Combined Small Cell Carcinoma of Lung

Combined Small Cell Carcinoma of Lung

Articlecombinedsmallcellcarcinomalung
Healthy Lungs
Diseases & Conditions
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Contributed byKrish Tangella MD, MBAMar 21, 2020

What are the other Names for this Condition? (Also known as/Synonyms)

  • Combined SCLC
  • Combined Small Cell Lung Carcinoma
  • Pulmonary Combined Small Cell Carcinoma

What is Combined Small Cell Carcinoma of Lung? (Definition/Background Information)

  • Lung cancer is a high mortality cancer that affects the lungs. Any individual can develop lung cancer, although individuals who smoke cigarettes remain at the highest risk for the condition. It is the most common cause of cancer-related death in the world
  • Small cell carcinoma of lung is a high-grade lung cancer that exhibits neuroendocrine features. Combined Small Cell Carcinoma of Lung is a small cell lung carcinoma with an additional non-small cell carcinoma histological component of any proportion. The tumor is diagnosed under a microscope, on examination of the cancer cells by a pathologist
  • The non-small cell carcinoma component may include any of the following:
    • Adenocarcinoma
    • Squamous cell carcinoma
    • Large cell carcinoma
    • Large cell neuroendocrine carcinoma
    • In some cases, spindle cell carcinoma or giant cell carcinoma component may be present
  • Almost all individuals affected by small cell lung carcinoma (SCLC) are heavy to very heavy smokers. The cause of development of Combined Small Cell Carcinoma of Lung type is unknown, but several genetic mutations (especially involving the RB1 and TP53 genes) and chromosomal abnormalities have been recorded
  • Combined Small Cell Carcinoma of Lung arises in the proximal airways of the lung and can cause chest pain, breathing difficulties, fatigue, and other general signs and symptoms, such as fever, weight loss, and appetite loss
  • Chemotherapy, surgery, radiation therapy, and other treatment measures may be used for treating Combined Small Cell Carcinoma of Lung based on the assessment of the physician
  • The prognosis depends on many factors including the subtype and stage of cancer, progression of the condition, response to treatment, and overall health of the individual. In general, the prognosis of Combined Small Cell Carcinoma of Lung is poor

Who gets Combined Small Cell Carcinoma of Lung? (Age and Sex Distribution)

  • Individuals under the age of 40 years are rarely diagnosed with lung cancer. The majority of Combined Small Cell Carcinoma of Lung cases are detected and diagnosed in adults over the age of 65 years
  • Both males and females are affected
  • Current studies do not show any racial or ethnic predilection

What are the Risk Factors for Combined Small Cell Carcinoma of Lung? (Predisposing Factors)

The following factors have been identified as increasing the risk for Combined Small Cell Carcinoma of Lung:

  • Smoking: Smoking cigarettes, cigars, or pipes, increase the risk due to damaging chemicals being inhaled into the lungs. Prolonged smoking damages the lung, resulting in reduced clearance of the chemical carcinogens that accumulate in the lungs
  • It has been noted that almost all the individuals with small cell carcinoma of lung are heavy smokers (smoking for over 30 years)
  • The presence of lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD), can increase the risk. This may compound the risk or act as independent risk factors

In general, physicians believe that certain factors may increase an individual’s risk for lung cancers and these include:    

  • Advancing age: The risk increases with age and most cases occur in individuals over the age of 65 years
  • Air pollution: Exposure to polluted air may increase any individual’s risk. This is true, especially in the case of smokers, who are exposed to air pollution, than non-smokers
  • Exposure to arsenic and other hazardous substances
  • Exposure to asbestos and other harmful chemicals and heavy metals: Prolonged exposure to asbestos and other harmful chemicals including chromium, nickel, and tar
  • Exposure to secondhand smoke: Individuals, who do not smoke, but live with smokers, also have an increased risk
  • Radon causing indoor air pollution: Radon, a colorless, odorless, and tasteless radioactive gas is produced by the natural breakdown of uranium in soil and rocks. In certain geographical regions, hazardous levels of radon gas can develop inside building or households. Individuals exposed to excessive amounts of radon gas are vulnerable to lung cancer
  • Family history: Individuals with one or more immediate family members or relatives with a history of lung cancer
  • Personal history: Individuals who have previously had lung cancer have an increased risk of its recurrence
  • Certain longstanding lung diseases: Lung diseases, such as lung fibrosis, tuberculosis, and bronchitis, over a prolonged period of time, may increase an individual’s risk
  • Radiation therapy to the chest: Individuals who had radiation therapy to the chest for another cancer are increasingly prone to lung cancer
  • Working in mines
  • The presence of alpha 1 antitrypsin deficiency disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Combined Small Cell Carcinoma of Lung? (Etiology)

The exact cause of Combined Small Cell Carcinoma of Lung is unknown.

