Lung Cancer Hassan Ghobadi MD, Pulmonologist Assistant Professor of Internal Medicine Ardabil University of Medical Science

Introduction The incidence of lung cancer peaks between ages 55 and 65 years. Lung cancer accounts for 29% of all cancer deaths (31% in men, 26% in women). Lung cancer is responsible for more deaths in the United States each year than breast cancer, colon cancer, and prostate cancer combined.

Risk Factors 1- Smoking 2- Radiation Exposure 3- Environmental 4- Occupational Exposure Asbestos Radon Passive smoke Tobacco use is the leading cause of lung cancer 87% of lung cancers are related to smoking

Pathology Tumors arising from the resp. epithelium (bronchi, bronchioles, and alveoli). Four major cell types make up 88% of all primary lung neoplasms. 1- Squamous or epidermoid carcinoma, 2- Small cell carcinoma (also called oat cell), 3- Adenocarcinoma (bronchioloalveolar) 4- Large cell carcinoma.

Pathology (2) Major treatment decisions are made on the basis of whether a tumor is classified: Small cell lung carcinoma (SCLC) or Non-small cell lung cancer (NSCLC). SCLCs are initially very responsive to combination chemotherapy (>70% responses, with 30% complete responses) and to radiotherapy (>90% responses). NSCLCs have objective tumor shrinkage following radiotherapy in 30–50% of cases and response to combination chemotherapy in 20–35% of cases.

Pathology (3) SCLCs usually have already spread such that surgery is unlikely to be curative. NSCLCs that are clinically localized at the time of presentation may be cured with either surgery or radiotherapy. It is important to differentiate whether a tumor is SCLC or NSCLC for both prognostic and therapeutic reasons.

Etiology Most lung cancers are caused by carcinogens and tumor promoters inhaled via cigarette smoking. Prevalence of smoking in the USA is 28% for males and 25% for females (age 18 years or older) . The relative risk of developing lung cancer is increased about 13-fold by active smoking and about 1.5-fold by long-term passive exposure to cigarette smoke. Women have a higher relative risk per given exposure than men (~1.5-fold higher).

Etiology (2) About 15% of lung cancers occur in individuals who have never smoked. The majority of these are found in women. Preventing people from starting to smoke is thus very important . People exposed to high levels of radon or receiving thoracic radiation therapy have a higher than normal incidence of lung cancer, particularly if they smoke.

Molecular Pathogenesis Activation of dominant oncogenes: RAS family of oncogenes , mutations in the tyrosine kinase , myc family oncogenes ,overexpression of bcl-2 Inactivation of tumor-suppressor: p53 and retinoblastoma (RB) tumor-suppressor gene. People with inherited mutations in RB and p53 genes may develop lung cancer.

Clinical Manifestations Local tumor growth, Obstruction of adjacent structures, Regional nodes through lymphatic spread, Distant metastatic sites Remote effects of tumor products (paraneoplastic syndromes)

Symptoms Cough Dyspnea Hemoptysis Recurrent infections Chest pain

Syndromes/Symptoms 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

Clinical Manifestations Although 5–15% of patients with lung cancer are identified while they are asymptomatic. Endobronchial growth of the tumor may cause cough, hemoptysis, wheeze and striders, dyspnea, and post obstructive pneumonitis. Peripheral growth of the primary tumor may cause pain from pleural or chest wall involvement, dyspnea ,lung capitation. Regional spread of tumor in the thorax. Extrathoracic metastatic disease (SCC > Aden. > SCLC).

Imaging:

Screening 1- The role of screening high-risk patients (for example current or former smokers >50 years of age) for early stage lung cancers is debated. 2- Spiral CT has emerged as a possible new tool for lung cancer screening (without improving lung cancer mortality ). 3- Routine CT screening for lung cancer cannot be recommended for any risk group.

Diagnosis 1- Adenocarcinoma 1- Small cell A tissue diagnosis must be established. Two Lung Cancer Cells, Classified” Non Small Cell Lung Cancer (NSCLC) 1- Adenocarcinoma 2- Squamous Cell Carcinoma 3- Large Cell Carcinoma Small Cell Lung Cancer (SCLC) 1- Small cell 2- Oat Cell

Staging Anatomic staging: A determination of the location of tumor. Physiologic staging: An assessment of a patient's ability to withstand various anti tumor treatments. Resectability: In a patient with NSCLC, whether the tumor can be entirely removed. Operability:whether the patient can tolerate such a surgical procedure.

