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Carcinoma of the Pancreas
Carcinoma of the Pancreas KENNETH W. WARREN, M.D. JOHN W. BRAASCH, M.D. CHARLES W. THUM, M.D.
The pancreas is inaccessible to visual, tactile, and radiologic examination. Richly supplied by vascular and lymphatic channels suitable as pathways for neoplastic spread, it is contiguous with vital structures that cannot be violated. Consequently, it is not surprising that the management of neoplasms of the pancreas is most difficult and requires the highest skill from operating surgeons. Because there are still many misconceptions in the management of malignant pancreatic lesions, it is worthwhile to review our concepts of treatment and emphasize the progress that has been made in reducing the postoperative mortality and morbidity. It is also appropriate to discuss and compare the management of other periampullary malignant tumors since these other lesions have a favorable prognosis following resection for cure and since their precise differentiation from primary carcinoma of the pancreas can be most difficult even at laparotomy.
HISTORY A historical review of the recognition and treatment of carcinoma of the pancreas indicates that progress has been made only in the last 30 years and shows us the direction in which further advances lie. Mondiere,22 who reported two patients in 1836, was the first to describe the gross characteristics of carcinoma of the pancreas. By 1858, Da Costal l had collected 37 patients who died from malignant tumors of the pancreas. Antemortem diagnosis, however, was slow in developing. It remained for Bard and Pic 2 in 1888 to relate autopsy findings in seven patients with the signs and symptoms of the disease. Pain was not mentioned as an important feature until Chauffard7 in 1908 described it as a predominant symptom. The classic sign on physical examination of a palpable, distended gallbladder was noted by Courvoisier9 in 1890. Early attempts at surgical management of carcinoma of the pancreas are summarized by Sauve28 in the French literature. Among early surgeons who were interested in the pancreas was Codivilla,8 who in Surgical Clinics of North America- Vol. 48, No.3, June, 1968
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KENNETH W. WARREN, JOHN W. BRAASCH, CHARLES W. THUM
Gastroduo- .-+---,:.,..r ,",no 1 A.
FIRST OPERATION
SECOND OPERATION
END STAGI
Figure 1. Original illustration of Whipple's operation. (From Whipple, A. 0., et al., Annals of Surgery, 102:765, October, 1935.)
1908 performed an en bloc resection of the head of the pancreas and part of the duodenum. In the American literature, Halsted 17 reported in 1899 the local excision of a periampullary tumor with reimplantation of the biliary and pancreatic ducts. In the years 1912 to 1922, Hirschel,'8 Kausch,20 and TenanPl performed en bloc resections of carcinoma of the ampulla of Vater to include portions of the duodenum, lower bile duct, and head of the pancreas. It remained, however, for Whipple:18 and his associates to develop and popularize a technique that permitted successful resection of carcinomas of the periampullary region (Fig. 1). In the first of three patients reported by Whipple et al.,38 only a local resection of the tumor was performed. In the second and third patients, successively larger amounts of the head of the pancreas and the duodenum were removed. Since Whipple's paper in 1935, the extent of the resection of the
603
CARCINOMA OF THE PANCREAS
duodenum and the stomach has been increased so that now6 removal of the entire duodenum and at least 50 to 70 per cent of the stomach is acceptable and necessary to avoid the development of gastrojejunal ulceration. In the last 30 years, surgeons have also been removing increasing amounts of the pancreatic gland so that now the pancreas is sectioned at the neck at a point convenient for reconstruction of the pancreatic duct outflow tract or at a point appropriate for excision of the malignant lesion with an adequate margin. Whipple,37 in his earlier experience, did not recognize the importance of the preservation of the pancreatic duct outflow, and the stump of the distal pancreas was closed. It soon became apparent that steatorrhea, pancreatic fistulas, and hemorrhage were prevalent postoperatively, leading Hunt,'9 in 1941, to invaginate the cut surface of the pancreas into the jejunum and Zinninger,.' in 1942, to anastomose the pancreatic duct to the jejunum. We will describe further refinements in this technique later in this communication. In the early years, reconstruction of the biliary tract after resection was accomplished by cholecystoenterostomy, with ligation of the distal common duct. Because of leakage of the ligated common duct and because cholecystoenterostomy frequently did not drain the biliary tract, Whipple37 in 1941 recommended choledochojejunostomy as the preferable biliary tract anastomosis. This procedure is in common usage today. Early surgeons favored a two-stage procedure for pancreatoduodenectomy; however, by 1949 Cattell and Pyrtek 6 recognized that some cases were suitable for a one-stage resection. Today, we reserve the two-stage procedure, that of external biliary drainage followed later by the resection, for certain poor-risk patients with high levels of blood bilirubin or cardiorespiratory-renal abnormalities. DIAGNOSIS Periampullary carcinoma and carcinoma of the body and tail of the pancreas have many clinical characteristics in common. However, jaundice is of primary importance in the former and in the latter, abdominal and back pain are the cardinal symptoms. Signs and Symptoms PAIN. Often the initial symptom of carcinoma of the body and tail of the pancreas and periampullary carcinoma, pain is at first typically dull and vague, sometimes localized to the epigastrium, but often extending to the left or right upper quadrants or to the back. At times the pain is initially episodic and related to meals, but later it becomes constant, severe, and extending to the back. Severe pain suggests malignant extension into the posterior parietes around the celiac axis with invasion of its associated neural plexus. WEIGHT Loss. Rapid and severe weight loss is one of the consistent features of carcinoma of the body of the pancreas. 35 It is also one of the most common features of periampullary carcinoma, averaging 15.6
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KENNETH W. WARREN, JOHN W. BRAASCH, CHARLES W. THUM
pounds in patients with carcinoma of the head of the pancreas. It is present in 96 per cent of patients with resectable tumors and often precedes all other symptoms. HEMATEMESIS AND MELENA. Massive gastrointestinal hemorrhage may be caused by pancreatic neoplasia in a variety of ways. Carcinomas of the pancreas may infiltrate the duodenum or the gastric wall causing ulceration and bleeding. They may obstruct the duodenum, thus stimulating acid-pepsin secretion and producing a benign bleeding peptic ulcer. A tumor may cause compression of the portal venous system producing portal hypertension and bleeding esophageal varices. THROMBOPHLEBITIS. There has been controversy regarding the incidence of thrombophlebitis associated with pancreatic carcinoma. Trousseau 32 and Sproupo have suggested that many patients dying from carcinoma of the body or tail of the pancreas have an associated thrombophlebitis. Others3 • 16 have failed to confirm this observation. Migratory thrombophlebitis requires full investigation, but it does not specifically indicate pancreatic carcinoma, nor does it by itself justify a diagnostic laparotomy. DIABETES. Diabetes has long been associated with pancreatic neoplasm. Approximately 50 per cent of patients with malignant disease of the pancreas have hyperglycemia and glycosuria with an abnormal glucose tolerance curve. I. 5 Malignant pancreatic lesions should be considered in any person more than 40 years of age who becomes diabetic. JAUNDICE. Jaundice occurs in 75 per cent of all patients with carcinoma of the pancreas and, depending upon the site of origin, in 35 to 100 per cent of patients with resectable periampullary carcinoma. 35 Associated with jaundice are other signs and symptoms of extrahepatic obstruction of the b\liary tract. These include pruritus, chills and fever, a palpable gallbladder, and hepatic enlargement. In the differentiation of malignant obstructive jaundice from jaundice resulting from hemolysis, intrahepatic hepatocellular disease and intrahepatic obstructive disease, we rely on the many important features of a carefully taken history and precise physical examination. Early in the course of disease in a jaundiced patient, liver function tests can be of great value. We pay particular attention to the alkaline phosphatase, serum bilirubin, cephalin flocculation, and prothrombin time determinations. 34 Table 1 presents the usual patterns of historic information, physical findings, and laboratory results associated with some of the different causes of jaundice.
Diagnostic Adjuncts RADIOLOGY. Wise and Johnston4o have reviewed the radiologic findings in malignant periampullary lesions and have underlined the necessity for close attention to detail in the recognition of small but possibly resectable tumors. The wide duodenal loop with elevation of the distal stomach suggests enlargement of the pancreatic head. However, the wide-loop sign is actually more common in the normal obese indi-
Table 1.
