Oncology

Neuroendocrine Tumors

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Neuroendocrine Tumors

What every physician needs to know:

Neuroendocrine tumor (NET) and particularly NF-NET (non-functional-NET) patients are commonly misdiagnosed and/or diagnosed late in their disease course as their symptoms are nonspecific, insidious in onset and present for years. Presenting symptoms include those attributable to a specific clinical syndrome and/or tumor-related symptoms such as involuntary weight loss, pain, jaundice, night sweats, nausea or emesis. All functional NETs are symptomatic, but not all symptomatic patients have functional NETs.

Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms that range from the benign and multi-focal to the highly malignant and metastatic. NETs arise from neuroendocrine cells such as the Kulchitsky or enterochromaffin cells that are widely dispersed throughout the body but concentrated in certain areas. The less ambiguous term “well-differentiated neuroendocrine tumor” is preferred over “carcinoid” to more accurately communicate biologic behavior of a specific primary site rather than a term linked to an indolent disease process characterized by serotonin over-secretion.

While generally considered to be uncommon, with an incidence between 3-5 cases per 100,000, NETs constitute the second most prevalent (35 cases per 100,000) gastrointestinal neoplasm and exceed the number of stomach, pancreatic, esophageal and hepatobilliary malignancies because of their general indolent behavior (Figure 1).

Figure 1.

NET Prevalence U.S. 2004/2005

Between 1973 and 2004, the annual age-adjusted incidence of NETs significantly increased from 1 in 100,000 to 5 in 100,000, with approximately 40% arising from the foregut, 30% midgut, 20% hindgut and 10% unclassifiable. The increase is most likely secondary to better reporting, greater awareness and more screening procedures being performed.

For well-differentiated neuroendocrine carcinomas (NECs), about two-thirds arise from the distal small bowel and proximal large intestine and one-fourth from the bronchopulmonary system. Approximately one fourth of patients present with metastatic disease.

NECs are divided into low (well-differentiated), intermediate (moderately well-differentiated) and high-grade (poorly-differentiated) categories according to their mitotic or proliferative index (Table I). Patients with low or intermediate-grade NETs can be further divided into either functional (secretory) or nonfunctional (nonsecretory) groups depending upon whether a hormonal-related recognizable clinical syndrome is present.

Table I.

NET Grading System.

Occasionally, multiple hormones can be secreted and produce concomitant syndromes and tumors that are initially nonfunctional but become functional over time. Pancreatic and intestinal NETs are commonly referred to as gastroenteropancreatic NETS (GEPNETs).

Functional NETs include those that over-secrete amines and/or peptides such as well-differentiated and intermediate-grade tumors such as those arising from the lung, thymus, stomach, pancreas, ovary, small and large bowel. Specific functional tumor types include carcinoid syndrome, insulinomas, gastrinomas (Zollinger-Ellison syndrome), VIPomas (Verner-Morrison syndrome, WDHA [watery diarrhea, hypokalemia and achlorhydria syndrome], pancreatic cholera), glucagonomas (“Sweet” syndrome), somatostatinomas and other more rare syndromes.

Nonfunctional NETs (NF-NETs) can arise from the lung, thymus, skin, stomach, pancreas, appendix, ovary, kidney, small and large intestine. Those with a pancreatic origin are sometimes referred to as PPomas as pancreatic polypeptide levels are frequently elevated but no clinical syndrome is present.

These NF-NETs have similar histologic characteristics to the functional subgroup. Elevated hormonal levels of chromogranin A, pancreastatin, human chorionic gonadotropin subunits (HCG), neuron specific enolase (NSE), neurokinin A (NKA or Substance K) and pancreatic polypeptide may be present and assist with NET diagnosis.

Are you sure your patient has a neuroendocrine tumor? What should you expect to find?

Patients presenting with a primary mass with or without metastatic spread and a specific clinical syndrome are included in the functional well-differentiated or intermediate-grade NET category and include:

  • carcinoid syndrome

  • insulinomas

  • gastrinomas

  • VIPomas

  • glucagonomas

  • Cushings syndrome

  • somatostatinomas

  • Other less frequent functional NETs are considered on a case-by-case basis depending upon the clinical circumstances

The presence of either a primary mass and/or metastatic disease and the absence of a recognizable clinical syndrome would be characteristic of a nonfunctional well-differentiated or intermediate-grade NET. These cases may have elevations of biomarkers including pancreatic polypeptide, chromogranin A, neuron specific enolase and pancreastatin. Occasionally patients present with only hepatic disease and no easily discernible primary. The SEER database classifies this latter group as “liver” primary with essentially no one alive at 10 years.

NETs signs and symptoms that are hormonally driven include:

  • carcinoid and its syndrome: flushing, secretory diarrhea, cardiac valvular disease (tricuspid insufficiency, pulmonic stenosis) and wheezing.

  • insulinoma: hypoglycemia, hypokalemia, syncope, involuntary weight gain.

  • gastrinoma: abdominal pain, dyspepsia, chronic diarrhea, gastrointestinal bleeding.

  • VIPoma and serotonin-producing: dehydration, electrolyte imbalance (hypokalemia, hypomagnesemia, hypocalcemia), flushing.

  • glucagonoma: diabetes accompanied by the “4D’s”: dermatosis (necrolytic migratory erythema), depression, diarrhea, deep venous thrombosis.

  • somatostatinomas: the triad of cholelithiasis, hyperglycemia and steatorrhea.

  • Cushing’s syndrome: relative rapid onset of hypercortisolism causing central obesity, moon face, buffalo hump, hypertension, diabetes and hirsutism.

Tumor-related and non-specific symptoms secondary to either a primary tumor mass or its metastases include:

  • chest pain

  • wheezing

  • dyspnea

  • coughing

  • hemoptysis

  • abdominal pain and/or cramping

  • fatigue

  • night sweats

  • nausea

  • weight loss

  • emesis

  • steatorrhea

  • melena

  • hematemesis

  • dermatosis (urticaria, pellagra, café au lait)

  • jaundice

Often the diagnosis of a NET is made serendipitously or incidentally at the time of an exploratory laparotomy, female pelvic surgery, laparoscopic cholecystectomy, esophagogastroduodenoscopy, colonoscopy, bronchoscopy or chest surgery.

The definitive diagnosis of a NET is made pathologically and not from a constellation of signs and symptoms or biochemical tests.

