I'm Greg Kalemkerian, medical oncologist and professor of Medicine at the University of Michigan. In this lecture, we'll be talking about small-cell lung cancer giving an overview of the disease. The objectives of the talk are to review the epidemiology of small cell lung cancer, review the characteristics of small cell, and review the staging and initial evaluation of patients with small cell. Small cell lung cancer is an aggressive neuro-endocrine malignancy with early metastatic potential and spread. Small cell lung cancer comprises only 15 percent of all lung cancer cases but it's still a major public health problem. The proper initial evaluation of patients is imperative for appropriate therapeutic decision-making. Our pre-lecture question, which of the following statements regarding small cell lung cancer is true. Most patients are lifelong non-smokers, two-thirds of patients present with hematogenous metastases, paraneoplastic syndromes occur in almost half of patients, and small cell lung cancer accounts for about 30 percent of all cases of lung cancer. We'll come back to the answer to this question at the end of the lecture. So, back in 1993, John Ruckdeschel, who is a prominent thoracic oncologist, made the comment that in no other area of medical oncology has so much promise brought so little therapeutic gain over the past decade in reference to small cell lung cancer. I think this is a situation that unfortunately has continued on for the next couple of decades and that there has been very little therapeutic gain in the field of small cell lung cancer over the past 30 years. Even though small cell lung cancer only accounts for approximately 15 percent of all cases of lung cancer, it still is a major public health problem. Lung cancer, in general, is the second most common cancer diagnosed in the United States and the leading cause of cancer-related death. When we subset out small cell lung cancer, we still see that it is the seventh leading cause of cancer-related death within the United States. On this slide, we see data from the SEER Registry in the United States from 1973 up through 2002. The incidence of small cell lung cancer rose and peaked in the 1980s and since then has been declining. This is primarily driven by a decline in the incidence of small cell lung cancer in males whereas the incidence in females has risen and plateaued. On the bottom of this slide, we see survival, and we see that the survival of patients with small cell lung cancer has not changed much in the past 30 years with only a slight rise in two year survival and almost no change in five year overall survival. So, small cell lung cancer is almost always associated with tobacco smoking with approximately 98 percent of people being former or current smokers. In the 25 years I've been taking care of people with lung cancer, I have seen less than a handful of nonsmokers with small cell lung cancer. It is primarily a central tumor that occurs within the bronchus and within the submucosal compartment of the bronchus and then spreads from there, usually associated with bulky mediastinal and hilar lymph nodes, and early hematogenous metastases. It is a neuroendocrine tumor and as such, when we do immunohistochemical staining in order to define the nature of the disease, we see that it stains for chromogranin, CD56 which is also known as neural cell adhesion molecule, and synaptophysin. We also seen endocrine and neurological paraneoplastic syndromes associated with small cell lung cancer. Histologically, small cell lung cancer is characterized by a tumor with no discrete architecture, really sheets of undifferentiated cells with a high nuclear to cytoplasmic ratio and nuclear molding, meaning that the nuclei tend to mold to each other's shapes. There also can be areas of necrosis within the tumor, as we see down here, due to the high growth rate of the disease. So, paraneoplastic syndromes are an interesting aspect of small cell lung cancer and these are brought about by the fact that small cells have endocrine potential and also have neurological antigens on their surface that can stimulate a immune response that can then cross-react with other components of the nerve system. Endocrine paraneoplastic syndromes can be seen in about 5-10 percent of patients with the commonest being the syndrome of inappropriate ADH secretion causing hyponatremia, and much more rarely, Cushing's syndrome with the ectopic production of ACTH. An important question that comes up on boards exams is that humoral hypercalcemia is rarely seen with small cell lung cancer and is much more commonly seen in non-small cell lung cancer. The neurologic paraneoplastic syndromes are less common occurring in 1-5 percent of patients and examples of such syndromes are subacute cerebellar degeneration, limbic encephalopathy, or Lambert-Eaton myasthenic syndrome; all of which have specific antibodies associated with their occurrence. Small cell lung cancer is one of the very few cancers remaining that are not staged based on the TNM staging system in routine practice. So, we usually use the VA staging system which is a simplified two-stage scheme. With limited-stage being confined to one hemithorax, or that can be included within a tolerable radiation port. Approximately one-third of patients present with limited-stage disease. Extensive stage disease is more common occurring in about two-thirds of patients and is any disease that's beyond limited-stage, so that would include pleural effusions, pericardial effusions, distant metastases, or disease that has spread to the contralateral lung. The TNM system can be applied to small cell lung cancer and when we look at the classifications of stages one through four, we see that there is prognostic significance to the TNM staging classification and there is a move afoot for us to move towards using the TNM staging system, more commonly in small cell lung cancer. The staging work-up for small cell lung cancer is driven by the very high frequency of asymptomatic metastases. Should be started with obviously a history in physical examination, routine laboratories, including an LDH which is quite prognostic in this disease, measurements of renal and liver function in order to determine the appropriateness of different forms of therapy. CT scans of the chest and abdomen with contrast should be obtained and an MRI of the brain or a CT scan of the brain should be obtained in all patients due to the high frequency of brain metastases. In patients who are found to have clinical limited-stage disease, a PET scan is helpful in order to detect the distant metastasis. Bone scans can be done but if a PET scan is obtained, then a bone scan does not need to be done since the sensitivity of PET scan and bone scan for bone metastases are similar. As mentioned earlier, small cell lung cancer likes to spread and the common sites of spread include mediastinal lymph nodes, liver, bone, adrenal glands, pleural effusions, and the brain. So, coming back to our initial question, which of the following statements regarding small cell lung cancer is true, most patients are lifelong non-smokers, two-thirds of patients present with hematogenous metastases, paraneoplastic syndromes occur in almost half of patients, and small cell lung cancer accounts for 30 percent of all cases of lung cancer. The correct answer is that most patients present with hematogenous metastases. We know that most patients are smokers and that paraneoplastic syndromes occur in only a small fraction of patients and that small cell lung cancer accounts for about 15 percent of all cases of lung cancer. So, the take-home points for this lecture are that small cell is an aggressive smoking-related malignancy, nearly all patients have a large central primary tumor and bulky mediastinal lymph nodes, 70 percent of patients present with hematogenous metastases, and the VA staging system, using limited and extensive definitions, provides clinically relevant guidance for therapeutic decision-making. I want to thank you for listening to this lecture.