(j
Clinical Features of Various Causes of Jaundice~' CHOLESTATIC DRUG
ACUTE VIRAL HEPATITIS
JAUNDICE
CARCINOMA OF THE COMMON BILE DUCT STONES
PERIAMPULLARY REGION
~
o
History Previous history
Pain Jaundice Weight loss
Contact with hepatitis, injection or transfusion; viral type illness before onset of jaundice None or mild ache over liver Develops rapidly and decreases slowly Slight
.., >oj
Drug ingestion (for Dyspepsia; previous biliary example, chlorpromazine) colic; previous positive cholecystogram None Develops rapidly and decreases slowly Slight
~.... Z o g;
'1:1
>
Epigastric pain or biliary colic Develops slowly; may fluctuate Slight
± Epigastric or back pain
Moderate Sometimes Enlarged; slightly tender
Deep
Develops slowly and progressively Considerable
Z
("J
~ >
CIl
Examination Depth of jaundice Fever Liver Palpable gallbladder Palpable spleen Ascites
Variable At onset Enlarged; slightly tender
Variable At onset Slightly enlarged
Occ asionally In severe cases
Enlarged; non tender Occasionally With peritoneal metastasis
Laboratory Findings Color of feces Urinary urobilinogen Leukocytosis Serum bilirubin, mg. per 100 ml. Serum alkaline phosphatase, KingArmstrong units Transaminase (SGOT)
Variable + Early
Pale
Variable
Clay-colored
Variable
Intermittently pale Occasionally + Often 3-8
Occasionally Rises steadily to 15-20
13-30
Usually >30
Usually >30
Very high, 30-100
Raised considerably
Slightly raised
Normal
Normal Q)
"Adapted from Warren, K. W., and Kune, G. A., Hospital Medicine, 1966.
= ~
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KENNETH W. WARREN, JOHN W. BRAASCH, CHARLES W. THUM
Figure 2. Change in the mucosa of the duodenal loop caused by carcinoma of the head of the pancreas. Note irregularity and destruction of mucosa.
vidual and by itself is of little significance. Of more importance is the appearance of the mucosa on the inner aspect of the loop. Irregularity and either or both destruction and compression (Fig. 2) are the hallmarks of adjacent underlying malignant disease. In the radiologic demonstration of carcinoma of the body and tail of the pancreas, far-advanced tumors may cause compression or displacement of neighboring organs. Thus, the stomach may be displaced anteriorly on barium study, or the kidneys may be displaced inferiorly on the roentgenogram of the abdomen or intravenous pyelogram. Since most patients with malignant periampullary tumors are jaundiced when they first consult a physician, the use of intravenous cholangiography is severely limited. Occasionally, the serum bilirubin level is below 2.5 mg. per 100 mi., and if so, visualization of the common duct is possible and may serve to rule out lesions such as common duct calculi. Several other interesting approaches to the radiographic delineation of the pancreas have been attempted. We are currently evaluating the role of selective celiac axis angiography in the diagnosis of pancreatic tumors and frequently find displacement of the splenic artery and splenic vein (Fig. 3). Another radiographic adjunct is the pancreatic scanning procedure. 4 The gland that is completely involved by tumor or pancreatitis will not be visualized (Fig. 4). The gland partially replaced by tumor or cyst will show a scan defect (Fig. 5). In the past, too much reliance has been placed upon negative findings on gastrointestinal roentgenograms. Unfortunately, to date,
CARCINOMA OF THE PANCREAS
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Figure 3. Displacement of plenic vein on celiac angiogram caused by carcinoma of the head of the pancrea .
selective celiac axis angiography or pancreatic scanning will not reveal malignant tumors of the pancreas until they are incurable surgically. If progress in the current diagnosis of carcinoma of the pancreas is to be made, more reliance must be placed upon the early history, and
Figure 4. Pancreatic scan showing failure to visualize gland when diffusely involved by carcinoma.
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Figure 5. creatic scan.
KENNETH W. WARREN, JOHN W. BRAASCH, CHARLES W. THUM
Partial replacement of pancreas by carcinoma in head, as shown on pan-
abdominal exploration must be performed before persistent abdominal and back pain occur, reflecting invasive cancer. ANALYSIS OF DUODENAL CONTENTS. Laboratory techniques for the determination of pancreatic enzymes and sodium bicarbonate in the duodenal contents have been developed as an aid in the diagnosis of periampullary carcinoma. 1o These tests are based on the effects of obstruction of the duct of Wirsung by the neoplastic tumor. While these tests are occasionally of considerable value, they are time-consuming and supply limited information. The diagnosis of carcinoma of the pancreas, biliary tract, and duodenum using cytologic methods has been reviewed by Raskin and his co-workers.26 These investigators have been able to recover malignant cells in 28 of 43 patients with periampullary neoplasms. We have had no experience with this technique. CLOSED LIVER BIOPSY. Even the most experienced clinical pathologist has difficulty differentiating intrahepatic cholestasis from extrahepatic bile duct obstruction, particularly when the obstruction has been present for a long time. Therefore, the diagnostic accuracy of the interpretation of a closed liver biopsy sample is limited. PREDNISOLONE TEST. The administration of prednisolone, 30 mg. per day for seven days, is at times helpful in the differentiation of intrahepatic cholestatic jaundice from extrahepatic obstructive jaundice. 39 In the former, a rapid fall in level of serum bilirubin is often observed during the first few days of the test. PERCUTANEOUS TRANSHEPATIC CHOLANGIOGRAPHY. When there is a diagnostic problem, percutaneous transhepatic cholangiography is at times useful in the recognition of extrahepatic obstructive jaundice.
CARCINOMA OF THE PANCREAS
609
Experience '3 , 15 has shown that, if bile can be aspirated from the probing cannula, dilation of the intrahepatic biliary tree, and, therefore, organic biliary tract obstruction are indicated. In our experience, this procedure was only rarely helpful, as in most instances in which extrahepatic obstruction was shown by transhepatic cholangiogram, the diagnosis was evident without the test. LAPAROTOMY. Patients should have exploratory operation when an obvious diagnosis of cholestatic jaundice of mechanical etiology is established or when this possibility definitely cannot be excluded by any other technique. However, exploration for obstructive jaundice is never an emergency procedure except in acute suppurative cholangitis.
SURGICAL MANAGEMENT Pancreatoduodenectomy It is important to perform this demanding operative procedure in the following order: (1) Exploration of the abdominal and pelvic cavities; (2) division of the gastrocolic ligament and exploration of the body and tail of the pancreas; (3) mobilization of the head of the pancreas and duodenum with exploration of the periampullary area; (4) elevation of the neck of the pancreas from the superior mesenteric and portal veins; (5) mobilization of the distal segment of the common bile duct; (6) division of the stomach; (7) mobilization and division of the proximal jejunum; (8) division of the neck of the pancreas and common bile duct; (9) removal of the specimen by division of the blood supply to the duodenum and to the uncinate process, and division of the uncinate process; (10) reconstruction of the digestive tract by anastomosis of the pancreatic duct, common bile duct, and stomach to the jejunum, in that order. The extent of the operation and the structures to be removed are shown in Figure 6. In this sequence of maneuvers, the most important are the exploration of the pancreas and adjacent structures and the preparation and anastomosis of the distal pancreas to the jejunum. A detailed description of the procedure will be confined to these steps. RECOGNITION OF IDENTITY AND RESECTABILITY OF LESION. After the abdomen is opened, a complete exploration of the abdominal and pelviC cavities is carried out. Any tissues showing fixation, puckering, or implantation should be biopsied for a frozen section examination. Attention should be focused on the liver, the caudal surface of the mesocolon, and the ligament of Treitz for biopsy material. Generally, involvement of these areas by tumor indicates nonresectability. The gastrocolic ligament is divided in its entirety, allowing direct approach to the pancreas through the lesser sac. A radical Kocher's maneuver is accomplished so that a careful survey of the head of the gland and the periampullary area can be conducted. Any extension of the tumor outside the head of the pancreas or the body and tail of the pancreas and any fixation of the head or neck of the gland to the inferior vena cava, superior mesenteric vein, splenic vein, or portal vein in-
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Figure 6. Extent of resection for pancreatoduodenectomy.
