Neuroendocrine tumors comprise a broad family of tumors, the most common of which are carcinoid and pancreatic neuroendocrine tumors. The NCCN Neuroendocrine Tumors Guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine tumors. Most of the recommendations pertain to well-differentiated, low- to intermediate-grade tumors. This updated version of the NCCN Guidelines includes a new section on pathology for diagnosis and reporting and revised recommendations for the surgical management of neuroendocrine tumors of the pancreas.

Abstract

Neuroendocrine tumors comprise a broad family of tumors, the most common of which are carcinoid and pancreatic neuroendocrine tumors. The NCCN Neuroendocrine Tumors Guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine tumors. Most of the recommendations pertain to well-differentiated, low- to intermediate-grade tumors. This updated version of the NCCN Guidelines includes a new section on pathology for diagnosis and reporting and revised recommendations for the surgical management of neuroendocrine tumors of the pancreas.

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Overview

Neuroendocrine tumors are thought to arise from cells throughout the diffuse endocrine system. They comprise a broad family of tumors, the most common of which are carcinoid and pancreatic neuroendocrine tumors. Other neuroendocrine tumors include those arising in the parathyroid, adrenal, and pituitary glands, and in calcitonin-producing cells of the thyroid (causing medullary thyroid carcinoma).

An analysis of the SEER database estimated that the incidence of neuroendocrine tumors in the United States was 5.25 cases per 100,000 people in 2004.1 This analysis suggested that the diagnosed incidence of neuroendocrine tumors is increasing, and that the prevalence of individuals with neuroendocrine tumors in the United States may exceed 100,000.1

Most neuroendocrine tumors seem to be sporadic; risk factors for sporadic neuroendocrine tumors are poorly understood. Neuroendocrine tumors may also arise in the context of inherited genetic syndromes, including multiple endocrine neoplasia types 1 (MEN 1) and 2 (MEN 2). MEN 1, associated with mutations in the menin gene, is characterized by multiple tumors of the parathyroid, pituitary, and pancreatic glands.2 MEN 2, associated with mutations in the RET proto-oncogene, is characterized by the development of medullary thyroid cancer, pheochromocytoma (often bilateral), and hyperparathyroidism.3 Neuroendocrine tumors have also been associated with von Hippel-Lindau disease, tuberous sclerosis complex, and neurofibromatosis.4,5

Patients with neuroendocrine tumors may or may not have symptoms attributable to hormonal hypersecretion. These symptoms include intermittent flushing and diarrhea in patients with carcinoid syndrome,6 hypertension in patients with pheochromocytoma,7 and symptoms attributable to secretion of insulin, glucagon, gastrin, and other peptides in patients with pancreatic neuroendocrine tumors.8 Patients with hormonal symptoms are considered to have “functional” tumors, and those without symptoms are considered to have “nonfunctional” tumors.

F1NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors Version 1.2012

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F2NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors Version 1.2012

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F3NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors Version 1.2012

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F7NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors Version 1.2012

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F10NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors Version 1.2012

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Appropriate diagnosis and treatment of neuroendocrine tumors often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists.

These NCCN Guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine tumors and are intended to assist with clinical decision-making. Most of the guideline sections pertain to well-differentiated, low- to intermediate-grade tumors; for poorly differentiated/high-grade/anaplastic or small cell carcinomas, please refer to Poorly Differentiated (High Grade or Anaplastic)/Small Cell (available online, in these guidelines, at NCCN.org [ANAP-1]) and Poorly Differentiated Neuroendocrine Tumors or Small Cell Tumors (available online, in these guidelines, at NCCN.org [MS-20]). Medical practitioners should note that unusual patient scenarios (presenting in < 5% of patients) are not specifically discussed in these guidelines.

Histologic Classification and Staging of Neuroendocrine Tumors

Neuroendocrine tumors are generally subclassified by site of origin and histologic characteristics. Pancreatic neuroendocrine tumors arise in endocrine tissues of the pancreas; carcinoid tumors most commonly arise in the lungs and bronchi, small intestine, appendix, rectum, or thymus.

Neuroendocrine tumors are classified histologically based on tumor differentiation (well or poorly differentiated) and tumor grade (grades 1-3). Most neuroendocrine tumors fall into 3 broad histologic categories: well-differentiated, low-grade (G1); well-differentiated, intermediate-grade (G2); and poorly differentiated, high-grade (G3). The latter are also sometimes referred to as high-grade neuroendocrine carcinomas or small cell carcinoma.8 These tumors are characterized by a high mitotic rate and an aggressive clinical course.9,10

Tumor differentiation and grade often correlate with mitotic count and Ki-67 proliferation index. In most cases, well differentiated, low-grade tumors have a mitotic count of less than 2/10 high-power field (HPF) and a Ki-67 index of less than 3%. Well-differentiated, intermediate-grade tumors usually have a mitotic count of 2 to 20/10 HPF and a Ki-67 index of 3% to 20%. In high-grade tumors, the mitotic count usually exceeds 20/10 HPF and the Ki-67 index exceeds 20%. Most commonly used histologic classification schemes, including both the European Neuroendocrine Tumor Society (ENETS) and WHO systems, incorporate mitotic rate and Ki-67 index.8,11 Numerous studies have confirmed that increased mitotic rate and high Ki-67 index are associated with a more aggressive clinical course and worse prognosis.12,13

Neuroendocrine tumors are staged according to the American Joint Committee on Cancer (AJCC) tumor (T), node (N), metastasis (M) staging system. The AJCC introduced its first TNM staging system for the classification of neuroendocrine tumors in the 7th edition AJCC Cancer Staging Manual.14 Carcinoids of the stomach, duodenum/ampulla/jejunum/ileum, colon/rectum, and appendix have separate staging systems. The association of tumor stage with prognosis has been confirmed in analyses of the SEER database.15-19

Carcinoids of the lungs and bronchi are staged in the same manner as more common lung carcinomas. As in lung carcinoma, more advanced tumor stage for carcinoid tumors of the lungs and bronchi is associated with worse prognosis.14

The TNM staging system for the classification of pancreatic neuroendocrine tumors in the 7th edition AJCC Cancer Staging Manual is the same as for exocrine pancreatic carcinoma.14 The primary tumor (T) is differentiated based on size and involvement of major vessels or other organs (see the staging table, available online, in these guidelines, at NCCN.org [ST-1]). A recent retrospective analysis of 425 patients with pancreatic neuroendocrine tumors treated at H. Lee Moffitt Cancer Center & Research Institute between 1999 and 2010 validated this system, with 5-year overall survival rates of 92%, 84%, 81%, and 57% for stages I through IV, respectively (P < .001).20 Although the trends of this analysis are consistent with population-based studies, the survival rates were significantly higher than those seen in population-based studies.21,22 For example, in the SEER database analysis of pancreatic neuroendocrine tumors, the 5-year survival rate for patients with metastatic disease was only 19.5%.22

In addition to information on histologic classification and stage, the margin status (positive or negative) and the presence of vascular or perineural invasion should be indicated on the pathology report, because they may also have prognostic significance.23,24

Sporadic Neuroendocrine Tumors

Carcinoid Tumors

Approximately one-third of carcinoid tumors arise in the lungs or thymus, and two-thirds arise in the gastrointestinal tract. Sites of origin within the gastrointestinal tract include the stomach, small intestine, appendix, and rectum.1 The prognosis for patients with carcinoid tumors varies according to the stage at diagnosis, histologic classification, and primary site of the tumor (see Histologic Classification and Staging of Neuroendocrine Tumors, opposite page).

