Guide Pancreatic Cancer: Pathogenesis, Diagnosis, and Treatment

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Basic and translational research into its pathogenesis has further deepened our understanding of PC. Patients with PC most commonly present with abdominal pain, weight loss, asthenia, and anorexia, with some patients also having jaundice.

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Once a pancreatic mass is detected, contrast-enhanced computed tomography is sufficient to determine the initial stage and decide the treatment options. Contrast-enhanced endoscopic ultrasonography CE-EUS , EUS elastography, or a biopsy of the mass accomplished by EUS-guided fine needle aspiration might help in the early detection of PC, especially for asymptomatic pancreatic masses that cannot be identified by imaging [ 2 ].

In addition, endoscopic retrograde cholangiopancreatography ERCP can provide tissue samples for diagnosis by guiding ductal brushing and lavage [ 2 ]. Currently available serum biomarkers, such as carcinoembryonic antigen and carbohydrate antigen , have been used in clinics for many years; however, their sensitivity is suboptimal.

To date, there are no specific biomarkers for PC [ 2 ]. Novel and more sensitive biomarkers are still needed for early diagnosis of this deadly disease. Surgery remains the only curative therapy for patients with PC. Even so, the impact of pancreatectomy on patient quality of life and long-term survival remains questionable. The surgical approach has evolved from what was, a few decades ago, a high-risk procedure, to a challenging, yet relatively safe, procedure today [ 3 ].

The poor outcomes associated with surgery alone mean that the roles of adjuvant therapies, such as chemotherapy and radiotherapy during or after the surgical procedure, have been extensively evaluated. Patients with stage III borderline resectable cancers should undergo neoadjuvant therapy prior to resection. For over a decade, gemcitabine was the standard first-line treatment for PC.

However, in , Moore et al.

Diagnosis and Management of Pancreatic Cancer

The role of adjuvant radiation therapy is controversial. Compared with chemotherapy alone, chemoradiation showed no survival benefit in patients with locally advanced PC [ 6 ]. Almost all patients will receive subsequent therapies with the inevitable disease progression that follows first-line therapy [ 7 ]. However, minimal data exist on second-line therapies for PC. EUS offers a platform for a wide variety of direct tumor therapies, including the implantation of I seeds [ 8 ], celiac neurolysis [ 9 ], and fiducial placement for stereotactic body radiation therapy [ 10 ]. ERCP is an established endoscopic procedure that is important in elucidating indeterminate biliary structures and preoperative biliary drainage for patients with cancer of the pancreatic head [ 11 ].

Rational incorporation of endoscopic-based therapies into tumor studies may provide new hope for PC patients. Immunotherapy is considered to be a promising treatment for many cancer types [ 12 ]. The use of T cell checkpoints, including cytotoxic T lymphocyte protein 4 and programmed cell death protein 1 PD-1 , has shown much promise in several cancer types. However, PC is a notable exception [ 13 ]. The application of immunotherapy in PC is yet to be explored.

Precision medicine is an emerging concept in oncology that offers improved outcomes by individualizing patient therapy. The complexity of the PC genome indicates that methods to individualize therapy are required.

What Causes Pancreatic Cancer?

Sophisticated analyses using large numbers of tumors have revealed novel insights into PC pathophysiology [ 15 ]. The testing of novel precision medicine therapies by way of clinical trials is encouraged. However, most of these agents were ineffective, possibly because of the high molecular heterogeneity of the disease.

An assessment of biomarkers is needed to identify the potential benefit from targeted therapy, and this may also provide important information to guide the use of precision medicine in clinical practice. The tumor microenvironment has attracted much research interest in the past decade. The pancreatic tumor microenvironment contains an abundant fibrotic stroma, which includes a variety of cell types and extracellular matrix ECM components, such as collagen, fibronectin, hyaluronic acid, and N-acetyl-glucosamine.

The stroma — not just a barrier for cancer cells — is critical in a variety of cellular processes, including tumor formation, invasion, metastasis, and drug resistance in PC. Recent studies have shown that PC stroma is associated with the modification of cancer cell metabolism, immune cell recruitment and the regulation of acinar-to-ductal metaplasia in the progression of PC. However, none of these genes are currently druggable. Several new markers and therapeutic targets have been investigated, including mucins, mesothelin, and heavy metal transporters [ 17 , 18 , 19 ].

