TUMORS OF LUNG AND PLEURA

TUMORS OF LUNG AND TUMORS OF LUNG AND PLEURAPLEURA

TUMORS OF THE LUNGTUMORS OF THE LUNG

TYPESTYPES : :

• Carcinomas – 90-95 %Carcinomas – 90-95 %

• Carcinoids – 5%Carcinoids – 5%

• Mesenchymal tumour – 2-5 %Mesenchymal tumour – 2-5 %

HISTOLOGIC CLASSIFICATION OF HISTOLOGIC CLASSIFICATION OF MALIGNANT EPITHELIAL LUNG TUMORSMALIGNANT EPITHELIAL LUNG TUMORS

• Squamous Cell Carcinoma Squamous Cell Carcinoma

• Small Cell CarcinomaSmall Cell Carcinoma

• AdenocarcinomaAdenocarcinoma

Acinar, papillary, bronchiolo-alveolar, Acinar, papillary, bronchiolo-alveolar, solid, mixedsolid, mixed

• Large Cell Carcinoma Large Cell Carcinoma

• Large Cell Neuroendocrine CarcinomaLarge Cell Neuroendocrine Carcinoma

• Adenosquamous CarcinomaAdenosquamous Carcinoma

• Carcinomas with pleomorphic, Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements sarcomatoid, or sarcomatous elements

• Carcinoid tumorCarcinoid tumor– Typical Typical – Atypical Atypical

. . Carcinoma of salivary gland type Carcinoma of salivary gland type

. . Unclassified CarcinomaUnclassified Carcinoma

Etiology and pathogenesisEtiology and pathogenesis

• Several environmental factors are Several environmental factors are known to cause genetic damage that known to cause genetic damage that transform benign bronchial transform benign bronchial epithelium to neoplastic tissueepithelium to neoplastic tissue

1 -Tobacco Smoking1 -Tobacco Smoking

• Overwhelming evidence Overwhelming evidence

• 87% lung carcinoma occurs in 87% lung carcinoma occurs in smokerssmokers

• 10 fold greater risk – Average smoker10 fold greater risk – Average smoker

• 60 fold greater risk – Heavy smokers60 fold greater risk – Heavy smokers

• Passive smoking – 3000 deaths per Passive smoking – 3000 deaths per yearyear

Histologic sequence of Histologic sequence of events: events:

• Normal epitheliumNormal epithelium

• Squamous MetaplasiaSquamous Metaplasia

• Squamous DysplasiaSquamous Dysplasia

• Carcinoma in situCarcinoma in situ

• Invasive CarcinomaInvasive Carcinoma

CytogeneticsCytogenetics : :• Mutations in p53 geneMutations in p53 gene

( G: C > T: A)( G: C > T: A)

Carcinogens in cigarette smokeCarcinogens in cigarette smoke::• Polycyclic aromatic hydrocarbons – BenzopyrinePolycyclic aromatic hydrocarbons – Benzopyrine• Phenol derivativesPhenol derivatives• Radioactive elementsRadioactive elements

– Polonium – 210Polonium – 210– Carbon – 14Carbon – 14– Potassium - 40Potassium - 40

Other Contaminants :Other Contaminants :• Arsenic Arsenic

• NickelNickel

• MoldsMolds

• AdditivesAdditives

2 -Industrial Hazards2 -Industrial Hazards

• High dose Ionizing RadiationHigh dose Ionizing Radiation; ; High High incidence in Hiroshima / Nagasaki atomic incidence in Hiroshima / Nagasaki atomic bomb survivorsbomb survivors

• UraniumUranium – – 4 times increased risk in 4 times increased risk in nonsmoker uranium minersnonsmoker uranium miners

• AsbestosAsbestos – 5 times increased risk in – 5 times increased risk in nonsmokers, 50-90 times in smokersnonsmokers, 50-90 times in smokers

• Latent periodLatent period – – 10-30 years10-30 years

3 -3 -Air PollutionAir Pollution

• Indoor air pollution – RadonIndoor air pollution – Radon

• Increased incidence in miners .Increased incidence in miners .

Molecular GeneticsMolecular Genetics

-For all practical purposes, lung cancer is -For all practical purposes, lung cancer is divided into two clinical subgroups : divided into two clinical subgroups :

• aa - Small Cell Carcinoma - Small Cell Carcinoma

• b b - Nonsmall Cell Carcinoma- Nonsmall Cell Carcinoma

-Supported by some specific molecular -Supported by some specific molecular lesionslesions in each subgroup . in each subgroup .

