Paraneoplastic Syndromes Associated with Rare Neuroendocrine Tumors: An Overview

What Are Neuroendocrine Tumors?

Tumors that begin in the neuroendocrine cells within the neuroendocrine system are known as neuroendocrine tumors (NETs). They are rare tumors. Neuroendocrine cells exhibit traits of both nerve and hormone-producing endocrine cells. NETs are essential for maintaining the connection between the neurological and endocrine systems, which is required for hormonal regulation.

What Is Paraneoplastic Syndrome?

Paraneoplastic neurologic syndromes (PNS) or paraneoplastic syndromes impact the neurological system in cancer patients, including the brain, spinal cord, nerves, and muscles. A protein or hormone secreted by the tumor may impact the body's biological system. These secretions bring changes to the body that are not directly related to cancer and might lead to symptoms. The immune system releases antibodies to eradicate tumors in paraneoplastic disorders. The antibodies also cause harm to healthy cells in this process (autoimmune reaction). Numerous bodily systems and organs, such as the neurological system, the endocrine system (hormones), the kidneys, the bones, joints, skin, and blood, can be impacted by paraneoplastic syndrome. The presence of cancer can be manifested due to the presence of symptoms associated with paraneoplastic syndrome. These neurological symptoms could appear before a cancer diagnosis.

What Is the Connection Between Paraneoplastic Syndrome and Neuroendocrine Tumors?

A PNS may arise at any stage of cancer development. It can manifest before the underlying cancer is diagnosed and assist in the early detection of a previously undetected tumor. Thus, it helps identify the recurrence and presence of neoplasia. It also helps in regulating the effectiveness of the treatment and disease progression. Thus, the clinical outcomes may be significantly improved by a timely and accurate identification and treatment of PNS.

How Are Paraneoplastic Syndromes Associated With Neuroendocrine Tumors Classified?

Based on clinical manifestations, they are classified as:

Humoral PNS

• Hypercalcemia:

  • Humoral hypercalcemia is a prevalent paraneoplastic condition that is frequently associated with a poor prognosis in cancer patients, particularly those with advanced malignancies. It may happen when the body secretes abnormal amounts of hormones, causing it to create too much calcium. PTHrP (parathyroid hormone-related protein), which is overproduced in over 80 percent of instances, is the main reason.

  • Symptoms like vomiting, nausea, constipation, frequent urination, cognitive impairments, and even coma may result from the overproduction of PTHrP. The amount of calcium in the blood and how quickly it rises to determine how severe these symptoms are.

  • Treating the underlying tumor is the primary course of treatment for humoral hypercalcemia. Long-acting somatostatin analogs (SSAs) and peptide receptor radionuclide therapy (PRRT) have demonstrated efficacy in PTHrP-related instances. Medications such as Denosumab and Zoledronic acid can help reduce calcium levels in extreme situations. Cinacalcet and the tyrosine kinase inhibitor Sunitinib may also be administered in some circumstances. Prompt treatment of hypercalcemia is crucial.

• Cushing Syndrome (CS):

  • In a condition known as ectopic Cushing's syndrome (ECS), non-pituitary tumors release the hormone ACTH (adrenocorticotropic hormone), which causes symptoms resembling those of Cushing's disease. The degree of ECS is based on how aggressive the tumor is. Some tumors, such as lung carcinoids and pheochromocytomas, generate slower-developing, weaker ECS symptoms. Others, such as pancreatic neuroendocrine tumors and small cell lung cancers, cause more severe symptoms to appear faster, such as weight loss, elevated blood pressure, and elevated blood sugar.

  • It can be difficult to detect ECS, particularly in cases where the tumors are small. The distinction between Cushing's illness, which is caused by the pituitary gland, and ECS is frequently difficult to make. It could take a while to diagnose a tumor after the onset of ECS symptoms, but early detection is essential.

• Hypoglycemia:

  • Specific tumor types and results in low blood sugar bring on paraneoplastic hypoglycemia. A possible mechanism for this is non-islet cell tumor hypoglycemia (NICTH), a condition in which tumors create an amino acid known as “big-IGF2”. This molecule interacts with insulin and IGF (insulin growth factor) receptors, lowering insulin and suppressing growth hormone (GH) levels, leading to hypoglycemia.

  • The IGF-2 to IGF-1 ratio is used to diagnose NICHT. A high ratio denotes increased IGF2 secretion. Tumors of different sources, such as neuroendocrine tumors (NET), pheochromocytomas, and mesenchymal and epithelial tumors, are frequently linked to this.

  • Insulin production tumors can also result in hypoglycemia. The tumor's type, stage, and grade determine the course of treatment. Remission or a decrease in hypoglycemia may result from surgical tumor excision. Human growth hormone and glucocorticoids are two drugs that can be used to treat the illness. Treatment should be customized to the particular tumor and its features.

  • The most effective way to cure ECS is to remove the tumor that is causing it, either right away or after taking medicine to reduce cortisol levels. ECS management also requires treating any underlying malignancy or other health conditions.

• Acromegaly:

  • Acromegaly occurs when the body overproduces growth hormone (GH), which causes abnormal tissue and organ growth. GH-releasing hormone (GHRH) excess produced by some tumor forms, such as pheochromocytomas, pancreatic neuroendocrine tumors (pNENs), small cell lung cancers (SCLCs), and bronchial and thymic carcinoids, is the main cause of it in most cases.