Carcinoid tumors may secrete various hormones and vasoactive peptides. Bronchial carcinoids have been associated with adrenocorticotropic hormone (ACTH) production and are a cause of Cushing syndrome.25 Carcinoid tumors arising in the small intestine or appendix are more commonly associated with carcinoid syndrome, related to the secretion of serotonin, histamine, or tachykinins into the systemic circulation causing episodic flushing and diarrhea.26 Additionally, 10% to 30% of patients with carcinoid syndrome develop valvular cardiac complications consisting of tricuspid regurgitation and/or pulmonary stenosis.26

The metabolic products released by intestinal carcinoid tumors are rapidly destroyed by liver enzymes in the portal circulation, thus the classical syndrome, occurring in approximately 8% of patients with carcinoid tumors,27 is not usually observed unless liver metastases or rarely retroperitoneal disease have occurred, in which case hepatic metastases release metabolic products directly into the systemic circulation via the hepatic veins.

These NCCN Guidelines address 7 major subtypes of carcinoid tumors: 1) jejunal/ileal/colon, 2) duodenal, 3) appendix, 4) rectal, 5) gastric, 6) bronchopulmonary, and 7) thymus.

Evaluation of Carcinoid Tumors: Patients who present with suspected carcinoid tumors should be evaluated with imaging studies to assess disease burden and possible primary location. Commonly used techniques include CT and MRI. Carcinoid tumors are highly vascular and can appear isodense with liver on CT scan, depending on contrast phase. Multiphase CT or MRI scans should therefore be used for evaluation of liver metastasis. Because most carcinoid tumors express high-affinity receptors for somatostatin,26,28 radiolabeled somatostatin receptor scintigraphy, performed using the radiolabeled somatostatin analog [111In-DTPA]-octreotide (Octreoscan) may also be used in the initial evaluation of patients with carcinoid tumor. Additional recommendations vary by disease site and include colonoscopy and small bowel imaging as appropriate for jejunal, ileal, and colon carcinoids; endoscopic ultrasound (EUS) and/or esophagogastroduodenoscopy as appropriate for duodenal and gastric carcinoids; proctoscopic examination for rectal carcinoids; and bronchoscopy as appropriate for bronchopulmonary and thymic carcinoids.

Management of Locoregional Disease: The management of locoregional carcinoid tumors depends on tumor size and primary site, and the general condition of the patient. Resection is the primary treatment approach for most localized carcinoid tumors. Specific recommendations for management of carcinoid tumor subtypes are described below.

Gastric Carcinoid Tumors: Three types of gastric carcinoid tumors are generally recognized: type 1 gastric carcinoids (associated with chronic atrophic gastritis), type 2 (associated with Zollinger-Ellison syndrome), and type 3 (sporadic).29 Types 1 and 2 gastric carcinoids are both associated with hypergastrinemia; the major difference between them is that patients with type 1 gastric carcinoids generally have atrophic gastritis and absent acid secretion, whereas those with type 2 gastric carcinoids have evidence of acid hypersecretion secondary to gastrinoma (Zollinger-Ellison syndrome).29 For hypergastrinemic patients whose tumors are 2 cm or smaller and either solitary or multiple, options include 1) endoscopic resection, if feasible, with biopsy of the tumor and adjacent mucosa; 2) observation; or 3) octreotide for patients with gastrinoma and Zollinger-Ellison syndrome (category 2B recommendation). For hypergastrinemic patients with tumors larger than 2 cm and either solitary or multiple, endoscopic resection (if possible) or surgical resection is indicated. Patients with nonmetastatic gastric carcinoid and normal gastrin levels (type 3) have more aggressive tumors and are usually treated with radical resection of the tumor with regional lymphadenectomy.

Thymic Carcinoid Tumors: Localized and locoregional carcinoid tumors in the thymus are treated with surgical resection, generally without adjuvant therapy. After incomplete resection of locoregional disease, however, radiation therapy (RT) alone is recommended; the addition of chemotherapy can also be considered (category 3). If chemotherapy is offered, capecitabine or 5-fluorouracil at radiosensitizing doses may be considered. Cisplatin or carboplatin with etoposide may be appropriate for patients with atypical or poorly differentiated tumors.

Bronchopulmonary Carcinoid Tumors: For localized or locoregional bronchopulmonary tumors, please refer to the Lung Neuroendocrine Tumors algorithm, which is part of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (to view the most recent version of these guidelines, visit NCCN.org).

Carcinoid Tumors of the Duodenum, Small Intestine, and Colon: For localized lesions arising in the duodenum, endoscopic resection is recommended if feasible. Transduodenal local excision with or without lymph node sampling and pancreatoduodenectomy are other options for primary treatment of nonmetastatic duodenal carcinoid tumors.

For patients presenting with tumors in the jejunum, ileum, or colon, surgical resection of the bowel with regional lymphadenectomy is recommended. The surgical procedure should include careful examination of the entire bowel, because multiple synchronous lesions may be present. If future treatment with octreotide is anticipated, a prophylactic cholecystectomy should be considered given the association between long-term treatment with somatostatin analogs and the development of biliary symptoms and gallstones.30

Appendiceal Carcinoid Tumors: Most appendiceal carcinoid tumors are identified incidentally, during appendectomy performed for appendicitis. Most appendiceal carcinoid tumors have well-differentiated histology, and for most appendiceal tumors 2 cm or smaller and confined to the appendix, simple appendectomy is sufficient, because metastases are uncommon.31,32

However, some controversy exists regarding the management of appendiceal carcinoids measuring less than 2 cm with more aggressive histologic features. A recent population-based study analyzing the SEER database found evidence that lymph node metastases can develop in some patients with appendiceal carcinoids 2 cm or smaller.33 Some NCCN Member Institutions thus consider more aggressive treatment for 1- to 2-cm tumors with poor prognostic features, such as lymphovascular or mesoappendiceal invasion or atypical histologic features.

Patients with an incomplete resection or tumors smaller than 2 cm are at risk for locoregional or distant metastases. These patients should be staged with abdominal/pelvic CT or MRI scans. If no distant disease is identified, they should undergo reexploration with a right hemicolectomy. Additionally, a small proportion of appendiceal carcinoids may also contain evidence of adenocarcinoma (i.e., “adenocarcinoid” or “goblet cell carcinoid”). These tumors should be managed according to the NCCN Guidelines for Colon Cancer (available at NCCN.org).