Recently, it has been shown that the zinc transporter ZIP4 is overexpressed in PC, and promotes tumor growth, metastasis, and cancer cachexia [ 20 , 21 ]. Targeting ZIP4 might be a novel treatment strategy for PC patients with dysregulated zinc homeostasis. PC remains a challenging disease to treat. Although survival statistics for PC patients are currently bleak, our understanding of the complicated etiology and molecular mechanisms of PC has improved tremendously in recent years.

Early identification of PC is the most desirable objective. Efforts should be made to determine appropriate biomarkers for early tumor detection, and to open new perspectives on immunotherapy.

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  • Precision medicine and multidisciplinary team collaboration should become a trend in the treatment of PC, and will deliver the best therapeutic schedule for individual patients. Cancer statistics, CA Cancer J Clin. Challenges in diagnosis of pancreatic cancer. World J Gastroenterol.

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    Improvement of surgical results for pancreatic cancer. Lancet Oncol. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol. Moore MJ. Brief communication: a new combination in the treatment of advanced pancreatic cancer. Semin Oncol. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: the LAP07 randomized clinical trial.

    Endoscopic ultrasonography-guided interstitial implantation of iodine seeds combined with chemotherapy in the treatment of unresectable pancreatic carcinoma: a prospective pilot study. Regardless of a tumor's location, the most common symptom is unexplained weight loss, which may be considerable. Tumors in the head of the pancreas typically also cause jaundice, pain, loss of appetite , dark urine, and light-colored stools.

    Tumors in the body and tail typically also cause pain. People sometimes have recent onset of atypical type 2 diabetes that is difficult to control, a history of recent but unexplained blood vessel inflammation caused by blood clots thrombophlebitis known as Trousseau sign , or a previous attack of pancreatitis. Medical imaging techniques, such as computed tomography CT scan and endoscopic ultrasound EUS are used both to confirm the diagnosis and to help decide whether the tumor can be surgically removed its " resectability ".

    A biopsy by fine needle aspiration , often guided by endoscopic ultrasound, may be used where there is uncertainty over the diagnosis, but a histologic diagnosis is not usually required for removal of the tumor by surgery to go ahead. CA carbohydrate antigen The most common form of pancreatic cancer adenocarcinoma is typically characterized by moderately to poorly differentiated glandular structures on microscopic examination. There is typically considerable desmoplasia or formation of a dense fibrous stroma or structural tissue consisting of a range of cell types including myofibroblasts , macrophages , lymphocytes and mast cells and deposited material such as type I collagen and hyaluronic acid.

    This creates a tumor microenvironment that is short of blood vessels hypovascular and so of oxygen tumor hypoxia. Pancreatic cancer is usually staged following a CT scan. To help decide treatment, the tumors are also divided into three broader categories based on whether surgical removal seems possible: in this way, tumors are judged to be "resectable", "borderline resectable", or "unresectable".

    Locally advanced adenocarcinomas have spread into neighboring organs, which may be any of the following in roughly decreasing order of frequency : the duodenum , stomach , transverse colon , spleen , adrenal gland , or kidney.

    Very often they also spread to the important blood or lymphatic vessels and nerves that run close to the pancreas, making surgery far more difficult. Apart from not smoking, the American Cancer Society recommends keeping a healthy weight, and increasing consumption of fruits, vegetables, and whole grains , while decreasing consumption of red and processed meat , although there is no consistent evidence this will prevent or reduce pancreatic cancer specifically.

    In the general population, screening of large groups is not considered effective and may be harmful as of A key assessment that is made after diagnosis is whether surgical removal of the tumor is possible see Staging , as this is the only cure for this cancer.

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    Whether or not surgical resection can be offered depends on how much the cancer has spread. The exact location of the tumor is also a significant factor, and CT can show how it relates to the major blood vessels passing close to the pancreas. The general health of the person must also be assessed, though age in itself is not an obstacle to surgery. Chemotherapy and, to a lesser extent, radiotherapy are likely to be offered to most people, whether or not surgery is possible.

    Specialists advise that the management of pancreatic cancer should be in the hands of a multidisciplinary team including specialists in several aspects of oncology , and is, therefore, best conducted in larger centers. Whether or not surgical resection can be offered depends on various factors, including the precise extent of local anatomical adjacency to, or involvement of, the venous or arterial blood vessels, [2] as well as surgical expertise and a careful consideration of projected post-operative recovery. One particular feature that is evaluated is the encouraging presence, or discouraging absence, of a clear layer or plane of fat creating a barrier between the tumor and the vessels.

