Lung Neoplasia

Arunabh Talwar , MD , FCCP

Pulmonary Critical Care Medicine

What Are the Risk FactorsWhat Are the Risk Factors for Lung Cancer? for Lung Cancer?

• Tobacco Most people who develop lung cancer today have Tobacco Most people who develop lung cancer today have either stopped smoking years earlier or have never smokedeither stopped smoking years earlier or have never smoked

• Second-hand smokeSecond-hand smoke • AsbestosAsbestos • Radon Radon • HIVHIV• Genetic Factors –family h/o lung ca Genetic Factors –family h/o lung ca • Male to female ratio 1.5 :1Male to female ratio 1.5 :1

Histological origins of lung cancer cells - summary chart

Frequency of Cell Types

Cell type % frequency ChangeSquamous cell 30

Adenocarcinoma 35

Small cell 25

Large cell 10

all others 5

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ADENOCARCINOMA• 33%

• - usually peripheral

• - Originates from glandular epithelial cells in airway mucus glands

• - often metastases before primary lesion is symptomatic

- Bronchoalveolar ca - subtype of adenoca - grows along tracheobronchial tree and alveolar walls

Adenocarcinoma (AdCa)• Surpassed Squamous cell cancer as most common lung

cancer.• Adenocarcinoma overall fraction of lung cancers is

increasing• Most in smokers , But in women non smokers• Women – 42% , Men – 28%• ~20% present with distant metastases• Local recurrence not as common as SCC• Often arises often arises out of chronic inflammatory or lung

damage conditions ----chronic granulomatous lesions , scar tissue from prior infections (e.g. TB)

Adenocarcinoma

Thyroid Transcription Factor -1 [TTF-1] is the most important marker for this disease

Bronchiolalveolar carcinoma (BAC)

• Bronchioloalveolar cell carcinoma (BAC) - sub-group of adenocarcinomas of the lung, accounting for 2-9% of primary lung lesions

• 6th and 7th decades, with a 3:2 male predominance

•  The link of smoking as a predisposing factor is perhaps the weakest among primary lung neoplasms

three radiologic patterns: a solitary nodule (43%); consolidation (30%), or diffuse disease (27%)

Adeno Ca – molecular genetics• Epidermal growth Factor Receptor [ EGFR ] gene

mutations [Mutations in EGFR are more commonly but not exclusively found in patients who are female, younger and with no history of smoking ]

• Patients with this mutation are candidates for targeted molecular therapy with a drug that inhibits EGFR [erlotinib (tarceva) ] or [ afatinib (Gilotrif) ] or with monoclonal antibodies against EGFR{ ceftuximab (Erbitux)]

• K-RAS - ~30% -K-RAS mutations contraindicate therapy with EGFR tyrosine kinase inhibitors

AMANN J , KALYANKRISHNA S, MASSION PPCANCER RESEARCH 2005 Jan 1;65(1):226-35

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SQUAMOUS CELL CANCER

• 30-35%

• - usually central

• - develops in the epithelium of the proximal bronchi and are segmental in size or larger

• - /+/ sputum cytology with normal C xray - central necrosis & cavity formation

• - local invasion

• - mets to local LN & distant sites

Squamous cell carcinoma

• >90% smokers

• commonly occurs in large airway bronchial mucosa– ‘bronchogenic carcinoma’ -- tends to be located at

bifurcation of large airways• Central and peripheral in increase• 44% in males . 25% in females• Macroscopy – large, grey, firm, cavitary, post

obstructive pneumonia• Tumor spread - locally aggressive - less locoregional metastases - common locoregional recurrence

Squamous Cell

Squamous cell lung cancer - macro and micro views

In this squamous cell carcinoma at the upper left is a squamous eddy with a keratin pearl. At the right, the tumor is less differentiated and several dark mitotic figures are seen.

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SMALL CELL CA

• 25%

• - infiltrates major bronchi wall narrowing the lumen

• - early mets

• - usually distant spread at the time of diagnosis

Small cell lung carcinoma - SCLC• predominantly occurs in males

– typically in men with smoking history– often co-exposure to occupational hazards

• asbestos workers• uranium miners (radon)

• SCLC originates from Kulchitzky cells (K-cells) in airway mucosa– K-cells are rare neuroendocrine cells found in bronchial glands – neurosecretory -- produce and release regulatory peptides & neurotransmitters

• SCLC is a non-epithelial lung cancer -- specialized biological properties– ectopic production of peptide hormones

• ACTH (adrenocorticotropic hormone) and ADH (antidiuretic hormone)– APUD - amine precursor uptake and decarboxylation (neurotransmitter synthesis)

• extremely aggressive cancer -- virtually untreatable– small sized cancer cells that resemble oat flakes (‘oat cell’ carcinoma)

Small Cell Carcinoma

SmallCell Carcinoma

Small Cell Carcinoma

Note pleomorphic small cells with dense chromatinand neuropeptide secretory bodies (yellow arrow)

EMMed. power

What Are the Symptoms of Lung What Are the Symptoms of Lung Cancer?Cancer?