Beware of other conditions that can mimic neuroendocrine tumors:

Conditions that can mimic NETs include:

  • mastocytosis

  • diabetes mellitus

  • steatorrhea

  • pernicious anemia

  • chronic atrophic gastritis

  • physiologic flushing (female)

  • syncope

  • seizure disorder (hypoglycemic state)

  • panic attacks

  • irritable bowel syndrome

  • Crohn’s disease

  • adenocarcinoma

  • lymphoma

  • cystic lesions of the pancreas

  • autoimmune pancreatitis and chronic pancreatitis

Idiopathic flushing disorders or vasomotor instability with mildly elevated hormonal markers and symptoms responding to somatostatin analog treatment does not constitute the diagnosis of carcinoid syndrome.

Which individuals are most at risk for developing neuroendocrine tumors:

NETs occur sporadically and in various autosomal dominant inherited disorders. The median age of patients presenting with sporadic and MEN I is 60 and 28 years, respectively. Females are more likely to have lung, gastric, appendiceal or cecal primary sites while thymic, pancreas, small bowel and rectal primaries are more common in males.

Caucasians have lung primaries more often, while African Americans have a higher incidence of rectal primaries. For well-differentiated intestinal NETs, no causative factors are known. There are no established nutritional factors that increase the risk for NET development.

Inherited disorders

  • MEN I: in this autosomal dominant inheritable disorder, patients are at high risk (80-100% incidence) for pancreatic NET. MEN1 subjects commonly develop small, microscopic and nonfunctional tumors with only a few (<13%) having symptoms. Gastrinomas are the most common NET in MEN I whereas insulinomas are more common in sporadic cases.

  • von Hippel-Lindau syndrome (VHL): 10-17% of patients are diagnosed with a pancreatic NET.

  • Neurofibromatosis I or von Recklinghausen disease (NF-1): up to 10% of patients develop a pancreatic NET.

  • Tuberous sclerosis (TS): NET occurs occasionally in these pediatric patients.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, Ct/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

Obtaining a tissue diagnosis

Endoscopic procedures inclusive of ultrasound guidance, video endoscopy or double-balloon techniques can provide a tissue diagnosis and identify a primary site. Lung lesions may be approached via bronchoscopic or percutaneous routes with computed tomography (CT) guidance depending upon the location of the mass. For more localized disease, a laparotomy (either open or laparoscopic) or a thoracotomy/video-assisted thoracic surgery (VATS) may be required.

For patients who present with distant disease, hepatic lesions may be biopsied percutaneously with ultrasound or CT guidance for diagnostic and staging purposes. Sampling of a palpable lymph node may provide diagnostic and staging data in some patients. In patients presenting with bone metastases, a bone or bone marrow biopsy can diagnose and stage of the patient.

Pathologic analysis

NETs are identified by chromogranin and synaptophysin immunohistochemical stains. Most NETs are positive for both stains. A specific clinical situation is necessary to stain for specific peptide hormones. The College of American Pathology (CAP) requires the grade and mitotic rate (eye-balled estimate considered adequate) to be present in the final report. The size of the specimen in 3 dimensions, the presence of unusual histologic features (clear cell, gland-forming, oncocytic) and nonischemic tumor necrosis are also essential report components. Ki-67 or MIB-1 labeling index is considered optional in the U.S. but essential in Europe.

Laboratory testing

Disease location and clinical suspicion of any recognizable syndrome will determine which laboratory tests are most helpful. Chromogranin A is most sensitive for the diagnosis of a well-differentiated NET but least specific with regards to the primary site. If flushing symptoms are considered more pathologic rather than physiologic, a blood serotonin and 24-hour 5-HIAA may be diagnostic.

Should an intermediate grade or high grade neoplasm be suspected, neuron specific enolase may be elevated. For pancreatic masses, pancreatic polypeptide should be included in the initial work-up and clinically relevant blood levels for each hormonal syndrome as follows:

  • Well-differentiated NET or “carcinoid’: either all or selective tests depending upon clinical suspicion; blood serotonin, 24 hour 5-HIAA (> 6mg/24 hrs), chromogranin A, pancreastatin, neurokinin A, neuron specific enolase.

  • Intermediate-grade NET or “atypical carcinoid”: chromogranin A, neuron specific enolase.

  • High-grade or poorly-differentiated NET: neuron specific enolase.

  • Insulinomas: proinsulin, insulin, C-peptide and glucose levels during a monitored 48-72 hour fast. Hypoglycemic symptoms usually occur when blood sugar is below 50 mg/dL. The 6 criteria for insulinoma diagnosis are:

    • Blood glucose below 40 mg/dL.

    • Concomitant insulin level over 36 pmol/L.

    • C-peptide levels more than 200 pmol/L.

    • Proinsulin level less than 5 pmol/L.

    • β-hydroxybutyrate levels less than 2.7 mmol/L.

    • Absence of sulfonylurea (metabolites) in the plasma and/or urine.

  • Gastrinomas: gastrin level (fasting and off proton pump inhibitors/H2 antagonists for 2 or more weeks); levels more than 200 pg/ml are suggestive of gastrinoma; levels more than 1,000 pg/ml are diagnostic for gastrinomas. Gastric acid analysis: basal acid secretion more than 15 mEq/hr or basal-to-maximal acid output more than 0.6 supports gastrinoma diagnosis.

  • VIPomas: electrolytes, VIP determined during diarrheal symptoms; diagnostic VIPoma levels are more than 225 pg/ml with upper limit of normal being below 170 pg/ml. Hypokalemia and low bicarbonate levels reflect fecal loss from a secretory diarrheal condition (low fecal fat and normal stool osmolar gap.

  • Glucagonomas: glucagon/blood glucose; glucagon levels more than 1,000 pg/ml are diagnostic with levels between 150–1,000 pg/ml equivocal with levels less than 150 pg/ml within normal limits.

  • Rare NETs: specific hormonal elevation corresponding to the tumor type.

Chromogranin A (CgA) levels are elevated in pernicious anemia, renal insufficiency and with pharmacologic inhibition of gastric acid secretion. Early data suggest that pancreastatin, a subunit of CgA, levels are not elevated in the non-malignant conditions.

Predictive and prognostic biomarkers include 5-HIAA, CgA, pancreastatin and neurokinin A. CgA levels correlate with disease recurrence following resection and survival. Pancreastatin levels over 500 pmol/L predicts a shortened survival. Neurokinin A levels more than 50 pg/ml predict a near zero 3-year survival. 5-HIAA levels above 100 mg/24 hours are associated with carcinoid heart disease and shortened survival.

Imaging studies

CT, MRI:

Functional and nonfunctional NETs are best visualized using either a multiphasic contrasted CT or MRI as these tumors are highly vascular.

Ultrasound:

Endoscopic ultrasound can be useful in the evaluation of esophageal, gastric, insulinomas, small pancreatic tumors and rectal primaries.

