- Email: [email protected]
Pathology of the pancreas
Pathology
of the Pancreas
By HARLAN J. SPJUT, M.D., AND M. SIDNEY ANDERSON, M.D.
K
NOWLEDGE of the pathologic alterations of the pancreas and its effects
upon neighboring structures is important in the everyday practice of radiology. Several pancreatic diseases have systemic effects, e.g., diabetes mellitus and fibrocystic disease, and these have their own set of pathologic and radiologic manifestations. In this brief survey of the pathology of disease of the pancreas, only a few can be discussed and then only their salient features emphasized. CONGENITAL MALFORMATIONS OF THE PANCREAS
Heterotopic
Pancreas
Heterotopic pancreatic tissue, usually in the form of intramural nodules, may be found in the gastrointestinal tract in as many as 2 per cent of all postmortem examinations. The most common sites are the stomach, duodenum, small bowel and large bowel, in decreasing order of frequency. The lesions are usually submucosal but may be in the muscularis or even the serosa. They present as smooth nodules occasionally having a pit in the domelike center. This pit may at times give the radiologic appearance of an ulcer. Histologically, the lesion is composed of elements of the pancreas, usually the acinar and ductal structures, less frequently the islets of Langerhans. In rare circumstances, heterotopic pancreas of the small bowel may be the focus of an intussusception. Annular
Pancreas
This malformation of the pancreas is thought to be caused by failure of the ventral pancreatic evagination of the foregut to rotate dorsally with the duodenum during the seventh week of embryologic development. The head of the pancreas may completely or incompletely surround the duodenum. Occasionally, the lumen of the duodenum may actually be obliterated at the site of encirclement. The duodenal constriction may occur at, above or below the papilla of Vater. The lesion is most frequently encountered in newborn children; however, the possibility must not be ignored in the adult. Pathologically, the lesion consists of normal pancreatic parenchyma. However, a recent description indicates that there often is a mingling of pancreatic tissue with the duodenal muscularis. This has been suggested as one of the reasons why resection of the constricting pancreatic band sometimes fails to relieve the obstruction.g,13 Fibrocystic
Disease of the Pancreas
Fibrocystic disease of the pancreas is a hereditary disease of exocrine glands seen most frequently in children and young adults. Although it was once conHARLAN J. SPJUT, M.D., and M. SIDNEY ANDERSON, M.D.: Department of Pathology, Baylor University College of Medicine and the Methodist Hospital, Houston, Texas. SEMINARS
IN ROENTGENOLOGY,
VOL. 3, No. 3 (JULY ) , 1968
217
218
SPJUT
AND ANDERSOX
sidered predominantly a pancreatic disease, it is now recognized that this disorder involves many gland systems, including the sweat glands, the salivary glands, and those of the tracheobronchial, biliary and gastrointestinal mucosa.4 Thus, it is apparent that this disease may manifest itself in many organs. Pneumonia, bronchiectasis and meconium ileus are but a few of its many complications.h One of the commonest causes of prolapse of the rectum in infancy and childhood is fibrocystic disease of the pancreas. Focal biliary cirrhosis and mucocele of the gallbladder may also occur. Rarely is cystic fibrosis complicated by diabetes mellitus. Grossly, the pancreas is usually firm and of normal size. Cysts are inconspicuous but may be present in the advanced stages. Histologically, the acini and ducts are dilated. The latter contain inspissated material thought to be abnormal mucus. The pancreatic acini are usually atrophic and may be totally replaced by fibrous tissue in many of the lobules, PANCREATITIS
Acute Hemorrhagic Pancreatitis The etiology of acute hemorrhagic pancreatitis is not known, but biliary or pancreatic duct obstruction, reflux of bile, focal ischemia, infection, circulating proteolytic enzymes, autoimmunization, trauma and alcoholism certainly are contributing factors. Any one of these, or a combination of them, may result in acute hemorrhagic pancreatitis. Alcoholism frequently plays a dominant role. Grossly, the pancreas may be greatly enlarged and edematous. Areas of gray-white necrosis of the parenchyma, foci of freshly extravasated blood and chalky white areas of fat necrosis are commonly seen, Initially there may be extreme edema. This is soon followed by tissue destruction caused by the escape of enzymes, resulting in the characteristic fat necrosis. Necrosis of the blood vessels results in extravasation of blood and accounts for the hemorrhagic areas, which may be extensive. One of the most characteristic histologic features is focal fat necrosis in which the stroma of the pancreatic and peripancreatic fat presents as ghostlike structures. The fat cells are represented by granular pink material. These necrotic fatty foci may eventually become calcified. In addition to fat necrosis there is destruction of the exocrine portion of the pancreas by coagulative necrosis. Early in the disease, inflammation is represented by infiltration of neutrophils. Confluence of the liquefactive and coagulative necrosis may result in a pseudocyst.
