Cancer of the head of the pancreas.

Periampullary cancer - cancer of the head of the pancreas often develops. It can originate from the head of the gland itself (more often from the epithelium of the ducts than from the cells of the acinus), from the epithelium of the distal parts of the common bile duct, from the ampulla of Vater and the papilla of Vater, and less often from the mucous membrane of the duodenum. Tumors developing from any of these formations cause similar clinical manifestations. Therefore, they are combined into one group under the general name "pancreatic head cancer". However, these tumors differ significantly in their prognosis. Resectability for ampulla cancer is 87%, for duodenal cancer - 47%, and for cancer of the head of the pancreas itself - 22%.

Epidemiology

According to GLOBOCAN 2012 estimates, pancreatic cancer kills more than 331,000 people per year and is the seventh leading cause of cancer death in both sexes. The 5-year survival rate for pancreatic cancer worldwide is estimated to be about 5%.

Pancreatic cancer incidence rates for both sexes were highest in North America, Western Europe, Europe, and Australia/New Zealand. Rates were lowest in Middle Africa and South Central Asia.

There are some gender differences worldwide. For men, the highest risk of pancreatic cancer is in Armenia, the Czech Republic, Slovakia, Hungary, Japan, and Lithuania. The lowest risk for men is in Pakistan and Guinea. For women, the highest rates are in North America, Western Europe, Northern Europe, and Australia/New Zealand. The lowest rates for women are in Central Africa and Polynesia.

Incidence rates for both sexes increase with age; they are highest after age 70. Approximately 90% of all pancreatic cancer cases occur in people over age 55.

Risk factors

Risk factors for tumor development may include smoking, unbalanced diet, history of gastric resection, diabetes mellitus. In some cases, an aggravated family history is revealed, which allows us to think about a possible hereditary predisposition.

Other risk factors:

• Age over 55 years
• Obesity
• Chronic pancreatitis
• Cirrhosis
• Helicobacter pylori infection
• Exposure to chemicals when working in the chemical and metalworking industries

10% have a genetic cause such as genetic mutations or association with syndromes such as Lynch syndrome, Peutz-Jeghers syndrome, von Hypohl Lindau syndrome, MEN1 (multiple endocrine neoplasia type 1).

Possible risk factors include excessive alcohol consumption, coffee, insufficient physical activity, high red meat consumption, and two or more soft drinks per day.

Pathogenesis

In many cases of pancreatic cancer, mutations in the K-ras gene, particularly in codon 12, are detected relatively frequently compared with other tumors. The mutation can be detected by polymerase chain reaction on paraffin sections of formalin-fixed tissue and material obtained by needle biopsy. In 60% of pancreatic cancers, unusually increased expression of the p53 gene is observed, especially in ductal tumors. These changes are common in other tumors and therefore have no specific significance for understanding pancreatic carcinogenesis. Detection of K-ras mutations in pancreatic ductal brush biopsy material may improve diagnostic efficiency, but at present this method is used mainly for research purposes.

Morphological picture

Histologically, the tumors are adenocarcinomas, whether they originate in the pancreatic ducts or acini or in the bile duct. They are papillary, soft, polyp-like, and often low grade. Histological examination shows fibrosis. In contrast, acinar cell carcinomas are usually large and dense and tend to infiltrate.

Common bile duct obstruction

Obstruction of the common bile duct may be a consequence of tumor invasion, circumferential compression by the tumor, and tumor growth into the lumen of the duct. In addition, a tumor conglomerate may compress the duct.

As a result of obstruction, the bile ducts dilate and the gallbladder enlarges. Ascending cholangitis is rare. Changes characteristic of cholestasis develop in the liver.

Changes in the pancreas

Obstruction of the main pancreatic duct can occur directly in the area of its transition to the ampulla. Ducts and acini located distal to the obstruction site expand, their ruptures lead to the appearance of foci of pancreatitis and fat necrosis. Subsequently, all acinar tissue is replaced by fibrous tissue. Rarely, especially in acinar cell carcinoma, fat necrosis and suppuration can develop not only inside the pancreas, but also in the surrounding tissues.

Diabetes mellitus or decreased glucose tolerance often develops. The cause of this, in addition to the destruction of insulin-producing cells by the tumor, may be the production of amyloid polypeptide in the islet cells adjacent to the tumor.

Tumor spread

Unlike ampullar cancer, acinar pulmonary cancer often infiltrates the head of the pancreas and spreads along the wall of the bile duct. Invasion of the descending part of the duodenum with ulceration of the mucous membrane and secondary bleeding is possible. The tumor can grow into the splenic and portal veins, which entails their thrombosis and the development of splenomegaly.