Carcinoid Tumors of the Rectum:The treatment of rectal lesions is based on the size of the primary tumor. If the lesion is 2 cm or less, endoscopic or transanal excision is recommended. Given the higher risk of invasion with larger tumors, examination under anesthesia and/or EUS before the procedure should be considered for tumors 1 to 2 cm in size. Tumors larger than 2 cm, those with invasion of the muscularis propria, or those associated with lymph node metastases should be treated with low anterior resection or, in rare cases, an abdominoperineal resection.34

Surveillance: Surveillance of carcinoid tumors should include complete patient history and physical examination (H&P) and consideration of imaging studies, such as CT (abdominal and/or pelvic triple-phase) and MRI. Most patients with carcinoid tumors of the jejunum/ileum/colon, duodenum, rectum, and thymus, and type 3 gastric carcinoid lesions with normal gastrin levels should be reevaluated 3 to 12 months after resection (earlier if the patient is symptomatic) and every 6 to 12 months thereafter.

Chromogranin A may be used as a tumor marker (category 3); although not diagnostic, elevated levels have been associated with recurrence.35 Chromogranin A levels can be elevated in several concurrent medical conditions, including renal or hepatic insufficiency, and are also commonly elevated in the setting of concurrent proton pump inhibitors. Several panelists therefore caution that rising chromogranin A levels in an asymptomatic patient with a tumor that looks stable on imaging does not necessarily indicate that a patient should be initiated on a new therapy.

5-Hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin, in a 24-hour urine sample may also be considered as a biochemical marker in some cases, particularly in patients with small-intestinal carcinoid tumors. During monitoring of patients after treatment of a carcinoid tumor, decreasing levels of 5-HIAA indicate a response to treatment, whereas increasing or excessive concentration indicates that the treatment has not been successful. However, a patient with symptoms may still have a carcinoid tumor even if the concentration of 5-HIAA is normal. Diet and a variety of drugs can affect the 5-HIAA test. Therefore, patients should be advised not to eat avocados, bananas, cantaloupe, eggplant, pineapples, plums, tomatoes, hickory nuts, plantain, kiwi, dates, grapefruit, honeydew, or walnuts for 48 hours before the start of urine collection. Additionally, patients should avoid coffee, alcohol, and smoking for this period. Medications that can increase 5-HIAA include acetaminophen, ephedrine, diazepam, nicotine, glyceryl guaiacolate (an ingredient found in some cough medicines), and phenobarbital.

Somatostatin receptor scintigraphy (Octreoscan) is not routinely recommended for surveillance after definitive resection, but may be indicated to assess disease location and disease burden for comparison in cases of subsequent possible recurrence.

In specific cases, follow-up recommendations for patients with resected carcinoid tumors differ from the above general recommendations. For rectal tumors (< 1 cm), prognosis is excellent and no follow-up is usually required. Follow-up endoscopies are recommended for rectal tumors that are between 1 and 2 cm, 6 and 12 months after primary therapy, and then as clinically indicated. For appendiceal tumors (≤ 2 cm, without aggressive features), follow-up examinations are done as clinically indicated. Some institutions recommend a follow-up examination 1 year after simple appendectomy and then with decreasing frequency.

Follow-up recommendations also differ to some extent for patients with gastric carcinoid tumors. Hypergastrinemic (type 1 or 2) patients with small gastric carcinoid tumors who did not require endoscopic resection or treatment should be evaluated with H&P every 6 to 12 months. Imaging studies or surveillance may be performed on these patients as clinically indicated. Follow-up endoscopies are recommended for patients with type 1 and type 2 gastric carcinoid tumors. Surveillance every 6 to 12 months for the first 3 years and annually thereafter is appropriate if no evidence of recurrence or progression is seen. If clinically indicated, imaging studies should also be performed. Antrectomy to remove the source of gastrin production can be considered in patients with type 1 gastric carcinoids if new lesions or increasing tumor burden is observed.

Management of Locoregional Unresectable and/or Metastatic Carcinoid Tumors: Baseline imaging recommendations for patients suspected to have distant metastatic disease include multi-phase technique CT or MRI.36,37 Baseline levels of chromogranin A (category 3) or 5-HIAA may also be considered to monitor subsequent progression (discussed previously). Octreoscan can also be considered both to assess sites of metastases and to assess somatostatin receptor status if treatment with octreotide is being considered. The most common sites of metastases from intestinal carcinoids include regional/mesenteric lymph nodes, liver, and bones.

In some cases, patients with limited hepatic metastases or other sites of disease can undergo complete resection. In these patients, resection of the primary tumor and metastases should be performed. A recent study of 172 patients who underwent hepatic resection of metastatic neuroendocrine tumors showed that long-term survival can be achieved in many cases: the reported 10-year overall survival rate was 50.4%.38 Resection of the primary site in the setting of unresectable metastases is generally not indicated if the primary site remains asymptomatic and is relatively stable. However, it is not uncommon for patients with small bowel primary tumors to experience symptoms of intermittent abdominal pain from episodic bowel obstruction or bowel ischemia related to the primary tumor and surrounding fibrosis. Palliative small bowel resection is recommended in these patients.

Patients who have metastatic carcinoid tumors and carcinoid syndrome should be treated with octreotide.30 The long-acting release (LAR) formulation is used for the chronic management of patients with carcinoid syndrome. Standard doses of octreotide LAR are 20 to 30 mg intramuscularly every 4 weeks. Dose and frequency may be further increased for symptom control as needed. Therapeutic levels are not achieved for 10 to 14 days after LAR injection. Short-acting octreotide (usually 150-250 mcg subcutaneously 3 times daily) can be added to octreotide LAR for rapid relief of symptoms or for breakthrough symptoms.39-41 A cardiology consultation and echocardiogram to assess whether the patient has carcinoid heart disease should also be considered in patients with carcinoid syndrome with signs and symptoms of heart disease or with planned major surgery.30 Cardiac heart disease is frequent in patients with carcinoid syndrome; in one study, 59% of patients with carcinoid syndrome were diagnosed with tricuspid regurgitation.42,43 A recent study of 250 patients with carcinoid syndrome showed that patients with 5-HIAA levels of 300 mcmol or greater (57 mg) over 24 hours and with 3 or more flushing episodes per day were more likely to have carcinoid heart disease.44

In patients who have clinically significant tumor burden, initiation of octreotide LAR is recommended. The recommendation to consider octreotide in these patients is based on the results of the PROMID study, a placebo-controlled phase III trial of 85 patients with metastatic midgut carcinoid tumors, which showed median times to tumor progression of 14.3 and 6 months in the octreotide LAR and placebo groups, respectively (P = .000072).45 After 6 months of treatment, stable disease was observed in 66.7% of patients in the octreotide LAR group and 37.2% of patients in the placebo group.

No clear consensus exists on the timing of octreotide initiation in asymptomatic patients with metastatic carcinoid with low tumor burden. Although initiation of octreotide can be considered in these patients, deferring initiation of octreotide until evidence of tumor progression is seen may also be appropriate.

Patients with clinically significant progression of metastatic carcinoid tumors can pursue several options. In general, these patients should be started on treatment with octreotide if they are not already receiving it. For patients with hepatic-predominant disease, cytoreductive surgery or ablative therapies such as radiofrequency ablation (RFA) or cryoablation may be considered if near-complete treatment of tumor burden can be achieved (category 2B).46,47 For unresectable liver metastases, hepatic regional therapy (arterial embolization,48 chemoembolization,49,50 or radioembolization [category 2B])50-56 are recommended.