Acute Suppurative
Pancreatitis
Suppuration in the pancreas may result from infection in a neighboring organ, e.g., acute appendicitis or perforated peptic ulcer. According to a recent review, however, most instances of pancreatic abscess follow an episode of acute pancreatitis.l’j In this series, most of the abscesses were located in the left subphrenic or retroperitoneal space and originated in the tail or in the body. Usually the roentgen findings were helpful in establishing the diagnosis of abscess by revealing displacement of adjacent organs. The larger abscesses
Fig l.-Chronic pancreatitis with fibrous obliteration of the lobular pattern. Intraductal calcification is noted (arrows). The overlying duodenum is not remarkable.
are life-endangering undergo liquefaction calcified.
and require surgical intervention. Small abscesses may and eventual pseudocyst formation. Others may become
Chronic Pancreatitis Chronic pancreatitis represents a progressive destruction of the pancreatic parenchyma and frequently is associated with chronic alcoholism and biliary tract disease. Grossly, the pancreas is firm and sometimes nodular (Fig. 1). In acute exacerbations, one may see edema, acute inflammation, fat necrosis and destruction of parenchymal elements. But gradually fibrous replacement of much of the parenchyma, including the acinar and the islet cells, occurs (Fig. 2). Ducts may be obliterated or they may become dilated; they often contain calculi. Interstitial calcification is less frequent, but when present the calcification is often detectable radiographically. In one series, it was observed in 57 per cent of the patients. lo In 50 per cent or more of the patients with extensive destruction of the pancreatic parenchyma, there is exocrine pancreatic insufficiency or diabetes mellitus.1° Also of interest radiologically is calcification in the medullary cavity of a long bone. This is associated with fat necrosis in the marr0w.l PANCREATIC CYSTS Cysts of the pancreas may be classified as follows: (1) retention cyst, (2) congenital cyst, (3) pseudocyst, (4) parasitic cyst, and (5) neoplastic cyst. Retention cyst is usually associated with chronic pancreatitis, apparently resulting from duct obstruction. They are often multiple but each cyst is generally unilocular and communicates with adjacent ducts. The cysts are seldom of clinical significance but occasionally may enlarge to a diameter of 15 to 20 cm. The cyst fluid, like that of a pseudocyst, may show a high amylase level. Histologically, the cyst wall is often thin and fibrous and lined by a flattened to low cuboidal epithelium; in some, the epithelium has been destroyed. Inflammation, evidence of old and recent hemorrhage and calcification may be seen in the wall of the cyst. The retention cyst is considered to have its origin within the pancreas and is often located toward the tail. In contrast, the pseudocyst is generally believed to be an extrapancreatic lesion and is most often located near the body or head.7
SPJUT
AND
ANDERSON
Fig. 2.-Chronic panF i b r o si s, creatitis.
inflammation chronic and loss of acinar tissue are evident. Duct dilatation is minimal.
Congenital cysts are multiple and often associated with cysts of other organs, for example, the liver. At times they may enlarge to a diameter of 5 cm. Their walls are thin unless inflammation intervenes. The lining epithelium is usually flattened to cuboidal. The cysts are believed to be the result of malformation of the pancreatic ducts.’ Pseudocyst is most commonly seen in adults, especially men, although an occasional case has been reported in a child, The cyst usually develops as a complication of acute or chronic pancreatitis or after abdominal trauma. The cyst may be large, displacing surrounding structures, particularly the stomach, or widening the duodenal loop. Thus roentgen examination of the abdomen is usually helpful in making the diagnosis. The majority of pseudocysts are IOcated in the vicinity of the head or body of the pancreas with an occasional one being confined to the tail. They commonly involve the gastrohepatic omentum, the gastrocolic ligament or the transverse mesocolonl’ Occasional cases of extension superiorly into the mediastinum’” or inferiorly into the pelvis have been reported. Grossly, the cyst is unilocular and may contain several liters of fluid (Fig. 3). Histologically, the wall is fibrous and exhibits varying degrees of inflammatory alteration. There is no lining epithelium. Portions of the cyst wall may actually be lined by exudate or granulation tissue.
