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pulmonary tumors
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DANIL HAMMOUDI.MD
sinoe medical association
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 generality | types | Solitary Pulmonary Nodule | Superior Vena Cava Syndrome | Pancoast Syndrome | Squamous Cell Carcinoma | adenocarcinoma | Bronchioloalveolar Carcinoma | Large Cell Carcinoma & Giant Cell Carcinoma | Small Cell Carcinoma | Synchronous Tumors | Adenoid Cystic Carcinoma | Pulmonary Angiosarcoma | Carcinoid Tumors | Chondrosarcoma | Anterior Mediastinal Masses | Hamartoma | Mesothelioma | Mucoepidermoid Tumors | Histoplasmosis | Mediastinal Cysts | surgery of the lung | Contact Me | Related Links
BE GOOD CLINICIAN AND EXPEND TIME WITH YOUR PATIENT BE A MEDICAL DETECTIVE AND DO NOT MISS YOUR TARGET.
DO NOT FORGET A GOOD MEDICAL EXAM WITH GOOD QUESTION MAKE 75% OF THE DIAG.
MISSING A CANCER MEANS DEAD AND SUFFERING FOR THE PATIENT THAT YOU SAW.
ASK YOU SELF QUESTIONS IF SOMETHING SEEMS TO BE WRONG.
The vast majority (90 - 95%) of primary lung tumors are bronchogenic carcinomas, malignant tumors which arise from the bronchial or bronchiolar epithelium.  normal lung anatomy   normal stuff    The Type I Pneumocyte comprises 95% of the alveolar surface. These extremely flattened cells form an ultra-thin gas permeable membrane. Their dark staining, flattened nuclei indicated by the letter b, are seen in this specimen.The Type II Pneumocyte comprises 3 - 5% of the remaining alveolar cells. These cells function to secrete pulmonary surfactant, which reduces the surface tension within the alveoli, and allows the alveoli to inflate. These cells have large, rounded nuclei, with an extensive vacuolated cytoplasm, as indicated by the letter a in this specimen.  Alveolar Macrophages The alveolar marcophages, indicated by the arrow in this specimen, are derived from circulatory monocytes. These cells function to engulf foreign material including particulate matter. Larger particles are trapped in mucus secreted by goblet cells and conducted out of the bronchioles and bronchi by the cilliated cells. This mucus is then expectorated or swallowed. Small particles (usually less than 3 microns in diameter) may gain access to the alveoli, and are then ingested by alveolar macrophages.
Site of Lung Cancer
Right-sided primary bronchogenic carcinomas are the predominant cause of SVC syndrome. The carcinoma most commonly arises in the right upper lobe of the lung and extends directly to the SVC and adjacent lymph nodes. The following table is a summary of various studies that report the most common anatomic site of the tumor:
The anatomic site and lymphatic drainage of the lymph nodes surrounding the SVC explain the preponderance of obstructions occurring in lesions or the right bronchial origin.
 . Initial Clinical Manifestations of Lung CancerLocal growth Central Endobronchial (example) Submucosal (example - small cell CA)Compression or invasion of adjacent structuresEsophagus, trachea Recurrent laryngeal nerve Brachial plexusSuperior vena cavaPericardium, heartPeripheralParenchymal, pleural (example), chest wall (Showed example of lymphangitic and hematogenous spread in lung)Metastatic diseaseHematogenous CNS, bone, liver (example), adrenal Lymphatic - lymph nodesInteralveolarParaneoplastic syndromes7. Classification of Lung Carcinoma (Major Types)
Squamous cell carcinoma 35%
Adenocarcinoma 30%
Small cell carcinoma 25%
Large cell carcinoma 10%
8. Clinical Classification of Lung Carcinoma
Small cell carcinoma Non-small cell carcinoma Squamous cell carcinoma AdenocarcinomaLarge cell carcinomaClassification of Lung Carcinoma
Major types of lung carcinoma - all related to cigarette smoking Squamous cell carcinoma AdenocarcinomaSmall cell carcinomaLarge cell carcinomaHeterogeneous group of less common malignant lung tumors - not related to smokingCarcinoid 1-5% of lung tumors 5-10% distant metastases neuroendocrine differentiation (Kulchitsky cells)serotonin bombesin (gastrin-releasing peptide)calcitoninGross: usually central location (example)Microscopic: uniform cells in endocrine pattern with infrequent mitosis (example)Electron microsccopy: numerous neuroendocrine granulesAdenoid cystic carcinomaMucoepidermoid carcinoma=====================================================================================================================================
1 - 5% of the remaining primary lung tumors are bronchial carcinoids, formerly classified as"bronchial adenomas", a misnomer, as these tumors may be locally invasive and occasionaly metastatic. Bronchial carcinoids are of neuroendocrine cell origin, and these lesions may elaborate vasoactive amines.
