EARLY DIAGNOSIS OF LUNG CANCER

EARLY DIAGNOSIS OF LUNG CANCER

By

Dr: HODA ASAADLecturer of Chest diseasesAl-Azhar University forGirls

Lung cancer continues to be the leading cause of cancer-related

deaths worldwide .

5-year survival for lung cancer has remained relatively poor ( only 15%) despite many advances in imaging techniques and oncological care over

because by the time a diagnosis is made, lung cancer is often well advanced and treatment options are limited.

Globally, lung cancer has been the most common cancer diagnosed each year since 1985.

Lung cancer had a higher incidence among males worldwide than any other cancer, followed by prostate cancer (more common in developed countries) and stomach cancer (particularly in developing countries) .

Among females, lung cancer was the fourth most diagnosed cancer, behind breast cancer, cervical cancer (mostly in developing countries), and colorectal cancer.

The largest gain in life expectancy in lung cancer patients has been among those with localized disease versus those with regional or distant metastasis.

only 19% of lung cancers are localized at the time of diagnosis

Screening for cancer means looking for cancer BEFORE there are symptoms

Screening may identify early cases of

cancer that never have become clinically apparent.

Early Detection/Screening

early diagnosis of the disease or identification of truly high-risk populations may provide us

opportunity to successfully cure or prevent the disease

Goals

Early Symptoms of Lung Cancer

What are the early symptoms of lung cancer that you should be

on the lookout for?

Keep in mind that understanding the early symptoms of lung cancer is important for non-smokers as well as smokers.

At present, 50% of people who develop lung cancer are former smokers, and 15% have never smokedThe 60% to 80% 5-year survival rate with stage 1 lung cancer drops to 10% with stage 4 disease

About.com GuideUpdated February 17,

2012

nearly half of people have progressed to this advanced stage at the time of diagnosis

Early Symptoms of Lung CancerA) Cough That Doesn’t Go Away

Many people dismiss or adapt to a chronic cough, . But a cough that lasts more than a few weeks can be a sign of something else.

If you experience a persistent cough, check with your doctor, and ask for a second opinion if you don’t get a

clear answer

If you experience a persistent cough

check with your doctor, and ask for a second opinion if you don’t get a clear answer

Early Symptoms of Lung Cancer con,t

Wheezing chest

People should pay attention to wheezing if it occurs with persistent coughing and

other symptoms

Early Symptoms of Lung CancerShortness of Breath With Activity

Repeated Infections Such as Bronchitis and Pneumonia

Pain or Aching in Shoulder, Back, Chest, or Arm

Up to 50% of people with lung cancer have some chest or shoulder pain at the time of diagnosis, especially pain that increases with coughing and

breathing. shoulder pain is sometimes the first symptom of lung cancer

Non Invasive early diagnosis of

Lung Cancer

Sputum contains exfoliated airway epithelial cells and morphological analysis of sputum by cytology has been used for the early diagnosis of lung cancer, particularly central airway tumorInduced sputum has found to be better than spontaneous sputum

Sputum cytology

Limitation of sputum cytologyAs the structure of the airway each sputum sample may contain only cells derived from part of the airway and therefore is not representative.

the association was stronger for samples collected within 5 months of the diagnosis of lung cancer

the skill required for identifying subtle morphological abnormalities in cells this results in significant variation in intra- and inter observer agreement in determining cancer cells

Malignancy-associated change (MAC) is the change in the

distribution of DNA in the nuclei of cytologically normal cells

Computer-assisted sputum DNA analysis is the method used to detect (MAC) in exfoliated cells in sputum

Sputum cytometry

It is a powerful alternate to conventional cytology .

.Lung Sign is an image cytometry system analysis of sputum slides

The system automatically scans slides and images thousands of cell nuclei per slide

.It measures cell nuclear features and generates a single

score for each specimen .

Sputum cytometry

measuring the DNA content of cells (ploidy), detects large-scale chromosomal abnormalities associated with malignancy.