PATHOLOGY OF THE PANCREAS
221
Rare cases of echinococcus cyst of the pancreas have been described. NeopZa&c cysts will be discussed under the subject of Neoplasm. DIABETES MELLITUS
Grossly, the pancreas in diabetes mellitus may show no alterations. Changes in the islet cells vary with the type of diabetes. In the islets of the juvenile diabetic there is degranulation of the beta cells. Fibrosis of the islets may be present and, in some instances, a scattering of lymphocytes may be seen. In contrast, the adult type of diabetes exhibits a normal number of islets with the beta granulation normal or only moderately reduced. Extensive or focal hyalinization may be observed within the islets. However, approximately 20 per cent of adult diabetics will show no pathologic changes in the islets.14 Although pathologic changes in the pancreas of diabetic patients are seldom observed roentgenographically, the complication of diabetes mellitus (e.g., early vascular disease, urinary infection) often result in radiographic alterations in other parts of the body. NEOPLASMS OF THE PANCREAS
Adenocarcinoma The most common primary neoplasm of the pancreas is adenocarcinoma, usually of ductal origin, and this malignant lesion far exceeds benign growths in incidence and importance. More than 95 per cent of patients are over 40 years of age at the time of death and the tumor comprises 5 per cent of malignant tumors in patients over 40. In most series, men are afflicted more often than women by a ratio of about 2:l. The most common presenting symptom in the large series of Bell” was abdominal pain, usually epigastric, with radiation to the midback. Because the majority of lesions are located in the head of the pancreas, jaundice frequently results and was present in two thirds of the patients in Klintrup’s review.‘” The majority of patients die within a year of the initial symptoms. Grossly, the tumors are poorly demarcated, with firm to hard masses which deform the normal outline of the pancreas and obliterate the lobular pancreatic architecture (Fig. 4). Adenocarcinoma in the head of the pancreas commonly causes ductal obstruction and secondary inflammation and fibrosis
222
SPJUT
AND
ANDERSON
which contribute not only to the bulk of the lesion but also to its firmness. Neoplasms with excessive mucin production and those with large necrotic areas may be palpably soft and occasionally look like cysts. Fat necrosis with calcification and pancreatic lithiasis may be present. Tumors of only moderate size may infiltrate adjacent structures and alter their position and contours. The common bile duct is frequently involved by extrinsic pressure or by direct tumor invasion with resultant obstructive jaundice. The duodenum and stomach are invaded in 20 per cent of the patients, leading to fixation and even luminal ulceration and hemorrhage (Fig. 5). Nerve involvement appears to account for the pain in at least some cases of carcinoma of the pancreas. Drapiewski” identified nerve invasion in 85 per cent of his cases. The body or tail of the pancreas may be the primary site of the neoplasm. Lesions in these locations are often more extensive and completely nonresectable when detected. A large tumor in the tail of the pancreas may simulate primary neoplasm of the left kidney. At times, the entire pancreas may show diffuse neoplastic transfomration, or multiple separate discrete tumor nodules may be located at several points within the organ. Microscopically, adenocarcinoma of the pancreas is an infiltrating, glandforming neoplasm usually of ductal rather than acinar origin (Fig. 6). The small neoplastic glands are embedded in a proliferative fibrous connective tissue in which there is an inflammatory cell infiltrate. Direct continuity with residual pancreatic ducts may be identified. An uncommon variant is an adenocarcinoma with abundant mucin production in which the neoplastic glands are large and filled with mucin. Areas of necrosis and hemorrhage may be present with variable-sized cysts, Calcification in necrotic areas as well as in inflammatory foci in the adjacent fat can be recognized.
Islet Cell Tumor Islet cell tumor of the pancreas comprises a small but important group of lesions because they may be functional. It has b’een estimated that 70 per cent of islet cell tumors are associated with hyperinsulinism and hypoglycemia.ll Tumor size appears to be unrelated to the presence or severity of hypoglycemic attacks. It is difficult to establish pathologically whether an islet cell neoplasm is benign or malignant (Fig. 7). In a review of the literature, HOWard et al. found the incidence of malignancy to be 10 per cent.ll Metastases
PATHOLOGY
OF
THE
PANCREAS
223
may appear many years after the primary tumor is discovered. Most islet cell tumors are in the body or tail of the pancreas with only about 25 per cent in the head.
