Neuroendocrine tumors

Introduction and incidence

Neuroendocrine tumors (NETs) are a specific group of tumors that arise from neuroendocrine cells. One of the functions of these cells is to release hormones into the blood in response to signals from the nervous system. Such cells are found in the endocrine glands of the body, but also in virtually all other tissues, so neuroendocrine tumors can arise anywhere in the body. For this reason, they are listed collectively instead of by site of origin like most other tumors (e.g. pancreatic cancer). They most commonly arise in the digestive system, primarily in the small intestine and pancreas, followed by lung NETs. They are generally considered rare tumors (the annual incidence is estimated to be around 2.5-5 per 100,000), but it should be noted that their incidence in the world is constantly and significantly increasing.

Risk factors

Most NETs occur sporadically (without a clear cause), and the risk factors for developing this disease are poorly understood. Some NETs occur as part of inherited genetic syndromes, such as MEN1, MEN2, von Hippel-Lindau disease, and neurofibromatosis.

Signs and symptoms

Some of the symptoms of NETs may follow the location where they arise, so for example, aggressive neuroendocrine lung tumors can behave like other lung tumors due to pressure and ingrowth into surrounding structures and organs. However, given their ability to secrete hormones, NETs can also cause some specific symptoms. For example, pheochromocytomas (NETs of the adrenal cortex) can cause an increase in blood pressure due to the secretion of catecholamines, while pancreatic insulinomas can lead to low blood sugar levels (hypoglycemia) due to the secretion of insulin. In addition to the specific hormones secreted by neuroendocrine cells in various parts of the body, many of them also have common (non-specific) hormones and active substances that they can secrete. For example, many of them can secrete serotonin, which can lead to the so-called carcinoid syndrome (carcinoid is an older name for slow-growing NETs), which is characterized by flushing, diarrhea, asthma, abdominal cramps, and over time can lead to damage to heart valves and heart failure.

Diagnosis

Diagnosis of NETs is not significantly different from the procedure used to detect any other type of tumor in the organ or tissue being examined. For example, the procedure for detecting NETs in the small intestine is not significantly different from the procedure used to diagnose any other tumor in the small intestine. As a rule, a biopsy (tissue sample) is required before treatment, from which the degree of aggressiveness of the disease can be estimated based on the Ki-67 index (measures the proportion of cells that are aged). Among the tumor markers used are chromogranin A (CgA) from the blood, 5-hydroxyindoleacetic acid (5-HIIA) from 24-hour urine, neuron-specific enolase (NSE) from the blood, and occasionally some others. Read more about CgA in the Interesting facts at the bottom of the page. In addition to standard imaging tests, somatostatin receptor scintigraphy (tektrotide scintigraphy) or Ga-68 PET/CT scan are also very important in patients with NETs, ​​which examines the presence of receptors for the hormone somatostatin on tumor cells, which is important in deciding on treatment. You can read more about cancer diagnostics in a separate article.

Stage of the disease

There is no separate TNM classification of the stage of the disease for NETs in relation to other types of tumors in a specific organ, which means that, for example, the stage of pancreatic NETs is determined in the same way as the stage of other more common types of pancreatic cancer. The same applies to NETs that arise in other organs. Stage IV usually indicates the stage of metastatic disease, i.e. spread to other organs and tissues.

Treatment

The treatment of NETs is very complex and requires significant clinical experience, which is available in a small number of institutions and oncologists, given that these are rare tumors. As a rule, in the phase of localized disease (without distant metastases), local treatment methods are preferred, primarily surgical treatment. In the majority of patients, if the entire tumor mass has been removed by surgery, further oncological treatment is not necessary. In the phase of metastatic disease, treatment depends significantly on the degree of tumor differentiation (grade). Namely, although they are malignant tumors, NETs range from very slow-growing tumors to extremely aggressive carcinomas, which to a significant extent depends on the degree of differentiation of the cells from which the disease originated. The degree of differentiation is measured primarily by the previously mentioned Ki-67 index, with higher index values ​​indicating a more aggressive disease. In patients with lower grades (G1 and G2), i.e. those with a Ki-67 of less than 20%, in the case of a positive tektrotide scintigraphy finding, the first choice of treatment is usually somatostatin analogues, which block the receptors for somatostatin on tumor cells, thereby reducing symptoms and stabilizing or reducing the tumor mass. Peptide receptor radionuclide therapy (PRRT) is also an option during the treatment of these patients. It is a type of precise radiation in which the radionuclide (radioactive compound) binds to somatostatin receptors, enters the tumor cell and damages it with radiation, without significantly affecting the surrounding healthy tissue. In patients in whom the disease progresses on somatostatin analogues or in those who do not have a positive tectrotide scintigraphy, the treatment options are chemotherapy (one of the preferred protocols is capecitabine + temozolomide) or targeted therapy (everolimus and sunitinib are most often used). For high-grade patients (most of those with grade G3, i.e. Ki-67 greater than 20%), the main treatment choice is chemotherapy, primarily a combination of etoposide and a platinum compound, although even in this group, a subgroup of patients with a slightly better prognosis can be isolated in whom less aggressive treatment can be applied.

​Additional interesting facts

Chromogranin A (CgA) is one of the most commonly used tumor markers in neuroendocrine tumors. Its level depends on the size of the tumor mass and the advanced stage of the disease. It can be elevated in both functional (symptoms of increased secretion of a hormone from the tumor are present) and non-functional NETs. It is important to remember that it can be falsely elevated in patients with impaired renal function, those using proton pump inhibitors (for example, medications for gastritis!), and even in some patients with high blood pressure. Therefore, before measuring, it is necessary to temporarily exclude from therapy medications that can affect CgA levels, especially the aforementioned proton pump inhibitors.

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