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Pancreatic Adenocarcinoma

Adenocarcinoma of the Pancreas

Pancreatic adenocarcinoma is a type of malignancy affecting the pancreas. It is one of the cancers with the poorest prognosis, due to the fact that it is usually diagnosed at a late stage. The main symptoms include fatigue, weight loss, abdominal pain, and jaundice.

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Presentation

A considerable number of patients diagnosed with pancreatic cancer are simultaneously diagnosed with diabetes mellitus and nearly half of them exhibit decreased glucose tolerance [20] [21]; the inverse observation is not valid, however, in the sense that diabetes precedes pancreatic cancer almost always [22].

PA is a disease that is known to cause no symptomatology until it's advanced stages, which accounts for its high mortality and therapeutic failure. The symptoms it induces are also fairly non-specific and include:

Weight Loss
  • GP is a rare entity that should be suspected in patients with a history of heavy alcohol consumption who complain of chronic abdominal pain and weight loss.[ncbi.nlm.nih.gov]
  • A 35-year-old patient presented at 22 weeks of gestation for back pain and weight loss. Subsequent she was confirmed to have metastatic pancreatic adenocarcinoma. There were in total eleven case reports identified.[ncbi.nlm.nih.gov]
  • A 63-year-old woman presented to the hospital with persistent nausea, dyspepsia and weight loss for 6 months. Abdomen CT showed a low-attenuation mass, approximately 7.6 cm diameter, in the region of the body and tail of the pancreas.[ncbi.nlm.nih.gov]
  • A 33-year-old woman, gravida 1, para 0, was referred at 16 weeks' gestation due to weakness, weight loss and anemia.[ncbi.nlm.nih.gov]
  • The main symptoms include fatigue, weight loss, abdominal pain, and jaundice.[symptoma.com]
Painless Jaundice
  • This patient initially presented with painless jaundice and computed tomography (CT) revealed a mass in the head of the pancreas. Brushings obtained at endoscopic retrograde cholangiopancreatography (ERCP) were positive for adenocarcinoma.[ncbi.nlm.nih.gov]
  • jaundice The majority of pancreatic cancer is incurable at presentation 1 2 Whether or not pancreatic cancer is deemed curable, current surgical, endoscopic, and oncological management regimes can significantly improve quality of life Trials are currently[bmj.com]
  • […] multiple mole melanoma (FAMMM) hereditary pancreatitis ataxia-telangiectasia Peutz-Jeghers syndrome Perhaps surprisingly there is only a weak if at all present association with heavy alcohol consumption 1. pain (most common) Courvoisier’s gallbladder : painless[radiopaedia.org]
  • jaundice and enlarged gallbladder Trousseau’s syndrome : migratory thrombophlebitis new onset diabetes mellitus lipase hypersecretion syndrome (10-15%) 9 polyarthralgia and subcutaneous fat necrosis /- lytic bone lesions elevated serum lipase and eosinophilia[radiopaedia.org]
  • Common presenting symptoms include epigastric pain that radiates to the back, unexplained weight loss, painless jaundice, light clay-colored stools, dark urine, pruritus, nausea, and 10% develop spontaneously appearing and disappearing thromboses. 7,[nature.com]
Malnutrition
  • Six patients suffered from significant morbidities including recurrent cholangitis, second malignancy, malnutrition and bowel perforation. A rare subset of patients with pancreatic cancer achieve long-term survival without resection.[ncbi.nlm.nih.gov]
  • A patient affected by pancreatic cancer may report non-specific symptoms such as weight loss, anorexia, malnutrition, pain in the right upper side of the abdomen, back pain and jaundice.[symptoma.com]
Fever
  • One year after the second procedure, the patient enjoys good health and has been free of fever and abdominal pain and has not received any antibiotic therapy.[ncbi.nlm.nih.gov]
Abdominal Pain
  • GP is a rare entity that should be suspected in patients with a history of heavy alcohol consumption who complain of chronic abdominal pain and weight loss.[ncbi.nlm.nih.gov]