    Even when the operation appears to have been successful, cancerous cells are often found around the edges " margins " of the removed tissue, when a pathologist examines them microscopically this will always be done , indicating the cancer has not been entirely removed. For cancers involving the head of the pancreas, the Whipple procedure is the most commonly attempted curative surgical treatment. This is a major operation which involves removing the pancreatic head and the curve of the duodenum together "pancreato-duodenectomy" , making a bypass for food from the stomach to the jejunum "gastro-jejunostomy" and attaching a loop of jejunum to the cystic duct to drain bile "cholecysto-jejunostomy".

    It can be performed only if the person is likely to survive major surgery and if the cancer is localized without invading local structures or metastasizing. It can, therefore, be performed only in a minority of cases. Cancers of the tail of the pancreas can be resected using a procedure known as a distal pancreatectomy , which often also entails removal of the spleen. The most common complication of surgery is difficulty in emptying the stomach. In such cases, bypass surgery might overcome the obstruction and improve quality of life but is not intended as a cure. After surgery, adjuvant chemotherapy with gemcitabine or 5-FU can be offered if the person is sufficiently fit , after a recovery period of one to two months.

    In other cases neoadjuvant therapy remains controversial, because it delays surgery. Gemcitabine was approved by the United States Food and Drug Administration FDA in , after a clinical trial reported improvements in quality of life and a 5-week improvement in median survival duration in people with advanced pancreatic cancer. However, the combination of gemcitabine with erlotinib was found to increase survival modestly, and erlotinib was licensed by the FDA for use in pancreatic cancer in This is also true of protein-bound paclitaxel nab-paclitaxel , which was licensed by the FDA in for use with gemcitabine in pancreas cancer.

    A head-to-head trial between the two new options is awaited, and trials investigating other variations continue. However, the changes of the last few years have only increased survival times by a few months. The role of radiotherapy as an auxiliary adjuvant treatment after potentially curative surgery has been controversial since the s. Many clinical trials have tested a variety of treatment combinations since the s, but have failed to settle the matter conclusively. Radiotherapy may form part of treatment to attempt to shrink a tumor to a resectable state, but its use on unresectable tumors remains controversial as there are conflicting results from clinical trials.

    The preliminary results of one trial, presented in , "markedly reduced enthusiasm" for its use on locally advanced tumors. Treatment of PanNETs, including the less common malignant types, may include a number of approaches. The type of surgery depends on the tumor location, and the degree of spread to lymph nodes. For localized tumors, the surgical procedure may be much less extensive than the types of surgery used to treat pancreatic adenocarcinoma described above, but otherwise surgical procedures are similar to those for exocrine tumors.

    The range of possible outcomes varies greatly; some types have a very high survival rate after surgery while others have a poor outlook. As all this group are rare, guidelines emphasize that treatment should be undertaken in a specialized center. For functioning tumors, the somatostatin analog class of medications, such as octreotide , can reduce the excessive production of hormones. Radiation therapy is occasionally used if there is pain due to anatomic extension, such as metastasis to bone.

    Palliative care is medical care which focuses on treatment of symptoms from serious illness, such as cancer, and improving quality of life. Palliative care focuses not on treating the underlying cancer, but on treating symptoms such as pain or nausea, and can assist in decision-making, including when or if hospice care will be beneficial. This alters or, depending on the technique used, destroys the nerves that transmit pain from the abdomen. CPB is a safe and effective way to reduce the pain, which generally reduces the need to use opioid painkillers, which have significant negative side effects.

    Other symptoms or complications that can be treated with palliative surgery are obstruction by the tumor of the intestines or bile ducts. For the latter, which occurs in well over half of cases, a small metal tube called a stent may be inserted by endoscope to keep the ducts draining. Both surgery and advanced inoperable tumors often lead to digestive system disorders from a lack of the exocrine products of the pancreas exocrine insufficiency. These can be treated by taking pancreatin which contains manufactured pancreatic enzymes, and is best taken with food.

    Treatment may involve a variety of approaches, including draining the stomach by nasogastric aspiration and drugs called proton-pump inhibitors or H2 antagonists , which both reduce production of gastric acid. Pancreatic adenocarcinoma and the other less common exocrine cancers have a very poor prognosis , as they are normally diagnosed at a late stage when the cancer is already locally advanced or has spread to other parts of the body. These include both unfavorable genes, where high expression is related to poor outcome, for example C-Met and MUC-1 , and favorable genes where high expression is associated with better survival, for example the transcription factor PELP1.

