An Overview of Neuroendocrine Lung Tumors

Doctor pointing out a neuroendocrine lung tumor on chest X-ray

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Neuroendocrine lung tumors (neuroendocrine lung carcinomas) are cancers that arise in cells called neuroendocrine cells, and account for around 25 percent of lung cancers. The most common of these, small cell lung cancer and large cell lung cancer, are fairly well known, but typical and atypical carcinoid tumors are less well understood, even among oncologists.

Warning signs are similar to other lung cancers, with symptoms such as a persistent cough and recurrent lung infections, but carcinoid tumors are often missed early on, both due to lack of awareness, and the fact that these tumors may not show up on a chest X-ray.

Tests such as a CT scan are most commonly used in the diagnosis. Treatment for early-stage disease with surgery can offer a chance for a cure, though treatment is more challenging in the advanced stages of the disease.

Since small cell lung cancer and large cell lung cancer (a type of non-small cell lung cancer) are covered in detail elsewhere, this article will focus primarily on typical and atypical carcinoid tumors of the lung.

Typical carcinoid tumors account for roughly 1.8 percent of lung cancers, with atypical carcinoid tumors comprising roughly 0.2 percent of these cancers. For reasons that aren't certain, the incidence of pulmonary carcinoid tumors has increased significantly over the past 30 years, with some sources estimating that carcinoid tumors now account for up to six percent of lung cancers.

Neuroendocrine Tumors

Neuroendocrine tumors arise from neuroendocrine cells, cells that are responsible for healing epithelial tissues, such as the tissues that line the airways, the digestive organs, and more.

In the lungs, neuroendocrine cells are thought to respond to oxygen and carbon dioxide and play a role in air and blood flow. They also help control the growth and repair of other types of lung cells. (People who live at high altitudes have larger numbers of these cells in their lungs.) The lungs are the second most common site of neuroendocrine tumors following the digestive tract, with tumors also occurring in organs such as the thymus and ovary.

Neuroendocrine tumors are a heterogeneous group of tumors that differ widely in their aggressiveness, response to treatment, and prognosis. These cells behave in some ways like nerve cells, and in other ways like endocrine cells (hormone-producing cells), and some of these tumors produce substances that act like hormones in the body.

Types

The World Health Organization has broken down neuroendocrine tumors of the lungs into three different categories:

  • Low grade (well differentiated): Including typical carcinoid tumors
  • Intermediate grade (well differentiated): Including atypical carcinoid tumors
  • High grade (poorly differentiated): Including large cell lung cancer and small cell lung cancer

Small Cell Lung Cancer

Small cell lung cancer accounts for 15 percent to 20 percent of lung tumors and is usually a rapidly growing and aggressive cancer. It tends to spread early and is often metastatic at the time of diagnosis.

Large Cell Lung Cancer

Large cell lung cancer is one of the subtypes of non-small cell lung cancer and accounts for roughly three percent of lung cancers. These tumors also grow rapidly. Like small cell lung cancer, these tumors tend to occur centrally, near the large airways, and therefore often cause symptoms early on in the disease.

Carcinoid Tumors (Typical and Atypical)

Carcinoid tumors are considered low-grade tumors and usually grow slowly. They occur at a younger age than most lung cancers, with an average age between 50 and 60 at the time of diagnosis. Carcinoid tumors may occur at any age and are the most common lung tumor found in childhood.

There are two primary subtypes of carcinoid tumors:

  • Typical carcinoids are the most common type of carcinoid tumors, accounting for around 90 percent of these tumors. They tend to be low-grade, slow growing, and are often diagnosed in the early stages.
  • Atypical carcinoids are usually intermediate grade (in between well-differentiated and poorly differentiated as far as how normal the cells appear under the microscope). They are usually more aggressive than typical carcinoids, but less aggressive than most other lung cancers. Atypical carcinoids are more likely to metastasize or recur after treatment than typical carcinoid tumors.