The remining 2 - 5% of primary lung neoplasms are of mesenchymal origin and various other miscellaneous neoplasms, both benign and malignant. These tumors include benign tumors such as fibromas, leiomyomas, lipomas, hemagiomas, hemangiopericytomas, and chondromas; and the malignant tumors such as fibrosarcomas, leiomyosarcomas. In addition, lymphoreticular tumors such as those seen in Hodgkin's and non-Hodgkins lymphomas may affect the lungs.The lung is an important site of metastatic tumors, as the entire blood passes through the lungsLung cancer takes many years to develop. However, changes in the lung can begin almost immediately upon exposure to carcinogens (cancer-causing substances). Soon after exposure begins, microscopic examination of the tissue lining the bronchi (the main breathing tubes) will reveal a few unusual cells. With continued exposure, more abnormal cells appear. These cells may be on their way to becoming cancerous and forming a tumor. The symptoms of the cancer vary depending on several factors, including where in the lung the tumor is found. If the cancer is located in one of the bronchi, it can irritate the lining of the bronchus (one of the main airways that branches off of the trachea or windpipe) and cause a chronic cough. The cancerous area may bleed when a person coughs[hemoptysis see my hemoptysis lect]. If the tumor grows larger, it may gradually fill the bronchus so that air can't pass in or out. A blocked bronchus may also cause repeated lung infections or pneumonia. A tumor located in the outer part of the lung may not produce any symptoms until it is fairly large. Sometimes the first sign may be chest pain from the tumor growing into the lining of the lungs or the ribs and muscle of the chest wall.   A person's lungs have extensive networks of blood and lymph vessels. Cancer cells may grow into these vessels and be carried by the blood or lymph to circulate through the body. The cancer cells may then be deposited in other organs of the body. A new colony of cancer cells which started in another organ is known as metastasis.The first site of tumor metastasis is usually the lymph nodes within the lungs and the mediastinum (the space between the two lungs in the middle of the chest). It is possible for cancer cells that begin in other organs to spread to the lungs. These cases are very different medical problems, however. Depending on the organ of origin, such cases might be termed "primary breast cancer, metastatic to the lungs," or "primary kidney cancer,metastatic to the lungs." These cancers are less often treated with surgery or radiation therapy, but with chemotherapy. Classification of Lung CA
The WHO classification scheme divides bronchogenic carcinomas into four major categories, based on the tumor histology:
1-squamous cell carcinoma, accounts for 25 - 40% of all lung cancer
2- adenocarcinoma, also accounts for 25 - 40% of all lung cancer
3- small cell carcinoma, accounts for 20 - 25% of all lung cancer
4-large cell carcinoma, accounts for 10 - 15% of all lung cancer
Combined histology (eg. squamous cell + small cell) is not uncommon
The more commonly used classification among clinicians divides bronchogenic carcinomas into two categories, based on their response to therapy
1 small cell carcinomas are initially highly responsive to chemotherapy
2 non-small cell carcinomas are less responsive
After a few general comments about bronchogenic carcinomas as a group, the different histologic classifications will be discussed individually.
75% of all bronchogenic carcinomas arise from tissue lining first-, second-, and third-order bronchi, and are hence seen in and about the hilus of the lung. Note the hilar location of this tumor at the bifrucation of the trachea.