Nuclear medicine scans

Octreotide Scan:

Approximately 90% of well-differentiated NETs express the somatostatin receptor subtype 2 (sst2) that allows for scintigraphy to be incorporated into the baseline assessment and surveillance (Figure 2). Fusing the In-111 pentetreotide scan with CT or MRI (Figure 3) can assist the practitioner with anatomic disease localization, treatment planning and disease assessment.

Figure 2.

In-111 Pentetreotide scan in a pancreatic NET patient

Figure 3.

CT fused with an OctreoScan in an insulinoma.

MIBG:

MIBG scanning (Figure 4) detects the presence of the catecholamine transporter protein that is present in nearly all pheochromocytomas but only about two-thirds of intestinal well-differentiated NETs and one-third of bronchial and pancreatic NETs. Scanning with I-123 MIBG has therapeutic implications as those tumors that exhibit significant uptake, and therapy with I-131 MIBG is an option.

Figure 4.

I-123 MIBG scan in a NET patient.

Tumor histology predicts the likelihood of which nuclear medicine scans will be useful. Well-differentiated tumors generally exhibit sst2 and the In-111 pentetreotide scan would be the initial nuclear medicine scan to order. High-grade histology predicts FDG-PET positivity with SUVs more than 2.5.

Intermediate-grade tumors may exhibit both In-111 pentetreotide and FDG-PET positivity with the latter showing lower SUVs than in the high-grade tumors. PET scanning using Ga-68 linked to somatostatin analogs improves sensitivity when compared to traditional somatostatin receptor scintigraphy but is considered investigational in the U.S. and has limited availability.

With advancement in diagnostic techniques, assessment of hormonal gradient studies are rarely done. When traditional imaging and procedures are unsuccessful with disease localization, hormonal gradient studies with provocation (calcium injection for insulinomas, secretin for gastrinomas) using angiography can potentially localize a tumor. Intraoperative ultrasound is another option to identify and resect occult disease.

Integrating clinical, laboratory and imaging data

Integrating the clinical symptoms with the biochemical and radiographic/scintigraphic data allows for the development of a patient specific continuum of care plan. Initial and subsequent assessments include the degree of symptom control, biomarker response and tumor status. For the functional well-differentiated NET patient, symptoms are generally controlled with the somatostatin analogs. A rise in biomarker levels may precede either symptomatic or radiographic progression.

Symptom worsening may not be necessarily indicative of disease progression. The differential diagnosis of symptom progression ranges from an adverse drug effect (gall stones, weight loss, steatorrhea secondary to somatostatin analog-induced cholestasis and pancreatic insufficiency) to physiologic flushing (post-menopausal) to post-surgical intestinal changes (short-gut or blind loop) to bile acid colitis.

Biochemical progression should be assessed according to the degree of rise and the time interval between measurements. As biomarkers may have some intrinsic variance, confirming a rising concentration within 30 days may guide treatment decisions. With reproducible and conclusive evidence of biomarker progression, radiographic progression is anticipated within a 6 to 12 month time period if not sooner.

Change in management should be considered to control rising biomarkers and thus, prevent or delay radiographic and symptomatic progression. Specifically, with the failure of first-line therapy, second-line treatment might include tumor debulking should one dominant tumor area be present such as the liver. If not, consideration for a clinical trial or other treatment alternatives could be considered.

Staging

Table II. TNM staging for lung neuroendocrine tumors.

Table II.

TNM Staging of Lung Neuroendocrine Tumors

Table III. TNM staging for gastric neuroendocrine tumors.

Table III.

TNM Staging of Gastric Neuroendocrine Tumors

Table IV. TNM staging for pancreatic neuroendocrine tumors.

Table IV.

TNM Staging of Pancreatic Neuroendocrine Tumors

Table V. TNM staging for small intestine neuroendocrine tumors.

Table V.

TNM Staging of Small Intestine Neuroendocrine Tumors

Table VI. TNM staging for appendiceal neuroendocrine tumors.

Table VI.

TNM Staging of Appendiceal Neuroendocrine Tumors

Table VII. TNM staging for colorectal neuroendocrine tumors.

Table VII.

TNM Staging of Colorectal Neuroendocrine Tumors

What therapies should you initiate immediately i.e., emergently?

Therapies for initial NET management are dependent upon the astute recognition and correlation of the clinical circumstances to the specific hormone that is being over secreted. Clinical presentations are varied and range from patients being chronically misdiagnosed to acute and life-threatening conditions.

Carcinoid syndrome

Flushing, asthma and secretory diarrheal symptoms require immediate control with octreotide, a somatostatin analog. The severity of symptoms will determine which octreotide formulation and route of administration is optimal.

The subcutaneous (SC) route is satisfactory for most patients in order to control symptoms in a timely manner with eventual conversion, usually within 2 weeks, to the intramuscular or depot monthly formulation. SC octreotide is continued for 2 weeks after the initial intramuscular long acting release (LAR) injection as therapeutic levels are achieved. Breakthrough symptoms that occur after conversion to LAR may require SC dosing depending upon their severity and duration.

Carcinoid crisis

Carcinoid syndrome symptoms that are unremitting can be life-threatening and should be considered an oncologic emergency. Volume and electrolyte replacement combined with correcting acidosis and controlling diarrheal symptoms are key in reversing clinical deterioration. Identifying and treating the precipitating event such as sepsis, bleeding or a viral illness is also crucial in controlling the crisis. Corticosteroids, antibiotics and infusional somatostatin analogs may be necessary in gaining control of the illness.

Carcinoid crisis prophylaxis

In patients with the carcinoid syndrome undergoing an elective procedure, decreasing the risk of carcinoid crises with supplemental octreotide is recommended.

Insulinomas

Dextrose administration, glucagon (1mg subcutaneously, intramuscularly or IV and may repeat in 15 minutes) and potassium replacement may be required emergently to control symptoms of hypoglycemia. For more chronic control, diazoxide (3-8 mg/kg/day PO every 8-12 hrs), limiting energy expenditure and small frequent feedings are recommended. The adverse effects of diazoxide include fluid retention requiring diuretics and nausea at higher doses.

For insulinomas confined to the pancreas, the somatostatin analogs (octreotide, lanreotide) can control symptoms in approximately 50% of patients. For metastatic insulinomas, everolimus, Y-90 radioembolization, bland or chemoembolization and radiofrequency ablation may be effective in controlling symptoms and disease.

Gastrinomas

Replace blood loss and control bleeding from ulcers in the gastrointestinal tract in the acutely ill patient. Reducing gastric acid production with histamine H2-receptor antagonists or proton pump inhibitors (omeprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole) is effective in controlling ulceration.

