Neuroendocrine Tumors (Current Clinical Oncology)

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Phase II studies of everolimus demonstrated promising data in NETs originating within and outside of the pancreas. Although median PFS was longer with everolimus compared with placebo Moreover, there was a nonsignificant trend toward reduced OS with everolimus in this study. Food and Drug Administration approved everolimus for the treatment of advanced NETs of lung or gastrointestinal origin. An initial role for chemotherapy in NEN management dates back to the s, with the earliest investigations of streptozocin-based chemotherapy for progressive and advanced pNETs.

Although SSAs remain the cornerstone first-line treatment option for most patients with advanced, unresectable NETs based on their exceptionally favorable safety profile and their ability to inhibit tumor progression and palliate hormonal symptoms, most patients eventually experience disease progression while receiving first-line SSA treatment. The underlying principle of this treatment is rather simple; by attaching a radionuclide to an SSA, targeted radiation can be delivered systemically to tumors. Radiolabeled SSAs consist of a carrier molecule the SSA , a radionuclide isotope, and a chelator that binds and stabilizes the complex.

Tetra-azacyclododecane-tetra-acetic acid DOTA and diethylenetriamine penta-acetic acid have been the most commonly used chelators. The first-generation radionuclide used in PRRT was In, a gamma-emitting isotope that also emits Auger electrons with short particle range resulting in a weak cytotoxic effect.

The intermediate-range tissue penetration of Lu approximately 2 mm results in a relatively favorable therapeutic index. Until recently, most studies evaluating radiolabeled SSAs consisted of prospective registries or small single-arm studies and institutional retrospective databases. Differences in eligibility criteria, response criteria, and treatment doses render comparisons difficult. Dutch nationals followed a standard, prospectively defined evaluation program allowing for accurate assessment of outcomes.

Acute and subacute side effects associated with PRRT include cytopenias, caused by irradiation of the bone marrow. The most serious long-term toxicity associated with PRRT is irreversible myelotoxicity. Eligible patients were required to have had baseline radiographic progression by RECIST criteria while receiving standard doses of octreotide over a period of no more than 3 years. Another key eligibility requirement was evidence of SSTR expression on all target lesions, at least as high as normal liver parenchyma Krenning grade 2 uptake on SSTR scintigraphy.

The control arm received 60 mg of high-dose octreotide LAR every 4 weeks, a treatment that was selected given the absence of any other proven second-line systemic treatments in this population. The primary endpoint was PFS by blinded central radiology review. The median duration of PFS was 8. Although more mature follow-up is needed to evaluate OS per the statistical plan, the interim analysis showed an HR of 0. A standard therapeutic course consists of four cycles administered approximately 8 weeks apart. Further treatments can be administered if patients experience progression after a reasonable period of disease response or stability, typically defined as greater than 12 months.

Repeat treatments often consist of two cycles each, and data indicate that salvage PRRT is a reasonable treatment option with a median time to progression of approximately 17 months. Given many therapeutic advances for NETs in recent years, there have been multiple efforts to identify predictive biomarkers for select NET therapies; unfortunately, few predictive biomarkers have been clearly identified to date. Evidence demonstrating a role for alkylating agents in NET management dates back several decades.

Although early efforts suggested possible utility of MGMT assays, more recent investigations with a larger number of patients failed to show that MGMT deficiency by immunohistochemistry or promoter hypermethylation could predict response. The treatment strategy for patients with advanced NETs is multidisciplinary and includes systemic therapies, liver-directed treatments i. Although surgery and liver-directed therapies are important treatment modalities in NETs particularly for liver dominant disease , these treatment options are outside the scope of this review, which centers on systemic NET treatments.

For the treating clinician, choice of systemic therapy for NETs depends on several factors Table 1. Specifically, as will be discussed, factors that impact drug choice include tumor functional status, avidity on SSTR imaging, tumor pathologic grade, disease bulk, and disease behavior. In those NETs that are hormone secreting i. For patients with advanced NETs and carcinoid syndrome, SSAs are typically initiated first line and can offer control of both hormonal symptoms and tumor progression. Use of SSAs has demonstrable activity in the control of functional symptoms from NETs secreting vasoactive intestinal peptide as well as glucagon.

For those functional NETs initially treated with an SSA, after disease progression, future treatment decisions with regard to systemic options should take into consideration control of both hormone release as well as other tumor-specific features. Options for ongoing control of hormone release in the absence of disease progression include escalation of long-acting SSA dose, introduction of short-acting SSAs, and tumor debulking surgical and liver-directed therapies.

For patients with refractory diarrhea related to carcinoid syndrome, the novel oral serotonin inhibitor telotristat combined with an SSA has been demonstrated to reduce the number of daily bowel movements compared with placebo.

The activity of SSAs in clinically aggressive tumors has not been well studied. No prospective data are availableto guide sequencing of therapies after progression on first-line SSA treatment. To date, no trial has specifically investigated sequencing of these systemic therapies. To date, although important strides have been made with rigorous investigation of novel systemic treatments in NETs, there remains a lack of prospective data on how to sequence these therapies.

It is well recognized that future research efforts should include studies that compare the different active drugs and address the topic of sequencing, to clarify treatment paradigms for our patients. Currently, there are two ongoing multicenter clinical trials poised to address these issues for the NET patient population. SEQTOR NCT is a prospective, randomized, open-label study to evaluate the efficacy and safety of chemotherapy fluorouracil and streptozotocin followed by everolimus versus everolimus followed by fluorouracil and streptozotocin in advanced and progressive pNETs.

These clinical trials represent our first efforts to gain a better understanding of sequential therapy in NETs. As we look to the future, continued and ongoing clinical investigation, similar to these two prospective studies, will help elucidate how to sequence the growing number of available systemic therapies for NETs. The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated.

Relationships are self-held unless noted. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www. Consulting or Advisory Role: Merck Serono Inst , Novartis Inst. Article Tools Gastrointestinal Noncolorectal Cancer. Search for articles by this author. American Society of Clinical Oncology Statement: A Randomized Controlled Trial. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. Everolimus for advanced pancreatic neuroendocrine tumors.