  • This cancer type is very strongly associated with smoking; prolonged exposure to cigarette smoke is shown to induce genetic mutations. All cases of small cell carcinomas affecting the lung are seen in individuals who have been continuously smoking for several decades (up to 30 years or more)
  • Many genetic and chromosomal anomalies have been reported, which include:
    • Gene amplification seen in FGFR1, MYCL, E2F2, and CCN2 genes
    • Gene mutation seen in CREBBP, EP300, MLL, PTEN, SLIT2, and EPHA7 genes
    • And gene inactivation seen in TP53 and RB1 genes (in many cases)
  • No preinvasive lesions, such as diffuse idiopathic pulmonary neuroendocrine hyperplasia (DIPNECH), or genetic mutations on MEN1 gene, which are both noted in pulmonary carcinoid tumors, are observed
  • It is believed that there may also be certain other factors contributing to the condition, which include exposure to radon, and prolonged exposure to asbestos and other harmful chemicals (arsenic, chromium, nickel, and tar)
  • In general, it is known that cancers form when normal, healthy cells begin transforming into abnormal cells - these cancer cells grow and divide uncontrollably (and lose their ability to die), resulting in the formation of a mass or a tumor
  • The transformation of normally healthy cells into cancerous cells may be the result of genetic mutations. Mutations allow the cancer cells to grow and multiply uncontrollably to form new cancer cells
  • These tumors can invade nearby tissues and adjoining body organs, and even metastasize and spread to other regions of the body

What are the Signs and Symptoms of Combined Small Cell Carcinoma of Lung?

The features of Combined Small Cell Carcinoma of Lung may include:

  • It is a rapidly-growing, poorly-differentiated tumor that shows a sudden onset of signs and symptoms
  • Due to its sudden growth, the tumors are found to be larger in sizes on imaging studies, and diagnosed at more advanced stages, when compared to non-small cell carcinomas of the lung (such as adenocarcinoma and squamous cell carcinoma)
  • A majority of the tumors originate from the central airways (proximal lung region); rarely, the tumors are seen in the peripheral lung regions. However, tumors may be present anywhere in the lung
  • Large masses are known to obstruct the bronchus (main airways) and also involve the lymph nodes
  • When the cancer is present in the outer lung region (periphery), it may be visible as a solitary nodule

Early-stage lung cancer rarely causes any signs and symptoms and initially makes for a difficult diagnosis. Besides, several of the primary symptoms may result from non-malignant disorders too. The overlapping signs and symptoms may result in a delayed diagnosis of lung cancer in some cases.

However, due to fast-growing tumors into the thoracic region, spread of tumor outside the lungs, the presence of paraneoplastic symptoms, or a combination of any of these factors, the signs and symptoms of Combined Small Cell Carcinoma of Lung are known to appear suddenly.

The common signs and symptoms may include the following:

  • Shortness of breath that gets worse with time; difficulty in breathing
  • Cough that may be persistent; blood in cough/sputum (hemoptysis)
  • Chest pain, heaviness in the chest
  • Changes to voice, hoarseness, or loss of voice

Signs and symptoms associated with Combined Small Cell Carcinoma of Lung, which may emerge during the later stages of the condition, include:

  • High temperatures (fever) and excessive night sweats (may be recurrent)
  • Sudden weight loss; unintentional weight loss; changes in appetite
  • The individual is easily tired, resulting in fatigue even with minimal activity
  • Headache
  • Low blood pressure
  • The tumor can affect the superior vena cava (a major blood vessel)

Paraneoplastic syndrome associated symptoms:

  • Paraneoplastic and endocrine syndrome is commonly observed in lung cancer. The association of this condition to small cell lung carcinoma is the highest compared to all other histological subtypes of lung cancer
  • Paraneoplastic syndrome associated symptoms are a set of signs and symptoms that occur in the body due to the presence of cancer, due to changes in the immune system
  • The tumor is known to express hormones, such as antidiuretic hormone (ADH) and adrenocorticotropic hormone (ADCH), and gastrin-releasing peptides including calcitonin
  • Paraneoplastic symptoms can also occur due to brain involvement leading to neurological signs and symptoms. These may be seen many months before lung cancer is diagnosed

How is Combined Small Cell Carcinoma of Lung Diagnosed?