 WHAT CAUSES LUNG CANCER?Smoking is the number one cause of lung cancer. It is thought that more than 80% of lung cancers result from smoking. Cigarette smoke contains more than 4,000 different chemicals, many of which are proven carcinogens, while hundreds of others increase the cancer-causing power of carcinogens. Many of these chemicals also affect the nonsmoker inhaling "secondhand" or sidestream smoke,* making "passive smoking" another important cause of lung cancer. In a 1993 report, the U.S. Environmental Protection Agency (EPA) concluded that involuntary or "passive" smoking causes 3,000 lung cancer deaths in nonsmokers each year. *Sidestream smoke, with its high concentration of carcinogens, goes directly into the air from burning tobacco (cigarettes, cigars, etc.) and is inhaled by both smokers and nonsmokers. If you smoke, you are much more likely to develop the disease; men who smoke are estimated to be 22 times more likely to develop lung cancer, while women who smoke are estimated to be 12 times more likely. The more you smoke and the longer you smoke, the greater your risk of lung cancer. But if you stop smoking, the risk of cancer decreases steadily each year as abnormal cells are replaced by normal cells. In ten years, the risk decreases to a level that is 30 to 50 percent of the risk for people who continue to smoke. In addition, quitting smoking dramatically reduces the risk of developing other smoking-related diseases, such as heart disease and stroke, and significantly reduces the risk of serious emphysema and chronic bronchitis. Radon, by its own action and by its interaction with cigarette smoking, is considered to be the second leading cause of lung cancer in the U.S. today. Radon is a radioactive gas that is found in the earth's rock and soil and is formed by the natural breakdown of radium, which is a radioactive product of decaying uranium. It is estimated that 15,000 American die each year from residential radon induced lung cancer.Radon problems have been identified in every state. The EPA estimates that nearly 1 out of every 15 homes in the U.S. has indoor radon levels at or above the EPA's recommended action guideline level of four picocuries per liter of air (pCi/L) on a yearly average. Radon can be a problem in schools and workplaces, too. Because radon is invisible and odorless, the only way to determine if you are being exposed to the gas is by measuring radon levels. In addition, exposure to radon, in combination with cigarette smoking, significantly increases the risk of lung cancer. Therefore, for smokers, exposure to radon is an even greater health risk. Another leading cause of lung cancer is on-the-job exposure to carcinogens. Asbestos is perhaps the best known of the industrial substances associated with lung cancer, but there are many cancer-causing substances that people may deal with at work. These include asbestos,uranium, arsenic, certain petroleum products, and others. In addition, it is important to realize that there are many different jobs that may involve exposure. Some examples are working with certain types of insulation, working in certain environments, such as with coke ovens, and repairing brakes. As is the case with radon, when exposure to job-related carcinogens is combined with smoking, the risk of getting lung cancer is sharply increased. WHO GETS LUNG CANCER?Lung cancer occurs most often in people over fifty who have long histories of cigarette smoking.The incidence of lung cancer in women as a whole has climbed at an alarming rate, and these increases are clearly attributable to the increases in the number of women who have smoked. In 1987, lung cancer exceeded breast cancer for the first time as the major cancer cause of death in women. It has been estimated that there will be 164,100 new cases of lung cancer in the U.S. in 2000; 89,500 among men and 74,600 among women. The rate of lung cancer among men as a whole in the U.S. has been declining in recent years; for example, dropping from a high of 86.5 per 100,000 men in 1984 to a level of 70.0 in 1996. Although the lung cancer incidence rates for both black and white males decreases between 1984 and 1996, the rate in black males (101.4 per 100,000) is almost 50 percent