eMedicine Specialties > Oncology > Carcinomas of the Lung and Other Intrathoracic Carcinomas

Lung Cancer, Oat Cell (Small Cell)

Author: Irfan Maghfoor, MD, Consulting Oncologist, Department of Oncology, King Faisal Specialist Hospital and Research Center, Saudi Arabia
Coauthor(s): Michael Perry, MD, MS, MACP, Nellie B Smith Chair of Oncology Emeritus, Professor, Department of Internal Medicine, Division of Hematology and Oncology, University of Missouri/Ellis Fischel Cancer Center
Contributor Information and Disclosures

Updated: May 22, 2009

Introduction

Background

Small cell lung cancer (SCLC) is considered distinct from other lung cancers, called non–small-cell lung cancers (NSCLCs), because of their clinical and biologic characteristics. Small cell lung cancer exhibits aggressive behavior, with rapid growth, early spread to distant sites, exquisite sensitivity to chemotherapy and radiation, and frequent association with distinct paraneoplastic syndromes. Surgery usually plays no role in its management, except in rare situations.¹

Pathophysiology

Small cell carcinomas arise in peribronchial locations and infiltrate the bronchial submucosa. Widespread metastases occur early in the course of the disease, with common spread to mediastinal lymph nodes, liver, bones, adrenal glands, and brain. In addition, production of a variety of peptide hormones leads to a wide range of paraneoplastic syndromes. The most common paraneoplastic syndromes are the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and the syndrome of ectopic adrenocorticotropic hormone (ACTH) production. In addition, autoimmune phenomena may lead to various neurological syndromes.

Molecular pathogenesis

Recent studies have identified both activation of oncogenes and inactivation of tumor suppressor genes in small cell lung cancer. To what extent these changes are causal events in the development of small cell lung cancer is not clearly known and remains an area of active research.

Oncogenes

Amplification of the myc family of oncogenes is the most common molecular abnormality identified in small cell lung cancer cell lines, xenografts in nude mice, and fresh tumor specimens. This change, however, is not identified in all small cell lung cancer tumors. Therefore, myc expression is unlikely to be an initial event in the pathogenesis of small cell lung cancer. C-myc, a member of the myc family, is found more commonly in relapsed tumors than in untreated tumors, and its expression in small cell lung cancer may carry a worse prognosis.

Other members of the myc oncogene family include N-myc and L-myc, which have been found to be amplified in small cell lung cancer. N-myc amplification in small cell lung cancer also has been associated with resistance to therapy and poorer prognosis. Overall, the exact role of amplification of the myc family of oncogenes in the pathogenesis of small cell lung cancer is not clearly understood at present and requires further study.

Other oncogenes that have been found to be amplified in small cell lung cancer include c-raf, c-erb -b1, and c-fms, but their association with pathogenesis and prognosis is even less clear.

Tumor suppressor genes

The retinoblastoma (RB) tumor suppressor gene is on chromosome 13 (13q14), and a high percentage of small cell lung cancers (as many as 60%) do not express RB messenger ribonucleic acid (mRNA). This high frequency of inactivation of a tumor suppressor gene suggests that this may be an important step in the molecular pathogenesis of small cell lung cancer. The most common molecular abnormality, however, is deletion of part of chromosome 3 (3p14). Mutations of the p53 tumor suppressor gene are commonly found in both small cell lung cancer and non-small-cell lung cancer, but their precise role in pathogenesis is not clear. Tobacco smoking and radon exposure are associated with p53 gene mutations.

Frequency

United States

Lung cancer is the second most common malignancy in both sexes, second only to prostate cancer in men and breast cancer in women. More women die of lung cancer each year than die of breast cancer. About 215,020 new lung cancer cases (114,690 in men and 100,330 in women) are expected to be diagnosed in the United States in 2008,  and 161,840 people (90,810 men and 71,030 women) are expected to die from lung cancer in 2008,  accounting for approximately one third of all cancer related deaths in the United States in 2008.² The epidemiology of small cell lung cancer (SCLC) has not changed over the last 30 years. The incidence of small cell lung cancer was about 20-25% of all newly diagnosed lung cancers in the past. It currently stands at 13%.

International

Globally, lung cancer is the most frequent malignancy in males, while it is the fifth most common cancer in females. According to World Health Organization (WHO) statistics, slightly more than 1 million cases of lung cancer are diagnosed annually around the world. This is less than expected, and the disparity most likely results from lack of diagnosis and/or underreporting in the developing countries.

