LUNG CANCER Dr.

Villa January 20, 2014 Group 4 Lung Cancer: Incidence and Mortality - New cases in 2013: 228, 190 o 40% with stage IV disease at presentation (~90,000) - ~160,000 deaths in 2013, comparable to prostate, pancreas, breast and colon cancer combined - 5-yr relative survival rate: 15.7% overall; 3.7% for patients with distant-stage disease ETIOLOGY Smoking Genetic predisposition Occupational/environmental exposure

specifically the CYP1A1 1st degree relatives with lung cancer (2-3x risk) RB protein mutations (retinoblastoma conditions) Alterations in 5p15, 15q25, 6p21, and epidermal growth factor receptor (EGFR)

Occupational Exposure Arsenic Cobalt Chromium Cadmium Asbestos Long latency period, usually 30-35 years Most patients also smoke, so its difficult to pinpoint which one that actually caused the lung cancer Ionizing radiation Those who are treated for cancer, like lymphoma and breast cancer Exposed for 15 years before they develop lung cancer

Smoking 40 chemicals are potent carcinogen NNK binds to nicotinic acetyl cholinergic receptors on respiratory epithelium activates AKT signaling, k-ras, upregulates DNA methyltransferase activity in pneumocytes augment process of multiplication leading to tumor growth PAH (poly-aromatic hydrocarbon) forms DNA adducts induce mutations within tumor suppressor gene impair normal repair Nicotine activates AKT, raf-1 kinase phosphorylation of Rb Environmental Tobacco Smoke Contribute 25% of those with lung cancer, lesser than those who actively smoke Genetic Predisposition Chromosome 6q2-25 Lung cancer at an early age Families with multiple afflicted members Li-Fraumeni syndrome (p53 mutation) Other genetic predispositions: - Genetic polymorphisms in p450 enzymatic systems,

Molecular Pathogenesis : 6 Hallmark Capabilities of cancer cells 1. Self-sufficiency in growth signals 2. Insensitivity to antigrowth signals 3. Evading apoptosis 4. Limitless replicative potential 5. Sustained angiogenesis 6. Tissue invasion and metastasis PATHOLOGY Classification: Non-small cell lung cancer o Adenocarcinoma o Bronchoalveolar carcinoma o Large cell carcinoma o Squamous cell carcinoma o Adenosquamous carcinoma o Carcinoids Small cell lung cancer Lung Cancer: Histology

10-15% 25-30% 10-15%

Small-cell carcinoma Large-cell carcinoma Squamous cell carcinoma

Mucinous BAC on CT Scan

40%

Adenocarcinoma

Adenocarcinoma Periphery of the lung Histologically in smaller airways Atypical alveolar hyperplasia (AAH) type II pneumocytes- precursor lesion AAH Bronchoalveolar Ca (BAC) Only 1-5% who will develop lung cancer

Large Cell Carcinoma Large cells without cytoplasmic differentiation Poorly differentiated adenocarcinoma Prognosis is same with adenocarcinoma Tend to occur peripherally and are poorly differentiated Usually consists of large sheets of large malignant cells with associated necrosis 2 variants: Basaloid carcinoma may present as endobronchial lesion and resemble a high-grade neuroendocrine tumor Lymphoepithelial-like carcinoma related to the Epstein-Barr virus

Bronchoalveolar Carcinoma a subtype of adenocarcinoma that grows along the alveoli without invasion - Females - Non-smoker - Asian descent - With EGFR mutation - Pure BAC is relatively rare 2 types: Mucinous type - Malignant mucous containing goblet cells - Multifocal and fatal - Tends to be multicentric Non-mucinous type - Type II pneumocytes - Spreads in alveolar walls in monolayer - Tends to be solitary

Squamous Cell Carcinoma Periphery of the lung(accdg. to the lecture) Can be detected in cytologic examination at its earliest stage Bronchial exfoliation allows the detection of malignant cells in the sputum Slow growing Morphologically identical to extrapulmonary squamous cell carcinomas Occurs centrally (Harrisons 18th ed, p. 738) Classically associated with smoking Histology: infiltrating nest of tumor cells that lack intercellular bridges, usually associated with presence of keratin

Pulmonary manifestations Result of extrathoracic spread Paraneoplastic disorders Histology Extent of loco-regional invasion Tumors arising in large airways: o Cough o Wheezing o Hemoptysis o Atelectasis with/without pneumonia Involvement of pleural surface: o Pleuritic pain o Pleural effusion o Dyspnea Symptoms secondary to peripheral growth of primary tumor: o Pleural pain o Cough o Dyspnea on a restrictive basis o Lung abscess syndrome from tumor cavitation Regional spread of tumor: o Tracheal obstruction o Dysphagia o Hoarseness of voice o Phrenic nerve paralysis o Horners syndrome o SVC o Pericardial effusion Paraneoplastic syndrome: o Hypercalcemia o Cushings syndrome o SIADH o Eaton-Lambert syndrome o Pulmonary hypertrophic osteoarthropathy o Anemia o DIC

