability to cope with both the operation and the subsequent reduction of lung volume and function II. Surgery is effective treatment for NSCLC, but the disease is operable only in small minority of cases: Prognosis is poor (5-years survival rate is less

a. b. c.

Lung cancer 65 2/3 of cases are inoperable due to, advanced age, poor respiratory function, other medical condition, and evidence of tumor spread. 15-15% of cases are rejected because of mediastinal spread at mediastinoscopy. Only about 12-15% of all patients presented with NSCLC have a potentially of being curable by operation.

III. Types of operations: 1. Pneumonectomy: it involves: i. ii. iii. bronchial stump at the level of carina. iv. enable more accurate pathological staging. v. 2. Lobectomy: it involves: i. segmental level. ii. 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. iii. the remaining lobe or lobes. 3. Bronchoplastic procedures: i. ii. 2. 3. left side. Removal of tumor and yet conserve part of the lung subtended by the involved bronchus. Sleeve resection is the most common procedures. Resection of tumor extending from the right upper lobe bronchus into the right main and intermediate bronchi. 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, in order to stabilize the mediastinum. Hilar and accessible mediastinal lymph node should be removed and labeled according to their site of origin in order to Ligation of pulmonary veins. Division of pulmonary artery. Suturing or stapling of the

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

Lung cancer 69 1. 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. Small numbers of large fraction are less effective than large numbers of small fractions (even the total dose is fixed). Split-course therapy: i. course. ii. Advantage: It added the advantage of initial palliation due to tumor shrinkage with the same side effect. Give chance of further assessment of extra-thoracic spread before second course of treatment. iii. 3. Disadvantage: Cell kinetic studies have demonstrated that tumors may repopulate in the standard intervals between treatments. 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. Results:

2.

Regimen: the same total dose is given in two half-dose courses with a rest period of about 4 weeks, have the same results of continues

Survival results of radical radiotherapy in inoperable patients are generally disappointing. Many authors report good 1- year survival of 30-40%, while 5- Year survival rarely exceeds 20%. Survival rates are better with in patients with stage I NSCLC. Radiotherapy itself may because radiographic changes in normal lung that makes the detection of local recurrence difficult.

2.

Palliative radiotherapy:

a. metastasis.

Indications: it is indicated in patients with extrathoracic metastasis to relive symptoms by reducing tumor growth and not cure. Methods: Planning field of treatment: Chest irradiation as in radical radiotherapy. Extra-thoracic radiotherapy, according to site of

b. in up to 10 fractions:

Lung cancer 70 Dose. Total dose is usually small (20-30 Gy) given Fit patients: two treatments of 8.5 Gy 7 days apart are equal efficacy to 3 Gy 10 days apart. Unfit patients: one treatment of 10 Gy are effective as two treatment of 8.5 Gy.

palliative radiotherapy: A. Haemoptysis (80%)

Thoracic symptoms that relived by

B. Chest pain, which is due to chest wall or rib involvement (70%), more diffuse discomfort is not responding. C. Distressing cough (60%). D. Dysphagia due to esophageal compression by lymph node responds in (60-86%) E. Dyspnoea due lymphangitis carcinomatosis, is unrelieved F. Ares of atelectasis, partially re-expand (>25%). G. SVC obstruction responds in (60-86%).

compression: a. 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. Improvement is small and dense neurological deficit rarely respond. Median survival for untreated patients with brain metastasis is about 3 months. Dexamethasone is given initially in dose of 16mg/ day may produce temporary relief by decrease intra-cranial pressure;

b. spinal cord compression due to tumor: Corticosteroids should be given Neurosurgery If neurosurgery id not advised palliative radiotherapy is indicated.

c. Bone metastasis: pain is responding to palliative radiotherapy in most cases.

Lung cancer 71 d. Cervical lymph node enlargement, is not responding to radiotherapy e. Systemic symptoms is not responding to palliative radiotherapy f. Recurrent laryngeal or frank nerve palsy is not respond. g. Paraneoplastic syndromes, its response is variable and unpredictable. XI. 1. undergoing radical radiotherapy. 2. Since the aim in palliative radiotherapy is to relief symptoms and not cure tumor any side effects should be kept to a minimum. Side effects of radiotherapy Dose related, so it is more common in patients

1.
1. 2. 3.
4.

general side effects:

General side effects, Flu-like symptoms

such as feeling sick (nausea) and tiredness.

for a few days, or chest pain. These side effects can be can usually be effectively treated by anti-emetics.

mild or more troublesome, depending on the strength of the radiotherapy dose.

Feeling sick Nausea Dysphagia:

2. 3. 4.
5.

Time of start: Towards the end of the course of treatment. Symptoms: difficulty in swallowing, heartburn and indigestion. Causes: This happens because the radiotherapy can narrow oesophagus.
Tiredness. Skin care:

6.
7.

Some people develop a skin reaction similar to sunburn. Pale skin may become red and sore or itchy Darker skin may develop a blue or black tinge..

Hair loss:

With external radiotherapy, hair will fall out within the treatment area, such as chest hair for men, or head hair if you are given prophylactic cranial radiotherapy. The hair usually grows back, although occasionally the hair loss is permanent.

All the side effects should disappear gradually once your course of treatment is over, but it is important to tell your doctor if they continue.

2.

local side effects:

Occur following radical radiotherapy. Radiological changes becoming evident 2-6 months after the completion of treatment. PCX-ray show non-specific hazy infiltrate, its margin is characteristically straight, matching the shielding around field of treatment.