Oncogenes :Oncogenes :

• C-MycC-Myc

• KrasKras

• EGFREGFR

• c-METc-MET

• c-KITc-KIT

Tumor Suppression Genes :Tumor Suppression Genes :

• p53p53

• RB1RB1

• p16 ( INK 4a) p16 ( INK 4a)

• Genes on chromosome 3p (FHIT, Genes on chromosome 3p (FHIT, RASSF RASSF 1A ) 1A )

Small Cell Carcinoma Genes :Small Cell Carcinoma Genes :

• C-KITC-KIT

• MYC NMYC N

• MYC LMYC L

• p53p53

• 3p ( Early genetic change )3p ( Early genetic change )

• RBRB

• BCL 2BCL 2

Non Small Cell Carcinoma Non Small Cell Carcinoma Genes :Genes :

• EGFREGFR

• KRAS ( Late genetic change)KRAS ( Late genetic change)

• p53p53

• p16 INK4ap16 INK4a

MORPHOLOGYMORPHOLOGY

• OriginOrigin : :– ¾ in the hilus – Bronchi¾ in the hilus – Bronchi– ¼ in the periphery – Alveolar ¼ in the periphery – Alveolar

septal cells, terminal septal cells, terminal

bronchiolesbronchioles

PRECURSOR LESION PHASE PRECURSOR LESION PHASE

• ( Squamous metaplasia ,Dysplasia, ( Squamous metaplasia ,Dysplasia, Carcinoma in situ )Carcinoma in situ )– Preceed invasive carcinoma Preceed invasive carcinoma – May last for many yearsMay last for many years– AsymptomaticAsymptomatic– No X-Ray changes; Small lesionNo X-Ray changes; Small lesion– Positive diagnostic test ;Positive diagnostic test ; CytologyCytology ( Sputum, Bronchial lavage ( Sputum, Bronchial lavage

fluid/ fluid/ brushings )brushings )

• PRECURSOR LESIONPRECURSOR LESION

POST INVASION PHASEPOST INVASION PHASE

• Larger tumour massLarger tumour mass

• Symptomatic, obstruct major bronchus Symptomatic, obstruct major bronchus – Infection ( Pneumonia )Infection ( Pneumonia )– Atelectasis Atelectasis

.. Grow inside the bronchus; fungating mass Grow inside the bronchus; fungating mass

. . Penetrate the wall of the bronchus into the Penetrate the wall of the bronchus into the peribronchial tissueperibronchial tissue

POST INVASION PHASEPOST INVASION PHASE

INVASIVE LESIONINVASIVE LESION

• Cauliflower like intraparenchymal massCauliflower like intraparenchymal mass

• Grey white, firm to hardGrey white, firm to hard

• Yellowish white mottling and softening Yellowish white mottling and softening

• Extension to pleural surface and cavityExtension to pleural surface and cavity

• Involve pericardiumInvolve pericardium

• Regional lymph node involvement Regional lymph node involvement (Tracheal, Bronchial, Mediastinal )(Tracheal, Bronchial, Mediastinal )

MetastasisMetastasis

• Via both lymphatics and Via both lymphatics and hematogenous spreadhematogenous spread

• May be the first manifestationMay be the first manifestation

• Any organ; most commonly Any organ; most commonly – Adrenals ( 60 %)Adrenals ( 60 %)– Liver ( 30-50%)Liver ( 30-50%)– Brain ( 20% )Brain ( 20% )– Bone ( 20% )Bone ( 20% )

ADENOCARCINOMAADENOCARCINOMA

• Malignant epithelial tumour with Malignant epithelial tumour with glandular differentiation or mucin glandular differentiation or mucin productionproduction

• Patterns of growth :Patterns of growth :– AcinarAcinar– Papillary Papillary – BronchioloalveolarBronchioloalveolar– Solid with mucin formation Solid with mucin formation

ADENOCARCINOMA; ADENOCARCINOMA; CHARACTERISTICSCHARACTERISTICS

Most common type in :Most common type in :• Woman Woman • Non-smokers ( 75% v/s > 98% )Non-smokers ( 75% v/s > 98% )• Lesion more peripherally located Lesion more peripherally located • Smaller sizeSmaller size• Slow growthSlow growth• Early and widespread metsEarly and widespread mets• Cytogenetics ; Cytogenetics ;