  • Abdominal pain and back pain were the presenting symptoms in 75% and 33.3% of patients respectively. Pancreatic adecnocarcinoma is a rare cancer in pregnancy. A high index of suspicion is required in case of atypical symptoms.[ncbi.nlm.nih.gov]
  • A 70-year-old female was referred to our hospital for dull abdominal pain and tiredness for 1 month. Computed tomography (CT) discovered a 1.0   1.7 cm mass in the area of the left adrenal gland.[ncbi.nlm.nih.gov]
  • One year after the second procedure, the patient enjoys good health and has been free of fever and abdominal pain and has not received any antibiotic therapy.[ncbi.nlm.nih.gov]
  • The main symptoms include fatigue, weight loss, abdominal pain, and jaundice.[symptoma.com]
Nausea
  • A 63-year-old woman presented to the hospital with persistent nausea, dyspepsia and weight loss for 6 months. Abdomen CT showed a low-attenuation mass, approximately 7.6 cm diameter, in the region of the body and tail of the pancreas.[ncbi.nlm.nih.gov]
  • A 70-year-old Caucasian male presented with vague complaints of nausea, vomiting and abdominal distention, with subsequent development of jaundice.[ncbi.nlm.nih.gov]
  • Most patients experienced mild toxicities, including nausea, vomiting, and anorexia. One patient developed grade 3 infection.[ncbi.nlm.nih.gov]
  • Osphyalgia Weight loss Cachexia or malnutrition Jaundice Anorexia Episodes of pancreatitis Nausea Emesis The evolution of imaging modality technology has positively affected the success rates in the diagnosis of pancreatic cancer during the past years[symptoma.com]
  • However, this treatment does have increased toxicity and there is a higher likelihood of experiencing side effects such as poor immunity, nausea and vomiting .[myvmc.com]
Loss of Appetite
  • However, pancreatic cancer can have the following symptoms: Upper abdominal pain that may spread to the back Yellowing of the skin and the whites of the eyes ( jaundice ) Loss of appetite Weight loss Depression Blood clots Cleveland Clinic News & More[my.clevelandclinic.org]
  • Call for an appointment with your provider if you have: Abdominal or back pain that does not go away Persistent loss of appetite Unexplained fatigue or weight loss Other symptoms of this disorder Preventive measures include: If you smoke, now is the time[nlm.nih.gov]
  • They include: loss of appetite unintentional weight loss abdominal (stomach) or lower back pain blood clots jaundice (yellow skin and eyes) depression Pancreatic cancer that spreads may worsen preexisting symptoms.[healthline.com]
  • Other symptoms include weight loss, fatigue, discomfort in the abdomen, loss of appetite, and glucose intolerance. In addition, the patient may experience pain in the abdomen and back.[bioinformatics.org]
  • […] of appetite, changes to bowel habit, diarrhoea, jaundice, nausea and vomiting.[express.co.uk]
Dyspepsia
  • A 63-year-old woman presented to the hospital with persistent nausea, dyspepsia and weight loss for 6 months. Abdomen CT showed a low-attenuation mass, approximately 7.6 cm diameter, in the region of the body and tail of the pancreas.[ncbi.nlm.nih.gov]
  • UK 2 Department of Surgery, St Mark’s Hospital, Harrow, Middlesex Correspondence to: G Bond-Smith gelsmith{at}yahoo.co.uk Accepted 30 March 2012 Summary points Pancreatic cancer can present with non-specific symptoms, such as abdominal or back pain, dyspepsia[bmj.com]
  • Dyspepsia : The feeling of an upset stomach or indigestion. Dyspepsia can result from benign or more serious conditions. Constipation : Having fewer than three bowel movements per week.[webmd.com]
Chronic Abdominal Pain
  • GP is a rare entity that should be suspected in patients with a history of heavy alcohol consumption who complain of chronic abdominal pain and weight loss.[ncbi.nlm.nih.gov]
  • Maged Rizk, director of the Chronic Abdominal Pain Center at the Cleveland Clinic who specializes in gastroenterology and hepatology.[cnn.com]
Jaundice
  • A 70-year-old Caucasian male presented with vague complaints of nausea, vomiting and abdominal distention, with subsequent development of jaundice.[ncbi.nlm.nih.gov]
  • This patient initially presented with painless jaundice and computed tomography (CT) revealed a mass in the head of the pancreas. Brushings obtained at endoscopic retrograde cholangiopancreatography (ERCP) were positive for adenocarcinoma.[ncbi.nlm.nih.gov]