Fig. 6.-Adenocarcinoma of the pancreas,
diffusely infiltrating, poorly differentiated. Same patient as Fig. 4. Nerve invasion is noted at the upper right-hand corner.
Fig. 7.-Islet cell tumors. A. Solitary tumor, considered to be benign, of the head of the pancreas in a child. (Courtesy of Dr. Harvey Rosenberg, Texas Children’s Hospital, Houston, Texas.) B. Malignant tumor of the head of the pancreas. Duodenal mucosa partly covered the mass, which measured 7 cm. in greatest dimension. Bone and calcium were present. A metastasis was found in one regional lymph node.
SPJUT
AND
ANDERSON
Fig. 8.-Islet cell carcinoma. Photomicrograph of the tumor in Fig. 7B. The cells are of uniform size and arranged in narrow ribbons. Numerous thinwalled vessels are present. Although this field is taken from the metastasis, it is indistinguishable from a benign tumor.
A fulminating peptic ulcer diathesis with gastric hypersecretion associated with noninsulin-producing islet cell tumors has been reported by Zollinger and Ellison.6~1s The tumors are multiple in about half of the cases; 19 per cent of these are microadenomas and scattered throughout the pancreas, About 60 per cent of these tumors are malignant and 44 per cent of these have metastases. Tumors of other endocrine glands may be associated with this syndrome. Islet cell tumors are well circumscribed and generally small, varying from a few millimeters up to 5 cm. in diameter. A fibrous connective tissue capsule surrounds the red-gray lesion, and calcification and true bone formation may appear centrally as the result of degenerative changes. We have also seen bone formation in peripancreatic lymph node metastases from islet cell carcinoma. Malignant lesions are recognized by capsular invasion and metastases to the regional lymph nodes and liver. Microscopically, the cells resemble those of the normal islands of Langerhan’s (Fig, 8). Special staining technics are employed to demonstrate cytoplasmic granules and the lesions usually are predominantly composed of beta ceIIs. Cystadenomu
and Cystadenocarcinomu
The cystadenoma is a rare but distinctive benign neoplasm which arises from pancreatic ducts, usually in the tail of the pancreas. It occurs predominantly in females. Distinction should be made from pseudocyst and retention cyst. The cystadenoma is spherical and varies from 2 to 15 cm. or more in diameter. A tense capsule surrounds the tumor, which is firm or rubbery and nodular. Visible on the cut surface are honeycombed cystic spaces ranging from microscopic to several centimeters in diameter and filled with viscous fluid (Fig. 9). Fibrous connective tissue stroma separates the individual cystic spaces. The fibrous capsule as we11 as the connective tissue septa may contain calcium, producing a stellate radiographic pattern. The epithelium that lines the cystic spaces varies from flat to tall columnar (Fig. 10). Occasionally, papillary areas are present; these may create difficulty in distinguishing microscopically benign from malignant lesions. The unusual cystadenocarcinoma presents many clinical radiographic and
PATHOLOGY
OF
THE
PANCREAS
225
surgical similarities to its benign counterpart. The course may be slowly progressive with a tendency for recurrent disease to remain localized.’ Even more rare neoplasms of the pancreas have been described. Lymphangioma may involve the pancreas, and leiomyoma and leiomyosarcoma have been reported. Carcinoid is difficult to distinguish from islet cell neoplasm. Primary neoplasm of the duodenum or stomach may invade the pancreas, and carcinoma of the lung or breast may metastasize to it.
Fig. 9.-Cystadenoma in the body of the pancreas. A. Outer surface is nodular and covered by a fibrous capsule. B. The cut surface shows multicystic and fibrous areas. The tumor is well circumscribed.
Fig. 10. - Cystadenoma. Same case as in Fig. 9. Note the thinwalled papillary projections. The lining epithelium is flat to cuboidal.
