What are the other Names for this Condition? (Also known as/Synonyms)

• Neuroendocrine Carcinoma of Pancreas
• Pancreatic Neuroendocrine Carcinoma, NOS
• PNEC (Pancreatic Neuroendocrine Carcinoma)

What is Pancreatic Neuroendocrine Carcinoma? (Definition/Background Information)

• Pancreatic Neuroendocrine Carcinoma (PNEC) is a malignant, aggressive tumor that originates from the neuroendocrine cells. These types of cells are distributed throughout the body
• PNEC is rare and constitutes less than 3% of all pancreatic neuroendocrine tumors. It is seen in adults. This type of malignant tumor can occur in the head, body or tail regions of the pancreas, and may be associated with excess synthesis of adrenocorticotrophic hormone (ACTH)
• The exact cause of Pancreatic Neuroendocrine Carcinoma formation is unknown. However, many factors, such as genetics, smoking, exposure to chemicals, and a previous history of cancer are thought to play a role in its development
• The symptoms of Pancreatic Neuroendocrine Carcinoma may include diarrhea, lump in the abdomen, pain in the back, acid reflux, rashes, easy bruising of skin, and excessive thirst or hunger
• The carcinoma can cause complications, such as weight loss, metastasis to liver and peritoneum, gastrointestinal and biliary tract obstruction (causing jaundice), and diabetes (if sufficient numbers of islet cells of pancreas are destroyed)
• The type, location and size of tumor, overall health of the affected individual, and his/her response to treatment may determine the prognosis for Pancreatic Neuroendocrine Carcinoma

Pancreatic Neuroendocrine Carcinomas may be present as irregular sheets of cells, and frequently exhibit areas of cell death (necrosis). PNECs are classified as the following:

• Small cell NEC of pancreas, which are characterized by 3 distinct features, namely
  • A characteristic arrangement of nuclei known as “nuclear molding”
  • Very little cytoplasm
  • Fine granular (“salt and pepper”) arrangement of nuclear material known as chromatin
• Large cell NEC of pancreas, in which
  • The majority of cells in the tumor are large, with large nuclei
  • A clumping of nuclear material called chromatin is observed, and
  • A “nesting” pattern (islands of cells in a circular pattern) is noted

The pancreas is an important organ of the digestive system.

• Functionally, the pancreas can be divided into 2 parts, namely:
  • Exocrine pancreas, which produces digestive enzymes, and constitute about 95% of this important organ
  • Endocrine pancreas, which secretes hormones such as insulin, glucagon, gastrin, and somatostatin. Insulin and glucagon regulate sugar levels in blood

Pancreatic tumors (benign and malignant) can arise from both the exocrine and the endocrine components of the organ. Most endocrine tumors are benign and develop at a slower rate than exocrine tumors.

• Based on the anatomy of the pancreas, it can be divided into 3 main parts, namely the:
  • Head,
  • Body, and
  • Tail

Pancreatic tumors can affect the head, body, and tail region of the pancreas. Some tumors can affect one region of the pancreas more than the other.

Who gets Pancreatic Neuroendocrine Carcinoma? (Age and Sex Distribution)

• Pancreatic Neuroendocrine Carcinoma is an infrequent form of pancreatic cancer. It forms less than 3% of all pancreatic neuroendocrine tumors
• The cancer is seen in adults and may affect both males and females, belonging to any racial or ethnic background

What are the Risk Factors for Pancreatic Neuroendocrine Carcinoma? (Predisposing Factors)

The underlying cause of Pancreatic Neuroendocrine Carcinoma is unknown at this time, although it is believed that certain factors may increase one’s risk for the condition. However, in general, the risk factors for pancreatic cancer include:

• Advancing age
• Smoking habit
• Exposure to toxic chemicals
• A family history of pancreatic cancer
• Certain genetic syndromes, such as the following:
  • Multiple endocrine neoplasia type 1 (MEN 1), caused by genetic mutations in the MEN1 gene. This condition may increase the risk of tumors in the parathyroid gland, the pituitary gland, and the islet cells of the pancreas
  • Neurofibromatosis, type 1, caused by genetic mutations in the NF1 gene. This syndrome may lead to an increased risk of developing many different types of tumors, such as somatostatinomas
  • Von Hippel-Lindau syndrome, which occurs owing to genetic mutations in the VHL gene. This syndrome may lead to an increased risk of pancreatic cancer and ampullary carcinoma
  • Tuberous sclerosis complex (TSC): It occurs as a result of mutations in the TSC1 and TSC2 genes. This inherited condition predisposes an affected individual to three different types of lesions in the brain, as well as other organs of the body
• Uncontrolled diabetes
• Chronic pancreatitis
• Cirrhosis of the liver
• Infections of the gastrointestinal tract

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Pancreatic Neuroendocrine Carcinoma? (Etiology)

The exact cause of Pancreatic Neuroendocrine Carcinoma development is unknown.