dicate nonresectability. If the primary tumor seems to be in the pancreas and if frozen section shows that nodes in the immediate area are involved by tumor, it is best to carry out a palliative procedure. The differentiation of carcinoma of the pancreatic head from carcinoma of the ampulla, carcinoma of the lower duct, carcinoma of the duodenum, impacted stone, peptic duodenal ulcer, and chronic relapsing pancreatitis is essential. Generally, malignant obstruction of the bile duct is characterized by the presence of a dilated, thin-walled, bluish common bile duct with dilatation of the gallbladder. In addition, in decreasing order of frequency, carcinomas of the head of the pancreas, ampullary area, and lower common bile duct cause obstruction and dilatation of the duct of Wirsung, which can be palpated distal to the obstructing tumor. Obstruction of the biliary system as a result of chronic relapsing pancreatitis can produce dilatation of the common bile duct; however, the periampullary tissues are edematous and show other signs of chronic inflammation, such as a thickening of the wall of the proximal bile duct. In these cases, this structure does not have the bluish sheen that is apparent with malignant obstruction. The location of the tumor mass is of importance in deciding the origin of the tumor. Carcinomas of the ampulla can be palpated as marble-like projections in the area of the ampulla. Advanced tumors of the ampulla can present as plaque-like or ulcerating masses in this area. The main mass of carcinomas which are primary in the lower bile duct is just proximal to the ampulla. Calculi in the distal bile duct often have an area of induration surrounding them; however, this area of induration is usually circum-
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CARCINOMA OF THE PANCREAS
611
scribed, and gallstones will be present in 93 per cent of patients with intact gallbladders. The proximal choledochus may also contain stones, and the gallbladder is rarely distended. Benign and malignant obstruction of the duct of Wirsung usually causes changes of chronic pancreatitis in the body and tail of the pancreas. However, in the case of malignant obstruction, a definite mass in the head of the pancreas, which is distinct from the rest of the pancreatic substance, can usually be appreciated. In cases of chronic relapsing pancreatitis, the body, tail, and head of the gland are uniformly indurated, and no one area will be unusually hard. We do not recommend the use of biopsy procedures in the diagnosis of periampullary neoplasms and in the differentiation of the types of these neoplasms. If the surgeon feels that it is necessary to establish a diagnosis by biopsy and frozen section examination, these biopsies should be taken from nodes surrounding the pancreas or from extension of the tumor into the surrounding structures. Direct biopsy of the pan-
Figure 7. A, Placement of initial hemostatic sutures to control longitudinal pancreatic arteries. B, Hemostatic control of proximal end of severed pancreas. Note sutures placed in duct of Wirsung in preparation for pancreatojejunostomy. C, Completion of closure of distal pancreas.
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KENNETH W. WARREN, JOHN W. BRAASCH, CHARLES W. THUM
Figure 8.
Details of two-layer pancreatojejunostomy.
creatic gland should not be performed. If the surgeon feels this is necessary, it should be carried out by the transduodenal route using a bone curet. PANCREATOJEJUNOSTOMY. Since most of the morbidity and mortality following pancreatoduodenectomy results from leakage at the site of pancreatojejunostomy, we will describe our method of preparation of the distal pancreas for anastomosis and the technique of this anastomosis. Before the neck of the pancreas is sectioned, the longitudinal pancreatic arteries are controlled with suture ligatures of silk (Fig. 7, A). After the gland is sectioned, four fine silk sutures are placed in the four quadrants of the distal duct (Fig. 7, B), and a catheter is threaded into this duct. Bleeding from the gland on either side of the point of division is controlled by silk mattress sutures, which compress the anterior and posterior surfaces of the gland. Care must be taken that the duct of Wirsung is not compromised by these sutures (Fig. 7, B and C). Using interrupted silk sutures, the dorsal surface of the neck of the pancreas is sutured to the proximal jejunum. A small opening is made in the jejunum to permit a precise mucosa-to-mucosa anastomosis between it and the duct of Wirsung. The segment of rubber catheter in the duct of Wirsung is now anchored with a fine silk suture to the posterior wall of the divided duct. The four sutures previously placed in the duct of Wirsung are used to anastomose it to the opening made in the jejunum. The segment of catheter previously placed in the pancreatic duct is inserted into the lumen of the jejunum before the anterior ductal suture is tied. The anastomosis is completed by placing a series of silk sutures, which approximates the anterior wall of the jejunum to the anterior surface of the neck of the pancreas (Fig. 8).
CARCINOMA OF THE PANCREAS
613
Using this technique, we are able to accomplish an anastomosis of even the smallest duct of Wirsung to the jejunum. We feel that the success of this anastomosis is to a large extent responsible for our current satisfactory morbidity and mortality rate following pancreatoduodenectomy. Distal Pancreatectomy Following abdOIninal exploration with specific attention to the celiac axis, the root of the mesentery, splenic hilus, and the liver, the entire gastrocolic ligament and the short gastric vessels are divided permitting full evaluation of and access to the lesser sac. If there is no demonstrable spread of the primary tumor in the body or tail of the pancreas, we proceed with distal pancreatectomy. The initial maneuver in this resection should be elevation of the neck of the pancreas, which permits visualization of the splenic-portal vein junction. This is followed by ligation of the splenic artery in this area. Mobilization of the spleen and body and tail of the pancreas permits sectioning of the gland at a place appropriate for the extent and location of the tumor. The proximal stump of the pancreas is then closed with silk mattress sutures after the pancreatic duct has been ligated by suture. Total Pancreatectomy Theoretical reasons support the suggestion that total pancreatectomy may be indicated for malignant pancreatic disease. The extent of a tumor arising in the head of the pancreas and ampullary region cannot always be determined by inspection and palpation. Malignant cells have been found within the ductal system27 at operation, and transection of the duct may lead to seeding. Ductal carcinoma may be multicentric, since pancreatic ducts have been observed to be involved in diffuse adenomatous change. 29 A wider excision of tissues about the celiac axis in the body of the pancreas is permitted. Finally, the pancreatic anastomosis is avoided. Appealing as these advantages might seem, we have performed total pancreatectomy only for cystadenoma, cystadenocarcinoma, or ductal carcinoma apparently confined to the pancreas. The technique of total pancreatectomy involves mobilization of the body and tail of the pancreas and elevation and freeing of the pancreatic head, duodenum, distal bile duct, and stomach. Gastrointestinal continuity is restored using the same techniques as used following pancreatoduodenectomy without pancreatojejunostomy. Temporizing Procedures The surgeon may feel that a tumor is resectable, but wish to refer the patient to an appropriate surgical center, or he may wish to resect the tumor himself after a period of biliary decompression. In this situation, a cholecystostomy or a T tube choledochostomy is indicated. We do not advise any form of anastomosis in these circumstances, since this will interfere with subsequent resection.
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KENNETH W. WARREN, JOHN W. BRAASCH, CHARLES W. THUM
Palliative Procedures If a lesion is deemed nonresectable, three procedures must be considered for palliation. The most common requirement is biliary tract drainage, either by cholecystojejunostomy or choledochojejunostomy, each with a diverting entero-enterostomy. If the duct of Wirsung is dilated, further palliation and improved nutrition may be achieved by pancreatojejunostomy. If duodenal obstruction is imminent, gastroenterostomy is indicated.
RESULTS Mortality of Pancreatoduodenectomy Fish and Cleveland 12 collected from the literature 514 cases of pancreatoduodenectomy performed for carcinoma of the head of the pancreas and found a mortality rate of 21.2 per cent. Many of these operations were performed during the early experience with this procedure. Table 2 shows the mortality in this institution in the treatment of 253 periampullary cancers by pancreatoduodenectomy to be 13.5 per cent from 1942 through 1965. During the years 1966 and 1967, we performed this operation for malignant tumors 35 times with 1 postoperative death, a mortality of 2.9 per cent. In 1966, Longmire and Shafey21 reported one death in their last 17 patients for a mortality rate of 5.9 per cent. Monge et al. 24 reported 65 patients treated by pancreatoduodenectomy for malignant tumors in the years 1949 through 1955 with an overall mortality rate of 12.3 per cent. This improvement in the postoperative mortality rate results from a better selection of cases and from advances in the technique of pancreatojejunostomy.
Survival Following Pancreatoduodenectomy Reports in the literature indicate that the five-year survival following pancreatoduodenectomy for ductal carcinoma of the head of the pancreas varies from 0 to 14.3 per cent. 12 • 23. 25. 33 Our survival rate after pancreatoduodenectomy for periampullary cancer is shown in Table 3. In patients with carcinoma of the head of the pancreas, it is 12.5 per cent and for carcinoma of the ampulla, distal bile duct, and duodenum it varies between 30 and 41 per cent. Table 2.
Mortality Following Pancreatoduodenectomy at the Lahey Clinic Foundation
Cancer of head of pancreas Ampullary cancer Cancer of distal bile duct Duodenal cancer TOTAL
NUMBER OF
MORTALITY
CASES
(per cent)
97 93 26
37
11.4 10.8 19.2 21.6
253
13.5
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CARCINOMA OF THE PANCREAS
,
Table 3.