Mortality/Morbidity

Approximately 65-70% of patients with small cell lung cancer have disseminated or extensive disease at presentation. Extensive-stage small cell lung cancers are incurable, and patients with extensive disease have a median survival duration of 6 weeks. Patients presenting with localized disease (ie, limited stage) have a median survival duration of about 12 weeks. These survival figures are for untreated patients. The median survival of patients with small cell lung cancer who are treated with multiple agent chemotherapy and multimodality therapy are as follows:

• For limited disease, 20 months with a 2-year survival rate of 45% and a 5-year survival rate of 20%
• For extensive disease, 12 months with a 2-year survival rate in 1973 of 1.5% and 2-year survival rate in 2000 of 4.6%

Race

Separate data for small cell carcinoma are not available. Among men, the age-adjusted incidence of lung cancer (per 100,000) ranges from 14 in Native Americans, 42-53 for Hispanic and Chinese Americans, 71-89 for Vietnamese and whites, to 117 among blacks. Among women, the age-adjusted incidence of lung cancer ranges from 15 among Japanese persons, 16-25 among Hispanic and Chinese persons, 31-44 among Vietnamese, white, and black persons to 51 among Alaskan natives. Among each ethnic group, the incidence is at least twice as high in males as in females. Age-adjusted mortality rates among different ethnic groups follow a similar pattern.

Sex

The incidence of lung cancer is twice as high in males as in females. See Frequency. The incidence of lung cancer started to decline among males in the early 1980s and has continued to do so over past 20 years. By contrast, the incidence in women started to increase in the late 1970s and only recently reached a plateau.

Age

According to information from the American Cancer Society, the probabilities of developing lung cancer among males are as follows: from birth to 39 years, 0.04%; 40-59 years, 1.24%; 60-79 years, 6.29%; and from birth to death, 8.09%. Among females, the probabilities are as follows: from birth to 39 years, 0.03%; 40-59 years, 0.92%; 60-79 years, 4.04%; and birth to death, 5.78%. As with other histopathological cases of lung cancer, most cases of small cell lung cancer occur in individuals aged 35-75 years; incidence peaks in persons aged 55-65 years.

Clinical

History

For patients with small cell lung cancer (SCLC) to present without any symptoms is very unusual. Fewer than 5% of patients have a small, asymptomatic primary tumor at presentation. Small cell lung cancer typically presents with a relatively short duration of symptoms. The onset of symptoms is usually within 8-12 weeks prior to presentation. The symptoms can result from local tumor growth, intrathoracic spread, distant spread, and/or paraneoplastic syndromes. Symptoms include the following:

• Constitutional symptoms
  • Fatigue
  • Anorexia
  • Weight loss
• Symptoms due to primary tumor
  • Cough
  • Dyspnea
  • Hemoptysis
• Symptoms due to intrathoracic spread
  • Superior vena cava obstruction
  • Hoarseness (ie, palsy of the recurrent laryngeal nerve)
  • Phrenic nerve palsy
  • Dysphagia (ie, compression of esophagus)
  • Stridor (ie, compression of the trachea mainstem bronchus)
• Symptoms due to distant spread
  • Neurological dysfunction (ie, brain metastasis, spinal cord compression)
  • Bone pain (bone metastasis)
  • Abdominal/right upper quadrant pain (ie, liver metastasis)
• Local tumor growth: Small cell carcinomas usually are centrally located and may cause irritation, obstruction, or both of the major airway. Common symptoms resulting from local tumor growth include cough, dyspnea, and hemoptysis. Patients give a short history of symptoms of recent onset, with rapid worsening. Rapid tumor growth may lead to obstruction of major airways, with distal collapse and consequent postobstructive pneumonitis. Fever may result from infections distal to obstruction or from the tumor itself.
• Intrathoracic spread: Small cell carcinomas grow in size rapidly and metastasize to the mediastinal lymph nodes relatively early in the course of the disease. At presentation, patients may have a very large intrathoracic tumor, and distinguishing primary tumor from lymph node metastasis may be impossible. Pressure on mediastinal structures can cause a variety of symptoms.
  • Superior vena cava obstruction: Malignancy is the most common cause of superior vena cava (SVC) obstruction, and lung cancer accounts for the overwhelming majority of cases (60-90%). Small cell lung cancer causes SVC obstruction more often than non-small-cell lung cancer (NSCLC) does. Patients present with swelling of the face and upper extremities. Headache, dizziness, and other neurological symptoms are late occurrences.
  • Paralysis of the recurrent laryngeal nerve: The recurrent laryngeal nerve may be compressed by a mediastinal mass (ie, primary tumor or lymph node metastasis) as it traverses up on the left to supply the vocal cords. Patients complain of hoarseness of recent onset.
  • Phrenic nerve palsy: Compression of the phrenic nerve causes paralysis of the ipsilateral hemidiaphragm, contributing to respiratory symptoms.
  • Esophageal compression: Compression of the esophagus can lead to dysphagia and odynophagia.
  • Tracheal compression: Compression of the mainstem bronchi and trachea can cause severe shortness of breath and stridor.
• Symptoms from distant spread: These symptoms depend upon the site of spread. Common sites of spread include brain, bones, liver, adrenals, and bone marrow.

Table 1. Paraneoplastic Syndromes*

Open table in new window

*For more information, see Paraneoplastic Syndromes.