Interferon alpha has been shown in several large series to be associated with an antitumor effect, and can also be considered in patients with progressive metastatic carcinoid tumors (category 3).40,57-61 In general, responses to cytotoxic chemotherapy regimens are rare in patients with advanced, well-differentiated carcinoid tumors, and these regimens have not been shown to result in improved progression-free survival. The panel lists cytotoxic chemotherapy for carcinoid tumors as a category 3 recommendation.

Everolimus for Advanced Carcinoid Tumors: For patients with progressive metastatic carcinoid tumors, everolimus can also be considered (category 3). Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), which has been the subject of recent trials in patients with advanced neuroendocrine tumors. It was well tolerated and showed promising antitumor effects in patients with advanced carcinoid tumors when given with octreotide LAR in a phase II trial.62 In the randomized phase III RADIANT-2 trial, 429 patients with advanced carcinoid tumors and carcinoid syndrome were randomized to receive octreotide LAR with everolimus or placebo.63 Based on central review, patients receiving octreotide plus everolimus had a median progression-free survival of 16.4 months, compared with 11.3 months for patients receiving octreotide alone (P = .026). This difference in the primary end point of progression-free survival did not, however, meet the predefined threshold for statistical significance. Adverse events associated with everolimus included stomatitis, rash, fatigue, and diarrhea.63 Other side effects have also been described.64 The panel lists consideration of everolimus for carcinoid tumors after progression as a category 3 recommendation.

Radiolabeled Somatostatin Analogs for Advanced Carcinoid Tumors: Treatment with radiolabeled somatostatin analogues has been reported to result in tumor responses in patients with advanced carcinoid tumors.65-69 This approach remains investigational, and randomized trials to further evaluate the relative benefit and potential toxicities of radiopeptide therapy in advanced carcinoid are needed.70

Liver Transplantation for Liver Metastases of Carcinoid Tumors: Liver transplantation has been performed in patients with carcinoid tumors whose metastases are confined to the liver.71-75 Although some highly selected patients have experienced long-term survival, the panel acknowledged the considerable associated risks and deemed liver transplantation to be investigational and not part of routine care at this time.

Neuroendocrine Tumors of the Pancreas (Islet Cell Tumors)

According to a population-based study, malignant pancreatic endocrine tumors account for approximately 1% of pancreatic cancers by incidence and 10% of pancreatic cancers by prevalence.76 Although the peak incidence of occurrence is between ages 40 and 69 years, a significant number of patients diagnosed with pancreatic neuroendocrine tumors are younger than 35 years.76,77 Based on an analysis of pancreatic neuroendocrine tumors in the SEER database from 1973 to 2000, the annual incidence per 1 million was 1.8 in women and 2.6 in men.22 An estimated 40% to 91% of pancreatic neuroendocrine tumors are nonfunctional. The remainder manifest with clinically evident hormonal symptoms.8,22 The characteristics of functional endocrine tumors of the pancreas are summarized in Table 1.77 Of these functioning tumors, up to 70% are insulinomas, and approximately 90% of these are benign. Approximately 15% are glucagonomas. Gastrinomas and somatostatinomas account for another 10%; most (80%-90%) of these are associated with a relatively high risk for metastases.77 The remaining rare islet cell tumors include vasoactive intestinal polypeptide tumor (VIPoma) and pancreatic polypeptidoma (PPoma). Islet cell tumors occurring in patients with MEN 1 are typically multiple and require different treatment strategies from those used for patients with sporadic pancreatic endocrine tumors, which are usually solitary (see next section). Gastrinoma and insulinoma are the most common pancreatic islet cell tumors in patients with MEN 1.78

Table 1

Characteristics of Neuroendocrine Tumors of the Pancreas

Table 1

Evaluation of Neuroendocrine Tumors of the Pancreas: Family history should be considered to rule out MEN 1 syndromes. For nonfunctioning islet cell tumors, the recommended evaluation includes multiphasic CT or MRI scan. Serum chromogranin A (category 3) and PPoma (category 3) may be tested as clinically appropriate. Functional tumors may give significant clinical symptoms even when very small, and lesion identification can therefore be difficult.79 Multiphasic, contrast-enhanced CT or MRI is recommended, and Octreoscan and EUS can also be considered.

Chromogranin A levels are elevated in 60% or more of patients with either functioning or nonfunctioning pancreatic endocrine tumors.80-82 Care should be taken in measuring chromogranin A and interpreting the results, because spuriously elevated levels of chromogranin A have been reported in patients using proton pump inhibitors, those with renal or liver failure, those with hypertension, and those with chronic gastritis.

Gastrinomas: Gastrinoma is often suspected in patients with severe gastroduodenal ulcer symptoms, such as dyspepsia, usually accompanied by diarrhea. Evaluation of a patient with suspected gastrinoma includes measurement of basal and stimulated gastrin levels.83 Diagnosis of gastrinoma can be confounded by the concurrent use of proton pump inhibitors, which will elevate serum gastrin levels. Importantly, most patients who are found to have an elevated level of serum gastrin do not have a gastrinoma, but have achlorhydria or are receiving proton pump inhibitors or antacids. Gastrin levels (basal or stimulated) must be measured after the patient is off proton pump inhibitor therapy for at least 1 week. In addition, imaging studies (multiphasic CT/MRI scan) often aid not only in localizing the tumor but also in confirming the diagnosis. Other tests, such as an Octreoscan, EUS, and chromogranin A levels (category 3), may be performed as appropriate. Approximately 70% of patients with MEN 1 and gastrinoma have tumors situated in the duodenum.

Insulinomas: Insulinomas are generally small tumors that are best localized with EUS, which has been shown to localize approximately 82% of pancreatic endocrine tumors.84 Insulinomas can also be localized by injecting calcium into selective pancreatic arteries and measuring the insulin levels in the right (usually) or left hepatic vein (Imamura-Doppman procedure).85 Most experts recommend this test only for patients with persistent or recurrent insulinoma or when other localization tests are equivocal or negative.

If the diagnosis of insulinoma is uncertain, determining the insulin/glucose ratio after a 48- to 72-hour observed or inpatient observed fast may also be helpful. An insulin level greater than 3 mcIU/mL (usually > 6 mcIU/mL) when blood glucose is less than 40 to 45 mg/dL, with an insulin-to-glucose ratio of 0.3 or greater reflecting the inappropriate secretion of insulin at the time of hypoglycemia, indicate the presence of these tumors.86-88 Patients with insulinoma also have elevated levels of C-peptide.86 Testing for urinary sulfonylurea helps rule out factitious hypoglycemia.