• Research scientists believe that Pancreatic Neuroendocrine Carcinoma develop primarily due to genetic mutations that leads to tumor formation
• The genetic material ‘DNA’ gives instructions to the cell and directs it to proliferate and/or mature into the type of cell that the body needs at each specific location
• Some individuals may be born with a preexisting abnormality in their DNA that predisposes them to certain types of cancer compared to other individuals in the general population
• Some gene mutations that are associated with Pancreatic Neuroendocrine Carcinoma include:
  • MEN1 gene - it codes for the protein menin, a tumor suppressor
  • NF1 gene - it codes for neurofibromin, a tumor suppressor protein
  • TSC1 and TSC2 genes - these tumor suppressor genes code for hamartin and tuberin, respectively. They interact and control cellular growth and size
  • VHL gene - the protein coded for by this gene regulates the removal of proteins no longer required by the cell
  • p53 gene - it plays a role in tumor suppression
  • RB gene - it codes for the retinoblastoma protein and is a tumor suppressor gene
  • ATRX gene - it makes a protein possibly involved in regulation of gene expression through chromatin remodeling
  • DAXX gene - it codes for death domain associated protein, which localizes to several regions within the cell and plays a role in programmed cell death (apoptosis)
• Two genetically distinct types of Pancreatic Neuroendocrine Carcinomas have been reported, thus far with:
  • ATRX and DAXX gene mutations
  • RB and p53 gene mutations (carcinomas with these mutations have a higher proliferation rate)
• However, DNA can be altered or damaged sporadically as well, which causes cells to become malignant (cancerous). DNA damage may trigger the transformation of normal cells into cancerous cells
• Conditions that can cause spontaneous damage to the DNA, resulting in the development of tumors and cancers include:
  • Exposure to certain toxins and poisons, such as some dyes used in tanning hides, industrial chemicals, and cigarette smoke
  • Certain types of bacterial and viral infection

What are the Signs and Symptoms of Pancreatic Neuroendocrine Carcinoma?

The sign and symptoms of Pancreatic Neuroendocrine Carcinoma depend on a number of factors such as:

• Size of the tumor
• Histological type of the tumor
• Whether the tumor is a cyst or a solid mass
• Whether the tumor produces hormones
• Local spread of the tumor
• Rupture of the cystic mass
• Extent of bleeding within the tumor
• Whether the tumor is present as part of a syndrome, in which case, the signs and symptoms associated with the accompanying syndrome may be noted

Typically, the signs and symptoms of Pancreatic Neuroendocrine Carcinoma do not occur until later stages of the disease. The type and severity of symptoms may vary among affected individuals, and include: 

• Anorexia (loss of appetite)
• Jaundice, manifested as yellowing of the skin and white part of the eyes
• Dark urine, also a sign of jaundice
• Pain in the upper part of the abdomen or middle of the back
• Fluid accumulation in the abdomen (ascites), abdominal swelling
• Persistent feeling of abdominal bloating with nausea or vomiting
• Feeling full soon after eating less (having a feeling of satiety after eating less)
• Changes in bowel movements, such as constipation
• Fatty stools
• The formation of blood clots in veins, swelling of legs
• Frequent urination (polyuria), excessive thirst, and blurred vision - all signs of elevated blood sugar levels in the body
• Fatigue, feeling tired easily
• Unintended weight loss
• Confusion
• Depression

If the tumors produce adrenocorticotropic hormone, the following additional symptoms may occur:

• Rashes 
• Easy bruising of skin
• Fatty lump between shoulders and neck
• Weakening of bones
• Increased blood pressure
• Irritability

Some Pancreatic Neuroendocrine Carcinomas may be associated with hypercalcemia, a condition that causes increased levels of calcium in blood. This may result in:

• Bone and muscle pain
• Muscle weakness
• Confusion

Some other features of PNEC tumors include:

• The tumor may present as a single mass or multiple nodules within the organ
• If there is cyst formation, it may occasionally rupture, spilling its contents into the belly
• These tumors are aggressive, meaning that the tumor may spread to local areas

How is Pancreatic Neuroendocrine Carcinoma Diagnosed?