• Fatigue (tiredness)Fatigue (tiredness) • CoughCough • Shortness of breathShortness of breath • Chest pain Chest pain • Loss of appetite Loss of appetite • Coughing up phlegm Coughing up phlegm • Hemoptysis (coughing up blood)Hemoptysis (coughing up blood)• If cancer has spread, symptoms include bone pain, difficulty If cancer has spread, symptoms include bone pain, difficulty

breathing, abdominal pain, headache, weakness, and confusionbreathing, abdominal pain, headache, weakness, and confusion

Lung Cancer: Clinical Presentation

Local Symptoms– cough– dyspnea– hemoptysis– recurrent infections– chest pain

Lung Cancer: Clinical Presentation

Syndromes/Symptoms secondary to regional metastases:– Esophageal compression dysphagia– Laryngeal nerve paralysis hoarseness– Symptomatic nerve paralysis Horner’s syndrome– Cervical/thoracic nerve invasion Pancoast syndrome– Lymphatic obstruction pleural effusion– Vascular obstruction SVC syndrome– Pericardial/cardiac extension effusion, tamponade

Lung Cancer: Clinical Presentation

• Symptoms secondary to distant metastases– pain– organ-related

• General Symptoms– weight loss– fatigue

Lung Cancer: Metastatic Sites

• Lymph nodes

• Brain

• Bones

• Liver

• Lung/pleura

• Adrenal gland

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Paraneoplastic syndromes

• Endocrine - Cushing syndrome - SCLC - SIADH - SCLC - carcinoid syndrome - SCLC - Hypercalcemia - Sqamous / PTH like substance/ - Gynecomastia - Large cell / gonadotropin production/

• Neuromuscular - neuro-myopathy - Eaton-Lambert

Syndrome -SCLC -- proximal muscle weakness, depressed tendon reflexes, posttetanic potentiation, and autonomic changes

Lung Cancer Diagnosis and Therapy

DiagnosisDiagnosis

sputumsputumcytologycytology

bronch-bronch-oscopyoscopy

transthoracicneedle biopsy

openbiospy

leastleastinvasiveinvasive

mostmostinvasiveinvasive

lesslessdefinitivedefinitive

moremoredefinitivedefinitive

Diagnosis in Periphery

Lung Cancer: Diagnosis

• History and Physical exam• Diagnostic tests

– Chest x-ray– Biopsy (bronchoscopy, needle biopsy, surgery)

• Staging tests– CT chest/abdomen– Bone scan– Bone marrow aspiration– PET scan

PET Tracer: FDG

Glucose

FDG

Glucose

FDG

Glucose-6-P

FDG-6-P

Plasma Cell

18F-fluorodeoxyglucose (FDG) is taken up by cells proportionate to their metabolic rates

Normal PET/CT scan

QuickTime™ and a decompressor

are needed to see this picture.

PET

CT

PET/CT

Abnormal PET - CT Body Scan

Problems and Pitfalls

• False positive findings

Normal physiology

Granulomas and other infections

Adenomas

Tumor histology

Lesions smaller than 8 mm

Diabetes/Non-fasting patients

• False negative findings

Radiology for Diagnosis of Lung cancer

1. CT is the first imaging test of choice in most cases

2. PET - CT is more accurate than CT alone

• Characterizing lesions difficult to biopsy

• Detecting occult cancer

• Determining extent of cancer and response to therapy

3. PET - CT changes management 36%

Stage I Non-Small Cell Lung Stage I Non-Small Cell Lung CancerCancer

• Cancer is found only in the Cancer is found only in the lung lung

• Surgical removal Surgical removal recommendedrecommended

• Radiation therapy and/or Radiation therapy and/or chemotherapy may also be usedchemotherapy may also be used

Stage II Non-Small Cell Lung Stage II Non-Small Cell Lung CancerCancer

• The cancer has spread to The cancer has spread to lymph nodes in the lung lymph nodes in the lung