In almost a third of cases, metastases to regional lymph nodes are detected during surgery. The tumor often spreads along perineural lymphatic pathways. Invasion of the splenic and portal veins can be a source of hematogenous metastases to the liver and lungs. In addition, metastases to the peritoneum and omentum are possible.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ], [ 6 ], [ 7 ], [ 8 ]

Symptoms cancer of the head of the pancreas

In men, pancreatic head cancer occurs twice as often. Mostly people aged 50 to 69 years are affected.

Symptoms of pancreatic head cancer consist of symptoms of cholestasis, pancreatic insufficiency, as well as general and local manifestations of the malignant process.

Jaundice begins gradually and gradually increases; in case of ampullar tumors it may be moderate and intermittent. Itching develops frequently, but not always, and appears after jaundice. Cholangitis develops rarely.

Pain in pancreatic head cancer is not always observed. Pain in the back, epigastric region, right upper quadrant of the abdomen may appear; it is usually constant, intensifies at night, and is sometimes relieved by bending forward. Eating may intensify the pain.

Weakness and weight loss are progressive and usually appear at least 3 months earlier than jaundice.

Although overt steatorrhea rarely develops, patients often complain of intestinal dysfunction (usually diarrhea).

When the tumor spreads to the descending part of the duodenum, vomiting and intestinal obstruction may occur. Ulceration of the duodenum may be accompanied by erosive bleeding, often hidden, less often it manifests itself as bloody vomiting.

Often, difficulties in establishing a diagnosis cause depression in the patient. This may serve as grounds for suspecting a mental illness or neurosis.

The patient is jaundiced, signs of rapid weight loss are visible. Theoretically, the gallbladder should be enlarged and palpable (Courvoisier's symptom). In reality, it is palpable only in half of the cases, although subsequently, during laparotomy, an enlarged gallbladder is detected in three-quarters of patients. The liver is enlarged, its edge is sharp, smooth, dense. Metastases to the liver are rarely detected. A tumor of the pancreas usually cannot be palpated.

The spleen is palpated in cases of splenic vein thrombosis as a result of tumor invasion. Tumor spread to the peritoneum results in ascites.

Metastases to the lymph nodes in pancreatic body cancer are observed more often than in head cancer. However, sometimes an increase in axillary, cervical and inguinal, as well as left supraclavicular (Virchow's gland) lymph nodes is noted.

Occasionally (venous thrombosis is widespread and resembles migratory thrombophlebitis (thrombophlebitis migrans).

Stages

• Stage I: The tumor is in the pancreas and has not spread elsewhere.
• Stage II: The tumor infiltrates the bile duct and other nearby structures, but the lymph nodes are negative.
• Stage III: any positive lymph nodes.
• Stage IVA: metastases to nearby organs such as the stomach, liver, diaphragm, adrenal glands.
• Stage IVB: The tumor has spread to distant organs.

Complications and consequences

Postoperative complications following surgery include pancreatic fistula, delayed gastric emptying, anastomotic leak, bleeding, and infection.

Diagnostics cancer of the head of the pancreas

Laboratory tests for pancreatic head cancer

In 15-20% of cases of pancreatic head cancer, glucosuria develops; glucose tolerance also decreases.

Biochemical blood test. Alkaline phosphatase activity is significantly elevated. In ampullar cancer, amylase and lipase activity are sometimes persistently elevated. Hypoproteinemia is possible, subsequently leading to peripheral edema.

There are no serum tumor markers with sufficient specificity for practical use. The sensitivity of the CA242 tumor marker test is somewhat higher than that of CA19/9, but at early stages of tumor development the results are positive in only half of the cases.

Hematological changes. Anemia is not observed or is weakly expressed. The number of leukocytes may be normal or slightly increased, relative neutrophilia is noted. ESR is usually increased.

Visual diagnostic methods

Ultrasound examination (US) and computed tomography (CT) can detect a volumetric formation up to 2 cm in diameter in the pancreas, as well as dilation of the bile ducts and pancreatic duct, liver metastases and extrahepatic spread of the primary tumor. Although ultrasound is more accessible and its cost is lower, the study can be difficult due to increased gas formation in the intestine. CT is often preferable, and its modern modifications - spiral CT and dynamic CT with high resolution - allow to establish a diagnosis in more than 95% of cases. Currently, no advantages of magnetic resonance imaging have been identified.

Targeted puncture biopsy of a volumetric pancreatic lesion under ultrasound or CT control is safe and allows for diagnosis in 57-96% of patients. The risk of tumor metastasis through the puncture channel is low.

Endoscopic retrograde cholangiopancreatography (ERCP) usually allows visualization of the pancreatic duct and bile ducts, biopsy of the ampulla, collection of bile or pancreatic juice, and brush biopsy of the stricture site for cytologic examination.