Most typical carcinoid tumors grow near the large airways of the lungs. Atypical carcinoids may occur either centrally or peripherally, with roughly equal numbers of these tumors found in each location.

The incidence of carcinoid tumors is increasing and may be more common than once thought. A study published in the World Journal of Surgical Oncology expressed concern that carcinoid tumors are often misdiagnosed as being lung adenocarcinomas. Since treatment options, other than for early-stage disease, differ between these types, this could have an impact on outcomes if not properly classified.

Symptoms

As noted earlier, neuroendocrine tumors often occur near the large airways, and the first symptoms of the disease are often related to obstruction of the airways by the tumor. That said, a significant number of people with carcinoid tumors are asymptomatic at the time of diagnosis.

Signs and symptoms may include:

Less commonly (and usually in the advanced stages) people may experience chest pain, shortness of breath, hoarseness, unexplained weight loss, and a general feeling of being unwell.

Some carcinoid tumors can also produce unique symptoms due to substances (hormones and hormone-like substances) produced and secreted by the tumors. Carcinoid syndrome is a constellation of symptoms caused by substances produced by the tumors (such as serotonin) and can include flushing of the face and neck, diarrhea, and other symptoms.

Tumors that secrete a hormone called adrenocorticotropic hormone (ACTH) may cause Cushing's syndrome, a syndrome characterized by weight gain, weakness, darkening of the skin, and excess hair growth on the face and body (hirsutism). (ACTH stimulates the adrenal glands to produce cortisol and other hormones.)

Tumors that secrete growth hormone may cause acromegaly, a condition that includes growth of the hands and feet in adults. Other tumors may produce substances that lead to an elevated blood calcium (hypercalcemia) with muscle cramps and confusion among other symptoms.

Causes and Risk Factors

While the causes of neuroendocrine tumors are uncertain, several risk factors have been identified.

Small cell and large cell lung cancers are strongly related to smoking, and risk factors are similar to other general risk factors for lung cancer.

Carcinoid tumors, however, have not been clearly linked with cigarette smoking or environmental toxins. These tumors can be found in young adults and even children, and as noted, the incidence is increasing for unknown reasons. They are more common in women than in men, and more common in whites than in blacks, Asians, or Hispanics.

Carcinoid tumors are slightly more common in people who have a family history of the disease, but most people who are diagnosed do not have a family history. Carcinoid tumors are associated with some genetic syndromes, such as multiple endocrine neoplasia 1 (MEN1). Roughly five percent to eight percent of people with MEN1 will develop a carcinoid tumor of the lung.

Diagnosis

The diagnosis of neuroendocrine tumors (specifically carcinoid tumors) may include a combination of blood tests, imaging studies, and a lung biopsy.

Blood tests

Blood tests are not used to diagnose neuroendocrine tumors directly but can help distinguish subtypes of the disease or identify specific functions of the cells (and consequently, potential treatment options).

The Ki67 proliferation index may be used to distinguish high-grade tumors (such as small cell lung cancer) from low-grade tumors (carcinoids). With carcinoids, tumors with a higher Ki67 (more than 15 percent) may be more likely to respond to chemotherapy, whereas those with low levels (less than 10 percent) may be more likely to respond to somatostatin analogs (see below).

Some neuroendocrine cells make substances (peptides or amines) that can be found in the blood or urine, such as ACTH, growth hormone, melanocyte stimulating hormone, and others.

A general chemistry panel is done as well, looking for changes that may be associated with the spread of these tumors to the liver or bones.

Imaging Studies

A chest X-ray is often the first test done when a person sees their doctor, but carcinoids can be easily missed (chest X-rays miss around 25 percent of carcinoids). With carcinoids, doctors most often recommend a CT of the abdomen along with a CT of the chest.