- K RAS ( Specific for adenocarcinoma )- K RAS ( Specific for adenocarcinoma )- p53 , RB1, p16- p53 , RB1, p16

- EGFR ( mutation, amplification )- EGFR ( mutation, amplification ) - C-MET- C-MET

Bronchioloalveolar Bronchioloalveolar CarcinomaCarcinoma

• Arises in terminal bronchioloalveolar Arises in terminal bronchioloalveolar regionregion

• 1-9 %1-9 %

• Gross :Gross :– Single / multiple nodules in lung Single / multiple nodules in lung

peripheryperiphery– Solid, grey white areas like pneumoniaSolid, grey white areas like pneumonia

Bronchioloalveolar CarcinomaBronchioloalveolar Carcinoma

HistologyHistology : :

• Growth along the preexisting structuresGrowth along the preexisting structures

• Preservation of alveolar architecturePreservation of alveolar architecture

• No stromal, vascular or pleural invasionNo stromal, vascular or pleural invasion

Sub types :Sub types :

- - MucinousMucinous: Tall columnar cells with : Tall columnar cells with cytoplasmic / intraalveolar mucincytoplasmic / intraalveolar mucin

- - Non-mucinousNon-mucinous: Columnar or cuboidal cells : Columnar or cuboidal cells

SEQUENCE OF EVENTSSEQUENCE OF EVENTS

--Atypical adenomatous hyperplasiaAtypical adenomatous hyperplasia (Well demarcated focus of cuboidal to low (Well demarcated focus of cuboidal to low

columnar epithelium)columnar epithelium) ||

--Bronchioloalveolar CarcinomaBronchioloalveolar Carcinoma || --Invasive AdenocarcinomaInvasive Adenocarcinoma

(Poorly demarcated invasive lesion/tumor(Poorly demarcated invasive lesion/tumor))

SQUAMOUS CELL SQUAMOUS CELL CARCINOMA CARCINOMA

• Most common lung cancer in MalesMost common lung cancer in Males

• Strong correlation with smokingStrong correlation with smoking

• Arise from segmental bronchiArise from segmental bronchi

HISTOLOGY :HISTOLOGY :– Sheets / clusters of atypical squamous cells Sheets / clusters of atypical squamous cells – Keratinization / squamous pearls varies with Keratinization / squamous pearls varies with

grade of tumourgrade of tumour– Intercellular bridgesIntercellular bridges

Histologic GradesHistologic Grades : :• Well differentiated Well differentiated • Moderately differentiatedModerately differentiated• Poorly differentiated Poorly differentiated

Cytogenetics :Cytogenetics :- p53 mutation; Most common- p53 mutation; Most common- RB1, p16 ( INK4a), EGFR- RB1, p16 ( INK4a), EGFR- Alleles at 3p, 9p, 17p Alleles at 3p, 9p, 17p

- EGFR overexpressionEGFR overexpression

SMALL CELL CARCINOMASMALL CELL CARCINOMA

• Highly malignant tumourHighly malignant tumour• Strong correlation to cigarette Strong correlation to cigarette

smoking (Only 1% in non-smokers)smoking (Only 1% in non-smokers)• May arise centrally or peripherallyMay arise centrally or peripherally• No percursor / preinvasive lesionNo percursor / preinvasive lesion• Widely metastatic Widely metastatic • Surgically incurableSurgically incurable• Ectopic hormone production Ectopic hormone production

Small Cell CarcinomaSmall Cell Carcinoma

• CytogeneticsCytogenetics : :

- p53 mutation - p53 mutation

- RB1 mutation- RB1 mutation


HistologyHistology : :• Clusters of relatively small round/oval/spindle Clusters of relatively small round/oval/spindle

shaped neoplastic epithelial cells with scant shaped neoplastic epithelial cells with scant cytoplasm, illdefined cell borderscytoplasm, illdefined cell borders

• Salt and pepper chromatinSalt and pepper chromatin• Absent /inconspicuous nucleoli Absent /inconspicuous nucleoli • Prominent nuclear moldingProminent nuclear molding• High mitotic countHigh mitotic count• Azzopardi effectAzzopardi effect• NecrosisNecrosis