higher than the rate in white males (68.4 per 100,000).Unlike their male counterparts, incidence rates in both black and white women has risen substantially. Between 1984 and 1996, incidence rates increased 22 percent overall, 25.6 percent in white women and 18.9 percent in black women. Between 1995 and 1996, the incidence rate of lung cancer increased 10% in black women.That lung cancer and lung cancer deaths are occurring among some groups of Americans at rates higher than the national average, such as African-American men and women and white women, and that these increases may be largely due to preventable causes, such as smoking, has caused special concern among public health officials. HOW IS LUNG CANCER DETECTED? In its early stages and even later, lung cancer is usually silent. When symptoms occur, the cancer is often advanced. Symptoms of lung cancer include:
• Chronic cough
• Hoarseness
• Coughing up blood or rusty-colored sputum
• Weight loss & loss of appetite
• Shortness of breath
• Fever without a known reason
• Wheezing
• Recurring infections such as bronchitis & pneumonia
• Chest pain
These conditions are also symptomatic of many other lung problems; thus, when they occur, they warrant medical investigation. When a person goes for an examination, his or her doctor will take an extensive medical history, noting any possible hazardous exposure. This is followed by a thorough physical examination. If the patient has a productive cough (a cough that produces sputum), the sputum may be examined for cancer cells. The doctor will order a chest X-ray or specialized X-ray such as the CAT scan, which help to locate any abnormal spots in the lungs. The doctor may do a bronchoscopy to look inside the bronchial tubes and lungs and biopsy the tumor. A bronchoscope is a small tube inserted through the nose or mouth, down the throat, into the bronchial tubes. During this procedure the doctor may also obtain a biopsy or other sample of lung tissue and cells which are viewed under a microscope to determine if they are cancerous and if so, to identify the type of cancer involved. Biopsies of lung tissue or of the lymph nodes between the lungs may be performed using other techniques as well. Pancoast tumor apical density (superior pulmonary sulcus) destruction or adjacent rib or vertebra Horner's syndrome pain in arm usually bronchogenic Ca (squamous type) also: mets, malignant neurogenic tumor HOW IS LUNG CANCER TREATED? Surgery may cure lung cancer. It is used in limited stages of the disease.
Radiation therapy is a form of high energy X-rays. It is used:
• In combination with chemotherapy and sometimes with surgery
• To offer relief from pain or blockage of the airways
Chemotherapy is the use of drugs that are effective against cancer cells. It may be used:
• In conjunction with surgery
• In more advanced stages of the disease
• In all stages of small cell carcinoma
In addition, discoveries in the diagnosis and treatment of lung cancer are being made. Among the most promising research efforts are:
Excessive number of certain specific oncogenes (abnormal genes associated with tumors) that have been found in some lung cancer cells. It is hoped that an oncogene test may soon be invented that will help in planning lung cancer treatment. The ultimate goal of oncogene research is to find drugs that "turn off" the abnormal genes, ending cancer growth.
New studies have provided evidence of "markers" within an individual's genetic makeup that are related to the risk of developing lung cancer. This finding may help in identifying people at high risk of lung cancer, who should be more carefully observed for evidence of early lung cancer.
Use of monoclonal antibodies that recognize only lung cancer cells. These antibodies are proteins that attach themselves to parts of the cancer cells, causing the cells to be destroyed in various ways. The antibodies are already aiding in diagnosis and treatment in clinical experiments.
Stimulation of the immune system (the body's inborn ability to fight disease) using natural substances such as interferon and interleukin-2, which already show promise for the treatment of many types of cancer. These substances may one day be a valuable part of lung cancer treatment.
