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The Pancreas > Pancreatic Diseases
PANCREATIC NEOPLASM
Pancreatic and periampullary neoplasms are an heterogeneous group of lesions arising from pancreatic acini, islet cells, pancreatic ducts, common bile duct, ampulla of Vater, and duodenum. Their biological behaviour and the prognosis varies greatly according to the tumor type and tumor stage. The therapy of pancreatic neoplasms is mostly surgical. Click on the above link for more information.

INFLAMMATORY DISEASES
Inflammatory diseases of the pancreas (acute and chronic pancreatitis) are mostly caused by biliary stones and alcohol abuse. Acute pancreatitis has a great variability in severity. Whereas it runs a self-limiting course in most patients, in others it can take a severe form with multi-organ failure. Chronic pancreatitis is characterized by irreversible fibrotic replacement of normal pancreatic tissue. This type of inflammation can lead to chronic abdominal pain and/or impairment of endocrine and exocrine function of the pancreas. Click on the above link for more information.

PERIAMPULLARY NEOPLASMS

OVERVIEW

Ductal adenocarcinoma is by far the most common type of pancreatic neoplasms. It is a very aggressive disease, representing the fourth leading cause of cancer death in the Western world. The risk of developing pancreatic ductal adenocarcinoma increases as people age (the median age at the time of diagnosis is 71), and men are 30% more likely to develop this neoplasm than women. The vast majority of ductal adenocarcinomas is sporadic, only a small fraction being familial.
Ductal adenocarcinoma begins when, because of damage to the DNA, cells in the pancreas start to grow out of control and form a tumor. The genetic and molecular basis of pancreatic ductal adenocarcinoma are still poorly understood and represent the focus of intense research.  
Known risk factors for pancreatic ductal adenocarcinoma are:
  • Age (> 60 years)
  • Male sex
  • Cigarette smoking
  • Alcohol abuse
  • Obesity and diabetes mellitus
  • Chronic pancreatitis
  • Other pancreatic neoplasms
  • Family history of pancreatic cancer
  • Genetic syndromes such as BRCA2 mutation and colonic polyposis
Unfortunately very few of pancreatic ductal adenocarcinomas are found early. Patients usually have poorly specific symptoms or even no symptoms until the cancer has spread to other organs. Routine radiologic investigation (such as ultrasound) or physical examination are not able to detect small tumors. Right now, there are no blood tests to find early cancers of the pancreas. The most common gastrointestinal symptoms associated with pancreatic ductal adenocarcinoma are:
  • Weakness
  • Digestive problems (lack of appetite, dyspepsia; pale, bulky and greasy stools)
  • Epigastric and back pain
  • Weight loss
  • Sudden onset of diabetes mellitus
Cancers that begin in the head of the pancreas usually cause symptoms while they are still fairly small. These include jaundice and duodenal obstruction, which may allow these tumors to be found in an earlier stage.
Jaundice: it is the yellowing of the eyes and skin caused by the buildup of bilirubin in the body. Bilirubin is a dark yellow-brown substance that is made in the liver. Normally, the liver excretes bilirubin into bile, which flows through the common bile duct into the intestines. When the portion of common bile passing within the pancreatic head becomes compressed or infiltrated by the tumor, bile can’t reach the intestines, and the level of bilirubin builds up. The first sign of jaundice is darkening of the urine, which becomes brown in color. Furthermore, a person may notice their stools becoming lighter in color. When bilirubin builds up in the skin, it turns yellow and starts to itch. Of note, pancreatic ductal adenocarcinoma and other tumors arising in the periampullary area, including ampullary cancer and distal cholangiocarcinoma, are not the most common cause of jaundice. Other causes, such as gallstones, hepatitis, and other liver diseases, are much more common.
Intestinal obstruction: the neoplasm may infiltrate the far end of the stomach or the duodenum, partly blocking them. This can cause nausea, vomiting, and pain that tend to be worse after a meal.
Cancers that begin in the body or tail of the pancreas do not compress the biliary duct until they have spread through the pancreas. By this time, the cancer may have also spread beyond the pancreas.
When a pancreatic ductal adenocarcinoma is suspected by a physician, referral to a multidisciplinary team with experience in the field is strongly advised. Estimation of the extent of disease on cross-sectional imaging (tumor staging) is the most important factor in choosing treatment options and predicting a patient’s outlook. A biopsy to be sure about the diagnosis may be also performed.