Physical

Physical findings in small cell lung cancer (SCLC) depend upon the extent of local and distant spread and the organ system involved.

• Respiratory system: Patients usually complain of shortness of breath, and examination may reveal use of accessory muscles of respiration (scalene muscles, intercostal muscles, flaring of alae of nose). In addition, by virtue of central tumor location, patients may develop distal atelectasis and postobstructive pneumonia. With pleural effusion, examination reveals dullness to percussion and decreased or absent breath sounds on the side of the effusion.
• Cardiovascular system: Small cell lung cancer may cause pericardial effusion and is the malignancy that most often causes obstruction of the SVC.
  • Pericardial effusion: Pericardial effusions may be asymptomatic when small or may result in tamponade if they are large or accumulate over a short period. Patients are usually short of breath. Heart sounds may be distant on auscultation. Jugular venous pulsation is elevated; paradoxically, it rises with inspiration.
  • Pulsus paradoxus is a classic sign of pericardial tamponade. The diagnosis is established with cardiac catheterization, which reveals equalization of pressures in cardiac chambers. Tamponade is an emergency and requires immediate decompression of the pericardium. Definitive management may include chemotherapy and/or surgical creation of a pleuropericardial window.
• Central nervous system: Patients with small cell lung cancer may have asymptomatic brain metastasis in 5-10% of cases, which may be picked up on staging workup.
  • Brain metastasis: Patients with symptomatic brain metastases may have raised intracranial pressure secondary to mass lesions, as well as surrounding brain edema, and may complain of headache (usually worse early in the morning), blurring of vision, photophobia, nausea, vomiting, and various localizing symptoms, such as weakness of an extremity. The physical findings again are dependent upon site of the brain lesions.
    • The examination should include funduscopy to look for signs of raised intracranial pressure and a detailed neurologic examination, including evaluation of cerebellar function, coordination, and gait.
    • The diagnosis is established with a CT scan of the brain with contrast (if renal function is adequate). In difficult cases, a magnetic resonance scan of the brain may be appropriate. Since MRI is more sensitive than CT scan with contrast for detection of brain metastasis, it is used as the first-line imaging study in many institutions.
    • Management includes high doses of corticosteroids (eg, dexamethasone 10 mg IV initially, followed by 4-6 mg IV/PO q6h) and immediate radiation therapy.
  • Vertebral and paraspinal metastases: The importance of early recognition of these metastases is due to their close proximity to the spinal cord, potentially leading to permanent loss of neurological function if diagnosis is delayed. The initial symptom is usually back pain, with or without neurological dysfunction.
    • The main objective is to establish diagnosis early, before neurological dysfunction is established. Once present, neurological dysfunction can progress very rapidly (ie, within hours) to cause quadriplegia or paraplegia, depending upon the location. This condition is an oncologic emergency.
    • Even though a CT myelogram can establish the diagnosis, MRI is noninvasive and very sensitive in establishing the diagnosis.
    • Patients in whom spinal cord compression is suspected should receive a dose of intravenous corticosteroids even before being sent to the MRI suite. The typical dose is 10 mg of dexamethasone IV, followed by 4-6 mg IV/PO every 6 hours. The authors prefer the intravenous route because of the reliability of drug delivery.
    • If the etiological cause is known (ie, a prior histologic diagnosis of SCLC), definitive management is radiation therapy, which should be started without any delay. Otherwise, if the patient presents with spinal cord compression and no prior diagnosis of cancer, surgical resection, if technically feasible, provides both immediate decompression and tissue diagnosis of the cancer.
• Gastrointestinal system: The liver is the common site of spread, and physical examination may reveal icterus (secondary to widespread liver metastasis or obstruction of biliary outflow) or hepatomegaly. However, most patients do not have any specific finding related to the gastrointestinal tract on examination.
• Lymphatic system: Lymph node examination should be carried out carefully. Currently, enlarged ipsilateral supraclavicular lymph nodes are included in limited stage, but enlarged axillary lymph nodes upstage the diagnosis to extensive-stage disease.
• Extremities: Examination of the extremities may reveal clubbing, cyanosis, or edema. In the presence of SVC obstruction, the right upper extremity usually is edematous.

Causes

The predominant cause of small cell lung cancer, as of non-small-cell lung cancer, is tobacco smoking. Of all histologic types of lung cancer, in fact, small cell lung cancer and squamous cell carcinoma have the strongest correlation to tobacco. Some 98% of patients with small cell lung cancer have a smoking history. Patients with diagnosed small cell lung cancer should be encouraged or required to stop smoking; this may contribute to improved survival.

• Uranium mining: All types of lung cancers occur with increased frequency in uranium miners, but small cell lung cancer is most common. The incidence is increased further in persons who smoke tobacco.
• Radon exposure: Exposure to radon, which is an inert gas developing from the decay of uranium, also has been reported to cause small cell lung cancer.

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