DR SHAHIR ASFAHANRESIDENT, DEPT OF PULMONARY

MEDICINEAJMER, INDIA

DIAGNOSIS OF LUNG CANCER

Lung cancer

The incidence of lung cancer is on the rise.From being 1% of all cancers in 1958 in india

to nearly a millon new cases in india 2008, lung cancer has come a long way.

Today it is the leading cause of cancer in men and a dismal 5 year survival.

Pulmonologists are at the frontline this battle, hence it is most essential to know the strategies to diagnose it.

RISK FACTORSTobacco smokingEnvironmental tobacco smokeAirpollution- domestic fuels and

petroleum combustionPulmonary diseases- copd,

IPF,pneumoconiosisEnvironmental exposure to radon,

arsenic,nickel, chromium,asbestosHIVAlcohol consumptionGenetic factors

SCREENING

CONCEPT-IMPROVEMENT IN MORTALITYRADIOLOGICAL- A STUDY INVOLVING

55000 SUBJECTS IN 1960s DIDNT DEMONSTRATE ANY IMPACT ON MORTALITY

SUBSEQUENTLY IN 1970 FOUR RCTS CONCLUDED THE SAME

LOW-DOSE CT SCREENING

IN 1990s A 3 YEAR POPULATION BASED STUDY WITH MOBILE CT SCANNER WAS DONE IN RURAL SETUP- IT DEMONSTRATED INCREASED DETECTION OF RESECTABLE TUMORS AND IMPROVED SURVIVAL.

EARLY LUNG CANCER ACTION PROJECT (ELCAP) IN USA- 96% OF TUMORS DETECTED WERE RESECTABLE. SAMPLE SIZE WAS DEEMED SMALL.

MAYO CT SCREENING STUDY DID FIND INCREASED N0. OF RESECTABLE CANCERS BUT NO IMPACT ON MORTALITY AND INCREASED DETECTION OF NON-CANCEROUS NODULES LEADING TO HEALTH CARE BURDEN.

The National Lung Screening Trial

TO SPECIFICALLY DETECT DECREASE IN MORTALITY.

RCT INVOLVING 53524 PARTICIPANTSTWO ARMS- 1) ANNUAL CHEST RADIOGRAPH

2) ANNUAL LOW DOSE CT.24% OF CT SCREEN S/O LUNG CANCER OF

WHICH 96% WERE FALSE POSITIVE.CT GROUP HAD 63.2% RESECTABLE CANCERS

WHILE CXR GROUP HAD 48% RESECTABLE CANCERS

CT GROUP HAD 20% DECREASE IN LUNG CANCER SPECIFIC MORTALITY

GUIDELINES FOR SCREENING

ANNUAL DOW DOSE CT SCREENING between 55 and 74 years of age, with a

minimum of 30 pack-years of smoking. Former smokers meeting the 30 pack-year requirement could participate if they had quit within the previous 15 years

ADULTS ABOVE 50YRS IF OTHER RISK FACTORS ARE PRESENT

Sputum cytologyAlso called “the poor

man’s bronchoscopy”.In a meta-analysis by

Duke university centre, it had a sensitivity of 66% and specificity of 99%.

More useful in central airways tumors.

Can also detect dysplastic changes in pre-neoplastic stages.

CXR

Due to the widespread availability of simple chest radiography, the first suspicion of lung cancer is raised most often by a CXR.

It can present as SPN(<3cm) or as a mass(>3m), atelectasis of segment, lobe or lobes of lung, airspace consolidation,pleural effusion, reticular septal infiltration, chestwall/osseos/mediastinal invasion or a combination of the above.

Favors benign Favors malignant

Location-no predilectionSize- no definite correlationMargins-usually round in

shape with smooth marginsPresence of fat is highly s/o

of hamartomasCalcification- central,

laminated, diffuse, popcornCavity-wall thickness

<5mmContrast

enhancement<15HUTDT- <30 days >2yrs

Located more in upper lobes Size >3cm to be considered

malignant until proven otherwise

Margins- spiculated margins is highly s/o malignancy

Fat rarely present in metastases from RCC or liposarcoma

Calcification-amorphous or eccentric

Cavity wall>15mm Contrast enhancement>20HU TDT- btw 30 days and 2 yrs.

