Neuroendocrine tumor

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PET / CT of a neuroendocrine tumor of the pancreas, recorded with the tracer 68 Ga-DOTATOC (DOTATOC is bound very specifically, therefore the PET images show almost no background activity.)

Neuroendocrine tumors (NET) , also known as neuroendocrine neoplasias (NEN) , are benign or malignant tumors that originate from the neuroectoderm ( neural crest ) and whose cells resemble the endocrine gland cells in the immunohistochemical characterization . Epithelial neuroendocrine tumors occur mainly in the gastrointestinal tract and in the pancreas . For neuroendocrine tumors in the stomach and intestines, the old term carcinoid (carcinoma-like tumor) is still very common. Like the term APUDom ( amine precursor uptake and decarboxylation ), this should no longer be used. The small cell lung cancer as well as Merkel cell carcinoma of the skin are also among the neuroendocrine tumors. Closely related are the nerve-like neuroblastomas , pheochromocytomas , and paragangliomas . 75% of all neuroendocrine tumors are located in the gastroenteropancreatic system ( gastroenteropancreatic neuroendocrine tumor - abbr. GEP-NET) .

The GEP tumors develop from endocrine (hormone-producing) cells that are found everywhere in the digestive system or related parts of the body and have the task of producing certain substances that control the digestive process.

In terms of their properties, these cells have similarities with nerve cells and, in terms of their function, they belong to the internal glands. Hence they are called neuroendocrine cells .

history

A carcinoid on the wall of the small intestine

The first description of neuroendocrine tumors goes back to Otto Lubarsch . Twenty years later the term carcinoid was first used by Siegfried Oberndorfer to differentiate the newly discovered form of tumors in the digestive tract from the much more aggressive adenocarcinomas. In the following years the neuroendocrine origin of the tumor cells could be confirmed.

Epidemiology

Neuroendocrine tumors of the gastrointestinal tract and the pancreas ( GEP-NET , for gastro-entero-pancreatic neuroendocrine tumors , formerly called carcinoids ) occur about once or twice per 100,000 inhabitants per year. Neuroendocrine tumors predominantly affect patients aged 50 to 70 years; Women and men about equally often. In addition to the random (sporadic) cases of disease, there are two forms of hereditary multiple endocrine neoplasms .

Hormone production

About 30–50% of neuroendocrine tumors produce hormonally effective amine derivatives that are also produced by normal neuroendocrine cells, such as gastrin from the gastric mucosa, vasoactive intestinal peptide from the duodenum, insulin and glucagon from the pancreas. The excessive hormone concentration of these so-called functionally active tumors can produce characteristic symptoms. A gastrin-producing neuroendocrine tumor, gastrinoma , causes Zollinger-Ellison syndrome (hyperacidity, stomach ulcers), VIP-producing tumors cause severe diarrhea, glucagonomas cause high blood sugar, and insulinomas cause dangerous hypoglycaemia . An important sign of tumors of the small intestine is the serotonin- associated carcinoid syndrome (abdominal cramps, diarrhea, flushes , heart damage).

Diagnosis

Endocrine-disrupting tumors (functional NETs) can be suspected at an early stage from the clinical symptoms and can be detected in the blood by targeted laboratory tests (for example, in histologically confirmed NENs, the determination of chromogranin A in serum ). Inactive tumors (non-functional NET) often only become noticeable late due to their size or as a result of metastases . Imaging methods can reveal the location of the tumor: sonography , computer and magnetic resonance tomography , or also special scintigraphies such as somatostatin receptor scintigraphy with indium -111 or MIBG scintigraphy . Positron emission tomography with radioactively labeled DOPA or edotreotide (DOTATOC) has been newly developed , the sensitivity and specificity of which is up to 30% superior to classic scintigraphy with somatostatin analogs.

classification

In the current WHO -Classification (2010), neuroendocrine tumors according to their degree of degeneracy divided into three stages (1a = benign ( benign ), 1b = low malignant (malignant), 2 = high malignant). A specific TNM classification was proposed by ENETS ( European Neuroendocrine Tumor Society ) back in 2006/2007 . In 2012, ENETS published a revised version of the classification of neuroendocrine tumors. The tumor is classified according to the rate of cell division and proliferation using the Ki-67 index: grade 1 (proliferation index <2%), grade 2 (proliferation index 2 to 20%) or a neuroendocrine carcinoma (> 20%). This differentiation, as well as the additional TNM staging, are important prognostic factors that also have a decisive influence on the further therapeutic steps.

Immunohistochemistry

The cells of neuroendocrine tumors usually express the proteins synaptophysin , neuron-specific enolase , 5-hydroxyindolylacetic acid (5-HIAA) in the urine and chromogranin A in the immunohistochemical staining .

therapy

(For the therapy of small cell lung cancer, see there.)