HOW CAN YOU PREVENT LUNG CANCER?If you are a smoker, STOP SMOKING. Your local American Lung Association has books, videos, and group programs to help you quit for good. If you are a nonsmoker, make sure that your rights to a smoke-free environment are upheld. Strive for a smoke-free environment both at home and at work. Test your home for radon if you live in an area known to have high levels. Ask questions about your work environment if you are exposed to industrial dusts and fumes. Lung cancer is the leading cancer killer in the United States and until there is a cure, the only way to defeat lung cancer is to prevent it from ever happening. Contact your local American Lung Association to learn how you can help eliminate lung cancer hazards.Formulas
Bayes' Theorem:Current Odds = Prior Odds x Likelihood Ratios
Likelihood Ratio = Probability in patients with disease / Probability in subjects without disease
= Sensitivity/(1 - specificity)
Probability(%) = [Odds/(Odds +1)] x 100
Definition of a Solitary Pulmonary Nodule (SPN)
The statistics used by this program are based upon a population with solitary pulmonary nodules meeting the following criteria:
The nodule may be of any size. The nodule should not produce any referable symptoms. There is no evidence of a primary cancer at another site, nor evidence of metastatic disease. Lung cancer is the second most common form of cancer and the leading cause of cancer death in both men and women in the United States. Lung cancer can be clinically silent or may present with signs and symptoms referable to the chest or associated with metastatic diseaseEarly stage nonsmall cell lung cancers are best treated surgically and later stage nonsmall cell lung cancers are best treated with either chemotherapy, radiation therapy, or some combination of the two modalities. For these reasons, the initial clinical evaluation must be tailored to the individual. It is clinically inappropriate and prohibitively expensive to evaluate every patient with lung cancer with multiple testsMost patients with lung cancer present with symptoms related to the respiratory tract. Symptoms caused by local tumor growth depend on the initial tumor size and location and on the involvement of adjacent structures. Symptoms can be related to local tumor growth in an airway, to chest wall invasion, to mediastinal invasion, to metastasic disease, or to a tumor related paraneoplastic syndrome. A careful search for these signs and symptoms provides information about the tumor and directs further evaluation. Local Tumor Growth Tumors are classified based on their location as either central (endobronchial or mediastinal) or peripheral (distal to the major bronchi). Those arising in large airways or centrally located can produce local symptoms including cough, localized wheezing, hemoptysis, focal atelectasis, dyspnea, or post obstructive pneumonitis. A cavitating tumor or post obstructive pneumonitis mimics a primary infection or abscess and can produce symptoms of fever, chills and productive cough. Tumors arising in small airways or peripherally located are usually asymptomatic but may present with hemoptysis. Consequently, more peripheral than central tumors are found incidentally on a chest x-ray. Local/Regional Invasion When the tumor grows and invades adjacent structures or spreads to the mediastinal nodes, systemic symptoms are more common. In this setting, systemic symptoms include fatigue, weight loss, anorexia, cachexia, and fever. Mediastinal invasion can cause some specific syndromes related to tumor involvement of adjacent structures. With mediastinal invasion on the left side, the recurrent laryngeal nerve may become entrapped or compressed. These patients will present with hoarseness and ipsilateral vocal cord paralysis. Involvement of the recurrent laryngeal nerve classifies these tumors as stage IIIB. The phrenic nerve can also be involved with mediastinal invasion. Phrenic nerve involvement manifests as diaphragmatic paralysis and positional dyspnea. Rarely the esophagus is involved and may produce dysphagia. With esophageal invasion the patients may also develop a bronchoesophageal fistula with recurrent aspiration and pneumonia. Right upper lobe tumors or paratracheal adenopathy can compress the superior vena cava (SVC) and cause the SVC syndrome. An apical lung tumor, also known as a Pancoast tumor, may invade local neural structures and produce a characteristic syndrome of pain and possible Horner's syndrome. Horner's syndrome may occur with a Pancoast tumor or whenever a tumor impinges on the sympathetic chain. Intrathoracic Metastases The thoracic manifestations of metastatic lung cancer result from hematogenous, lymphatic or intra-alveolar tumor dissemination. Detecting these nodal and distant metastases is essential in properly staging the patient. Lung cancers may involve any of the normal chest structures. Large cancers eventually affect the heart in 15-35% of cases. Pericardial involvement is more common than myocardial involvement. Pericardial involvement causes pericardial effusions, tamponade, or dysrhythmias, and is suggested by an enlarging heart silhouette on chest x-ray, by a paradoxical pulse, by a pericardial friction rub or Kussmaul's sign, by new congestive failure or by venous engorgement. The diagnosis is confirmed using echocardiography. Pleural