Most pNENs - sporadical. Some individuals may have a genetic predisposition to developing pNENs. But may not be expressed unless it is triggered or activated under certain circumstances, such as due to certain environmental factors. As part of a larger genetic syndrome such as; 1. Multiple endocrine neoplasia type I (MEN1),  2. Von Hippel-Lindau syndrome (VHL) or  3. Neurofibromatosis type I (NF-1).

1. W.P. Rivindu H. Wickramanayake
Group no. 04a
5th Year 1st Semester – 2019 June
Tbilisi State Medical University, Georgia
Pancreatic
Neuroendocrine
Neoplasms (PNENs)

2. Synonyms
• Pancreatic endocrine tumors
• Pancreatic islet cell tumors
• Pancreatic neuroendocrine tumors
• pNET
• Islet cell carcinoma
• Islet cell tumors
Subdivisions
• ACTHoma
• Calcitoninoma
• Gastrinoma
• Glucagonoma
• GRFoma
• Insulinoma
• PPHrPoma
• Ppoma
• Somatostatinoma
• VIPoma

3.  Arise from Islet and Gastrin-producing cells and often produce many hormones.
 Most often in the pancreas
 May appear in other organs, particularly the duodenum, jejunum, and lung.
 These tumors have two general manifestations:
1) Functioning
2) Nonfunctioning
1)Nonfunctioning tumors
- May cause obstructive symptoms of the biliary tract or duodenum, bleeding
into the GI tract, or abdominal masses.
2) Functioning tumors
- Hypersecrete a particular hormone, causing various syndromes.
- Can also occur in multiple endocrine neoplasia, in which tumors or
hyperplasia affects two or more endocrine glands, usually the parathyroid, pituitary,
thyroid, or adrenals.

4.  The exact cause is unknown. Most pNENs - sporadical.
 Some individuals may have a genetic predisposition to
developing pNENs.
 But may not be expressed unless it is triggered or activated
under certain circumstances, such as due to certain
environmental factors.
 As part of a larger genetic syndrome such as;
1. Multiple endocrine neoplasia type I (MEN1),
2. Von Hippel-Lindau syndrome (VHL) or
3. Neurofibromatosis type I (NF-1).
Causes

5.  PNENs seem to affect women slightly more often than men.
 Any ethnic or racial group.
 Usually develop sporadic pNENs between the ages of 30-60.
 When pNENs occur as part of a genetic syndrome,
- They tend to occur during childhood or young adulthood.
 Affect approximately ~1 in 100,000 individuals in the
general population per year.
 Approx. 2-4 percent of all pancreatic neoplasms.
Affected Populations

6. Signs & Symptoms
 Can vary greatly from one person to another even w/ same type of malignancy.
Asymptomatic Neoplasms
 Nonfunctioning pNENs may not cause any symptoms.
 Grow undetected. When detected, they are often quite large.
 More than half are metastasized upon diagnosis.
 Symptoms related to their size and specific location.
 Abdominal pain and an abdominal mass – Most common
 Nausea, diarrhea, indigestion and unintended weight loss.
 Additional - size & bulk --> obstruction/compression of nearby structures.
 Yellowing of the skin (icterus) and Whites of the eyes (jaundice).
 Nonfunctioning pNENs can potentially bleed into the gastrointestinal tract.

7. Symptomatc Neoplasms
 Symptoms of
functional pNENs vary
widely.
 Usually one hormone
is produced more than
the others and
 May have symptoms
relating to the
hormone that is chiefly
produced.

8.  Mostly small and 90% benign.
 The most common form of pancreatic neuroendocrine neoplasms.
 Produce Insulin, a hormone that helps to regulate blood sugar levels by promoting the movement of glucose
(a simple sugar) into cells for energy production or into the liver and fat cells for storage.
 Low blood sugar (hypoglycemia) and slow gain of weight – Most
common
 Can be present for years before a diagnosis is made.
 Untreated hypoglycemia  headaches, visual disturbances,
personality changes, seizures and, in severe cases, coma and death.
 Additional - irritability, confusion, weakness, tremors, loss of
muscular coordination (ataxia), palpitations, a rapid heartbeat
(tachycardia) and excessive sweating (diaphoresis).
 Tx. - Enucleation of the insulinoma, pancreas protective operation.
Insulinomas

9.  Produce gastrin, which stimulates the stomach to release too much acid.
 Abdominal pain, diarrhea, excess fat in the feces (steatorrhea),
backflow of contents of stomach into the esophagus (GE reflux)
 Erosions on the lining of the stomach (peptic ulcers) may bleed.
 Peptic ulcers  an intense, burning sensation in the stomach that
may last from a few minutes to several hours.
 In individuals with gastrinomas, peptic ulcers may keep coming
back even after treatment.
 > 50 % of gastrinomas are malignant and can potentially spread
(metastasize).
 The symptoms would present as Zollinger-Ellison syndrome.
 MEN1, a family cancer syndrome are more likely to be associated
Gastrinomas

