Carcinoid Tumor Treatment

Origin and general involvement and presentation

Carcinoid tumors are derived from primitive stem cells in the gut wall but can be seen in other organs (Broaddus, 2003), including the lungs (Moraes, 2003), mediastinum, thymus (Soga, 1999), liver, pancreas, bronchus, and ovaries (Piura, 1995). In children, most tumors occur in the appendix and are benign and asymptomatic. Although rare, aggressive and metastatic disease (eg, to the brain) does occur; even tumors in the appendix can metastasize (Hlatky, 2004; Volpe, 2000). Depending on size and location, carcinoid tumors can cause various symptoms, including carcinoid syndrome. Carcinoid tumors of the ileum and jejunum, especially those larger than 1 cm, are most prone to produce this syndrome, at least in adults.

Classification

Carcinoid tumors generally are classified based on the location in the primitive gut (ie, foregut, midgut, hindgut) that gives rise to the tumor. Foregut carcinoid tumors are divided into sporadic primary tumors and tumors secondary to achlorhydria. The term sporadic primary foregut tumor encompasses carcinoids of the bronchus, stomach, proximal duodenum, and pancreas. Midgut tumors are derived from the second portion of the duodenum, the jejunum, the ileum, and the right colon. These account for 60-80% of all carcinoid tumors (especially those of the appendix and distal ileum) in adults and are also seen in children (Schmittenbecher, 2001). Appendicular carcinoid tumors are most common (Bethel, 1997; Pelizzo, 2001). In children, more than 70% of these tumors occur at the tip of the appendix and are often an incidental finding in appendectomy specimens. In one study, carcinoid tumors were found in 0.169% of 4747 appendectomies (Doede, 2000). Bulky tumors are relatively rare and require somewhat extensive cecectomy or, when tumor infiltration is beyond the cecum, ileocecal resection (Soreide, 2000; D'Aleo, 2001; Pelizzo, 2001).

Hindgut carcinoid tumors include those of the transverse colon, descending colon, and rectum. Carcinoid tumors can also arise from the Meckel diverticulum, cystic duplications, and the mesentery. Each of these entities has distinctive clinical, histochemical, and secretory features. For example, foregut carcinoids are argentaffin negative and have low serotonin content but secrete 5-hydroxytryptophan (5-HTP), histamine, and several polypeptide hormones. These tumors can metastasize to bone and may be associated with atypical carcinoid syndrome, acromegaly, Cushing disease, other endocrine disorders, telangiectasia, or hypertrophy of the skin in the face and upper neck.

Midgut carcinoids are argentaffin positive and can produce high levels of serotonin 5-hydroxytryptamine (5-HT), kinins, prostaglandins, substance P (SP), and other vasoactive peptides. These tumors have a rare potential to produce corticotropic hormone (previously adrenocorticotropic hormone [ACTH]). Bone metastasis is uncommon. Hindgut carcinoids are argentaffin negative and rarely secrete 5-HT, 5-HTP, or any other vasoactive peptides. Therefore, they do not produce related symptomatology. Bone metastases are not uncommon in these tumors.

Pathophysiology

Carcinoid tumors are of neuroendocrine origin and are derived from primitive stem cells, which can give rise to multiple cell lineages. In the intestinal tract, these tumors develop deep in the mucosa, growing slowly and extending into the underlying submucosa and mucosal surface. This results in the formation of small firm nodules, which bulge into the intestinal lumen. These tumors have a yellow, tan, or gray-brown appearance that can be observed through the intact mucosa. The yellow color is a result of cholesterol and lipid accumulation within the tumor. Tumors can have a polypoid appearance and occasionally become ulcerated. With expansion and infiltration through the submucosa into the muscularis propria and serosa, carcinoid tumors can involve the mesentery. Metastases to the mesenteric lymph node and liver, ovaries, peritoneum, and spleen can occur.

Upon histologic examination, carcinoid tumors have 5 distinctive patterns: (1) solid, nodular, and insular cords; (2) trabecular or ribbons with anastomosing features; (3) tubules and glands or rosettelike patterns; (4) poorly differentiated or atypical patterns; and (5) mixed patterns. A combination of these patterns is often observed. Tubules can contain mucinous secretions, and individual tumor cells can contain mucin-positive material, which includes the various acidic and neutral intestinal mucin. Tumors rarely have eosinophilic stroma. Capillaries are often prominent. Cells are uniformly round or polygonal with a central nucleus and punctate chromatin, as well as small nucleoli and infrequent mitosis. The cytoplasm can be slightly acidophilic, basophilic, or amphophilic. Eosinophilic granules may be present.