The following procedures and tools may be used in the diagnosis of Combined Small Cell Carcinoma of Lung:

  • Physical examination: During a physical exam, a physician will check the individual’s overall health status, listen to their breathing, and check for possible fluid buildup in the lungs (auscultation)
  • Pulmonary function tests can help determine the extent of lung damage; it can also help the healthcare provider assess the ability of lungs to deliver oxygen to the body
  • Chest X-ray: Two-dimensional pictures using tiny amounts of radiation are taken, in order to detect any tumors or other medical issues associated with the lungs, such as pneumonia. Tumors inside the lung can be detected using a chest X-ray; although sometimes, these tumors are too small to visualize (tumors less than 1 cm in size may be missed on a chest X-ray)
  • Computerized tomography (CT) scan: Also known as CAT scan, this radiological procedure creates detailed three-dimensional images of structures inside the body. CT scans may be helpful in detecting recurrences, or if the cancer has metastasized to the surrounding lymph nodes of the lungs
  • Magnetic resonance imaging (MRI) scan: An MRI scan uses magnetic fields that create high quality pictures of certain body parts, such as tissues, muscles, nerves, and bones. These high-quality images may indicate to a physician, if any tumor is present
  • Positron emission tomography (PET): A PET scan is a nuclear medicine imaging technique that uses three-dimensional images to show how tissue and organs are functioning. A small amount of radioactive material may be injected into a vein, inhaled or swallowed. A PET scan is also helpful in detecting recurrences, or if any metastasis (to the surrounding lymph nodes of the lungs) has occurred
  • Sputum cytology: Sputum cytology is test that involves the collection of mucus (sputum), coughed-up by a patient. After the mucus is collected, a pathologist examines it in an anatomic pathology laboratory, to see if any cell abnormalities are present indicative of the tumor
  • Bone scan: A bone scan is a nuclear imaging test that involves injecting a radioactive tracer into an individual’s vein. Bone scans are primarily used to detect if the cancerous cells have metastasized to the bones and formed secondary tumors
  • Bone marrow biopsy: Bone marrow is a soft tissue found within bones. Occasionally, with Combined Small Cell Carcinoma of Lung, a bone marrow biopsy is used to detect blood abnormalities, or if a physician believes that metastasis to the bone marrow may have occurred

A biopsy refers to a medical procedure that involves the removal of cells or tissues, which are then examined by a pathologist. Different biopsy procedures include:

  • Tissue biopsy from the affected lung:
    • A biopsy of the tumor is performed and sent to a laboratory for a pathological examination. A pathologist examines the biopsy under a microscope. After putting together clinical findings, special studies on tissues (if needed) and with microscope findings, the pathologist arrives at a definitive diagnosis. Examination of the biopsy under a microscope by a pathologist is considered to be gold standard in arriving at a conclusive diagnosis
    • Biopsy specimens are studied initially using Hematoxylin and Eosin staining. The pathologist then decides on additional studies depending on the clinical situation
    • Sometimes, the pathologist may perform special studies, which may include immunohistochemical stains, molecular testing, flow cytometric analysis and very rarely, electron microscopic studies, to assist in the diagnosis
  • The biopsy may be performed through any of the following procedures:
    • Bronchoscopy: A special medical instrument, called a bronchoscope, is inserted through the nose and into the lungs to collect small tissue samples
    • Thoracentesis: During thoracentesis, physicians use a special medical device called a cannula, to remove fluid between the lungs and the chest wall for examination
    • Thoracoscopy: A medical instrument called a thoracoscope is inserted into the chest through tiny incisions, in order to examine and remove tissue from the chest wall, which is then analyzed further
    • Thoracotomy: Thoracotomy is a surgical invasive procedure with special medical instruments to open-up the chest and remove tissue from the chest wall or the surrounding lymph nodes of the lungs
    • Mediastinoscopy: A medical instrument called a mediastinoscope is inserted into the chest wall to examine and remove samples
    • Fine needle aspiration biopsy (FNAB) or transthoracic needle biopsy: A device called a cannula is used to extract tissue or fluid from the lungs, or surrounding lymph nodes
    • Open lung biopsy

A differential diagnosis with respect to other lung cancer types may be necessary prior to establishing a definite diagnosis, by excluding the following tumors:

  • Large cell neuroendocrine carcinoma and carcinoid tumor (both typical and atypical) of lung
  • Ewing’s family of tumors
  • Primary non-small cell carcinomas (adenocarcinoma and squamous cell carcinoma, including the basaloid variant)
  • Secondary lung tumors that have metastasized from other regions to the lung

Note: An accurate diagnostic evaluation is crucial for staging and treatment purposes.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Combined Small Cell Carcinoma of Lung?