DIAGNOSTIC WORK-UP AND STAGING

The most widespread and available imaging modality is transabdominal ultrasonography, which is able to identify pancreatic masses. However, ultrasound is poorly accurate in depicting the characteristics of the tumor, because the pancreas is located deep in the abdomen. On ultrasonography, pancreatic ductal adenocarcinoma appears as an hypoechoic mass (darker than the surrounding pancreas). The associated dilation of the common bile duct, when present, is well detectable.
In jaundiced patients, it may be necessary to place a stent (a small tube made of plastic or of metal) to relieving a blocked common bile duct and resolve jaundice. This is usually done through an endoscopic procedure called ERCP (endoscopic retrograde cholangiopancreatography). The procedure consists of two distinct phases:
  • Diagnostic phase: a very small catheter is endoscopically guided through the ampulla of Vater into the common bile duct. A small amount of contrast material is then injected, and x-rays are taken. This dye outlines the bile duct and the pancreatic duct, and shows the site and the morphology of biliary blockage that might be due to pancreatic cancer.
  • Operative phase: a small cut is made on the ampullary orifice (papillotomy), then the stent is passed through the endoscope and is placed into the bile duct. The stent helps keep the common bile duct open and resists compression from the surrounding cancer.
In the course of an ERCP it is possible to perform a brushing biopsy of the common bile duct to check for neoplastic cells, especially if the pancreatic duct has been extensively infiltrated by the pancreatic neoplasms. This type of biopsy is however poorly accurate. ERCP is an invasive procedure which is associated with a specific complication profile, including severe acute pancreatitis. Furthermore, ampullary cannulation may be difficult, and guidewire and stent placement may fail if the bile duct is small or tortuous. In such cases, jaundice can be resolved placing a percutaneous transhepatic biliary drainage (PTBD). A thin catheter is placed percutaneously within the intrahepatic bile ducts until the common bile duct.
The finding of a pancreatic mass suspicious for ductal adenocarcinoma requires high-quality cross-sectional imaging to confirm the radiologic diagnosis and to stage the neoplasm. A staging system is a standardized way in which the cancer care team describes the extent that a cancer has spread, and contains different pieces of information, including:
  • The size of the primary tumor
  • Whether the tumor has spread to nearby organs or vessels
  • Whether the tumor has spread to nearby lymph nodes
  • Whether the tumor has spread (metastasized) to distant organs
Here are described the imaging tests to diagnose and stage pancreatic ductal adenocarcinoma.
  • Contrast-enhanced computed tomography (CT). The CT scan is an x-ray test (it uses ionizing radiations) that produces detailed cross-sectional images of the body. 3D reconstruction softwares allow detailed tumor characterization. CT scans show the pancreas fairly clearly and often can confirm the location of the tumor, which appears hypodense and poorly enhanced. CT scans can also show the organs near the pancreas, as well as lymph nodes and distant organs where the cancer might have spread.
  • Magnetic resonance imaging (MRI). MRI scan use radio waves and strong magnets instead of x-rays. It is a multiplanar imaging modality. MRI is less employed than CT-scan for the staging of pancreatic ductal adenocarcinoma, but it may be very useful when the tumor has a complex morphology (mixed lesion with solid and cystic areas), or when the differential diagnosis with other pancreatic neoplasms is unclear.
  • Contrast-enhanced ultrasonography (CEUS). This is an new imaging technique that involves the use of microbubble contrast agents to show real-time tissue perfusion information. In CEUS examination, ductal adenocarcinoma typically shows poor enhancement during all the dynamic phases. Loco-regional CEUS staging of ductal adenocarcinoma in expert hands is accurate. Both margins and size of the lesion are more visible, improving the detection of vascular infiltration. In addition, CEUS improves hepatic staging.