Solid pulmonary nodule

AMERICAN ASSOCIATION OF THORACIC SURGERY GUIDELINES-2012

ADENOCARCINOMA

CXR-ILL DEFINED SPICULAR OR WELL DEFINED LOBULER WITH ASSO HILAR LYMPHADENOPATHY

CT-PERIPHERAL MASS WITH SPICULATED OR LOBULER MARGINS.

CAVITATION IN UPTO 15%.CALCIFICATION USUALLY

ECCENTRIC IN UPTO 10% OF PATIENTS.

CONTRAST ENHANCEMENT

BAC

CT-COMMONLY GROUND GLASS OPACITIES WITH AIR-BRONCHOGRAMS AND INTRATUMORAL CYSTIC SPACES.

ALSO PRESENT AS NODULE, MASS OR CONSOLIDATION

the greater the degree of ground-glass attenuation, the better outcome, with 5-year survival

SQUAMOUS CELL CARCINOMA

CXR-CENTRAL MASS FREQUENTLY WITH SECONDARY ATELECTASIS OR OBSTRUCTIVE PNEUMONIA

CAVITATION, LYMPHADENOPATHY CT-CENTRAL MASS WITH ABRUPT

OBSTRUCTION OF BRONCHIAL LUMEN

POST OBSTRUCTIVE CONSOLIDATION ATELECTASIS WITH CONRAST ENHANCEMENT OF MASS MORE THAN LUNG IN CECT

CAVITATION - CENTRAL OR ECCENTRIC WITH IRREGULAR INNER SURFACE

MEDIATINAL OR SOFT TISSUE INVASION WITH LYMPHADENOPATHY MAY BE PRESENT.

SMALL CELL LUNG CANCER

Central mass near major bronchi; submucosal tumor with rare mucosal or endoluminal growth

Bronchial encasement with extrinsic stenosis/obstruction

Vascular invasion/encasement

Peripheral nodule or mass (approximately 5% of cases)

Lymphadenopathy

LARGE CELL LUNG CANCER

Large. typically peripheral tumors ; often measure over 3 cm at presentation

Frequent necrosisFREQUENT

INVASIONHILAR

LYMPHADENOPATHY

POSITRON EMISSION TOMOGRAPHY

a standardized uptake value (SUV) cutoff of 2.5 often was used to suggest malignancy,

a sensitivity of about 90% to 95% (range, 83% to 100%),

a specificity of about 80% (range, 52% to 100%), and

an accuracy of about 90% (range, 86% to 100%) were reported

FALSE POSITIVE FALSE NEGATIVE Mycobacterial or fungal

infection Granulomatous disorders

(sarcoidosis, Wegener granulomatosis)

(Rheumatoid) arthritis (anthracosilicosis) Bronchiectasis organizing pneumonia Bone marrow expansion post

chemotherapy Colony-stimulating factors Salivary gland adenoma

(Warthin tumor) Thyroid adenoma Adrenal adenoma

Small-sized lesionBronchioloalveolar

carcinomaCarcinoid tumorsGround glass opacity

neoplasmsHyperglycemiaParavenous FDG injectionIncreased time between

injection and scanning

POSITRON EMISSION TOMOGRAPHY

CT-PET

allow more precise evaluation of chest wall and mediastinal infiltration or

correct differentiation between tumor and peritumoral inflammation or atelectasis.

more accurate lymph node staging than CT alone, with an overall sensitivity of 80% to 90% and a specificity of 85% to 95%

illustrates the location of suspect lymph nodes, thereby helping to direct tissue sampling procedures

FOR DETECTION OF METASTASIS Uniformly superior to CT alone, except in brain imaging, for which sensitivity is unacceptably low owing to the high glucose uptake in normal surrounding brain tissue. CT and, even better, MRI remain the methods of choice for brain imaging.

bronchoscopy

Bronchoscopy most commonly is performed in the evaluation of patients with suspected lung cancer.