  • CASE REPORT: A 38-year-old man with a synchronous 6-month history of thyroid swelling, presented with epigastric pain and signs of obstructive jaundice.[ncbi.nlm.nih.gov]
  • The main symptoms include fatigue, weight loss, abdominal pain, and jaundice.[symptoma.com]
  • Bond-Smith gelsmith{at}yahoo.co.uk Accepted 30 March 2012 Summary points Pancreatic cancer can present with non-specific symptoms, such as abdominal or back pain, dyspepsia, and unexplained weight loss, as well as the classic presentation of painless jaundice[bmj.com]
Hepatomegaly
  • Patients presenting with or developing advanced intra-abdominal disease may have ascites, a palpable abdominal mass, hepatomegaly from liver metastases, or splenomegaly from portal vein obstruction.[emedicine.medscape.com]
Gallbladder Enlargement
  • Assessing symptoms The physician will pay special attention to common symptoms such as: abdominal or back pain weight loss poor appetite tiredness irritability digestive problems gallbladder enlargement blood clots, deep venous thrombosis ( DVT ), or[medicalnewstoday.com]
Back Pain
  • A 35-year-old patient presented at 22 weeks of gestation for back pain and weight loss. Subsequent she was confirmed to have metastatic pancreatic adenocarcinoma. There were in total eleven case reports identified.[ncbi.nlm.nih.gov]
  • pain, dyspepsia, and unexplained weight loss, as well as the classic presentation of painless jaundice The majority of pancreatic cancer is incurable at presentation 1 2 Whether or not pancreatic cancer is deemed curable, current surgical, endoscopic[bmj.com]
  • A patient affected by pancreatic cancer may report non-specific symptoms such as weight loss, anorexia, malnutrition, pain in the right upper side of the abdomen, back pain and jaundice.[symptoma.com]
  • Back pain is another one, because the pancreas is very posterior in the body. Back pain is also the most common complaint that patients go to an emergency room for, and most of the time it's just muscle pain—it's not pancreatic cancer.[scientificamerican.com]
  • Symptoms can include tummy (abdominal) and back pain, weight loss and changes to bowel habits. Read more about the symptoms of PDAC . Rare exocrine cancers One in a hundred pancreatic cancers (1%) are rare exocrine cancers.[pancreaticcancer.org.uk]
Mid Back Pain
  • Mid-back pain or discomfort Where a bra strap would sit and may be eased by leaning forward. Indigestion Not responding to medication. Pale and smelly stools That don’t flush easily.[pancreaticcanceraction.org]
Pruritus
  • Urine darkening, stool changes, and pruritus are often noticed by patients before clinical jaundice. Pruritus may accompany and often precedes clinical obstructive jaundice. Pruritus can often be the patient's most distressing symptom.[emedicine.medscape.com]
  • Common presenting symptoms include epigastric pain that radiates to the back, unexplained weight loss, painless jaundice, light clay-colored stools, dark urine, pruritus, nausea, and 10% develop spontaneously appearing and disappearing thromboses. 7,[nature.com]
Dark Urine
  • […] either diarrhoea or severe constipation jaundice (yellowish skin and eyes, and dark urine). Less common signs include: severe back pain onset of diabetes (10-20% of people with pancreatic cancer develop diabetes).[cancer.org.au]
  • Symptoms of pancreatic cancer include: Diarrhea Dark urine and clay-colored stools Fatigue and weakness Sudden increase in blood sugar level (diabetes) Jaundice (a yellow color in the skin, mucous membranes, or white part of the eyes) and itching of the[nlm.nih.gov]
  • Often the first signs of pancreatic cancer are long-standing pain that radiates from the upper abdomen through to the back, weight loss , decreased appetite, jaundice (a yellow tinge to the skin and the whites of the eyes), dark urine and pale clay-coloured[myvmc.com]
  • Signs and symptoms of the most common form of pancreatic cancer may include: dark urine yellow skin loss of appetite light-colored stools abdominal or back pain unexplained weight loss Statistics: Pancreatic Cancer The American Cancer Society's most recent[disabled-world.com]