CT or MRI scans should be performed to rule out metastatic disease. Ninety percent of insulinomas pursue an indolent course and can be cured surgically. Insulinomas are less consistently octreotideavid than other pancreatic neuroendocrine tumors, and Octreoscan may consequently be less useful as an imaging technique in insulinomas than in other tumor subtypes. Octreoscan should be performed only if octreotide is being considered as a treatment. Octreotide should only be administered to patients whose tumors are Octreoscan-positive, because in the absence of somatostatin receptors, octreotide can profoundly worsen hypoglycemia (see Preoperative Management, below).89

Glucagonomas and VIPomas: For patients with recent-onset diabetes, cachexia, and/or a necrolytic erythematous skin rash, the panel recommends a blood test for glucagon and blood glucose, multiphase contrast-enhanced CT or MRI, and Octreoscan as appropriate. For VIPomas with characteristic watery diarrhea, testing for vasoactive intestinal polypeptide (VIP) and electrolytes is recommended. A CT or MRI scan may be useful for identifying large tumors or metastatic disease, and is recommended routinely for suspected VIPoma. Octreoscan can also be considered as appropriate.

Primary Treatment of Locoregional Resectable Neuroendocrine Tumors of the Pancreas: Resection is the primary treatment approach for localized pancreatic neuroendocrine tumors when possible, and can result in excellent outcomes. Exceptions include patients with other life-limiting comorbidities or high surgical risk.

Preoperative Management: Surgical resection is the optimal treatment for locoregional pancreatic endocrine tumors. Before excision, however, any symptoms of hormonal excess must be treated. Octreotide can be considered in most pancreatic neuroendocrine tumor subtypes. For insulinomas, the panel advises stabilizing glucose levels with diet and/or diazoxide. Octreotide should be used with caution in patients with insulinoma because it can also suppress counterregulatory hormones, such as growth hormone, glucagon, and catecholamines. In this situation, octreotide can precipitously worsen hypoglycemia, and can result in fatal complications in some cases.89

For gastrinomas, gastrin hypersecretion may be treated with proton pump inhibitors. VIPomas and glucagonomas are generally sensitive to octreotide.30 Because severe weight loss is common in patients with glucagonoma, total parenteral nutrition (TPN) may also be considered. All patients who might require splenectomy should receive preoperative trivalent vaccine (i.e., pneumococcus, haemophilus influenzae b, and meningococcus group c).

Surgical Management of Nonfunctioning Pancreatic Neuroendocrine Tumors: Patients with localized pancreatic neuroendocrine tumors should generally undergo surgical resection, absent any contraindications. Exceptions include patients with other life-limiting comorbidities, high surgical risk, or widely metastatic disease. Resection for larger (> 2 cm) or malignant-appearing nonfunctional tumors should include total removal of the tumor with negative margins (including adjacent organs) and regional lymph nodes.

Results of a recent retrospective analysis of 139 consecutive patients with incidentally found, nonfunctional pancreatic neuroendocrine tumors showed that even small tumors can be aggressive, including those originally classified as benign.90 In general, resection together with lymph node dissection should be considered, because pancreatic neuroendocrine tumors that are 1 to 2 cm have a small but real risk of lymph node metastases.91,92

However, another retrospective study of patients with incidentally discovered, nonfunctioning, early-stage pancreatic neuroendocrine tumors who opted against surgical resection suggested that in some cases these tumors can be safely followed, and some panel members have recommended interval follow-up and monitoring for selected patients with incidentally discovered small (≤ 1.5 cm) pancreatic neuroendocrine tumors.93

Surgical Management of Gastrinomas: The treatment approach for gastrinoma usually depends on the results of preoperative localization studies and on findings during exploratory laparotomy. In patients with occult gastrinoma (i.e., no primary tumor or metastasis is seen on imaging), the panel recommends either observation or exploratory surgery, including duodenotomy and intraoperative ultrasound with enucleation or local resection of tumors if identified at operation, and removal of periduodenal nodes.

Gastrinomas in the duodenum are treated with duodenotomy and intraoperative ultrasound with local resection or enucleation of tumors and periduodenal node dissection.

Gastrinomas in the head of the pancreas that are exophytic or peripheral as determined by imaging and are not immediately adjacent to the pancreatic duct should be enucleated. The periduodenal nodes should also be removed. Gastrinomas in the pancreatic head that are deeper or invasive and those with proximity to the main pancreatic duct should be managed with pancreatoduodenectomy.

Gastrinomas in the distal pancreas are treated with distal pancreatectomy with or without splenectomy.

Surgical Management of Insulinomas:The primary treatment for exophytic or peripheral insulinomas, because they are primarily benign, is enucleation. This procedure can be performed laparoscopically for localized solitary tumors within the body and tail of the pancreas. Sporadic tumors are usually solitary, whereas familial tumors are multiple. If enucleation is not possible because of invasion or the location of the tumor within the pancreas, then pancreatoduodenectomy for tumors in the head of the pancreas or distal pancreatectomy with preservation of the spleen for smaller tumors not involving splenic vessels may be considered. Distal pancreatectomy can be performed laparoscopically.

Surgical Management of Glucagonomas: Most glucagonomas are malignant and calcified and located in the tail of the pancreas, with regional node involvement. The recommended treatment is distal pancreatectomy with resection of the peripancreatic lymph nodes and splenectomy. For tumors in the pancreatic head, pancreatoduodenectomy with resection of the peripancreatic lymph nodes is recommended. Small (< 2 cm) peripheral glucagonomas are rare; enucleation or local excision with peripancreatic lymph dissection may be considered for small peripheral tumors of the head or distal pancreas. For glucagonomas, perioperative anticoagulation should be considered because of the increased risk of pulmonary emboli.

Surgical Management of VIPomas: Distal VIPomas are treated with distal pancreatectomy with resection of peripancreatic lymph nodes and spleen. Pancreatoduodenectomy with dissection of peripancreatic nodes is recommended for tumors in the head of the pancreas. Small (< 2 cm) peripheral VIPomas are rare; enucleation or local excision with peripancreatic lymph dissection may be considered for small peripheral tumors of the head or distal pancreas.

Surgical Management of Rare Tumors: The treatment recommendations for rare tumors, such as somatostatinoma, adrenocorticotropin hormone-secreting tumor (ACTHoma), parathyroid hormone-related protein (PTH-rP)-secreting tumors, and PPoma, are similar to those for nonfunctioning tumors. Tumors that are small (< 2 cm) and peripheral can be enucleated with or without removal of regional nodes, or distal pancreatectomy can be performed with or without removal of regional nodes and with or without splenectomy. Deeper, larger (> 2 cm), or invasive tumors are treated with pancreatoduodenectomy if they are located in the head of the pancreas, and with distal pancreatectomy and splenectomy if they are distally localized. Resection for larger (> 2 cm) or malignant-appearing tumors should include total removal of the tumor with negative margins (including adjacent organs) and regional lymph nodes.

Surveillance: Disease recurrence has been observed in 21% to 42% of patients with pancreatic neuroendocrine tumors and can occur after many years.94-96 Patients should undergo follow-up 3 to 12 months after resection, or earlier if the patient presents with symptoms, and every 6 to 12 months thereafter with an H&P, appropriate tumor markers, and imaging studies such as CT/MRI as clinically indicated. Octreoscan and PET scan are not recommended for routine surveillance. Surgical resection is recommended for resectable locoregional or oligometastatic recurrence.