The complications of Combined Small Cell Carcinoma of Lung can include:

  • Dyspnea (shortness of breath): If the cancerous tumor expands to block important, large, or small airways of the chest or lung
  • Hemoptysis (coughing-up blood): Individuals may cough-up blood, due to excessive amounts of blood in the airways
  • Pain: Advanced stages that has metastasized to the pleural cavity (lining surrounding the lungs), invaded the chest wall, or other areas of the body may cause excessive pain
  • Pleural effusion (fluid in the chest): Excessive fluid accumulation, resulting from cancerous cells spreading inside the lungs, or outside of the lungs
  • Pericardial effusion; fluid accumulation around the heart
  • Irreversible lung damage such as due to lung fibrosis
  • Development of pneumothorax (collapsed lung)
  • Recurrence following surgical removal of the tumor

Involvement of local and distant organs in Combined Small Cell Lung Carcinoma:

  • Metastasis may occur to any part of the body and most cases are diagnosed during advanced stages; the cancer is also locally aggressive
  • Some of the sites/organs involved include the brain, liver, bone, adrenal glands, and other lung regions
  • Local lymph nodes are affected with bulky disease, which can also cause superior vena cava syndrome
  • Loss of function of the organ/area to which cancer has spread due to systemic involvement

There may be complications related to the methods used in treating the condition and may include:

  • Side effects of radiation therapy that may include sunburn-like rashes, where radiation was targeted, red or dry skin, heaviness of the breasts, and general fatigue
  • Side effects of chemotherapy, which may include nausea, vomiting, hair loss, decreased appetite, mouth sores, fatigue, low blood cell counts, and a higher chance of developing infections
  • The treatment can also cause infertility in men and women. Hence, measures to protect the individual’s fertility must be considered, before starting chemotherapy

How is Combined Small Cell Carcinoma of Lung Treated?

Treatment options available for individuals with Combined Small Cell Carcinoma of Lung are dependent upon the following:

  • Type of cancer
  • Location of the cancer
  • The staging of the cancer: If lung cancer is diagnosed, staging helps determine whether it has spread and which treatment options are best-suited for the individual
  • Personal preferences
  • Overall health status of the individual
  • Type of gene mutation involved: This factor can determine the treatment possibilities or relative treatment resistance

In many cases, due to advanced nature of the tumors at the time of diagnosis, surgery may not be a treatment option. In rare cases, when the tumor is detected at an early stage, the following treatment options may be considered.

The surgical options include:

  • Wedge resection: Wedge resection is a partial removal of the wedge-shape portion of the lung that contains cancerous cells (along with any surrounding healthy tissue)
  • Segmentectomy: It is the partial removal of the cancerous lung and any surrounding healthy tissue
  • Pulmonary lobectomy: It is a type of surgical procedure performed to partially remove a portion of a lung
  • Sleeve lobectomy: It is another surgical procedure to partially remove a portion of the lung and a part of the airway (bronchus)
  • Pneumonectomy: It is the surgical removal of the entire lung

Chemotherapy:

  • Chemotherapy drugs are typically taken as pills, or injected directly into a vein. These drugs travel through the body to kill any cancer cells
  • But, they can also kill healthy cells, located within the gastrointestinal tract and in hair follicles. The side effects include vomiting, nausea, and hair loss

Radiation therapy:

  • Radiation therapy involves using x-rays to kill cancerous cells. High-powered radiation beams are directed to particular body regions to target cancer. In the process, healthy cells can also be damaged
  • Radiation therapy can be administered in the following ways:
    • Either by a machine, placed outside the body (called external beam radiation)
    • Or it may be administered internally, by a device positioned directly at, or close to the malignant tumor, inside the lungs (called brachytherapy)

Since surgery may not be viable in a majority of cases, chemotherapy and/or radiation therapy remain the best treatment options. Radiation therapy and chemotherapy can be used as a combination therapy. Combinational therapy increases the effects of both types of treatment. However, the side effects are cumulative.

Targeted drug therapy: Targeted drug therapy is a relatively new medical treatment used to target abnormal cancer cells and reduce the chance of cancer spreading to other parts of the body.

How can Combined Small Cell Carcinoma of Lung be Prevented?