286
SPJUT
AND
ANDERSON
REFERENCES 1. Bank, S., Marks, I. N., Farman, J., and Immelman, E. J.: Further observations on calcified medullary bone lesions in chronic pancreatitis. Gastroenterology 51:224, 1966. 2. Becker, W. F., Welsh, R. A., and Pratt, H. S.: Cystadenoma and cystadenocarcinoma of the pancreas. Ann. Surg. 161: 845, 1965. 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, 1957. 4. di Sant’Agnese, P. A., and Lepore, M. J.: Involvement of abdominal organs in cystic fibrosis of the pancreas. Gastroenterology 40:64, 1961. 5. Drapiewski, J. F.: Carcinoma of the pancreas : A shady of neoplastic invasion of nerves and its possible clinical significance. Amer. J. Clin. Path. 14:549, 1944. 6. Ellison, E. H., and Wilson, S. D.: The Zollinger-Ellison syndrome: Re-appraisal and evaluation of 260 registered cases. Ann. Surg. 160: 152, 1964. 7. Frantz, V. K.: Tumors of the Pancreas. Armed Forces Institute of Pathology, 1959. 8. Grossman, H., Berdon, W. E., and Baker, D. H.: Gastrointestinal findings in cystic fibrosis. Amer. J. Roentgen. 97:227, 1966. 9. Harcourt, K. F., and Chandler, J. J.: Annular pancreas in the newborn. Northwest Med. 64:746, 1965.
10. Hermann, R. E.: Clinical aspects of pancreatitis: An analysis of 100 consecutive cases. Postgrad. Med. 36:135, 1964. 11. Howard, J. M., Moss, N. H., and Rhoads, J. E.: Hyperinsulinism and islet cell tumors of the pancreas: With 398 recorded tumors. Surg. Gynec. Obstet. 90:417, 1950. 12. Hyden, W. H.: The true nature of annular pancreas. Ann. Surg. 157:71, 1963. 13. Klintrup, H. E.: Carcinoma of the pancreas: A statistical, clinical and pathological study. Acta Chir. Stand. Suppl. 362: 1, 1966. 14. Lacy, P. E.: Pathology of the islets of Langerhans. In Sommers, S. C. (Ed.): Pathology Annual. New York, AppletonCentury-Crofts, 1966. 15. Laird, C. A,, and Clagett, 0. T.: Mediastinal pseudocyst of the pancreas in a child: Report of a case. Surgery 60:465, 1966. 16. Steedman, R. A., Doring, R., and Carter, R.: Surgical aspects of pancreatic abscess. Surg. Gynec. Obstet. 125:757, 1967. 17. Walker, L. G., Jr., Stone, H. H., and Apple, D. G.: Pseudocysts of the pancreas: A review of 59 cases. Southern Med. J. 60: 389, 1967. 18. Zollinger, R. M., and Ellison, E. H.: Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Arm. Surg. 142:709, 1955.
of the Pancreas
By HARLAN J. SPJUT, M.D., AND M. SIDNEY ANDERSON, M.D.
K
NOWLEDGE of the pathologic alterations of the pancreas and its effects
upon neighboring structures is important in the everyday practice of radiology. Several pancreatic diseases have systemic effects, e.g., diabetes mellitus and fibrocystic disease, and these have their own set of pathologic and radiologic manifestations. In this brief survey of the pathology of disease of the pancreas, only a few can be discussed and then only their salient features emphasized. CONGENITAL MALFORMATIONS OF THE PANCREAS
Heterotopic
Pancreas
Heterotopic pancreatic tissue, usually in the form of intramural nodules, may be found in the gastrointestinal tract in as many as 2 per cent of all postmortem examinations. The most common sites are the stomach, duodenum, small bowel and large bowel, in decreasing order of frequency. The lesions are usually submucosal but may be in the muscularis or even the serosa. They present as smooth nodules occasionally having a pit in the domelike center. This pit may at times give the radiologic appearance of an ulcer. Histologically, the lesion is composed of elements of the pancreas, usually the acinar and ductal structures, less frequently the islets of Langerhans. In rare circumstances, heterotopic pancreas of the small bowel may be the focus of an intussusception. Annular
Pancreas