Small Cell Lung Cancer 95% due to tobacco smoking Incidence rate mirrors smoking pattern Characterized by rapid tumor growth Early metastatic spread Associated with paraneoplastic syndrome (signs and symptoms that the patient present that is not related to the tumor) o Hypertrophic osteoarthropathy o SIADH o Cushings Syndrome o Neurologic paraneoplastic syndrome Tend to occur centrally Histology: scant cytoplasm, salt and pepper chromatin pattern, and prominent nuclei Tumors may be arranged in patterns such as rosettes, trabeculae, or peripheral palisading of cells at the periphery of nests Tumors may produce specific peptide hormones (ACTH, vasopressin, atrial natriuretic factor, gastrin releasing peptide) that cause paraneoplastic syndrome Cells of neuroendocrine origin have been implicated as precursors

CLINICAL MANIFESTATIONS Constitutional Fatigue, anorexia and weight loss

Non Small Cell Lung Cancer

Large airways

Pleural surface

Small Cell Lung Cancer

Peripheral growth

Regional spread of tumor DIAGNOSIS History o Smoking history o Occupational/environmental exposure o Family history Physical exam o Supraclavicular/cervical lymphadenopathy o Organomegaly o Pain referable to visceral or skeletal metastasis Chest X-ray Fail to detect 80% of histologically proven CT lung cancer 2cm or more in diameter

CT scan of the chest Sensitivity of 60% Specificity of 80% Unreliable for detection of mediastinal lymph node metastasis SCLC

NSCLC

Thoracocentesis Bloody Diagnosis of cancer can be established in 70% of malignant effusion Fluid is sent for cell block and cytology Sputum cytology Rapid Inexpensive Sensitivity of 65% Enhanced in centrally located lesions, squamous cell carcinomas and large tumors

FDG-PET Superior to CT scan in detecting N1 disease Useful in detecting bone and visceral metastasis Cancer cells are known to take in sugar, so they light-up when seen Not all that light-up is cancer, just like inflammation, so you always have to confirm it with biopsy

MRI Not useful for diagnosis and staging Useful for evaluation of spine, great vessels or brachial plexus Brain MRI is superior to cranial CT in detecting occult intracranial metastasis

Percutaneous fine needle aspiration Excellent method >95% positive yield Uses fluoroscopic or CT guided techniques CT scan is used to localize the tumor and the interventional radiologist or surgeon pokes the tumor to get a specimen Now, it is very advisable to get core needle biopsy instead of fine needle in case of additional studies, but core needle has a complication of bleeding Fiberoptic bronchoscopy Visualize tracheobronchial tree Evaluate mediastinal lymph node Obtain cytologic or histologic specimens >90% yield in cytologic brushings Sometimes there is now outright tumor seen, and these patients are diagnosed via bronchial lavage Mediastinoscopy, Mediastinotomy & Endoscopic Ultrasound Fine Needle Aspiration

Most accurate method to assess paratracheal, peribronchial and subcarinal lymph nodes Important if surgery will be done Approach to Solitary Pulmonary Nodule

Summary: Lung Cancer Evaluation - Suspected disease evaluated using chest radiography consisting of CT, or PET imaging to evaluate a lesion - Diagnosis confirmed through pathologic evaluation of biopsy - Pathologic assessment after biopsy provides information on tumor histology and molecular abnormalities that may be useful in selecting therapy STAGING Lung cancer staging consists of 2 parts: 1. Determination of the location of the tumor and possible metastatic sites (anatomic staging) 2. Assessment of patients ability to withstand various

antitumor treatments (physiologic staging) Based on TNM Criteria: Tumor (T1-T4) size, site, local involvement Node location Metastases organs involved Tumor
Tx Primary tumor cannot be assessed Tumor proven by the presence of malignant cells in sputum or bronchial washing but no visualized by imaging or bronchoscopy No evidence of primary tumor Carcinoma in situ Tumor 3 cm or less surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion, more proximal than the lobar bronchus 2 cm or less in greatest dimension >2 cm but not > 3 cm in greatest dimension

T0 Tis T1

T1a T1b

T2

T2a T3

Tumors >3 cm but not > 7 cm or tumors with the ff features: Involves main bronchus; 2 cm or more distal to the carina Invades visceral pleura With atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung >3 cm but not >5 cm in greatest dimension >7 cm or one that involves: - chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium -Tumor in the main bronchus less than 2 cm distal to the carina but w/o involvement of the carina -associated atelectasis or obstructive pneumonitis of the entire lung -separate tumor nodules in the same lobe as the primary Tumor of any size that invades: - mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina Separate tumor nodules in a different ipsilateral lobe to that of the primary