The detection of a bile or pancreatic duct stricture strongly suggests a malignancy, but sometimes ERCP results may be inaccurate, requiring morphological examination to establish a diagnosis. It is especially important to detect atypical tumors, such as lymphoma, as they respond to traditional treatments.

In patients who are vomiting, a barium study can assess the degree of invasion and obstruction of the duodenum.

Definition of pancreatic head cancer

Tumor staging is important for assessing resectability. Undoubted evidence of metastasis can be demonstrated by clinical examination, chest radiography, CT, or ultrasound. Dynamic contrast-enhanced CT can establish inoperability of a tumor, but does not provide a definitive assessment of resectability. Dynamic CT can detect vascular invasion but is less useful for assessing underlying tissue invasion and local or distant metastases. Angiography is as effective as dynamic CT in determining resectability; however, occlusion of large vessels, especially when tightly bound by tumor, is a contraindication to surgery. Although the need for angiography has diminished in some specialized centers because of the widespread use of CT, its use before surgery is often useful to clarify vascular anatomy, since vascular anomalies occur in about one third of patients undergoing surgery.

Laparoscopy allows to detect small metastases in the liver, as well as seeding of the peritoneum and omentum and perform a biopsy. If metastases are not detected by laparoscopy, CT and angiography, a favorable outcome of the operation is possible in 78% of patients.

CT portography also allows detection of liver metastases, but is of little use in assessing local changes caused by the pancreatic tumor itself.

Endoscopic ultrasound has been proposed recently. It allows using an endoscope with an ultrasound sensor at the end to visualize the pancreas and surrounding tissues through the wall of the stomach and duodenum. In experienced hands, the accuracy of tumor stage (T) assessment reaches 85%, detection of vascular invasion - 87%, and damage to regional lymph nodes (N) - 74%. Experience in using this method is still limited. The results of the study largely depend on the qualifications of the doctor, and the study itself is time-consuming, so the method has not entered everyday clinical practice.

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Differential diagnosis

The disease should be excluded in all patients over 40 years of age suffering from progressive or even intermittent cholestasis. Persistent abdominal pain, often without an obvious cause, weakness and weight loss, diarrhea, glucosuria, occult blood in the stool, hepatomegaly, palpable spleen or migratory thrombophlebitis indicate the tumor.

Treatment cancer of the head of the pancreas

The decision to perform pancreatoduodenal resection is made based on the results of the patient's clinical examination and imaging methods that allow the cancer stage to be determined. The operation is complicated by limited access to the pancreas, which is located on the back wall of the abdominal cavity near vital organs. Only a small proportion of patients are operable.

The classic version of pancreaticoduodenal resection is the Whipple operation, which is performed in one stage, removing regional lymph nodes, the entire duodenum and the distal third of the stomach. [ 11 ] In 1978, this operation was modified to preserve the function of the pylorus and antrum of the stomach (pylorus-preserving pancreaticoduodenal resection). Due to this, the clinical manifestations of post-gastrectomy syndrome and the frequency of ulcers are reduced, and digestion is improved. Survival is no different from that after the classic operation. To restore the passage of bile, the common bile duct is anastomosed with the jejunum. The duct of the remaining part of the pancreas is also anastomosed with the jejunum. Intestinal patency is restored by duodenojejunostomy.

It is imperative to conduct a study of frozen sections of the edges of resected organs.

The prognosis is determined by the size of the tumor, histologically detected vascular invasion, and the condition of the lymph nodes. The histological picture is most important when examining the lymph nodes. If there are no metastases in them, the five-year survival rate is 40-50%, and if they are detected, it is 8%. The prognosis also depends on the histological signs of vascular invasion (if they are detected, the average life expectancy is 11 months, if they are absent, it is 39 months).

The method of choice for ampulla cancer is also pancreatoduodenal resection. In some cases, local excision of the tumor (ampulectomy) is performed in such patients. In inoperable patients, it is sometimes possible to achieve remission or a decrease in the size of ampulla cancer by endoscopic photochemotherapy. This method involves endoscopic irradiation of the tumor, sensitized by intravenous administration of hematoporphyrin, with red light (wavelength 630 nm).

• Postoperative and rehabilitation care

For patients with stage IV metastatic pancreatic cancer, it is very important to discuss treatment with the patient. Chemotherapy can be done. However, the life extension will be months at best, but this will affect the toxicity and effects of chemotherapy. It is important that nutrition is the focus of the patient, as nutrition can affect wound healing.

Palliative interventions for pancreatic head cancer

Palliative interventions include the creation of bypass anastomoses and endoscopic or percutaneous transhepatic endoprosthetics (stenting).

