malignancy by dr bashir ahmed dar associate professor medicine sopore kashmir

MALIGNANCY

BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE

CHINKI PORA SOPOREKASHMIR

Email –[email protected]

MMMC Annual night

MMMC Annual NightCarol-I will always love you

The cell

The cell

• The cell contains nucleus and in the nucleus are chromosomes.

Chromosomes Chromosomes

are the rod-shaped, filamentous structures, which become visible during cell division.

Chromosomes

• Chromosomes are composed of thin chromatin threads

• Each chromatin thread in turn is made of DNA.

Chromosomes

• A chromosome is about 0.004 mm long

• The DNA is about 4 cm long• This is about 10 000 times

longer than the chromosome• So it has to twist like a

corkscrew and coil to fit inside

• If you unraveled these coils, you'd have a six-foot long double strand of deoxyribonucleic acid-DNA.

Chromosomes

• DNA is wrapped tightly around histones and coiled tightly to form chromosomes

Chromosomes

DNA

• DNA is made of• Nucleotide = nitrogen base (purine or

pyrimidine) + phosphate group + pentose sugar ( ribose or deoxyribose)

• They are units of DNA.

DNA Nucleotide

OO=P-O O

Phosphate Group

NNitrogenous base (A, G, C, or T)

CH2

O

C1C4

C3 C2

5

Sugar(deoxyribose)

RNA

• RNA is made of• Nucleoside= nitrogen base(purine or

pyrimidine)+ pentose sugar(ribose), but without phosphate group

• They are units of RNA.

DNA

• Nitrogenous base is in the centre and phosphate and sugar at the legs of ladder.

• The ladder coils on itself to form double helix structure.

• You've got six billion of these pairs of nucleotides in each of your cells, and amongst these six billion nucleotide pairs are roughly 30,000 genes.

DNA Double Helix

NitrogenousBase (A,T,G or C)

“Rungs of ladder”

“Legs of ladder”

Phosphate &Sugar Backbone

Nitrogenous Bases

• PURINES1. Adenine (A)

2. Guanine (G)

• PYRIMIDINES3. Thymine (T)

4. Cytosine (C) T or C

A or G

Chargaff’s Rule

• Adenine must pair with Thymine

• Guanine must pair with Cytosine

• Their amounts in a given DNA molecule will be about the same.

G CT A

DNA Double Helix

P

P

P

O

O

O

1

23

4

5

5

3

3

5

P

P

PO

O

O

1

2 3

4

5

5

3

5

3

G C

T A

BASE-PAIRINGS

CG

H-bonds

T A

DNA DOUBLE HELIX

GENES

• Genes are segments of DNA which contain set of instructions that decide what the organism is like, how it survives, and how it behaves in its environment

• Each person's DNA is different - this is what makes each of us unique.

Genes

• Genes are the means by which a cell produces proteins, each of which have a very specific role.

Genes

• A mutated gene can cause overproduction of a protein, underproduction of a protein, or alteration of a protein that may be unable to carry out its purpose.

Genes

• Oncogenes typically produce more of their protein product when mutated, while tumor suppressor genes typically produce less of their protein product when mutated.

Your genes decide

• Whether you are tall or not• The color of your hair• The color of your skin• Whether you are more likely to develop certain

diseases• Whether you are good at sports• How you respond to environmental triggers• What you look like inside and out• And so many other things

Genetic Diversity…• Different arrangements

of NUCLEOTIDES in a nucleic acid (DNA) provides the key to DIVERSITY among living organisms.

Genes

• The particular order of the bases is called the DNA sequence. The sequence gives the exact genetic instructions needed to create a particular organism with its own unique traits.

Genes

• Specific sequence of bases also carry the information needed for constructing proteins.

• These proteins are produced through process of transcription ,translation etc

Genes

• Proteins provide the structural components of cells and tissues as well as enzymes for essential biochemical reactions. The human genome is estimated to be made of more than 30,000 genes.

34

MUTATIONS

• Loss of DNA• Gain of DNA• Changes in nucleotides• Epigenetic effects

DAMAGE TO DNA OR MUTATIONS

• Any change in DNA sequence of base pairs


Because of Deletions A deletion could be as small as a single base or as large as the gene itself.

• .