Survival After Pancreatoduodenectomy for Periampullary Cancer FIVE-YEAR SURVIVORS
Number Head of pancreas Ampulla Distal bile duct Duodenum
9
20 5
7
Per cent 12.5 29.8 35.7 41.2
Survival Following Palliative Bypass Procedures, or Only Laparotomy In our experience, the survival time after operation in 332 patients who had a biliary bypass procedure averaged 6.5 months. The survival in 231 patients who had only laparotomy averaged five months. It is apparent that there is little increase in survival time after a palliative bypassing procedure, but it is also apparent to us that this survival time is improved in quality by relief, however temporary, of the symptoms of biliary tract obstruction. Survival Following Resection of Carcinoma of the Body and Tail of the Pancreas To our knowledge, there has never been a long-term survival following resection of ductal carcinoma of the body or tail of the pancreas. Glenn 14 has reported five patients with carcinoma of this portion of the pancreas who had resection and all died within two years. We have likewise resected ten primary ductal carcinomas of the body and tail without long-term survival. All patients died within 12 months of the operation; the average survival was 6 months. It is important to note that in four patients with islet cell tumors of the body and tail of the pancreas which were resected, one died of unrelated causes at 6 years, and three were living at 8, 8, and 11 years after resection. For this reason, any lesion confined to the body or tail of the pancreas should be resected, since the operative recognition of islet cell tumors has not been precise. Survival After Total Pancreatectomy In the years 1942 to 1965 inclusive, we performed total pancreatectomy for ductal carcinoma of the pancreas in six patients. One died in the postoperative period, and the others died within a year; the average survival was eight months. In the years 1966 and 1967, we performed this operation in five patients without a postoperative death. These results make it unlikely that this operation is justified for ductal carcinoma of the pancreas except in most unusual circumstances. It probably should be reserved for massive cystadenocarcinomas or large islet cell tumors. COMMENT The only effective treatment for a malignant tumor of the pancreas is operation. The symptoms, signs, and radiologic appearance of car-
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KENNETH W. WARREN, JOHN W. BRAASCH, CHARLES W. THUM
cinoma of the pancreas may be mimicked by conditions that are treated most successfully by surgery. Therefore, despite the poor prognosis associated with the diagnosis of carcinoma of the pancreas, any patient who does not have signs of metastatic disease and who might have a malignant tumor of the pancreas must have a laparotomy to establish the precise diagnosis and to determine the appropriate operative procedure. If this operation is not carried out, it is entirely possible that a successful resection of a carcinoma of the lower segment of the bile duct, ampulla, or duodenum might not be performed, and therefore, a 30 to 40 per cent chance for five-year survival lost. There are many false assumptions that lead to tragedies in the treatment of cancer of the pancreas and periampullary region. These are as follows: 1. The patient has hepatitis. Such patients are treated medically for an inordinately long time before operation is advised. Frequently the diagnosis of hepatitis is based on some exotic liver function test. 2. The physician thinks all periampullary tumors have the same poor prognosis. There is a vast difference in the prognosis of ductal cancer in the head of the pancreas on the one hand, and carcinomas of the ampulla of Vater, the distal common bile duct, and the duodenal mucosa surrounding the ampulla of Vater, on the other. These tumors vary in their cellular characteristics and, therefore, also in their growth potential and ultimate prognosis. 3. The mortality of pancreatoduodenectomy is prohibitive. In 1967, 35 pancreatoduodenectomies for malignant disease were performed at the Lahey Clinic Foundation with 1 postoperative death. Thus, the mortality rate with this operation, if it is performed by an experienced pancreatic surgeon, is low. The ultimate mortality with palliative procedures is 100 per cent. 4. An exploratory operation with failure to establish the diagnosis does not influence the outcome. Previous exploration makes the diagnosis at secondary operation more difficult, increases the technical difficulties of resection, and diminishes the prospect of cure.
CONCLUSIONS In the vast majority of cases, carcinoma of the pancreas does not lend itself to successful early diagnosis or definitive surgical, chemotherapeutic, or radiation treatment. Some patients with this disease, particularly if it is located in the head of the gland, should not be denied their chance for cure by resection. Furthermore, it should be recognized that other periampullary malignant tumors are frequently curable by pancreatoduodenectomy and at times cannot be distinguished from carcinoma of the head of the pancreas. In the last decade, with increasing experience in the selection of patients for resection and in the technique of this operation, the mortality and the morbidity rates have been lowered to 10 per cent or less. Palliative bypassing operations do not significantly prolong life but they do serve to make remaining life more comfortable.
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CARCINOMA OF THE PANCREAS
It is possible that the survival rate after resection for carcinoma of the pancreas can be increased if cases are recognized earlier. This would involve making the diagnosis of carcinoma of the pancreas before the biliary tract is obstructed and before afferent pain pathways are invaded with malignant cells. It is in this area of earlier diagnosis that progress for the future lies.
REFERENCES 1. Arkin, A., and Weisberg, S. W.: Carcinoma of pancreas, a clinical and pathologic study of 75 cases. Gastroenterology 13:118-126 (Aug.) 1949. 2. Bard, L., and Pic, A. 0.: Contribution a l'etude clinique et anatomo-pathologique du cancer primitif du pancreas. Rev. de Med. 8:257-282 (April) 1888. 3. Bell, E. T.: Carcinoma of the pancreas. I. A clinical and pathologic study of 609 necropsied cases. II. The relation of carcinoma of the pancreas to diabetes mellitus. Amer. J. Path. 33:499-523 (May-June) 1957. 4. Burke, G., and Goldstein, M. S.: Radioisotopic photoscanning in the diagnosis of pancreatic disease. Amer. J. Roentgen. 92:1156-1161 (Nov.) 1964. 5. Burke, J. 0., and Plummer, K.: Carcinoma of pancreas - clinical and laboratory observations in 29 proven cases. Virgin a Med. Month. 80:333-335 (June) 1953. 6. Cattell, R B., and Pyrtek, L. J.: Appraisal of pancreatoduodenal resection; follow-up study of 61 cases. Ann. Surg. 129:840-849 (June) 1949. 7. Chauffard, M. A.: Communication. Le cancer du corps du pancreas. Bull. Acad. de Med. 60:242-255 (Oct. 20) 1908. 8. Codivilla (1898): Quoted by Sauve, L. (Ref. 28). 9. Courvoisier, L. G.: Kasuistisch-statistische Beitrage zur Pathologie und Chirurgie der Gallenwege. Leipzig, F. C. W. Vogel, 1890, p. 58. 10. Crozier, R E., and McGinley, E. M.: The secretin test: An appraisal of technique and early results. Lahey Clin. Found. Bull. 13:237-244 (July-Sept.) 1964. 11. Da Costa, J. M.: Cancer of the pancreas. N. Amer. Med.-Chir. Rev., Phila., 2:883-909, 1858. 12. Fish, J. C., and Cleveland, B. R: Pancreaticoduodenectomy for peri-ampullary carcinoma. Analysis of 38 cases. Ann. Surg. 159:469-476 (March) 1964. 13. Flemma, F. J., and Shingleton, W. W.: Clinical experience with percutaneous transhepatic cholangiography. Amer. J. Surg. 111:13-22 (Jan.) 1966. 14. Glenn, F., and Thorbjarnarson, B.: Carcinoma of the pancreas. Ann. Surg. 159:945-958 (June) 1964. 15. Glenn, F., Evans, J. A., Mujahed, Z., and Thorbjarnarson, B.: Percutaneous transhepatic cholangiography. Ann. Surg. 156:451-462 (Sept.) 1962. 16. Gore, I.: Thrombosis and pancreatic carcinoma. Amer. J. Path. 29: 1093-1103 (Nov.-Dec.) 1953. 17. Halsted, W. S.: Contributions to the surgery of the bile passages, especially of the common bile-duct. Boston Med. and Surg. J. 141 :645-654 (Dec. 21) 1899. 18. Hirschel, G.: Die Resektion des Duodenums mit der Papille wegen Karzinoms. Miinchen. med. Wchnschr. 61: 1728-1729 (Aug.) 1914. 19. Hunt, V. C.: Surgical management of carcinoma of the ampulla of Vater and of the periampullary portion of the duodenum. Ann. Surg. 114:570-602 (Oct.) 1941. 20. Kausch, W.: Das Carcinom der Papilla duodeni und seine radikale Entfernung. Beitr. z. klin. Chir. 78:439-486 (May) 1912. 21. Longmire, W. P., Jr., and Shafey, O. A.: Certain factors influencing survival after pancreaticoduodenal resection for carcinoma. Amer. J. Surg. 111 :8-12 (J an.) 1966. 22. Mondiere, J. T.: Recherches pour servir a l'histoire pathologique du pancreas. Memoires et observations. Arch. Gen. de MM. 2:36-58 (May); 2:265-294 (July); 3:133-164 (Oct.) 1836. 23. Monge, J. J., Judd, E. S., and Gage, R P.: Radical pancreatoduodenectomy: a 22-year experience with the complications, mortality rate, and survival rate. Ann. Surg. 160: 711-722 (Oct.) 1964. 24. Monge, J. J., Dockerty, M. B., Wollaeger, E. E., et al.: Clinicopathologic observations on radical pancreatoduodenal resection for periampullary carcinoma. Surg. Gynec. Obstet. 118:275-283 (Feb.) 1964. 25. Morris, P. J., and Nardi, G. L.: Pancreaticoduodenal cancer. Experience from 1951 to 1960 with a look ahead and behind. Arch. Surg. 92:834-837 (June) 1966. 26. Raskin, H. F., Wenger, J., Sklar, M., et al.: The diagnosis of cancer of the pancreas, biliary tract, and duodenum by combined cytologic and secretory methods. I. Exfolia-
618 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41.
