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

• Familial Pancreatic Cancer (FPC)
• FPC (Familial Pancreatic Cancer)

What is Inherited Pancreatic Cancers? (Definition/Background Information)

• Inherited Pancreatic Cancer is a general term that is used to describe the occurrence of an abnormally high rate of pancreatic cancers in certain families. It constitutes about 5-10% of all pancreatic cancers diagnosed
• Families are considered to have Inherited Pancreatic Cancer, if at least two first-degree relatives (parents, brothers, sisters, and/or children), or at least three close family members have pancreatic cancer (grandparents, grandchildren, aunts, uncles, nieces, nephews, and/or cousins)
• Having a certain type of gene mutation or a syndrome may increase the risk of Inherited of Familial Pancreatic Cancer (FPC), which is inherited in an autosomal dominant pattern
• Even though the exact mechanism resulting in pancreatic cancer formation is unknown, current research has shown an increased susceptibility when individuals inherit mutations in certain genes
• There are no known methods to prevent Inherited Pancreatic Cancer. Individuals with such cancers may benefit from increased surveillance and regular checkups. However, the surveillance methods are not well-defined and are currently being researched
• A combination of surgical measures, chemotherapy, and radiation therapy may be used in treating Inherited Pancreatic Cancer. With timely and adequate treatment, the prognosis may be improved

Who gets Inherited Pancreatic Cancer? (Age and Sex Distribution)

• Approximately, 5-10% of all diagnosed pancreatic cancer cases belong to Inherited Pancreatic Cancer category
• This cancer type can affect individuals of both male and female genders, of all ethnic groups and races

What are the Risk Factors for Inherited Pancreatic Cancer? (Predisposing Factors)

The risk factors for Inherited Pancreatic Cancer may include:

• Having a family history of pancreatic cancer
  • A history of pancreatic malignancy occurs in a family wherein two or more first-degree relatives (parents, brothers, sisters and children) have been diagnosed with the condition
  • Three or more close relatives (first degree relatives, grandparents, aunts, uncles, nieces, nephews, grandchildren and cousins) are diagnosed with pancreatic malignant tumors and one relative is diagnosed before the age of 50 years
  • If one first-degree relative is diagnosed with pancreatic cancer, the risk for being diagnosed with the same becomes 3-5 times higher than the general population
  • The risk substantially increases with each additional first-degree relative being diagnosed with the cancer. A 30-fold higher risk exists, if 3 members of an individual’s immediate family have the malignancy
• Mutations in the following genes have been implicated:
  • p53 gene
  • BRCA1 gene
  • BRCA2 gene
  • PALB2 gene
  • ATM gene
  • CDKN2A gene
  • APC gene
  • MLH1 gene
  • MSH2 gene
  • MSH6 gene
  • PMS2 gene
  • PRSS1 gene
  • STK11 gene
  • EPCAM gene
• A family history of the following conditions:
  • Hereditary pancreatitis
  • Lynch syndrome
  • Peutz-Jeghers syndrome
  • Familial malignant melanoma and pancreatic cancer (FMM-PC)
  • Hereditary breast and ovarian cancer syndrome (HBOC)
  • Hereditary non-polyposis colorectal cancer (HNPCC)
  • Li-Fraumeni syndrome (LFS)
  • Familial adenomatous polyposis (FAP)

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 Inherited Pancreatic Cancer? (Etiology)

Inherited Pancreatic Cancer is caused by mutations in cells that result in the development of the cancer. Common gene mutations in Inherited Pancreatic Cancer include:

• RAF gene - part of a pathway controlling cell division, movement and death
• p53 gene - plays a role in tumor suppression
• BRCA2 gene - codes for a tumor suppressor protein
• PALB2 gene - codes for a protein possibly involved in tumor suppression
• BRCA1 gene - codes for a tumor suppressor protein
• ATM gene - has instructions for a nuclear protein, which controls the rate of cells’ growth
• CDKN2A gene - this gene provides instructions for synthesis of many proteins, including p16(INK4a) and p14(ARF) proteins. These are tumor-suppressor proteins that prevent cells from dividing abnormally
• APC gene - the protein coded by this gene regulates how and when a cell divides, and also how cells interact/attach with each other
• MLH1 gene - the protein coded by this gene is involved in DNA repair
• MSH2 gene - codes for a protein that corrects mistakes in DNA synthesis
• MSH6 gene - similar to MLH1 and MHS2, this gene also codes for a protein involved in DNA repair
• PMS2 gene - this gene also codes for a protein involved in correcting mistakes made in DNA replication
• PRSS1 gene - codes for an enzyme called cationic trypsinogen; this enzyme is secreted in the pancreas, and cuts certain proteins to small pieces 
• STK11 gene - this gene is also known as LKB1. This gene codes for an enzyme, serine/threonine kinase 11. This enzyme regulates the pace of cell growth, as well as promotes cell death when needed
• EPCAM gene - codes for epithelial cell adhesion molecule, and keeps epithelial cells adhering to each other
• TGFBR2 gene - codes for transforming growth factor beta receptor type 2, and is involved in regulation of growth and development
• VHL gene - the protein coded for by this gene regulates the removal of proteins no longer required by the cell
• MEN1 gene - codes for menin, a tumor suppressor protein
• NF1 gene - codes for neurofibromin, a tumor suppressor protein

The exact mechanism of development of cancer due to the genes mentioned above is not clear. Many of the gene mutation(s) are inherited in an autosomal dominant manner.

Autosomal dominant type of inheritance: In this type of inheritance, a single copy of the defective gene in every cell of an individual is sufficient to cause the condition. An affected individual typically inherits the defective gene copy from an affected parent.

What are the Signs and Symptoms of Inherited Pancreatic Cancer?

The signs and symptoms of Inherited Pancreatic Cancer 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 Inherited Pancreatic Cancer do not occur until later stages of cancer development. 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 and increased abdominal girth
• 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
• Depression

Some of the other features of Inherited Pancreatic Cancer include:

• The tumor may present as a single mass or multiple nodules within the organ
• The tumors can cause para-endocrine signs and symptoms
• If there is cyst formation, it may occasionally rupture, spilling its contents into the belly
• These tumors can be locally aggressive, meaning that the tumor may spread to local areas

How is Inherited Pancreatic Cancer Diagnosed?

Frequently, pancreatic tumors are difficult to detect/diagnose in the early stages. The signs and symptoms can be very similar to other conditions. Since the pancreas is in the peritoneal cavity, behind many organs, there is a lot of space for the tumor to grow (often unnoticed). The following are the diagnostic methods that may be used to detect Inherited Pancreatic Cancer:

• A thorough physical examination and a complete medical history is very important
• Complete blood count with differential
• Blood tests that may involve tumors markers, such as:
  • Carcinoembryonic antigen (CEA)
  • CA 19.9
  • CA 15.3
  • Alpha fetoprotein (AFP)
• Radiological studies that may include:
  • Abdominal ultrasound: A procedure where high-frequency sound waves are used to produce real-time images
  • Endoscopic ultrasound: It is a minimally-invasive procedure that uses high-frequency sound waves to obtain detailed images of the pancreas
  • CT scan of abdomen: It may be helpful in detecting recurrences, or if metastasis to other organs has occurred
  • MRI scan of abdomen: It helps produce high-quality pictures of certain body parts including the tissues, muscles, nerves, and bones
• Additionally, the following magnetic resonance imaging procedures may be used particularly in individuals suspected of having pancreatic tumor/cancer:
  • MR cholangiopancreatography (MRCP)
  • MR angiography (MRA)
• Endoscopic retrograde cholangiopancreatography (ERCP): This technique is used when symptoms of pancreatic cancer are present in the individual. A special equipment and dye injections are used to obtain a series of images. If required, a biopsy sample may also be collected during the procedure
• Invasive diagnostic procedures such as:
  • Laparoscopy: A special device is inserted through a small hole into the abdomen, to visually examine it. If necessary, a tissue sample is obtained for further analysis. Exploration of the abdomen using a laparoscope is called ‘exploratory laparoscopy’
  • Laparotomy: The abdomen is opened through an incision for examination, and if required, a biopsy sample obtained. Exploration of the abdomen using laparotomy procedure is called ‘exploratory laparotomy’
• Tissue biopsy: A tissue biopsy is performed and sent to a laboratory for a pathological examination to the pathologist, who 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

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
• Molecular genetic testing, when there is a family history of pancreatic cancer or syndromes associated with this type of cancer

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 Inherited 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 Inherited Pancreatic Cancer?