DAMAGE TO DNA OR MUTATIONSInsertions are mutations in which extra base pairs are inserted into a new place in the DNA. Because of insertion

DAMAGE TO DNA OR MUTATIONSA substitution is a mutation that exchanges one base for another Or reciprocal translocation

DAMAGE TO DNA OR MUTATIONSIn an inversion mutation, an entire section of DNA is reversed. Because of inversion


• Errors may occur during replication, transcription, or translation.

MUTATIONS OR DAMAGE TO DNA

TerminalDeletion

RingChromosome

RobertsonianTranslocation

Deletion Reciprocaltranslocation

IsochromosomesInsertion Inversion

Duplication

MUTATIONS OR DAMAGE TO DNA

Nucleotide Deletions

Nucleotide Insertions

Nucleotide Substitutions


• Before a cell divides, the DNA is checked to make sure it has replicated correctly. (If DNA does not copy itself correctly, a gene mutation occurs.


• A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair.

• As was shown in previous slides.


• Point mutations that occur in non-coding sequences are most often without consequences, although there are exceptions.


• If the mutated base pair is in the promoter sequence of a gene, then the expression of the gene may change.


• An organism's DNA affects how it looks, how it behaves, and its physiology for example division of cells , growth etc. So a change in an organism's DNA can cause changes in all aspects of its life.

• Your DNA contains a set of instructions for "building" a human. These instructions are inscribed in the structure of the DNA molecule through a genetic code.


• The sequence of these bases encodes instructions. Some parts of your DNA are control centers for turning genes on and off, some parts have no function, and some parts have a function that we don't understand yet. Other parts of your DNA are genes that carry the instructions for making proteins — which are long chains of amino acids. These proteins help build an organism.


• Somatic mutations occur in non-reproductive cells and won't be passed onto offspring.

• The only mutations that matter to large-scale evolution are those that can be passed on to offspring. These occur in reproductive cells like eggs and sperm and are called germ line mutations.


• There are many types of mutations that change not the protein itself but where and how much of a protein is made. These types of changes in DNA can result in proteins being made at the wrong time or in the wrong cell type. Changes can also occur that result in too much or too little of the protein being made.

Carcinogen or Mutagen

• A carcinogen or mutagen is any substance or agent that, damages or alters cell DNA.


• A carcinogens may be the initiator — the agent that alters or damages DNA, the basic coding system of cells.

• They may also be promoters — encouraging out-of-control cell growth


Human viral pathogens

• Oncogenic RNA Viruses, Oncogenic DNA Viruses

• Retroviruses (HIV)• Epstein-Barr viruses• Herpesviruses-HSV-2 • HBV• Papovaviruses• Adenoviruses


• Ionizing radiation• UV from the sun and

tanning lamps• X-rays: medical and dental• Radon, cosmic rays, and

gamma radiation


• Solar UV radiation is associated with skin cancers – squamous CA, basal cell CA, malignant melanoma, air-skinned and elderly are susceptible


• Earlier use of X-rays caused skin cancer, leukemia and papillary thyroid CA

• Radiotherapy causes radiation-induced malignancy 10-30 yrs later – usually sarcomas

• Diagnostic X-rays are considered to have no increased risk except in abdominal x-rays which increase incidence of leukemia in the fetus.


• Radioisotopes• Osteosarcoma common among factory workers

who use radium-containing paints• Radioactive mineral mining in Europe and USA

associated with lung cancer• Thorium increases risk of liver cancer –

hepatocellular, angiosarcoma, cholangiocarcinoma• Radioactive iodine – increased risk of cancer 15-25

years later.


• Nuclear Fallout• Hiroshima, Nagasaki (atomic blasts), Marshall

islands (atmospheric testing of nuclear device containing radioactive iodine), Chernobyl, 1986.

Carcinogen or Mutagen• Nutritional deficiency (having antioxidant effect)• Protein deficiency• Carotenes and retinoid - deficiency• Tocopherols - deficiency• Selenium (glutathione peroxidase) - deficiency• Zinc deficiency• Flavanoids (enzyme inhibition) - deficiency• Vit C deficiency• Vit E deficiency• High fat• Low-fiber diet and colonic CA• Fatty diet with breast ca• Betel leaves with oral ca

Carcinogen or Mutagen• Industrial chemicals

• Exposure to pesticides• Agricultural chemicals• Asbestos • vinyl chloride • benzene• Hydrocarbons in cigarette smoke• Aflatoxin: fungal product• Nitrosamines and amides Converted

to nitrites by gut bacteria• food preservatives• food dyes

Carcinogen or Mutagen• Aromatic amines and azo

dyes• Polycyclic aromatic

hydrocarbons• Tobacco smoke• benzene• carbon tetrachloride• vinyl chloride • asbestos fibers • pesticides• dioxins


• Carcinogenic substances may be inhaled, absorbed through the skin or even ingested in some cases. Effect of carcinogenic chemicals used in industrial processes is felt beyond the workplace

• Often water is contaminated and air is polluted by carcinogens, causing additional cancers in surrounding communities.

