Metastatic insulinoma

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A metastatic insulinoma is a rare form of a malignant insulinoma involving metastatic growth. [1] [2] An insulinoma is a small tumor localized to the pancreas, originating from islet beta cells, which produce an excess of insulin. [3] The increase in insulin ultimately leads to hypoglycemia. Insulinomas are commonly benign tumors, but can metastasize and become malignant. The metastatic growth can be characterized as a local invasion or distal metastasis. [3] However, insulinomas are often difficult to detect due to their relatively small size, with a diameter oftentimes less than 2 cm. Therefore, clinical appearance and pathology are not sufficient in diagnosing a malignant insulinoma. [3] Malignant insulinomas are not easily treated, as they require various treatments dependent on each person's case. [3]

Contents

Signs and symptoms

Metastatic insulinomas are commonly preceded by hypoglycemic symptoms and the Whipple triad. Majority of the hypoglycemic symptoms will manifest as neuroglycopenic symptoms and/or autonomic symptoms. [3] Common neuroglycopenic symptoms include: generalized confusion, significant behavioral changes, coma, and seizure. Common autonomic symptoms include: diaphoresis, weakness, palpitations, and hunger. [3] Thus, there are various presenting symptoms observed in patients. This is primarily attributed to the fact that metastatic insulinoma is initially diagnosed as another disease, such as benign insulinoma, which has the potential to progress and metastasize. [3]

Cause

Insulinomas generally occur sporadically. To date, the current cause of metastatic insulinomas is unknown. This is primarily due to their form as an already rare disease, insulinoma. Metastatic insulinomas are even less prevalent than insulinomas, and commonly begin as benign insulinomas which metastasize into metastastic insulinoma. [3]

Mechanisms

Patients with an insulinoma initially exhibit symptoms of hypoglycemia resulting from excess insulin secretion from the islet beta cells within the pancreatic tumor or from non-pancreatic tumor cells. The excess insulin secretes into the blood stream and causes a significant drop in the blood glucose level, also known as hypoglycemia. Hypoglycemia is accompanied by many of the above listed neuroglycopenic and/or autonomic symptoms. In metastatic insulinoma, cancerous cells from the initial insulinoma begin to break away and enter into either the bloodstream or the lymphatic system. Upon spreading and entering another part of the body, the process of metastasis has successfully occurred. The cancerous cells can now more rapidly divide and further spread. The main sites of metastasis for pancreatic cancer are the: liver, lung and peritoneum. [4]

Diagnosis

Diagnosis can occur via two distinct ways. The first is inclusive of a patient initially diagnosed with benign insulinoma. After the initial presentation of hypoglycemic symptoms, blood tests are taken in order to confirm hypoglycemia. A glucose, insulin and C-peptide are drawn. Initial diagnoses routinely also include a pre-operative CT to confirm an insulinoma. Upon completion of bloodwork and required radiology, majority of metastatic insulinomas are diagnosed if present. [5] The most common treatment option for those diagnosed with benign insulinomas are treated by isolated removal of the insulinoma. But, some of these patient cases progress and metastasize into a metastatic insulinoma. This occurs when cancerous cells break away from the insulinoma and enter the bloodstream or lymphatic system. Thus, it is possible to later develop malignancy after the initial diagnosis of insulinoma, and even after operative removal of the insulinoma. In these cases, the most common site of metastases is the liver, [3] as well as the lymph nodes. [5] However, the second type of diagnoses of metastatic insulinoma involves a patient who presents with symptoms of an insulinoma, and is taken for a pre-operative CT. [3]

Blood tests

The following blood tests are needed to diagnose insulinoma:[ citation needed ]

A significant blood glucose level < 3 mmol/L insulin level > 3 μIU/mL, and C-peptide level > 0.6 ng/mL [3] is indicative of hypoinsulinemic hypoglycemia.[ citation needed ]

Diagnostic Imaging

Less invasive imaging such as US, CT scan and MRI can be utilized to confirm the presence of an insulinoma. More specifically, a transabdominal ultrasound and CT are typically the first diagnostic images ordered. Further testing includes an endoscopic ultrasound or MRI.[ citation needed ]

Treatment

Patients who are diagnosed with general insulinoma are commonly treated with surgical removal of the insulinoma. But, in those patients with metastatic insulinoma surgery is not enough. Thus, medical therapies are widely considered and reserved for those especially with unresectable insulinoma. [5]

Cytoreductive surgery, alongside other anti-tumor therapies are part of the initial treatment plans utilized for potential removal of the insulinoma. But, in patients with metastatic insulinoma, cytoreductive surgery has an effective rate of less than 10%. [5] The surgery has however been shown to improve symptomatology and overall survival rate. [6]