Management of Locoregional Unresectable and/or Metastatic Neuroendocrine Tumors of the Pancreas: Patients with malignant neuroendocrine tumors of the pancreas frequently present with liver metastases. In patients with limited hepatic disease, surgical excision of both the primary tumor and liver metastases should be considered when possible and can be performed in a staged or synchronous fashion. When performing staged pancreatoduodenectomy and liver resection, hepatectomy should be considered before pancreatic resection to reduce the risk of perihepatic sepsis from the contaminated biliary tree.97 Although resection may provide clinical benefit, most patients with metastatic disease will experience recurrence.98 Additional resection or ablation may be possible; a recent study of 172 patients who had liver resection of metastatic neuroendocrine tumors (55 with the primary tumor in the pancreas) showed that significant long-term survival can be achieved after recurrence in many patients, with a 10-year overall survival rate of 50.4%.38

Unfortunately, most patients with advanced pancreatic neuroendocrine tumors have unresectable disease. For patients with unresectable disease who are asymptomatic and have low tumor burden and stable disease, observation is recommended with marker assessment and imaging every 3 to 12 months until clinically significant disease progression occurs.

For unresectable symptomatic patients, those who initially present with clinically significant tumor burden, or those with clinically significant disease progression, several different options can be considered. Systemic options include treatment with biologically targeted agents (everolimus or sunitinib, category 2A), treatment with cytotoxic chemotherapy (category 2A), or treatment with octreotide (category 2B). These options, and hepatic-directed therapies, are discussed in more detail in the following sections.

Biologically Targeted Therapies: The biologically targeted agents everolimus and sunitinib have recently been confirmed to have antitumor activity and to improve progression-free survival in patients with advanced pancreatic neuroendocrine tumors. Everolimus, administered orally at a dose of 10 mg once daily, was evaluated in a multicenter study (RADIANT-3) enrolling 410 patients with advanced, progressive pancreatic neuroendocrine tumors.61 In this study, the median progression-free survival duration for patients randomized to everolimus was 11.0 months, compared with 4.6 months for patients receiving placebo, (P < .001). Subset analyses of RADIANT-3 showed that the progression-free survival effect of everolimus is independent of prior or concurrent somatostatin analog therapy or prior chemotherapy.99,100 Adverse events associated with everolimus include stomatitis, hyperglycemia, and, in rare cases, pneumonitis.61 Other side effects have also been described.64

Sunitinib, administered orally at a dose of 37.5 mg once daily, was compared with placebo in a multicenter randomized study of patients with advanced progressive metastatic pancreatic neuroendocrine tumors.101 The study was designed to enroll 340 patients but was discontinued after enrollment of 171 patients, before the predefined efficacy analysis. At discontinuation, patients who received sunitinib had a median progression-free survival duration of 11.4 months, compared with 5.5 months for patients receiving placebo (P < .001). The objective response rate seen with sunitinib was 9.3%.101 A large proportion of patients on the placebo arm subsequently received sunitinib at progression, and no significant difference in overall survival was observed between the arms.102 Adverse events associated with sunitinib include fatigue and, in rare cases, congestive heart failure.103 Other side effects have also been described.

Somatostatin Analogs: Patients with symptoms of hormone secretion should, in most cases, receive treatment with octreotide and/or other medication to manage their symptoms as previously described. Patients without hormone-related symptoms who have a positive Octreoscan can also be considered for treatment with octreotide (category 2B). Although no randomized studies to date have shown an antitumor effect of octreotide in pancreatic neuroendocrine tumors, the PROMID trial showed an improvement in its primary end point of time to tumor progression (14.3 vs. 6 months; P = .000072) in carcinoid tumors of the midgut.45 The ongoing phase III CLARINET study is comparing lanreotide with placebo in patients with locally advanced or metastatic nonfunctioning pancreatic or intestinal neuroendocrine tumors (ClinicalTrials.gov identifier: NCT00353496).

Cytotoxic Chemotherapy: Cytotoxic chemotherapy is another option (category 2A) for patients with unresectable or metastatic pancreatic neuroendocrine tumors. Streptozocin is FDA approved for use in patients with advanced pancreatic neuroendocrine tumors. The combination of doxorubicin and streptozocin was initially reported to be associated with an overall response rate of 69% and a survival benefit in a relatively small randomized study of patients with advanced pancreatic neuroendocrine tumors.104 A more recent retrospective review from MD Anderson Cancer Center reported an objective response rate of 39% with the combination of 5-FU, doxorubicin, and streptozocin.105 More recently, oral temozolomide-based therapy has become increasingly used in patients with advanced pancreatic neuroendocrine tumors. Temozolomide has been administered using different schedules and either alone or in combination with other agents.106-110 A retrospective series reported that the combination of temozolomide with capecitabine was associated with an objective radiographic response rate of 70% and a median progression-free survival of 18 months.110

Hepatic-Directed Therapies: Hepatic-directed therapies may be considered in patients with hepatic-predominant disease. The panel also lists cytoreductive surgery or ablative therapy (radiofrequency ablation, cryotherapy, microwave46,47) as category 2B recommendations for these patients. Although some groups report that the risks of cytoreductive surgery outweigh its benefits,111 others have reported good outcomes.112,113 No high-level evidence exists assessing cytoreductive surgery.114

Additional options include hepatic regional therapies, such as arterial embolization,115 radioembolization (category 2B),51-56 and chemoembolization.116 To date, no randomized clinical trials have assessed the effectiveness of these therapies, and prospective data for these interventions are limited.

Liver Transplantation: Liver transplantation has been performed in patients with pancreatic neuroendocrine tumors whose metastases are confined to the liver.71-75,117 Although some highly selected patients have experienced long-term survival, the panel acknowledged the considerable associated risks and deemed liver transplantation to be investigational and not part of routine care at this time.

Adrenal Gland Tumors

Adrenocortical carcinomas (ACCs) are rare (incidence, 1-2 per million).118-120 A bimodal age distribution is seen, with peak incidences in early childhood and the fourth to fifth decades of life. The female-to-male ratio is approximately 1.5 to 1.121,122 Most cases are sporadic; however, ACCs have been observed in association with several hereditary syndromes, including Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, and MEN 1.2,123-126 The underlying mechanisms of carcinogenesis in sporadic ACCs have not been fully elucidated; however, inactivating somatic mutations of the p53 tumor suppressor gene (chromosome 17p13127,128) and alterations at the 11p15 locus (site of the IGF-2 gene129,130) seem to occur frequently.

Approximately 60% of patients present with evidence of adrenal steroid hormone excess, with or without virilization.118,131-133 Signs and symptoms associated with hypersecretion of cortisol, called Cushing syndrome, include weight gain, weakness (primarily in proximal muscles), hypertension, psychiatric disturbances, hirsutism, centripetal obesity, purple striae, buffalo hump, supraclavicular fat pad enlargement, hyperglycemia, and hypokalemia. Aldosterone-secreting tumors may present with hypertension, weakness, and hypokalemia. Androgen-secreting tumors in women may induce hirsutism, deepening of the voice, and oligo/amenorrhea.131 In men, estrogen-secreting tumors may induce gynecomastia and testicular atrophy. Hormonally inactive ACCs typically produce symptoms related to tumor burden, including abdominal pain, back pain, early satiety, and weight loss.131,134

Evaluation and Treatment of Adrenal Gland Tumors: Evaluation of patients with adrenal gland tumors should take into account whether patients have a history of prior malignancy, which may raise suspicion that the tumor is metastatic. In these patients, an image-guided needle biopsy is recommended after a functioning adrenal neoplasm (in particular pheochromocytoma) is ruled out. If the clinical suspicion for pheochromocytoma is low and plasma metanephrines are less than 2 times the upper limit of normal, it is reasonable to proceed with an adrenal biopsy. If the tumor is determined to be a metastasis from another site, treatment should be according to the appropriate NCCN disease-specific treatment guideline (to see the NCCN Guidelines Table of Contents, visit NCCN.org). If biopsy reveals adrenal cortical tissue, than morphologic and functional evaluation should proceed as described here.