• Treatment is surgery to Treatment is surgery to remove the tumor and remove the tumor and nearby lymph nodesnearby lymph nodes

• Chemotherapy Chemotherapy recommended; recommended; rradiation adiation therapy sometimes given therapy sometimes given after chemotherapyafter chemotherapy

Stage III Non-Small Cell Lung Stage III Non-Small Cell Lung CancerCancer

• The cancer has spread to the lymph nodes The cancer has spread to the lymph nodes located in the center of the chest, outside the located in the center of the chest, outside the lunglung

• Stage IIIA cancer has spread to lymph nodes Stage IIIA cancer has spread to lymph nodes in the chest, on the same side where the cancer in the chest, on the same side where the cancer originatedoriginated

• Stage IIIB cancer has spread to lymph nodes Stage IIIB cancer has spread to lymph nodes on the opposite side of the chest, under the on the opposite side of the chest, under the collarbone, or the pleura (lining of the chest collarbone, or the pleura (lining of the chest cavity) cavity)

• Surgery or radiation therapy with Surgery or radiation therapy with chemotherapy recommended for stage IIIAchemotherapy recommended for stage IIIA

• Chemotherapy and sometimes radiation Chemotherapy and sometimes radiation therapy recommended for stage IIIB therapy recommended for stage IIIB

Stage IV Non-Small Cell Lung Stage IV Non-Small Cell Lung CancerCancer

• The cancer has spread to The cancer has spread to different lobes of the lung or to different lobes of the lung or to other organs, such as the brain, other organs, such as the brain, bones, and liverbones, and liver

• Stage IV non-small cell lung Stage IV non-small cell lung cancer is treated with cancer is treated with chemotherapychemotherapy

Small Cell Lung Cancer–All StagesSmall Cell Lung Cancer–All Stages

• Small cell cancer s –Small cell cancer s –divided into limited and Extensive stagedivided into limited and Extensive stage

• Patients with Patients with limited stage limited stage (confined to one area of the chest) small cell (confined to one area of the chest) small cell lung cancer are treated with simultaneous radiation therapy and lung cancer are treated with simultaneous radiation therapy and chemotherapy chemotherapy

• Patients with Patients with extensive stage extensive stage (not confined to one area of the chest) small (not confined to one area of the chest) small cell lung cancer are treated with chemotherapy onlycell lung cancer are treated with chemotherapy only

• Because small cell lung cancer can spread to the brain, preventative Because small cell lung cancer can spread to the brain, preventative radiation therapy to the brain is routinely recommended to all patients radiation therapy to the brain is routinely recommended to all patients whose tumors disappear following chemotherapy and radiation therapy whose tumors disappear following chemotherapy and radiation therapy

Lung Cancer Staging

• Refer to handout for TNM description

• T= Tumor

• N= Nodes

• M= Metastases

TNM descriptionPrimary Tumor (T)TX Primary tumor cannot be assessed; tumor proven by bronchial sputum cytology but not seen on imaging or bronch.

TO No evidence of primary tumorTis Carcinoma in situT1 Tumor >3 cm in greatest dimension, surrounded by lung or

visceral pleura; not involving main bronchusT2 Tumor with any of the following features of size or extent

(a) > 3 cm in greatest dimension; (b) involves main bronchus, > 2 cm distal to the carina; (c) invades the visceral pleura; (d) Associated with atelectasis or obstructive pneumonitis that

extends to the hilar region but not involving entire lungT3 Tumor of any size that directly invades any of the following: chest wall (incl. superior sulcus tumors),

diaphragm, mediastinal pleura, parietal pericardium or tumor in main bronchus < 2 cm distal to the carina but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung

T4 Tumor of any size that invades any of the following : mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina; or tumor with a malignant pleural or pericardial effusion; or with satellite tumor nodules within the ipsilateral primary-tumor lobe of the lungRegional Lymph Nodes (N)

NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis to ipsilateral peribronchial and/or ipsilateral hilar nodes and intrapulmonary nodes involved by direct

extension of the primary tumorN2 Metastasis to ipsilateral mediastinal and/or subcarinal lymph nodesN3 Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular

Distant Metastasis (M)MX Presence of distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasis present

Classification• IA - T1N0M0 • IB - T2N0M0 • IIA - T1N1M0 • IIB - T2N1M0 or T3N0M0 • IIIA - T1-3N2M0 or

T3N1M0 • IIIB - Any T4 or any

N3M0 • IV - Any M1

Lung Cancer Staging

STAGE• Stage 0• Stage 1A• Stage 1B• Stage 2A• Stage 2B• Stage 3A• Stage 3B• Stage 4

TNM Subsets• CIS• T1N1MO• T2N0M0• T1N1M0• T2N1M0, T3N0M0• T3N1M0• T4NanyM0,TanyN3M0• TanyNanyM1

How is Lung Cancer Treated?How is Lung Cancer Treated?

