Lung Cancer Classification, Staging and Diagnosis By: Laurie E. Stallings, PharmD, BCNP Coordinating Editor and Director of Pharmacy Continuing Education William B. Hladik III, MS, RPh College of Pharmacy University of New Mexico Health Sciences Center Managing Editor Julliana Newman, ELS Wellman Publishing, Inc. Albuquerque, New Mexico Editorial Board George H. Hinkle, MS, RPh, BCNP William B. Hladik III, MS, RPh Jeffrey P. Norenberg, MS, RPh, BCNP Laura L. Boles Ponto, PhD, RPh Timothy M. Quinton, PharmD, MS, RPh, BCNP Guest Reviewer David G. Landsnes, MD Department of Radiology Wilson Memorial Hospital Johnson City, New York While the advice and information in this publication are believed to be true and accurate at press time, the author(s), editors, or the publisher cannot accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Copyright 2001 University of New Mexico Health Sciences Center Pharmacy Continuing Education Albuquerque, New Mexico LUNG CANCER CLASSIFICATION, STAGING AND DIAGNOSIS STATEMENT OF OBJECTIVES Upon completion of this material, the reader should be able to: 1. Discuss the histologic and clinical classification of bronchial carcinoma and how each type differs in its clinical features, metastatic spread, and response to therapy. 2. Outline the clinical presentation of lung cancer, with respect to local tumor effects, extrapulmonary signs and symptoms associated with metastatic involvement, and paraneoplastic syndromes. 3. Describe TNM staging and give patient/disease-related variables that affect therapeutic management options and prognosis. 4. Describe the mechanisms of action of each radiopharmaceutical used in the imaging of neoplastic lung disease. 5. List the advantages and disadvantages of using 18FDG PET vs. 99mTC-depreotide SPECT. 6. List the clinical indications for 18FDG PET 7. Discuss the clinical utility of these functional imaging agents and how they fit in the diagnostic algorithm of lung cancer. I. INTRODUCTION V. DIAGNOSIS OF LUNG CANCER A. Epidemiology A. Screening and B. Etiology and Pathophysiology II. HISTOLOGIC CLASSIFICATION Patient Evaluation A. Major Cell Types B. Problematic Diagnosis of 1. Squamous Cell Carcinoma Single Pulmonary Nodule 2. Adenocarcinoma 3. Large Cell Carcinoma C. 18FDG Pet 4. Small Cell Carcinoma 1. Mechanism of Action B. Clinical Distinction of 2. Imaging with 18FDG PET SCLC vs. NSCLC C. Metastatic Tumors of the Lung 3. Image Interpretation III. CLINICAL PRESENTATION 4. PET Indications A. Primary Tumor and Mediastinal Spread D. Radionuclide Imaging B. Extrapulmonary Metastatic Spread 1. 67Ga Citrate C. Paraneoplastic Syndromes 2. 201Tl Chloride IV. STAGING OF LUNG CANCER A. NSCLC 3. 99mTc-sestamibi and 1. TNM Staging 99mTc-tetrofosmin 2. Prognosis 4. 99mTc-depreotide 3. Treatment Options Based on Staging B. SCLC VI. CONCLUSION 1 EPIDEMIOLOGY chronic inflammation leads to genetic and Lung cancer is the leading cause of cytologic mutations, with the activation of cancer mortality in both men and women in cellular oncogenes and stimulation of cellular the United Sates, accounting for 28% of all proliferation by growth factors.7 cancer deaths.1,2 It is estimated by the Cigarette smoking is responsible for American Cancer Society that 164,100 new >90% of bronchogenic cancers.2 A dose cases were diagnosed in the year 2000, response relationship between smoking pack- representing no significant decrease in years and cancer risk has been established, incidence, despite vigorous smoking cessation with the curve steepest for small cell lung campaigns.2,3 With approximately 156,900 cancer (SCLC) and least steep for deaths attributed in 2000 alone, lung cancer adenocarcinoma.7 Smoking cessation has been the leading cause of cancer death in decreases the risk, but a long latency period men since the early 1950’s, and surpassed exists between smoking cessation and risk breast cancer in 1987 as the leading cause of normalization. It requires about 5 years of cancer deaths in women.3,4 The mean survival non-smoking before any significant reduction time for untreated lung cancer is only six in risk is realized, and 25 years before the months.5 The 5 year survival rates for patients cancer risk equals that of a lifelong diagnosed with lung cancer is only 14% for nonsmoker.8 whites, 11% for blacks, and remains Occupational and environmental unchanged over the past 20 years.