The morphologic evaluation should include an adrenal protocol CT or MRI to determine the size, heterogeneity, lipid content (MRI), contrast washout (CT), and margin characteristics. Functional evaluation should include evaluation for hyperaldosteronism, Cushing syndrome, and pheochromocytoma, as described here.

Functional Evaluation for Pheochromocytoma: A pheochromocytoma should be excluded with fractionated plasma free metanephrine, and measurements of 24-hour urine fractionated metanephrines and catecholamines for confirmation. Elevated levels of metanephrines are suggestive of pheochromocytoma.135,136 Concurrent medications should be reviewed before metanephrine testing for those that interfere with plasma metanephrines evaluation, including acetaminophen, certain beta- and alpha-adrenoreceptor blocking drugs, serotonin-reuptake inhibitors, and monoamine oxidase inhibitors.137 Elevations in metanephrine levels that are 4 times above the upper limit for normal are diagnostic. Treatment of pheochromocytoma is discussed in the full guidelines, available at NCCN.org.

Evaluation and Treatment of Hyperaldosteronism: When hyperaldosteronism (also called primary aldosteronism) is suspected, plasma aldosterone and renin activity should be assessed. Patients with primary aldosteronism have elevated plasma levels of aldosterone and low levels of renin activity. The plasma aldosterone-to-renin ratio in patients with primary hyperaldosteronism is usually greater than 30.138 Confirmatory testing with the saline suppression test or salt loading test may be indicated, because both false-positives and false-negatives can occur. Electrolytes should also be measured, because excessive aldosterone production causes both retention of sodium and excretion of potassium. The Endocrine Society has developed detailed guidelines for the detection, diagnosis, and treatment of primary aldosteronism.139

Hyperaldosteronism is rarely malignant, but malignancy should be suspected if the tumor has an irregular morphology, is lipid-poor, does not wash out on contrast-enhanced CT, is larger than 3 cm, or is secreting more than one hormone. When malignant hyperaldosteronism is suspected, an open adrenalectomy is recommended, because these tumors are prone to rupture.140,141

Benign hyperaldosteronism is much more common and can be caused by a unilateral adrenal adenoma or bilateral adrenal hyperplasia. Adrenal vein sampling for aldosterone is considered the standard for distinguishing these 2 causes of benign hyperaldosteronism and should be considered if the patient is a surgical candidate, because CT imaging is not always reliable. It may be reasonable, however, to exclude adrenal vein sampling in patients younger than 40 years when imaging only shows one affected gland, because bilateral hyperplasia is rare in this population. Laparoscopic adrenalectomy is recommended for adenoma, whereas medical management with spironolactone or eplerenone for hypertension and hypokalemia is recommended for patients with bilateral adrenal hyperplasia and for nonsurgical candidates.

Evaluation and Treatment of Cushing Syndrome: When patients present with symptoms of Cushing syndrome, levels of serum ACTH, cortisol, and the sex steroid dehydroepiandrosterone sulfate (DHEAS) are assessed. A confirmatory test (dexamethasone suppression [except when ACTH is already suppressed], repeated midnight salivary cortisol, or 24-hour urine) is recommended if cortisol levels are elevated.131,142 Elevated levels of cortisol are indicative of Cushing syndrome. Patients who experience symptoms secondary to increased adrenocortical steroid levels may require treatment for palliation of symptoms, such as hypertension, hyperglycemia, hypokalemia, and muscle atrophy.

Elevated levels of ACTH indicate that excessive cortisol secretion is not coming from the adrenal gland. Pituitary tumors, which are usually benign, and ectopic tumors in the lung, thyroid, pancreas, or bowel are probable sources. If an ectopic tumor is found, it should be removed if possible. If the primary tumor is unresectable, a bilateral laparoscopic adrenalectomy or medical management (see following discussion) is recommended.

Cushing syndrome can also be caused by a benign adrenal tumor (adrenal adenoma) or a malignant adrenal tumor, neither of which produce ACTH. Malignancy should be suspected if the tumor is larger than 5 cm or is inhomogeneous with irregular margins and/or local invasion. Imaging of the chest, abdomen, and pelvis is required to evaluate for metastases and local invasion. For malignant disease, see later discussion of adrenal carcinoma. Benign adrenal tumors are removed through laparoscopic adrenalectomy, when feasible. Postoperative corticosteroid supplementation is required until recovery of the hypothalamus-pituitary-adrenal (HPA) axis.

ACTH-independent Cushing syndrome can also rarely be caused by bilateral multinodal hyperplasia. When the tumor appears benign and the contralateral gland appears abnormal, adrenal vein sampling of cortisol production determines treatment. If cortisol production is asymmetric, the laparoscopic unilateral adrenalectomy with removal of the most active side is recommended, again with postoperative corticosteroid supplementation. If cortisol production is symmetric, medical management is indicated.

Medical management of hypercortisolism is achieved with adrenostatic agents, including ketoconazole and mitotane. Ketoconazole is most commonly used (at doses of 400-1200 mg/d) because of its easy availability and relatively tolerable toxicity profile. Octreotide can also be considered for ectopic Cushing syndrome if the tumor is Octreoscan-positive, although it may be less effective in controlling ectopic ACTH secretion than it is in other contexts. Bilateral adrenalectomy is recommended when medical management of severe ectopic Cushing syndrome fails.

Treatment of Nonfunctioning, Benign Adrenal Tumors: Adrenal tumors that do not secrete hormones are often discovered incidentally during scans for unrelated reasons and are thus sometimes called incidentalomas. Most nonfunctioning tumors are benign and can be left untreated. Masses showing radiographic features of myelolipoma are considered benign. In addition, tumors smaller than 4 cm that are homogenous, with smooth margins, and that appear lipid-rich according to CT or MRI criteria are also usually benign. If no change in size is noted on repeat imaging in 6 to 12 months, no further follow-up is required. Adrenalectomy can be considered if more than 1 cm growth of the mass occurs in 1 year. Alternatively, these masses can be observed with short-interval follow-up. Larger tumors (4-6 cm) with benign-appearing features can also be left untreated, but repeat imaging is recommended sooner (3-6 months). Without evidence of growth, repeat imaging can be performed in 6 to 12 months. If these larger tumors continue to grow, however, malignancy should be suspected and adrenalectomy is recommended. This procedure can be performed laparoscopically, with a planned conversion to an open procedure if evidence of local invasion is observed during surgery.