Stage 2

Stage 3

Stage 4

Tumors 3-7cm in diameter With involvement of ipsilateral peribronchial and hilar lymph nodes Stage 3 Tumor >7cm in diameter With mediastinal and subcarinal LN involvement Tumor extension to neighboring structures Pulmonary nodule in same lobe Invasion of other organs distant to the primary tumor

Surgery Pre-op chemo Radiation

Surgery (rarely done) Radiation (concurrent chemoradio is commonly done) Chemotherapy

T4

Radiation therapy Combinations of chemotherapy and/or innovative therapies

Regional Lymph Nodes

Nx N0 N1 N2 Cannot be assessed No metastasis Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes Metastasis in ipsilateral mediastinal and/or subcarinal lymph node Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph node

N3

Distant Metastasis
M0 M1 M1a None Distant metastasis Separate tumor nodules in a contralateral lobe;Tumour with pleural nodules or malignant pleural effusion or pericardial effusion Distant metastasis

Small Cell Lung Cancer Staging Limited Disease - Lung - Hilar - Mediastinal lymph nodes - Cancer that is confined to the ipsilateral hemithorax - Contralateral lymph nodes, recurrent laryngeal nerve involvement, and superior vena caval obstruction can all be part of limited disease Extensive Disease - Other organs - Overt metastatic disease by imaging or physical examination - Cardiac tamponade, malignant pleural effusion, and bilateral pulmonary parenchymal involvement DISTANT METASTASIS Pattern of Metastasis Metastasis is a process where cancer cells spread from their initial location, known as the primary tumor, to form a tumor in another part of the body. If the cancer cells spread from the primary tumor to form one or more secondary tumors, they take the name of their primary source. The speed, aggressiveness and destination of the spreading vary greatly by cancer type. Metastasis directly impacts the patients life expectancy and strongly influences the cancers staging and treatment.

M1b

Non-Small Cell Lung Cancer: AJCC Staging Changes in staging: M1 is subdivided into o M1a malignant pleural or pericardial effusion, pleural nodules, nodules in contralateral lung o M1b distant metastasis
Stage Stage 1 Characteristics Tumor 2-3 cm or less No nodal involvement Treatment Surgery


Clinical Findings Suggestive of Metastatic Disease
Symptoms elicited in history Signs found on physical examination Constitutional: weight loss >10 lb Musculoskeletal: focal skeletal pain Neurologic: headaches, syncope, seizures, extremity weakness, recent change in mental status Lymphadenopathy (>1 cm) Hoarseness, superior vena cava syndrome Bone tenderness Hepatomegaly (>13 cm span) Focal neurologic signs, papilledema Soft-tissue mass Hematocrit: <40% in men, <35% in women Elevated alkaline phosphatase, GGT, SGOT, and calcium levels

Through lymphatics

Common Sites for SCLC Metastasis

Liver 5% 15% 10% 10% 15% 20% 25% Bone marrow Adrenal Glands Opposite Lung Brain Skin or lymph nodes Pancreas

Routine laboratory tests

Factors Affecting Metastasis How does cancer spread? Through the bloodstream TREATMENT

NSCLC: Prognostic Factors in Advanced Disease For patients with inoperable disease, prognosis is adversely affected by Poor performance score Weight loss of >10% Male sex Advanced age alone has not been shown to influence response or survival with therapy but may be associated with co-morbidities limiting therapeutic options Choice of treatment is limited in those with co-morbidities

Stage Stage 1 Stage 2

Characteristics Tumor 2-3 cm or less No nodal involvement Tumors 3-7cm in diameter With involvement of ipsilateral peribronchial and hilar lymph nodes Stage 3 Tumor >7cm in diameter With mediastinal and subcarinal LN involvement Tumor extension to neighboring structures Pulmonary nodule in

Treatment Surgery Surgery Pre-op chemo Radiation

Stage 3

Surgery (rarely done) Radiation (concurrent chemoradio is commonly done) Chemotherapy

same lobe

Stage 4

Invasion of other organs distant to the primary tumor

Radiation therapy Combinations of chemotherapy and/or innovative therapies

Prognosis Philippines: 1st population-based survival data, lung cancer showed the lowest survival rate regardless of the treatment received Median survival: 6 months o 5 year survival: 5% o 10 years survival: 2.60%

Management

Compiled by: Sameon, N Iwag, MD Gregore, A Sources: Lecture Notes and Audio Harrisons