The chronic pharmacologic maintenance of the achlorhydric state can produce B-12 and iron deficiencies. Somatostatin analogs lower gastrin levels and can control symptoms and disease in some patients. Peptide receptor radiotherapy (PRRT) is investigational for some agents (Y-90, Lu-177, Rh-188) and considered standard practice for others (In-111).

VIPomas

Blood volume, electrolytes and acid-base balance corrections are initial interventions in patients with secretory diarrhea from VIP over secretion. Somatostatin analogs are indicated for chronic control.

Glucagonomas

Hyperglycemia, anemia and nutritional deficiencies require immediate management. Somatostatin analogs are effective for long-term management.

Other functional neuroendocrine tumors

For GRFomas, ACTHomas and somatostatinomas therapy with variable responses to somatostatin analog therapy.

Carcinoid heart disease

Initiate diuretics that can improve edema but may decrease left sided cardiac output leading to fatigue and dyspnea. Serial exams, echocardiograms and selective exercise testing every 6 months to determine optimal timing of valve replacement.

What should the initial definitive therapy for the cancer be?

NETs comprise a heterogeneous group of neoplasms, definitive therapy is dependent upon primary site, tumor grade and stage.

Bronchial neuroendocrine tumors

Bronchial NETs are usually well-differentiated or intermediate grade and may be associated with the carcinoid syndrome. Surgical extirpation for local disease management may be curative. Cytotoxic chemotherapy and/or hormonal therapy are options for metastatic disease.

Gastric neuroendocrine tumors

Gastric NETs are of 3 types:

  • Type I: elevated gastrin, small tumors (<1cm), multi-focal, low malignant potential, the most common type (~70%) and associated with chronic atropic gastritis/pernicious anemia.

  • Type II: elevated gastrin and associated with MEN I syndrome.

  • Type III: normal gastrin, typically solitary, nodule larger than 1cm and invasive; behaves more like gastric adenocarcinoma.

Surgical management for type III is the definitive treatment of choice for localized disease. Types I and II are more indolent generally requiring medical treatment for control of symptoms and endoscopic surveillance.

Duodenal neuroendocrine tumors

The five kinds of duodenal NETs are:

  • Gastrin secreting

  • Somatostatin secreting

  • Nonfunctional

  • Paraganglioma-like

  • Poorly differentiated

Most duodenal NETs are usually benign but the 10% that are malignant, metastasize to regional lymph nodes and liver and behave in an aggressive manner. Surgical excision for early disease and medical management for metastatic disease are recommended.

Neuroendocrine tumors in small and large intestine

Jejunal, ileal, cecal and proximal colon NETs are usually well-differentiated and when metastatic, associated with the carcinoid syndrome. Common sites of metastases are regional lymph nodes and liver. A local cicatricial or desmoplastic reaction may be present at the time of diagnosis and responsible, at least in part, for some of the early symptoms of partial bowel obstruction, pain and cramping. Excision of local disease or removal of primary when metastastic disease is present are management options to control symptoms and potential disease complications.

Appendiceal neuroendocrine tumors

Appendiceal NETs are usually benign and located towards the tip. Tumors at the base of the appendix regardless of size and those that are larger than 2cm should be considered malignant. A right hemicolectomy and lymph node dissection is recommended for these tumors. Carcinoid syndrome is rarely associated with appendiceal primaries.

Adenocarcinoid or goblet cell carcinoid, or ‘crypt cell carcinoma’, a hybrid tumor arising from appendiceal crypt cells, is a more aggressive form of malignancy than its classical appendiceal counterpart. Clusters of mucin containing goblet cells combined with an admixture of Paneth cells and endocrine cells are seen histologically.

As the tumor nests are interspersed within the muscle and stroma of the appendiceal wall, suspecting the lesion visually is difficult. Metastatic spread to regional lymph nodes, peritoneum and the ovary is observed. As excess hormonal secretion is unusual, goblet cell carcinoids more closely resemble exocrine than endocrine tumors. Primary excision for localized disease is recommended.

Rectal neuroendocrine tumors

Rectal NETs are usually small, sometimes multi-focal and usually benign. Of the 10% that are malignant, an aggressive surgical approach is recommended. These tumors seldom are associated with hormonal over-secretion and usually are sst2 negative.

Neuroendocrine tumors at other sites

Other sites for NETs include gonads, kidney, breast and skin. Ovarian primaries can be associated with carcinoid syndrome in the absence of metastatic spread and is related to the venous drainage of the left ovary that bypasses the hepatic portal system. Renal primaries are highly malignant and metastasize to lymph nodes, liver and bone. Breast as a primary site is rare and usually reflects an aggressive natural course. NETs of the skin, Merkel Cell, are usually poorly-differentiated and more closely resemble small cell carcinoma of the lung.

Neuroendocrine tumors of unknown primary site

NETs of unknown primary site are well described and are usually of intestinal origin. Patients may present with liver only disease and no apparent primary detectable on scans or endoscopy. As intestinal primary sites may be small and submucosal, regional lymphatic metastases is suggestive of a ‘midgut’ primary. These tumors may be functional or nonfunctional.

Supportive care

Carcinoid syndrome patients even already on depot octreotide may require supplemental octreotide for elective procedures such as endoscopy, laparoscopy, thoracotomy and dental to lower the risk of carcinoid crisis.

Multi-disciplinary care is usually required as any clinical syndrome requires medical stabilization prior to any surgical or radiologic intervention. Endocrinologists, medical oncologists, endocrine and surgical oncologists, interventional radiologists and gastroenterologists comprise the core management team with pathology, diagnostic radiology, nuclear medicine and therapeutic radiation support.

In addition, nutritional, pain, psychological, geriatric, social services and palliative care teams are important in the supportive aspects of NET disease management. Specialities less commonly involved include solid organ transplant teams, cardiology and pulmonary medicine. Referral to tertiary care centers can assist the local healthcare team with formulating and initiating a comprehensive continuum of care plan inclusive of surveillance.

Surgery

Surgical extirpation for localized NET disease is the only curative modality. For unresectable low and intermediate-grade tumors, debulking is commonly performed to not only improve symptoms and tumor control but to decrease disease-related complications such as pancreatic insufficiency from chronic pancreatic duct obstruction and intestinal ischemia arising from obstruction of mesenteric vessels by lymphatic metastases.

Local hepatic therapies

Local hepatic therapies (Figure 5) (hepatic embolization or chemoembolization, radioembolization, radiofrequency ablation) may be combined with systemic therapy on an individual basis. For patients with 30-60% liver involvement by tumor, hepatic debulking prior to progression is suggested. Prescribing local therapy for patients with more than 60% liver involvement is based on individual factors and comorbidities.

Figure 5.

NET Hepatic Metastases Management.