N Engl J Med. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. Phase 3 trial of Lu-dotatate for midgut neuroendocrine tumors. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. International Agency for Research on Cancer ; Predictive and prognostic factors for treatment and survival in patients with advanced gastrointestinal neuroendocrine carcinoma WHO G3: Treatment response and outcomes of grade 3 pancreatic neuroendocrine neoplasms based on morphology: The high-grade WHO G3 pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms.

Am J Surg Pathol. Long-term outcomes and prognostic factors in neuroendocrine carcinomas of the pancreas: Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Whole-genome landscape of pancreatic neuroendocrine tumours. The genomic landscape of small intestine neuroendocrine tumors. Reubi JC , Waser B. Concomitant expression of several peptide receptors in neuroendocrine tumours: Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy.

Appetecchia M , Baldelli R. Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumours, current aspects and new perspectives. Currently, similar tumors have also been described in other anatomic areas and in some of them time has proven that the behavior is not necessarily of a benign tumor.

We also consider that the term neuroendocrine carcinoma with their different grades of differentiation denotes the spectrum of differentiation that these tumors may show. Small cell carcinoma of the cervix: Neuroendocrine carcinomas carcinoid tumor of the testis: Am J Clin Pathol. Reyes A, Moran CA. Low-grade neuroendocrine carcinoma carcinoid of the prostate. Arch Pathol Lab Med. Gosset A, Masson P.

The non-benign nature of bronchial carcinoids and cylindromas. Neoplasms of bronchus commonly designated as adenomas. Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg. Atypical carcinoid tumor of the lung: Am J Surg Pathol. Neuroendocrine cells and neuroendocrine neoplasms of the lung. Neuroendocrine neoplasms of the bronchopulmonary tract. Bronchopulmonary Kultchitsky cell carcinoma: Atypical carcinoid of the lung: Atypical carcinoid tumour of the lung: Clinical-pathologic analysis of 40 patients with large cell neuroendocrine carcinoma of the lung.

Survival analysis of pulmonary neuroendocrine tumors with classification of criteria of atypical carcinoid and its separation from typical carcinoid. A twenty-five year follow-up of ninetythree resected typical carcinoid tumors of the lung. Carcinoids associated with multiple endocrine neoplasia syndromes. Rosai J, Higa E. Mediastinal endocrine neoplasm of probable thymic origin related to carcinoid tumor.

Mediastinal endocrine neoplasm in patients with multiple endocrine adenomatosis: Thymic carcinoid in familial multiple endocrine adenomatosis. Mediastinal tumor of thymic origin and related to carcinoid tumor. Carcinoid tumour of the thymus with systemic manifestations: Carcinoid tumour of the thymus gland: Sundstrom C, Wilander E. Acta Pathol Microbiol Scand. Calcitonin in spindle cell thymic carcinoid tumors. Chalk S, Donald KJ. Carcinoid tumour of the thymus. Pigmented carcinoid tumour of the thymus. Lokich JJ, Li F. Carcinoid of the thymus with hereditary hyperparathyroidism.

Carcinoid tumor of the thymus: Carcinoid tumor of the thymus associated with recurrent pericarditis. Carcinoid tumor of the thymus with multiple endocrine adenomatosis. Roentgenologic diagnosis of primary corticotropin-producing carcinoid tumors of the mediastinum. Fetissof F, Boivin F. Microfilamentous carcinoid of the thymus: A case of ectopic ACTH syndrome: Thymic carcinoid tumors with hyperparathyroidism.

Carcinoid tumor of the thymus associated with a parathyroid adenoma. Blom P, Johannessen JV. Mediastinal mass in a young man. Neuron-specific enolase in neuroendocrine tumors of the thymus, bronchus, and skin. Primary malignant mediastinal tumors. Carcinoid tumor of the thymus. Thymic carcinoid with cutaneous hyperpigmentation. Letters to the case.

Carcinoid tumors of the thymus: Melanocytic neuroendocrine carcinoma of the thymus. Carcinoid tumors of the thymus. Multidirectional carcinoma of the thymus with neuroendocrine and sarcomatoid components and carcinoid syndrome. J Clin Endocrinol Metab. Adrenocorticotropin hormone-producing thymic carcinoid in a teenager. Atypical carcinoid tumour of the thymus: Carcinoid tumours of the thymus. Carcinoid tumor of the thymus with divergent sarcomatoid differentiation: Thymic neuroendocrine carcinoma carcinoid: Expression of prohormone convertase, PC2, in adrenocorticotropin-producing thymic carcinoid with elevated plasma corticotropin-releasing hormone.

J Clin Endrocrinol Metab. Rao U, Takita H. Carcinoid tumour of possible thymic origin: Fishman ML, Rosenthal S. Optic nerve metastasis from a mediastinal carcinoid tumour. Primary mediastinal carcinoid tumors. Ectopic secretion of ACTH and met-enkephalin from a thymic carcinoid. An ectopic ACTH producing oncocytic carcinoid tumor of the thymus: Lesions of the thymus. A study of 53 cases. Isr J Med Sci. Thymic carcinoid in association with MEN syndromes.

Virchows Arch A Pathol Anat. Pulmonary and thymic carcinoid tumors.

Thymus carcinoid in multiple endocrine neoplasms type I. Moran CA, Suster S. Neuroendocrine carcinomas carcinoid tumor of the thymus: Primary neuroendocrine carcinomas of the thymus. Kay S, Willson MA. Ultrastructural studies of an ACTH-secreting thymic tumor. The gastroenteropancreatic neuroendocrine cell system and its tumors. Ann N Y Acad Sci. Oat-cell tumours of mediastinal glands. Wick MR, Rosai J. Neuroendocrine neoplasms of the thymus. Thymic neuroendocrine carcinomas with combined features ranging from well-differentiated carcinoid to small cell carcinoma. Spindle cell neuroendocrine carcinomas of the thymus spindle-cell thymic carcinoid: Angiomatoid neuroendocrine carcinoma of the thymus: Primary neuroendocrine Carcinoma thymic carcinoid of the thymus with prominent oncocytic features: Suster S, Moran CA.