• The idea of carcinogens (in soot)was first put forward in 1775 as doctors discovered a high incidence of scrotal cancer among chimney sweeps in uk.


• Hormonal Oncogenesis & drugs (promotors)

• Promoters enhance proliferation of initiated cells. Expand population of initiated cells

• Increase risk of additional mutations (during DNA synthesis)• Oral Contraceptives• Estrogens/ Progesterones/Androgens• prolactin, thyroxin• Phenobarbital• Estrogen – breast ca,enodmetrial hyperplasia -> endometrial

cancer• Diethylstilbestrol (DES) – vaginal and uterine ca


• Breakdowns in immunity

• Healthy immune system can target and destroy cancer cells. When cancer cells have altered proteins at its surface, cells are not destroyed. Risk of cancer increases With age.

• HIV infection• Immunosuppressant drugs• Anxiety and depression


• Inflammation like• Chronic hepatitis -> hepatocellular carcinoma• Colitis -> colon cancer• Osteomyelitis sinus tracts -> squamous cancer• Chronic bronchitis -> lung cancer

Carcinogen or Mutagen• Genetic Oncogenesis (Role of Inheritance)

• Association with inherited diseases,Mendelian Inheritance, Dominant or Recessive.

• Examples• Retinoblastoma • Wilm’s tumor • Neurofibromatosis (type 1 von Recklinghausen’s disease)• Multiple endocrine adenomatosis (MEN)• Familial polyposis coli• Nevoid basal cell carcinoma syndrome• Syndromes of immunodeficiency


• Besides• O2 free radicals DNA

damage• Foreign bodies

Normal Cell/Mutated Cell

DNA of a normal cell DNA of mutated cell

Damage to p53 gene

• When DNA is damaged there might also occur damage to p53 gene. Due to damage to p53 gene the DNA repair protein gets inactivated and there fore does not repair DNA.

Damage to p53 gene

• p53 gene damage also leads to inhibition of apoptosis. So that damaged cell if not repaired would get killed and destroyed by immune system & killer cells had there been no damage to p53 gene.

APOPTOSIS

Programmed cell death

Orderly & normal cellular self destruction

APOPTOSIS: important in embryogenesis

Morphogenesis (eliminates excess cells):

Selection (eliminates non-functional cells):

APOPTOSIS: important in embryogenesis

Immunity (eliminates dangerous cells):Self antigen

recognizing cell

Organ size (eliminates excess cells):

APOPTOSIS: important in adults

Maintains organ size and function:

Apoptosis+ cell division

Cells lost by apoptosis are replaced by cell division

X

APOPTOSIS: Role in Disease

TOO MUCH: Tissue atrophy

TOO LITTLE: Hyperplasia

NeurodegenerationThin skin

etc

CancerAthersclerosis

etc

APOPTOSIS: Role in DiseaseCancer

Most cancer cells are defective in apoptotic response(damaged, mutant cells survive)

High levels of anti-apoptotic proteinsor

Low levels of pro-apoptotic proteins===> CANCER

Immune Surveillance System

• Apoptosis normally eliminates aged and damaged cells or excess cells that are not needed through different mechanisms e.g through immune surveillance system as follows

• through • 1) Natural killer (NK) cells • 2) Cytotoxic T-cells


• 3) B-cells :• Tumor associated antigens stimulate

production of specific antibodies by host B-cells

• These specific antibodies bind together on tumor cell surface leading to destruction of tumor through cytotoxic T-cells that kill IgG-coated tumor cells


• Healthy immune system would target and destroy mutated cells. But the mutated cells have developed altered proteins at their cell surfaces,neoantigens & tumor-associated antigens. Therefore escape recognition and destruction by immune system.(Failure of Immune Surveillance)


• Risk of cancer increases: With age When an immune system has been suppressed for a long time , HIV infection, Immunosuppressant drugs. Anxiety and depression

Tumor EscapeMechanisms by which tumor escape immune defenses:

1) Reduced levels or absence of MHCI molecule on tumor so that they can not be recognized by CTLs

2) Some tumors stop expressing the antigens These tumors are called “antigen loss variants”

3) Production of immunosuppressive factors by tumor e.g. transforming growth factor (TGF-β)

4) Tumor antigens may induce specific immunologic

tolerance

Tumor Escape5) Tumor cells have an inherent defect in antigen

processing and presentation

6) Blocking of receptors on T-cells by specific antigen antibodies complex (after shedding of tumor Ag) prevents them from recognizing and attacking tumor cells

7) Antigens on the surface of tumors may be masked by sialic acid-containing mucopolysaccharides

8) Immune suppression of the host as in transplant patients who show a higher incidence of

malignancy

2. Normal Chemical Signals tell Normal cell when to start and stop dividing.

http://www.cancerquest.org/index.cfm?page=193

Damage to p53 gene

• Two genes involved in apoptosis are the tumor suppressor gene p53 and the bcl-2 proto oncogene.

• Tumor-suppressor genes p53, function like brakes, keep cell numbers in check .

Control of the Cell Cycle

• Cell division or Mitosis goes through several stages such as

• Prophase • Metaphase • Anaphase • Telophase • and Cytokinesis


• Then the cell enters Interphase, which is an intervening stage at which the cell prepares for the next cell division or goes into resting phase where the cells undergo differentiation to specific cell type.


• Interphase consists of sub-stages such as G1, S and G2; where, G stands for the gap in knowledge


• The G1 phase is----preparatory phase for DNA replication.

• The S-phase is for DNA replication and repair if needed

• and G2 stage is a preparatory phase for M-phase(Mitosis)

Cell cycle checkpoints

• The major checkpoints lie in between G1 and S phase and G2 and M-phase and another control point exists within the M-phase events at anaphase.


• Cell cycle checkpoints are biochemical signaling pathways that sense damage to the DNA structure or impaired chromosome function and elicit complex cellular repair responses.


• These checkpoints rapidly induce cell cycle delay, generally at the G1, S, and G2 checkpoints, allowing time for the activation of DNA repair mechanisms.


• The checkpoints also maintain cell cycle arrest while the repair takes place and initiate cell cycle progression once repair is complete . If the DNA cannot be repaired adequately, the cell then undergoes permanent cell cycle arrest and apoptosis.

Function of check points

• Can DNA synthesis begin?

• Has DNA synthesis been completed correctly? And go for mitosis

• Are all chromosomes attached to spindle?

• Can sister chromatids separate correctly?


• Damage to p53 also causes disturbance in proof reading of DNA prior to replication at G1 phase of mitosis.(failure at check point)

• Cancer cells lose normal restraints for replication of damaged DNA and G1/S progression of cells with damaged DNA


• If cell receives “GO” signal, it divides• By Internal signals: cell growth (size), cell

nutrition • By external signals: “growth factors”

• If cell does not receive signal, it exits cycle & switches to G0 phase, non-dividing, working state


Other mechanisms for controlling progress through the cell cycle are

Length of TelomeresChemical Signals from within and outside

the cell

Chemical Signals that Control the Cell Cycle

1. Cyclin and Kinase-proteins that initiate mitosis -requires buildup of cyclin to pair with kinase

2. Hormones-chemical signals from specialized glands that stimulate mitosis

3. Growth Factors-chemical factors produced locally that stimulate mitosis

Failure to Stop atCell Cycle Checkpoints

Mutation in a gene that usually slows the cell cycle

Rate of cell division is accelerated.

Failure to pause for DNA repair

Faulty DNA leads to unregulated cell growth.

Loss of control over telomere length

Cancer cells have telomerase, an enzyme that elongates telomeres. Cells continue to divide after 50 mitoses.


• Incorrectly repaired DNA, however, continues to replicate, leading to accumulation of the mutation and, thus, elevated cancer risk. Studies have shown that mutations in cell cycle control genes, such as p53 and p21, are directly linked to chromosomal aberrations and genomic instability


• Mutation is thus passed on to daughter cells that results in Successive accumulation of mutations.

1st & 2nd Mutations

• The genetically altered cells have, over time, reproduced unchecked, crowding out the surrounding normal cells. The growth may contain one million cells and be the size of a pinhead. At this point the cells continue to look the same as the surrounding healthy cells.

http://www.cancerquest.org/index.cfm?page=193

Contact Inhibition: (density-dependent inhibition of growth)

• Two or more normal cells come in contact with each other, they tend to stop dividing and form a single layer or sheet of cells called a confluent monolayer.