• Treatment depends on the stage and type of lung cancer Treatment depends on the stage and type of lung cancer

• SurgerySurgery

• Radiation therapyRadiation therapy

• Chemotherapy (options include a combination of drugs)Chemotherapy (options include a combination of drugs)

• Targeted therapyTargeted therapy

• Lung cancer is usually treated with a combination of therapies Lung cancer is usually treated with a combination of therapies

Cancer Treatment: Surgery Cancer Treatment: Surgery • The tumor and the nearby lymph nodes in the The tumor and the nearby lymph nodes in the

chest are typically removed to offer the best chest are typically removed to offer the best chance for curechance for cure

• For non-small cell lung cancer, a lobectomy For non-small cell lung cancer, a lobectomy (removal of the entire lobe where the tumor is (removal of the entire lobe where the tumor is located), has shown to be most effectivelocated), has shown to be most effective

• Surgery may not be possible in some patientsSurgery may not be possible in some patients

Cancer Treatment: ChemotherapyCancer Treatment: Chemotherapy • Drugs used to kill cancer cellsDrugs used to kill cancer cells

• A combination of medications is often used A combination of medications is often used

• May be prescribed before or after surgery, or before, May be prescribed before or after surgery, or before, during, or after radiation therapyduring, or after radiation therapy

• Can improve survival and lessen lung cancer symptoms Can improve survival and lessen lung cancer symptoms in all patients, even those with widespread lung cancerin all patients, even those with widespread lung cancer

Cancer Treatment: Radiation Cancer Treatment: Radiation TherapyTherapy

• The use of high-energy x-rays or other particles to destroy The use of high-energy x-rays or other particles to destroy cancer cellscancer cells

• Side effects include fatigue, malaise (feeling unwell), loss of Side effects include fatigue, malaise (feeling unwell), loss of appetite, and skin irritation at the treatment site appetite, and skin irritation at the treatment site

• Radiation pneumonitis is the irritation and inflammation of Radiation pneumonitis is the irritation and inflammation of the lung; occurs in 15% of patients the lung; occurs in 15% of patients

• It is important that the radiation treatments avoid the healthy It is important that the radiation treatments avoid the healthy parts of the lungparts of the lung

NSCLC: Treatment by Stage

Stage Description Treatment Options

Stage I a/bTumor of any size is found only in the lung

Surgery

Stage II a/bTumor has spread to lymph nodes associated with the lung

Surgery

Stage III a

Tumor has spread to the lymph nodes in the tracheal area, including chest wall and diaphragm

Chemotherapy followed by radiation or surgery

Stage III bTumor has spread to the lymph nodes on the opposite lung or in the neck

Combination of chemotherapy and radiation

Stage IVTumor has spread beyond the chest

Chemotherapy and/or palliative (maintenance) care

Surgery

• Associated with highest cure rates

• Appropriate for stages I and II and ? IIIa

• Stage I patients benefit the most but only 25% of incident cases are stage I!!

Possible Operations

• Lobectomy

• Pneumonectomy

• Segmentectomy

• Lesser resections– wedge– local excision

R L

Majorfissure

Majorfissure

Minorfissure

LUNG ANATOMY

Preoperative Evaluation

• Complete history and physical

• Pulmonary Function Tests

• Measure of gas exchange (oximetry, ABG)

• Appropriate imaging studies– CT scan, PET scan

• Additional work-up as needed

Medical Therapy

• Chemotherapy and/or radiation• 70% of NSCLC patients receive this form of

treatment• Prognosis much worse for non-resectable patients• Therapy can be primary, adjuvant (post surgery),

neoadjuvant (before surgery) or palliative (to relieve symptoms only)

NSCLC: Treatment

• Surgery– Mediastinoscopy– Video-assisted Thoracoscopy (VAT)– Thoracotomy: Lobectomy. Pneumonectomy