Normal epithelial cells in sputum consist mostly of resting (diploid) cells.

The observation of a significant fraction of hyper diploid cells in sputum is atypical and may represent the presence of a DNA aneuploid cell line.

The detection of DNA aneuploidy has diagnostic and prognostic significance in lung cancer

Sputum cytometry

molecular diagnosis of lung cancer

the molecular diagnosis of lung cancer

.Development of lung cancer requires repeated insult of carcinogens, mainly from tobacco smoke over a long period of time.

The process so called carcinogenesis takes a few decades and results in accumulation of multiple molecular abnormalities in cells, which is the basis of malignant transformation and tumor progression

the molecular diagnosis of lung cancer

Recent advances in understanding biological basis of lung tumor genesis provide new tools for detecting malignant cells or the process of malignant transformation and progression .

Along with identification of molecular abnormalities in the early lung tumor genesis, advanced molecular analytic technologies have been emerged, which may facilitate development of rapid and effective methods for early diagnosis and risk assessment

Some genetic abnormalities occur in the early carcinogenic process in lungs of chronic smokers and certain abnormalities may persist for many years after smoking cessation . such as

mutations in the p53 tumor suppressor gene and K-ras proto-oncogene hypermethylation of the p16 tumor suppressor gene

loss of heterozygosity (LOH) in multiple critical chromosome regions.

the molecular diagnosis(con)

The Cell Cycle and Cancer

There are several factors that regulate the cell cycle and assure a cell divides correctly.

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 .

DNA replication animation:click on DNA

picture

p53The p53 gene involved in the cell cycle control

DNA repair, cell differentiation, genomic stability and programmed cell death)

• This protein is rapidly degraded in normal cells so its concentration is very low.

•In response to DNA damage in G1, the protein level of p53 rises dramatically due to the activation of a checkpoint protein kinase (chk2) that phosphorylate p53 and make it less susceptible to degradation

Mutations of the p53 tumor suppressor gene play an important

role in lung tumor genesis and occur in about

(50% of NSCLC and more than 70% of SCLC)

Frequent accumulation of p53 protein has been found in preneoplastic bronchial lesions, such as

(bronchial metaplasia, dysplasia, and

carcinoma in-sit

p53

Mutations of K-ras proto-oncogene is the most commonly mutated gene in the ras gene family,

representing approximately 90% of the mutations identified.

In lung cancer, mutations in K-ras gene are found in about 20% of the tumors.. Common in lung adenocarcinomas, accounting for about 30% of these tumors, but rare in other subtypes

mutations in K-ras may be important in development of adenocarcinoma of the lungs and early progression.

K-ras proto-oncogene

Abnormal protein expression

Both epidermal growth factor (EGF) and its receptor (EGFR) over express in more than 60% of NSCLC

Abnormal expression of Cyclin-dependent kinase (CDK4) was found expressed in about 90% of NSCLC and the expression associated with poor differentiation

(p16) is inactivated by hypermethylation in many tumor types including lung cancer

. )% lesions .

detecting aberrant methylation of p16 in the shedding cells

from airway after sputum induction from radio graphically

cancer-free persons could be a biomarker for impending disease.

THE (P16) TUMOR SUPPRESSOR GENE

Ethylated p16 could represent a critical step in the genesis of NSCLC by allowing the uncontrolled clonal expansion of some of these premalignant lesions to cancer

Methylated (p16 )

Aberrant methylation of the p16 and/or 6-methyl-guanine-DNA methyltransferase (MGMT) can be detected by PCR in 100% of patients

with squamous cell lung carcinoma up to 3 years before clinical diagnosis.

About 10% of sputum from cancer-free, high-risk subjects also contained the methylated DNA

sequence

the frequency of p16 methylation increased during disease progression

basal cell hyperplasia (17%)

squamous metaplasia (24%)

carcinoma in situ (50%).

.