  • These tumors induce acromegaly, which has symptoms and blood test results comparable to pituitary gland problems. GH remains elevated following a glucose test, and insulin-like growth factor 1 (IGF1) is among them.

  • With periodic pituitary imaging, identifying the exact cause of acromegaly can be difficult, and even skilled radiologists can make mistakes. Serum GHRH levels, however, can aid in disease monitoring and diagnosis.

  • Surgery is the main treatment for acromegaly brought on by these tumors, and it is performed either to remove the tumor completely or to minimize its size. If surgery is not an option or if the malignancy has spread, Somatostatin analogs (SSAs) are drugs that can be used to manage the tumor and control the symptoms of acromegaly.

Neurological PNS

• Paraneoplastic neurological syndrome (PNS) can cause neurological symptoms in some people with specific types of neuroendocrine tumors (NET). These symptoms include dysphagia, tremors in the muscles, difficulty speaking, and more. Here are some important details:

• Peripheral neuropathy and encephalopathy were among the neurological symptoms experienced by certain patients with gastrointestinal NET. Several of these patients had high levels of antineuronal antibodies. Following tumor removal surgery and corticosteroid and immunosuppressive medication treatment, their symptoms improved, indicating that an immunological reaction to the tumors may have caused neurological problems.

Other Less Common Manifestations:

• Cancer-associated retinopathy (CAR) can cause vision issues in some patients with small cell lung cancer (SCLC) and some neuroendocrine tumors. Autoantibodies generated by cancer cells that target a particular 23-kDa retinal antigen are the cause of CAR. Changes in the size of the blood vessels in the eyes and a loss of peripheral vision may result from this disorder.

• These patients may experience nephrotic syndrome, which is a kidney disease that results in an excess of protein in the urine, and orthostatic hypotension, a decrease in blood pressure upon standing. Glomerulonephritis, which is a kidney disease defined by abnormal kidney function, has been shown to cause nephrotic syndrome in patients with neuroendocrine tumors, such as duodenal NET.

How Is Diagnosis for Paraneoplastic Syndromes Associated With Neuroendocrine Tumors Done?

Identifying paraneoplastic syndromes (PNS) originating from neuroendocrine tumors has benefited greatly from the widespread use of modern diagnostic methods. Medical professionals must understand how a PNS presents clinically and the laboratory tests, imaging modalities, and other procedures that enable an efficient diagnosis and course of therapy. Several clinical, biochemical, and histological requirements must be fulfilled to classify a variety of symptoms as Paraneoplastic Neurological Syndromes (PNS)

• Clinical Criteria:

  • Existence of a particular clinical syndrome connected to secretory product production.

  • Noticing the improvement or remission of the syndrome following treatment, as well as its recurrence when the underlying condition relapses.

• Biochemical Criteria:

  • Presence of excessive secretory products that are abnormally controlled.

  • There is a significant difference between the tumor's venous discharge and the arterial concentration of the same substance.

• Histochemical Criteria:

  • Demonstrating the product's synthesis and secretory abilities in vitro using tumor cells.

  • Detecting relevant mRNA for the secretory product and bio or immuno-reactive elements in the tumor tissue.

• Neuron-specific enolase (NSE) and circulating biomarkers such as chromogranin A (CgA) are frequently associated with neuroendocrine tumors (NET). Other possible biomarkers, such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), histone modifications, mRNA transcripts (NeTest), and miRNAs, are also being investigated by researchers. These components could function as predictors of the prognosis and response to treatment.

• When a patient has a neuroendocrine tumor (NET), traditional imaging methods, including magnetic resonance imaging (MRI), computed tomography scan (CT scan), gastroscopy, endoscopic ultrasonography, and colonoscopy are frequently done to identify the main tumor and any metastatic growths.

• Somatostatin receptor imaging can also identify NETs because they are characterized by a high density of somatostatin receptors (SSTRs). For whole-body scans, this can be accomplished with 68Ga-labeled (Gallium-labeled) positron emission tomography (PET) or 111In-labeled (Indium-labeled) scintigraphy (a diagnostic procedure that uses gamma rays from radioactive isotopes to make images of the body's tissues and internal organs).

• Of all these techniques, 68Ga-labeled somatostatin analog PET is the most accurate in diagnosis and NET staging. Furthermore, for G3 malignancies, 18F-fluorodeoxyglucose (FDG) PET (assesses glucose metabolism) is more accurate than somatostatin receptor scintigraphy (SRS).

Conclusion

Patients with neuroendocrine neoplasms (NENs) often develop paraneoplastic syndromes (PNS), which are indicative of the tumors' capacity to create biologically active chemicals and autoantibodies that can result in specific clinical syndromes. These symptoms may present before a tumor is diagnosed, and quantifying the causing components can help with therapy monitoring and recurrence detection. Most PNSs are linked to synthesizing peptidic hormones, which produce symptoms similar to those brought on by the regular secretion of chemicals. To develop evidence-based diagnostic and treatment guidelines, it is essential to recognize and record NET cases, which are predicted to grow due to more awareness and better diagnostic instruments.