  • Ecoendoscopic ultrasound (EUS). Endoscopic ultrasound is performed using an ultrasound probe that is attached on the tip of an endoscope. This allows direct vision of the duodenum and of the papillary region as well as a very detailed ultrasonography of the pancreas, which sits next to the duodenum. It is probably better than CT scan for spotting small tumors. If a tumor is seen, a trans-gastric or a trans-duodenal biopsy can be performed during this procedure.
  • Positron-emission tomography (PET). PET-scan involves the use of a very small dose of a intravenous radiotracer (known as 18-fluorodeoxyglucose or FDG). Neoplastic cells absorb large amount of FDG, which is detected by the scanner. These functional images have however insufficient spatial resolution; hence PET-scan is combined with CT-scan (PET-CT) to provide detailed images of the primary tumor. PET-CT may be especially useful for spotting cancer that has spread beyond the pancreas.  
In the diagnostic work-up of pancreatic ductal adenocarcinoma, Ca 19.9 serum levels are often measured. Ca 19.9 is a simple blood test that measures the level of antigens released by pancreatic tumor cells. Ca 19.9 levels are elevated in the blood of many patients with pancreatic ductal adenocarcinoma. However, there are also some non-cancerous conditions that cause a high level of Ca 19.9, such as gallstones, pancreatitis, cystic fibrosis, liver disease, pulmonary and thyroid diseases. Furhermore, Ca 19.9 can be elevated in people with obstruction of the bile ducts, that is the case of many patients with pancreatic ductal adenocarcinoma. On the contrary, in patients who lack the Lewis antigen (a blood type protein on red blood cells), which is about 10% of the Caucasian population, Ca19.9 is not expressed, even in those with large tumors. That’s why Ca 19.9 is not particularly useful as a diagnostic test for pancreatic cancer. After the diagnosis of pancreatic cancer is confirmed and if the individual’s Ca 19.9 level was elevated before treatment, the Ca 19.9 test can be used as a prognostic factor.
Once the radiologic characterization has been obtained (tumor size, relation with peripancreatic vessels, lymph node status, presence of metastases), this information is combined to assign a stage. The current staging is based on the TNM system (tumor/node/metastasis), according to the American Joint Commitee on Cancer (AJCC). Tumor stage is expressed in Roman numerals I through IV. Here are the AJCC stage groups of pancreatic ductal adenocarcinoma (seventh edition, 2010):
  • Stage IA: The tumor is confined to the pancreas and is less than 2 cm in size. It has not spread to nearby lymph nodes or distant sites.
  • Stage IB: The tumor is confined to the pancreas and is larger than 2 cm in size. It has not spread to nearby lymph nodes or distant sites.
  • Stage IIA: The tumor is growing outside the pancreas but not into superior mesenteric artery or celiac trunk. It has not spread to nearby lymph nodes or distant sites.
  • Stage IIB: The tumor is either confined to the pancreas or growing outside the pancreas but not superior mesenteric artery or celiac trunk. It has spread to nearby lymph nodes but not distant sites.
  • Stage III: The tumor is growing outside the pancreas into superior mesenteric artery or celiac trunk. It may or may not have spread to nearby lymph nodes. It has not spread to distant sites.
  • Stage IV: The cancer has spread to distant sites.
Radiologic staging divides pancreatic ductal adenocarcinoma into groups based on whether or not it is likely it can be removed surgically:
  • Resectable disease (stage IA, IB, IIA, IIB)
  • Locally advanced unresectable disease (stage III)
  • Metastatic disease (stage IV)
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RESECTABLE DISEASE

