Neuroendocrine Tumors

non-functioning GEP - NET

non-functioning GEP - NET do not secrete / produce a measurable hormone in contrast to insulinoma, gastrinoma, glucagonoma. These tumors are not associated with a typical clinical syndrome.
Very often these tumors may represent clinically silent PPoma's

NET of the pancreas (p-NET, foregut tumors) / NET of digestive GI-tract (d-NET)
"non-functioning islet-cell tumors"
(majority of islet cell carcinomas)
non-functioning GEP-NET in GI-tract:
without clin. carcinoid-syndrome
frequently high index of malignancy.
well-differentiated p-NET or undifferentiated p-NET
Patho-anatomical criteria:
"limited risk tumors" (LRT) / "increased risk turmors" (IRT)

nuclear Ki67-expression, vascular and/or perineural invasion
non-functioning p-NET mostly are tumors presenting with circulating tumor markers (chromogranin A, NSE, HCG, PP, calcitonin). Eventually apparent hormonal secretion is insufficient to produce a clinical syndrome or symptoms
non-secreting p-NET are tumors presenting histochemical (immunofluorescence) peptide- or tumor marker expression.

reasons for classifying problems: see below

WHO-Classification of GEP-NET

Classification problems of non-functional GEP-NET may be due to,
1. : failure to test for "rare" peptides,
2. : failure to investigate the patient carefully and in depth (symptoms and history),
3. : seceretion of inactive precursors of the hormones without any known physiological function,
4. : secretion of peptides which do not have any clinically relevant action even if secreted in high quantities,
5. : secretion of peptides for which assays are not yet available,
6. : secretion of small amounts of peptides or simultaneous secretion of inhibitory peptides,
7. : regulated secretion of peptides, absence of autonomous secretion,
8. : failure to coordinate physiological function of peptide in question and clinical symptoms.

Non-functional GEP-NET sometimes are misclassified despite clear evidence for the presence of endocrine machinery (e.g. positive markers, positive immunohistochemistry).

Example: frequent pancreatic polypeptidoma (PPoma) or pancreatic calcitoninoma in the abesence of hypocalcemia or steatorrhea.

Exception: "Proinsulinoma" : Proinsulin which in comparison to insulin is a weak agonist may be the dominant peptide in many insulinomas and is causing the classical hypglycemia syndrome.

Therapeutical strategies - options
for the treatment of non-functioning GEP- tumors

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1. In111-Octreotid-Szintigraphye (Somatostatin-Receptor-Szintigraphy) is the most important first line action for diagnostic and therapeutic evaluation

3. Localisation , presence of metastases as well as patho-histological grade of differentiation have to be known LRT: "limited risk tumor", IRT: " increased risk tumor")

resection of primary tumor
resection of metastases / tumor-debulking by 1. metastasectomy, 2. hemihepatectomy, 3. radioablation (RITA, RFTA)
Hepatic chemoembolisation (transarterial chemoperfusion and -embolisation)
Somatostatin-analoga and interferon- 2alpha

Systemic chemotherapy

Radionuclide therapy: 90Yttrium-Somatostatin (DOTATOC)

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