This malformation of the pancreas is thought to be caused by failure of the ventral pancreatic evagination of the foregut to rotate dorsally with the duodenum during the seventh week of embryologic development. The head of the pancreas may completely or incompletely surround the duodenum. Occasionally, the lumen of the duodenum may actually be obliterated at the site of encirclement. The duodenal constriction may occur at, above or below the papilla of Vater. The lesion is most frequently encountered in newborn children; however, the possibility must not be ignored in the adult. Pathologically, the lesion consists of normal pancreatic parenchyma. However, a recent description indicates that there often is a mingling of pancreatic tissue with the duodenal muscularis. This has been suggested as one of the reasons why resection of the constricting pancreatic band sometimes fails to relieve the obstruction.g,13 Fibrocystic
Disease of the Pancreas
Fibrocystic disease of the pancreas is a hereditary disease of exocrine glands seen most frequently in children and young adults. Although it was once conHARLAN J. SPJUT, M.D., and M. SIDNEY ANDERSON, M.D.: Department of Pathology, Baylor University College of Medicine and the Methodist Hospital, Houston, Texas. SEMINARS
IN ROENTGENOLOGY,
VOL. 3, No. 3 (JULY ) , 1968
217
218
SPJUT
AND ANDERSOX
sidered predominantly a pancreatic disease, it is now recognized that this disorder involves many gland systems, including the sweat glands, the salivary glands, and those of the tracheobronchial, biliary and gastrointestinal mucosa.4 Thus, it is apparent that this disease may manifest itself in many organs. Pneumonia, bronchiectasis and meconium ileus are but a few of its many complications.h One of the commonest causes of prolapse of the rectum in infancy and childhood is fibrocystic disease of the pancreas. Focal biliary cirrhosis and mucocele of the gallbladder may also occur. Rarely is cystic fibrosis complicated by diabetes mellitus. Grossly, the pancreas is usually firm and of normal size. Cysts are inconspicuous but may be present in the advanced stages. Histologically, the acini and ducts are dilated. The latter contain inspissated material thought to be abnormal mucus. The pancreatic acini are usually atrophic and may be totally replaced by fibrous tissue in many of the lobules, PANCREATITIS
Acute Hemorrhagic Pancreatitis The etiology of acute hemorrhagic pancreatitis is not known, but biliary or pancreatic duct obstruction, reflux of bile, focal ischemia, infection, circulating proteolytic enzymes, autoimmunization, trauma and alcoholism certainly are contributing factors. Any one of these, or a combination of them, may result in acute hemorrhagic pancreatitis. Alcoholism frequently plays a dominant role. Grossly, the pancreas may be greatly enlarged and edematous. Areas of gray-white necrosis of the parenchyma, foci of freshly extravasated blood and chalky white areas of fat necrosis are commonly seen, Initially there may be extreme edema. This is soon followed by tissue destruction caused by the escape of enzymes, resulting in the characteristic fat necrosis. Necrosis of the blood vessels results in extravasation of blood and accounts for the hemorrhagic areas, which may be extensive. One of the most characteristic histologic features is focal fat necrosis in which the stroma of the pancreatic and peripancreatic fat presents as ghostlike structures. The fat cells are represented by granular pink material. These necrotic fatty foci may eventually become calcified. In addition to fat necrosis there is destruction of the exocrine portion of the pancreas by coagulative necrosis. Early in the disease, inflammation is represented by infiltration of neutrophils. Confluence of the liquefactive and coagulative necrosis may result in a pseudocyst.
Acute Suppurative
Pancreatitis
Suppuration in the pancreas may result from infection in a neighboring organ, e.g., acute appendicitis or perforated peptic ulcer. According to a recent review, however, most instances of pancreatic abscess follow an episode of acute pancreatitis.l’j In this series, most of the abscesses were located in the left subphrenic or retroperitoneal space and originated in the tail or in the body. Usually the roentgen findings were helpful in establishing the diagnosis of abscess by revealing displacement of adjacent organs. The larger abscesses
Fig l.-Chronic pancreatitis with fibrous obliteration of the lobular pattern. Intraductal calcification is noted (arrows). The overlying duodenum is not remarkable.
are life-endangering undergo liquefaction calcified.