Medical therapy

Medical therapy for advanced NETs is considered palliative with symptom and tumor control comprising the major goals. Anti-hormonal (somatostatin analogs), cytotoxic and targeted agents are initial options based on the tumor’s proliferative index. Specific regimens (including dose and schedule) are listed at the end of this section.

First-line systemic therapies

  • Well-differentiated tumor with hormonal syndrome: somatostatin analog (octreotide, lanreotide).

  • Intermediate-grade tumor without hormonal syndrome: cytotoxic agents (temozolomide ± capecitabine, 5-FU, streptozocin, doxorubicin).

  • Intermediate-grade tumor with hormonal syndrome: somatostatin analog + cytotoxic agents (temozolomide ± capecitabine, 5-FU, streptozocin, doxorubicin).

  • High grade tumor: cytotoxic agents (etoposide + cisplatin, see below).

Second-line systemic therapies

Second-line therapies are dependent upon primary site.

1. Pancreatic primaries

  • Well-differentiated tumor with hormonal syndrome: everolimus or sunitinib +/- somatostatin analog.

  • Intermediate-grade tumor without hormonal syndrome: everolimus or sunitinib.

  • Intermediate-grade tumor with hormonal syndrome: everolimus or sunitinib +/- somatostatin analog.

  • High-grade tumor: cytotoxic agents (irinotecan or topotecan +/- cisplatin or carboplatin).

2. Small and large bowel neuroendocrine tumors

  • Well-differentiated tumor with hormonal syndrome: interferon, 5-FU.

  • Intermediate-grade tumor without hormonal syndrome: interferon, 5-FU.

  • Intermediate-grade tumor with hormonal syndrome: interferon, 5-FU.

  • High grade tumor: cytotoxic agents (irinotecan or topotecan +/- cis- or carboplatin).

Third-line systemic therapies

Third-line therapies would include those agents not previously prescribed. Good performance status patients may then be considered for clinical trials or PRRT or I-131 MIBG treatment depending upon the degree of radioisotopic uptake on the diagnostic nuclear scans.

Regimens

Somatostatin analogs

  • Octreotide acetate (Sandostatin) 50-500 mcg subcutaneously q 8-12 hrs.

  • Octreotide acetate long acting release (Sandostatin LAR) 10, 20, 30 mg IM q 30 days.

  • Lanreotide (Somatuline Depot) 60, 90, 120 mg deep subcutaneous q 4 weeks (approved in U.S. for acromegaly only).

For immediate control of symptoms, short-acting somatostatin analog is the formulation of choice. Prior to initiating long-acting octreotide, a test dose (50-100 mcg) is recommended to test for an allergic reaction.

Short-acting somatostatin analog is necessary to control symptoms for approximately 2 weeks following the first LAR dose and for breakthrough symptoms thereafter. Dosing between 50-150 mcg SC every 8-12 hours and titrated in 50 mcg increments is recommended. Approximately one-third of patients will have breakthrough carcinoid syndrome symptoms that seem to cluster the week prior to LAR dosing.

Somatostatin analogs are continued regardless of disease progression as carcinoid syndrome symptoms remain responsive, at least in part, to somatostatin analogs.

Cytotoxic single-agent regimens

  • 5-FU 400-500 mg/m² x 5 days every 3-5 weeks when used in combination with other cytotoxic agents; single agent infusion schedule at 300 mg/m²/d for 30-180 days.

  • Capecitabine (Xeloda) 500-1000 mg/m² PO daily x 14 days followed by 7 days off or Mon to Fri dosing titrated to patient tolerance.

  • Streptozocin (Zanosar) 500 mg/m² IV daily for 5 days every 6 weeks; alternatively: 1000 mg/m² IV weekly, may increase with 3rd dose to a maximum of 1500 mg/m² per dose.

  • Doxorubicin (Adriamycin) 60-75 mg/m² IV over 3-5 minutes every 21 days when used as monotherapy and 40-60 mg/m² IV every 21 days when used in combination with other chemotherapeutic agents. The maximal cumulative dose is 550 mg/m² or 450 mg/m² if concomitant mediastinal XRT.

  • Temozolomide (Temodar) 150-200 mg/m² PO daily x 5 days every 28 days.

  • Etoposide 35-50 mg/m² IV daily x 4-5 days every 3-4 weeks.

  • Cisplatin (Platinol AQ) 75-100 mg/m² IV every 4 weeks; maintain adequate hydration/urine output before, during and 24 hours after dosing.

  • Irinotecan (Camptosar) 60 mg/m² weekly x 3 every month in combination with cisplatin; decrease dose if reduced UGT1A1 activity or in Gilbert’s syndrome.

  • Topotecan (Hycamtin) 1.5 mg/m² IV over 30 min daily times 5 every 21 days.

Combination cytotoxic regimens

  • EP: etoposide 80 mg/m² IV on days 1-3; cisplatin 80 mg/m2 IV on day 1 only. Repeat cycle every 21 days.

  • EC: etoposide 100 mg/m² on days 1-3; carboplatin AUC of 6, IV on day 1. Repeat cycle every 28 days.

  • Irinotecan + cisplatin: irinotecan 60 mg/m² IV on days 1, 8 and 15; cisplatin 60 mg/m² IV on day 1. Repeat cycle every 28 days.

  • Topotecan + cisplatin: topotecan 1.7 mg/m² orally on days 1-5; cisplatin 60 mg/m² IV on day Repeat cycle every 21 days up to 4 cycles or 2 cycles beyond best response.

  • Carboplatin + paclitaxel + etoposide: carboplatin AUC of 6, IV on day 1; paclitaxel 200 mg/m² IV over 1 hour on day 1; etoposide 50 mg alternating with 100 mg orally on days 1-10. Repeat cycle every 21 days.

  • Carboplatin + paclitaxel: carboplatin AUC of 2, IV on day 1, 8 and 15; paclitaxel 80 mg/m² IV on days 1, 8 and 15. Repeat cycle every 28 days for 6 cycles.

  • CAV: cyclophosphamide 1000 mg/m² IV on day 1; doxorubicin 40 mg/m² IV on day 1; vincristine 1mg/m2 IV on day 1 (maximum, 2mg). Repeat cycle every 21 days.

  • CAE: cyclophosphamide 1000 mg/m² IV on day 1; doxorubicin 45 mg/m² IV on day 1; etoposide 50 mg/m² IV on days 1-5. Repeat cycle every 21 days.

  • Capecitabine 750 mg/m² PO twice daily on days 1-14 + Temozolomide 200 mg/m² PO once daily on days 10-14. Repeat cycle every 28 days.

Targeted agents

  • Everolimus (Afinitor 2.5, 5, 10 mg tablets): 10 mg orally daily with dose titrated according to concomitant medications and tolerability.