In midgut carcinoids, cells are arranged in closely packed, round, regular, monomorphous masses. In the appendix, carcinoids appear as discrete yellow nodules in the lumen. Lesions associated with diffuse wall thickening are relatively uncommon. Carcinoid tumors commonly affect the tip of the appendix. Most carcinoid tumors invade the wall of the appendix, and lymphatic involvement is nearly universal. About 75% of patients have evidence of peritoneal involvement. However, only a few patients have regional or distant dissemination. The size of the tumor can be correlated with outcome of the disease; tumors smaller than 1.5 cm in diameter (after formalin fixation) rarely result in distant metastases or recurrences.

Carcinoid tumors can be associated with concentric and elastic vascular sclerosis that results in obliteration of vascular lumina and ischemia. A common finding is elastosis and fibrosis that surround nests of the tumor cells and that result in matting of the involved tissues and lymph nodes. Fibroblastic proliferation may result from the stimulation of fibroblast cells by growth factor. This stimulation may be a result of a local release of tumor growth factor (TGF)-beta, beta–fibroblast growth factor (beta-FGF), and platelet-derived growth factor.

Other products of carcinoid tumors include the following:

  • Acid phosphatase
  • Alpha-1-antitrypsin
  • Amylin
  • Atrial natriuretic polypeptide
  • Calbindin-D28k
  • Catecholamines
  • Dopamine
  • Fibroblast growth factor
  • Gastrin
  • Gastrin-releasing peptide (bombesin)
  • Glucagon, glicentin
  • 5-Hydroxyindoleacetic acid (5-HIAA)
  • 5-Hydroxytryptamine (5-HT)
  • Histamine
  • Insulin
  • Kallikrein
  • Kinins
  • Motilin
  • Neuropeptide
  • Neurotensin
  • Pancreastatin
  • Pancreatic polypeptide
  • Platelet-dermal growth factor
  • Prostaglandins
  • Pyroglutamyl-glutamyl-prolinamide
  • Secretin
  • Serotonin
  • Somatostatin (ie, SRIF)
  • Tachykinins
  • Neuropeptide K
  • Neuropeptide A
  • Substance P (SP)
  • Transforming growth factor-beta
  • Vasoactive intestinal polypeptide (VIP)
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Classic carcinoid tumor cells are argentaffinic and argyrophilic. At present, immunostain and hormonal markers are used for diagnosis. Carcinoids may have somatostatin receptors. Five identified somatostatin receptors are members of the G-protein receptor family. Five distinct genes on chromosomes 11, 14, 16, 17, and 20 encode somatostatin receptors. Somatostatin receptors are used to advantage for diagnosing and treating this disease.

Frequency United States

Carcinoids are the most common neuroendocrine tumors, with an estimated 1.5 clinical cases per 100,000 population. The incidence in autopsy cases is higher than this at 650 cases per 100,000 population. The exact incidence in children is not known. Most tumors occur in adults and are rarities in children.

International

In 1980-1989, the overall age-standardized incidence rate for male and female populations in England were estimated to be 0.71 (0.68-0.75 and 0.87 (0.83-0.91), respectively. In Scotland, the respective rates were 1.17 (0.91-1.44) per 100,000 population and 1.36 (1.09-1.63) per 100,000 population (Newton 1994).

Diagnosis and Treatment:

  • A number of imaging modalities have been used to detect carcinoid tumors. These modalities include plain radiography, upper- and lower-GI radiography with the use of oral contrast agents, CT, MRI, angiography, positron emission tomography (PET), scintigraphy with metaiodobenzylguanidine (MIBG) and octreotide (Monsieurs, 2001; Shi, 1998), radionuclide imaging with somatostatin analogs attached to the radioactive tracer, and technetium-99m bone scanning. Depending on the location of the tumor and metastasis, a combination of these may be used.
  • GI series, CT, and MRI may be helpful in some situations.
  • For the diagnosis of chest tumors, CT combined with scintigraphy with octreotide is preferred.
  • In the large bowel, the disease is often detected with colonoscopy and does not provide an imaging challenge. Imaging diagnosis of small-bowel carcinoids is relatively difficult. Small tumors in this location are difficult to detect on upper-GI series and CT scans, and other techniques are required.
  • Mesenteric invasion and liver metastasis are often detected on CT scans. MRI can also be helpful in the diagnosis of hepatic disease but is less sensitive than CT in detection of extrahepatic lesions.
  • With advances in imaging studies, angiography is rarely used and is reserved for equivocal situations.
  • PET scanning can be helpful and is increasingly used for diagnosis and follow-up of the tumors.
  • Scintigraphy with MIBG and octreotide scanning have been used to successfully detect carcinoid tumors (Kaltsas, 2001). Octreotide scanning appears to be more sensitive than MIBG imaging.
  • Radionuclide imaging with somatostatin analogs attached to radioactive tracer can be used to advantage for diagnosis of carcinoid tumors.
  • Radiotracers currently used include indium-111 diethylenetriamine pentaacetic acid (111 In-DTPA) and yttrium. Most neuroendocrine tumors have receptors for somatostatins. Five somatostatin receptor subtypes, designated SSTR-1 to SSTR-5, are identified. Binding affinity of somatostatin analogs to these subtypes may vary, with highest affinity for SSTR-2, medium affinity for SSTR-2 and SSTR-5, and lowest affinity for SSTR-1 and SSTR-4. Carcinoid tumors often express SSTR-1 to SSTR-3 and, infrequently, SSTR-2. Nevertheless, for tumors that measure less than 1 cm in diameter, the sensitivity of111 In-DTPA octreotide imaging reaches 80-90%.
  • This technique can be used to identify primary and metastatic disease and is approved for radionuclide scanning of carcinoid tumors. An advantage is that, if the result is positive, this technique can be used as a treatment modality.
  • In a study of 40 patients, somatostatin-receptor scintigraphy (SRS) helped in detecting localized tumors in 78% of patients versus 82% with CT scanning. However, SRS helped in identifying primary tumors in 2 patients missed on CT scanning. In 16% of patients, SRS depicted lesions not found with other modalities. No false-positive results were observed.
  • Overall, SRS appears to be the imaging method of choice for localizing and evaluating the extent of carcinoid tumor.
  • Bone metastasis is not uncommon in carcinoid tumors. In a study of 12 patients, 11 of whom had liver metastasis, 8 had bone involvement, as detected on SRS.
  • Technetium-99m bone scanning can aid in the detection of metastases.

Procedures:

Endoscopy, including bronchoscopy, esophagogastroscopy, gastroscopy, and colonoscopy, can be used for biopsy and diagnosis.

Medical Care

If metastases occur and surgical excision is not suitable, consider treatment with currently recommended chemotherapy.

  • Chemotherapeutic agents currently used in clinical trials to palliate metastatic carcinoid disease include the following:
    • Alkylating agents
    • Doxorubicin
    • 5-Fluorouracil
    • Dacarbazine
    • Actinomycin D
    • Cisplatin
    • Etoposide
    • Streptozotocin
    • Interferon alfa
    Somatostatin analogs with a radioactive load
  • A combination of the agents listed above is typically used.
  • In one study, 8 adults with carcinoid tumor metastatic to liver were treated with intra-arterial 5-fluorouracil and embolization of hepatic tumors with bovine collagen fiber admixed with iohexol, cisplatin, mitomycin C, and doxorubicin. This treatment resulted in symptomatic relief and tumor regression in 4 patients and stabilized the disease in the rest of the patients.
  • Octreotide, a somatostatin analog, is highly effective in reducing symptoms; however, in the pediatric age group, stunted linear growth is of concern.
    • Octreotide reduces the amount of the growth factor produced and, thus, theoretically impairs growth.
    • Intermittent and continuous infusions of octreotide have been reported, with superior results obtained with the latter.
    • Such treatment can result in near-normalization of the plasma insulinlike growth factor I and partial suppression of plasma growth hormone–releasing hormone (GHRH) (Lefebvre, 1995).
    • The availability of a long-acting somatostatin analog that can be given once a month has eliminated the need for injections 2-3 times per day, with equal efficacy (Rubin, 1999).
    • In metastatic carcinoid tumors, long-term use of octreotide is reported. However, receptor alteration induced during the use of this agent requires consecutive drug dosage increase to control the symptoms (Corleto, 2000).
    • At present, no formal, well-designed study has been performed to systematically measure the effects of this modality of therapy. Although experience is limited, adverse effects in children have been similar to those in adults. Adverse effects include gallstones and steatorrhea, which may sometimes require pancreatic enzyme replacement. Local irritation at the injection site is a common complaint. These adverse effects must be weighted against the potential benefits.
  • In situ targeted therapy with somatostatin analogs (eg, octreotide attached to a radioactive load using yttrium-90 or111 Indium-labeling agents) provides promise for patients with unresectable tumors. This therapy is currently used on an experimental basis in adults and children.
  • Surgical Care:

    The treatment of choice is surgical excision, if feasible. The surgical technique may vary according to the type or location of the tumor.

    • In most appendiceal tumors, simple appendectomy is sufficient for treatment. In intestinal carcinoids, block resection of the tumor with adjacent lymph nodes must be attempted. In the bronchial location, aggressive surgical resection, and not bronchoscopic removal, is recommended (Fink, 2001; Fauroux, 2005).
    • In localized tumors, surgical resection can result in cure, with 70-90% survival rate.
    • When total resection is not possible, debulking may provide symptomatic relief.
    • For hepatic tumors, surgical ligation of the hepatic artery can potentially deprive blood supply to the tumor cells and cause necrosis while preserving most of the normal live cells. However, new blood vessels develop over time and restore circulation.
    • Intra-arterial infusion of chemotherapeutic agents with chemoembolization of the hepatic artery may also provide effective, albeit short term, relief of symptoms due to hepatic metastasis in cases of carcinoid tumors.
    • If hepatic metastasis is present but resectable, surgical resection is preferred
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    Follow up Care:

    Complications
    • The most serious complication of carcinoid tumors is carcinoid crisis, which is often observed in patients who have foregut tumors and high levels of 5-HIAA.

    Prognosis

    • The prognosis for patients with completely resected localized disease is excellent. However, patients with metastasis have poor outcome (Spunt, 2000).
    • In general, the survival rate of patients with carcinoid tumors is directly related to the size of the primary tumor and to the degree of distant metastasis. Tumors larger than 2 cm, positive lymph nodes, and atypical histologic features are often associated with a poor prognosis.

    After your treatment is over, it is very important to keep all follow-up appointments. During these visits, your doctors will ask about symptoms, do physical exams, and may order blood tests or imaging studies such as CT scans or x-rays. Your doctor will most likely want to see you fairly frequently (every couple of months or so) at first. The time between visits may be extended if there are no problems. Although lung carcinoid tumors are often cured by the initial treatment, in a small number of cases the cancer can recur many years later, which is why doctors often advise close follow-up for at least 10 years.

    Follow-up is needed to check for cancer recurrence or spread, as well as possible side effects of certain treatments. This is the time for you to ask your health care team any questions you need answered and to discuss any concerns you might have. Almost any cancer treatment can have side effects. Some may last for a few weeks to several months, but others can be permanent. Don't hesitate to tell your cancer care team about any symptoms or side effects that bother you so they can help you manage them.

    If the cancer does recur at some point, further treatment will depend on the location of the cancer, what treatments you've had before, and your health. For more information on how recurrent cancer is treated, see the section "How are lung carcinoid tumors treated?" For more general information on dealing with a recurrence, you may also want to see the American Cancer Society document, When Your Cancer Comes Back: Cancer Recurrence. You can get this document by calling 1-800-ACS-2345. Seeing a new doctor At some point after your cancer diagnosis and treatment, you may find yourself in the office of a new doctor. Your original doctor may have moved or retired, or you may have moved or changed doctors for some reason. It is important that you be able to give your new doctor the exact details of your diagnosis and treatment. Make sure you have the following information handy:

    • a copy of your pathology report(s) from any biopsies or surgeries
    • if you had surgery, a copy of your operative report(s)
    • if you were hospitalized, a copy of the discharge summary that doctors must prepare when patients are sent home
    • if you had radiation therapy, a summary of the type and dose of radiation and when and where it was given
    • if you had chemotherapy or other medicines, a list of your drugs, drug doses, and when you took them

    It is also important to keep medical insurance. Even though no one wants to think of their cancer coming back, it is always a possibility. If it happens, the last thing you want is to have to worry about paying for treatment. Lifestyle changes to consider during and after treatment Having cancer and dealing with treatment can be time-consuming and emotionally draining, but it can also be a time to look at your life in new ways. Maybe you are thinking about how to improve your health over the long term. Some people even begin this process during cancer treatment. Make healthier choices Think about your life before you learned you had cancer. Were there things you did that might have made you less healthy? Maybe you drank too much alcohol, or ate more than you needed, or smoked, or didn’t exercise very often. Emotionally, maybe you kept your feelings bottled up, or maybe you let stressful situations go on too long.

