Pancreatic islet cell carcinoma
Synonyms and keywords:Islet cell carcinoma of pancreas, Pancreatic islet cell cancer

# Overview
Pancreas has 2 types of cells, acinar and islet that produce exocrine and endocrine hormones respectively. The pancreatic islet cell carcinomas are also known as neuroendocrine tumors. They are of 6 types depending on the type of hormone the tumor produces. They can occur sporadically or in association with other disorders such as multiple endocrine neoplasia type 1, Von Hippel Lindau disease, neurofibromatosis type 1 and tuberous sclerosis which are inherited in an autosomal dominant pattern. The most common metastatic sites are the liver, the lymph nodes, and the bones. The cancer usually presents with jaundice, light-colored stools, dark urine, and pain in the upper or middle abdomen and back, unexplained weight loss, anorexia, fatigue and symptoms according to the hormone produced. The treatment depends on the spread of the cancer and includes both medical and surgical treatment.

# Historical perspective
In 1869, pancreatic islet cells were discovered by Paul Langerhans and the first adenoma of islets was discovered by Nicholls in 1902.

# Classification
Pancreatic islet cell carcinoma is of 6 types: 
- Gastrinoma
- Insulinoma
- Vasoactive intestinal peptide releasing tumor (VIPoma)
- Somatostatinoma
- Glucagonoma
- Non functional islet cell tumor

# Pathophysiology
- Acinar cells and Islet cells are the 2 types of cells in pancreas.
- Acinar cells are responsible for secretion of enzymes and bicarbonate involved in the digestion process.
- Islet cells of pancreas play the endocrine organ role, by producing hormones such as insulin, gastrin, glucagon, somatostatin, and vasoactive intestinal polypeptide.
- The pancreatic islet cell carcinomas are also known as neuroendocrine tumors.
- They can occur sporadically or in association with other disorders such as multiple endocrine neoplasia type 1, Von Hippel Lindau disease, neurofibromatosis type 1 and tuberous sclerosis which are inherited in an autosomal dominant pattern.
- Islet cell carcinoma is divided into 6 types depending on the type of hormone produced.
- These tumors produce excessive amounts of hormones and cause symptoms similar to the hormones' action.
Insulinoma - hypoglycemia due to decreased glucose synthesis in liver.
Gastrinoma - Zollinger-Ellison syndrome, in which hypersecretion of gastrin causes hydrochloric acid release which causes peptic ulcers.
Glucagonoma - hyperglucagonemia, zinc deficiency, fatty acid deficiency, hypoaminoacidemia that may cause necrolytic migratory erythema.
VIPoma - Elevated serum VIP levels leads to increased intracellular cAMP which causes increased intestinal secretion of water along with Na+, K+, HCO3 -, and Cl- in the intestinal lumen, causing diarrhea and hypokalemia.
Somatostatinoma - increased release of somatostatin causes gallstones, diarrhea and fat malabsorption resulting in steatorrhea.
Non functional islet cell tumor- These do not produce any hormones, symptoms depend on the size and metastasis. 
- Insulinoma - hypoglycemia due to decreased glucose synthesis in liver.
- Gastrinoma - Zollinger-Ellison syndrome, in which hypersecretion of gastrin causes hydrochloric acid release which causes peptic ulcers.
- Glucagonoma - hyperglucagonemia, zinc deficiency, fatty acid deficiency, hypoaminoacidemia that may cause necrolytic migratory erythema.
- VIPoma - Elevated serum VIP levels leads to increased intracellular cAMP which causes increased intestinal secretion of water along with Na+, K+, HCO3 -, and Cl- in the intestinal lumen, causing diarrhea and hypokalemia.
- Somatostatinoma - increased release of somatostatin causes gallstones, diarrhea and fat malabsorption resulting in steatorrhea.
- Non functional islet cell tumor- These do not produce any hormones, symptoms depend on the size and metastasis. 
- The tumor cells are usually round with regular bland nuclei which produce large number of secretory granules with diffuse immunoexpression of neuroendocrinemarkers.
- The poorly differentiated neuroendocrine tumor (NET) shows an atypical, sheet-like, diffuse and irregular nuclei, less cytoplasmic secretory granules, and limited biomarker immunoexpression.
- Head of the pancreas is most commonly involved (75% of cases) followed by the tail.
- The most common metastatic sites are the liver, the lymph nodes, and the bones.
- Pancreatic islet cell carcinoma is divided into 3 grades by WHO.
2010 WHO grading system for pNETs

# Causes
There are no established causes of pancreatic islet cell carcinoma but there is an association with MEN 1 syndrome and rarely with Von Hippel-Lindau disease, Neurofibromatosis-1 and Tuberous sclerosis.

# Epidemiology and Demographics
- The incidence of pancreatic islet cell carcinoma is 1 in 100000 people.

## Age
- It mostly occurs in fourth to sixth decades of life.

## Gender
- Its incidence is equal in both males and females.

## Race
- Race has no effect on the incidence.

# Staging
Pancreatic cancer is staged according to the TNM staging system based on the primary tumor, lymph nodes involved and distant metastasis.