B. Radiation pneumonitis:

Lung cancer 72 Causes: initially inflammation and later fibrosis. Symptoms: It is usually not associated with symptoms, except in 10% of cases who complain from gradual onset of dyspnoea and dry cough. Treatment: Symptoms may respond to steroids if in early stage (inflammation). C. Radiation myelitis: radiotherapy. demyelination. D. Radiation pericarditis: o Occur 3-6 months after radiotherapy in about 4% of cases. o It is associated with, sternal discomfort, dyspnoea and ECG changes. o The condition is self-limiting and treatment is symptomatic. XII. Endobronchial radiotherapy treatments: Course: disappear gradually over a few weeks. Rarely, progression to complete paraplegia with loss of sphincter control may occur. Causes: It is due to spinal cord vascular damage and Most serious side effects. Transient and self limiting. Symptoms: Pain and paraesthesia occur 3 months after

Indications: it is used to palliate symptoms such as hemoptysis, and

critical obstruction of airways.

Types:

1.
A. radiation. B. Types:

Laser therapy:

Definitions of laser: Laser is an electrical device for producing an extremely powerful and narrow beam of light. 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. Various types of laser are available but, Nd-Yag laser is the most commonly used type in respiratory work: Carbon dioxide (CO2) lasers - CO2 lasers can remove a very thin layer of tissue from the surface of the skin without removing deeper layers. The CO 2 laser may be used to remove skin cancers and some precancer cells.

Lung cancer 73 Neodymium: yttrium-aluminum-garnet (Nd-Yag) lasers - Nd-Yag lasers can penetrate deeper into tissue and can cause blood to clot quickly. The laser light can be carried through optical fibers to reach less accessible internal parts of the body.

Laser-induced interstitial thermotherapy (LITT) - LITT uses lasers to heat areas of the body between organs (interstitial areas) that are near a tumor. The heat from the laser increases the temperature of the tumor, thereby shrinking, damaging, or destroying the cancer cells.

such as skin. C. 1. 2. 3.

Argon lasers - Argon lasers pass only through superficial layers of tissue, Photodynamic therapy (PDT) - PDT uses argon laser light to activate chemicals in the cancer cells. Mode of action: The beam is transmitted via bronchoscope. The fiber can be passed down the suction channel of FOB and the beam is directed against tissue. Its energy evaporates moisture and coagulates blood vessels to a depth of about 5mm. Disadvantages: used only as palliative treatment as most lesions is out of reach of FOB and so out of reach of laser. Cannot effectively treat extrinsic compression. The initial equipment cost is substantial, and special training and certification is necessary.

D.

E.

Uses: o Symptomatic relief of dyspnoea by de bulking proximal endobronchial or tracheal tumor. o Also in symptomatic relief of hemoptysis by coagulation of blood vessels.

2.
at bronchoscopy.

Techniques deliver high-dose via catheter:

a. Method: it delivers high dose- irradiation to the tumor via a catheter positioned next to tumor b. Duration of treatment: about 10 minutes. c. Indications: relief symptoms due to bronchial obstruction caused by tumor or extra-luminal pressure caused by lymph nodes. d. Complications: secondary hemorrhage.

3.
A. Method:

Photodynamic therapy:

1.

Lung cancer 74 It involves intravenous administration of a light sensitive drug e.g. haemtoporphyrin derivative (has affinity for malignant tissue) which makes tumors respond to the cold red laser light (that react to argon light).

2. 3. 4.

This drug is activated by laser light delivered at. Cells throughout the body absorb the chemicals, which last longer in cancer cells than in healthy cells. At the right time (After 24 to 48 hours,), when the healthy cells surrounding the tumor are relatively free of the chemicals, the red light of an argon laser can be focused directly (bronchoscopy)on the tumor.

5. 6.

The light activates the drug which produces a toxic form of oxygen that destroys tumor tissue, via necrosis and sluggish. One to two days after the laser treatment, destroyed tumor tissue is removed during a second bronchoscopy procedure.

B.

Indications: PDT can be used to: help open up a blocked airway, and can use for retreating cancers and also for treating very early (in-situ) lung cancers.

C.

Advantages: It is performed on an outpatient basis It is relatively pain free It requires minimum sedation It has minimal side effects

D.

Disadvantages. Its results are delayed; there is a requirement for multiple bronchoscopies for debridement and possibly retreatment.

E.

Side effects of photodynamic therapy. The side effects of photodynamic therapy are relatively mild and may include: 1. 2. 3. A small amount of damage to healthy tissue. Also, a patients skin and eyes are sensitive to light for 6 weeks or more after treatment is completed. Depending on the area that is treated, patients may experience other temporary side effects.

4. Lung Brachytherapy:
Brachytherapy, 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

Lung cancer 75 Lung brachytherapy can be used almost any time a tumor can be seen in an airway on bronchoscopy.

1.

Method: During bronchoscopy, a thin plastic tube is placed down the nose, and down into the airways of the lung, into the diseased bronchus. Once the bronchoscope is removed, a thin tube remains in place for about 45 minutes, delivering a high radioactive dose directly to that site through the segment of the tube which is lying against the cancer. This effectively treats the cancer from the inside-out. Lung brachytherapy can be used in the following situations:: A. NSCLC (Brachytherapy can treat submucosal and peribronchial lesions)

2.

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. Other intrathoracic malignancies, such as malignant pleural mesothelioma and malignant thymoma, have been treated with brachytherapy. 3. can be in the form of: brachytherapy, the placement of the source within the airway lumen
A.

Forms of Brachytherapy techniques: Endobronchial Interstitial brachytherapy, the placement of the isotope into a tumor bed where no lumen exists.
Permanent interstitial volume or planar implants (radioactive sources

permanently imbedded into the tumor or tumor bed).

B. Temporary interstitial or endoluminal implants (where

radioactive sources irradiate a tumor bed over a certain length of time and then are removed). 4. treatments can be delivered: Over a short interval (high-dose rate [HDR]), can be used intraoperative to deliver a large dose of radiation to a determined target area. Duration of brachytherapy: These

Lung cancer 76 5. Over a more protracted time (low-dose rate). 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. 6. limited. 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, the results are delayed, and doses are

medical condition is less than ideal to permit other therapeutic modalities.