• Cancer cells will continue to grow and pile up on top of each other even after forming the monolayer.

• Normally cells attach to each other by various cell junctions so that they are fixed in place

• Communicate with each other via Growth Factors

• But all such things are lost when cell is mutated.

• In other words cells Escape Regulations.

• Cancer cells do not respond to crowding; loss of contact inhibition

• Leads to a disorganized mass

Interaction of a Cell at Risk with a Carcinogen Can Produce

an Initiated Cell

• An initiated cell is the first step in formation of a tumor

• For an initiated cell to become a tumor both the Promotion and Progression stages have to occur

• The larger the number of initiated cells the higher the breast cancer risk

Cellsat

Ris k

Initiation Promotion Progression•Mutation•Cancer Gene

•Proliferation•Independence

•Mutation•Invade & Spread

Stages of Cancer Formation

UnspecializedCell

InitiatedCell

BenignTumor

MalignantTumor

Latency Period, 20 years or more

Third mutation

• Not all mutations that lead to cancerous cells result in the cells reproducing at a faster, more uncontrolled rate. For example, a mutation may simply cause a cell to keep from self-destructing. All normal cells have surveillance mechanisms that look for damage or for problems with their own control systems. If such problems are found, the cell destroys itself.

Over time and after many cell divisions, a third mutation may arise. If the mutation gives the cell some further advantage, that cell will grow more vigorously than its predecessors and thus speed up the growth of the tumour.

Fourth mutation

• The new type of cells grow rapidly, allowing for more opportunities for mutations. The next mutation paves the way for the development of an even more aggressive cancer.

At this point the tumour is still contained as has not broken basement membrane –carcinoma in situ.

Breaking through the membrane

• The newer, wilder cells created by another mutation are able to push their way through the epithelial tissue's basement membrane, which is a meshwork of protein that normally creates a barrier. The invasive cells in this tumour are no longer contained.

At this point the cancer is still too small to be detected.

Angiogenesis

• Often during the development of earlier stages of the tumour, or perhaps by the time the tumour has broken through the basement membrane (as pictured above), angiogenesis takes place. Angiogenesis is the recruitment of blood vessels from the network of neighbouring vessels.

• Without blood and the nutrients it carries, a tumour would be unable to continue growing. With the new blood supply, however, the growth of the tumour accelerates; it soon contains thousand million cells and, now the size of a small grape, is large enough to be detected as a lump

Invasion and dispersal

• The tumour has now invaded the tissue beyond the basement membrane.

Individual cells from the tumour enter into the network of newly formed blood vessels, using these vessels as highways by which they can move to other parts of the body. A tumour as small as a gram can send out a million tumour cells into blood vessels a day.

Tumour cells travel - metastasis

• What makes most tumours so lethal is their ability to metastasize -- that is, establish new tumour sites at other locations throughout the body.Secondary tumours.

• Metastasis is now underway, as tumour cells from the original cancer growth travel throughout the body. Most of these cells will die soon after entering the blood or lymph circulation.

Metastasis

• To form a secondary tumour, a tumour cell needs to leave the vessel system and invade tissue. The cell must attach itself to a vessel's wall. Once this is done, it can work its way through the vessel and enter the tissue.

Although perhaps less than one in 10,000 tumour cells will survive long enough to establish a new tumour site, a few survivors can escape and initiate new colonies of the cancer.

Changes observed when a normal tissue culture cell is transforming to a tumor

• Changes observed when a normal tissue cell is transforming to a tumour are as follows.

• 1. Alterations in the nucleus• 2. Plasma membrane related abnormalities• 3. Adherence abnormalities• 4. Growth and division abnormalities• 5. Defective differentiation

• 6. Inability to undergo apoptosis following DNA damage

• 7. Anaplasia: Loss of differentiation, meaning literally “without form”

• 8. Cell division fixes the mutation in daughter cells

• 9. hyperplasia and stimulate growth• 10.loose control over the cell division process• 11.do not adhere to each other• 12.do not resemble normal cells• 13.do not carry out functions of normal cells