Currently, there is no standard diagnostic method to accurately detect Pancreatic Neuroendocrine Carcinoma during the early stages. However, healthcare professionals and specialists may sometimes incidentally discover a pancreatic tumor when testing for other conditions.

There are a variety of tests that a healthcare provider may use, to detect, locate, and diagnose Neuroendocrine Carcinoma of Pancreas on appearance of the signs and symptoms. These tests and exams include:

• Physical examination and medical history evaluation: Diagnosing Pancreatic Neuroendocrine Carcinomas usually begins with a thorough physical examination and evaluation of complete medical history. During a physical exam, the overall health status and symptoms (such as pain, loss of appetite, and weight loss) of the affected individual are checked
• Computerized tomography (CT) scan of the pancreas: With this radiological procedure, detailed three-dimensional images of structures inside the body are created. CT scans may also be helpful in detecting recurrences, or if PNEC has metastasized to other organs
• Magnetic resonance imaging (MRI) scan of the pancreas: An MRI scan uses magnetic fields that create high-quality pictures of certain body parts, such as tissues, muscles, nerves, and bones. These high-quality images may indicate to a physician if any cancer is present
• In addition, there are certain specific types of MRI scans that can be used in an individual who may have pancreatic cancer. Such radiological procedures include:
  • MR cholangiopancreatography (MRCP): It is a noninvasive test that uses a powerful magnetic field to produce images of soft tissues, bones, organs, and all other internal body structures
  • MR angiography (MRA): It is a noninvasive test that uses a powerful magnetic field to evaluate the blood vessels
• Endoscopic ultrasound (EUS): This is a minimally invasive procedure recommended for individuals who are suspected to have Neuroendocrine Carcinoma of Pancreas. An ultrasound device is inserted through a thin tube (called endoscope) down the stomach and into a part of the small intestine. It uses high-frequency sound waves to generate detailed images of the pancreas
• Endoscopic retrograde cholangiopancreatography (ERCP): A procedure used when an individual has developed symptoms of Neuroendocrine Carcinoma of Pancreas. An ultrasound device is inserted through a thin tube (called endoscope) down the stomach and into the first part of the small intestine. A dye is injected into the pancreas and bile ducts. The movement of the dye is followed through a series of images. A small tissue sample (biopsy) can be collected during this procedure
• Tissue biopsy: A tissue biopsy of the cyst (including the fluid inside the cyst) or mass is performed and sent to a laboratory for a pathological examination. A pathologist examines the biopsy under a microscope. After putting together clinical findings, special studies on tissues (if needed) and with microscope findings, the pathologist arrives at a definitive diagnosis. Examination of the biopsy under a microscope by a pathologist is considered to be gold standard in arriving at a conclusive diagnosis
  • Biopsy specimens are studied initially using Hematoxylin and Eosin staining. The pathologist then decides on additional studies depending on the clinical situation
  • Sometimes, the pathologist may perform special studies, which may include immunohistochemical stains, molecular testing, and very rarely, electron microscopic studies, to assist in the diagnosis
• The tissue for diagnosis can be procured in multiple different ways, and they include:
  • Fine needle aspiration (FNA) biopsy of the pancreatic tumor: A FNA biopsy may not be helpful, because one may not be able to visualize the different morphological areas of the tumor. Hence, a FNA biopsy as a diagnostic tool has certain limitations, and an open surgical biopsy is preferred
  • Core biopsy of the pancreatic tumor
  • Open biopsy of the pancreatic tumor
  • Endoscopic retrograde cholangiopancreatography
• Positron emission tomography (PET): A PET scan is a nuclear medicine imaging technique that generates three-dimensional images to show how tissue and organs are functioning. A small amount of radioactive material may be injected into a vein, inhaled or swallowed. A PET scan is also helpful in detecting recurrences, or if any metastasis (to the surrounding lymph nodes of the pancreas) has occurred
• A number of blood tests can also be helpful in the diagnosis of Pancreatic Neuroendocrine Carcinomas or to help determine the treatment options. These may include:
  • Checking the levels of adrenocorticotropic hormone (ACTH)
  • Checking the levels of calcium in blood
• For Pancreatic Neuroendocrine Carcinomas, genetic testing for the type of mutations within the tumor may help determine the type of therapy to be employed for the affected individual. Extremely aggressive tumors carry p53 and RB gene mutations

The diagnostic tests aid in determining the extent of cancer, based on a system of classification, such as the “AJCC system for staging of pancreatic cancer”.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

Determination of type and extent of cancer:

Once a diagnosis of pancreatic cancer has been made, the extent to which the tumor has spread is assessed, known as staging. The system used most often to stage pancreatic cancer is the American Joint Committee on Cancer (AJCC) TNM system, which is based on 3 key pieces of information.