At the time of diagnosis, only about 20% of pancreatic ductal adenocarcinomas appear to be amenable of potentially curative surgical resection.
As seen in the diagnostic work-up and staging section, a pancreatic ductal carcinoma is considered resectable when it doesn’t extend into superior mesenteric artery and/or celiac trunk, and when has not spread in other distant organs (especially liver and lung). Tumor extension into superior mesenteric vein/portal vein is no longer a contraindication to radical surgery, but pancreatic resections with synchronous venous resection are very complex operations associated with increased morbidity.  
Although recent advances of cross sectional imaging allow detailed evaluation of the pancreas, the accuracy of radiologic staging is not 100%. In some cases it may be even hard to stage pancreatic cancer accurately using imaging tests. Therefore, when there is a good chance the tumor can be completely removed, surgery is undertaken, and the surgical exploration still plays the key role for the finally assessment of resectability. Sometimes an unexpected locally advanced or a metastatic disease is found. In this case, the surgeon may continue the operation as a palliative procedure to relieve or prevent symptoms.
However, the anatomy of the tumor is not the whole story. Other patient-related factors are equally as important to the decision-making process. Foremost among these include comorbidities and functional status. Comorbidities refer to other diseases that the patient may suffer from, such as heart disease or diabetes. Functional status refers to nutritional status, the ability to go through a major surgery, and to function independently after the operation. So assessment of resectability requires a complex evaluation of tumor anatomy, age, comorbidities, functional status and the results of a blood test (Ca 19.9) to determine the risk-benefit profile of surgery.
In some cases, neoadjuvant therapy may be advised. Neoadjuvant therapy is medical therapy (chemo or chemo-radiotherapy) administered in resectable or borderline resectable disesase prior to the operation. The rationale for neoadjuvant therapy in pancreatic cancer is multifold. Preoperative therapy may theoretically sterilize peripheral extent of tumor infiltration, decrease tumor volume, and regional nodal disease. Furthermore, patients who receive neoadjuvant therapy are more likely to complete their full course of therapy compared to patients given post-operative chemotherapy. Additionally, neoadjuvant therapy administered to undissected, well-oxygenated tissue may maximize any cytotoxic benefit gained from treatment. Lastly, and perhaps most importantly, patients who exhibit disease progression during their neoadjuvant therapy self-select themselves as poor responders who are least likely to gain benefit from resection and may forego the morbidity of pancreatic resection. Results of studies evaluating the role of neoadjuvant therapy have shown promising results, despite large randomized trials are still lacking.
Formal surgical resections for pancreatic ductal adenocarcinoma include pancreaticoduodenectomy and left pancreatectomy with splenectomy. The goal of surgical resection is a complete tumor clearance, without leaving behind cancer residual. This concept is known as R0 surgery (without residual disease). Furthermore, formal pancreatic resections for cancer include regional lymphadenectomy. The role of extended lymph node dissection is controversial and does not seem to be beneficial. After resection, intraoperative frozen rection of the pancreatic resection margin is performed to rule out microscopic disease residual (R1) in the pancreatic remnant. Extension of the resection, up to total pancreatectomy with splenectomy may be necessary when the resection margin is positive for tumor cells.
The resection specimen is examined by the Pathologist. Histological examination confirms the diagnosis and assigns the pathologic tumor stage (according to the TNM system, AJCC). Although not formally part of the TNM system, other histologic features are of paramount importance. The grade of the cancer (how abnormal the cells look under the microscope) is listed on a scale from G1 to G4, with G1 cancers looking the most like normal cells and having the best outlook. As seen, another important factor is the tumor clearance, whether or not all of the tumor is removed. This is listed on a scale from R0 (where all visible and microscopic tumor was removed) to R2 (where some visible tumor could not be removed). Furthermore, lymph nodes are analyzed to look for cancer involvement (lymph node status). The ratio between positive and total number of lymph nodes harvested (lymph node ratio) has been shown to be of prognostic relevance.
Patients are given chemotherapy or chemo-radiotheraphy after the cancer has been surgically removed to try to eliminate any cancer cells that have been left behind. This type of treatment is called adjuvant treatment, and lowers the chance that the cancer will recur. The Verona Pancreatic Surgery Unit has participated to the ESPAC (European Study group for Pancreatic Cancer) trials, a series of randomized controlled trials that assessed the role of different regimens of chemo- and chemo-radiotherapy.
Patients who underwent a potentially curative pancreatic resection will be enrolled in a strict periodic follow-up, consisting of a detailed clinical examination, cross-sectional imaging, and serum Ca 19.9 measurement.