Thymic carcinoid with prominent mucinous stroma: Coexisting undifferentiated thymic carcinoma and thymic carcinoid tumor. Neuroendocrine carcinomas of the lung: Oberndorfer S, Frankfurt Z. Karzinoide tumoren des Duenndarms.

Gastrointestinal (Noncolorectal) Cancer

Pathology and genetics of tumours of the lung, pleura, thymus, and heart. AJCC cancer staging manual. Diagnostic histopathology of tumors. The first disorder, multiple endocrine neoplasia type I MEN 1 also known as Wermer syndrome , described patients with familial pituitary, parathyroid, and pancreatic islet cell tumors. The second syndrome, multiple endocrine neoplasia type II MEN 2 also known as Sipple syndrome , was associated with familial pheochromocytomas, medullary thyroid carcinoma MTC , and hyperparathyroidism.

The third syndrome, called multiple endocrine neoplasia type III MEN 3 , included patients with papillary thyroid carcinomas and nonfamilial parathyroid tumors. This chapter discusses the clinical manifestations, diagnosis, genetic testing, treatments, and prognosis of each syndrome. Over the next 70 years, the contributions of multiple case reports led to the description of various familial N.

In , Paul Wermer, an internist at Columbia University, recognized the autosomal dominant transmission of a syndrome initially described by Underdahl in [1, 2]. This disorder, referred to as Wermer syndrome, was characterized by adenomas of the anterior pituitary gland, parathyroid gland, and islet cells of the pancreas. Similarly, in John Sipple, a pulmonologist at the State University of New York Upstate Medical Center in Syracuse, reported an association with carcinoma of the thyroid gland and pheochromocytoma, later referred to as Sipple syndrome [1].

The first disorder, multiple endocrine neoplasia type I MEN 1 also known as Wermer syndrome , described patients with familial pituitary, parathyroid, and pancreatic islet cell tumors [1]. The second syndrome, multiple endocrine neoplasia type II MEN 2 also known as Sipple syndrome , was associated with familial pheochromocytomas, medullary thyroid carcinoma MTC , and hyperparathyroidism [1]. The third syndrome, called multiple endocrine neoplasia type III MEN 3 , included patients with papillary thyroid carcinomas and nonfamilial parathyroid tumors [1].

MEN 2B patients had MTC, pheochromocytoma, no evidence of hyperparathyroidism, and an abnormal physical appearance including neuromas of the tongue and oral mucosa, thickened and everted eyelids, and other mesodermal irregularities. Multiple Endocrine Neoplasia Type I Overview MEN 1 is an autosomal dominant disorder caused by germline mutations of the MEN1 gene, a tumor suppressor gene located on chromosome 11q13 that encodes the protein menin.

The exact function of menin is unknown, but it is involved in DNA replication and repair, transcription, and chromatin modification [4].

Affected individuals are predisposed to develop tumors primarily of the anterior pituitary, parathyroid, and endocrine pancreas. However, combinations of over 20 various endocrine and nonendocrine tumors have been described in patients with MEN 1 [5]. Associated nonendocrine tumors include facial angiofibromas and collagenomas.

Thyroid nodules, meningiomas, ependymomas, leiomyomas, and lipomas have been reported to occur with increased frequency in MEN 1 patients. However, whether there is a true association versus fortuitous increased detection is unclear. The initial manifestation of individuals with MEN 1 usually occurs during late adolescence or early adulthood.

The specific endocrine gland involved and the age of onset is variable among individuals and families, but primary hyperparathyroidism PHPT is commonly the initial endocrinopathy [4—6]. The youngest reported MEN 1 related tumor was a pituitary adenoma in a child 5 years of age [5, 7]. The high penetrance of MEN 1 is evident in that half of affected patients show biochemical manifestations of the disease by 20 years of age [8]. PHPT may be completely asymptomatic or present as nephrolithiasis, osteopenia or osteoporosis, fatigue, peptic ulcer disease, myopathy, and neurocognitive deficits including depression and problems with sleep [9, 10].

High-risk patients or patients who are identified with a MEN1 mutation may be screened for PHPT starting at age 8 years with annual serum calcium and parathyroid hormone PTH levels [5]. The diagnosis is rendered with elevated or high normal serum calcium and a concomitant inappropriate elevation of PTH. Once PHPT is diagnosed, surgical intervention is indicated when there is objective evidence of disease i.

After biochemical confirmation of disease, we recommend obtaining an ultrasonographic examination of the cervical region to identify concomitant thyroid disease before proceeding to operative intervention. One surgical approach is subtotal parathyroidectomy, bilateral upper thymectomy, and possible cryopreservation of the parathyroid glands. The second operative approach is a total parathyroidectomy with autotransplantation, bilateral upper thymectomy, and possible cryopreservation of the parathyroid glands [12]. This surgery carries a risk of permanent hypoparathyroidism in up to one third of patients secondary to autograft failure [14—16].

Bilateral thymectomy is recommended for MEN 1 patients with PHPT because they are at a higher risk of developing a thymic carcinoid tumor. Also, resection of the thymus removes supranumerary parathyroid glands. The decision to pursue subtotal or total parathyroidectomy in MEN 1 patients is controversial. At the University of Texas MD Anderson Cancer Center MDACC , we recommend three and a half gland parathyroidectomy, transcervical thymectomy, and parathyroid cryopreservation as insurance in the event of aparathyroidism. If hyperparathyroidism recurs, we then recommend completion total parathyroidectomy with autografting and cryopreservation of the remaining parathyroid tissue [15].