10.  Produce glucagon, which increases the amount of glucose in the blood  hyperglycemia.
 Distinct skin rash (dermatitis) usually on the face, stomach or legs.
 Mild diabetes, blood clots may develop, especially in the lungs
potentially causing shortness of breath, cough or pain in the chest.
 Blood clots in extremities  DVT - painful and swollen.
 Anemia, unintended weight loss, and inflammation or sores on the
mucous membrane lining the inside of the mouth (stomatitis).
 Tend to grow quite large and approx. 70% - malignant with the
potential to spread (metastasize).
Glucagonomas

11.  Produce vasoactive intestinal polypeptide, which increases secretions from the
intestines and relaxes certain muscles within the gastrointestinal tract.
 Large amounts of chronic, watery diarrhea that can eventually result
in dehydration, unintended weight loss, and loss of potassium in body
(hypokalemia).
 Abdominal pain and cramping, lethargy, nausea, and flushing or
redness of the face.
 Many are malignant by the first diagnose & already metastasized.
 VIPomas and their associated symptoms may also be known as
Verner-Morrison syndrome or pancreatic cholera.
VIPomas

12.  Produce somatostatin, which inhibits the secretion of other hormones.
 Cause excessive glucose (hyperglycemia) levels in the blood.
 Diabetes mellitus, gallstones (cholelithiasis), diarrhea, unintended
weight loss and excess levels of fat in the feces (steatorrhea).
 Abdominal pain, nausea, and vomiting.
 Most are large and have spread (metastasized) upon diagnosis.
Somatostatinomas
 Produce growth hormone release factor, stimulates production of growth hormone.
 Result in acromegaly, a disorder characterized by abnormal
enlargement of bones of the arms, legs and head.
GRFomas

13.  Produce adrenocorticotropin, stimulates adrenal glands to overproduce cortisol.
 Cortisol is released in response to stressful situations.
 Cortisol increases blood pressure and blood sugar and inhibits the
immune system.
 ACTHomas  Cushing’s syndrome, a disorder characterized by
excessive amounts of weight gain (central obesity).
 Affected individuals may have a round, moon-shaped face, thin, fragile
skin that bruises easily, high blood pressure (hypertension), generalized
muscle weakness, behavioral changes, facial flushing, and weakened
bones that fracture easily (osteoporosis).
ACTHomas

14.  Extremely rare pNENs
 Secrete parathyroid hormone-related protein  hyperparathyroidism
PPHrPomas
Calcitoninomas
 Secrete calcitonin  watery diarrhea and facial flushing
Neurotensinomas
  low blood pressure (hypotension), flushing, diarrhea,
unintended weight loss, and diabetes.
PPoma
 Secrete pancreatic polypeptide, but no any discernable symptoms.

15.  Based upon identification of characteristic symptoms (if
present),
 A detailed patient history,
 A thorough clinical evaluation and
 A variety of specialized tests including
- Advanced imaging techniques (octrotide-scintigraphy,
CT, MRI, PET-CT, PET-MRI),
- Blood tests (Chromogranin A, NETest),
- Biochemical tests, and also
- Biopsies.
Diagnosis

16.  Carcinoid syndrome
- A combination of symptoms, physical manifestations, and
abnormal laboratory chemical findings caused by a carcinoid tumor.
 A carcinoid tumor is an old word for a neuroendocrine neoplasm that
secretes large amounts of serotonin, along with a number of other
active peptides.
 In the gastrointestinal tract and from there may spread (metastasize)
to the liver.
 Sometimes develop in the lung.
 Only about 10% with carcinoid tumors will develop the carcinoid
syndrome.
 Hot, red facial flushing, diarrhea and wheezing.
Differential Diagnosis

17.  Pancreatic adenocarcinoma
 Often w/o early signs or symptoms. When diagnosed it is advanced.
 Pain or discomfort in the upper portion of the abdomen, fatigue,
weakness, nausea, loss of appetite, dark urine, clay-colored stools,
 Yellowing of the skin and whites of the eyes (jaundice).
 Additional - back pain, difficulty sleeping, blood clots, diarrhea and
indigestion.
 Malignant and often spreads (metastasizes) rapidly.
 Carcinoid syndrome occurs when the tumor produces excessive
amounts of serotonin in an individual with liver metastases.
 In patients who have no spread to the liver, the serotonin released by
an intestinal tumor will be broken down to an inactive substance;
thus, carcinoid syndrome does not occur.