If vomiting occurs against the background of jaundice due to obstruction of the duodenum, choledochojejunostomy and gastroenterostomy are performed. In case of isolated obstruction of the bile duct, some authors recommend prophylactically applying a gastroenteroanastomosis during the imposition of a biliodigestive anastomosis. However, most surgeons decide this issue based on the size of the tumor and the patency of the duodenum during intraoperative revision.

The choice between surgical and non-surgical treatment depends on the patient's condition and the surgeon's experience.

Endoscopic stenting is successful in 95% of cases (60% on the first attempt); the 30-day mortality rate is lower than with biliodigestive anastomosis. If the endoscopic procedure is unsuccessful, percutaneous or combined percutaneous and endoscopic stenting can be performed.

The results of percutaneous stenting, mortality, and complication rates are similar to those of palliative surgeries; the average survival time of patients after these interventions is 19 and 15 weeks, respectively. Complications of stenting include bleeding and bile leakage. Endoscopic endoprosthetics is less likely to cause complications and death than percutaneous endoprosthetics.

In 20-30% of patients, plastic stents have to be replaced within 3 months after installation due to obstruction by bile clots. Expandable stents made of metal mesh are inserted both endoscopically and percutaneously. These stents remain patent longer than plastic ones (on average 273 and 126 days, respectively). However, given the high cost of such stents, they are installed mainly in those patients with unresectable periampullary cancer, in whom slow tumor growth is noted during replacement of a plastic stent due to blockage and a relatively longer life expectancy is assumed.

Stenting of bile ducts without abdominal incision is especially indicated in elderly patients from high-risk groups who have a large unresectable pancreatic tumor or extensive metastases. In younger patients with unresectable tumors who are expected to have a longer life expectancy, a biliodigestive anastomosis can be used.

According to modern approaches to the treatment of pancreatic head cancer, the patient should not die with unresolved jaundice or suffering from unbearable itching.

Adjuvant treatments for pancreatic head cancer

The results of preoperative chemotherapy and radiotherapy are disappointing. In some cases, improvement can be achieved by using combined radiotherapy and chemotherapy after radical resection. In the case of unresectable tumors, no radiation or chemotherapy regimens have yielded positive results.

Celiac plexus block (percutaneous under X-ray control or intraoperative) can reduce pain for several months, but in more than half of cases it reappears.

Most patients considered potentially resectable for pancreatic cancer should receive neoadjuvant chemotherapy. The two main regimens used are FOLFIRINOX and gemcitabine plus protein-bound paclitaxel.[ 12 ] Many younger, healthier patients with minimal comorbidities are offered FOLFIRINOX (a combination of 5-fluorouracil, oxaliplatin, and irinotecan). This regimen is highly toxic and is only suitable for younger patients. For older and/or less healthy patients, gemcitabine and protein-bound paclitaxel may be offered. Protein-bound paclitaxel is a taxane that is conjugated to albumin and has a lower risk profile than FOLFIRINOX. It should be noted that these two regimens were originally intended for postoperative use. However, these regimens are now being considered pre- and postoperatively. The typical duration of each regimen is 4 to 6 months.[ 13 ]

Pain relief is extremely important. Pancreatic cancer is one of the most painful malignancies. Opioids, antiepileptic drugs, and corticosteroids are effective in relieving pain.

Forecast

The prognosis for pancreatic cancer is unfavorable. After the imposition of a biliodigestive anastomosis, the average survival is about 6 months. The prognosis for acinar cell carcinoma is worse than for ductal carcinoma, since regional lymph nodes are affected earlier. The tumor is resectable in only 5-20% of patients.

The mortality rate after radical surgery is 15-20%, but recently in specialized centers, where many more operations are performed and surgeons have more experience, it has been possible to reduce it to 5%. In a recent report from one specialized center, there were no deaths after 145 pancreatoduodenal resections. However, this is an exceptional case.

In parallel with the reduction in postoperative mortality, the five-year survival rate has increased to 20%. This may reflect earlier diagnosis due to the use of modern imaging methods or may be a consequence of the selection of patients with less widespread lesions for surgery. However, the problem of combating tumor recurrence remains unresolved. Total pancreatectomy does not provide a longer life expectancy compared to the smaller Whipple pancreatoduodenal resection and causes exocrine pancreatic insufficiency and severe diabetes.

Overall, the outlook for pancreatic cancer is poor: in one study of 912 patients, 23 were alive after 3 years and only 2 patients could be considered cured.

The prognosis for ampulla cancer is more favorable, the five-year survival rate after radical surgery for a tumor that does not extend beyond the sphincter of Oddi was 85%, and for more severe invasion - 11-25%. The method of choice is pancreatoduodenal resection. In some cases, local excision of the tumor can be performed.

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