Moreover, women are more likely than men to develop pituitary adenomas [18]. Compressive symptoms include headache, visual field deficits, hypopituitarism, cranial nerve dysfunction cranial nerves III or VI , temporal lobe epilepsy, and mild hyperprolactinemia from stalk compression [19].

Symptoms associated with prolactinomas include amenorrhea or galactorrhea in women, or signs of hypogonadism in men sexual dysfunction or gynecomastia. MEN 1-associated prolactinomas have a worse response to treatment when compared to sporadic counterparts [8, 17, 18]. Prolactinomas are initially treated with cabergoline or bromocriptine, which are long acting dopamine agonists [20]. Surgical resection is indicated when patients are unresponsive or intolerant to medical therapy [19].

If the adenoma develops before puberty, the patient develops gigantism, whereas adult-onset tumors result in acromegaly. Patients with acromegaly may develop frontal bossing, coarse facial features, and enlargement of the hands, feet, and lower jaw. Other clinical manifestations include sweating, dental malocclusion, carpal tunnel syndrome, osteoarthritis, diabetes, hypertension, nephrolithiasis, skin tags, and colon polyps [19]. Serum GH may or may not be elevated in this setting. Surgical resection is typically the first treatment for somatotropinomas [19]. Focused irradiation after surgical debulking may be beneficial in some cases.

Patients who are high risk for operative resection may be considered for medical therapy using a dopamine agonist, somatostatin analog, or the GH receptor blocker pegvisomant [19]. Symptoms include central weight gain, mood changes, thinning of the skin, easy bruising, diabetes, hypertension, and osteoporosis [19].

Urinary free cortisol measurement is the most reliable test to identify excess cortisol production. Other screening tests include plasma ACTH level, dexamethasone suppression test, and midnight salivary cortisol levels [19]. The treatment of choice for corticotropin secreting tumors is surgical resection. If unsuccessful, other options include focused irradiation or bilateral adrenalectomy. Ketoconazole and metyrapone, drugs that inhibit adrenal steroid production, may be used on a short-term basis for symptom control.

However, these drugs should not be used long term due to the side effects such as liver toxicity with ketoconazole [19]. In this case, the elevated prolactin level is secondary to stalk compression. Surgical resection is indicated for growing tumors or if symptomatic [12]. Patients who are determined to be high risk or have an MEN1 mutation should be screened with annual serum prolactin and IGF-1 levels beginning as early as age 5 years. Also, MRI of the brain should be considered every 2—3 years [5, 8].

The majority of PNETs will develop malignant progression over time [23]. PNETs typically become symptomatic in the fourth or fifth decade of life, but hormonal symptoms may be apparent earlier [24]. Often, the ambiguity of the symptoms from excess hormones produced by PNETs results in a delay in diagnosis [25]. Asymptomatic MEN 1 patients have occasionally been identified with nonfunctioning tumors of the pancreas before 20 years of age [26].

Grossly, these tumors may be solitary or multifocal, functional most commonly gastrinoma or insulinoma or nonfunctional, and solid or cystic [8]. Pathologically, the pancreas is often found to have multiple microadenomas, islet cell hypertrophy, hyperplasia, and dysplasia [8]. The majority of these neoplasms stain positive for chromogranin A, synaptophysin, and neuron-specific enolase with immunohistochemistry [8]. Success rates in localizing PNETs depend on tumor size and imaging modality. Endoscopic ultrasound, the most sensitive technique for identifying PNETs, has detected neoplasms as small as 0.

In addition, octreotide imaging may be beneficial for the localization of PNETs [25]. PP levels should be obtained when patients are fasting. In addition, clinicians must be aware that chromogranin A may be falsely elevated among patients on proton-pump inhibitors. Similarly, PP may also be elevated in patients with older age, alcoholism, renal failure, and inflammatory conditions [25]. Nonfunctional PNETs are often diagnosed late in the course of the disease because symptoms are not apparent until the tumor grows large enough to produce compression of adjacent structures.

Clinical manifestations include abdominal pain, weight loss, and jaundice. According to the NCCN guidelines, patients with nonfunctional PNETS should undergo surgical resection with regional lymph node dissection for localized disease [12]. Patients with distant metastasis should undergo surgical intervention if a complete resection can be achieved [12]. Gastrinomas are often multifocal and can be located anywhere within the pancreas, duodenum, or the gastrinoma triangle [28]. The gastrinoma triangle includes the duodenum, the pancreatic head, and the hepatoduodenal ligament [29].

Patients with MEN 1 develop gastrinomas approximately 10 years younger than their sporadic counterparts 35 vs. Gastrinomas secrete gastrin, a hormone which induces hyperchlorhydria. Patients with a suspected gastrinoma should be screened with a fasting gastrin level 2 weeks after discontinuing antisecretory medications such as proton pump inhibitors PPIs if feasible [25]. Withdrawal of PPI among patients with gastrinoma should, however, be done with caution as perforation can occur if not carefully monitored.

Clinicians should be aware that other causes of hypergastrinemia include PPI use, autoimmune pernicious anemia, Helicobacter pylori gastritis with atrophy, vagotomy, fundectomy, gastric outlet obstruction, large intestinal resection, or chronic renal failure [25].

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The surgical management of a gastrinoma in patients is controversial because the symptoms associated with gastric acid hypersecretion can be controlled with medications and recurrence is likely after surgical resection [23]. Patients with concomitant hyperparathyroidism should undergo parathyroidectomy first, since correcting hypercalcemia can decrease serum gastrin levels [8]. If a tumor can be identified on imaging, enucleation or resection is recommended with a regional lymph node dissection [12].

One analysis of 81 patients with MEN 1 and gastrinomas demonstrated that patients with locally advanced gastrinomas who have surgical resection have a similar survival as patients with localized tumors [30]. The hypersecretion of insulin associated with these tumors results in hypoglycemic episodes especially during periods of fasting or exercise. Neuroglycopenic symptoms may occur such as confusion, visual changes, altered consciousness, or convulsions [25].