• Dysplasia• Abnormal change in the size, shape, and

organization of cells in a tissue• Often an early step toward cancer• Microscopic characteristics of cancer cells• Behave differently from normal cells• they are precancerous stages and turn into

cancer

Growth Factors Regulate When Cells Divide

NORMAL CELLGrowth factorGrowth factor receptor

Signal transduction

Activation of transcription

cytoplasm

nucleus

Relationship between gene products of proto oncogene

Growth factors eg IGFGrowth factor receptors Eg erb-2, ret

Signal transducing factorsEg cytoplasmic kinases

DNA binding proteins concerned with transcription

cell cycle proteins eg cyclin D

NEOPLASTIC CELLS

IncreasedIn growth factor

IncreasedIn growth factorreceptors

Increased in signal transduction

Increase in activation of transcription

Length of Telomeres

Telomeres are structures at the ends of chromosomes that shorten with each cell division. After 50 divisions, the shortened length of telomeres causes mitosis to stop.

telomeres

Summary

• Cancer develops through four definable stages:

• initiation • promotion • progression • and malignant conversion.

Summary

• The first stage, initiation in which DNA damage takes place

• If repair does not take place will lead to promotion phase in which mutated cell is stimulated to grow and divide faster and becomes a population of cells.

Summary

• During progression, there is further growth and expansion of the tumor cells over normal cells and leads then further mutations in daughter cells until conversion occurs and cell does not resemble normal cell at all but becomes a tumor cell

Summary

• In a 2000 article by Hanahan and Weinberg, the biological properties of malignant tumor cells were summarized as follows

Summary

• Acquisition of self-sufficiency in growth signals, leading to unchecked growth.

• Loss of sensitivity to anti-growth signals, also leading to unchecked growth.

• Loss of capacity for apoptosis, in order to allow growth despite genetic errors and external anti-growth signals.

Summary

• Loss of capacity for senescence, leading to limitless replicative potential (immortality)

• Acquisition of sustained angiogenesis, allowing the tumor to grow beyond the limitations of passive nutrient diffusion.

Summary

• Acquisition of ability to invade neighbouring tissues, the defining property of invasive carcinoma.

• Acquisition of ability to build metastases at distant sites

Classification of bronchogenic carcinoma


• Correct classification of lung cancer cases are necessary to assure that lung cancer patients receive optimum management


• There are two types of lung cancers

• 1.Non-small cell lung cancer• 2.Small cell lung cancer

Non-small cell lung cancer

• Consist of three subtypes• Squamous cell (epidermoid) carcinoma• Adenocarcinoma (previously called

bronchioloalveolar carcinoma)• Large cell (undifferentiated) carcinoma

Non-small cell lung cancer

• The cells in these subtypes differ in size, shape, and chemical make-up when looked at under a microscope. But they are grouped together because the approach to treatment and prognosis (outlook) are very similar.

Squamous cell (epidermoid) carcinoma

• These cancers start from squamous cells, which are flat cells that line inside of the airways in the lungs.


• Squamous cell carcinoma usually starts in one of the larger airways. Therefore, these tumors tend to be located in the central area(middle) of the lung near the bronchus.


• This form of NSCLC has decreased in frequency over the past three decades, but is still the most common form of lung cancer among men who are current or former smokers or over age 65 years of both sexes.

Adenocarcinoma of lung

• Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Adenocarcinoma of the lung tends to stain mucin positive as it is derived from the mucus producing glands of the lungs.


• Similar to other adenocarcinoma, if this tumor is well differentiated (low grade) it will resemble the normal glandular structure.


• Poorly differentiated adenocarcinoma will not resemble the normal glands (high grade) and will be detected by seeing that they stain positive for mucin (which the glands produce).


• This cancer usually is seen peripherally in the lungs, as opposed to small cell lung cancer and squamous cell lung cancer, which both tend to be more centrally located,


• Generally, adenocarcinomas grow more slowly than the other subtypes.


• Adenocarcinoma is a non-small cell lung carcinoma, and as such, it is not as responsive to radiation therapy as is small cell lung carcinoma, but is rather treated surgically, for example by pneumonectomy or lobectomy.


• The solitary appearance of this neoplasm suggests that the tumor is primary rather than metastatic.


• Adenocarcinoma is the most common form of lung cancer found in women, and is often found in non-smokers.


• Most common type of lung cancer among all Asians.

• Appears to be increasing in young, non-smoking women.


• Lung adenocarcinoma has been increasing in recent years, whereas another form of non-small cell lung cancer, squamous cell carcinoma, has been decreasing. It is thought by some that the addition of filters to cigarettes allows smoke to be inhaled more deeply into the lungs where adenocarcinoma occurs.