  • Sunitinib (Sutent 12.5, 25, 50 mg tablets): 37.5 mg orally daily and dose titrated to tolerability.

Interferons

  • Intron A – 3-5 million units, 3-5 times a week subcutaneously.

  • Pegylated formulations.

  • Peginterferon alfa 2a (Pegasys) 80-180 mcg SC q wk.

  • Peginterferon alfa 2b (PegIntron) 80-120 mcg SC q wk.

A typical care plan for a patient with metastatic sst2-positive terminal ileal NET with carcinoid syndrome, elevated 5-HIAA, CgA and disease limited to the primary, regional lymph nodes and the liver would be to initiate somatostatin analog therapy and follow the patient for both a clinical and biochemical response. Should the disease be amenable to debulking procedures (dependent upon disease location and amount of disease), removal of the primary tumor and prophylactic cholecystectomy can be considered. If less than 30% of the liver is involved by tumor, then monitoring the patient with serial clinical exams, biomarkers and scans are suggested.

At the time of hepatic progression, debulking procedures or consideration for a clinical trial are options. Should more than 30% of the liver be replaced by tumor, consideration for debulking procedures such as radiofrequency ablation, radioembolization, chemoembolization or bland embolization are options. At the time of subsequent progression, additional debulking options should be considered along with a change in systemic treatment. Somatostatin analogs are continued regardless of disease progression as carcinoid syndrome symptoms remain responsive, at least in part, to somatostatin analogs.

What other therapies are helpful for reducing complications?

Supportive care measures include:

Diarrheal control

  • Loperamide (Imodium): 4-8 mg/day PO every day to TID. Start 4 mg PO x 1; then 2 mg PO after each loose stool until control; maximal dose: 16 mg/day.

  • Diphenoxylate atropine (Lomotil): initial dose: 2 tabs PO QID or 10 ml solution PO QID until achieving initial control. Maximal dose: 20 mg/day; reduce the dose to meet individual requirements; maintenance dose: 5 mg/day (10 ml/day of solution).

  • Deodorized tincture of opium (DTO): 50 mg morphine anhydrous/5 mL: 0.6 ml QID, range 0.3-1 ml QID; decrease dose gradually over 2-4 weeks.

  • Cyproheptadine (Periactin): 4 mg PO TID; usual range is 4-20 mg/day PO; maximal dose is 0.5 mg/kg/day.

  • Corticosteroids: prednisone 5-60 mg/d PO in 2-4 divided doses or dexamethasone 0.5-9 mg/day PO divided q 6-12 hrs.

  • Pancreatic enzymes or pancrelipase (Creon, Zenpep): start with 500 lipase units/kg PO per meal; maximal dose: 2,500 lipase units/kg PO per meal (or <10,000 lipase units/kg/day, or <4,000 lipase units/g fat ingested/day.

  • Cholestyramine (Questran): 4 g mixed with water or other liquid PO qd-BID and titrate to a maintenance dose of 8-16 g BID and a maximal dose of 24 g/day. (Colestid): 2 g PO BID and increased monthly up to 16 g/day qd-BID.

Appetite stimulants

  • Megestrol acetate (Megace, Megace ES) (100-800 mg PO qd)

  • Dronabinol (Marinol) 2.5 mg PO BID and titrate to 20 mg/day in divided doses. Maximal daily dose: 20 mg.

Weight gain

  • Oxandrolone (Oxandrin) 2.5-20 mg PO BID-QID x 2-4 weeks and repeat intermittently as indicated; Maximal daily dose: 20 mg/day.

Nausea and emesis management

  • Prochlorperazine (5-10 mg PO tid-qid).

  • 5-HT3 antagonists (ondansetron 8 mg PO BID x 1-2 days after completion of chemotherapy, granisetron 2 mg PO qd, palonosetron 0.5 mg PO 1 hour prior to chemotherapy).

Rash prevention

  • Glucagonomas with zinc therapy (Zinc-220): one capsule daily with meals.

Thrombosis prevention

  • Thrombosis prevention using anticoagulants in glucagonoma patients with warfarin (Coumadin) dosed to maintain an INR between 2.0-3.0.

  • For acute management of a thromboembolic event, enoxaparin (Lovenox) 40 mg SC q d up to 17 days; warfarin should be initiated within 72 hrs; enoxaparin to be continued for more than 5 days and until therapeutic (INR 2.0-3.0) anti-coagulant effect has been achieved.

  • For patients intolerant to warfarin, a vena cava filter may be considered.

Iron-deficiency and chemotherapy-induced anemia treatment

  • Hematinics including oral (ferrous gluconate or sulfate) or intravenous iron agents (iron dextran), cyanocobalamin (Vitamin B12), folic acid and erythropoietin.

Pain control

  • Non-opioid and opioid analgesics.

Diuretics

  • Used control the lower extremity edema secondary to carcinoid heart disease.

What should you tell the patient and the family about prognosis?

The goals in the treatment of neuroendocrine tumors are:

  • To remove or reduce the signs and symptoms of the disease.

  • To control the size of the NET tumor.

  • To reduce the biochemical markers of NETs to normal.

  • To anticipate and prevent medical conditions related to the complications of NETs.

  • To maximally extend survival while maintaining a good quality of life.

NETs having an embryologic foregut origin include thymus, bronchial, gastric, duodenal and pancreas are usually more aggressive than the midgut NETs, typically lack aromatic amino acid decarboxylase and thus less frequently have elevated serotonin levels.

Tumors with a jejunal, ileal, cecal, appendiceal or proximal colonic or midgut origin are more likely to be indolent, diagnosed at a late stage with lymph node and hepatic metastases. Hindgut tumors include those arising from the distal colon and rectum and are seldom hormonally active. Of the 10% of hindgut tumors that are malignant, their natural history is more similar to adenocarcinoma than it is to midgut well-differentiated NETs.

Thymic NETs are usually intermediate or high-grade and highly lethal. They may be hormonally active, secrete ACTH among other substances and hereditary as part of MEN 1.

The overall 5-year survival for localized and metastatic midgut well-differentiated NEC ranges between 52-77%. The size of the primary and depth of invasion predicts metastases to local-regional and metastatic sites. Approximately 75% of primary tumors exceeding 1cm in size metastasize versus 31.5% for those between 6-10mm and only 16% for those tumors less than 6mm.

The overall 5-year survival for non-metastatic midgut well-differentiated NEC is approximately 90%.

What if scenarios.

1. If histologic grade cannot be definitively ascertained by available biopsy material, consider a core needle biopsy or other procedure to acquire an adequate sample.