LOCALLY ADVANCED DISEASE

Pancreatic ductal adenocrcinoma is defined locally advanced (stage III) when has spread to the superior mesenteric artery and/or to the celiac trunk. Adenocarcinoma of the pancreatic head usually spreads to the
superior mesenteric artery
, that supplies with oxygen-rich bood the intestine; tumors of the body-tail of the pancreas spread more often to the
celiac trunk
, whose branches supply the liver, the stomach and the spleen.
When cross-sectional imaging reveals a locally advanced pancreatic ductal adenocarcinoma, it is necessary to obtain a pathologic diagnosis (usually cytologic). The procedure used most often to diagnose pancreatic ductal adenocarcinoma is called a fine needle aspiration biopsy. For this test, a thin needle is inserted through the skin and into the pancreas. Ultrasonography is used to look at the position of the needle and make sure that it is in the tumor. Biopsies can be also performed using endoscopic ultrasound, placing the needle directly through the wall of the stomach or through the duodenum into the tumor. In either case, small tissue samples can be removed through the needle. Tissue samples are then examined under a microscope. The abnormal cells are found and examined by the Pathologist, who decides on a diagnosis.
If the neoplasm has caused symptoms, a palliative treatment may be necessary to relieve them:
  • A plastic or metal stent can be placed endoscopically to relieve the jaundice caused by blocked common bile duct. This is very common in pancreatic head neoplasms. Alternatively, a percutaneous biliary drainage may be placed.
  • If necessary, surgery can reroute the flow of bile from the common bile duct directly into the small intestine, bypassing the pancreas (bypass operation). The stomach connection to the duodenum can be rerouted at this time as well to relieve or prevent duodenal obstruction. Furthermore, intraoperative biopsies may be performed.
The first-line treatment of locally advanced pancreatic ductal adenocarcinoma is medical therapy. Chemotherapy involves the use of medications to kill cancer cells, and may be given intravenously or by mouth. These drugs are usually given in cycles, with alternating periods of treatment and recovery, and may be given alone or in conjunction with radiation therapy (chemo-radiotherapy). The Oncology team chooses the best treatment plan for any given patient. Once the treatment schedule has been completed, re-staging is performed. This involves a detailed clinical examination, the measurement of serum Ca 19.9, and cross-sectional imaging (CT-scan or PET-CT). The results are discussed within our multidisciplinary team. Outcomes after first-line medical treatment for locally advanced pancreatic ductal adenocarcinoma include:  
  • Disease regression (down-staging). This means that the disease has become resectable, at least on the basis of cross-sectional imaging. The Surgeon may decide for surgical exploration, if it is likely the neoplasm can be completely removed surgically. Thanks to new chemotherapy regimens, pancreatic resections performed after disease downstaging are increasingly being reported.
  • Stable disease. This means that no new tumors have developed, and that the neoplasm has not spread to any new regions of the body (in other words, the neoplasm is not getting better or worse). In such a situation, the management is tailored to the single patient, after multidisciplinary discussion. Additional chemotherapy or chemo-radiotherapy may be advised, as well as the inclusion into experimental protocols, including radiofrequency ablation.
  • Disease progression. This means that the tumor has progressed locally (has grown in size) or has spread to other organs of the body (has metastasized). The most common metastatic site is the liver. In such a situation, second-line chemotherapy may be indicated, as well as the inclusion into experimental clinical trials. Radiofrequency ablation may be advised in non-metastatic disease.
In any case, patients will be followed-up and re-evaluated periodically.