• Because lung adenocarcinoma often begins in the outer parts of the lungs, well-known symptoms of lung cancer such as a chronic cough and coughing up blood may be less common until later in the disease.


• Seen here is the multifocal variant


• that appears grossly as a pneumonic consolidation.

• Most of the upper lobe toward the right has a pale tan to grey appearance.


• Microscopically, the bronchioloalveolar carcinoma is composed of columnar cells that proliferate along the framework of alveolar septae. The cells are well-differentiated. These neoplasms in general have a better prognosis than most other primary lung cancers.

Large cell (undifferentiated) carcinoma

• It may appear in any part of the lung. It tends to grow and spread quickly, which can make it harder to treat.


• The cells of large cell carcinoma (LCC) are the largest of the various types of NSCLC. The cells are generally highly undifferentiated or immature in appearance.


• Some experts believe these tumors represent adenocarcinomas or squamous cell carcinomas that are so undifferentiated as to be unrecognizable.


• The prognosis for large cell carcinoma is generally less favorable than for other forms of NSCLC.

OTHER CANCERS IN THE LUNGS

• There are other types of non-epithelial cancers that arise in the lungs. They are all relatively uncommon compared to SCLC and NSCLC.

OTHER CANCERS IN THE LUNGS

• Examples of these cancers include • Carcinoid tumors, malignant pleural

mesotheliomas, fibrosarcomas, and leiomyosarcomas. The lungs are also a frequent location for metastatic tumors from other locations in the body.

SMALL (OAT) CELL CARCINOMA

• Small (Oat) cell carcinoma accounts for about 20-30% of all lung cancers

• It has, in the past, been called oat cell cancer because the cells resemble oat grains.


• when seen under a microscope the cells appear small round or oval, or shaped like oat grains.


• it is thought to originate from neuroendocrine cells (APUD cells) in the bronchus called Feyrter cells (named for Friedrich Feyrter)

• Hence, they express a variety of neuroendocrine markers, and may lead to ectopic production of hormones like ADH and ACTH that may result in paraneoplastic syndromes and Cushing's syndrome.


• The tumor cells cause increased secretion of adrenocorticotropic hormone (a hormone from the adrenal gland), causing Cushing’s disease, which is characterized by a puffy face, weight gain, hump on the lower neck, or elevated blood sugar levels.


• Antidiuretic hormone, also secreted by these tumor cells, lead to water retention and low sodium, which(SIADH)can cause confusion. Small cell carcinoma antibodies also can cause weakness by the tumor-producing antibodies against normal tissues (autoantibodies).


• Small cell lung cancer is a neuroendocrine carcinoma that exhibits aggressive behavior, rapid growth, early spread to distant sites, exquisite sensitivity to chemotherapy and radiation, and frequent association with distinct paraneoplastic syndromes.

• The cancer spreads easily because of the constant flow of blood and lymph through the lungs. The fluids can carry cancer cells to the other lung, lymph nodes, and organs outside of the chest.


• There is usually early involvement of the hilar and mediastinal lymph nodes.


• Prognosis

• In limited-stage disease, median survival with treatment is 14–20 months, and about 20% of patients with limited-stage small-cell lung carcinoma live 5 years or longer.


• The prognosis is far worse in extensive-stage small-cell lung carcinoma, with treatment, median survival is just 8–13 months, and only 1–5% of patients with extensive-stage small-cell lung carcinoma treated with chemotherapy live 5 years or longer.


• Approximately half of all individuals diagnosed with Lambert-Eaton myasthenic syndrome (LEMS) will eventually be found to have a small-cell carcinoma of the lung.


• Arising centrally in this lung and spreading extensively is a small cell anaplastic (oat cell) carcinoma. The cut surface of this tumor has a soft, lobulated, white to tan appearance.


• The tumor seen here has caused obstruction of the main bronchus to left lung so that the distal lung is collapsed. Oat cell carcinomas are very aggressive and often metastasize widely before the primary tumor mass in the lung reaches a large size.


• Here is an oat cell carcinoma which is spreading along the bronchi. The speckled black rounded areas represent hilar lymph nodes with metastatic carcinoma.


• These neoplasms are more amenable to chemotherapy than radiation therapy or surgery, but the prognosis is still poor. Oat cell carcinomas occur almost exclusively in smokers.


