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SaaraMetso

Rare Endocrine Tumours

See also article Adrenal tumours Adrenal Tumours.

Essentials

  • Many gastroenteropancreatic neuroendocrine tumours (GEP-NETs) present as asymptomatic incidental findings.
    • Persistent abdominal pain and a change in bowel function may sometimes reveal a NET in the small intestine.
    • A metastatic NET of the small intestine may cause the classic carcinoid syndrome caused by secretion of serotonin (diarrhoea, abdominal pain and flush).
    • A pancreatic insulinoma secreting insulin may cause hypoglycaemia episodes, and a gastrinoma may cause duodenal ulcers.
  • GEP-NETs mostly grow slowly and have a good prognosis.
  • The only curative treatment is surgery.
    • Metastatic or inoperable tumours can often be treated with somatostatin receptor analogues.
  • Multiple endocrine neoplasias (MEN syndromes) are hereditary. Patients with MEN have tumours of various endocrine glands and symptoms due to hormonal hypersecretion from such glands.

Neuroendocrine tumours of the gastrointestinal tract and pancreas

  • Neuroendocrine tumours (NETs) and neuroendocrine carcinomas (NECs) of the small intestine, appendix and pancreas are classified as gastroenteropancreatic neuroendocrine tumours (GEP-NETs).
  • GEP-NETs are divided into well differentiated tumours (NET Grades 1-3) and carcinomas (NECs). Carcinomas are divided by type of growth into small- and large-cell carcinomas. In addition, there are mixed neuroendocrine non-neuroendocrine neoplasms (MINENs). See Table T1.
  • The incidence of GEP-NETs is about 4 per 100 000 persons per year.
    • Their incidence has increased in the past few decades, as abdominal imaging has become more common, diagnostic methods and classification have become more accurate, and awareness of GEP-NETs has increased.
  • Their prevalence is clearly higher than their incidence, 35 per 100 000 persons, because GEP-NETs mostly grow slowly and have a good prognosis.
  • At the time of diagnosis, 50% of tumours are localized and 40% metastasized.

Neuroendocrine tumours of the gastrointestinal tract and pancreas according to the WHO 2019 classification

Tumour classDifferentiationProliferation index (PI; Ki-67)1 Mitoses/2 mm1
NET, Grade 1Well differentiated< 3 %< 2
NET, Grade 2Well differentiated3-20 %2-10
NET, Grade 3Well differentiated> 20 %>20
NEC; small- or large-cellPoorly differentiated>20 %>20
MINENOften poorly differentiated--
NET =neuroendocrine tumour, NEC = neuroendocrine carcinoma, MINEN = mixed neuroendocrine non-neuroendocrine neoplasm
1 Determined by counting at least 500 tumour cells in the regions of highest labeling (hot-spots).
Clinical picture

Neuroendocrine tumours of the small intestine and appendix

  • Persistent abdominal pain and a change in bowel function or acute symptoms of intestinal obstruction may sometimes reveal a NET in the small intestine.
  • Many small tumours are completely asymptomatic, and a NET in the appendix is usually an incidental histopathological finding made in association with appendectomy.
  • The classic carcinoid syndrome (diarrhoea, abdominal pain and flush) and carcinoid heart disease (fibrous plaques in valve structures, impaired valve function and right heart failure) develop in consequence of liver or retroperitoneal metastases of a tumour originating in the small intestine, allowing serotonin to enter the circulation through the hepatic veins.
    • Hormonal symptoms are rare in association with tumours of the appendix.

Neuroendocrine tumours of the pancreas

  • About 80% are hormonally inactive and often found incidentally in association with abdominal imaging.
    • Large inactive NETs may cause abdominal pain and weight loss.
  • Insulinoma
    • Causes symptoms of hypoglycaemia, such as disturbances of consciousness, visual disturbances, lack of concentration, convulsions, feeling of hunger and sweating. Hypoglycaemia is due to inappropriate insulin secretion caused by the tumour.
  • Gastrinoma
  • Vipoma
    • Causes the WDHA syndrome characterized by watery diarrhoea, hypokalaemia and acidosis.
  • Glucagonoma
    • Very rare and typically malignant
    • Symptoms include rash (erythema), weight loss and cachexia, anaemia, thromboembolism, mild diabetes, diarrhoea, stomatitis and glossitis.
  • Somatostatinoma