    Globally pancreatic cancer is the 11th most common cancer in women and the 12th most common in men. The annual incidence of clinically recognized PanNETs is low about 5 per one million person-years and is dominated by the non-functioning types. The earliest recognition of pancreatic cancer has been attributed to the 18th-century Italian scientist Giovanni Battista Morgagni , the historical father of modern-day anatomic pathology , who claimed to have traced several cases of cancer in the pancreas.

    Many 18th and 19th-century physicians were skeptical about the existence of the disease, given the similar appearance of pancreatitis. Some case reports were published in the s and s, and a genuine histopathologic diagnosis was eventually recorded by the American clinician Jacob Mendes Da Costa , who also doubted the reliability of Morgagni's interpretations. By the start of the 20th century, cancer of the head of the pancreas had become a well-established diagnosis. Regarding the recognition of PanNETs, the possibility of cancer of the islet cells was initially suggested in The first case of hyperinsulinism due to a tumor of this type was reported in Zollinger and E.

    Ellison, who gave their names to Zollinger—Ellison syndrome , after postulating the existence of a gastrin-secreting pancreatic tumor in a report of two cases of unusually severe peptic ulcers published in Small precancerous neoplasms for many pancreatic cancers are being detected at greatly increased rates by modern medical imaging. One type, the intraductal papillary mucinous neoplasm IPMN was first described by Japanese researchers in Early operations were compromised partly because of mistaken beliefs that people would die if their duodenum were removed, and also, at first, if the flow of pancreatic juices stopped.

    Later it was thought, also mistakenly, that the pancreatic duct could simply be tied up without serious adverse effects; in fact, it will very often leak later on. In —, after some more unsuccessful operations by other surgeons, experimental procedures were tried on corpses by French surgeons.

    In the German surgeon Walther Kausch was the first to remove large parts of the duodenum and pancreas together en bloc. In it was demonstrated, in operations on dogs, that it is possible to survive even after complete removal of the duodenum, but no such result was reported in human surgery until , when the American surgeon Allen Oldfather Whipple published the results of a series of three operations at Columbia Presbyterian Hospital in New York. Only one of the patients had the duodenum entirely removed, but he survived for two years before dying of metastasis to the liver.

    The first operation was unplanned, as cancer was only discovered in the operating theater. Whipple's success showed the way for the future, but the operation remained a difficult and dangerous until recent decades. The rate of these operations had increased steadily over this period, with only three of them before , and the median operating time reduced from 8. Early-stage research on pancreatic cancer includes studies of genetics and early detection, treatment at different cancer stages, surgical strategies, and targeted therapies , such as inhibition of growth factors , immune therapies , and vaccines.

    A key question is the timing of events as the disease develops and progresses — particularly the role of diabetes , [] [] and how and when the disease spreads. Keyhole surgery laparoscopy rather than Whipple's procedure , particularly in terms of recovery time, is being evaluated. Efforts are underway to develop new drugs, including those targeting molecular mechanisms for cancer onset, [] [] stem cells , [73] and cell proliferation.

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    Archived from the original on 13 November Retrieved 13 November Retrieved 9 September World Health Organization. Chapter 5. Archived from the original PDF on 14 January Retrieved 5 December Defining Cancer". Archived from the original on 25 June Archived from the original PDF on 9 January January 22—24, ". Journal of the Pancreas. Archived from the original on 8 December Retrieved 11 February Clinical Gastroenterology. Retrieved 5 April Retrieved 4 April Archived from the original on 22 October Retrieved 24 November Epidemiology of Chronic Disease.

    Archived from the original on 24 June Annals of Oncology. Archived from the original on 11 October New York: Springer. Archived from the original on 10 September Retrieved 12 June Chapter Cancer of the Pancreas: Surgical Management.


    Cancer and its Management 7th ed. Johns Hopkins Medicine. Archived from the original on 8 October Retrieved 18 November Archived from the original on 9 September Retrieved 7 September Historically, PanNETs have also been referred to by a variety of terms, and are still commonly called "pancreatic endocrine tumors". Current Treatment Options in Oncology. Archived from the original on 5 January Retrieved 5 January Am Fam Physician. Manual of clinical oncology. The Lancet. Manual for Staging of Cancer 2nd ed. American Joint Committee on Cancer.

    Archived PDF from the original on 29 November World Journal of Gastrointestinal Oncology. NHS Choices. National Health Service, England. Archived from the original on 6 November Clinical Therapeutics. Front Physiol. Archived PDF from the original on 18 December Br J Cancer.