Method:

A. Prior application of CT-guided bronchoscopic barium marking facilitates the performance of brachytherapy and effectively shortens the procedure time. B. After marking and calculation of the treatment plan, brachytherapy can be performed under fluoroscopic guidance.
Advantages:

1. 2.

Delivering an appropriate radiation dose from inside the lesions while minimizing damage to surrounding normal tissue. As the dose is administered from inside the lesion, radiation delivery is not affected by respiratory movements or by cardiac movements.

and experience.

There are no contraindications to the procedure other than those that would contraindicate basic bronchoscopy.
Disadvantages: it is technical difficulty.

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, because the hemorrhage is from larger blood vessels. a. CT-guided percutaneous brachytherapy: Can feasibly be performed with good results.

b. c.

Lung cancer 77 However; the transbronchial approach allows the use of thicker catheters than those permitted by a transthoracic approach. Iatrogenic infection and pneumothorax are not significant concerns with a transbronchial approach, in contrast to a transthoracic approach.

5.

Tomotherapy :

Tomotherapy is one of the most advanced and targeted forms of radiation available today. Tomotherapy technology enables to re-treat previously treated areas that have a recurrence of cancer. 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. Advantages: Traditional radiation therapies project radiation on a tumor from a few directions. Tomotherapy allows delivering precise and powerful doses of radiation from 360-degrees. Method: 1. 2. Use a PET/CT scan to find all the active cancer, and then use tomotherapy to target it. We add amifostine, a radioprotectant drug, to reduce the damage that radiation can cause to healthy lung tissue.
Two ways that IMRT differs from conventional radiation are:

o location o

IMRT employs a powerful, advanced computer program to plan a precise dose of radiation in three dimensions, based on individual tumor size, shape and IMRT directs radiation at the tumor and modulates the intensity of radiation with laser accuracy

3.

Chemotherapy :

o 2.

Indications: 1. Patients have metastatic disease at time of presentation. Failure of treatment due to occurrence of disease at distant site. cytotoxic drugs. 3. In both of these conditions there is a need for systemic treatment that is most commonly

Survival:

 o o o Etoposide or Vinorelbine.

Lung cancer 78 NSCLC are relatively resistant to the drugs currently available. Some authors have claimed prolonged survival for patients who respond compared with non-responder. The average increase in survival is only 6 weeks

Drug regimen: Cisplatin or Carboplatin, + Gemcitabine, Paclitaxel, Docetaxel, In metastatic lung cancer, the addition of Bevacizumab when added to Carboplatin and Paclitaxel was found to improve survival. Cisplatin and Carboplatin use is limited by toxicity and inherent resistance. These considerations have prompted research into new platinum agents, such as the trinuclear platinum agent BBR3464 , the platinum complex ZD0473 and Oxaliplatin. These compounds could be developed in combination with agents such as Paclitaxel, Gemcitabine or Vinorelbine in patients with advanced and/or refractory NSCLC solid tumors

4.

Combined modality treatment: A. surgery and radiotherapy: a. Preoperative radiotherapy: Some tumor may initially inoperable but after radiotherapy and shrinkage of tumor mass become resectable. No change in survival. The exception to this is Pancoast tumor.

b. Postoperative radiotherapy: i. it shown to improve local control to chest in stage I and II. ii. It also indicated if residual from tumor is left in chest. B. surgery and chemotherapy: indications: a. 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. b. 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

Lung cancer 79 This led to the interest in combining good local control (surgery) with systemic treatment (chemotherapy).

a.

Time of chemotherapy: In the Past give postoperatively (adjunct therapy). Recently: Better results obtained from given it before operation. The results of surgical treatment on stage IIIA is poor, if chemotherapy is given with surgery there is good response and some cases may show increased respectability. b.

K-RAS oncogene is found to be a significant prognostic marker in resected specimens (responders). At present, it is standard practice to offer patients with resected stage 2-3A NSCLC adjuvant 3rd generation Platinum based chemotherapy (e.g. Cisplatin and Vinorelbine).

C. radiotherapy and chemotherapy: Aim: is to optimize local control and to control distant metastasis. There was definite for combined therapy compared with radiation alone. The optimal sequence of chemotherapy before or during radiotherapy is not known. Platinum- based chemotherapy before chemotherapy gives the modest survival, possibly due to its role in prevention of micro metastasis. 5. Targeted therapy 1. inhibitor for EGF). 2. 3. 4. from gefitinib
Erlotinib (Tarceva) :

In recent years, various molecular targeted therapies have been developed for the treatment of advanced lung cancer, 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. it was not shown to increase survival, although females, Asians, nonsmokers and those with the adenocarcinoma cell type appear to be deriving most benefit

i. advanced NSCLC. ii. iii. help to stop the cancer cells from growing so quickly iv. 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, Asians, non-smokers and those with the adenocarcinoma. Mechanism of action: it attaches them to the EGFR inside the cell, and prevents the receptor from being activated, this can Indications: It is sometimes used -Cancer has come back after initial treatment - Not responded to at least one course of chemotherapy.

v. vi. and include diarrhea, a rash, nausea and tiredness.

Route of administration: tablet. Side effects are generally mild

6.

Other methods of treating lung cancer:

1. Endobronchial cryotherapy Cryotherapy uses extreme cold to freeze and destroy cancer cells. Using a bronchoscope, an instrument, called a cryoprobe put, close to the tumor. Liquid nitrogen is then circulated through the probe to freeze the tumor. The introduction and availability of small, flexible cryoprobes that can be passed through FOB make it easier to perform. Materials used: Current systems utilize nitrous oxide. Advantages: -Safe -With no danger of bronchial wall perforation
-

No radiation danger

- No risk of electrical accidents or fires - Does not require laser training and certification.

 1.