Workup

The evolution of imaging modality technology has positively affected the success rates in the diagnosis of pancreatic cancer during the past years. A computerized tomography scan (CT) or a magnetic resonance imaging scan (MRI) can both be used to diagnose pancreatic cancer and stage the disease, which is a useful tool for the surgeon to develop a proper therapeutic strategy. Other modalities that can be employed include the multi-detector computed tomography (MDCT) and the endoscopic ultrasound (EUS). The latter also allows for tissue sampling, which provides the material for a histological analysis, the gold standard for a definitive diagnosis. A positron emission tomography (PET) scan can also provide useful information under some circumstances [23].

Staging of the disease requires the detection of metastatic disease, the possible locations of metastasis can be identified via the performance of a contrast-enhanced thin slice CT scan [24] [25].

Treatment

Depending on the cancerous progression, different therapeutic interventions can be performed. Accurate staging is required prior to the initiation of any therapeutic regime.

In general, patients with a tumor that is believed to be operable may proceed to a pancreatectomy with or without prior chemotherapy. The administration of chemotherapy is greatly affected by the accuracy of the staging process prior to surgery [25] [26]. Studies have shown that the best prognosis is reserved for those patients who receive neoadjuvant chemotherapy, followed by excision of the malignant tumor [27]. Chemotherapy also contributes to better surgical results if the patient will also need vein resection [28].

On the other hand, progressed disease is always initially treated with the administration of chemotherapy. Patients who are diagnosed with the metastatic disease are faced with an extremely poor prognosis, as the average survival rate ranges between 3 to 6 months. However, tumors that have locally expanded can be downstaged with the administration of chemotherapy to a size that is deemed operable; the prognosis for these patients does not differ from that of the patients who were initially considered good candidates for excision without neoadjuvant chemotherapy [29]. The agents commonly used are Fluorouracil or Gemcitabine.

Prognosis

Pancreatic adenocarcinoma is usually diagnosed at an advanced stage, since in the early stages of the disease, no symptoms are usually produced. Following a pancreaticoduodenectomy, the associated mortality rate is low, approximately 2%, and greatly depends on the experience of the surgeon and the facilities it is carried out in [17] [18]. Even after a successful pancreaticoduodenectomy, complications are frequently reported, including wound infection, delayed gastric emptying, fistulas, cardiac pathologies, abscesses and cholangitis [17].

In general, a surgical intervention aimed at the excision of the pancreatic tumor is followed by a 5-year survival rate of maximum 25%. Prognosis is adversely affected by excessive tumor expansion, poor differentiation and infiltrated lymph nodes. Mutations of the SMAD4 gene are also linked to a higher risk of metastatic disease, even after surgical excision [19].