Diagnostic investigations

  • The primary method for imaging GEP-NETs is computerized tomography (CT). It can be replaced by abdominal MRI in young patients or if iodine enhancement agents are contraindicated.
  • PET-CT of somatostatin receptors is used to confirm the type of tumour:
    • if there is clinical and biochemical suspicion of a NET and sampling fails
    • to stage the disease before surgical treatment
    • to confirm the result of radical surgery or
    • to investigate the suitability of nuclear medicine therapy.
  • Chromogranin A (CgA) is a universal marker of NETs best suited for follow-up and assessment of response to treatment of NETs.
    • Being unspecific, CgA testing is not suitable for general screening, because increased CgA concentrations are seen in association with liver, kidney and heart failure, atrophic gastritis and treatment with proton pump inhibitors.
  • In patients with NETs of the small intestine, serotonin secretion is reflected in the level of serum 5-hydroxyindoleacetic acid (5HIAA).
    • In patients with carcinoid syndrome, increased proBNP concentrations warrant echocardiography to see whether carcinoid heart disease has developed.
  • In the diagnosis of insulinoma, it is essential to demonstrate hypoglycaemia in the presence of inappropriate insulin secretion.
    • A 72-h fasting test should be done to provoke hypoglycaemia, and interrupted if plasma glucose falls below 3 mmol/l in a patient with symptoms or below 2.5 mmol/l in the absence of clear symptoms of hypoglycaemia.
    • The diagnosis can be confirmed by measurement of plasma glucose < 3.0-2.5 mmol/l, insulin ≥ 3.0 mU/l and C-peptide≥ 0.2 nmol/l during symptomatic hypoglycaemia.
  • Hormonal activity of other pancreatic NETs can be examined by determining fasting plasma vasoactive (poly)peptide (VIP), fasting serum gastrin and plasma glucagon.
  • The finding of a NET may point to a tumour syndrome, such as multiple endocrine neoplasia type 1 (MEN1), von Hippel-Lindau syndrome (VHL), neurofibromatosis 1 or Carney complex.
    • The MEN1 syndrome should be suspected in association with the investigation of a pancreatic NET in a patient with gastrinoma, a patient below 35 years of age or with a family history suggesting multiple endocrine neoplasia, or a patient with more than 2 endocrine tumours consistent with multiple endocrine neoplasia (parathyroid hyperactivity, pituitary adenoma, pancreatic NET).
    • Several pancreatic NETs and phaeochromocytoma should arouse the suspicion of the von Hippel-Lindau syndrome.
    • Somatostatinoma may suggest neurofibromatosis.

Treatment

  • The only curative treatment of NETs of the small intestine or appendix is surgery.
    • Regardless of the size of the primary tumour, by the time of diagnosis more than 80% of NETs of the small intestine have spread to mesenteric lymph nodes, which must also be removed.
    • Serotonin metabolites secreted by the tumour increase the amount of connective tissue, and disease that has spread to lymph nodes may therefore cause intestinal ischaemia or obstruction.
  • Low-grade NETs less than 1 cm in size in the appendix metastasize extremely rarely. For patients with such tumours, appendectomy is sufficient, and no additional hemicolectomy or follow-up for recurrence is necessary.
    • Tumours larger than 2 cm require right hemicolectomy and surveillance for cancer.
    • Tumours of 1-2 cm in the appendix should be treated by hemicolectomy if more than 2 risk factors for metastatic disease are found or if the tumour reaches the margin of the surgical specimen.
  • The prognosis of an inactive pancreatic NET depends on its grade and stage.
    • Surgical treatment is the primary choice and the only curative treatment option but, due to the risks associated with pancreatic surgery, some patients with a small, single, hormonally inactive pancreatic NET are followed up until the size of the tumour exceeds 2 cm.
  • As more than 90% of NETs have somatostatin receptors, metastatic or inoperable NETs can be treated with somatostatin receptor analogues (octreotide and lanreotide).
    • These are synthetic intestinal hormones used for the treatment of grade 1-2 NETs to control symptoms caused by an active tumour or to slow down its growth.
  • Depending on the intensity of somatostatin uptake in PET-CT, 177 lutetium-octreotate-based radionuclide treatment of metastases or locally advanced disease can be considered.
  • Liver metastases can sometimes be removed by surgery. Other forms of treatment include hepatic arterial chemoembolization, radiofrequency therapy or other radiological procedures targeting liver metastases.

Multiple endocrine neoplasias

  • Rare syndromes with an autosomal dominant inheritance pattern predisposing to tumours in various endocrine glands and symptoms caused by hormonal hypersecretion from such glands.
  • Review of family history and genetic investigations are always warranted.
  • Follow-up takes place at an outpatient clinic of endocrinology and continues lifelong.
  • A multiprofessional team is needed for treatment.