Non-Small Cell Lung Cancer The TNM International Staging System should be used for cases of NSCLC . T (tumor size), N (regional node involvement), M (presence or absence of distant metastasis)

Small Cell Lung Cancer Limited-stage disease As disease confined to one hemithorax and regional lymph nodes (including mediastinal, contralateral hilar, and usually ipsilateral supraclavicular nodes). Extensive-stage disease Is defined as disease exceeding those boundaries.

Staging Procedures (All Patients) Complete history and physical examination Complete blood count with platelet determination Measurement of serum electrolytes, glucose, and calcium; renal and liver function tests Electrocardiogram Skin test for tuberculosis Chest x-ray CT scan of chest and abdomen CT or MRI scan of brain and radionuclide scan of bone if any finding suggests the presence of tumor metastasis in these organs Fiberoptic bronchoscopy with washings, brushings, and biopsy of suspicious lesions unless medically contraindicated or if it would not alter therapy X-rays of suspicious bony lesions detected by scan or symptom Barium swallow radiographic examination if esophageal symptoms exist Pulmonary function studies and arterial blood gas measurements if signs or symptoms of respiratory insufficiency are present

Staging Procedures (NSCLC) All the above procedures, plus the following: PET scan to evaluate mediastinum and detect metastatic disease Pulmonary function tests and arterial blood gas measurements Coagulation tests CT or MRI scan of brain if symptoms suggestive Cardiopulmonary exercise testing if performance status or pulmonary function tests are borderline If surgical resection is planned: surgical evaluation of the mediastinum at mediastinoscopy or at thoracotomy If the patient is a poor surgical risk or a candidate for curative radiotherapy: transthoracic fine-needle aspiration biopsy or transbronchial forceps biopsy of peripheral lesions if material from routine fiberoptic bronchoscopy is negative

Staging Procedures (Small Cell Ca.) All the procedures under "All Patients” plus the following: CT or MRI scan of brain Bone marrow aspiration and biopsy (if peripheral blood counts abnormal)

Resectability and Operability Major contraindications to curative surgery or radiotherapy alone: Eextrathoracic metastases; Superior vena cava syndrome; Vocal cord and phrenic nerve paralysis; Malignant pleural effusion; Cardiac tamponade; Tumor within 2 cm of the carina Metastasis to the contralateral lung; Bilateral endobronchial tumor Metastasis to the supraclavicular lymph nodes; Contralateral mediastinal node metastases Involvement of the main pulmonary artery.

Physiologic Staging Uncontrolled major arrhythmias, FEV1 <1 L, Myocardial infarction within the past 3 months is a contraindication to thoracic surgery. An infarction in the past 6 months is a relative contraindication. Other major contraindications include: Uncontrolled major arrhythmias, FEV1 <1 L, CO2 retention (resting PCO2 >45 mmHg), DLCO <40%, Severe pulmonary hypertension.

Treatment (NSCLC) Stages IA, IB, IIA, IIB, and some IIIA: Surgical resection for stages IA, IB, IIA, and IIB Surgical resection with complete-mediastinal lymph node dissection and consideration of neoadjuvant CRx for stage IIIA disease with "minimal N2 involvement" Consider postoperative RT for patients found to have N2 disease Stage IB: adjuvant CRx; not routinely given Stage II: Adjuvant CRx Curative potential RT for "nonoperable" patients

Treatment (NSCLC) [2] Stage IIIA with selected types Tumors with chest wall invasion (T3): en bloc resection of tumor with involved chest wall and consideration of postoperative RT . Superior sulcus (Pancoast's) (T3) tumors: preoperative RT (30–45 Gy) and CRx followed by en bloc resection of involved lung and chest wall with postoperative RT . Stages IIIA "advanced, clinically evident N2 disease“ & Stage IIIB disease Concurrent RT + CRx Stage IV and more advanced IIIB disease: Consider CRx

Superior Sulcus or Pancoast Tumors Patients should have the usual preoperative staging procedures, including mediastinoscopy and CT and PET scans. If mediastinoscopy is negative, curative approaches may be used in treating Pancoast's syndrome. The best results reported with concurrent preoperative irradiation + en bloc resection. The 2-year survival rate was 55% to 70% .

