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

• Pancreatic Intra-Epithelial Lesion
• PanIN (Pancreatic Intraepithelial Neoplasia)

What is Pancreatic Intraepithelial Neoplasia? (Definition/Background information)

• Pancreatic Intraepithelial Neoplasia (PanIN) is an abnormality in the pancreatic epithelium, which results in dysplasia of the epithelial lining of the duct. A dysplasia in the epithelium refers to abnormal growth that results in loss of normal tissue organization
• Depending on the extent of dysplasia, PanIN may be classified as
  • PanIN 1A - flat epithelial lesions, minimal changes in cells and the architecture of the epithelial layer
  • PanIN 1b - microscopic changes to cells, flat lesions
  • PanIN 2 - changes to cells more apparent, with flat or raised lesions. Typically, no cell death is observed
  • PanIN 3 - full thickness dysplasia of the epithelial layer, with significant changes in the structure of cells, as well as cell death
• Pancreatic Intraepithelial Neoplasia may be more prevalent in older individuals and those with heterotopic pancreas - where the pancreas grows in a location not typical for its existence, and there may not be normal blood vessel or tissue connections (heterotopic pancreas may or may not be a congenital disorder)
• Additionally, mutation(s) in the KRAS genes are reported to increase the severity of dysplasia in PanIN (36%, 44% and 87% of lesions showed KRAS mutations in PanIN 1A, PanIN 1B, and PanIN 2 and 3, respectively)
• Pancreatic Intraepithelial Neoplasia typically does not present with symptoms. The finding of PanIN is incidental, and detailed tests may be required for an accurate diagnosis
• PanIN 1 and PanIN 2 generally do not require treatment, but the affected individuals are monitored to observe progression, if any
• Surgical excision of PanIN 3 lesions may be necessary, since there is a likelihood of progression of such lesions to pancreatic ductal adenocarcinoma. For this reason, PanIN lesions are also known as precursor lesions to pancreatic ductal adenocarcinoma
• The prognosis is dependent on the stage of PanIN lesions. If treated early, the outcome may be favorable. An early diagnosis and excision of PanIN 3 lesions is typically recommended

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 Intraepithelial Neoplasia? (Age and Sex Distribution)

• Pancreatic Intraepithelial Neoplasia is more prevalent in older individuals, when compared to youngsters
• PanIN is reported in both males and females worldwide

What are the Risk Factors for Pancreatic Intraepithelial Neoplasia? (Predisposing Factors)

The risk factors for Pancreatic Intraepithelial Neoplasia may include:

• A family history of pancreatic cancer
• Advancing age

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 Intraepithelial Neoplasia? (Etiology)

Pancreatic Intraepithelial Neoplasia originates in the epithelial lining of the pancreatic ducts. The epithelial cells undergo disorganization (dysplasia) to varying degrees, and are classified thus:

• PanIN 1A and 1B are characterized by minimal, but distinct alterations to the cells and flat lesions. Such changes may be present in up to 40% of normal pancreas
• PanIN 2 - changes to the epithelial lining are more apparent, with lesion formation. No cell death is observed in such lesions
• PanIN 3 - it is rare in non-cancerous pancreas, and may be a precursor to ductal adenocarcinoma of pancreas

Mutations in KRAS gene:

• The KRAS family of oncogenes code for K-Ras proteins that play a role in regulating cell division
• The KRAS gene is mutated in about 95% of pancreatic ductal adenocarcinomas
• KRAS2 gene mutations have been reported in Pancreatic Intraepithelial Neoplasia, in about 87% of PanIN 3 cases

What are the Signs and Symptoms of Pancreatic Intraepithelial Neoplasia?

Pancreatic Intraepithelial Neoplasia does not typically present with symptoms. However, in some individuals with PanIN 3, the lesions may progress to pancreatic ductal adenocarcinoma. In such cases, the following symptoms may be present:

• 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
• Depression

How is Pancreatic Intraepithelial Neoplasia Diagnosed?

The diagnosis of Pancreatic Intraepithelial Neoplasia is generally incidental, since individuals with PanIN do not present with symptoms. However, once the PanIN lesion is identified, the following may be required to arrive at an accurate diagnosis and rule out pancreatic cancer:

• Physical examination and medical history (personal and family) evaluation
• Computerized tomography (CT) scan of the pancreas: With this radiological procedure, detailed three-dimensional images of structures inside the body are created
• 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 pancreatic 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 pancreatic cancer. 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 pancreatic cancer. 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 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
• Molecular genetic testing of PanIn lesions to check for KRAS gene mutations

• A number of blood tests can also be helpful in the diagnosis of pancreatic cancer or to help determine the treatment options. Such tests may include:

A number of blood tests can also be helpful in the diagnosis of pancreatic cancer or to help determine the treatment options. Such tests may include:

• Liver function blood tests
• Blood tests that may involve tumor markers, such as carcinoembryonic antigen (CEA) and CA 19.9

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.

What are the possible Complications of Pancreatic Intraepithelial Neoplasia?

• Pancreatic Intraepithelial Neoplasia 1A, 1B and 2 do not generally result in complications 
• The lesions of PanIN 3 can increases in size to become large lesions

PanIN 3 can also progress to pancreatic ductal adenocarcinoma. In such cases, the potential complications may include:

• 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 Pancreatic Intraepithelial Neoplasia Treated?

• Pancreatic Intraepithelial Neoplasia grades 1A, 1B and 2 may not require treatment beyond routine and periodic monitoring
• PanIN 3, owing to the possibility of its progression to ductal adenocarcinoma of pancreas, may require a surgical excision and removal of the lesion
  • Surgical excision may not be a preferred option for older individuals, whose pancreatic reserves may be depleted
  • Younger individuals may benefit from resection so that progression to invasive cancer may be prevented
• If PanIN 3 remains undiagnosed resulting in the development of pancreatic ductal adenocarcinoma, surgery, and a combination of chemotherapy, targeted therapy, radiation therapy or biological therapy may be required to treat the cancer

How can Pancreatic Intraepithelial Neoplasia be Prevented?

Presently, no specific methods or guidelines exist for the prevention of Pancreatic Intraepithelial Neoplasia.

• If there is a family history of pancreatic cancer, genetic testing to check for KRAS gene mutations may help detect PanIn lesions early
• Regular medical screening at periodic intervals with blood tests, scans, and physical examinations, particularly for those who have a family history of pancreatic cancer, may be helpful in diagnosing Pancreatic Intraepithelial Neoplasia early

What is the Prognosis of Pancreatic Intraepithelial Neoplasia? (Outcomes/Resolutions)

• The prognosis for Pancreatic Intraepithelial Neoplasia 1A, 1B and 2 may be favorable
• An early diagnosis and prompt treatment may lead to good outcomes for those with PanIN 3
• In many, the PanIN 3 lesions may not be diagnosed till the condition has progressed to pancreatic ductal adenocarcinoma, the outcome of which may depend on the following:
  • The size of the tumor
  • If metastasis has occurred
  • Whether the tumors respond to treatment
  • If the tumor is diagnosed for the first time, or has recurred after treatment

Additional and Relevant Useful Information for Pancreatic Intraepithelial Neoplasia:

• 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