KENNETH W. WARREN, JOHN W. BRAASCH, CHARLES W. THUM
tive cytology and a description of a rapid method of duodenal intubation. Gastroenterology 34: 996-1 008 (J une) 1958. Ross, D. E.: Cancer of pancreas; plea for total pancreatectomy. Amer. J. Surg. 87:20-33 (Jan.) 1954. Sauve, L.: Des pancreatectomies et specialement de la pancreatectomie cephalique. Rev. de Chir. 37:113-152, 335-385 (Feb.) 1908. Sommers, S. C., Murphy, S. A., and Warren, S.: Pancreatic duct hyperplasia and cancer. Gastroenterology 27:629-640 (Nov.) 1954. Sproul, E. E.: Carcinoma and venous thrombosis: The frequency of association of carcinoma in the body or tail of the pancreas with multiple venous thrombosis. Amer. J. Cancer 34: 566-585 (Dec.) 1938. Tenani, 0.: Contributo alla chirurgia della papilla del Vater. Policlinico 29:291-300 (May 15); 333-348 (June 15) 1929. Trousseau, A.: Quoted by Sproul, E. E. (Ref. 30). Warren, K. W., and Kune, G. A.: Surgical approach to jaundice. Hosp. Med. 2:46-55 (Sept.) 1966. Warren, K. W., and McDonald, W. M.: Indications for surgical intervention in the jaundiced patient. SURG. CLIN. N. AMER. 44:685-705 (June) 1964. Warren, K. W., Veidenheimer, M. C., and Pratt, H. S.: Pancreatoduodenectomy for periampullary cancer. SURG. CLIN. N. AMER. 47:639-645 (June) 1967. Warren, K. W., Cattell, R. B., Blackburn, J. P., and Nora, P. F.: A long-term appraisal of pancreaticoduodenal resection for peri-ampullary carcinoma. Ann. Surg. 155 :653662 (May) 1962. Whipple, A. 0.: Rationale of radical surgery for cancer of the pancreas and ampullary region. Ann. Surg. 114:612-615 (Oct.) 1941. Whipple, A. 0., Parsons, W. B., and Mullins, C. R.: Treatment of carcinoma of the ampulla of Vater. Ann. Surg. 102:763-779 (Oct.) 1935. Williams, R., and Billing, B. H.: Action of steroid therapy in jaundice. Lancet 2:392-396 (Aug. 19) 1961. Wise, R. E., and Johnston, D. 0.: The roentgenologic diagnosis of malignancy of the pancreas. SURG. CLIN. N. AMER. 36:699-706 (June) 1956. Zinninger, M. M.: Radical resection of duodenum and head of pancreas for carcinoma of ampulla of Vater. Repair of pancreatic fistula using vitallium tube. Cincinnati J. Med. 23:174-176 (June) 1942.
The pancreas is inaccessible to visual, tactile, and radiologic examination. Richly supplied by vascular and lymphatic channels suitable as pathways for neoplastic spread, it is contiguous with vital structures that cannot be violated. Consequently, it is not surprising that the management of neoplasms of the pancreas is most difficult and requires the highest skill from operating surgeons. Because there are still many misconceptions in the management of malignant pancreatic lesions, it is worthwhile to review our concepts of treatment and emphasize the progress that has been made in reducing the postoperative mortality and morbidity. It is also appropriate to discuss and compare the management of other periampullary malignant tumors since these other lesions have a favorable prognosis following resection for cure and since their precise differentiation from primary carcinoma of the pancreas can be most difficult even at laparotomy.
HISTORY A historical review of the recognition and treatment of carcinoma of the pancreas indicates that progress has been made only in the last 30 years and shows us the direction in which further advances lie. Mondiere,22 who reported two patients in 1836, was the first to describe the gross characteristics of carcinoma of the pancreas. By 1858, Da Costal l had collected 37 patients who died from malignant tumors of the pancreas. Antemortem diagnosis, however, was slow in developing. It remained for Bard and Pic 2 in 1888 to relate autopsy findings in seven patients with the signs and symptoms of the disease. Pain was not mentioned as an important feature until Chauffard7 in 1908 described it as a predominant symptom. The classic sign on physical examination of a palpable, distended gallbladder was noted by Courvoisier9 in 1890. Early attempts at surgical management of carcinoma of the pancreas are summarized by Sauve28 in the French literature. Among early surgeons who were interested in the pancreas was Codivilla,8 who in Surgical Clinics of North America- Vol. 48, No.3, June, 1968
601
602
KENNETH W. WARREN, JOHN W. BRAASCH, CHARLES W. THUM
Gastroduo- .-+---,:.,..r ,",no 1 A.
FIRST OPERATION
SECOND OPERATION
END STAGI
Figure 1. Original illustration of Whipple's operation. (From Whipple, A. 0., et al., Annals of Surgery, 102:765, October, 1935.)
1908 performed an en bloc resection of the head of the pancreas and part of the duodenum. In the American literature, Halsted 17 reported in 1899 the local excision of a periampullary tumor with reimplantation of the biliary and pancreatic ducts. In the years 1912 to 1922, Hirschel,'8 Kausch,20 and TenanPl performed en bloc resections of carcinoma of the ampulla of Vater to include portions of the duodenum, lower bile duct, and head of the pancreas. It remained, however, for Whipple:18 and his associates to develop and popularize a technique that permitted successful resection of carcinomas of the periampullary region (Fig. 1). In the first of three patients reported by Whipple et al.,38 only a local resection of the tumor was performed. In the second and third patients, successively larger amounts of the head of the pancreas and the duodenum were removed. Since Whipple's paper in 1935, the extent of the resection of the
603
CARCINOMA OF THE PANCREAS
duodenum and the stomach has been increased so that now6 removal of the entire duodenum and at least 50 to 70 per cent of the stomach is acceptable and necessary to avoid the development of gastrojejunal ulceration. In the last 30 years, surgeons have also been removing increasing amounts of the pancreatic gland so that now the pancreas is sectioned at the neck at a point convenient for reconstruction of the pancreatic duct outflow tract or at a point appropriate for excision of the malignant lesion with an adequate margin. Whipple,37 in his earlier experience, did not recognize the importance of the preservation of the pancreatic duct outflow, and the stump of the distal pancreas was closed. It soon became apparent that steatorrhea, pancreatic fistulas, and hemorrhage were prevalent postoperatively, leading Hunt,'9 in 1941, to invaginate the cut surface of the pancreas into the jejunum and Zinninger,.' in 1942, to anastomose the pancreatic duct to the jejunum. We will describe further refinements in this technique later in this communication. In the early years, reconstruction of the biliary tract after resection was accomplished by cholecystoenterostomy, with ligation of the distal common duct. Because of leakage of the ligated common duct and because cholecystoenterostomy frequently did not drain the biliary tract, Whipple37 in 1941 recommended choledochojejunostomy as the preferable biliary tract anastomosis. This procedure is in common usage today. Early surgeons favored a two-stage procedure for pancreatoduodenectomy; however, by 1949 Cattell and Pyrtek 6 recognized that some cases were suitable for a one-stage resection. Today, we reserve the two-stage procedure, that of external biliary drainage followed later by the resection, for certain poor-risk patients with high levels of blood bilirubin or cardiorespiratory-renal abnormalities. DIAGNOSIS Periampullary carcinoma and carcinoma of the body and tail of the pancreas have many clinical characteristics in common. However, jaundice is of primary importance in the former and in the latter, abdominal and back pain are the cardinal symptoms. Signs and Symptoms PAIN. Often the initial symptom of carcinoma of the body and tail of the pancreas and periampullary carcinoma, pain is at first typically dull and vague, sometimes localized to the epigastrium, but often extending to the left or right upper quadrants or to the back. At times the pain is initially episodic and related to meals, but later it becomes constant, severe, and extending to the back. Severe pain suggests malignant extension into the posterior parietes around the celiac axis with invasion of its associated neural plexus. WEIGHT Loss. Rapid and severe weight loss is one of the consistent features of carcinoma of the body of the pancreas. 35 It is also one of the most common features of periampullary carcinoma, averaging 15.6
604
KENNETH W. WARREN, JOHN W. BRAASCH, CHARLES W. THUM