involvement occurs in 8-15% of lung cancer patients. Common symptoms of pleural involvement are dyspnea, cough and chest pain. Pleural involvement manifests as pleural effusions, pleural masses or rarely pneumothorax. Pleural effusion from lung cancer can arise because of lymphatic obstruction or due to direct pleural invasion by the tumor. This is an important distinction for the clinician because a small percentage of patients with pleural effusion due to lymphatic obstruction are still candidates for surgical resection. Direct pleural invasion by the tumor is diagnosed by thoracentesis, closed pleural biopsy or pleuroscopy. The sensitivity of these procedures in diagnosing pleural involvement increases in that respective order. Tumor growth into the chest wall, ribs, or vertebral bodies most commonly produces localized pain, pleural effusions, or paresis. Intra-alveolar spread is most often seen with bronchioloalveolar carcinoma and results in multicentric lung involvement with bronchorrhea in about half the cases. This type of spread gives an alveolar pattern on chest X-ray and CT scan. Extrathoracic Metastases Distant metastases from lung cancer have been found in every organ. However, the four most common sites for metastases are adrenal, bone, brain, and liver. The frequency of metastases and specific locations vary with histological tumor type. Brain and bone metastases can produce signs and symptoms detectable through careful history and physical exam, however detecting liver and adrenal metastases usually requires radiographic and/or laboratory evaluation. Brain metastasis carry a poor prognosis and high morbidity. Common symptoms of brain metastases are headaches, focal neurologic dysfunction, or seizures. Symptoms will depend on the area of CNS involved. Metastatic lesions can present as solitary or multiple intracranial masses , as meningeal carcinomatosis, or with spinal cord involvement. Skeletal system metastases are reported in up to 30% of non small cell lung cancer patients. Patients with bone metastases often present with localized pain, however, some patients may present only with elevated calcium or elevated alkaline phosphatase on laboratory screen. Liver metastases are found in 10-20% of non small cell lung cancer patients. Patients with metastatic disease present in one of three ways: (1) symptoms from the lung primary with asymptomatic liver involvement discovered during evaluation; (2) nonspecific symptoms such as weakness, fever, sweating , or weight loss and liver abnormalities on liver or abdominal CT scan; (3) clinical features of liver disease including abdominal pain, ascites or hepatomegaly. Lung cancer frequently metastasizes to the adrenal glands without causing any specific signs or symptoms. Because these lesions are clinically silent, chest CT scans to evaluate for lung cancer should include cuts through the adrenals. All patients with small cell lung cancer should be staged with a head CT scan because between 20-50% of patients have brain metastases, some of which are clinically silent. Bone You can suspect lung metastases in nonsmall cell lung cancer based on symptoms or laboratory findings. Notable laboratory abnormalities include elevated calcium or elevated alkaline phosphatase. The current method of choice for detecting metastases is the highly sensitive Technetium 99m methylene diphosphate bone scan. The 99mTc scan detects increased bone metabolism and is sensitive enough to detect a 10% change in bone metabolic activity. Typically these changes appear as asymmetric areas of increased uptake, most often in the axial skeleton. The choice of which patient to evaluate with bone scan is based on history, physical and laboratory evaluations. Any patients with new, unexplained pain should be evaluated with bone scan. Similarly any patient with biochemical evidence for bony involvement (elevated calcium, elevated alkaline phosphatase) should be evaluated with a bone scan. If the bone scan is questionable, equivocal, or if weight bearing bones are involved, the patient should be evaluated with plain films of the involved bones. Again in small cell lung cancer, all patients should undergo bone scanning and/or bone marrow biopsy. As many as 25% of patients with small cell lung cancer will have bone marrow involvement at the time of initial diagnosis. Liver Liver disease secondary to lung cancer can present without symptoms. Therefore, initial chest CT scans for lung cancer should always include the liver and adrenals. Two of the keys to identifying lesions as malignant on CT scan are their vascularity and size. Metastatic lesions are vascular and, therefore, detectable on contrast enhanced CT. Ultrasound is helpful in separating solid lesions from cystic lesions in the liver. Although abnormal liver function tests are common in patients with liver metastases, the abnormalities are mild and nonspecific. The most commonly elevated liver enzyme is alkaline phosphatase. Other laboratory signs of widespread metastatic disease include hypoalbuminemia, anemia, and elevation of transaminases. Adrenals  Adrenal involvement from lung cancer is usually asymptomatic. For this reason, the initial chest CT scan needs to include sections through the adrenals. Normally, the adrenals are clearly visible on contrast enhanced CT scans of the abdomen.