Also, patients may develop a sympathetic overdrive during an insulin surge manifested by sweating, weakness, tremors, hyperphasia, and palpitations [25]. An insulin-to-glucose ratio of 0. Octreotide scanning is of limited benefit since some insulinomas especially smaller localized ones may not express somatostatin receptor-2 [5]. As with other PNETs, insulinomas can be multifocal and may be located throughout the pancreas. The primary treatment is surgical resection since medical therapy is not effective.

Prior to surgery, glucose levels should be controlled with frequent small meals and diazoxide, a drug that inhibits insulin release and promotes glycogenolysis [12, 25]. Distal pancreatectomy with enucleation of pancreatic head tumors using intraoperative ultrasound is the most common operative approach [8, 12, 14]. Glucagonomas are characterized by excess secretion of glucagon resulting in glucose intolerance, weight loss, and necrolytic migratory erythema. However, clinicians should be aware that elevated glucagon levels may also be present in patients with cirrhosis, pancreatitis, diabetes mellitus, prolonged fasting, renal failure, burns, sepsis, familial glucagonemia, and acromegaly [25].

Treatment usually entails surgical resection with regional lymph node dissection [12]. VIPomas are characterized by large volume diarrhea, electrolyte imbalances, dehydration, hyperglycemia, hypercalcemia, and flushing [25]. Prior to operative intervention, patients should be hydrated, electrolytes should be normalized, and octreotide should be administered [12]. The operative approach involves resection with regional lymph node dissection as these tumors do have malignant potential [5, 12, 14]. Somatostatinomas may be located in the pancreas or duodenum.

Affected patients develop diabetes mellitus, cholelithiasis, steatorrhea, weight loss, anemia, and diarrhea. Surgical resection with regional lymph node dissection is appropriate for these patients [12]. Recommended screening for high-risk patients or patients identified with an MEN 1 mutation is to obtain annual serum fasting glucose, insulin, gastrin, chromogranin-A, glucagon, and proinsulin levels. CT or MRI is recommended every 1—3 years to evaluate for nonfunctioning pancreatic tumors [5]. The majority of these abnormalities include nonfunctional nodular hyperplasia or adenomas [31]. Adrenal lesions in MEN 1 patients are usually small, benign, and nonfunctional.

However, there have been reports of patients with functioning tumors such as aldosterone-secreting tumors, cortisol-secreting tumors, and rarely, pheochromocytomas or adrenocortical carcinomas [8, 31, 32]. The diagnosis and treatment of adrenal disease is the same as the sporadic counterparts. The average age of onset is 35 years, which is no different than the sporadic counterpart [4].

Thymic carcinoids are the most aggressive and carry a poor prognosis [33]. Even prophylactic thymic resection as part of a surgery for PHPT does not eliminate the risk of future development of thymic carcinoids [8]. Carcinoid tumors of the stomach and duodenum are often multiple and have malignant potential. Gastric carcinoids may be a result of hypergastrinemia from MEN 1 related gastrinoma [8]. In these cases, suppression of gastrin may lead to regression of gastric carcinoid [34]. The management of the hepatic metastasis of carcinoid tumors achieves the best survival with surgical resection, but other modalities such as radiofrequency ablation and chemoembolization can safely be performed [35].

Diagnosis of MEN 1 and the Role of Genetic Testing MEN 1 is diagnosed clinically for patients who develop two or more of the classic tumors associated with the disease pituitary, parathyroid, or endocrine tumors of the pancreas or duodenum , or for patients who have one of the classic tumors and at least one close relative with a clinical diagnosis of MEN 1 [5]. On the other hand, MEN 1 may be diagnosed prior to the development of the clinical manifestations using genetic testing if a deleterious germline mutation of the MEN1 gene is identified.

The remainder of patients with classic MEN 1 may have a mutation not detected by the methodology used i. In addition, some patients with features of MEN 1 may actually represent phenocopies coincidental occurrence of MEN 1-related tumors in a person without a germline MEN1 mutation , particularly those that are nonfamilial with older-onset hyperparathyroidism.

It is not clear whether familial isolated hyperparathyroidism is a distinct subtype of MEN 1, whether some of the families with MEN1 mutations might have had other clinically occult disease, or whether additional diseases can develop in the future. New genetic mutations have been recognized among individual families.

Her father, diagnosed with acromegaly, and her sister, found to have renal angiomyolipoma nonendocrine tumor associated with MEN 1 , both had mutations in CDKN1B. The CDKN1B gene encodes the protein, p27, which is a cyclin-dependent kinase inhibitor involved in cell cycle progression [38].

Neuroendocrine Tumors (Current Clinical Oncology)

There is a wide range of mutation types within the MEN1 gene and often specific mutations are unique to each family. To date, no genotype—phenotype correlations have been established [34]. Even so, genetic testing for MEN 1 is still beneficial for some patients. The two main benefits of genetic testing are to: Moreover, affected patients may use this information to consider reproductive planning options such as preimplantation genetic diagnosis or prenatal genetic testing.

An accurate family history is the most important tool to identify MEN 1 patients. In addition, the patient can be provided with anticipatory guidance and counseling about reproductive risks and prenatal genetic testing options, should they wish to use the information in planning a pregnancy. Also, the cost of the test as well as the psychological consequences should be discussed [36]. In the past, clinicians did not find genetic testing for the early diagnosis of high risk individuals to be beneficial.

However, biochemical evidence of tumor development may be found as early as 10 years before the patient becomes symptomatically apparent [22]. Prompt recognition and treatment of functioning neoplasms may help prevent complications associated with long-term hormonal excess. Monitoring and early intervention of pancreatic and duodenal tumors may help to prevent the development of advanced malignancies.

It is recommended that screening of children at risk for inheriting MEN disease should begin as early as age 5 years, given that this is the youngest diagnosis of an MEN 1-related tumor. However, it is not clear that screening children, as opposed to waiting to begin screening until early adulthood, will reduce morbidity and mortality.

Life-threatening manifestations of MEN 1 are rare in young children, and testing in childhood has potential to cause psychosocial harm.