18.  Surgery is the treatment of choice.
 Other techniques;
- Hormonal and drug therapy,
- Chemotherapy and
- Supportive therapy.
 In most cases,
these therapies are used in
conjunction with one another.
 Liver therapy
 Investigational therapy
Treatment

19. Surgery
 The only curative therapy for pNENs.
 A variety of different surgical techniques may be used based upon the
size, location and spread of the tumor.
 Such techniques include;
- Removal of only the tumor (enucleation),
- Removal of as much as the tumor as possible (debulking), and
- Removal of tumor, nearby tissue & structures (e.g., a portion of the pancreas).
 If the cancer has spread, surgical removal of affected areas (e.g.,
affected lymph nodes or liver metastases) may be necessary.
 In special cases, liver transplantation may be considered for treatment
of metastasized pNENs.

20.  Radiofrequency ablation
- Uses high energy radio waves to destroy cancer cells.
- A small, thin tube is run through the skin and into the tumor.
- The tip of the tube contains tiny electrodes that release the
high energy radio waves that destroy the tumor cells.
 Cryosurgery (also known as cryoablation)
- Uses extreme cold to destroy cancer cells.
- A metal instrument is passed through the skin and inserted into
the tumor
- where a substance like liquid nitrogen or liquid carbon dioxide
is uses to freeze and destroy the tumor cells.

21.  With somatostatin analogue, a
drug (such as octreotide) that
mimics the effects of somatostatin.
 Somatostatin is a hormone that
blocks the activity of other
hormones in the body.
 Ocetreotide can block the effects of
hormones that are released by
pNENs & has improved symptoms
in most cases with pNENs.
Hormone Therapy

22.  For those who have locally advanced, metastatic, or recurrent
disease, therapy with certain anticancer drugs (chemotherapy) may
also be recommended,
 Possibly in combination with surgical procedures; combination
therapy with multiple chemotherapeutic drugs that have different
modes of action in destroying tumor cells and/or preventing them
from multiplying.
 Afinitor® (everolimus)
- In individuals with unresectable (cannot be treated surgically),
- locally advanced or metastatic disease.
 Afinitor delays tumor growth and reduces the risk of disease
progression.
Chemotherapy

23.  When metastasized to the liver.
 Embolization
- Non-surgical procedure that hampers blood flow in small blood vessels,
thereby decreasing the blood supply to the tumor sites within the liver and can
control disease for some time.
 Chemoembolization
- Chemotherapy drugs, which are directly injected into small blood vessels
that supply tumors with blood.
These procedures block the flow of blood through the hepatic artery, which is
the main artery that supplies blood to the liver & stop tumor growth and reduce
symptoms .
 In some cases, surgical removal of a portion of the liver may be necessary.
 In very rare cases, may require a liver transplant.
Liver Therapy

24.  Reduces symptoms of a disease or minimizes side effects of other
therapies but does not cure or change the course of a disease.
 For example, gastrinomas (which cause an increase in stomach acid
production) can be treated by drugs that block the production of
stomach acid (proton pump inhibitors) such as omeprazole.
 Severe diarrhea in VIPomas may be treated by i.v. replacing fluids
and electrolytes.
 Glucagonomas may have significant loss of essential nutrients,
requiring blood transfusions and/or total parenteral nutrition.
 Somatostatinomas may require supplemental nutrition and should
have their sugar levels monitored.
Supportive Care

25.  Immunotherapy
- is the enhancement or suppression of the body’s natural
immune system to fight disease such as cancer.
- Interferon alpha is a type of immunotherapy that has been
used to treat individuals with pNENs.
 Radioimmunotherapy
- Uses radiation along with cancer-specific antibodies to
attack cancer cells.
 More research is necessary to determine the long-term safety and
effectiveness of these potential therapies for individuals with
pNENs.
Investigational Therapies

26. References;
 https://rarediseases.org/rare-diseases/pancreatic-neuroendocrine-neoplasms-
pnens/
 https://www.us.afinitor.com/
 https://www.clinicaltrials.gov/
 Jensen RT. Endocrine Tumors of the Gastrotintestinal Tract and Pancreas. In:
Harrison’s Endocrinology. Jameson JL, editors. 2006 McGraw-Hill
Companies, Columbus, OH. Pp:367-386.
 Lairmore TC.Islet Cell Tumors of the Pancreas.NORD Guide to Rare
Disorders.Lippincott Williams & Wilkins. Philadelphia, PA. 2003:408-409.
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3845620/
 https://www.pancreaticcancer.org.uk/information-and-support/facts-about-
pancreatic-cancer/types-of-pancreatic-cancer/pancreatic-neuroendocrine-
tumours-pancnets/