Somatostatin receptor scintigraphy may also be used. In these scans, a person is given a hormone-like substance called octreotide that is attached to a radioactive particle (indium-111). Octreotide binds to carcinoid tumors, and a scan can then detect where radioactivity occurs in the body to locate the tumor.

With typical carcinoids, further staging tests are not usually needed but are often done with atypical carcinoids. These include a CT or MRI to look for evidence of liver metastases. PET scans are tests that look for increased metabolic activity in cancer cells. Since carcinoid tumors do not usually have increased metabolic activity, these scans are not usually very helpful (carcinoids may appear benign on a PET scan).

Bronchoscopy

A bronchoscopy is a test in which a flexible tube is threaded through the mouth and down into the bronchi. Since many carcinoid tumors are located in or near the large airways, this procedure can allow physicians to visualize a tumor, and often do a biopsy (around 75 percent of carcinoids can be found on bronchoscopy).

Biopsy

When a carcinoid tumor is suspected, a lung biopsy is usually needed to make a definitive diagnosis. This may be done with a needle biopsy, by brushings during a bronchoscopy, or via an endobronchial ultrasound (a test in which an ultrasound is used to locate tumors near but deep to the airway, and then a needle biopsy is done with ultrasound guidance from within the airway).

Staging

After carcinoid tumors are diagnosed, they are broken down into four stages the same way as other lung cancers. Doctors use something called TNM staging, that looks at the size of the tumor, whether the tumor has spread to any lymph nodes, and whether it has metastasized, to determine the stage. Stages 1, 2, and 3A are often referred to as early-stage lung cancer, whereas stage 3B and stage 4 are considered advanced.

Typical carcinoids are often diagnosed at stage 1, whereas half of atypical carcinoids are at least stage 2 or stage 3 at the time of diagnosis.

Treatments

The treatment options for carcinoid tumors will depend on the stage of the disease, the location of the tumor, and more.

Unfortunately, some of the newer treatments for lung cancer, such as targeted therapies and immunotherapy, are of limited use with carcinoid tumors. That said, the prognosis of carcinoid tumors is much better than other types of lung cancer, and when caught in the early stages, surgery can be curative. Since relatively few studies have looked at the best treatment options for advanced carcinoids, there is currently no standard of care for these tumors.

(The treatment of small and large cell lung cancers is discussed separately under those articles).

Surgery

With early-stage carcinoids, lung cancer surgery is the treatment of choice and can be curative. Depending on the size of the tumor, a doctor may recommend a wedge resection, in which the tumor and a wedge of tissue surrounding the tumor is removed, a lobectomy, in which a lobe of the lung is removed (the right lung has three lobes and the left lung has two lobes), or a pneumonectomy, in which an entire lung is removed.

While a pneumonectomy sounds like a major procedure (and it is), many people, especially those who are in good general health prior to their surgery, are able to live full, active lives with only one lung.

Surgery may be done by a large incision in the chest (via a thoracotomy), but the use of minimally invasive lung surgery is becoming much more common (and involves a shorter hospital stay and more rapid recovery). In video-assisted thoracoscopic surgery, several small incisions are made in the chest, and a section or lobe of the lung is removed with special instruments.

Depending on the size of the tumor, lymph node biopsies may be taken of lymph nodes near the area where the bronchi enter the lungs (hilar lymph nodes) and/or lymph nodes in the area between the lungs (mediastinal lymph nodes).

Unlike many types of lung cancer, adjuvant treatment (chemotherapy and/or radiation therapy following surgery to "clean up" any remaining cells) is not usually used, even with the more advanced stages of carcinoid tumors.

Biological Therapy/Everolimus

The treatment of carcinoid tumors is more challenging once the disease is advanced or spreads to other regions of the body. The biological drug Afinitor (everolimus) was approved in 2016 as the only approved first-line treatment for lung carcinoid tumors. It is recommended for progressive and inoperable carcinoids that do not secrete hormone-like substances (nonfunctional carcinoids). For both typical and atypical carcinoids, Afinitor has been found to decrease the progression of the disease and improve survival.