Immunohistochemistry :Immunohistochemistry :

• SynaptophysinSynaptophysin

• ChromograninChromogranin

• CD 57CD 57

• Parathyroid hormone- like productParathyroid hormone- like product

Electron MicroscopyElectron Microscopy : :

Dense core neurosecretory granulesDense core neurosecretory granules

LARGE CELL CARCINOMALARGE CELL CARCINOMA

• Large neoplastic cells Large neoplastic cells • Increased N/C ratioIncreased N/C ratio• Prominent NucleoliProminent Nucleoli• Represent poorly differentiated Squamous Cell Represent poorly differentiated Squamous Cell

Carcinoma and AdenocarcinomaCarcinoma and Adenocarcinoma• Histologic variantsHistologic variants : :

– Large cell neuroendocrine carcinoma; organoid Large cell neuroendocrine carcinoma; organoid nests, trabeculae, rosette-like and pallisading nests, trabeculae, rosette-like and pallisading patternspatterns

– Neuroendocrine features both on Neuroendocrine features both on Immunohistochemistry and Electron MicroscopyImmunohistochemistry and Electron Microscopy

Combined CarcinomaCombined Carcinoma

• Histology similar to two or more of Histology similar to two or more of usual lung carcinomasusual lung carcinomas

Complications of CA LungComplications of CA Lung

• EmphysemaEmphysema• AtelectasisAtelectasis• Severe suppurative /ulcerative bronchitisSevere suppurative /ulcerative bronchitis• Bronchiectasis Bronchiectasis • Lung AbscessLung Abscess• Superior vena cava syndromeSuperior vena cava syndrome• PericarditisPericarditis• PleuritisPleuritis

CLINICAL PRESENTATIONCLINICAL PRESENTATION

• Cough Cough

• Weight lossWeight loss

• Chest painChest pain

• DyspnoeaDyspnoea

INVESTIGATIONSINVESTIGATIONS

• Chest X-RayChest X-Ray

• Sputum for CytologySputum for Cytology

• Bronchial washings / brushings for Bronchial washings / brushings for CytologyCytology

• CT guided lung biopsy CT guided lung biopsy

• CT Scan / MRICT Scan / MRI

TREATMENTTREATMENT

Early stage diseaseEarly stage disease ( 15% ) ( 15% )– Lobectomy Lobectomy – PneumonectomyPneumonectomy

Last stage DiseaseLast stage Disease– ChemotherapyChemotherapy– RadiotherapyRadiotherapy– EGFR inhibitorsEGFR inhibitors

SURVIVAL RATESURVIVAL RATE

•Early stage : 48% Early stage : 48%

•Last stage : 10-15 %Last stage : 10-15 %

NEUROENDOCRINENEUROENDOCRINE NEOPLASMSNEOPLASMS

1 1 .Benign tumorlet.Benign tumorlet : : Small nests of hyperplastic Small nests of hyperplastic

neuroendocrine cells adjacent to neuroendocrine cells adjacent to scarring / chronic inflammation scarring / chronic inflammation

2 .2 .Carcinoids Carcinoids - Typical - Typical - Atypical- Atypical

3. 3. Small Cell CarcinomaSmall Cell Carcinoma 4. 4. Large Cell Neuroendocrine CarcinomaLarge Cell Neuroendocrine Carcinoma

Carcinoid tumour Carcinoid tumour

• 1-5 % 1-5 %

• < 40 years of age< 40 years of age

• 20-40 % nonsmokers20-40 % nonsmokers

• Behavior; low grade malignant epithelial Behavior; low grade malignant epithelial neoplasmneoplasm

• Subclassified into :Subclassified into :• Typical Typical

• AtypicalAtypical

• Central / peripheral originCentral / peripheral origin

Carcinoid TumorCarcinoid Tumor

Morphology Morphology ::

• Gross :Gross :– Finger- like or spherical polypoidal Finger- like or spherical polypoidal

massesmasses– Project into the lumen of mainstem Project into the lumen of mainstem

bronchibronchi– Covered by intact mucosaCovered by intact mucosa– Size ;usually < 3-4 cmSize ;usually < 3-4 cm

CarcinoidCarcinoid Tumor Tumor

HistologyHistology ::

• Patterns – Organoid, trabecular, pallisading, Patterns – Organoid, trabecular, pallisading, ribbon or rosette-like ribbon or rosette-like

• Delicate fibrovascular stromaDelicate fibrovascular stroma• Regular, uniform, round cells with moderate Regular, uniform, round cells with moderate

cytoplasmcytoplasm• Mitosis; < 2 /10 x HPF – Typical Carcinoid.Mitosis; < 2 /10 x HPF – Typical Carcinoid.