Lung cancer 81 Disadvantages: include delayed results and the requirement for multiple endoscopies to remove debris or to retreat. Indications for cryotherapy: Malignant lesions, usually squamous cell or adenocarcinoma of the lung, Treatment is usually palliative for hemoptysis and dyspnoea but the effect is delayed. ( inappropriate for management of acute airway obstruction), 2. 3. 4. obstruction. 5. and mucus plugs. It can be useful in helping extract foreign bodies, clots, Benign lesions such as granulation tissue and papillomas may be treated with cryotherapy. Lesions such as suspected carcinoid tumors might be frozen first to reduce the risk of hemorrhage during biopsy. 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. There appears to be evidence of a favorable impact on subsequent radiation response when cryotherapy is used initially to debulk the lesion being treated.

Use of cryotherapy with curative intent in early lesions (carcinoma in situ). But there is evidence, 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.

2. Airway stents Sometimes an airway can become blocked by pressure on it from the outside, which makes it close. This can sometimes be relieved using a small device, called a stent, which is put inside the airway to hold it open. The most commonly used stent is a little wire frame. 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, like an umbrella. This pushes the walls of the narrowed airway open. Stents are usually put in under a general anesthetic. The stent can stay in lung permanently and should not cause any problems.

Lung cancer 82 Stents may also be used if SVC has become blocked by the cancer. This can usually be relieved by radiotherapy, or by putting a stent in the blood vessel to keep it open. The stent is inserted through a small cut in the groin and passed up through the blood vessels to the chest. The stent can usually be put in under local anesthetic.

3. Diathermy Diathermy, which is sometimes known as electrocautery, uses an electrical current passed through a needle, to destroy cancer cells.

Guidelines for treatment of NSCLC

The following recommendations for treatment are based on guidelines produced by the National Cancer Institute:
Stage 0:

1. Surgical resection 2. Alternatively with endoscopic phototherapy in some patients.

Stage IA and IB

1. Surgery is the treatment of choice 2. . Inoperable patients may be given radiotherapy in an attempt to cure. 3. Patients who have undergone resection should be considered for trial chemotherapy to combat the occurrence of metastases.
Stage IIA and IIB

1. Stage IIA and IIB NSCLC should be treated similarly to Stage IA and IB NSCLC with surgery, radiotherapy with curative intent. 2. Again careful pre-operative assessment of the patient must be undertaken before surgery.
Stage IIIA

1. Prognosis is poor; however there is a long term survival benefit in 5% to 10% of patients with radiotherapy. 2. 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. Such trials examining: Fractionation schedules Endobronchial laser therapy Brachytherapy Combinations of treatment modalities may improve survival in this category.

3. Surgery alone is indicated in a very select number of cases, with postoperative radiotherapy likely to improve local control.
Tumors in the superior sulcus:

1. 2.

Often cause problems due to local invasion and have a reduced tendency for distant metastases. Local therapy for such tumors is therefore more likely to achieve cure.

3. 4.

Lung cancer 83 Surgery and radiotherapy separately or in various combinations may be curative in some patients. Tumors directly invading the chest wall can often be cured with surgery alone.

Stage IIIB: Stage IIIB is best managed with chemotherapy and radiotherapy alone or in

combinations.
Stage IV

1. Stage IV patients are suitable for palliative relief of local symptoms by radiotherapy. 2. Chemotherapy can be offered to patients, there are many combination regimens associated with a similar outcome: - Cisplatin + Vinblastine + Mitomycin - Cisplatin + Vinorelbine - Cisplatin +P - Cisplatin + Gemcitabine - Carboplatin +Paclitaxel

II. Treatment of Small cell lung cancer

1. Patients usually present with short history and evidence of metastasis. Without treatment the median survival for patients with limited disease is 6-8 weeks, and patients with extensive disease have worse survival. The disease expressed in terms of limited and extensive disease. At presentation 70% have extensive disease. Chemother apy: o o o SCLC is sensitive to chemotherapy, so this now is considered the accepted modality for most patients presented with SCLC. Many drugs are effective against this tumor, but if used singly their duration of action is brief with minimal effect on survival. Response in range of 10-40% (if used alone) is seen with: 1. Cyclophosphamide 2. Doxorubicin. 3. Vincristine 4. Cisplatin. 5. Ifosfamide. When agents are combined together the results are better.

Lung cancer 84 The cytotoxic substances used in chemotherapy act on different stages in the process of cell division. For example: spindle formation, Vincristine inhibits the formation of microtubules preventing

Doxorubicin inhibits DNA and RNA synthesis. These drugs, targeting the process of cell division, thus have a greater effect on cells that are rapidly dividing than those that are not. As cancers are rapidly dividing, they are affected more than normal cells. This activity also accounts for side effects such as alopecia and myelosuppression caused by such drugs.

Median survival rate is: - 14-16 months in limited disease. - 8-10 months in extensive disease.

o o

Disease may show objective response (partial or complete). Drug regimens that used are and give predictable results are: Cyclophosphamide + Doxorubicin + Vincristine. Cyclophosphamide+ Doxorubicin+ Etoposide. Cisplatin + Etoposide. recently: 1. 2. 3. Cisplatin or Carboplatin, + Etoposide or Ifosfamide; combinations with Gemcitabine, Paclitaxel, Vinorelbine, Topotecan and Irinotecan are being studied In metastatic lung cancer, the addition of Bevacizumab when added to Carboplatin and Paclitaxel was found to improve survival.

Route of administration: i. injection or sometimes as tablets. ii. usually lasts a few days. iii. effects of the treatment. iv. The number of sessions will depend on the type of cancer and how well it is responding to the drugs. After having chemotherapy there is a rest period of a few weeks (3-4 weeks), 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.