Afinitor is a mTOR inhibitor, a drug that interferes with a signal that causes the cancer cells to divide and grow. It is taken as a daily pill and is usually tolerated very well, with only around 10 percent of people having significant side effects.

Somatostatin Analogues

Somatostatin analogs have been used for people with carcinoid tumors of the digestive tract and may be effective in people who have tumors that secrete the substances that lead to carcinoid syndrome. They are recommended as first-line treatments for patients with indolent slow growing somatostatin-receptor-positive carcinoid lung tumors. Sandostatin (octreotide), Somatuline (lanreotide), and Signifor (pasireotide) may reduce the symptoms of carcinoid tumor and temporarily reduce the size of a carcinoid tumor, but are not curative treatments.

Chemotherapy

Carcinoid tumors are not very responsive to chemotherapy, but chemotherapy may be used for tumors that are not responding to other treatments, especially tumors that have a high Ki67 proliferation index.

Radiation Therapy

Radiation therapy may be an option if a tumor is early stage, but surgery is not possible. Specialized techniques such as stereotactic radiosurgery (SBRT) deliver high doses of radiation to a small area of tissue, and may, at times, provide results similar to those attainable with surgery.

Radioactive drugs, such as the combination of octreotide combined with a radioactive particle used for scans, may be used in higher doses to treat carcinoid tumors. This approach has been effective for some people with advanced carcinoids that were not responding to any other treatments but is still considered investigational.

Treatment of Metastases

With other forms of lung cancer, solitary or only a few metastases (oligometastases) are sometimes treated with the goal of long-term survival. Since much less research has been done on carcinoid tumors, it's uncertain whether specific treatment of bone metastases or liver metastases could make a difference in survival.

Clinical Trials

There are currently clinical trials in place looking at better ways to treat carcinoid tumors of the lungs. The targeted drug Sutent (sunitinib) has been found helpful in pancreatic carcinoids. Angiogenesis inhibitors, such as Avastin (bevacizumab) are also being evaluated.

Palliative

Palliative care, or the treatment of symptoms related to cancer, can greatly improve the quality of life for people living with advanced lung cancers such as advanced carcinoid tumors. In addition to managing pain, airway obstruction, and other physical symptoms, this care aims to help people with the emotional and spiritual concerns associated with cancer as well.

While hospice is considered a form of palliative care, palliative care may be used even for people with highly curable tumors. Many cancer centers now offer palliative care consults.

Prevention and Screening

While screening for carcinoid tumors is not recommended for the general public, some physicians recommend screening for people with multiple endocrine neoplasia 1. For these people, chest CT scans every 3 years starting at age 20 have been proposed, but we don't have any data showing whether this improves survival.

Screening for large cell and small cell neuroendocrine tumors follows the general lung cancer screening guidelines.

Prognosis

The prognosis for small cell and large cell lung cancer is discussed separately under those articles.

The prognosis for carcinoid tumors, however, is much better than that of other forms of lung cancer. The prognosis is better for early-stage tumors than advanced tumors, with the overall 5-year survival rate for typical carcinoid tumors of the lung between 85 percent and 90 percent, and 5-year survival rate for atypical carcinoids, 50 percent to 70 percent.

A Word From Verywell

Despite an increasing incidence of lung carcinoid tumors, relatively little research has focused on these cancers, and awareness by both the public and physicians is greatly needed. For this reason, it's important to be your own advocate in your care and ask a lot of questions. There are many reasons why getting a second opinion is important, and it's often recommended (with uncommon tumors such as carcinoids) that a second opinion be obtained at a larger cancer center or National Cancer Institute-designated cancer center. These centers are more likely to have oncologists on staff who specialize in lung cancer alone, or even carcinoid tumors specifically. Seeking support and information from others facing the same journey is also invaluable, and there is a very active lung cancer support community online.

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