pounds in patients with carcinoma of the head of the pancreas. It is present in 96 per cent of patients with resectable tumors and often precedes all other symptoms. HEMATEMESIS AND MELENA. Massive gastrointestinal hemorrhage may be caused by pancreatic neoplasia in a variety of ways. Carcinomas of the pancreas may infiltrate the duodenum or the gastric wall causing ulceration and bleeding. They may obstruct the duodenum, thus stimulating acid-pepsin secretion and producing a benign bleeding peptic ulcer. A tumor may cause compression of the portal venous system producing portal hypertension and bleeding esophageal varices. THROMBOPHLEBITIS. There has been controversy regarding the incidence of thrombophlebitis associated with pancreatic carcinoma. Trousseau 32 and Sproupo have suggested that many patients dying from carcinoma of the body or tail of the pancreas have an associated thrombophlebitis. Others3 • 16 have failed to confirm this observation. Migratory thrombophlebitis requires full investigation, but it does not specifically indicate pancreatic carcinoma, nor does it by itself justify a diagnostic laparotomy. DIABETES. Diabetes has long been associated with pancreatic neoplasm. Approximately 50 per cent of patients with malignant disease of the pancreas have hyperglycemia and glycosuria with an abnormal glucose tolerance curve. I. 5 Malignant pancreatic lesions should be considered in any person more than 40 years of age who becomes diabetic. JAUNDICE. Jaundice occurs in 75 per cent of all patients with carcinoma of the pancreas and, depending upon the site of origin, in 35 to 100 per cent of patients with resectable periampullary carcinoma. 35 Associated with jaundice are other signs and symptoms of extrahepatic obstruction of the b\liary tract. These include pruritus, chills and fever, a palpable gallbladder, and hepatic enlargement. In the differentiation of malignant obstructive jaundice from jaundice resulting from hemolysis, intrahepatic hepatocellular disease and intrahepatic obstructive disease, we rely on the many important features of a carefully taken history and precise physical examination. Early in the course of disease in a jaundiced patient, liver function tests can be of great value. We pay particular attention to the alkaline phosphatase, serum bilirubin, cephalin flocculation, and prothrombin time determinations. 34 Table 1 presents the usual patterns of historic information, physical findings, and laboratory results associated with some of the different causes of jaundice.
Diagnostic Adjuncts RADIOLOGY. Wise and Johnston4o have reviewed the radiologic findings in malignant periampullary lesions and have underlined the necessity for close attention to detail in the recognition of small but possibly resectable tumors. The wide duodenal loop with elevation of the distal stomach suggests enlargement of the pancreatic head. However, the wide-loop sign is actually more common in the normal obese indi-
Table 1.
(j
Clinical Features of Various Causes of Jaundice~' CHOLESTATIC DRUG
ACUTE VIRAL HEPATITIS
JAUNDICE
CARCINOMA OF THE COMMON BILE DUCT STONES
PERIAMPULLARY REGION
~
o
History Previous history
Pain Jaundice Weight loss
Contact with hepatitis, injection or transfusion; viral type illness before onset of jaundice None or mild ache over liver Develops rapidly and decreases slowly Slight
.., >oj
Drug ingestion (for Dyspepsia; previous biliary example, chlorpromazine) colic; previous positive cholecystogram None Develops rapidly and decreases slowly Slight
~.... Z o g;
'1:1
>
Epigastric pain or biliary colic Develops slowly; may fluctuate Slight
± Epigastric or back pain
Moderate Sometimes Enlarged; slightly tender
Deep
Develops slowly and progressively Considerable
Z
("J
~ >
CIl
Examination Depth of jaundice Fever Liver Palpable gallbladder Palpable spleen Ascites
Variable At onset Enlarged; slightly tender
Variable At onset Slightly enlarged
Occ asionally In severe cases
Enlarged; non tender Occasionally With peritoneal metastasis
Laboratory Findings Color of feces Urinary urobilinogen Leukocytosis Serum bilirubin, mg. per 100 ml. Serum alkaline phosphatase, KingArmstrong units Transaminase (SGOT)
Variable + Early
Pale
Variable
Clay-colored
Variable
Intermittently pale Occasionally + Often 3-8
Occasionally Rises steadily to 15-20
13-30
Usually >30
Usually >30
Very high, 30-100
Raised considerably
Slightly raised
Normal
Normal Q)
"Adapted from Warren, K. W., and Kune, G. A., Hospital Medicine, 1966.
= ~
T 606
KENNETH W. WARREN, JOHN W. BRAASCH, CHARLES W. THUM
Figure 2. Change in the mucosa of the duodenal loop caused by carcinoma of the head of the pancreas. Note irregularity and destruction of mucosa.
vidual and by itself is of little significance. Of more importance is the appearance of the mucosa on the inner aspect of the loop. Irregularity and either or both destruction and compression (Fig. 2) are the hallmarks of adjacent underlying malignant disease. In the radiologic demonstration of carcinoma of the body and tail of the pancreas, far-advanced tumors may cause compression or displacement of neighboring organs. Thus, the stomach may be displaced anteriorly on barium study, or the kidneys may be displaced inferiorly on the roentgenogram of the abdomen or intravenous pyelogram. Since most patients with malignant periampullary tumors are jaundiced when they first consult a physician, the use of intravenous cholangiography is severely limited. Occasionally, the serum bilirubin level is below 2.5 mg. per 100 mi., and if so, visualization of the common duct is possible and may serve to rule out lesions such as common duct calculi. Several other interesting approaches to the radiographic delineation of the pancreas have been attempted. We are currently evaluating the role of selective celiac axis angiography in the diagnosis of pancreatic tumors and frequently find displacement of the splenic artery and splenic vein (Fig. 3). Another radiographic adjunct is the pancreatic scanning procedure. 4 The gland that is completely involved by tumor or pancreatitis will not be visualized (Fig. 4). The gland partially replaced by tumor or cyst will show a scan defect (Fig. 5). In the past, too much reliance has been placed upon negative findings on gastrointestinal roentgenograms. Unfortunately, to date,
CARCINOMA OF THE PANCREAS
607
Figure 3. Displacement of plenic vein on celiac angiogram caused by carcinoma of the head of the pancrea .
selective celiac axis angiography or pancreatic scanning will not reveal malignant tumors of the pancreas until they are incurable surgically. If progress in the current diagnosis of carcinoma of the pancreas is to be made, more reliance must be placed upon the early history, and
Figure 4. Pancreatic scan showing failure to visualize gland when diffusely involved by carcinoma.
608
Figure 5. creatic scan.
KENNETH W. WARREN, JOHN W. BRAASCH, CHARLES W. THUM
Partial replacement of pancreas by carcinoma in head, as shown on pan-
abdominal exploration must be performed before persistent abdominal and back pain occur, reflecting invasive cancer. ANALYSIS OF DUODENAL CONTENTS. Laboratory techniques for the determination of pancreatic enzymes and sodium bicarbonate in the duodenal contents have been developed as an aid in the diagnosis of periampullary carcinoma. 1o These tests are based on the effects of obstruction of the duct of Wirsung by the neoplastic tumor. While these tests are occasionally of considerable value, they are time-consuming and supply limited information. The diagnosis of carcinoma of the pancreas, biliary tract, and duodenum using cytologic methods has been reviewed by Raskin and his co-workers.26 These investigators have been able to recover malignant cells in 28 of 43 patients with periampullary neoplasms. We have had no experience with this technique. CLOSED LIVER BIOPSY. Even the most experienced clinical pathologist has difficulty differentiating intrahepatic cholestasis from extrahepatic bile duct obstruction, particularly when the obstruction has been present for a long time. Therefore, the diagnostic accuracy of the interpretation of a closed liver biopsy sample is limited. PREDNISOLONE TEST. The administration of prednisolone, 30 mg. per day for seven days, is at times helpful in the differentiation of intrahepatic cholestatic jaundice from extrahepatic obstructive jaundice. 39 In the former, a rapid fall in level of serum bilirubin is often observed during the first few days of the test. PERCUTANEOUS TRANSHEPATIC CHOLANGIOGRAPHY. When there is a diagnostic problem, percutaneous transhepatic cholangiography is at times useful in the recognition of extrahepatic obstructive jaundice.