2. If there is discordancy between the mitotic and Ki-67 index, the higher value should be taken.

3. If there is heterogeneity between the primary and metastatic disease sites, the higher mitotic lesion should guide therapy.

4. If the OctreoScan is negative and hormonal symptoms are present, a trial of somatostatin analog therapy should be undertaken.

5. If the OctreoScan is negative, a FDG-PET scan should be considered especially if the histology is intermediate grade.

6. If there is no or minimal response to therapy for a high-grade NET, consider therapy for an intermediate grade tumor.

7. If there is a scheduled surgery for a NET patient, consider a prophylactic cholecystectomy as a long-term complication of chronic somatostatin analog therapy is cholelithiasis.

8. If involuntary weight loss occurs and is not attributable to progressive disease, consider steatorrhea as an expected side effect from somatostatin analog therapy. Distinguishing the etiology will determine whether somatostatin analog dose escalation may be helpful versus initiating pancreatic enzyme therapy.

9. If there is celiac and/or superior mesenteric vessel encroachment by lymph nodal metastases, surgical intervention should be considered to determine whether resectability is possible.

10. If chronic pain from celiac plexus involvement is present, consider a celiac block at the time of laparotomy.

11. If there is hypoglycemia that is refractory to diazoxide or cytotoxic chemotherapy, consider everolimus, peptide receptor radiotherapy (PRRT), liver debulking using Y-90 microspheres, bland or chemo-embolization.

12. If a gastrinoma patient’s symptoms no longer respond to H2-antagonists/PPI therapy, somatostatin analog therapy and/or tumor debulking are options.

13. When treating steatorrhea, if one (Creon, Zenpep) commercial preparation of pancreatic enzymes is ineffective despite titration, substitute the other preparation before declaring no benefit.

Follow-up surveillance and therapy/management of recurrences.

General surveillance guidelines consist of

  • Identifying any disease related symptom(s).

  • Biochemical markers (specific and nonspecific).

  • Imaging assessment to determine the precise tumor localization and possible metastases by CT/MRI scans and somatostatin receptor scintigraphy.

Surgical patients are typically re-evaluated three months post-operatively to establish a new “baseline”.

Tumor markers to consider are dependent upon the primary site:

  • CgA is the most sensitive but the least specific.

  • 5-HIAA is the most specific but not sensitive for diagnosing early disease.

  • Pancreastatin, a fragment of the much larger CgA molecule, may be more sensitive than 5-HIAA or chromogranin A in accessing acute changes in tumor burden.

  • Serotonin is recognized as a variable and labile tumor marker, but may be useful in making a diagnosis but confusing when followed serially.

Radiologic imaging modalities include CT/MRI scanning with triple-phase helical CT scans being the preferred imaging protocol when liver disease is present or strongly suspected. In the contrast-sensitive patient, MRI (enhanced and unenhanced) is recommended. For patients unable to undergo CT/MRI, serial OctreoScans are suggested.

Clinical scenarios with recommended frequencies of office visits, tumor markers and scans in newly diagnosed patients who have either undergone a complete resection (R0) or have micro-metastatic (positive margins (R1) and/or lymph node positivity) or macro-metastatic disease (scan positivity) are as follows:

Well-differentiated (grade 1) and intermediate (grade 2) neuroendocrine tumors arising from the midgut (excluding appendiceal primaries less than 2cm)

Negative lymph nodes:

  • History and physical examinations with tumor markers every six months for years 1-4 years and then annually.

  • Tumor markers to consider include: CgA, pancreastatin, serotonin, 5-HIAA.

  • Frequencies of imaging studies (CT/MRI or OctreoScan) after establishing a baseline are as clinically indicated.

Positive lymph nodes:

  • History and physical examinations every 6 months.

  • Tumor markers (serotonin, 5-HIAA, CgA, pancreastatin) every 3-6 months for 4 years then every 6 months.

  • Baseline CT/MRI/OctreoScan followed by annual CT/MRI for 4 years and OctreoScans to be repeated as clinically indicated.

Metastatic disease:

  • History and physical examinations with tumor markers every 3-6 months.

  • Tumor markers to consider include: 5-HIAA, CGA, pancreastatin, serotonin.

  • Baseline CT/MRI/OctreoScan followed by CT/MRI every 6-12 months and OctreoScan as clinically indicated.

  • At the time of progressive disease on somatostatin analogs, see management of metastatic disease.

Poorly-differentiated/anaplastic neuroendocrine tumors (grade 3):

Negative lymph nodes:

  • History and physical examinations with tumor markers every 3 months for 5 years.

  • Tumor markers (NSE) as clinically indicated.

  • CT/MRI at baseline then every 3-4 months for 3 years then every 6 months for 2 years then annually as clinically indicated.

  • FDG-PET scan as clinically indicated.

  • OctreoScan is not usually indicated.

Positive lymph nodes:

  • History and physical examinations every 2-3 months for 3 years then every 6 months for 2 years;

  • Tumor markers as clinically indicated (example: neuron specific enolase) every 2-3 months for 3 years then every 6 months for 2 years.

  • CT/MRI as baseline then every 3 months for 2 years then as clinically indicated.

  • FDG-PET at baseline and repeated as clinically indicated.

  • OctreoScan is not usually indicated.

Metastatic disease:

  • as cytotoxic chemotherapy is the preferred treatment, follow-up should be in accordance with the chemotherapy protocol adopted.

Well-differentiated and intermediate grade neuroendocrine arising from the pancreas (foregut):

  • History and physical examinations with tumor markers every 6 months for years 1-4 years and then annually.

  • Tumor markers to consider include: CgA, pancreastatin, pancreatic polypeptide.

  • Frequencies of imaging studies (CT/MRI or OctreoScan) after establishing a baseline are as clinically indicated.

Positive lymph nodes:

  • History and physical examinations every 6 months.

  • Tumor markers (CgA, pancreastatin, pancreatic polypeptide) every 3-6 months for 4 years then every 6 months.

  • Baseline CT/MRI/OctreoScan followed by annual CT/MRI for 4 years.

  • OctreoScans to be repeated as clinically indicated.

Metastatic disease in functional and nonfunctional patients:

  • History and physical examinations with tumors markers every 3-4 months.

  • Tumor markers to consider include: 5-HIAA, CGA, pancreastatin, serotonin, gastrin, calcitonin, insulin, glucagon, somatostatin, VIP, substance P, PTHrP.

  • Baseline CT/MRI/OctreoScan followed by CT/MRI every 6-12 months.

  • OctreoScan as clinically indicated.

  • At the time of progressive disease on somatostatin analogs, see management of metastatic disease.