One clinical challenge in lung cancer is to differentiate adrenal metastases from benign adrenal enlargement (e.g. adenomas, cysts). Using only size criteria, the false-positive rate is as high as 80%. Metastases should be considered when the size is greater than 1 cm, the normal sharp adrenal borders are lost, or the tissue attenuation is lower than glandular tissue in contrast enhanced scans. Ultimately, histologic confirmation is required, and CT guided needle biopsy is the method of choice
Metastatic Disease
Unfortunately, mestastatic lesions often present as the first manifestation of an occult bronchogenic lesion. No organ is spared, but certain sites are seen much more frequently than others.
€ adrenals are involved 50% of the time
€ liver is involved 30 - 50% of the time
€ brain metastases occur 20% of the time
€ bone metastases are seen 20% of the time
This specimen demonstrates a fairly well circumscribed mass occupying most of the adrenal cortex. As with tuberculosis invasion of the adrenal glands, when approximately 90% of the adrenal cortex of both adrenals is destroyed by a metastatic lesion, the patient will develop Addison's disease -- primary, chronic adrenal insufficiency
Paraneoplastic Syndromes
About 10% of lung cancer patients develop a paraneoplastic syndrome. The pathophysiology of these syndromes is poorly understood but many are related to ectopic hormone production. Although many of these syndromes have been reported, few are clinically important. Ectopic hormone production is most often associated with small cell lung cancer. Especially common are the syndrome of inappropriate antidiuretic hormone (SIADH) and ectopic ACTH production. While ectopic ACTH production is not unusual, Cushing's syndrome is unusual because patients do not often survive long enough to develop the full clinical syndrome. Hypercalcemia due to ectopic PTH-like hormone is most often associated with squamous cell carcinoma. Digital clubbing and hypertrophic osteoarthropathy (HPO) also occur with lung cancer. Neuromuscular disorders occur in lung cancer patients with up to 5% of patients having some neuromyopathy. Probably the best described syndrome is Eaton-Lambert syndrome. This is a myasthenic-like syndrome, however, it differs from myasthenia gravis because motor strength improves with repetitive stimulation while in myasthenia gravis muscle strength decreases with repetitive stimulationNEUROENDOCRINE TUMORS OF LUNG
Carcinoid Tumors
 The ultrastructural features of lung carcinoids are well known to electron microscopists. The dominant property is the presence of dense-core granules and they are probably present in every tumor though they vary in number and to some degree in appearance. Most carcinoids have round granules, but in fewer than 10%, the granules are large and angular. Morphometric analysis of the granules in lung carcinoids has confirmed that they range in caliber from an upper limit of approximately 400 nm down to about 100 nm. In any one tumor, the granules fall within a narrow range of diameters. As a rule, the granules are numerous and present in most of the cells, but they vary in frequency and some cells have few or no visible granules within a plane of section. There does not appear to be a relationship between the size or appearance of the granules and the immunostaining properties.