MEN1 (multiple endocrine neoplasia type 1)

  • Caused by a mutation in the MEN1 gene, affecting the structure and activity of the menin protein produced by the gene.
    • Menin normally acts as a growth restrictor, or tumour suppressor, and prevents transformation of certain tissue cells to tumour cells.
    • More than 750 different gene mutations have been detected in the MEN1 syndrome.
    • Find out about locally observed more common mutations.
  • Endocrine tumours are typically detected in the parathyroid glands, duodenum, pancreas and pituitary gland.
    • In addition, there may be endocrine tumours in the suprarenal glands, the thymus, lungs and stomach.
    • There may also be tumours in other tissues, such as skin tumours, lipomas, brain tumours (meningioma, ependymoma), and myomas of the uterus.
    • In women with the MEN1 syndrome, the risk of breast cancer is 2-3-fold compared to the normal population.
  • MEN1 can be diagnosed in 3 ways.
    • A clinical diagnosis is based on the patient having 2 typical tumours associated with the syndrome.
    • A familial diagnosis is based on the patient having one typical tumour associated with the MEN1 syndrome and an established MEN1 in near relatives.
    • Genetic diagnosis with genetically confirmed MEN1
  • The diagnosis must always be confirmed by doing a MEN1 genetic test in blood.
    • The gene mutation is not found in all those with the clinical diagnostic criteria.
  • The median age at manifestation of the first tumours is 14-17 years.
  • The first tumours detected are parathyroid tumours, prolactinomas, inactive pituitary adenomas, inactive neuroendocrine pancreatic tumours and insulinomas.
    • Primary hyperparathyroidism is the first manifestation of the syndrome in about 90% of patients, detected in practically all by the age of 50 years.
  • In those carrying the gene mutation, tumour screening should be started in childhood, already.
  • MEN1 tumours are screened for lifelong by laboratory tests (serum calcium, parathyroid hormone, prolactin and hormones produced by specific tumours) and imaging (ultrasonography, MRI, certain nuclear medicine tests).
    • Tests are done every 1-5 years, on an average.
    • To reduce radiation exposure, CT has largely been abandoned.
  • See also Orphanet http://www.orpha.net/en/disease/detail/652.

MEN2 (multiple endocrine neoplasia type 2)

  • Caused by a genetic mutation in a certain area of the RET proto-oncogene.
  • Patients have malignant thyroid tumours (medullary thyroid cancer), parathyroid hyperactivity and phaeochromocytomas.
  • Divided into two types depending on whether the patient has neuromas of the mouth or gastrointestinal tract (ganglioneuroma). These do not occur in MEN2A but do occur in every patient with MEN2B.
  • The diagnosis of the MEN2 syndrome should be confirmed by a RET gene test.
  • When the gene mutation causing the syndrome has been identified, the patient's near relatives should be tested for carriership.
    • The gene test is normally done no later than at the age of 5-6 years (for certain gene mutations, even at a younger age).
  • Thyroidectomy is performed in those carrying the mutation before manifestation of a malignant disease.
    • The appropriate age for thyroidectomy depends on the underlying gene mutation.
  • Suprarenal and parathyroid gland activity are followed up by regular chemical tests. Such follow-up is tailored individually.
  • See also Orphanet http://www.orpha.net/en/disease/detail/653.

von Hippel-Lindau disease (VHL)

  • VHL is caused by a mutation in the VHL tumour suppressor gene.
  • VHL is divided into 2 types.
    • Phaeochromocytomas are rare in patients with type 1 disease.
    • In patients with type 2 disease, they are common.
  • Hemangioblastomas of the CNS occur in as many as 80% of patients.
    • Most lesions appear in patients aged 18 to 35.
  • In about 70% of patients, hemangioblastomas also develop on the retina and in the ophthalmic nerve. Regular ophthalmologic follow-up should be started in early childhood, already.
  • Renal cysts and clear cell carcinomas develop in about 70% of patients.
    • They are most common in patients aged 25 to 50 years.
    • Clear cell carcinomas are often multiple and bilateral.
  • Pancreatic cysts (in 75%), cystadenomas (in 10%) and neuroendocrine tumours (in 10-20%) are common in patients with VHL.
    • They are most frequent in patients aged 25 to 35.
  • Phaeochromocytomas occur in patients with type 2 VHL. They are often bilateral.
  • Papillary cystadenomas in the inner ear (endolymphatic sac tumours, ELST) may cause tinnitus, hearing loss, dizziness and facial palsy.
  • Patients are followed up and treated by multiprofessional teams coordinated by an endocrinologist.
    • In known VHL families, screening and follow-up of carriers of the gene mutation are started in childhood, already.
    • After diagnosis, patients are followed up frequently for the rest of their lives.
  • See also Orphanet http://www.orpha.net/en/disease/detail/892.

    References

    • Janson ET, Knigge U, Dam G, et al. Nordic guidelines 2021 for diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms. Acta Oncol 2021;60(7):931-941 [PubMed]
    • Pavel M, Öberg K, Falconi M, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020;31(7):844-860 [PubMed]
    • Larouche V, Akirov A, Alshehri S, et al. Management of Small Bowel Neuroendocrine Tumors. Cancers (Basel) 2019;11(9): [PubMed]
    • Strosberg JR, Halfdanarson TR, Bellizzi AM, et al. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Midgut Neuroendocrine Tumors. Pancreas 2017;46(6):707-714 [PubMed]

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