Treatment (SCLC) Limited stage (good performance status): combination CRx + concurrent chest RT Extensive stage (good performance status): combination CRx Complete tumor responders (all stages): Consider prophylactic cranial RT Poor-performance-status patients (all stages): Modified-dose combination CRx Palliative RT

Solitary Pulmonary Nodule

Definition: SPN, defined as an x-ray density completely surrounded by normal aerated lung, with circumscribed margins, of any shape, usually 1–6 cm in greatest diameter. Approximately 35% of all such lesions in adults are malignant, most being primary lung cancer, Less Than 1% are malignant in nonsmokers <35 years of age.

SPN (Approach to patient’s) Complete history, including a SMK, Physical examination, Routine laboratory tests, Chest CT scan, and old chest x-rays or CT scans are obtained if available. Fiberoptic bronchoscopy, PET scans

SPN (Risk Factors) History of cigarette smoking; Age > 35 years; Relatively large lesion; Lack of calcification; Chest symptoms; Associated atelectasis, pneumonitis,or adenopathy; Growth of the lesion revealed by comparison with old x-rays/CT scans; Positive PET scan

SPN (Management) Nonsmoking patients <35 years (Low Risk) Followed with serial CT every 3 months for 1 year and then yearly patients >35 years and all patients with a smoking history (High Risk), Histologic diagnosis must be made, regardless of whether the lesion is PET positive or negative.

Causes of solitary pulmonary nodules Malignant 1- Bronchogenic carcinoma Adenocarcinoma  Squamous cell carcinoma Large cell carcinoma Small cell carcinoma 2- Metastatic lesions Breast Head and neck Melanoma Colon Kidney Sarcoma Germ cell tumor 3- Pulmonary carcinoid Benign 1- Infectious granuloma    Histoplasmosis Tuberculosis Atypical mycobacteria 2- Other infections Bacterial abscess Echinococcus cyst 3- Benign neoplasms Hamartoma Lipoma Fibroma 4- Vascular Arteriovenous malformation 5- Developmental Bronchogenic cyst

SPN algorithm

Benign Lung Neoplasm's

Benign Lung Neoplasm's Representing <5% of all primary tumors include : Bronchial adenomas Bronchial hamartomas (90% of such lesions) Uncommon benign neoplasms (bronchial papillomas, fibroepithelial polyps; chondromas, fibromas, lipomas, hemangiomas, leiomyomas, pseudolymphomas. They can present as central masses causing airway obstruction, cough, hemoptysis, and pneumonitis. They are usually accessible to fiberoptic bronchoscopy. They can present without symptoms as SPNs and are evaluated accordingly.

Bronchial Adenomas Bronchial adenomas (80% are central) are slow-growing endobronchial lesions. Adenomas present in patients 15–60 years old (average age 45) as endobronchial lesions. Patients may have a chronic cough, recurrent hemoptysis, or obstruction with atelectasis, lobar collapse, or pneumonitis and abscess formation. Because they are hypervascular, they can bleed profusely after bronchoscopic biopsy. Surgical excision is the primary treatment of bronchial adenomas. Five-year survival rate after surgical resection is 95%, decreasing to 70% if regional nodes are involved.

Carcinoid Tumors Including: 1- Typical carcinoid, 2- Atypical carcinoid These tumors are characterized by histologic features. Carcinoids are low- and intermediate-grade tumors. Carcinoids, like SCLCs, may secrete other hormones, such as ACTH or AVP, and can cause paraneoplastic syndromes.

Hamartomas Pulmonary hamartomas have a peak incidence at age 60 . Pulmonary hamartomas are more frequent in men than in women. Histologically, they contain normal pulmonary tissue components (smooth muscle and collagen) in a disorganized fashion. They are usually peripheral, clinically silent, and benign in their behavior. Radiographic findings are pathognomonic for hamartoma, with "popcorn" calcification. VATS may minimize the surgical complications.

SPN-Hamartoma

Pulmonary Hamartoma

Metastatic Pulmonary Tumors The lung is a frequent site of metastases from primary cancers outside the lung. The development of an SPN or a mass on chest x-ray in a patient known to have an extrathoracic neoplasm. This nodule may represent a metastasis or a new primary lung cancer. In some cases multiple metastatic pulmonary nodules can be resected with curative intent. (1) the patient can tolerate the contemplated pulmonary resection, (2) the primary tumor has been definitively and successfully treated (disease-free for >1 year), and (3) all known metastatic disease can be encompassed by the projected pulmonary resection.

Conclusion Smoking cessation is essential for prevention of lung cancer. New screening tools under way. Clinical trials under way. New treatments under way. Treatment can palliate symptoms and improve quality of life.