Poorly differentiated neuroendocrine tumors arising from the pancreas (foregut):

This is a sufficiently rare circumstance (<5% of the cases) that recommendations would follow clinical indications as most patients would receive cytotoxic chemotherapy.

Well-differentiated (grade 1) and intermediate (grade 2) neuroendocrine arising from the hingut:

Smaller than 2cm:

  • History and physical examinations at 6 and 12 months than as clinically indicated.

  • Tumor markers are not usually necessary.

  • Proctoscopy at 6 and 12 months and then as clinically indicated.

  • Scans are not routinely performed.

More than 2cm with or without positive lymph nodes:

  • History and physical examinations at 6 and 12 months.

  • Tumor markers not usually helpful (GLP-1, PYY optional).

  • Proctoscopy at 6 and 12 months then as clinically indicated.

  • Baseline abdominal/pelvic CT/MRI scan and repeat as clinically indicated.

Metastatic disease:

  • History and physical examinations every 3 months or as clinically indicated.

  • Tumor markers not usually helpful (GLP-1, PYY optional).

  • Baseline abdominal/pelvic CT/MRI scan every 3-4 months or as clinically indicated.

  • OctreoScan not usually indicated.

  • At the time of progressive disease, see management of metastatic disease.

Poorly-differentiated (grade 3) neuroendocrine arising from the distal colon and rectum (hindgut):

More than 2cm:

  • History and physical examinations at 3, 6, 9 and 12 months than as clinically indicated.

  • Tumor markers are not usually necessary.

  • Proctoscopy at 3, 6 and 12 months and then as clinically indicated.

  • Baseline abdominal/pelvic CT/MRI scan and repeated every 3-4 months for 2 years then every 6 months for 3 years then as clinically indicated.

  • OctreoScan is not routinely performed.

More than 2cm with or without positive lymph nodes:

  • History and physical examinations every 3-4 months for 3 years then every 6 months for 2 years then as clinically indicated.

  • Tumor markers are not usually necessary.

  • Proctoscopy at 3, 6 and 12 months and then as clinically indicated.

  • Baseline abdominal/pelvic CT/MRI scan and repeated every 3-4 months for 3 years then every 6 months for 2 years then as clinically indicated.

  • OctreoScan is not routinely performed.

Metastatic disease:

  • Cytotoxic chemotherapy is the preferred treatment, follow-up should be in accordance with the chemotherapy protocol adopted.

Pathophysiology

The molecular genetics of NETs involve different genes, each of which may be associated with several different abnormalities that include gene deletions, point mutations, DNA methylation, chromosomal losses and gains. Depending upon its embryologic origin, NETs develop via different molecular pathways. Deletions and mutations of the MEN1 gene give rise to pancreatic NET, whereas ileal NETs have losses of chromosome 18, 11q and 16q and rectal NETs express transforming growth factor-alpha and the epidermal growth factor receptor.

Bronchial NETs have a loss of chromosome 3p as the most frequent change. p53 mutations and chromosomal loss of 5q21 are associated with more aggressive tumors and poor survival. Methylation frequencies of the retinoic acid receptor-beta, E-cadherin and RAS-associated domain family genes increase with the severity of lung NETs. The development and progression of NETs is associated with specific genetic abnormalities that indicate involvement of different molecular pathways.

Studies of hereditary NETs and pancreatic exocrine cancer have contributed to the understanding of sporadic NETs. Environmental risk factors for sporadic pancreatic NETs may be similar to those for pancreatic exocrine cancer and include a family history of any cancer, chronic pancreatitis, high alcohol consumption and recent-onset diabetes.

Genetic karyotyping in a small pancreatic NETs series demonstrated clonal chromosomal abnormalities in moAre than 50% of the specimens. HER-2/neu proto-oncogene amplification can occur in gastrinomas. In insulinomas, high levels of mRNA expression of the alpha subunit of the cell cycle protein, Gs, is reported. The cyclin-dependent kinase inhibitor, p27kip1, is abundantly expressed in well-differentiated pancreatic NETs but minimally present in less differentiated disease.

Mutations in chromosome 11q13 region result in alterations in the Menin gene that encodes menin, a 610-amino acid nuclear protein that influences cell division, regulation of transcription, genomic stability and cell cycle control. MEN I patients develop parathyroid adenomas (95-100%), pituitary adenomas (54-65%), adrenal adenomas (27-36%), carcinoid tumors (gastric, lung, thymic; 0-10%), thyroid adenomas (up to 10%), various skin tumors (80-95%), central nervous system tumor (up to 8%) and smooth muscle tumors (up to 10%). LOH (loss of heterozygosity) at 11q13 also occurs in some sporadic pancreatic NET patients.

What other clinical manifestations may help me to diagnose neuroendocrine tumors?

MEN1: Have you ever had kidney stones or a diagnosis of hyperparathyroidism? Any family members with kidney stones or abnormalities in their calcium?

Carcinoid: What parts of the body are affected by the flushing? (Physiologic flushing generally encompasses the whole body whereas carcinoid flushing is usual facial, neck and upper torso, palms of hand and soles of feet.) Does diaphoresis accompany your flushing? ("Wet" flushing implies estrogen withdrawal in the female or may be night sweats accompanying bulky hepatic metastases.) Do your bowels move during the night? (Diarrhea associated with IBS or irritable bowel syndrome occurs while the subject is awake. Nocturnal stools should trigger consideration for diagnoses other than IBS). What is the duration of your flushing symptoms? (Midgut primaries associated with 'typical' flushes lasting several seconds to several minutes. Foregut primaries may cause 'atypical' flushing symptoms persisting for minutes to hours and periorbital edema.)

Insulinomas: Does eating make your symptoms better? Do symptoms occur during the night?

Gastrinomas: Have you ever needed a blood transfusion or been diagnosed with iron or vitamin B-12 deficiency? Chronic diarrhea with peptic ulcer disease?

VIPomas: Does your diarrhea respond to fasting?

Glucagonomas: Have you had an unusual rash that responds poorly to empiric therapy?

Carcinoid heart disease: Is there a) swelling of both lower extremities b) dyspnea c) tricuspid insufficiency or pulmonary stenosis murmurs?

What other additional laboratory studies may be ordered?

CTID (Cancer TYPE ID or a 92-gene real-time PCR assay) performed by Biotheranostics, Inc. for primary site identification when NETs present as unknown primary (usually liver dominant disease). Distinguishing between pancreatic and bowel primary sites is important when prescribing certain targeted agents as everolimus and sunitinib as they are indicated in the former but not the latter.

Neurokinin A blood level is prognostic in ileal primary tumors. Should the neurokinin A rise above 50pg/ml and significant disease be present, there should be serious consideration for a more aggressive approach as the 3-yr survival approaches zero.

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