( p16 ) ) (tumor suppressor gene con

January 9, 1998; Accepted July 29, 1998

Summary of the frequency for p16 methylation in premalignant lesions ,

.Telomeres don’t determine whether or not we live,but whether or not we age, which ultimately affects how long we live.

Telomeres are often described as “clocks” that regulate aging

Telomere shortening leads to decreased ability of stem cells to leave the stem cell niche and to regenerate tissues

Telomerase

TelomeraseTelomerase is a ribonucleo protein enzyme complex that maintains the length of telomeres It actually is not found in normal somatic cells, but it is found in 'immortal' cells, or cells which divide rapidly, including germ cells, inflammatory cells, and tumor cells.the telomeres being the caps on DNA ends. If the telomeres are shortened, cells age.

Conversely, if telomerase activity is high, telomere length is maintained, and cell longevity is increased

telomerase

The role of telomerase appears to be manipulating the life of the cell by presiding over the mechanism that controls how long the cell lives.

Some cancer researchers believe that the creation of a targeted telomerase inhibitor may actually be able to stop a cancer cell's ability to divide thus stopping the spread of cancer

Telomerase in Action

Telomerase

Although activation of telomerase alone may not

transform a normal cell to a cancer cell, it can

substantially prolong the lifespan of cells and

therefore permit time for accumulation of

molecular damages under insult of carcinogens

.

Telomerase. Telomerase activation can be detected in almost all SCLC and 80-85% of NSCLC indicating telomerase reactivation is important in lung tumor genesis and the major cause of cell immortality in primary NSCLC Telomerase activity may also be detected in precancerous lesions in lungs reflecting the early involvement of the molecule in lung tumor genesis

Volatile biomarkersAmong totally non-invasive tests, the analysis of exhaled air for volatile organic compounds (VOCs)seems to be

very promising for early diagnosis of lung cancer :

exhaled breath contains a pattern of VOCs which distinguishes patients with and without lung cancer

.

In 1999 Phillips et al. used, for the first time in medicine, the term “breathalyzer” for lung cancer.

lung cancer patients metabolism is different than the metabolism of healthy people. And so the molecules that make up cancer patients' exhaled breath are different too

ScienceDaily (Nov. 17, 2011) —

gaseous chemical sensing devices have been developed. Thepremise of these sensors is absorption of gases causing a change in conductivity, mass vibration or color of the sensor, thus altering the output

Volatile biomarkers

A new device uses gold nanoparticles to trap and define these molecules in exhaled breath.

Like the human nose, its electronic counterpart responds in concert to a given odor to generate a pattern or 'smellprint,' which is analyzed, compared with stored patterns and recognized By comparing these molecular signatures to control groups, the device can tell not only if a lung is cancerous, but if the cancer is small-cell or non-small-cell, and adenocarcinoma or squamous cell carcinoma

New Device Uses Gold Nanoparticles to Test for Lung Cancer

This new device could eventually help doctors quickly, simply, and inexpensively define patients' lung cancer subtypes, allowing them to pair therapies with subtypes early in the treatment process.

Nanotechnology is an emerging field that may have potentials

to make advanced changes in the detection, treatment, and prevention of cancer .

The development of biocompatible nanoparticles for molecular targeted diagnosis and treatment is an area of considerable interest .

One nanometer (nm) is equal to one-billionth of a meter .A human hair is approximately 80,000 nm wide

QUANTUM DOTS 

QUANTUM DOTS Quantum dots are semiconducting nanocrystals, which range in size from 2 nm to 10 nm. They can be used for both diagnosis and drug delivery,

especially for cancer treatments .

QD is made ready for injection. The QD enters the bloodstream and attaches itself to a cancer cell using the antibodies. The cancer cell takes in the QD, and the location is radiated with infrared light. This causes the QD to emit photons, allowing the site of the tumor to be located, and release the anti-cancer drug directly into the cancer cell.