Lung cancer 85 Assessments: A. treatment. B. i. diameter. ii. Measuring a shadow on PCX-ray gives definite data but, it is not often known whether the changes in radiographic opacity are due to tumor or perhaps to atelectasis or consolidation around tumor. Complete response: Total removal of all tumors as evaluated by physical examination, radiology, scanning or bronchoscopy. Seen in approximately 50% of patients with limited disease, and 25% with extensive disease. 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. Unless the disease is progressive or patient cannot tolerate the

a.

High-dose chemotherapy:
Combination of 2 or 3 drugs give better results than single drug (dose-response relation ship). The main problem with increasing drugs is that the side effects also increased. The principle drug-related toxicity that threatens life is myelosuppression. Which can be overcome by: Autologous bone marrow transplantation: chemotherapy. marrow after harvesting. Give high dose chemotherapy that normally cause complete bone marrow failure and eradication of disease. Replacement of patients own bone marrow. Disadvantage: Malignant cells may be harvested as well as normal bone marrow cells (patient received untreated cancer cells). Attempts to overcome this by cleansing the bone Bone marrow taken from patient before starting

b.

Lung cancer 86 Other strategy involves the use of hematopoietic growth factors that can stimulate normal haematopiosis e.g. Granulocytes colony stimulating factor.

Scheduling: patients receive chemotherapy for SCLC should receive, if possible no less than 4 courses and no more than 6 courses of induction therapy. Maintenance therapy is of no value but retreatment on relapse is worth while.

1.

Side effects of chemotherapy: Chemotherapy can cause

unpleasant side effects. However, many people have few side effects:
Lowered resistance to infection:

Causes: the chemotherapy can reduce the production of WBCs by the bone marrow. Duration: This effect can begin seven days after treatment and resistance to infection usually reaches its lowest point 1014 days after chemotherapy. Course: Blood cells will then increase steadily and will usually have returned to normal before next course of chemotherapy. Sign of infections: - Temperature goes above 38C (100.5F) - Suddenly feel unwell (even with a normal temperature).

2. 3. 4.

Organisms: staph. Aureus, Ps. Aeruginosa, and E.coli Treatment of infection: immediate .broad spectrum antibiotic. Precautions: a blood test before having more chemotherapy.
Bruising or bleeding, Anemia

chemotherapy can also reduce the production of platelets.

This may make you feel tired and breathless. It is also due to bone marrow Some of the drugs used to treat lung cancer may cause nausea and

suppression.
Feeling sick

vomiting. There are now very effective IV anti-emetics (metoclopromide and ordansetron) to prevent or reduce nausea and vomiting. 5. 6.
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.
Hair loss

Unfortunately, hair loss is another common side effect of some but not all

chemotherapy drugs. Some people prefer to use hats or scarves rather than a wig (). If fall out, it will grow back over a period of 36 months. 7.
Tiredness

You may feel tired and have a general feeling of weakness. It is important to

allow yourself plenty of time to rest.

Although they may be hard to bear at the time, these side effects will gradually disappear once your treatment is over.

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.. 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, a feature not seen with radiotherapy. 1. 2. Some authors believe that patients who have no symptoms should be left until they develop symptoms and then palliated. 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. 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. Recently, the use of simple more gentle chemotherapy regimens that have minor side effect and good palliation of symptoms is tried, oral Etoposide form the bases of this regimen. Dose of palliative chemotherapy: Etoposide capsule were administrated for 5 days to a total dose of 800mg /m2.

2.

Radiotherapy: SCLC is more radiosensitive than NSCLC. Indications: The precise role of radiotherapy in SCLC remain undefined, it may fulfill a useful role in palliation of: 1. Distressing symptoms (haemoptysis, localized pain, intractable cough). 2. Symptoms arising from CNS metastasis, bone metastasis, and SVC obstruction.

1.

Primary tumor control:

The primary site is by far the most common location for disease to relapse after failure of chemotherapy, and so it is to be expected that the combining radiotherapy with chemotherapy might improve survival. 2. toxicity. Dose: At least 40 Gy are required for a clinical response, but this dose is associated with

 3.

Lung cancer 88 Scheduling effect is also important (therapeutic ratio of radiotherapy increased with division of total dose into fractions). A large than standard dose 2 Gy produces a large kills of tumor cells, but it may also affect normal cells. Dividing the total daily dose into smaller fractions (hyper fractionation) improve therapeutic index. Accelerated fractionation allow for frequent treatment to be given in shorter time. The theory behind hyper fractionation and accelerated schedule is to optimize the effects of radiotherapy and allowing normal cells to recover. Indications: in order to submit patients with SCLC to chest radiotherapy as an

adjunct to chemotherapy they should have: Limited disease at presentation. Show complete regression with chemotherapy. Or have local symptoms attributable to the disease.

Prophylactic cranial irradiation:

1. The use of prophylactic cranial irradiation is controversial. 2. The reasons for its use are: barrier. The incidence of brain metastasis increase as survival prolonged by chemotherapy. 3. Irradiation of the brain dose not of course prevents new metastasis in relapsed patients (so term prophylactic is inappropriate). 4. Indications: Not advised as a routine treatment in SCLC. Should only be given to patients with limited stage SCLC, who are in complete remission after chemotherapy. Palliative cranial irradiation is often helpful in relieving symptoms due to cerebral metastasis. 5. Disadvantages: Acute organic syndrome, with memory loss, confusion and additional neurological deficits. Seen 6-8 weeks after treatment. Brain is the common site for spread of SCLC. Cytotoxic drug in general do not cross blood brain

Lung cancer 89 Late neurological toxicity. 6. Dexamethasone is also useful in patients with cranial metastasis from SCLC. 3. o Surgery: Patients with limited SCLC treated with chemotherapy and chest radiotherapy have high incidence of local recurrence, and this led investigator to re-explore role of surgery in combination with other treatment in limited stage SCLC. o Studies done on group of patients with limited disease treated with preoperative chemotherapy followed by surgical resection show that: 1. High local control rate. 2. High incidence of mixed histology or a conversion to NSCLC histology following chemotherapy. So they conclude that, combined modality therapy is possible in SCLC.

