Neuroendocrine tumor

Neuroendocrine tumors ( NET) are benign or malignant tumors, which take their origin from the neuro- ectoderm ( neural crest ) and their cells in the immunohistochemical characterization of the same endocrine cells. Epithelial neuroendocrine tumors occur mainly in the gastrointestinal tract and pancreas. For neuroendocrine tumors in the stomach and intestine also the old term carcinoid is ( carcinoma -like tumor ) is still very common. This should be like the term APUDom ( amine precursor uptake and decarboxylation ) are no longer used. Small cell lung cancer as well as the Merkel cell carcinoma of the skin are also among the neuroendocrine tumors. Closely related are the nerves like neuroblastomas, pheochromocytomas, and paragangliomas. 75 % of all neuroendocrine tumors are localized in the gastroenteropancreatic system ( neuroendocrine tumor of gastro - Abbr GEP -NET).

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

By their very nature, these cells have similarities to nerve cells and their function, they are among the endocrine glands. Therefore they are called neuroendocrine cells.

Neuroendocrine tumors of the gastrointestinal tract and pancreas ( GEP-NETs, neuroendocrine gastro- entero - pancreatic for tumors, carcinoids earlier ) called occur at about one to two times per 100,000 population per year. Neuroendocrine tumors affect mainly patients aged from 50 to 70 years; Women and men about equally. In addition to the random ( sporadic ) disease cases there are two forms of hereditary multiple endocrine neoplasia.

Hormone production

Approximately 30-50% of neuroendocrine tumors produce hormonally active Aminabkömmlinge, which 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 may produce characteristic symptoms. You can see that gastrin -producing neuroendocrine tumor, gastrinoma, Zollinger- Ellison syndrome ( hyperacidity, stomach ulcers), VIP - producing tumors cause severe diarrhea, and insulinomas cause dangerous hypoglycemia. An important sign of tumors of the small intestine is the serotonin -associated carcinoid syndrome ( abdominal cramps, diarrhea, blushing, heart damage ).

Diagnostics

Endocrine- active tumors can be suspected from the early clinical symptoms and confirmed by specific laboratory tests of blood. Inactive tumors are often late conspicuous by their size or due to metastases. Imaging techniques can the location of the tumor reveal: sonography, computer and magnetic resonance imaging, or even specific scintigraphy as the somatostatin receptor scintigraphy with indium -111 or MIBG scintigraphy. Newly developed positron emission tomography with radiolabeled DOPA or Edotreotid ( DOTATOC ), whose Sensititivtät and specificity of classical scintigraphy is superior to somatostatin analogs by up to 30 %.

Classification

In the current WHO classification of neuroendocrine tumors are classified according to their degree of degeneracy in three steps (1a = benign ( benign), 1b = low malignant ( cancerous ), 2 = high grade ). A specific TNM classification has been proposed in the years 2006/2007 of the eNets (European Neuroendocrine Tumor Society ). In 2012, the eNets has issued a revised version of the classification of neuroendocrine tumors. The classification of the tumor on the speed of cell division, proliferation takes place on the basis of Ki-67 index: grade 1 ( proliferation index <2%), grade 2 ( proliferation index of 2 to 20 %) or a neuroendocrine cancer ( > 20%). This distinction, as well as the thereto complementary TNM staging are important prognostic factors, which affect the other therapeutic steps significantly.

Immunohistochemistry

The cells of neuroendocrine tumors express in immunohistochemical staining in general, the proteins synaptophysin, neural specific enolase, 5 - Hydroxyindolylessigsäure (5- HIAA ) in the urine and chromogranin A.

Therapy

( for the treatment of small cell lung cancer, see there.)

In the first place of the treatment of the gastrointestinal neuroendocrine tumors, the operation can stop. Even very large or metastatic tumors are usually surgery to reduce the tumor burden ( debulking ). This is, we look at the current eNets recommendations, however, dependent on the stage, the primary site of the tumor and the stage of progression of metastasis. Then, a primary chemotherapy, in case one of pancreatic NET follow ( Streptozotocin/5FU in neuroendocrine tumors, G1 -2, etoposide, cisplatin in neuroendocrine carcinoma, G3). Interferon has been previously used in patients with low- grading in order to slow the growth of the tumor. Today, however, much more modern and targeted substances such as lanreotide and octreotide are in the case of a small tumor load. Clinical studies could significantly improve progression-free interval in patients with a low proliferative pancreatic NET. Different antibodies and thalidomide are the subject of preliminary and not yet available for patient treatment.

A labeled with iodine -131 MIBG and labeled with yttrium -90 Edotreotid ( DOTATOC ) are still in clinical development and not yet approved. Because of patent disputes to a radio peptide therapy ( RPT) are used peptides, eg, DOTATOC, DOTANOC, DOTATATE common in Germany. Currently, there is a patent right to the peptide DOTATOC, why some treatment centers refrain from the use of this peptide. Alternatively, this form of therapy can also be used with lutetium -177. The advantage of lutetium -177 is smaller tumors in the shorter range, and reduced toxic effect on the kidney tissue. The RPT has already found its way into the current guidelines of the eNets but absent prospective randomized studies that could demonstrate the advantage of this treatment over other approaches clear. Modern approaches are targeted therapies that modulate focused the tumors which signaling cascades. The two currently approved drugs are tyrosine kinase inhibitors such as sunitinib or mTOR inhibitors such as everolimus. Both substances have since 2011 been approved for treatment of NET of the pancreas.