 Small Cell Carcinoma =OAT CELL CARCINOMA
Small cell carcinomas account for 20% to 25% of primary carcinomas of the lung and it is now widely acknowledged that they form the aggressive end of the spectrum of neuroendocrine lung tumors. This can be a difficult light microscopic diagnosis, particularly when the amount and quality of the material available for study are less than optimal, and electron microscopy is useful if an adequate specimen is available. Fine needle aspirates are suitable for ultrastructural study provided they have been properly procured and processed.Some variation in cell and nuclear size and shape can be appreciated among small cell lung carcinomas by light microscopy and there have been attempts to define subtypes. However, these features generally vary within a particular tumor, and they are influenced by artefactual changes and are consequently not sufficiently reproducible for use as criteria in paraffin sections, nor is there evidence that the suggested subtypes have clinical relevance. Morphometry performed using low magnification electron micrographs has shown that there is an overlap in cell and nuclear size and shape with other lung tumors, but the nuclear-cytoplasmic ratio is significant. The scanty cytoplasm is often strikingly obvious to the electron microscopist. Organelles are generally sparse. Cell junctions range from a few small well-formed desmosomes to scattered tiny densities on the apposed cell membranes. The nuclear chromatin is customarily finely clumped and evenly distributed, obscuring small nucleoli, but in a few otherwise typical small cell carcinomas, the chromatin is fine and nucleoli prominent.Neuroendocrine differentiation is manifested ultrastructurally by the presence of dense-core granules. They are consistently small in caliber in small cell lung carcinoma cells, measuring roughly 100 nm and resembling the granules in extrapulmonary neuroendocrine carcinomas and neuroblastomas. In my experience, they are never as plentiful as granules in a typical carcinoid, and are rarely numerous. More often, scattered granules are found in only some of the cells. In roughly one third of cases, granules are extremely difficult to find or seem to be absent, and the possibility that these are true neuroendocrine tumors can not be confirmed from their ultrastructure. Since the lower end of the range of granule size in carcinoid cells is of the order of 100 nm, this feature alone will not discriminate between carcinoids and small cell carcinomas when the granules are small. Most carcinoids have larger granules, however, and the other ultrastructural features make distinction an easy one.In a small proportion of small cell lung carcinomas, a non-small cell component is present, and the ultrastructural of both parts of these combined variants is fairly typical. Cells of the two types can be connected by small desmosomes.  Non-Small Cell Carcinoma With Neuroendocrine Features
At the present time, there is limited information on the ultrastructure of the tumors that fall in this category and more examples need to be studied with the electron microscope. By light microscopy, a large cell neuroendocrine carcinoma with many mitoses has been defined and recognized to be an aggressive tumor with a survival rate similar to that of small cell lung carcinoma. For its identification, neuroendocrine features in large cell carcinomas must be evident by light microscopy and their presence verified by immunoperoxidase studies (chromogranin and synaptophysin are the best markers) or electron microscopy.Some non-small cell lung carcinomas which look like typical adenocarcinomas or less frequently squamous cell carcinomas have been documented to possess neuroendocrine properties by immunoperoxidase methods. The clinical relevance of this observation has not been adequately defined. In my experience, it is an unusual occurrence to encounter numerous dense bodies which are morphologically acceptable as neuroendocrine granules in cells of an adenocarcinoma, and they are distinctly rare in squamous carcinomas.===============================================================================================================================================================================
Cough can be divided into two categories that are not mutually exclusive (Grade II-2, II-3):acute, lasting less than 3 weeks; or chronic, lasting at least 3 to 8 weeks. Acute cough is most frequently due to the common cold (Grade III). Chronic cough is often simultaneously due to more than one condition. A single cause of cough has been found from 38 to 82% of the time, multiple causes from 18 to 62%. Multiply caused cough has been due to three diseases up to 42% of the time (Grade II-2, II-3). In patients seeking medical attention, the most common causes of chronic cough in nonsmokers in all age groups are PNDS from a variety of upper respiratory tract conditions, asthma, and GERD (Grade II-2, II-3). This is true whether the cough is described as dry or productive (Grade II-2). PNDS, asthma, and/or GERD are likely to be the cause(s) of chronic cough approximately 100% of the time in nonsmoking patients who are not taking an ACEI drug and who have normal chest radiographs (Grade II-2). 
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Other aspects of the ultrastructure of lung carcinoids can be useful in defining the criteria used by light microscopy to separate them from small cell and non-small cell carcinomas, and to explain light microscopic appearance such as oncocytic transformation. Morphometric studies have shown that the size of carcinoid tumor cells and their nuclei are of limited value in differential diagnosis as there is considerable overlap between carcinoids and the other lung tumors, but the quantity of cytoplasm and appearance of the nuclear chromatin are helpful. The variety of architectural patterns seen among lung carcinoids by light microscopy can be appreciated in low-magnification micrographs but they have little correlation with the fine structure of the component cells.