(2,3) Due in carcinogens result in pulmonary neoplasms in part to ineffective screening mechanisms, about 15% of men and 5% of the women about 47% of patients will have advanced exposed to pulmonary toxins.7 The list pulmonary neoplastic disease (stage IV) at the includes: asbestos, chloroethyl methyl ether, time of diagnosis.6 heavy metals such as nickel and chromium, It is clear that the current approach of arsenic (glass, pesticides, paints), aromatic using modalities based on the detection of hydrocarbons, radon, and ionizing radiation.7 anatomical and morphological changes is The fact that only about 10% of heavy insensitive for diagnosing bronchogenic smokers die of lung cancer suggests a possible cancer in its early and most treatable stages. genetic component to the pathogenesis of lung Furthermore, invasive procedures for tissue cancer.1 There may be a genetic predisposition sampling, such as bronchoscopy, for the activation of certain enzymes by percutaneous needle biopsy, thorascopy, and smoking to convert hydrocarbons to open lung biopsy, represent significant cost, in carcinogens. terms of patient morbidity and hospital stay. Dietary factors may also have a role in Since physiopathologic and biochemical the development of cancer. Studies show a changes occur before gross structural and relationship between the increased intake of anatomical changes, noninvasive functional fresh vegetables and a lower cancer risk, imaging could detect changes earlier in the possibly linked to the chemoprotective effects course of disease and, in selected patients, of beta-carotene.1 decrease morbidity associated with invasive procedures. HISTOLOGIC CLASSIFICATION ETIOLOGY AND PATHOPHYSIOLOGY Major Cell Types The pathogenesis of a neoplastic As classified by the World Health lesion begins with the exposure of pluripotent Organization (WHO), four major cell types epithelial cells to carcinogens. Subsequently, account for more than 90% of primary lung 2 tumors9: squamous cell carcinoma, adeno- the most frequently occurring cell type in non- carcinoma, large cell, and small cell smokers.4 Lesions usually arise in the carcinoma. This histologic classification is peripheral lung and follow a glandular and necessary because of differences in natural papillary pattern. Spreading through the history, radiologic features, clinical bloodstream and lymphatics, there is an presentation, and response to treatment of the increased likelihood of early metastasis, even different cell types. Based on differences in before diagnosis.7 Organs targeted for management strategy and overall prognosis, a metastatic spread include the contralateral clinical distinction is made between small cell lung, liver, bone, adrenal glands, kidneys, and lung cancer (SCLC; ~20% of cases) and non- the central nervous system. Adenocarcinomas small cell lung cancer (NSCLC; 80% of and large cell carcinomas are the cell types cases), which encompasses squamous cell most likely to metastasize to the brain.1 carcinoma, adenocarcinoma, and large cell carcinoma. Large Cell Carcinoma Squamous Cell Carcinoma Large cell carcinoma (about 14%-19% Squamous cell carcinoma accounts for of all lung cancers) is NSCLC, which is not 25 - 30% of all lung cancer, with an increased classified as either adenocarcinoma or incidence in smokers and males.10 This squamous cell carcinoma by light microscopy. pathologic cell type usually arises from the It is comprised of two major subtypes: giant epithelium of larger, more proximal bronchi cell and clear cell.1 This tumor type usually and commonly extends into, and obstructs, the presents as a large, bulky, undifferentiated bronchial lumen. Light microscopy reveals lesion found in the lung periphery and keratinization and “pearls” (flattened cells generally follows the same presentation and surrounding a central core of keratin) and metastatic patterns as adenocarcinomas. intercellular bridges.1 Squamous cell carcinoma is the type least likely to Small Cell Carcinoma metastasize (54% compared to 82% for Small cell lung cancer accounts for adenocarcinoma, 86% for large cell only about 20-25% of all lung cancers,11 but 1 carcinoma), although it can metastasize via has the most aggressive clinical course of all lymphatic spread to hilar and mediastinal pulmonary tumors. These neoplastic cells lymph nodes, liver, adrenal glands, kidney, have round to oval nuclei with very little bone and the gastrointestinal tract.7 In cytoplasm. Characteristic electron microscope addition, brain metastases are found in greater features include the presence of than 50% of patients on post mortem neurosecretory granules and neurofilaments. examination.1 Hypercalcemia is common secondary to the secretion of a parathyroid Enzymes are released that decarboxylate hormone-like compound, and the tumor may amino acids, resulting in biologically active also cause secretion of growth hormone, amines and hormones (i.e., ADH, ACTH).11 corticotropin, calcitonin, and follicle Seventy percent of SCLC is diagnosed from a stimulating hormone.