QUANTUM DOTS QD based detection is rapid, easy and economical

enabling quick point-of-care screening of cancer markers .

QDs have got properties which make them ideal for detecting tumors. These include intense and stable fluorescence for a longer time; resistance to photo bleaching , large molar extinction coefficients, and highly sensitive detection due to their ability to absorb and emit

light very efficiently .

Various types of biomarkers such as proteins, specific DNA or mRNA sequences and circulating tumor cells have been identified for cancer diagnosis from serum samples .

Therefore, QD based identification of many biomarkers would lead to more effective diagnosis of cancer .

In this illustration, quantum dots are depicted as gold spheres that attract DNA strands linked to cancer risks. When the quantum dots are exposed to certain types of light, they transfer the energy to fluorescent molecules, shown as pink globes, that emit a glow .

This helps researchers to detect and count the DNA strands linked to cancer .

Applications of Nanotechnology in early diagnosis of lung cancer

 :

Nanoprobes (miniature machines) can attach themselves to particles in the body (e.g., antibodies) and emit a magnetic field. Probes that aren’t attached to anything don’t create a detectable magnetic

Nano-tracking may be able to detect tumors that are a few cells in size. (Alivisatos, 2001)

bronchoscopy

Recent endoscopic techniques have been developed to more effectively detect and localize critical, early pathologic changes occurring in the bronchial epithelial and subepithelial regions in vivo.

This includes.1

1.autofluorescence bronchoscopy

2.optical fluorescence and reflectance spectroscopy

3 .high-magnification bronchovideoscopy

4.high-frequency endobronchial ultrasound

5.more recently, optical coherence tomography.

AFB was first developed at the British Columbia Cancer Research Centre and became commercially available in 1998

The original system, used a helium–cadmium laser for illumination and detected the emitted red and green autofluorescent light with two image-intensified charge-coupled device (CCD) cameras.

Normal areas appear green and abnormal areas appear reddish brown,

1.autofluorescence bronchoscopy

Fluorescence bronchoscopy is based on observation that premalignant and malignant bronchial mucosa fluoresce less than normal tissue, SO allow detection of lesions (e.g., CIS) that may have a normal appearance during conventional white-light BRONCHPSCOPY

AFB (con)

AFB also have an important impact on the staging of potentially curable central lung cancers prior to endobronchial therapy, through more accurate assessment of the lesion size and margins

Right main bronchus carcinoma in situ under a) white light imagingb) autofluorescence imaging

Subsequent technological improvements includ the combination of fluorescence and reflectance imaging in order to enhance contrast between normal and abnormal tissues.

A red reflectance image is captured in combination with the green autofluorescence image .

2.optical fluorescence

and reflectance spectroscopy

3-Optical coherence tomography(oct)

Is a promising endoscopic imaging method that enables micron-scale resolution of the bronchial epithelium

It may become an imaging modality that helps address the relatively high false-positive rate of autofluorescence imaging. OCT is a noncontact method that delivers near-infrared light to the endobronchial tissue via a small probe via a bronchoscope.

It allows imaging of cellular and extracellular structures from analysis of the back-scattered light depth penetration of ∼2 mm to provide near-histological images in the bronchial wall

Early studies have shown that dysplasia can be differentiated from metaplasia, hyperplasia or normal tissue and that carcinoma in situ can be differentiated from invasive cancer

OCT technology could prove useful for structural and functional assessment of suspicious lesions, staging (invasion of basement membrane) and feedback during endobronchial therapy

(oct)

.Severity of the histopathology grade was associated with a progressive increase in the epithelial thickness and the nuclei of the cells also became darker and less light was scattered. The basement membrane became disrupted or disappeared with invasive carcinoma

(oct)

Optical coherence tomography image of early hilar-type lung cancer. Arrow symbols show a border of early cancer.

(oct)

a–c) Representative optical coherence tomography (OCT) images and d–f) corresponding (H&E)-stained histological sections

(a, d ) mild dysplasia, b, e) moderate dysplasia

and c, f) severe dysplasia.