METASTATIC DISEASE

Metastatic cancer is cancer that has spread, through the bloodstream or lymphatic system, from the place where it first started to another place in the body. The ability of a cancer cell to metastasize depends on its individual properties; the properties of the noncancerous cells, including immune system cells, present at the original location; and the properties of the cells it encounters in the lymphatic system or the bloodstream and at the final destination in another part of the body. Pancreatic ductal adenocarcinoma most frequently metastasizes to the liver, distant lymph nodes, the peritoneum and the lung (stage IV).

Standard medical treatment for metastatic pancreatic ductal adenocarcinoma typically involves chemotherapy. There appear to be interesting and potentially promising combinations of several two or more conventional medical treatment drug agents which are in practice and under study for the treatment of metastatic pancreatic ductal adenocarcinoma, such as 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX regimen). Additionally, there is a wide range of single-mode medical treatment approaches currently in clinical trials against pancreatic adenocarcinoma. These include some of the newer experimental therapies which are aimed more at molecular targets and at interrupting genetic signaling pathways, newer chemotherapy drug agents, and even vaccines against cancer.
Individualized medical treatment regimens as tailored by expert oncologists involving single agents or combination therapy for metastatic pancreatic ductal adenocarcinoma may prolong survival and quality of life. And finally, clinical trials remain an option.




INFLAMMATORY DISEASES

Acute pancreatitis is an inflammatory disease initiated by intrapancreatic enzyme activation, with variable involvement of other regional tissues or remote organ-systems.
The principal symptom of acute pancreatitis is abdominal pain, localized in the upper quadrants and irradiated to the back. Nausea, vomit and fever may be also present. The course of acute pancreatitis is highly variable, and the clinical evolution often unpredictable. Whereas in the majority of patients the inflammatory process is confined to the pancreas, in other it can take a severe course with multi-organ involvement and increased mortality. According to the Atlanta classification, acute pancreatitis is divided in mild and severe forms:
  • Mild acute pancreatitis (85% of cases) is characterized most of the times by pancreatic oedema, and it is a self-limiting process associated with minimal organ dysfunction and unevenful recovery. Mortality is below 2%, and depends on severe comorbidities.
  • Severe acute pancreatitis (15% of cases) is associated with distant organ failure (respiratory, renal, or hepatic failure) and local complications such as necrosis, abscess or pseudocyst. Sepsis with multi-organ failure may occur, representing the principal cause of death in these patients. Mortality can be as high as 15-20%.
The etiology of acute pancreatitis not associated with disease severity. The principal causes of acute pancreatits include:
  • Gallstones or common bile duct stones (biliary acute pancreatitis)
  • Alcohol abuse (alcoholic acute pancreatitis)
These two types of acute pancreatitis account for 80% of cases. The remaining 20% is caused by other factors, such as:
  • Severe hypertriglyceridemia, hyperparathyroidism, hypercalcemia
  • Mechanic obstruction of main pancreatic duct (e.g. tumors)
  • Pancreatic trauma and iatrogenic causes (post-operative pancreatitis, post-ERCP pancreatitis
  • Drugs
  • Unknown causes
The diagnosis is based on symptoms, measurement of serum amylase, lipase, C-reactive protein and other inflammatory markers, and on cross-sectional imaging (CT-scan, magnetic resonance imaging).
The treatment of acute pancreatitis is initially supportive, according to the episode severity. There are not specific drugs against inflammation of the pancreas. The mainstays of therapy include fasting and enteral nutrition. Antibiotics should be limited to patients with proven infection. In severe cases with organ failure, intensive care is required. Collections and pancreatic necrosis are treated using a step-up approach. The first step is percutaneous drainage. In case of drain failure or development of large infected necrosis associated with clinical worsening, surgical drainage (with minimally invasive techniques or the classic open necrosectomy) is indicated.
If known, the cause of acute pancreatitis should be also treated (e.g. cholecistectomy, ERCP, discontinuation of alcohol intake).
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