Journal of Clinical Oncology

Therefore, patients should be carefully counseled regarding the timing of genetic testing in their children [36]. Multiple Endocrine Neoplasia Type 2 Overview MEN 2 is an autosomal dominant disorder caused by germline activating missense mutations of the RET rearranged during transfection proto-oncogene. The RET gene, located on chromosome 10q MEN 2 has been classified into three subtypes: All three subtypes are associated with a high risk for MTC.

The age of onset of MTC can range from children less than 10 years old to the fourth decade of life [3]. The majority of MEN 2A patients have mutations affecting cysteine residues in exons 10 and 11 most commonly in codon , but also in codons and , and less commonly in others [3]. A small percentage of patients with mutations in codon exhibit cutaneous lichen amyloidosis, a pruritic skin rash that develops on the dorsal torso [3, 27]. For instance, mutations in codons , , , , , , and are associated with low risks for pheochromocytoma and PHPT [3]. The physical characteristics of MEN 2B patients include an elongated face with enlarged and nodular lips, thickened and everted eyelids, and neuromas of the tongue and oral mucosa Fig.

Skeletal abnormalities include genu valgum, pes cavus, club foot, and kyphoscoliosis [44]. Ganglioneuromatosis of the GI tract may cause abdominal distention, megacolon, constipation, and diarrhea [44]. Calcitonin works to lower plasma calcium by inhibiting osteoclastic bone absorption and inducing urinary excretion of calcium and phosphate. In the familial form, the development of MTC is preceded by C-cell hyperplasia which can increase the serum calcitonin. C-cells are concentrated in the superior one third of the thyroid gland which is where the majority of MTC is identified [44].

The C-cells in MTC secrete increased amounts of calcitonin, and the presence of calcitonin after total thyroidectomy is an indicator of residual or persistent disease. The diagnosis may be confirmed with a pentagastrin stimulation test, identification of a thyroid mass, and positive cytologic evidence of MTC on ultrasound guided fine needle aspiration [44]. Patients with MTC often present with neck pain, a palpable neck mass, or diarrhea from the elevated serum calcitonin level.

Patients with dysphagia and hoarseness frequently have advanced disease. MTC is known for being an aggressive form of thyroid cancer. Initially, metastasis occurs in cervical or mediastinal lymph nodes, and later to the lung, liver, and bone [44]. Because MTC is resistant to chemotherapeutic or radioactive iodine therapies, surgical resection is the primary method of treatment. Also, since the biologic behavior of MEN 2 can be predicted by the specific RET mutation, the timing and extent of surgery can be individualized to achieve the best overall outcome [42].

Initial evaluation for MTC includes a cervical neck ultrasound, serum CEA, serum calcium, and a serum calcitonin level. Patients who have no evidence of local invasion and no lymph node metastasis should undergo total thyroidectomy with prophylactic central neck dissection. If distant metastatic disease is evident, less aggressive surgery may be considered in order to preserve speech and swallowing function [3].

Prior to operative intervention, patients should be evaluated for pheochromocytoma with serum metanephrine levels, and PHPT with serum calcium and PTH levels. The ATA recommends total thyroidectomy with therapeutic central lymph node dissection for patients who have identified central neck disease. The necessity of a lateral neck dissection for patients without evidence of lateral neck disease is not currently established.

Following thyroidectomy, patients should be given thyroid hormone replacement therapy rather than thyroid hormone suppression therapy, a treatment reserved for follicular and papillary thyroid cancer. Likewise, radioactive iodine is not an effective treatment for MTC. Two to 3 months following thyroidectomy, baseline serum calcitonin and CEA levels should be obtained.

These markers should initially be followed every 6—12 months, and then annually thereafter. Also, a baseline cervical ultrasound 6 months after surgical resection should be obtained. Patients with undetectable tumor markers may be followed with serial laboratory assessments. The role of adjuvant chemotherapy and external beam radiation is unclear in patients with unresectable disease, and the use of these treatments should be individualized [3].

Genetic counseling should be encouraged for all patients who undergo genetic testing in order to understand the purpose of testing, the natural history of the disease, the pattern of inheritance, and the psychological consequences. Patients who are diagnosed with MTC, primary C-cell hyperplasia, cutaneous lichen amyloidosis, early onset adrenergic pheochromocytoma, or MEN 2 should be offered genetic testing for RET mutations.

If a specific RET mutation is identified within a family, all first-degree relatives should be offered testing before the age of recommended prophylactic thyroidectomy if possible. By knowing the biological behavior of each RET mutation, the timing of prophylactic thyroidectomy can be determined to improve overall survival. The timing of prophylactic thyroidectomy for ATA levels A and B may be delayed beyond 5 years of age if serum calcitonin and neck ultrasound are normal, and the family history of MTC is not particularly aggressive.

These patients must be screened with annual serum calcitonin levels and cervical ultrasonography. If the ultrasound or calcitonin is abnormal, then surgical resection is indicated at that time.

Because patients with ATA level B mutations have slightly more aggressive disease, prophylactic thyroidectomy in a tertiary care setting may be considered prior to 5 years of age [3]. These patients should undergo prophylactic thyroidectomy at an experienced tertiary care center before 5 years of age [3].

Patients in this category have MEN 2B and have mutations in codon or They have the youngest age of onset and the highest risk of metastatic disease. Prophylactic total thyroidectomy is recommended within the first year of life in an experienced tertiary care setting [3]. It is most commonly associated with a mutation of codon MEN 2A patients with PHPT are often asymptomatic, but may present with nephrolithiasis and hypercalcemia like their sporadic counterparts [5]. Surgical options for the management of MEN 2A patients who have evidence of PHPT at the time of initial thyroidectomy include resection of visibly enlarged glands with possible forearm autograft, subtotal parathyroidectomy leaving one or a piece of one gland in situ, or total parathyroidectomy with forearm autograft [3].