The complications due to Inherited Pancreatic Cancer may include the following:

• Gastrointestinal obstruction and biliary tract obstruction (causing jaundice)
• Compression of adjoining organs if the tumor size is large, affecting their function
• Injury to local region
• If the tumor destroys enough islet cells of the pancreas, it can result in diabetes
• The tumor can metastasize to the liver and lymph nodes

How is Inherited Pancreatic Cancer Treated?

The following are treatments methods for Inherited Pancreatic Cancer:

• In most cases, a surgical excision and removal of the entire tumor is the preferred treatment option. This may be followed by radiation therapy and/or chemotherapy
• If the tumor is confined to the pancreas, a Whipple’s surgical procedure can be performed
• If the tumor has metastasized (in many cases, individuals are diagnosed with liver metastasis), then a combination of chemotherapy, radiation therapy, and invasive procedures may be used to treat the tumor
• Other treatment options may include:
  • Chemotherapy-radiotherapy: Where a combination therapy is used to treat the cancer
  • Biological/targeted therapy: It is used to target abnormal cancer cells and reduce the chance of cancer spreading to other parts of the body. Certain living organisms or their products may be used to start an immune reaction that targets the cancer cells and destroys them
• Post-operative care is important: One must maintain minimum activity levels, until the surgical wound heals
• Follow-up care with regular screening and check-ups are important and encouraged

How can Inherited Pancreatic Cancer be Prevented?

Inherited Pancreatic Cancer is a genetic disorder, and there is no definitive prevention measures available currently. Increased surveillance may help in early detection of the tumor.

• It is suggested that individuals with a family history of pancreatic cancer begin screening starting at the age of 50 years
• If a first-degree relative was diagnosed pancreatic cancer, then screening is recommended beginning 10 years earlier than when the said relative was first diagnosed. For example, if the relative got the first diagnosis at 52, a family member should begin screening from age 42 onwards
• Some experts believe that endoscopic ultrasound is the first choice for screening/surveillance for familial forms of pancreatic cancer
• If the individual develops symptoms, endoscopic retrograde cholangiopancreatography (ERCP) with biopsy is the method of choice
• If the endoscopic ultrasound and ERCP show atypical cells, then the possibility of total removal of pancreas (total pancreatectomy) should be considered
• The protocols for early detection of pancreatic cancer are still being established. Researchers are considering endoscopic ultrasound, endoscopic retrograde cholangiopancreatography (ERCP), high-resolution computerized tomography (CT scan) as possible screening tools

Due to the metastasizing potential and chances of recurrence of pancreatic cancer, 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 Inherited Pancreatic Cancer? (Outcomes/Resolutions)

• Inherited Pancreatic Cancers are malignant tumors and the prognosis depends upon a set of several factors, which include:
  • Stage of tumor: With lower-stage tumors, when the tumor is confined to site of origin, the prognosis is usually excellent with appropriate therapy. For 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 an excellent overall health have better prognosis compared to 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 a poorer prognosis 
  • Response to treatment: Tumors that respond to treatment have better prognosis compared to tumors that do not respond so well to treatment
• An early diagnosis and prompt treatment of the tumor generally yields better outcomes than a late diagnosis and delayed treatment
• However, Inherited Pancreatic Cancer is difficult to diagnose/treat, and the prognosis is typically poor
• Regular follow up visits with the healthcare provider are important

Additional and Relevant Useful Information for Inherited Pancreatic Cancer:

It is estimated that the average lifetime risk of developing pancreatic cancer is about 1.5%.