The nuclei in the epithelium become recognisable as darker dots with either moderate dysplasia or worse. The arrow in the OCT image of the area with severe dysplasia (c) points to the corresponding elevated area in the H&E section (f). e: epithelium; bm:

basement membrane ..

High-magnification video bronchoscopy

High-magnification bronchoscopy, combines both fibrotic and video bronchoscope technologies to produce 100–110× better magnification of the bronchial wall compared with standard video bronchoscopesHelp in the visualization of micro vascular networks in the bronchial mucosa.

Increased vessel density in the bronchial submucosa is often present in squamous dysplasia and may play an early role in cancer pathogenesisIncrease in microvascular density can be seen under high magnification in the majority of areas of abnormal autofluorescence

Narrow band imaging

Narrow band imaging is a novel system that also utilizes the changes seen in the microvascular networkUse narrowband Blue light, which has a shorter wavelength than visible light, reaches into shallow surfaces whichis helpful for detecting the submucosal vessels and patterns of vascularisation

Narrow band imaging

this technique provided more accurate images of microvessels compared to high-magnification video bronchoscopy

NBI, seemed to improve the detection dysplasia/malignancy when used as an adjunct to white light

EBUS Endobronchial ultrasound introduced into clinical hospital practice i2000, as

a new diagnostic procedure visualizing bronchial and peribronchial tumors, mediastinal lymph nodes and adjacent vascular structures, with the aim of assessing bronchial wall and extraluminal pathology

Endobronchial ultrasound probes have been developed for evaluation

The depth of invasion of malignant tumours in the central and peripheral bronchi

Evaluation of lymph nodes located in the mediastinum in patients with lung cancer.

Primary TumorEarly Carcinoma

Alteration of the mucosa is concomitant with alteration in the sonographic structure.(either very low to very high echodensity).

Sometimes submucosal tumor spreading was noticed by endobronchial ultrasound in spite of presence of intact mucosa.

Layers of the bronchial wall by EBUS

(Kurimoto et al., 1999: Chest 115, 1500-1506)# (Miyazu et al., 2002: Am J Respir Crit Care Med 165, 832–837)

#

Sq C C at the spure of B1+2&B3 of LtUL

The depth of tumor invasionEBUS vs Histopathology .

EARLY RADIOLOGICAL DIAGNOSIS OF LUNG CANCER

Spiral computed tomography (CT or CAT

scans are being tested as a new way to find early lung cancer in smokers and former smokers.

At present, however, questions remain about the technology’s risks and benefits as a screening tool .

Promising evidence from several studies shows that the scans can detect small lung cancers. But detecting these early tumors has not been proven to reduce the likelihood of dying from lung cancer, the gold standard for any cancer screening test

Positron emission tomography (PET)

PET is now an important cancer

imaging tool both for diagnosis and staging, as well as forprognostic information

It is give information about the body's chemistry that is not available with other imaging techniques

PET scan is nuclear medicine imaging, to produce 3-dimensional, color images of the functional processes within the human body

resonanc

e imaging

(M

RI )scan

s

A PET scan demonstrates the biological function of the body before anatomical changes take place

How PET Worksinjection of a glucose-based radiopharmaceutical (FDG), which travels through the body, eventually collecting in the organs and tissue..

.FDG undergoes the same uptake as glucose but is metabolically trapped and accumulated in the cancer cell after phosphorylation by hexokinase.

•which are assembled by the computer into a 3-D image of the patient's body.

• If an area is cancerous, the signals will be stronger there than in surrounding tissue, since more (FDG) will be absorbed in those areas

Combination of PET with CT or MRI

the combination ("co-registration") of PET /CT Or MRI giving both anatomic and metabolic information (i.e., what the structure is, and what it is doing biochemically) .

PET scanners are now available with integrated high multidetector-row CT scanners .