and require surgical intervention. Small abscesses may and eventual pseudocyst formation. Others may become
Chronic Pancreatitis Chronic pancreatitis represents a progressive destruction of the pancreatic parenchyma and frequently is associated with chronic alcoholism and biliary tract disease. Grossly, the pancreas is firm and sometimes nodular (Fig. 1). In acute exacerbations, one may see edema, acute inflammation, fat necrosis and destruction of parenchymal elements. But gradually fibrous replacement of much of the parenchyma, including the acinar and the islet cells, occurs (Fig. 2). Ducts may be obliterated or they may become dilated; they often contain calculi. Interstitial calcification is less frequent, but when present the calcification is often detectable radiographically. In one series, it was observed in 57 per cent of the patients. lo In 50 per cent or more of the patients with extensive destruction of the pancreatic parenchyma, there is exocrine pancreatic insufficiency or diabetes mellitus.1° Also of interest radiologically is calcification in the medullary cavity of a long bone. This is associated with fat necrosis in the marr0w.l PANCREATIC CYSTS Cysts of the pancreas may be classified as follows: (1) retention cyst, (2) congenital cyst, (3) pseudocyst, (4) parasitic cyst, and (5) neoplastic cyst. Retention cyst is usually associated with chronic pancreatitis, apparently resulting from duct obstruction. They are often multiple but each cyst is generally unilocular and communicates with adjacent ducts. The cysts are seldom of clinical significance but occasionally may enlarge to a diameter of 15 to 20 cm. The cyst fluid, like that of a pseudocyst, may show a high amylase level. Histologically, the cyst wall is often thin and fibrous and lined by a flattened to low cuboidal epithelium; in some, the epithelium has been destroyed. Inflammation, evidence of old and recent hemorrhage and calcification may be seen in the wall of the cyst. The retention cyst is considered to have its origin within the pancreas and is often located toward the tail. In contrast, the pseudocyst is generally believed to be an extrapancreatic lesion and is most often located near the body or head.7
SPJUT
AND
ANDERSON
Fig. 2.-Chronic panF i b r o si s, creatitis.
inflammation chronic and loss of acinar tissue are evident. Duct dilatation is minimal.
Congenital cysts are multiple and often associated with cysts of other organs, for example, the liver. At times they may enlarge to a diameter of 5 cm. Their walls are thin unless inflammation intervenes. The lining epithelium is usually flattened to cuboidal. The cysts are believed to be the result of malformation of the pancreatic ducts.’ Pseudocyst is most commonly seen in adults, especially men, although an occasional case has been reported in a child, The cyst usually develops as a complication of acute or chronic pancreatitis or after abdominal trauma. The cyst may be large, displacing surrounding structures, particularly the stomach, or widening the duodenal loop. Thus roentgen examination of the abdomen is usually helpful in making the diagnosis. The majority of pseudocysts are IOcated in the vicinity of the head or body of the pancreas with an occasional one being confined to the tail. They commonly involve the gastrohepatic omentum, the gastrocolic ligament or the transverse mesocolonl’ Occasional cases of extension superiorly into the mediastinum’” or inferiorly into the pelvis have been reported. Grossly, the cyst is unilocular and may contain several liters of fluid (Fig. 3). Histologically, the wall is fibrous and exhibits varying degrees of inflammatory alteration. There is no lining epithelium. Portions of the cyst wall may actually be lined by exudate or granulation tissue.
PATHOLOGY OF THE PANCREAS
221
Rare cases of echinococcus cyst of the pancreas have been described. NeopZa&c cysts will be discussed under the subject of Neoplasm. DIABETES MELLITUS
Grossly, the pancreas in diabetes mellitus may show no alterations. Changes in the islet cells vary with the type of diabetes. In the islets of the juvenile diabetic there is degranulation of the beta cells. Fibrosis of the islets may be present and, in some instances, a scattering of lymphocytes may be seen. In contrast, the adult type of diabetes exhibits a normal number of islets with the beta granulation normal or only moderately reduced. Extensive or focal hyalinization may be observed within the islets. However, approximately 20 per cent of adult diabetics will show no pathologic changes in the islets.14 Although pathologic changes in the pancreas of diabetic patients are seldom observed roentgenographically, the complication of diabetes mellitus (e.g., early vascular disease, urinary infection) often result in radiographic alterations in other parts of the body. NEOPLASMS OF THE PANCREAS