• Radiation– External Beam – Brachytherapy

NSCLC: Treatment

• Chemotherapy

– Standard• Cisplatin, Carboplatin• Newer agents: Gemcitabine, Paclitaxel,

Docetaxel, Vinorelbine, Irinotecan used alone and in combination

NSCLC: Treatment Outcomes

Stage

I

II

IIIa

IIIb

IV

5-Year Survival

60-80%

40-50%

25-30%

5-10%

<1%

Treatment Selection in Advanced NSCLC

– Rational– Emphasis on “targeted therapy”– Molecular targets– Histology guides therapeutic options

Small cell lung ca: Cell Types

• Oat Cell

• Intermediate

• Combined

SCLC: Treatment

• Limited Disease– Chemotherapy– Concomitant Radiation– Prophylactic Cranial Irradiation

• Extensive Disease– Chemotherapy– Palliative radiation

SCLC: Treatment

• Chemotherapy:– Most commonly used initial regimen:

Cisplatin or Carboplatin plus Etoposide x 4-6 cycles

– Newer agents under evaluation: Topotecan, Paclitaxel, Docetaxel, Irinotecan, Gemcitabine

SCLC: Treatment Outcomes

• Limited Disease– median survival 18 - 20 months – 5-year survival 10%

• Extensive Disease– median survival 10 - 12 months – 5-year survival 1 - 2%

PETER J. DIPASCO, MDDiagnosis & Surgical Management

of Carcinoid Tumors

IntroductionDefinition – “Carcinoid”

Applied to well-differentiated neuroendocrine tumors originating in the digestive tract, lungs, or rare sites such as kidneys or ovaries

Is not used to describe high grade / poorly differentiated neuroendocrine tumors

EpidemiologyPeak incidence within the

sixth to seventh decade>50% are found within the

GI tract, with the appendix as a very common site of origin50% are found within 2ft of

the ileocecal valve>30% are multifocal

Incidence is increasingCarcinoid is more common

than SB adenoC

PathologyCarcinoids are characterized by the

ability to produce peptides and other biologically active substancesSerotoninAminesTachykininsProstaglandins

Arise from enterochromaffin cells (GI tract, bronchi)

Usually tan, yellow, or gray-brown intramural or submucosal lesions

Multifocality comprises 30% of cases

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Clinical Findings - Lungs

Clinical Findings - abdomen Carcinoid could be referred to as a

“malignant neoplasm in slow motion”At the time of diagnosis…

40% have invaded the muscularis45% have metastasized to the liver

Tumors < 1cm rarely metastasize (2%)

Tumors > 2cm frequently metastasize (80%)

Massive metastatic lesions are also encountered from minute primaries

Clinical Findings• Small tumors are often asymptomatic• 30% cause symptoms of obstruction, pain, bleeding, or the

carcinoid syndrome• Carcinoid syndrome

– Cutaneous flushing– Diarrhea– Bronchoconstriction– Right sided heart valvular dysfunction (collagen deposition)

• Carcinoid Crisis– Usually precipitated by anesthesia, surgery or chemotherapy

• Usually refractory to fluid resuscitation or vasopressors• Octreotide should be given to all pts with metastatic or bulky disease

prior to the above events

Clinical Presentation• Varies depending on location and production of

biologically active substances

ForegutForegutMidgutMidgut

HindgutHindgut

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DiagnosisDiagnosis

• Bronchial Biopsy is diagnostic in 85% of cases.

• Biochemical identification - quantifying the excretion of 5-HIAA in a 24-hour urine sample. Normal values - 2 to 8 mg per 24-hour period.

• Bronchial Biopsy is diagnostic in 85% of cases.

• Biochemical identification - quantifying the excretion of 5-HIAA in a 24-hour urine sample. Normal values - 2 to 8 mg per 24-hour period.

TreatmentTreatment• Goals of therapy : Complete removal of tumor Relief of airway obstructionPreservation of as much normal lung as possible• Pulmonary resection is the treatment of choice for bronchial

carcinoids. • In properly selected patients, mainstem bronchial sleeve

resection with lung preservation can be performed safely and provides excellent relief of symptoms with good long-term survival.Cerfolio RJ, Deschamps C, Allen MS, Trastek VF, Pairolero PC. Ann Thorac Surg; 61(5):1458-62 1996

• Goals of therapy : Complete removal of tumor Relief of airway obstructionPreservation of as much normal lung as possible• Pulmonary resection is the treatment of choice for bronchial

carcinoids. • In properly selected patients, mainstem bronchial sleeve

resection with lung preservation can be performed safely and provides excellent relief of symptoms with good long-term survival.Cerfolio RJ, Deschamps C, Allen MS, Trastek VF, Pairolero PC. Ann Thorac Surg; 61(5):1458-62 1996