4. Newer drugs in the treatment of small cell lung cancer fail. Etoposide. SCLC. efficiency compared to Paclitaxel.
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. 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. SCLC.
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:

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. Combination Chemotherapy (with or without PCI) especially in patients with impaired PFT or poor performance status. 2. Surgical resection followed by chemotherapy or chemotherapy plus chest irradiation (with or without PCI) for patients in highly selected cases. Extensive stage SCLC: metastatic disease.

Chemotherapy regimens similar to those used in limited disease are used in extensive disease, 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. 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, especially brain, epidural and bone metastases. Second line therapy can achieve a survival benefit in patients with recurrences.

New therapeutics agent under trials in treatment of lung cancers: 1. EGFR antagonist: EGFR is transmembrane receptors which constitute a potential growth signals. Monoclonal antibodies against EGFR (C225, ImClone) are under trial in combination with chemotherapy. (NSCLC). 2. Tyrosine kinase inhibitors (CP35774, ZD1839- Iressa) are tried with advantage of being orally active. (NSCLC).

3.

Lung cancer 91 Clinical trials investigating chemotherapy combined with Trastuzumab (monoclonal antibody to Her2/ neu) are in progress. (NSCLC).

4.

Gastrin releasing peptide inhibitors with neutralizing monoclonal antibody, as well as GRP antagonist referred as Bombesin.

5.

The necessity for RAS protein to undergo farnesylation to become active has led to the development of specific inhibitors of farensyltransferase enzyme. Also trials of vaccination with mutant K-RAS peptides are under trials. Other potential also to block RAS include antisense treatment, and inhibition of protein expression.

6.

Therapeutics manipulation of MYC expression for instance the growth inhibition of SCLC cell line by all- trans-retinoic acid appears to e associated with increased L- MYC expression and decrease N-MYC expression. Antisense therapy strategies directed at down-regulating MYC expression are under trials.

7.

Among the anti-apoptosis strategies in preclinical trials are studies of antisense BCL2 in SCLC (down-regulate BCL2 protein expression). BCL- XL antisense in NSCLC, and specific BCL2BCL-xL antisense to target both SCLC and NSCLC.

8.

Preclinical studies showed that resorting of p53 function resulted in apoptosis of cancer cells, Adenoviral mediated p53 gene transfer delivered by direct tumor injection appear feasible when given in conjunction with radiation therapy. Vaccine trials with mutant p53 peptides are also being performed.

9. 10. 11.

In-vitro re-introduction of p16 into tumor cells of a wild RB suppresses SCLC growth. Flavopiridol is a compound which inhibits CDK is being tested in clinical trials. Targeting VEGF with humanized monoclonal anti-VEGF, but it may lead to unexpected bleeding from large necrotic lung tumor masses.

Treatment of advanced lung cancer

If the lung cancer is advanced it can sometimes cause problems such as breathlessness and a hoarse voice. Treatment can often be given that will not completely get rid of the tumor, but will help to relieve symptoms by.

Laser therapy Airway stents Cryosurgery Diathermy PDT

Lung cancer 92 Lung cancer screening and early detection Cancer screening Definition: Is testing performed on apparently healthy people to detect unrecognized cancer.

The purpose of cancer screening is to identify people with

the disease so that measures can be taken improve their prognosis.

There are several cancer screening programs in US. 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.

There is no screening program for lung cancer ? The reasons are complex and

There are two major problems: 1. There is a lack of understanding of premalignant conditions and the natural history of lung cancers. 2. It is also difficult to easily obtain a representative sample:
biopsy is too invasive bronchial unreliable. 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.

A Program Model
There are two known facts 1. Most lung cancers are present for many years before symptoms of the disease appear. 2. In the absence of lung cancer screening and early detection, most people with lung cancer cannot be cured because the disease is already too advanced at the time of diagnosis.

Given these two known facts, the outcome is dramatically better when
the disease is detected at an early stage and surgically treated.

Clinical researches of lung cancer screening and early detection suggest such a program should have the following components.

Lung cancer 93 1. An assessment of risk i.e. a questionnaire or interview to get information about lung cancer risk factors such as smoking history (tobacco, marijuana, crack cocaine), exposure to lung carcinogens, and family history of lung and other epithelial cancers .

2. An educational component to inform the general public especially those at risk of lung
cancer due to smoking history, occupation, or family history about appropriate testing.

3. A testing program which could have several components :

Imaging studies of the lungs and other early detection test; possible tests that might be used include standard chest x-rays, digital chest x-rays, helical/spiral CT scans, tumor markers, sputum-based tests, or other tests that are currently being developed Tests to determine genetic susceptibility to cancer; although we do not yet have such a test, this is an active area of research; 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. Primary prevention Smoking cessation is the most important preventative tool in this process. Policy interventions to decrease passive smoking (e.g. in restaurants and workplaces) Test your home for radon by radon detector 2. 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. Computed tomography (CT) scanning is now being actively evaluated as a screening tool for lung cancer, and it is showing promising results. EGFR antagonists:

On the surface of many types of cancer cells, are structures known as epidermal growth factor receptors (EGFRs). The receptors allow epidermal growth factor (a particular protein present in the body) to attach to them. When the EGF attaches to the receptor, it causes chemical processes inside the cell that make it grow and divide more quickly than it should.

Lung cancer 94 Drugs known as EGFR antagonists attach themselves to the EGF receptor inside the cell, and prevent the receptor from being activated. This can help to stop the cancer cells from growing so quickly.

Erlotinib (Tarceva),

i. ii.

Is an EGFR (epidermal growth factor receptor) antagonist. It is sometimes used to treat people with NSCLC, whose cancer has come back after initial treatment, or has not responded to at least one course of chemotherapy.

iii. iv.