Central lesions can appear as exophytic growth, extrinsic compression, submucosal infiltration or any combination of these.

Central lesions usually are sampled with a combination of bronchial washes, bronchial brushings, and endobronchial biopsies.

The yield of endobronchial biopsy is highest for exophytic lesions, with a diagnostic yield of approximately 80%

Attempts should be made to obtain the biopsy specimens from areas of the lesion that seem viable

EBNA should be obtained if lesion appears necrotic.

Peripheral lesions usually are sampled with a combination of bronchial wash, brushes, transbronchial biopsy, and TBNA.

The yield of bronchoscopy for lesions smaller than 3 cm varies, ranging from 14% to 50%,

diagnostic yield of 46% to 80% when the lesion is larger than 3 cm.

Electro-magnetic navigation

Ct scan and virtual bronchoscopy is performed and data stored in the console.

Electromagnetic field is generated and magnetic probe attached to the tip of bronchscope advanced under real time guidance.

EMN diagnostic sensitivity to range between 67% and 74%, independent of lesion size.

Autoflourescence bronchoscopy improved the detection of

dysplasia, carcinoma in situ, and invasive carcinoma of the central airways

AFB systems rely on the principle that infiltrating tumors disturb the fluorescence characteristics of normal tissue..

Bronchial tree is illuminated with blue light of wavelength 442nm.

Normal tissues emit light in the green spectrum while neoplastic tissues emit in the near-red spectrum.

the sensitivity for detecting high-grade dysplasia or carcinoma in situ was increased two- to six-fold on average

Narrow-band imaging

uses a unique filter to select light wavelengths that preferentially are absorbed by hemoglobin, thereby permitting superior microvasculature detection.

Because angiogenesis preferentially occurs in dysplastic and neoplastic lesions, NBI may identify early dysplastic lesions better than WLB or AFB.

Studies suggest similar sensitivity between AFB and NBI, but improved NBI specificity for detecting abnormal lesions

OPTICAL COHERENCE TOMOGRAPHY

near-infrared light transit time and reflection are used and provides a macroscopic optical cross-sectional view of hollow organs.

In the airway, dysplastic, invasive cancer appear to have unique OCT image patterns.

Provides “optical biopsy” and can be used for longitudinal follow-up for treatment response.

FIBERED CONFOCAL FLUORESCENCE MICROSCOPY

based on cellular and tissue autofluorescence on laser excitation.

The predominant source of airway wall autofluorescence is the subepithelial elastin fibers, and alterations in this elastin network can be detected in microinvasive and invasive proximal airway lesions.

transbronchial needle aspiration (TBNA)

Used for diagnosis and staging of bronchogenic carcinoma.

TBNA is highly specific for the identification of mediastinal metastases, with sensitivity depending heavily on the study population under investigation.

In studies that included patient populations with a prevalence of mediastinal metastases of 34%, sensitivity was only 39%,

whereas in a population with a prevalence of 81%, sensitivity for detection of metastases was 78%.

lack of needle monitoring, difficulties in anticipation of location of lymphnodes have limited its use.

ENDOBRONCHIAL ULTRASOUND TECHNIQUE

a curved linear array ultrasound transducer sits on the distal end and can be used either with direct contact to the mucosal surface or with an inflatable balloon that can be attached at the tip.

Ultrasound scanning is performed at a frequency of 7.5 to 12 MHz, with tissue penetration of 20 to 50 mm. An ultrasound processor generates the ultrasound image.

Lymph node stations that can be reached using EBUS are the highest mediastinal (station 1), the upper paratracheal (2land 2R), the lower paratracheal (4R and 4L), the subcarinal (station 7), the hilar (station 10) nodes, as well as the interlobar(station 11) and lobar (station 12) nodes.

EBUS-TBNA has been shown to have a high pooled sensitivity of 93% and specificity of 100%

EUS(endoesophageal ultrasound)

EUS-FNA has limited access, because only lymphnode stations 2, 4, 7, 8, and 9 are accessible through a transesophageal approach.