CARCINOMA OF THE PANCREAS
609
Experience '3 , 15 has shown that, if bile can be aspirated from the probing cannula, dilation of the intrahepatic biliary tree, and, therefore, organic biliary tract obstruction are indicated. In our experience, this procedure was only rarely helpful, as in most instances in which extrahepatic obstruction was shown by transhepatic cholangiogram, the diagnosis was evident without the test. LAPAROTOMY. Patients should have exploratory operation when an obvious diagnosis of cholestatic jaundice of mechanical etiology is established or when this possibility definitely cannot be excluded by any other technique. However, exploration for obstructive jaundice is never an emergency procedure except in acute suppurative cholangitis.
SURGICAL MANAGEMENT Pancreatoduodenectomy It is important to perform this demanding operative procedure in the following order: (1) Exploration of the abdominal and pelvic cavities; (2) division of the gastrocolic ligament and exploration of the body and tail of the pancreas; (3) mobilization of the head of the pancreas and duodenum with exploration of the periampullary area; (4) elevation of the neck of the pancreas from the superior mesenteric and portal veins; (5) mobilization of the distal segment of the common bile duct; (6) division of the stomach; (7) mobilization and division of the proximal jejunum; (8) division of the neck of the pancreas and common bile duct; (9) removal of the specimen by division of the blood supply to the duodenum and to the uncinate process, and division of the uncinate process; (10) reconstruction of the digestive tract by anastomosis of the pancreatic duct, common bile duct, and stomach to the jejunum, in that order. The extent of the operation and the structures to be removed are shown in Figure 6. In this sequence of maneuvers, the most important are the exploration of the pancreas and adjacent structures and the preparation and anastomosis of the distal pancreas to the jejunum. A detailed description of the procedure will be confined to these steps. RECOGNITION OF IDENTITY AND RESECTABILITY OF LESION. After the abdomen is opened, a complete exploration of the abdominal and pelviC cavities is carried out. Any tissues showing fixation, puckering, or implantation should be biopsied for a frozen section examination. Attention should be focused on the liver, the caudal surface of the mesocolon, and the ligament of Treitz for biopsy material. Generally, involvement of these areas by tumor indicates nonresectability. The gastrocolic ligament is divided in its entirety, allowing direct approach to the pancreas through the lesser sac. A radical Kocher's maneuver is accomplished so that a careful survey of the head of the gland and the periampullary area can be conducted. Any extension of the tumor outside the head of the pancreas or the body and tail of the pancreas and any fixation of the head or neck of the gland to the inferior vena cava, superior mesenteric vein, splenic vein, or portal vein in-
610
KENNETH W. WARREN: JOHN W. BRAASCH, CHARLES W. THUM
Figure 6. Extent of resection for pancreatoduodenectomy.
dicate nonresectability. If the primary tumor seems to be in the pancreas and if frozen section shows that nodes in the immediate area are involved by tumor, it is best to carry out a palliative procedure. The differentiation of carcinoma of the pancreatic head from carcinoma of the ampulla, carcinoma of the lower duct, carcinoma of the duodenum, impacted stone, peptic duodenal ulcer, and chronic relapsing pancreatitis is essential. Generally, malignant obstruction of the bile duct is characterized by the presence of a dilated, thin-walled, bluish common bile duct with dilatation of the gallbladder. In addition, in decreasing order of frequency, carcinomas of the head of the pancreas, ampullary area, and lower common bile duct cause obstruction and dilatation of the duct of Wirsung, which can be palpated distal to the obstructing tumor. Obstruction of the biliary system as a result of chronic relapsing pancreatitis can produce dilatation of the common bile duct; however, the periampullary tissues are edematous and show other signs of chronic inflammation, such as a thickening of the wall of the proximal bile duct. In these cases, this structure does not have the bluish sheen that is apparent with malignant obstruction. The location of the tumor mass is of importance in deciding the origin of the tumor. Carcinomas of the ampulla can be palpated as marble-like projections in the area of the ampulla. Advanced tumors of the ampulla can present as plaque-like or ulcerating masses in this area. The main mass of carcinomas which are primary in the lower bile duct is just proximal to the ampulla. Calculi in the distal bile duct often have an area of induration surrounding them; however, this area of induration is usually circum-
T
CARCINOMA OF THE PANCREAS
611
scribed, and gallstones will be present in 93 per cent of patients with intact gallbladders. The proximal choledochus may also contain stones, and the gallbladder is rarely distended. Benign and malignant obstruction of the duct of Wirsung usually causes changes of chronic pancreatitis in the body and tail of the pancreas. However, in the case of malignant obstruction, a definite mass in the head of the pancreas, which is distinct from the rest of the pancreatic substance, can usually be appreciated. In cases of chronic relapsing pancreatitis, the body, tail, and head of the gland are uniformly indurated, and no one area will be unusually hard. We do not recommend the use of biopsy procedures in the diagnosis of periampullary neoplasms and in the differentiation of the types of these neoplasms. If the surgeon feels that it is necessary to establish a diagnosis by biopsy and frozen section examination, these biopsies should be taken from nodes surrounding the pancreas or from extension of the tumor into the surrounding structures. Direct biopsy of the pan-
Figure 7. A, Placement of initial hemostatic sutures to control longitudinal pancreatic arteries. B, Hemostatic control of proximal end of severed pancreas. Note sutures placed in duct of Wirsung in preparation for pancreatojejunostomy. C, Completion of closure of distal pancreas.
612
KENNETH W. WARREN, JOHN W. BRAASCH, CHARLES W. THUM
Figure 8.
Details of two-layer pancreatojejunostomy.
creatic gland should not be performed. If the surgeon feels this is necessary, it should be carried out by the transduodenal route using a bone curet. PANCREATOJEJUNOSTOMY. Since most of the morbidity and mortality following pancreatoduodenectomy results from leakage at the site of pancreatojejunostomy, we will describe our method of preparation of the distal pancreas for anastomosis and the technique of this anastomosis. Before the neck of the pancreas is sectioned, the longitudinal pancreatic arteries are controlled with suture ligatures of silk (Fig. 7, A). After the gland is sectioned, four fine silk sutures are placed in the four quadrants of the distal duct (Fig. 7, B), and a catheter is threaded into this duct. Bleeding from the gland on either side of the point of division is controlled by silk mattress sutures, which compress the anterior and posterior surfaces of the gland. Care must be taken that the duct of Wirsung is not compromised by these sutures (Fig. 7, B and C). Using interrupted silk sutures, the dorsal surface of the neck of the pancreas is sutured to the proximal jejunum. A small opening is made in the jejunum to permit a precise mucosa-to-mucosa anastomosis between it and the duct of Wirsung. The segment of rubber catheter in the duct of Wirsung is now anchored with a fine silk suture to the posterior wall of the divided duct. The four sutures previously placed in the duct of Wirsung are used to anastomose it to the opening made in the jejunum. The segment of catheter previously placed in the pancreatic duct is inserted into the lumen of the jejunum before the anterior ductal suture is tied. The anastomosis is completed by placing a series of silk sutures, which approximates the anterior wall of the jejunum to the anterior surface of the neck of the pancreas (Fig. 8).