Erlotinib is given as a tablet. Side effects are generally mild and include diarrhea, a rash, nausea and tiredness.
SPECIAL PROBLEMS IN LUNG CANCERS

1. Superior vena cava obstruction:

Causes:

1.

Over 80% of SVC obstruction is caused by malignant disease (lung cancer 60% {SCLC}, 20% by lymphoma, mesothelioma, breast CA, thymic tumors, testicular CA, and metastatic from mediastinal adenopathy). mechanism:

The tumor usually compresses vessels from without Occasionally invades its wall. Intra-luminal thrombosis may occur (failure of treatment) 20% by benign conditions: Granulomatous diseases Cryptogenic mediastinal fibrosis (11%) Intra-thoracic goiter, or aneurysm As a complications of central venous catheterization Thrombosis Inflammatory lymphadenopathy Radiation fibrosis Idiopathic.

2.

Pathophysiology

SVC particularly prone to obstruction because of its thin walls, low pressure and the fact that it is surrounded by relatively firm nondistensible neighboring structures (eg trachea, sternum, right main bronchus).

Lung cancer 95 Symptoms depend to some extent on speed of progression of obstruction. 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. If the block allows the azygos to function as a bypass system most of the signs and symptoms are in the super-epigastric region. If not the collaterals must flow inferiorly to drain into the IVC

symptoms are due to poor venous return, increased intravenous pressure, collateral development and underlying disease process

Diagnosis:

A.

Symptoms sing: symptoms may be increase in prone position Swelling of face, neck and upper limbs. Distention of veins and venules across the chest, upper arms and neck. Collar compression. Orthopnoea common Headaches and nightmares which are lessened by sleeping upright. Vertigo, drowsiness, dry eyes or teary eyes. 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. 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. 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. Radiotherapy may be administrated to patients with benign conditions. 4. If radiotherapy is given first it may make the subsequent histological diagnosis difficult or impossible.

B.

Next step is to obtain histological confirmation:

Lung cancer 96 5. If the cause of obstruction is SCLC (respond to chemotherapy) so radiotherapy is not required. 6. SVC obstruction is not usually leading to mortality but primary cause may do, so it is important to determine primary cause as early and accurate as possible.

in 70% of patients

CXR. Abnormal in 80%. Superior mediastinal mass can be seen

C. CT with contrast Venography:

May be helpful in determine extent of disease. Venography is used to determine the field of treatment. This procedures is also required if stenting of the SVC is contemplated. Allows visualization of collateral system. localizes mass gives clues to other impending complications Treatment of lung cancer if it is the underling

Treatment:

a. cause : b. also been tried: SCLC:

Chemotherapy is given, adjunct radiotherapy has no benefit. However, patients who relapse with obstruction of SVC following primary chemotherapy should be treated with radiotherapy (relieve symptoms and sign) NSCLC: Radiotherapy is given, chemotherapy has no role. Corticosteroids may be used but have not been convincingly shown to be of benefit. The high initial dose of radiotherapy is followed by a lower daily dose to a total dose of 20 Gy spread over 2 weeks. 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). Intravascular Stents:

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.

Results of this procedure are impressive (90% success rate). There is no clear consensus on the need for thrombolysis or anticoagulant following stent insertion. 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. Thrombosis in SVC is not a contraindication to stenting as this can be dealt with by local thrombolysis or dispersed with mechanical device. Migration of stent to right ventricle from SVC has not bee reported. Disadvantages of stent: few complications have been reported. It is expensive.

2. Superior sulcus tumor= superior sulcus pulmonary tumor:

A. Definition: it s a carcinoma situated at the extreme apex of the lung. B. It re-present less than 5% of all bronchogenic carcinoma, of this tumor 90-95% are NSCLC. C. At presentation it is usually at advanced stage. D. Clinical picture of Pancoast tumor: this clinical manifestation is due to invasion of: 1. 2. 3. Eighths cervical nerve (ulnar nerve) First and second thoracic nerve trunks. Inferior sympathetic ganglia. Pain in the lower part of the shoulder and inner aspect of the arm (C8, T1 and T12 distribution), that may be severe and unremitting. It may accompanied by sensory loss in the same distribution. There may be weakness and wasting of small muscle of the hand and of the medial forearm, wrist, and finger flexors. Horner syndrome: ptosis, miosis, anhidrosis, and enophathalmous.

E. Causes: it is caused by a benign or malignant condition invading lower part of the brachial plexus, subclavian vessels, vertebral bodies, parietal pleura, apical ribs, and stellate ganglion.. F. 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, enophthalmos, miosis, and hypohidrosis of face). G. Radiological findings: Early, thick line over apex of lung (DD pleural thickening).

Lung cancer 98 Later, mass at lung apex with local evidence of bone destruction (first and second ribs), or of vertebral body or transverse process.

H. Any histological types of lung cancer can occur in this situation. I. Usually incomplete forms of this syndrome are present. J. Treatment: according to histological type of tumour. K. Diagnosis: Is usually obvious where all components of the syndrome are present. However, other diseases such as TB may occasionally produce confluent apical shadow. In this situation bronchoscopy should be carried out with submission of washing for cytology and microbiology. They rare difficult to diagnose with bronchoscopy, requiring percutaneous needle biopsy. We must exclude other causes of thoracic outlet syndrome.

L. Management: This tumor was originally regarded as uniformly inoperable. Encouraging results were reported for radiotherapy followed by lobectomy, with the completion of radiotherapy after surgical healing or placement of radioactive implants if the tumor is found to be unrespectable at thoracotomy. Some authors take the view that if the tumor appears resectable after staging, surgery should proceed directly, but if it is unrespectable, radiotherapy should be given as a single course.
3. Malignant pleural effusion:

1. 2. 3. 4.