The TNM classification for different types of pancreatic cancer is given below:

Tumor extent (T):

• TX: The main tumor cannot be assessed
• T0: No evidence of a primary tumor
• Tis: Carcinoma in situ (the tumor is confined to the top layers of pancreatic duct cells). (Very few pancreatic tumors are found at this stage.)
• T1: The cancer has not grown outside the pancreas and is 2 centimeters (cm) (about ¾ inch) or less across.
• T2: The cancer has not grown outside the pancreas but is larger than 2 cm across
• T3: The cancer has grown outside the pancreas into nearby surrounding structures but not into major blood vessels or nerves
• T4: The cancer has grown beyond the pancreas into nearby large blood vessels or nerves

Lymph node spread of cancer (N):

• NX: Nearby (regional) lymph nodes cannot be assessed
• N0: The cancer has not spread to nearby lymph nodes
• N1: The cancer has spread to nearby lymph nodes

Distant spread of cancer (M):

• M0: The cancer has not spread to distant lymph nodes (other than those near the pancreas) or to distant organs such as the liver, lungs, brain, etc.
• M1: The cancer has spread to distant lymph nodes or to distant organs

Stage grouping: Once the T, N, and M categories have been assigned, this information is combined to assign an overall stage in a process called stage grouping. The stages identify tumors that have a similar outlook and are treated in a similar way.

Stage 0 (Tis, N0, M0):

• The tumor is confined to the top layers of pancreatic duct cells and has not invaded deeper tissues. It has not spread outside of the pancreas
• These tumors are sometimes referred to as pancreatic carcinoma in situ or pancreatic intraepithelial neoplasia III (PanIN III)

Stage IA (T1, N0, M0):

• The tumor is confined to the pancreas and is 2 cm across or smaller (T1)
• The cancer has not spread to nearby lymph nodes (N0) or distant sites (M0)

Stage IB (T2, N0, M0):

• The tumor is confined to the pancreas and is larger than 2 cm across (T2)
• The cancer has not spread to nearby lymph nodes (N0) or distant sites (M0)

Stage IIA (T3, N0, M0):

• The tumor is growing outside the pancreas but not into major blood vessels or nerves (T3)
• The cancer has not spread to nearby lymph nodes (N0) or distant sites (M0)

Stage IIB (T1-T3, N1, M0):

• The tumor is either confined to the pancreas or growing outside the pancreas but not into major blood vessels or nerves (T1-T3)
• The cancer has spread to nearby lymph nodes (N1) but not to distant sites (M0)

Stage III (T4, Any, N, M0):

• The tumor is growing outside the pancreas and into nearby major blood vessels or nerves (T4)
• The cancer may or may not have spread to nearby lymph nodes (Any N). It has not spread to distant sites (M0)

Stage IV (Any T, Any N, M1): The cancer has spread to distant sites (M1).

(Source: “The AJCC system for staging pancreatic cancer”; information provided by the American Cancer Society, May 2016)

What are the possible Complications of Pancreatic Neuroendocrine Carcinoma?

Complications of Pancreatic Neuroendocrine Carcinoma may develop as the cancer progresses, and these may include:

• Jaundice owing to biliary tract obstruction
• Abdominal pain due to tumor growth pressing on the nerves in the abdomen
• Gastrointestinal obstruction
• Diabetes, if the tumor destroys enough islet cells of the pancreas
• Weight loss
• Metastases to the liver and lymph nodes
• Recurrence of carcinoma following treatment
• Side effects from the chemotherapy (such as toxicity) and radiation therapy

How is Pancreatic Neuroendocrine Carcinoma Treated?

The treatment methods for detect Pancreatic Neuroendocrine Carcinomas are determined by several factors, such as the type of cancer, how advanced the cancer is, the overall health of the affected individual, as well as his/her personal preference(s). The healthcare provider determines and plan the best course of treatment on a case-by-case basis.