Diazoxide is a medication used to primarily reduce the excess insulin secreted from the insulinoma cells. Insulin is suppressed by affecting the ATP-sensitive potassium channels. This can also lead to an excess of potassium and ultimately result in oedema from sodium retention in the body. In order to counteract this, Diazoxide is commonly used in combination with thiazide diuretics. Although Diazoxide has been noted to have an immediate effect on patients, over the course of time the dosage may need to be increased. [6]

Beta-blockers also have a positive effect in the overall reduction of insulin production. Therefore, resolving hypoglycemia.[ citation needed ]

Prognosis

The prognosis once diagnosed with metastatic insulinoma falls on a large spectrum. Patients can live anywhere from 5 months to 29 years after initial diagnosis. [3] The reason there is such a huge gap in the perspective life expectancy, is related to the minimal follow up information gathered on patients with metastatic insulinoma. Therefore, there is currently no reliable information regarding hard statistics or exact time intervals.[ citation needed ]

Epidemiology

Because of the extremely rare prevalence of this disease, there is not much information available regarding the epidemiology. General insulinoma is diagnosed in every one to four cases per one million people. Malignant insulinoma is an extremely rare form of an insulinoma, affecting only about 10% of the total insulinoma cases. [3] Insulinomas tend to have a slightly higher prevalence in females, at about 59% of the total diagnosed general insulinoma cases [7] and occur at a median age of about 47. [8]

Research

The minimal research that has been completed on metastatic insulinoma addresses specific patient cases and presenting signs and symptoms. Potential treatment options are also commonly discussed within these case studies. But, the research to date is not comprehensive and cannot be generalized to all patients diagnosed with metastatic insulinoma. Therefore, I recommend further research be conducted into potential treatment for all cases of metastatic insulinoma. I would also recommend greater follow up with patients to provide a concrete life expectancy interval.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Hypoglycemia</span> Health condition

Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose below 70 mg/dL (3.9 mmol/L), symptoms associated with hypoglycemia, and resolution of symptoms when blood sugar returns to normal. Hypoglycemia may result in headache, tiredness, clumsiness, trouble talking, confusion, fast heart rate, sweating, shakiness, nervousness, hunger, loss of consciousness, seizures, or death. Symptoms typically come on quickly.

<span class="mw-page-title-main">Brain tumor</span> Neoplasm in the brain

A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: malignant tumors and benign (non-cancerous) tumors. These can be further classified as primary tumors, which start within the brain, and secondary tumors, which most commonly have spread from tumors located outside the brain, known as brain metastasis tumors. All types of brain tumors may produce symptoms that vary depending on the size of the tumor and the part of the brain that is involved. Where symptoms exist, they may include headaches, seizures, problems with vision, vomiting and mental changes. Other symptoms may include difficulty walking, speaking, with sensations, or unconsciousness.

<span class="mw-page-title-main">Metastasis</span> Spread of a disease inside a body

Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, are metastases (mets). It is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer cells into neighboring tissues.

<span class="mw-page-title-main">Bone tumor</span> Medical condition

A bone tumor is an abnormal growth of tissue in bone, traditionally classified as noncancerous (benign) or cancerous (malignant). Cancerous bone tumors usually originate from a cancer in another part of the body such as from lung, breast, thyroid, kidney and prostate. There may be a lump, pain, or neurological signs from pressure. A bone tumor might present with a pathologic fracture. Other symptoms may include fatigue, fever, weight loss, anemia and nausea. Sometimes there are no symptoms and the tumour is found when investigating another problem.

<span class="mw-page-title-main">Insulinoma</span> Medical condition

An insulinoma is a tumour of the pancreas that is derived from beta cells and secretes insulin. It is a rare form of a neuroendocrine tumour. Most insulinomas are benign in that they grow exclusively at their origin within the pancreas, but a minority metastasize. Insulinomas are one of the functional pancreatic neuroendocrine tumour (PNET) group. In the Medical Subject Headings classification, insulinoma is the only subtype of "islet cell adenoma".

Hyperinsulinemic hypoglycemia describes the condition and effects of low blood glucose caused by excessive insulin. Hypoglycemia due to excess insulin is the most common type of serious hypoglycemia. It can be due to endogenous or injected insulin.

<span class="mw-page-title-main">Hyperinsulinism</span> Medical condition

Hyperinsulinism refers to an above normal level of insulin in the blood of a person or animal. Normal insulin secretion and blood levels are closely related to the level of glucose in the blood, so that a given level of insulin can be normal for one blood glucose level but low or high for another. Hyperinsulinism can be associated with several types of medical problems, which can be roughly divided into two broad and largely non-overlapping categories: those tending toward reduced sensitivity to insulin and high blood glucose levels (hyperglycemia), and those tending toward excessive insulin secretion and low glucose levels (hypoglycemia).

Whipple's triad is a collection of three signs that suggests that a patient's symptoms result from hypoglycaemia that may indicate insulinoma. The essential conditions are symptoms of hypoglycaemia, low blood plasma glucose concentration, and relief of symptoms when plasma glucose concentration is increased. It was first described by the pancreatic surgeon Allen Whipple, who aimed to establish criteria for exploratory pancreatic surgery to look for insulinoma.