Etiology

Pancreatic adenocarcinoma is characterized by an etiological analysis that has yet to be clearly defined. A certain genetic background has been proposed, given that a 10% of the patients affected by it also have a family history of pancreatic malignancy [3] [4]. Genes such as BRCA2, STK11, PALB2, and p16/CDKN2 have been identified as playing a role in the pathophysiology of this malignancy, as well as other low-penetrance genes [5] [6] [7] [8] [9]. Other risk factors that have been associated with pancreatic cancer are obesity, alcohol abuse, smoking, family history of this type of cancer and diabetes mellitus.

Epidemiology

PA is in the top five malignancies that are accompanied by the highest mortality rates in the USA [10]. A family history of pancreatic cancer does indeed increase the risk of malignancy in a first-degree relative of the affected person. In addition to familial cases of pancreatic cancer, first-degree relatives of patients who have been diagnosed with sporadic cancer surprisingly also have increased chances of suffering from the same disease [11].

Familial pancreatic cancer exhibits a poor prognosis, as it tends to lead to metastatic or synchronous malignancies in other organs and also evince a greater number of pre-neoplastic lesions [12] [13].

Sex distribution
Age distribution

Pathophysiology

The pancreas is an organ situated in the upper left part of the abdomen, in the region posterior to the stomach. The duality of its function makes it a structure indispensable to the body in order to perform vital functions. It acts an exocrine gland, producing enzymes that facilitate digestion, and an endocrine gland, which partakes in the production of hormones like insulin.

The majority of pancreatic malignancies are generated at the exocrine region of the organ and nearly all of them are identified as pancreatic adenocarcinomas, a type of pancreatic cancer that is known to progress rapidly. The primary issue is that pancreatic cancer causes no symptomatology until the tumor has reached considerable dimensions and the disease is many times too advanced for any treatment option to prove successful [14].

PA is a type of tumor that evolves from primary lesions which may occur at various occasions during the condition's development. Some of these pre-cancerous lesions are:

  • PanIN (Pancreatic intraepithelial neoplasia) is the lesion that precedes most pancreatic malignancies. Three stages have been established (I, II, III), characterized by a progressively greater number of atypical cells [15]
  • Intraductal papillary mucinous neoplasms
  • Mucinous cystic neoplasms

Genetic factors play an important role in the evolution of pancreatic number since a series of events has been found to lead to the final malignancy status. Initially, mutations occur in the K-RAS gene of the epithelial cells in the pancreas, this results in an increased cellular reproduction, with equally increased cellular survival and invasion potential. Later on, the p16 tumor suppressor gene is inhibited, leading to a cellular architectural loss. The deactivation of p53 tumor suppressor gene, which ensues in 70% of the cases, influences apoptosis and DNA repairment procedures and both processes are hindered. The final deviation from the normal genetic pattern includes the deactivation of the SMAD4 gene, which is detected in half of the patients affected by PA. [16]

Prevention

The consumption of foods with low-calorie count has been proven to augment the risks of developing pancreatic cancer. Therefore, every individual is advised to maintain healthy eating habits and follow a diet that contains fruit, vegetables, wholegrain products, and nuts. Consumption of these products leads to lower inflammation signalling and hinders the occurrence of vascular disorders, thus reducing the risks of pancreatic malignancy.

Summary

Pancreatic cancer usually affects the exocrine region of the organ, namely the one responsible for the production of digestive enzymes. The most common type is pancreatic adenocarcinoma (PA), a subtype that rapidly progresses. Pancreatic tumors develop on the ground of other, precursor lesions, the most common being PanINs, which stands for pancreatic intraepithelial neoplasm [1].

Various risk factors have been proposed to contribute to the pathogenesis of pancreatic adenocarcinoma, such as obesity, alcohol abuse, smoking, and diabetes. Even though the exact causes and pathophysiological mechanisms that underlie the disease have not yet been accurately identified, various genetic mutations occur gradually during the course of the disease evolution; each contributes to a specific type of function disruption that ultimately leads to a cancerous tumor [2]. More specifically:

  • K-RAS mutation is the first to occur. Disrupts the apoptotic process and DNA repair.
  • Inactivation of tumor suppressor genes, such as TP53 and p16/CDKN2A, ensues and leads to a loss of cellular architecture.
  • Inactivation of SMAD4 occurs in the final stages and in almost half of the patients.