Currently, there is no known prevention method for Combined Small Cell Carcinoma of Lung. Although there are no preventable measures for lung cancer, in general, various steps can be taken to help decrease the risk of its formation. These measures include:

  • Complete smoking cessation and avoiding exposure to secondhand smoke: The risk for lung cancer decreases drastically following quitting or giving up smoking
  • Physical activity: Individuals, who participate in a moderate amount of physical activity, may decrease their risk
  • Adequate consumption of fruits and vegetables: A healthy diet, low in saturated fats and rich in many fruits and vegetables, may help decrease one’s risk for lung cancer
  • Avoid exposure to certain materials and chemicals (including asbestos, arsenic, chromium, nickel, and tar): Individuals who work with such substances should follow proper usage principles and occupational safety instructions, since a prolonged exposure to harmful chemicals may increase the risk for lung cancer. This risk is multiplied in smokers who are exposed to these harmful chemicals
  • Avoid exposure to radioactive gas: Radon, a radioactive gas, produced by the natural breakdown of uranium in soil and rocks, may develop to hazardous levels inside building spaces. Individuals exposed to excessive amounts of radon gas are vulnerable to lung cancer
  • Limit alcohol consumption: Alcoholic beverages have been linked to increasing an individual’s risk for certain types of cancers, such as those affecting the lungs, mouth, throat, esophagus, breast, colon, and liver
  • CT screening in high-risk groups can decrease the incidence of lung cancer, or at least help detect such cancers early. It is generally known that CT scans are about 3-4 times better than X-ray studies

What is the Prognosis of Combined Small Cell Carcinoma of Lung? (Outcomes/Resolutions)

  • Combined Small Cell Carcinoma of Lung is a highly-aggressive malignancy. The prognosis of the condition is generally poor. Factors that may favor a positive prognosis include female gender, younger age of the patient, and a ‘confined’ tumor that can be surgically removed
  • Factors that dictate a negative prognosis include metastasis to the central nervous system and bone marrow, increased lactate dehydrogenase (LDH) levels, presence of paraneoplastic syndrome, and low hemoglobin levels. Continued smoking after cancer diagnosis is a strongly negative prognostic factor
  • The prognosis of lung cancer, in general, depends upon a set of several factors that include:
    • The grade of the lung tumor such as grade1, grade2, and grade 3. Grade1 indicates a well-differentiated tumor, grade 2 a moderately-differentiated tumor, whereas grade 3 indicates a poorly-differentiated tumor. Grade 3 tumors are higher prone to metastasis to the lymph nodes and recurrences
    • Stage of lung cancer: With lower-stage tumors, when the tumor is confined to site of origin, the prognosis is usually excellent with appropriate therapy. In higher-stage tumors, such as tumors with metastasis, the prognosis is poor
    • Histological subtype of the tumor: Some subtypes have better prognosis than others
    • The size of the lung tumor: Individuals with small-sized tumors fare better than those with large-sized tumors
    • Overall health of the individual: Individuals with overall excellent health have better prognosis compared with those with poor health
    • Age of the individual: Older individuals generally have poorer prognosis than younger individuals
    • Individuals with bulky disease of the lung cancer have a poorer prognosis
    • Involvement of the lymph node, which can adversely affect the prognosis
    • Involvement of vital organs may complicate the condition
    • The surgical respectability of the tumor (meaning, if the tumor can be removed completely)
    • Whether the tumor is occurring for the first time, or is a recurrent tumor. Recurring tumors have worse prognosis compared to tumors that do not recur
    • Response to treatment of lung cancer: Tumors that respond to treatment have better prognosis compared to tumors that do not respond to treatment
    • Progression of the condition makes the outcome worse
    • An early diagnosis and prompt treatment of the tumor generally yields better outcomes than a late diagnosis and delayed treatment
    • The combination chemotherapy drugs used, may have some severe side effects (like cardio-toxicity). This chiefly impacts the elderly adults, or those who are already affected by other medical conditions. Tolerance to the chemotherapy sessions is a positive influencing factor

It is important to have follow-up appointments with a physician, to evaluate the effects of the current treatment method, and to monitor for any returning tumors.

Additional and Relevant Useful Information for Combined Small Cell Carcinoma of Lung:

  • Lung cancer incidence is around 35 cases per 100,000 populations: The incidence of lung cancer in non-smokers is 1-2 cases per 20,000 populations per year; its incidence in smokers is 20-30 times higher than that of non-smokers
  • Smoking is highly-associated with squamous cell carcinomas and small cell carcinomas; nevertheless, for all lung cancer forms, smoking is the single most important risk factor
  • Historically, men have been affected over women by lung cancer; however, the lung cancer male-female incidence gap is steadily reducing (especially in high-income countries)
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Krish Tangella MD, MBA

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