The left adrenal can be reached and identified in 97% of cases. It has a characteristic “seagull” shape on ultrasound images and is particularly well visualized in cases of metastatic enlargement. Furthermore, the left lobe of the liver also can be reached.

Even in cases in which mediastinal lymph node enlargement is not seen on CT, EUS-FNA has been able to demonstrate metastases in 25% of patients with lung cancer.

Percutaneous biopsy

Percutaneous Biopsy Procedures- intrapulmonary lesion

In malignant disease, the techniques are analogous, with a sensitivity of 90% to 95% (Klein et al., 1996)

FNA and Core BIOPsy are analogous in sensitivity but core needle biopsy offers more tissue material for genetic studies

GENE MUTATIONS ASSOCIATED WITH LUNG CANCER

MAJOR ROLES PLAYED BY1) EGFR2) K-RAS3) EML-ALK44) P535) VEGF6) Telomerase7) BCL-2

EGFR

EPIDERMAL GROWTH FACTOR RECEPTOR ALSO KNOWN AS HER1, MEDIATES EXTRACELLULAR SIGNALS INTRA-CELLULARLY VIA TYROSINE KINASE PHOSPHORYLATION AND INHIBITS APOPTOSIS.

EGFR-activating mutations tend to be present in a minority of lung cancers (10% to 20%)

appear most commonly in nonmucinous adenocarcinomas exhibiting a well-differentiated acinar or papillary growth pattern.

presenting demographically in younger Asian women who were never-smokers or light smokers.

Targeted TKIs are effective for tumor regression when non–small cell carcinomas have activating EGFR mutations.

K-RAS

KRAS is an oncogene found on the short arm of chromosome 12 (12p)

shows mutations in approximately 20% of non–small cell lung cancers.

clinicopathologic correlations with older age combined with male gender,history of heavy cigarette smoking, and advanced disease at presentation, with relatively aggressive tumors and poor clinical outcome.

These high-grade adenocarcinomas also show lymphovascular invasion, mitotic activity, and tumor necrosis.

PRESENCE OF KRAS MUTATION IMPLIES RESISTANCE TO TKIs EVEN IN PRESENCE OF EGFR MUTATION.

EML-ALK4

echinoderm microtubule-associated protein-like 4–anaplastic lymphoma kinase.

occurring in less than 10% of non–small cell lung cancers

present in younger persons without significant smoking history

appears to be selective for adenocarcinomas.IMPLIES RESISTANCE TO TYROSINE

KINASE INHIBITORS.

Pleural fluid examination

cytologic study of the pleural fluid establishes the diagnosis of a malignant pleural effusion ranges from 40% to 87%.

Predictors of malignancy in pleural fluid-a symptomatic period of more than 1 month,

the absence of fever, the presence of serosanguineous pleural fluid, and a chest CT scan suggestive of pleural malignancy

Closed needle Pleural biopsy

Commonly used needles are Abram’s and Cope’s needle.

The percentage of positive pleural needle biopsies in patients with malignant pleural disease ranges from 39% to 75%.

thoracoscopy

It is considered the gold standard for diagnosis of malignant pleural effusion.

The sensitivity of thoracoscopy ranges from 92 to 97 % ,

and its specificity is 99–100 % for patients with a malignant pleural effusion

Tumor markers Patz et al used 2D difference gel electrophoresis

(DIGE) and MALDI-TOF MS they found that 4 of these proteins

(CEA, RBP, α1-antitrypsin and SCC antigen) were able to distinguish lung cancer cases from controls with 77.8% sensitivity and 75.4% specificity.

indirect ELISA tests for known lung cancer TAAs (p53, NY-ESO-1, cancer-associated antigen (CAGE), GBU4-5, Annexin 1 and SOX2) . These efforts yielded an assay with high reproducibility, precision, and linearity that was able to identify nearly 40% of primary lung cancers via a peripheral blood test

Future candidate markers- autoantibodies against the protein gene product 9.5 (PGP 9.5)

Thank you