The first place in the treatment of gastrointestinal neuroendocrine tumors can be surgery . Very large or metastatic tumors are also usually operated on to reduce the tumor burden ( debulking ). If one considers the current ENETS recommendations, however, this depends on the stage, the primary localization of the tumor and the stage of progression of the metastases. This can be followed by primary chemotherapy in the case of a pancreatic NET (also called PPom , derived from " pancreatic polypeptide ") (streptozotocin / 5FU for neuroendocrine tumors, G1-2, etoposide , cisplatin for neuroendocrine carcinoma, G3). Interferon was previously used in low-grade patients to slow the growth of the tumor. Today, however, far more modern and targeted substances such as the somatostatin analogues lanreotide and octreotide are available in the case of a low tumor burden. Clinical studies have significantly improved the progression-free interval in patients with a low proliferative pancreatic NET. Various antibodies and thalidomide are the subject of preliminary studies and are not yet available for patient treatment.

A MIBG labeled with iodine -131 and an edotreotide labeled with yttrium -90 (DOTATOC) are still in clinical development and not yet approved . Due to patent disputes, the peptides used for radiopeptide therapy (RPT), e.g. B. DOTATOC, DOTANOC, DOTATATE common in Germany. The DOTATOC peptide is currently patented, which is why some therapy centers do not use this peptide. Alternatively, this form of therapy can also be used with Lutetium -177-DOTATATE. The advantage of Lutetium-177 for smaller tumors lies in the shorter range and reduced toxic effects on the kidney tissue. The RPT has already found its way into the current ENETS guidelines, but there is a lack of prospective randomized studies that could clearly demonstrate the advantage of this form of therapy over other approaches. Modern approaches are targeted therapies which modulate the signal cascades of the tumors in a focused manner. The two currently approved drugs are tyrosine kinase inhibitors such as sunitinib or mTOR inhibitors such as everolimus . Both substances have been approved for the treatment of NET of the pancreas since 2011.

See also

literature

  • N. Begum et al .: Neuroendocrine tumors of the GI tract - data from the German NET Registry. In: Zentralblatt für Chirurgie. Volume 139, 2014, pp. 276-283.

Web links

Individual evidence

  1. ↑ U.-F. Pape, M. Böhmig, among others: Diagnostics and therapy of gastroenteropancreatic neuroendocrine tumors from an internal perspective . In: The oncologist. Volume 6, number 7, 2000, pp. 105-113, ISSN  0947-8965 , doi : 10.1007 / s007610050036
  2. ↑ Otto Lubarsch: About the primary cancer of the ileum together with remarks about the simultaneous occurrence of cancer and tuberculosis . In: Archives for pathological anatomy and physiology and for clinical medicine . tape 111 , no. 2 , February 1, 1888, ISSN  0720-8723 , p. 280-317 , doi : 10.1007 / BF01966242 ( springer.com [accessed January 21, 2018]).
  3. ↑ Oberndorfer S .: Carcinoid tumors of the small intestine. Ed .: Frankf Z Pathol. No. 1 , 1907, p. 425-429 .
  4. ^ Günter Klöppel: Oberndorfer and His Successors: From Carcinoid to Neuroendocrine Carcinoma . In: Endocrine Pathology . tape 18 , no. 3 , September 1, 2007, ISSN  1046-3976 , p. 141–144 , doi : 10.1007 / s12022-007-0021-9 ( springer.com [accessed January 21, 2018]).
  5. ↑ Cancer Center Freiburg: Kodierhilfe the cancer registry. ( Memento of the original from October 9, 2007 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. 2007, (PDF file) @1@ 2Template: Webachiv / IABot / www.krebs-webweiser.de
  6. ↑ David Binas. A.-K. Schubert, D. Wiese and others: Perioperative management in patients with carcinoid syndrome / neuroendocrine neoplasia. In: Anästh Intensivmed Volume 61, 2020, pp. 16–24, here: p. 20.
  7. ^ I. Buchmann, M. Henze u. a .: Comparison of 68Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumors. In: European journal of nuclear medicine and molecular imaging. Volume 34, Number 10, October 2007, pp. 1617-1626, ISSN  1619-7070 . doi : 10.1007 / s00259-007-0450-1 . PMID 17520251 .
  8. ↑ Y. Krausz, N. Freedman et al. a .: 68Ga-DOTA-NOC PET / CT imaging of neuroendocrine tumors: comparison with ¹¹¹In-DTPA-octreotide (OctreoScan®). In: Molecular imaging and biology. Volume 13, Number 3, June 2011, pp. 583-593, ISSN  1860-2002 . doi : 10.1007 / s11307-010-0374-1 . PMID 20652423 .
  9. ↑ a b c M. Pavel, E. Baudin a. a .: ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. In: Neuroendocrinology . Volume 95, Number 2, 2012, pp. 157-176, ISSN  1423-0194 . doi : 10.1159 / 000335597 . PMID 22262022 .
  10. ^ UF Pape, U. Berndt u. a .: Prognostic factors of long-term outcome in gastroenteropancreatic neuroendocrine tumors. In: Endocrine-Related Cancer . Volume 15, Number 4, December 2008, pp. 1083-1097, ISSN  1351-0088 . doi : 10.1677 / ERC-08-0017 . PMID 18603570 .
  11. ↑ Trojans against cancer - peptide receptor radionuclide therapy should help. At: 3sat.de broadcast nano, February 4, 2011.