Presence of malignant pleural effusion (cytology or biopsy) indicates inoperability and short life span. Once diagnosis is certain aspiration is necessary only if the effusion is of sufficient amount to cause dyspnoea. If re-accumulation is rapid or if repeated aspiration is required, then a chemical pleurodesis can be performed. If tetracycline is used for pleurodesis it may be mixed with local anaesthetic in order to reduce pleural pain.

4. Intracranial metastasis:

A. Symptoms, sign, and investigation as discussed before. B. Treatment: If intracranial metastasis become clinically evident in patients who is clearly dying of advanced metastasis, adequate narcotic analgesia is the most appropriate treatment.

Lung cancer 99 Sometimes the general condition of the patient requires more active supportive treatment, improvement is often obtained with oral high dose corticosteroids (dexamethasone 16 mg/ day), and then reduced according to response.

Cranial irradiation produces symptomatic relief in 80% of cases. Surgical treatment has small role in the management of intracranial or brain metastasis a. 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. in few cases. c. occult in the chest. 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. Tracheal tumor:

A. Origin: Trachea may be involved by direct extension of adjacent tumor, or rarely may be the site of primary malignancy. If it is the primary site, the slow- growing adenoid cystic carcinoma is the most common type. B. Symptoms: Tracheal malignancy may occur at any age and may be mistaken as asthma. The increasing stridor of a few weeks duration in young or middle aged adult should raise the possibility of tracheal malignancy. Hemoptysis may occur. PCX-ray: is frequently normal CT: may demonstrate mass in the trachea. Confirmation of diagnosis is made by bronchoscopy (FOB may occlude the a narrowed opening. Biopsy. 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. Radiotherapy may be administrated either externally or endotracheally. C. Investigations:

D. Treatment:

Lung cancer100 ND-YAG laser radiotherapy may be used to relieve asphyxia and allowing time for further diagnostic evaluation and planning of treatment. 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, England, France, Japan, 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 1.5 million people TSC-LAM in 30% of women Prevalence of 250,000 LAM occurs in males but is quite rare (Only 3 men with biopsy-proven LAM in the literature) Sporadic-LAM global prevalence 1 - 5 per million women, 25,000 to 50,000 patients LAM Foundation Registry (1028 patients) National Institutes of Health Registry (237 patients).
Inheritance

Sporadic-LAM

Tumor-suppressor syndromes like TSC are caused by Loss-of-function mutations in genes that control cell growth

Molecular Basis

Lung cancer101 TSC1 and TSC2 encode hamartin and tuberin proteins, which regulate signaling through the Akt pathway that controls cell size, growth, proliferation, and survival

Clinical features:

It Only Affects Women Other symptoms Cough Hemoptysis Chest pain Progressive dyspnoea over about 10 years. Symptoms related to reflux of chyle The peritoneum (Chylous ascitis) Pericardium (chylopericardium) Airways (chyloptysis) Urinary tract (chyluria) Genital tract (Chylous metrorrhea). Angiomyolipomas Hamartomas composed of Fat Smooth muscle Abnormal blood vessels. Location Abdomen (commonly kidney) Chest.

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.

Physical examination:

Lung cancer102

Crackles in 15% to 20% Rhonchi in less than 15% Clubbing in 4% Pleural effusion Ascitis Pneumothorax
Imaging

PCX-ray

1. Nonspecific 2. Early Normal Hyperinflation 3. Later Hyperinflation or frank emphysema. Reticulonodular infiltrates Summation of numerous cysts Diffuse Seldom profuse. Septal line Bilateral Symmetrical Basal predominance (summation effect) 4. Later stages Cysts, bullae, or a "honeycombing" 5. Characteristic feature Preservation of lung volumes despite increased interstitial markings 6. 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 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. Higher thoracic gas volume (pleothysmoraphy), than total lung capacity (helium dilution). This represents air trapping in cysts by peribronchial muscle hypertrophy. DLCO, it is the most sensitive functional abnormality, and abnormal in 82% - 97% Exercise-induced hypoxemia even with normal resting FEV1 and DLCO
Pathology

Grossly, enlarged lungs with diffuse cysts up to 2.0 cm

Microscopic: Focal smooth muscle cell infiltration lung parenchyma Airways lymphatic blood vessels

1. 2.

Lung cancer104 There is proliferation of spindle- shaped primitive smooth muscle cells around lymphatic through out the lungs or pleura. The airways obstruction is probably related to smooth muscle proliferation around bronchioles, leading to air trapping and thin walled cyst formation. Rupture of theses cysts causes' pneumothorax.

3.

Also there is perivenular muscle hypertrophy leads to capillary congestion which lead to hemoptysis.

Diagnosis:

1. Diagnosis of LAM may be established based on radiographic findings 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-Dub syndrome a. b. c. In smoking patients Langerhans cell histiocytosis Emphysema

Emphysema - Smokers - Upper lobes - Areas of low attenuation - Centrilobular - With or without visible walls Pneumatoceles Usually with acute pneumonia Transient Clinical presentation makes the diagnosis clear Pulmonary Fibrosis Honeycomb cysts

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.g., Norethindrone acetate 10 mg PO daily or twice a day Intramuscular e.g., Medroxyprogesterone acetate 400 mg IM each month No convincing evidence supports Oophorectomy. 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, if failed pleurodesis Transplantation 100 transplantations in the USA Survival 50% at 5 years. Renal Angiomyolipomas Embolization if bleeding occurs Resections for very large tumors Experimental: Rapamycine. Lung transplantation.
Prognosis

Slowly progressive: The Rate of decline in FEV1 is about 100 ml/year. Progressive increasing dyspnoea over about 10 years which may lead to death from respiratory failure. In postmenopausal women it is more slowly progressive (hormonal dependent). Progesterone and estrogen receptors have been demonstrated on lung biopsy material.

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

b. c. d. f.

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