Pancreatic adenocarcinoma is asymptomatic until a progressed stage has been reached; this accounts for the delayed diagnosis and the high mortality rates that accompany the disease, even after proper treatment has been administered. The symptoms that originate from pancreatic cancer are non-typical - fatigue, weight loss, anorexia, jaundice, abdominal pain, and osphyalgia.

PA is diagnosed with imaging modalities, such as an endoscopic ultrasound, a magnetic resonance imaging scan or a computerized tomography scan of the abdomen. Depending on the location and expansion of each tumor, patients may undergo surgical resection, chemotherapy, radiation therapy or a combination of the aforementioned options.

Patient Information

The pancreas is an organ that is situated in the back portion of the abdomen, behind the stomach. It is responsible both for the production of enzymes that, alongside bile, help to digest food. The pancreas is a unique organ whose function cannot be substituted.

Pancreatic cancer is a frequently diagnosed type of cancer. It is one of the top 5 causes of death due to cancer in the United States and every year, it is believed that it leads approximately 250,000 patients to death. This type of malignancy is followed by such mortality rates because the initial stages of the disease lead to no symptoms. Therefore, patients only present for a medical evaluation when the disease has progressed too far; intervention is, therefore, limited and therapeutic success rates are generally low.

Pancreatic cancer usually affects the part of the pancreas that produces digestive enzymes and most cases involve a pancreatic adenocarcinoma (PA). Although its is unknown how the disease is caused or triggered, a genetic predisposition has been established. It is known that first-degree relatives of patients affected by pancreatic cancer and have a family history of the condition have a higher risk of developing the malignancy themselves when compared to the general population. Other risk factors include excessive alcohol consumption and high-calorie intake, obesity, and diabetes. Genetic mutations that occur gradually during the development of the disease have been identified but they are not the actual causes of cancer. Each genetic mutation contributes to a certain abnormality that facilitates the evolution of cancer. Pancreatic malignant tumors develop on the grounds of other, pre-existing tumors.

A patient affected by pancreatic cancer may report non-specific symptoms such as weight loss, anorexia, malnutrition, pain in the right upper side of the abdomen, back pain and jaundice. The disease is diagnosed by a radiologic depiction of the tumors, which can be achieved with an abdominal CT or MRI scan, or an endoscopic ultrasound. When performing the latter, the physician is able to take some samples which can be biopsied, so that a definitive diagnosis can be achieved. The treatment depends on how progressed the disease is. Metastasis implies that the patient cannot be operated on; such people are expected to survive for 3 to 6 more months. On the other hand, patients who can be surgically treated have a better prognosis. Surgery involves a resection of the tumor, with or without a resection of a part of the duodenum. Chemotherapy and radiation therapy are also beneficial under some circumstances.

References

Article

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  2. Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015; 518: 495-501.
  3. Lynch HT, Smyrk T, Kern SE, et al. Familial pancreatic cancer: A review. Semin Oncol. 1996;23:251–275.
  4. Hruban RH, Canto MI, Goggins M, et al. Update on familial pancreatic cancer. Adv Surg. 2010; 44:293–311.
  5. Murphy KM, Brune KA, Griffin C, et al. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: Deleterious BRCA2 mutations in 17%. Cancer Res. 2002;62:3789–3793.
  6. Su GH, Hruban RH, Bansal RK, et al. Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. Am J Pathol. 1999;154:1835–1840.
  7. Lynch HT, Brand RE, Hogg D, et al. Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: The familial atypical mole melanoma-pancreatic carcinoma syndrome. Cancer. 2002;94:84–96.
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Last updated: 2018-06-21 21:28