• This is the microscopic pattern of a small cell anaplastic (oat cell) carcinoma in which small dark blue cells with minimal cytoplasm are packed together in sheets.

Pulmonary Hamartoma

• Here are two examples of a benign lung neoplasm known as a pulmonary hamartoma.

Pulmonary Hamartoma

• These uncommon lesions appear on chest radiograph as a "coin lesion" that has a differential diagnosis of granuloma and localized malignant neoplasm.

Pulmonary Hamartoma

• They are firm and discreet and often have calcifications in them that also appear on radiography. Most are small (less than 2 cm).

Metastatic carcinoma

• Multiple variably-sized masses are seen in all lung fields. These tan-white nodules are characteristic for metastatic carcinoma.

Metastatic carcinoma• Metastases to the lungs are

more common even than primary lung neoplasms simply because so many other primary tumors can metastasize to the lungs. Even the hilar nodes in this photograph demonstrate nodules of metastatic carcinoma. The nodules are usually in the periphery and do not cause major obstruction.

Mesothelioma

• The dense white encircling tumor mass is arising from the visceral pleura and is a mesothelioma. These are big bulky tumors that can fill the chest cavity.

Mesothelioma

• The risk factor for mesothelioma is asbestos exposure.

Signs symptoms of bronchogenic carcinoma


• Persistent cough• Persistent haemoptysis• Persistent wheeze & stridor• Persistent dyspnea


• Pneumonitis fever productive cough• Chest pain from pleural or chest wall

involvement• Symptoms of lung abcess from tumour

cavitation


• Haematogenous,lymphatic or direct spread to pleura resulting in malignant pleural effusion

• Superior vena caval obstruction resulting in superior vena caval syndrome

• Tracheal obstruction leading to stridor and dyspnea


• Oesophageal obstruction leading to dysphagia• Recurrent laryngeal nerve involvement with

resultant hoarsness of voice and bovine cough• Phrenic nerve involvement resulting in

diaphragmatic paralysis and dyspnea


• Sympathetic chain involvement leading to horner's syndrome(pancosts tumour)

• Direct extension to chest wall resulting in rib pain and pathological fractures, intercostal neuralgia

• T1 involvement• Pericardial and cardiac involvement with

resultant cardiac temponade,arrythemias or cardiac failure

Metastasis to other organs

• Brain metastasis with neurological deficits• Bone metastasis• Bone marrow involvement with pancytopenia• Liver metastasis• Lymph node metastasis• Metastasis to spinal cord & cord compression

Paraneoplastic syndrome(Result from peptide secretion of tumour)

• Endocrine • SIADH-Syndrome of inappropriate secretion of

antidiuretic hormone• resulting in hyponatremia,cushings syndrome,

ectopic production of parathyroid hormone resulting in hypercalcaemia and hypophosphatemia


• Neuromuscular• Eaton Lambert syndrome, peripheral

neuropathy,cerebellar degeneration, cortical degeneration,polymyositis


• Skeletal• Clubbing ,hypertrophic pulmonary

osteoarthropathy


• Haematological• Migratory venous

thrombophelbitis(Trousseaus syndrome),DIC,anaemia,granulocytosis or pancytopenia


• Cutaneous

• Dermatomyositis,acanthosis nigricans

• Renal

• Nephrotic syndrome,glomerulonaphritis

• and many more

Investigations

• x ray chest

• May show opacity,cavitation,effusion,collapse or consolidation

• Unilateral enlargement at hilum ,glandular enlargement

• Mediastinal widening due to mediastinal involvement

• etc etc

Investigations

• Cytological examination of the following may be positive for malignant cells

• Sputum• Bronchial brushing• Bronchial washings• Percutaneous needle aspiration biopsy of

peripheral tumour• Fine needle aspiration of lymph node, skin or

liver

Investigations

• CT SCAN(computed tomography) of chest and abdomen

• is an important investigation for staging• Evaluation of tumour size• CT guided biopsy• To assess response to treatment

Investigations

• Bronchoscopy• For visualisation and biopsy of intrabronchial

tumour• Collection of bronchial washings

Other investigations

• Scalene node biopsy• Mediastonoscopy• Pleural aspiration and biopsy• Barium swallow• Ultrasound abdomen• Bone scans• Bone marrow biopsy• CT brain• Whole body scan spine etc• Then all other routine tests and full blood count

malignancy by dr bashir ahmed dar associate professor medicine sopore kashmir

Education