Once the extent of cancer has been determined, the following treatment methods may be employed:

• A debulking surgery to reduce the tumor mass (followed by a combination of chemotherapy and radiation therapy may be employed in some instances)
• The debulking procedure helps the chemotherapy treatment in being more effective, since there is lesser tumor mass left for the drugs to act on

Surgery for tumors located in the pancreatic head: Pancreatoduodenectomy

• A surgical procedure that involves the removal of part of the pancreas, part of the small intestine, and the gallbladder
• This procedure is typically used when the tumor is confined to the head of the pancreas
• The technique is also known as a Whipple procedure

Surgery for tumors in the pancreatic tail and body of the pancreas: Distal pancreatectomy

• A surgical procedure that involves the removal of the lower half or tail end of the pancreas
• Post-operative care is important: A minimal physical activity is advised, until the surgical wound heals

After surgical treatment and post-operative care, the attending healthcare professional/specialist may discuss the details of the cancer with the individual. Based on this, further treatment measures may be required that include:

Chemotherapy: It may be administered before or after the debulking procedure, depending on the individual’s specific circumstances.

• Chemotherapy is a treatment that uses drugs to kill cancer cells. In this treatment, a combination of two or more chemotherapy drugs is generally used
• These drugs may be administered orally (by mouth), or intravenously (through a vein in the arm)
• Chemotherapy may be used in addition to radiation therapy (chemoradiation). Chemoradiation is usually used to treat pancreatic cancers that have spread to surrounding organs, but not to distant body regions
• This combination may also be used after surgery to decrease the risk of cancer recurrence

Radiation therapy:

• Radiation therapy attempts to destroy cancer cells by aiming high-energy beams at the cancer cells
• Radiation therapy can be administered either by a machine placed outside the body (external beam radiation), or internally, by a device positioned directly at, or close to the malignant tumor
• This technique may be used before surgery, to decrease the size of a tumor, thus allowing for its easy removal; or after surgery, to kill the remaining cancer cells
• Radiation therapy and chemotherapy are sometimes used as a combination tool

How can Pancreatic Neuroendocrine Carcinoma be Prevented?

• The US Preventive Services Task Force (USPSTF) currently does not have any recommendation for screening Pancreatic Neuroendocrine Carcinoma for the general population
• However, taking steps to modify certain behavioral/lifestyle choices may help decrease its risk. These measures include:
  • Smoking cessation: Smoking is the most significant risk factor associated with all types of pancreatic cancer. 20% to 30% of all pancreatic cancers develop due to smoking
  • Physical activity: Obesity increases the risk for pancreatic cancers due to increased levels of inflammation in the body, which negatively impacts the overall immunity. Individuals, who participate in a modest amount of physical activity, may decrease their risk
  • Adequate consumption of fruits and vegetables: A healthy diet, low in saturated fats and rich in many fruits and vegetables, may help decrease one’s risk for pancreatic cancer
• Those diagnosed with inherited conditions, such as multiple endocrine neoplasia (MEN) and neurofibromatosis, may develop Neuroendocrine Carcinoma of Pancreas at an earlier age than the normal population. Regular medical screening for tumors in the pancreas may help detect them early, in such individuals
• Individuals with a history of pancreatic cancer in the immediate family may be also recommended to undergo regular health check-ups to detect any abnormality in the pancreas

Due to the metastasizing potential and chances of recurrence of Neuroendocrine Carcinoma of Pancreas, regular medical screening at periodic intervals with blood tests, radiological scans, and physical examinations are often needed, once an individual is diagnosed with the cancer.

What is the Prognosis of Pancreatic Neuroendocrine Carcinoma? (Outcomes/Resolutions)

The prognosis of Pancreatic Neuroendocrine Carcinoma depends upon a set of several factors, which includes:

• Stage of tumor: With lower-stage tumors, when the tumor is confined to site of origin, the prognosis is usually excellent with appropriate therapy. In higher-stage tumors, such as tumors with metastasis, the prognosis is poor
• The surgical resectability of the tumor (meaning, if the tumor can be removed completely)
• Overall health of the individual: Individuals with overall excellent health have better prognosis compared with those with poor health
• Age of the individual: Older individuals generally have poorer prognosis than younger individuals
• Whether the tumor is occurring for the first time, or is a recurrent tumor. Recurring tumors have worse prognosis 
• Response to treatment: Tumors that respond to treatment have better prognosis compared to tumors that do not respond to treatment

Nevertheless, in a majority of cases, Pancreatic Neuroendocrine Carcinoma may not be diagnosed at an early stage, thereby making the prognosis guarded.

Additional and Relevant Useful Information for Pancreatic Neuroendocrine Carcinoma:

• It is estimated that the average lifetime risk of developing Pancreatic Cancer is about 1 in 67 (1.5%)
• Individuals can reduce their risk of developing pancreatic cancer through lifestyle or behavioral changes