<span class="mw-page-title-main">Congenital hyperinsulinism</span> Medical condition

Congenital hyperinsulinism (HI or CHI) is a rare condition causing severe hypoglycemia in newborns due to the overproduction of insulin. There are various causes of HI, some of which are known to be the result of a genetic mutation. Sometimes HI occurs on its own (isolated) and more rarely associated with other medical conditions.

<span class="mw-page-title-main">Benign tumor</span> Mass of cells which cannot spread throughout the body

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<span class="mw-page-title-main">Diazoxide</span> Medication used to treat low blood sugar and high blood pressure

Diazoxide, sold under the brand name Proglycem and others, is a medication used to treat low blood sugar due to a number of specific causes. This includes islet cell tumors that cannot be removed and leucine sensitivity. It can also be used in refractory cases of sulfonylurea toxicity. It is generally taken by mouth.

<span class="mw-page-title-main">Diabetic hypoglycemia</span> Medical condition

Diabetic hypoglycemia is a low blood glucose level occurring in a person with diabetes mellitus. It is one of the most common types of hypoglycemia seen in emergency departments and hospitals. According to the National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP), and based on a sample examined between 2004 and 2005, an estimated 55,819 cases involved insulin, and severe hypoglycemia is likely the single most common event.

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<span class="mw-page-title-main">Pancreatic neuroendocrine tumor</span> Medical condition

Pancreatic neuroendocrine tumours, often referred to as "islet cell tumours", or "pancreatic endocrine tumours" are neuroendocrine neoplasms that arise from cells of the endocrine (hormonal) and nervous system within the pancreas.

Glucose-elevating agents are medications used to treat hypoglycemia by raising blood glucose. In diabetics, hypoglycemia can occur as a result of too much insulin or antidiabetic medication, insufficient food intake, or sudden increase in physical activity or exercise. The most common glucose-elevating agents used to treat diabetic hypoglycemia are glucose and glucagon injections when severe hypoglycemia occurs. Diazoxide, which is used to counter hypoglycemia in disease states such as insulinoma or congenital hyperinsulinism, increases blood glucose and decreases insulin secretion and glucagon accelerates breakdown of glycogen in the liver (glycogenolysis) to release glucose into the bloodstream.

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References

  1. ↑ Hagel AF, Hagel WH, Lindner AS, Kammerer FJ, Neurath MF, Konturek PC, Harsch IA (August 2011). "Metastatic insulinoma - prolonged survival after multimodal approach". Medical Science Monitor. 17 (8): CS103-107. doi:10.12659/msm.881891. PMC   3539604 . PMID   21804467.
  2. ↑ Bernard V, Lombard-Bohas C, Taquet MC, Caroli-Bosc FX, Ruszniewski P, Niccoli P, et al. (May 2013). "Efficacy of everolimus in patients with metastatic insulinoma and refractory hypoglycemia". European Journal of Endocrinology. 168 (5): 665–74. doi: 10.1530/EJE-12-1101 . PMID   23392213.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 Yu J, Ping F, Zhang H, Li W, Yuan T, Fu Y, et al. (December 2018). "Clinical Management of Malignant Insulinoma: a single institution's experience over three decades". BMC Endocrine Disorders. 18 (1): 92. doi: 10.1186/s12902-018-0321-8 . PMC   6282250 . PMID   30522468.
  4. ↑ Meleth S, Whitehead N, Evans TS, Lux L, eds. (February 2013). "Common sites of metastasis for different primary sites". Technology Assessment on Genetic Testing or Molecular Pathology Testing of Cancers with Unknown Primary Site to Determine Origin. Rockville (MD): Agency for Healthcare Research and Quality (US).
  5. 1 2 3 4 Taye A, Libutti SK (August 2015). "Diagnosis and management of insulinoma: current best practice and ongoing developments". Research and Reports in Endocrine Disorders. 5: 125–33. doi: 10.2147/RRED.S86565 .
  6. 1 2 de Herder WW, van Schaik E, Kwekkeboom D, Feelders RA (September 2011). "New therapeutic options for metastatic malignant insulinomas". Clinical Endocrinology. 75 (3): 277–84. doi: 10.1111/j.1365-2265.2011.04145.x . PMID   21649688.
  7. ↑ Miranda G (June 2018). "Malignant insulinoma chemotherapy resistant, pancreatic neuroendocrine tumor of uncertain prognosis". Journal of Clinical and Translational Endocrinology: Case Reports. 8: 16–18. doi: 10.1016/j.jecr.2018.01.001 .
  8. ↑ Iglesias P, Díez JJ (April 2014). "Management of endocrine disease: a clinical update on tumor-induced hypoglycemia". European Journal of Endocrinology. 170 (4): R147-57. doi: 10.1530/eje-13-1012 . PMID   24459236.
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