Due to the risk of permanent hypoparathyroidism, most surgeons avoid total parathyroidectomy unless all four glands are abnormal [3]. Patients who develop PHPT after their initial thyroidectomy should undergo surgical resection of abnormal glands with forearm autografting based on preoperative imaging [3]. The ATA guidelines task force has also made recommendations regarding the management of devascularized normal parathyroid glands in MEN 2 patients.

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For instance, devascularized parathyroid glands in MEN 2B patients may be reimplanted in the sternocleidomastoid muscle. MEN 2A patients with a low risk of developing PHPT based on family history and their RET mutation may have devascularized parathyroid glands implanted into the sternocleidomastoid muscle or the forearm [3]. The risk of possible devascularization at a future dissection for recurrent MTC should be taken into consideration. Pheochromocytoma Up to half of MEN 2A patients will develop pheochromocytoma, a catecholaminesecreting tumor of the adrenal medulla.

Patients present with headache, sweating, heart palpitations, hypertension, and anxiety. Prior to developing a pheochromocytoma which is typically benign, MEN 2 patients may have hyperplasia of the adrenal medulla [44]. Pheochromocytomas in MEN 2 patients may be unilateral or bilateral synchronous or metachronous , and are mostly associated with codons and [5, 42].

However, these tumors have been identified in patients with most of the other RET mutations associated with MEN 2 [42]. Unlike other hereditary forms of pheochromocytoma i. As a result, MEN 2 patients more often present with heart palpitations, tremor, anxiety, and paroxysmal hypertension than patients with other forms of pheochromocytoma who have higher levels of norepinephrine [45].

Pheochromocytomas tend to develop 10—20 years earlier in MEN 2 patients when compared to sporadic counterparts. Diagnosis is achieved by obtaining plasma free metanephrines and normetanephrine or urine metanephrines [12]. After a biochemical diagnosis is confirmed, imaging with CT or MRI should be performed to identify an adrenal tumor. Meta-iodobenzyl guanidine scanning MIBG can also be helpful with preoperative localization [5]. Surgical resection is the primary treatment of choice for pheochromocytomas. Patients with MEN 2 who are also diagnosed with MTC should have the pheochromocytoma resected first to avoid a hypertensive crisis.

In order to minimize complications associated with hypertension and heart rate during surgery, patients should be hydrated and treated with an alpha antagonist at least 1—2 weeks prior to surgery [12, 46]. Beta-1 blockers atenolol The use of beta blockers alone would worsen hypertension in pheochromocytoma patients. Moreover, a specialized team consisting of a dedicated anesthesiologist, endocrinologist, endocrine surgeon, internist, and cardiologist is imperative to minimize the risks of complications during surgical resection.

The most common operative approach for a patient with a unilateral pheochromocytoma is laparoscopic adrenalectomy. At MDACC, we prefer retroperitoneoscopic adrenalectomy as the minimally invasive approach of choice for patients with modestly sized, clinically benign pheochromocytomas [47]. This technique is beneficial because it avoids intraabdominal solid organ mobilization. Moreover, patients with bilateral tumors do not require repositioning during the procedure [47].

Patients who undergo bilateral adrenalectomy are at risk for adrenal insufficiency which requires lifelong supplemental corticosteroids. Summary Multiple endocrine neoplasia is described by three distinct autosomal dominant syndromes: The role of genetic testing has significantly impacted patients with both MEN 1 and MEN 2 to allow for better screening among families and affected individuals.

Furthermore, the ability to correlate the specific RET genetic mutation to the phenotypic presentation in MEN 2 has allowed clinicians to optimize patient care to achieve the best clinical outcome overall survival. Familial multiple endocrine neoplasia: Genetic aspects of adenomatosis of endocrine glands. Molecular pathology of the MEN1 gene. Ann NY Acad Sci. Guidelines for diagnosis and therapy of MEN type 1 and type 2. Multiple endocrine neoplasia type 1.

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Pituitary macroadenoma in a 5-year-old: Textbook of endocrine surgery. Improvement of sleep disturbance and neurocognitive function after parathyroidectomy in patients with primary hyperparathyroidism. Primary hyperparathyroidism, cognition, and healthrelated quality of life. Guidelines for the management of asymptomatic primary hyperparathyroidism: NCCN clinical practice guidelines in oncology: J Natl Compr Canc Netw. Results of initial operation for hyperparathyroidism in patients with multiple endocrine neoplasia type 1. Multiple endocrine neoplasia syndromes.

Surg Clin North Am. Surgical treatment of hyperparathyroidism in patients with multiple endocrine neoplasia type 1. Is total parathyroidectomy the treatment of choice for hyperparathyroidism in multiple endocrine neoplasia type 1? Beckers A, Daly AF. The clinical, pathological, and genetic features of familial isolated pituitary adenomas.

Update in pituitary disease. Lethality of multiple endocrine neoplasia type I. Clinical genetic testing and early surgical intervention in patients with multiple endocrine neoplasia type 1 MEN 1. The surgical management of MEN-1 pancreatoduodenal neuroendocrine disease. Outcome of duodenopancreatic resections in patients with multiple endocrine neoplasia type 1.

Asymptomatic children with multiple endocrine neoplasia type 1 MEN1 mutations may harbour non-functioning pancreatic neuroendocrine tumors. Role of endoscopic ultrasonography in screening and treatment of pancreatic endocrine tumours in asymptomatic patients with multiple endocrine neoplasia type 1. Multiple endocrine neoplasia type 1: Management of sporadic and multiple endocrine neoplasia type 1 gastrinomas. Comparison of surgical results in patients with advanced and limited disease with multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome.

Adrenal involvement in multiple endocrine neoplasia type 1: Screening for MEN1 mutations in patients with atypical endocrine neoplasia. Thymic neuroendocrine carcinoma carcinoid in multiple endocrine neoplasia type 1 syndrome: Treatment of type II gastric carcinoid tumors with somatostatin analogues. Management of hepatic metastasis of gastrointestinal carcinoid tumors. Risk assessment and genetic counseling for multiple endocrine neoplasia type 1 MEN1.

Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Falchetti A, Brandi ML. Multiple endocrine neoplasia type I variants and phenocopies: Assessment of p27 cyclin-dependent kinase inhibitor 1B and aryl hydrocarbon receptor-interacting protein AIP genes in multiple endocrine neoplasia MEN1 syndrome patients without any detectable MEN1 gene mutations. Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet. Multiple endocrine neoplasia type 2: Multiple endocrine neoplasia type 2B.

Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. Preoperative management of the pheochromocytoma patient. Surgical management of hereditary pheochromocytoma. J Am Coll Surg. In others, such as von Hippel Lindau or Neurofibromatosis, NETs are found in a minorirty of the cases, but their frequency is much higher than seen in the general population, which means that NETs can be the tip of the iceberg of a hereditary cancer syndrome in these families.

Therefore it is important for the physician in care of a NET patient to take a detailed family history not only for other cancers in the extended family but also for peculiar clinical findings in relatives of the patients that could lead to a diagnostic of one of these syndromes.

Most of the hereditary cancer syndromes displaying neuroendocrine tumors are multiple endocrine neoplasias 1 and 2. Some cases of neuroendocrine B. In the present chapter, these rare syndromes will be described with emphasis to the presence of neuroendocrine tumors. Clinically, there are two distinguishable types of VHL, based mainly on the presence or absence of pheochromocytoma.

Clinical features of the VHL syndrome include the classical retinal von Hippel and cerebellar Lindau hemangioblastomas [1]. Hemangioblastomas in other neural structures can be observed, such as the brainstem and spine. The syndrome characteristically includes renal cysts, renal cell carcinomas, pancreatic cysts and islet cell tumors, cystadenomas of epididymis, and broad ligament and endolymphatic sac tumors [2].

Typically, they are frequently multiple bilateral adrenal and multifocal extra-adrenal , rarely become malignant, and tend to occur at a younger age than in sporadic cases [2]. Head and neck paragangliomas can be rarely associated to VHL syndrome. It is estimated that 5 in every 1, cases of VHL patients will present paragangliomas. Therefore, isolated cases of paraganglioma, a tumor commonly related to other hereditary cancer syndromes, as we will see ahead, should not be a indication for VHL testing unless there are other tumors in the family or in the individual which are part of VHL syndrome [4].

The VHL gene is a tumor suppressor gene located on the short arm of chromosome 3 3p25— Its three exons encode the two isoforms of the VHL protein whose multiple functions are related to the control of vessel production stimulated by tissue hypoxia. The VHL protein migrates from the nucleus to the cytoplasm, where it binds to various proteins, such as elongins B and C, Cul2 and Rbx1, and degrades alpha units of hypoxia inducible factor in an oxygen-dependent manner.

Lack of VHL function results in failure to regulate the hypoxia inducible factor, which leads to uncontrolled vascular production. VHL germline mutations are extremely variable, affecting almost any place of the three exons. Missense mutations seem to confer better prognosis and are more commonly detected in patients with pheochromocytoma [5]. The exact molecular mechanisms by which pheochromocytoma and gastroenteropancreatic GEP tumors develop in VHL mutation bearers are unknown. Specifically for GEP neuroendocrine tumors, the analysis of allelic losses spotted genetic loci distinct from and mapping close to VHL, within 3p.

For these individuals, the recommendations for screening are empiric. They are based on the age that tumors are observed in VHL mutation carriers and the recurrence rate seen in the ones that had a tumor diagnosed. The same program of screening is recommended for individuals of VHL family that have not been tested. The screening of pheochromocytoma and GEP include yearly clinical examination. Ultrasound of the abdomen should be initiated in childhood.

There seems to be no advantage in performing biochemical studies to help in finding subclinical pheochromocytoma, such as plasma or urine analysis of catecholamines and their metabolites in mutation carriers [7]. It is also unclear if surgery is necessary in clinically silent lesions found in screening tests. The wait and scan seems to be a safe option in children, but each case needs to be assessed individually. The treatment clinical or with radionuclide of neuroendocrine tumors in VHL syndrome does not differ from sporadic cases [2].

Neurofibromatosis Type 1 NF1 is primarily a mucocutaneous disease caused by autosomal dominant mutation with an incidence of approximately 1 in 3, individuals [8]. Approximately one-half of the cases are familial; the remainder are new mutations, which is the highest rate of new mutation of any known single-gene disorder [9]. The NF1 gene was mapped to chromosome 17q Neurofibromin, the protein encoded by the NF1 gene, is expressed in many tissues, including brain, kidney, spleen, and thymus. So, it is no surprise to observe that mutations in the NF1 gene cause a wide spectrum of clinical findings, including NF1-associated tumors.

Mutations in NF1 gene are always involved with loss of function of neurofibromin. The types of mutations include deletions, duplications, insertions, and multiple distinct point mutations, most of them producing a truncated nonfunctional protein [11]. Some phenotypic association can be found with certain types of genetic alterations in NF1. Such patients have a higher incidence of intellectual disability, dysmorphic facial features, and earlier appearance of neurofibromas [12]. There is no available data linking increased prevalence of malignant or neuroendocrine tumors in patients with large deletions of NF1 gene.

Neurofibromin belongs to a family of GTPase-activating proteins GAPs that downregulate a cellular proto-oncogene, pras, an important determinant of cell growth and regulation [13]. Ras uncontrolled activation is a central feature in many human tumors. In NF1 nerve sheath tumors, neurofibromin levels are almost undetectable, suggesting that both alleles of the gene should be inactivated, a typical feature of a tumor-suppressor gene.

Many other findings have been related to NF1 syndrome. In , a 54 B. Garicochea Consensus Conference sponsored by the NIH tried to define minimal criteria for the syndrome diagnosis. These criteria have been updated 10 years later.

According to this criteria, at least two of the following features must be observed for a clinical diagnosis of NF1:

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