    Now is not the time to feel guilty or to blame yourself. However, you can start making changes today that can have positive effects for the rest of your life. Not only will you feel better but you will also be healthier. What better time than now to take advantage of the motivation you have as a result of going through a life-changing experience like having cancer?

    You can start by working on those things that you feel most concerned about. Get help with those that are harder for you. For instance, if you are thinking about quitting smoking and need help, call the American Cancer Society Quitline® tobacco cessation program at 1-800-ACS-2345.

    Diet and nutrition

    Eating right can be a challenge for anyone, but it can get even tougher during and after cancer treatment. For instance, treatment often may change your sense of taste. Nausea can be a problem. You may lose your appetite for a while and lose weight when you don’t want to. On the other hand, some people gain weight even without eating more. This can be frustrating, too.

    If you are losing weight or have taste problems during treatment, do the best you can with eating and remember that these problems usually improve over time. You may want to ask your cancer team for a referral to a dietitian, an expert in nutrition who can give you ideas on how to fight some of the side effects of your treatment. You may also find it helps to eat small portions every 2 to 3 hours until you feel better and can go back to a more normal schedule.

    One of the best things you can do after treatment is to put healthy eating habits into place. You will be surprised at the long-term benefits of some simple changes, like increasing the variety of healthy foods you eat. Try to eat 5 or more servings of vegetables and fruits each day. Choose whole grain foods instead of white flour and sugars. Try to limit meats that are high in fat. Cut back on processed meats like hot dogs, bologna, and bacon. Get rid of them altogether if you can. If you drink alcohol, limit yourself to 1 or 2 drinks a day at the most. And don't forget to get some type of regular exercise. The combination of a good diet and regular exercise will help you maintain a healthy weight and keep you feeling more energetic.

    Rest, fatigue, work, and exercise Fatigue is a very common symptom in people being treated for cancer. This is often not an ordinary type of tiredness but a "bone-weary" exhaustion that doesn't get better with rest. For some, this fatigue lasts a long time after treatment, and can discourage them from physical activity.

    However, exercise can actually help you reduce fatigue. Studies have shown that patients who follow an exercise program tailored to their personal needs feel physically and emotionally improved and can cope better. If you are ill and need to be on bed rest during treatment, it is normal to expect your fitness, endurance, and muscle strength to decline some. Physical therapy can help you maintain strength and range of motion in your muscles, which can help fight fatigue and the sense of depression that sometimes comes with feeling so tired.

    Any program of physical activity should fit your own situation. An older person who has never exercised will not be able to take on the same amount of exercise as a 20-year-old who plays tennis 3 times a week. If you haven't exercised in a few years but can still get around, you may want to think about taking short walks. Talk with your health care team before starting, and get their opinion about your exercise plans. Then, try to get an exercise buddy so that you're not doing it alone. Having family or friends involved when starting a new exercise program can give you that extra boost of support to keep you going when the push just isn't there.

    If you are very tired, though, you will need to balance activity with rest. It is okay to rest when you need to. It is really hard for some people to allow themselves to do that when they are used to working all day or taking care of a household. Exercise can improve your physical and emotional health.

    • It improves your cardiovascular (heart and circulation) fitness.
    • It strengthens your muscles.
    • It reduces fatigue.
    • It lowers anxiety and depression.
    • It makes you feel generally happier.
    • It helps you feel better about yourself.

    And long term, we know that exercise plays a role in preventing some cancers. The American Cancer Society, in its guidelines on physical activity for cancer prevention, recommends that adults take part in at least 1 physical activity for 30 minutes or more on 5 days or more of the week. Children and teens are encouraged to try for at least 60 minutes a day of energetic physical activity on at least 5 days a week.


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