# Screening
Screening for pancreatic islet cell carcinoma is not done.

# Natural history, complications and prognosis

## Natural history
- The cancer usually presents with jaundice, light-colored stools, dark urine, pain in the upper or middle abdomen and back, unexplained weight loss, anorexia, fatigue and symptoms according to the hormone produced.
- Patients with VIPoma may progress to develop watery diarrhea, abdominal pain, bloating, nausea, vomiting, skin rash, backache, flushing, and lethargy.
- The symptoms of insulinoma are found in any age group and start with neuroglycopenic symptoms such as altered mental status, visual disturbances, confusion and adrenergic symptoms such as profuse sweating, palpitations and tremors.
- Zollinger Ellison syndrome presents with refractory peptic ulcer disease, severe gastroesophageal reflux disease (GERD), diarrhea, and finally death, mainly due to complications of the refractory peptic ulcer disease.
- Patients with glucagonoma may progress to develop necrolytic migratory erythema, cheilosis, stomatitis, diarrhea, polyuria, and polydipsia.
- Patients with somatostatinoma present with headaches, frequent urination, dry skin and mouth, or feeling hungry, thirsty, tired, or weak, diarrhea, steatorrhea and gallstones.
- If left untreated, patients may progress to develop exocrine pancreatic insufficiency arising from pancreatic duct obstruction leading to malabsorption, malnutrition and cachexia. Dudodenal obstruction and biliary obstruction may cause symptoms of bowel obstruction and jaundice.
- Metastasis may occur to different sites.

## Complications
- Hematemesis
- Anemia
- Duodenal ulcer perforation
- Weight loss
- Seizures
- Coma
- Neuropsychiatric manifestations include depression, dementia, psychosis, and agitation
- Dilated cardiomyopathy
- Cardiac arrest from low blood potassium level
- Dehydration
- Obstructive jaundice can present with features of cholangitis:
- Duodenal obstruction

## Prognosis
Prognosis of pancreatic islet cell carcinoma depends on the following: 
- Whether or not the tumor can be removed by surgery.
- The stage of the tumor, the size of the tumor, whether cancer has spread outside the pancreas.
- The patients general health.
- Whether the tumor has just been diagnosed or has recurred.
- The presence of metastasis is associated with a particularly poor prognosis. Grade 1 and 2 tumor have the most favorable prognosis.
- The 10-year event free survival rate is less than 51.6% with metastasis and 64.3% without metastasis.

# Diagnosis

## Diagnostic findings
- The dynamic spiral CT scan with contrast media (oral and IV) enhancement is the gold standard test for the diagnosis and staging of pancreatic cancer. 
- Morphological changes of the gland
Destruction of the peripancreatic fat and loss of the sharp margins with surrounding structures
Involvement of the regional lymph nodes and adjacent vasculature
Pancreatic ductal dilatation
Pancreatic atrophy
Obstruction of the common bile duct (CBD)
- Morphological changes of the gland
- Destruction of the peripancreatic fat and loss of the sharp margins with surrounding structures
- Involvement of the regional lymph nodes and adjacent vasculature
- Pancreatic ductal dilatation
- Pancreatic atrophy
- Obstruction of the common bile duct (CBD)
- Measuring hormone levels for specific tumor.

## History and symptoms
History includes: 
- episodes of altered mental status/confusion
- Visual disturbances
- Sweating
- Negative history for exogenous insulin or oral hypoglycemic agents such as Sulfonylureas
- Palpitations
- Seizures
- Tremors
- Behavioral disturbances
- Weakness
- Abdominal pain
- Weight loss
- Loss of appetite
- Diarrhea
- Heart burn
- Necrolytic migratory erythema (NME) is a classical symptom observed in patients with glucagonoma and is present in 80% of cases. Associated NME is characterized by the spread of erythematous blisters and swelling across areas subject to greater friction and pressure, including the lower abdomen, buttocks, perineum, and groin.
- Polyuria
- Polydypsia
- Weight loss
- Numbness caused due to hypokalaemia
- Flushing

## Physical examination
- Jaundice
- Excoriations of the skin from unrelenting pruritus
- Pallor 
- Migratory superficial thrombophlebitis (classic Trousseau's syndrome)
- Abdominal distension
- Abdominal tenderness
- Hepatomegaly
- Splenomegaly
- Fluid thrill and percussion depending on ascites
- Erythematous, ring shaped rash that blisters, erodes, and crusts over suggesting necrolytic migratory erythema.
- Ophthalmoscopic exam may be abnormal with findings of cotton wool spots, flame hemorrhage, and dot and blot hemorrhage
- Muscle atrophy may be present
- Altered mental status in insulinoma
- Tremors

# Treatment

## Medical Therapy

### Chemotherapy: 
- Paclitaxel
- Gemcitabine
- Erlotinib
- Streptozocin
- Doxorubicin

### Symptomatic treatment
- Octreotide
- Hepatic artery embolization
- Radiation
- Percutaneous ethanol injection/ Ethanol ablation
- Radiofrequency ablation (RFA)
- Cryoablation

## Surgery
- The different surgical techniques that may be used for resectable pancreatic cancer include pancreaticoduodenectomy (Whipple Procedure), pylorus sparing Whipple procedure, distal pancreatectomy and total pancreatectomy. 
- The method of surgical resectiondepends on the locally invasive characteristics and size of the neoplasm.
- Minimal invasive surgery such as laparoscopic surgery is preferred especially for small tumors.