2-10 /10 x HPF – Atypical Carcinoid. 2-10 /10 x HPF – Atypical Carcinoid.

HistologyHistology

Atypical CarcinoidAtypical Carcinoid : :

• Increased pleomorphismIncreased pleomorphism

• NecrosisNecrosis

• Disorganised growth patternDisorganised growth pattern

• Lymphatic invasionLymphatic invasion

• Mitoses 2-10 /10 HPFMitoses 2-10 /10 HPF

MISCLENOUS TUMOURS MISCLENOUS TUMOURS

• Inflammatory Myofibroblastic TumorInflammatory Myofibroblastic Tumor• FibromaFibroma• FibrosarcomaFibrosarcoma• LymphangioleiomyomatosisLymphangioleiomyomatosis• LeiomyomaLeiomyoma• HaemangiomaHaemangioma• HaemangiopericytomaHaemangiopericytoma• ChordomaChordoma• Langerhan Cell HistiocytosisLangerhan Cell Histiocytosis• HamartomaHamartoma

Inflammatory Myofibroblastic Inflammatory Myofibroblastic TumorTumor

Langerhan Cell Langerhan Cell HistiocytosisHistiocytosis

Hamartoma LungHamartoma Lung

METASTASIS TO LUNGMETASTASIS TO LUNG

• More common than any of the other More common than any of the other lung malignancy lung malignancy

• From any carcinoma/sarcoma From any carcinoma/sarcoma

• TUMORS OF PLEURATUMORS OF PLEURA

PLEURAL TUMORSPLEURAL TUMORS

Solitary Fibrous TumorSolitary Fibrous Tumor

• Size – Variable; small 1-2 cm to very Size – Variable; small 1-2 cm to very large tumourlarge tumour

• Histology :Histology :

-Whorls of reticulin and collagen fibres with -Whorls of reticulin and collagen fibres with scattered fibroblast- like spindle cellsscattered fibroblast- like spindle cells

• CD 34 +CD 34 +

• Keratin – Keratin –

• D/D : MesotheliomaD/D : Mesothelioma

Pleural TumorsPleural Tumors Malignant MesotheliomaMalignant Mesothelioma : :

• Asbestos exposure ; 7-10 %Asbestos exposure ; 7-10 %

• Latent period ; 25-45 yearsLatent period ; 25-45 years

--HistologyHistology : :

• Asbestos bodies in the lungAsbestos bodies in the lung

• Asbestos plaqueAsbestos plaque

--CytogeneticsCytogenetics ::Del 1p, 3pCq ,9p or 22qDel 1p, 3pCq ,9p or 22q

p16 mutation p16 mutation

p53 mutationp53 mutation

Malignant MesotheliomaMalignant Mesothelioma

MorphologyMorphology : : GrossGross : :• Thick layer of soft,gelatinous greyish Thick layer of soft,gelatinous greyish pink tumour “ensheathing” the lungpink tumour “ensheathing” the lung

HistologyHistology : : . Epithelioid- 60 %; Cuboidal /Columnar . Epithelioid- 60 %; Cuboidal /Columnar

cells, cells, tubules or papillary tubules or papillary .Sarcomatoid- 20%; spindle cell growth .Sarcomatoid- 20%; spindle cell growth

resembling Fibrosarcomaresembling Fibrosarcoma .Mixed- 20%.Mixed- 20%


- - Clinical Presentation Clinical Presentation ::

• Chest pain Chest pain

• DyspnoeaDyspnoea

• Recurrent pleural effusionsRecurrent pleural effusions

• Hilar LymphadenopathyHilar Lymphadenopathy

• Distant mets ; liver etc.Distant mets ; liver etc.

- - PrognosisPrognosis : :

50% die within 12 months50% die within 12 months


Treatment Treatment ::

• Extrapleural pneumonectomy Extrapleural pneumonectomy

• Chemotherapy Chemotherapy

• RadiotherapyRadiotherapy

TUMORS OF LUNG AND PLEURA

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