Evaluation and Treatment of Adrenal Carcinoma: Adrenal carcinoma should be strongly suspected in nonfunctioning tumors larger than 4 cm with irregular margins or that are internally heterogenous.143 On CT scans with intravenous contrast, adjacent lymph nodes or liver metastases may be present. On unenhanced CTs, the Hounsfield unit (HU) number is typically higher in carcinomas than in adenomas, and a threshold value of 10 HU has been proposed as a means of distinguishing benign from malignant adrenal tumors.144 If the HU attenuation value is greater than 10 on unenhanced CT, then enhanced CT and washout at 15 minutes is recommended. If the enhancement washout value is greater than 60% at 15 minutes, the tumor is likely benign.143 Chemical-shift MRI is highly sensitive and specific for differentiation of benign from malignant adrenal tumors, because most benign tumors contain fat, whereas most malignant tumors do not. MRIs more clearly document local invasion and involvement of the inferior vena cava than CT scans.145,146 Whether CT or MRI scans are performed, they should be performed after an adrenal protocol to determine size, heterogeneity, lipid content (MRI), contrast washout (CT), and margin characteristics.

Imaging of the chest, abdomen, and pelvis is also recommended to evaluate for metastatic disease and local invasion when the primary tumor is larger than 6 cm.

Treatment of Nonmetastatic Adrenal Carcinoma: Surgical resection of the tumor with removal of adjacent lymph nodes is recommended in patients with localized adrenal carcinoma, and may require removal of adjacent structures such as the liver, kidney, pancreas, spleen, and/or diaphragm for complete resection. Open adrenalectomy is preferred in tumors with a high risk of being malignant because of increased risk for local recurrence and peritoneal spread when performed laparoscopically.140,141

Because of the rarity of ACCs, no randomized, prospective trials of adjuvant therapy have been published. Most retrospective reports have examined the use of adjuvant mitotane, an oral adrenocorticolytic agent.147-149 The largest study retrospectively analyzed 177 patients with resected ACC (stages I-III) treated in Italy and Germany.150 In the Italian cohort, nearly half of the patients received adjuvant mitotane (47/102 patients) at doses ranging from 1 to 5 g/d, whereas none of the 75 German patients received adjuvant mitotane. The median duration of treatment was 29 months. In follow-up, disease-free and overall survivals were significantly longer in those treated with mitotane versus the controls, suggesting that adjuvant mitotane may be an effective postoperative strategy. The randomized phase III ADIUVO trial is currently underway to assess the efficacy of adjuvant mitotane in patients with ACCs considered to be at low to intermediate risk for progression (ClinicalTrials.gov identifier: NCT00777244). Disease-free survival is the primary end point.

Based on the available data, adjuvant mitotane therapy can be considered after resection of adrenal carcinoma (category 3). Because of the adrenolytic effects of mitotane, lifelong replacement doses of corticosteroids (hydrocortisone or prednisone) should be prescribed to prevent adrenal insufficiency. Because of the potential risks and uncertain benefits of adjuvant mitotane, several NCCN Member Institutions do not advocate its use for patients with resected adrenal carcinomas.

For patients with high-grade adrenal carcinoma, adjuvant radiation therapy to the tumor bed can also be considered, particularly if concern exists regarding tumor spillage or close margins after surgery. Follow-up imaging and biomarkers (for functioning tumors) should be performed every 3 to 6 months.

Management of Metastatic Adrenal Carcinoma: For low-grade tumors, resection may be considered if greater than 90% of the tumor and metastases can be removed. In low-grade tumors, observation with imaging and relevant biomarkers every 3 months can also be considered, with systemic treatment initiated at tumor progression. Otherwise, systemic therapy should be initiated. For high-grade tumors, systemic chemotherapy is generally initiated without further observation. Choices of systemic therapy for advanced adrenal carcinoma are mitotane monotherapy or various combinations of cisplatin, carboplatin, etoposide, doxorubicin, streptozocin, and mitotane.

Mitotane monotherapy has been studied in the setting of locally advanced or metastatic disease.151-153 Partial response rates are thought to be 10% to 30% at most.154 Several studies have evaluated the combination of mitotane with other cytotoxic agents, including cisplatin and etoposide. One of the larger studies analyzed the combination of mitotane (4 g/d) with cisplatin, etoposide, and doxorubicin in 72 patients with unresectable adrenal carcinoma, yielding an overall response rate of 49% (according to WHO criteria) and a complete hormonal response in 16 of 42 patients with functioning tumors.155 Another study examined the combination of mitotane with streptozocin and reported an objective response rate of 36%.156 Of 12 patients in this study with advanced disease, 3 (25%) were converted to a resectable status with this therapy and remained disease-free or with stable disease 3 to 18 years after surgery; 1 (8%) had stable disease for 3 months, and the other 8 (67%) showed no response. Analysis of results from an international randomized trial comparing treatment of metastatic adrenocortical carcinoma with etoposide, doxorubicin, cisplatin, and mitotane versus treatment with streptozotocin and mitotane (FIRM-ACT) is underway (ClinicalTrials.gov identifier: NCT00094497).157 The toxicity of concurrent chemotherapy plus mitotane should be considered when making treatment decisions.

The optimal doses and duration of mitotane treatment for metastatic disease have not yet been standardized, but some institutions recommend target levels of 14 to 20 mcg/mL if tolerated. Higher doses may be difficult for patients to tolerate, whereas lower doses may be less effective.154 Steady-state levels may be reached several months after initiation of mitotane. Because of the adrenolytic effects of mitotane, replacement doses of corticosteroids (hydrocortisone or prednisone) should be prescribed to prevent adrenal insufficiency.

Future Trial Design

Recent successes have shown that large randomized controlled trials studying treatments for neuroendocrine tumors can provide practice-changing results. The NCI recently convened a task force to set priorities for future studies and to recommend appropriate standards for trials in this disease.158 Among their recommendations are the following:

  • Pancreatic neuroendocrine tumors should be studied separately from tumors in other locations.

  • Well-differentiated and poorly differentiated neuroendocrine tumors should be studied in separate trials.

  • Progression-free survival is an appropriate primary end point for phase III trials and many phase II trials.

  • Trials studying treatment for hormonal symptoms are as critical as those assessing effects on tumor progression and should include quality-of-life end points.

Rigorous studies will allow continued progress in the development of improved treatments for patients with neuroendocrine tumors.

Individual Disclosures for the NCCN Neuroendocrine Tumors Panel

T2

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    NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors Version 1.2012

    Version 2.2012, 03-09-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors Version 1.2012

    Version 2.2012, 03-09-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors Version 1.2012

    Version 2.2012, 03-09-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors Version 1.2012

    Version 2.2012, 03-09-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors Version 1.2012

    Version 2.2012, 03-09-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors Version 1.2012

    Version 2.2012, 03-09-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors Version 1.2012

    Version 2.2012, 03-09-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors Version 1.2012

    Version 2.2012, 03-09-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors Version 1.2012

    Version 2.2012, 03-09-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors Version 1.2012

    Version 2.2012, 03-09-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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