CARCINOMA OF THE PANCREAS
613
Using this technique, we are able to accomplish an anastomosis of even the smallest duct of Wirsung to the jejunum. We feel that the success of this anastomosis is to a large extent responsible for our current satisfactory morbidity and mortality rate following pancreatoduodenectomy. Distal Pancreatectomy Following abdOIninal exploration with specific attention to the celiac axis, the root of the mesentery, splenic hilus, and the liver, the entire gastrocolic ligament and the short gastric vessels are divided permitting full evaluation of and access to the lesser sac. If there is no demonstrable spread of the primary tumor in the body or tail of the pancreas, we proceed with distal pancreatectomy. The initial maneuver in this resection should be elevation of the neck of the pancreas, which permits visualization of the splenic-portal vein junction. This is followed by ligation of the splenic artery in this area. Mobilization of the spleen and body and tail of the pancreas permits sectioning of the gland at a place appropriate for the extent and location of the tumor. The proximal stump of the pancreas is then closed with silk mattress sutures after the pancreatic duct has been ligated by suture. Total Pancreatectomy Theoretical reasons support the suggestion that total pancreatectomy may be indicated for malignant pancreatic disease. The extent of a tumor arising in the head of the pancreas and ampullary region cannot always be determined by inspection and palpation. Malignant cells have been found within the ductal system27 at operation, and transection of the duct may lead to seeding. Ductal carcinoma may be multicentric, since pancreatic ducts have been observed to be involved in diffuse adenomatous change. 29 A wider excision of tissues about the celiac axis in the body of the pancreas is permitted. Finally, the pancreatic anastomosis is avoided. Appealing as these advantages might seem, we have performed total pancreatectomy only for cystadenoma, cystadenocarcinoma, or ductal carcinoma apparently confined to the pancreas. The technique of total pancreatectomy involves mobilization of the body and tail of the pancreas and elevation and freeing of the pancreatic head, duodenum, distal bile duct, and stomach. Gastrointestinal continuity is restored using the same techniques as used following pancreatoduodenectomy without pancreatojejunostomy. Temporizing Procedures The surgeon may feel that a tumor is resectable, but wish to refer the patient to an appropriate surgical center, or he may wish to resect the tumor himself after a period of biliary decompression. In this situation, a cholecystostomy or a T tube choledochostomy is indicated. We do not advise any form of anastomosis in these circumstances, since this will interfere with subsequent resection.
614
KENNETH W. WARREN, JOHN W. BRAASCH, CHARLES W. THUM
Palliative Procedures If a lesion is deemed nonresectable, three procedures must be considered for palliation. The most common requirement is biliary tract drainage, either by cholecystojejunostomy or choledochojejunostomy, each with a diverting entero-enterostomy. If the duct of Wirsung is dilated, further palliation and improved nutrition may be achieved by pancreatojejunostomy. If duodenal obstruction is imminent, gastroenterostomy is indicated.
RESULTS Mortality of Pancreatoduodenectomy Fish and Cleveland 12 collected from the literature 514 cases of pancreatoduodenectomy performed for carcinoma of the head of the pancreas and found a mortality rate of 21.2 per cent. Many of these operations were performed during the early experience with this procedure. Table 2 shows the mortality in this institution in the treatment of 253 periampullary cancers by pancreatoduodenectomy to be 13.5 per cent from 1942 through 1965. During the years 1966 and 1967, we performed this operation for malignant tumors 35 times with 1 postoperative death, a mortality of 2.9 per cent. In 1966, Longmire and Shafey21 reported one death in their last 17 patients for a mortality rate of 5.9 per cent. Monge et al. 24 reported 65 patients treated by pancreatoduodenectomy for malignant tumors in the years 1949 through 1955 with an overall mortality rate of 12.3 per cent. This improvement in the postoperative mortality rate results from a better selection of cases and from advances in the technique of pancreatojejunostomy.
Survival Following Pancreatoduodenectomy Reports in the literature indicate that the five-year survival following pancreatoduodenectomy for ductal carcinoma of the head of the pancreas varies from 0 to 14.3 per cent. 12 • 23. 25. 33 Our survival rate after pancreatoduodenectomy for periampullary cancer is shown in Table 3. In patients with carcinoma of the head of the pancreas, it is 12.5 per cent and for carcinoma of the ampulla, distal bile duct, and duodenum it varies between 30 and 41 per cent. Table 2.
Mortality Following Pancreatoduodenectomy at the Lahey Clinic Foundation
Cancer of head of pancreas Ampullary cancer Cancer of distal bile duct Duodenal cancer TOTAL
NUMBER OF
MORTALITY
CASES
(per cent)
97 93 26
37
11.4 10.8 19.2 21.6
253
13.5
615
CARCINOMA OF THE PANCREAS
,
Table 3.
Survival After Pancreatoduodenectomy for Periampullary Cancer FIVE-YEAR SURVIVORS
Number Head of pancreas Ampulla Distal bile duct Duodenum
9
20 5
7
Per cent 12.5 29.8 35.7 41.2
Survival Following Palliative Bypass Procedures, or Only Laparotomy In our experience, the survival time after operation in 332 patients who had a biliary bypass procedure averaged 6.5 months. The survival in 231 patients who had only laparotomy averaged five months. It is apparent that there is little increase in survival time after a palliative bypassing procedure, but it is also apparent to us that this survival time is improved in quality by relief, however temporary, of the symptoms of biliary tract obstruction. Survival Following Resection of Carcinoma of the Body and Tail of the Pancreas To our knowledge, there has never been a long-term survival following resection of ductal carcinoma of the body or tail of the pancreas. Glenn 14 has reported five patients with carcinoma of this portion of the pancreas who had resection and all died within two years. We have likewise resected ten primary ductal carcinomas of the body and tail without long-term survival. All patients died within 12 months of the operation; the average survival was 6 months. It is important to note that in four patients with islet cell tumors of the body and tail of the pancreas which were resected, one died of unrelated causes at 6 years, and three were living at 8, 8, and 11 years after resection. For this reason, any lesion confined to the body or tail of the pancreas should be resected, since the operative recognition of islet cell tumors has not been precise. Survival After Total Pancreatectomy In the years 1942 to 1965 inclusive, we performed total pancreatectomy for ductal carcinoma of the pancreas in six patients. One died in the postoperative period, and the others died within a year; the average survival was eight months. In the years 1966 and 1967, we performed this operation in five patients without a postoperative death. These results make it unlikely that this operation is justified for ductal carcinoma of the pancreas except in most unusual circumstances. It probably should be reserved for massive cystadenocarcinomas or large islet cell tumors. COMMENT The only effective treatment for a malignant tumor of the pancreas is operation. The symptoms, signs, and radiologic appearance of car-
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KENNETH W. WARREN, JOHN W. BRAASCH, CHARLES W. THUM
cinoma of the pancreas may be mimicked by conditions that are treated most successfully by surgery. Therefore, despite the poor prognosis associated with the diagnosis of carcinoma of the pancreas, any patient who does not have signs of metastatic disease and who might have a malignant tumor of the pancreas must have a laparotomy to establish the precise diagnosis and to determine the appropriate operative procedure. If this operation is not carried out, it is entirely possible that a successful resection of a carcinoma of the lower segment of the bile duct, ampulla, or duodenum might not be performed, and therefore, a 30 to 40 per cent chance for five-year survival lost. There are many false assumptions that lead to tragedies in the treatment of cancer of the pancreas and periampullary region. These are as follows: 1. The patient has hepatitis. Such patients are treated medically for an inordinately long time before operation is advised. Frequently the diagnosis of hepatitis is based on some exotic liver function test. 2. The physician thinks all periampullary tumors have the same poor prognosis. There is a vast difference in the prognosis of ductal cancer in the head of the pancreas on the one hand, and carcinomas of the ampulla of Vater, the distal common bile duct, and the duodenal mucosa surrounding the ampulla of Vater, on the other. These tumors vary in their cellular characteristics and, therefore, also in their growth potential and ultimate prognosis. 3. The mortality of pancreatoduodenectomy is prohibitive. In 1967, 35 pancreatoduodenectomies for malignant disease were performed at the Lahey Clinic Foundation with 1 postoperative death. Thus, the mortality rate with this operation, if it is performed by an experienced pancreatic surgeon, is low. The ultimate mortality with palliative procedures is 100 per cent. 4. An exploratory operation with failure to establish the diagnosis does not influence the outcome. Previous exploration makes the diagnosis at secondary operation more difficult, increases the technical difficulties of resection, and diminishes the prospect of cure.
CONCLUSIONS In the vast majority of cases, carcinoma of the pancreas does not lend itself to successful early diagnosis or definitive surgical, chemotherapeutic, or radiation treatment. Some patients with this disease, particularly if it is located in the head of the gland, should not be denied their chance for cure by resection. Furthermore, it should be recognized that other periampullary malignant tumors are frequently curable by pancreatoduodenectomy and at times cannot be distinguished from carcinoma of the head of the pancreas. In the last decade, with increasing experience in the selection of patients for resection and in the technique of this operation, the mortality and the morbidity rates have been lowered to 10 per cent or less. Palliative bypassing operations do not significantly prolong life but they do serve to make remaining life more comfortable.
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It is possible that the survival rate after resection for carcinoma of the pancreas can be increased if cases are recognized earlier. This would involve making the diagnosis of carcinoma of the pancreas before the biliary tract is obstructed and before afferent pain pathways are invaded with malignant cells. It is in this area of earlier diagnosis that progress for the future lies.
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