Adenocarcinoma The most common primary neoplasm of the pancreas is adenocarcinoma, usually of ductal origin, and this malignant lesion far exceeds benign growths in incidence and importance. More than 95 per cent of patients are over 40 years of age at the time of death and the tumor comprises 5 per cent of malignant tumors in patients over 40. In most series, men are afflicted more often than women by a ratio of about 2:l. The most common presenting symptom in the large series of Bell” was abdominal pain, usually epigastric, with radiation to the midback. Because the majority of lesions are located in the head of the pancreas, jaundice frequently results and was present in two thirds of the patients in Klintrup’s review.‘” The majority of patients die within a year of the initial symptoms. Grossly, the tumors are poorly demarcated, with firm to hard masses which deform the normal outline of the pancreas and obliterate the lobular pancreatic architecture (Fig. 4). Adenocarcinoma in the head of the pancreas commonly causes ductal obstruction and secondary inflammation and fibrosis
222
SPJUT
AND
ANDERSON
which contribute not only to the bulk of the lesion but also to its firmness. Neoplasms with excessive mucin production and those with large necrotic areas may be palpably soft and occasionally look like cysts. Fat necrosis with calcification and pancreatic lithiasis may be present. Tumors of only moderate size may infiltrate adjacent structures and alter their position and contours. The common bile duct is frequently involved by extrinsic pressure or by direct tumor invasion with resultant obstructive jaundice. The duodenum and stomach are invaded in 20 per cent of the patients, leading to fixation and even luminal ulceration and hemorrhage (Fig. 5). Nerve involvement appears to account for the pain in at least some cases of carcinoma of the pancreas. Drapiewski” identified nerve invasion in 85 per cent of his cases. The body or tail of the pancreas may be the primary site of the neoplasm. Lesions in these locations are often more extensive and completely nonresectable when detected. A large tumor in the tail of the pancreas may simulate primary neoplasm of the left kidney. At times, the entire pancreas may show diffuse neoplastic transfomration, or multiple separate discrete tumor nodules may be located at several points within the organ. Microscopically, adenocarcinoma of the pancreas is an infiltrating, glandforming neoplasm usually of ductal rather than acinar origin (Fig. 6). The small neoplastic glands are embedded in a proliferative fibrous connective tissue in which there is an inflammatory cell infiltrate. Direct continuity with residual pancreatic ducts may be identified. An uncommon variant is an adenocarcinoma with abundant mucin production in which the neoplastic glands are large and filled with mucin. Areas of necrosis and hemorrhage may be present with variable-sized cysts, Calcification in necrotic areas as well as in inflammatory foci in the adjacent fat can be recognized.
Islet Cell Tumor Islet cell tumor of the pancreas comprises a small but important group of lesions because they may be functional. It has b’een estimated that 70 per cent of islet cell tumors are associated with hyperinsulinism and hypoglycemia.ll Tumor size appears to be unrelated to the presence or severity of hypoglycemic attacks. It is difficult to establish pathologically whether an islet cell neoplasm is benign or malignant (Fig. 7). In a review of the literature, HOWard et al. found the incidence of malignancy to be 10 per cent.ll Metastases
PATHOLOGY
OF
THE
PANCREAS
223
may appear many years after the primary tumor is discovered. Most islet cell tumors are in the body or tail of the pancreas with only about 25 per cent in the head.
Fig. 6.-Adenocarcinoma of the pancreas,
diffusely infiltrating, poorly differentiated. Same patient as Fig. 4. Nerve invasion is noted at the upper right-hand corner.
Fig. 7.-Islet cell tumors. A. Solitary tumor, considered to be benign, of the head of the pancreas in a child. (Courtesy of Dr. Harvey Rosenberg, Texas Children’s Hospital, Houston, Texas.) B. Malignant tumor of the head of the pancreas. Duodenal mucosa partly covered the mass, which measured 7 cm. in greatest dimension. Bone and calcium were present. A metastasis was found in one regional lymph node.
SPJUT
AND
ANDERSON
Fig. 8.-Islet cell carcinoma. Photomicrograph of the tumor in Fig. 7B. The cells are of uniform size and arranged in narrow ribbons. Numerous thinwalled vessels are present. Although this field is taken from the metastasis, it is indistinguishable from a benign tumor.
A fulminating peptic ulcer diathesis with gastric hypersecretion associated with noninsulin-producing islet cell tumors has been reported by Zollinger and Ellison.6~1s The tumors are multiple in about half of the cases; 19 per cent of these are microadenomas and scattered throughout the pancreas, About 60 per cent of these tumors are malignant and 44 per cent of these have metastases. Tumors of other endocrine glands may be associated with this syndrome. Islet cell tumors are well circumscribed and generally small, varying from a few millimeters up to 5 cm. in diameter. A fibrous connective tissue capsule surrounds the red-gray lesion, and calcification and true bone formation may appear centrally as the result of degenerative changes. We have also seen bone formation in peripancreatic lymph node metastases from islet cell carcinoma. Malignant lesions are recognized by capsular invasion and metastases to the regional lymph nodes and liver. Microscopically, the cells resemble those of the normal islands of Langerhan’s (Fig, 8). Special staining technics are employed to demonstrate cytoplasmic granules and the lesions usually are predominantly composed of beta ceIIs. Cystadenomu
and Cystadenocarcinomu
The cystadenoma is a rare but distinctive benign neoplasm which arises from pancreatic ducts, usually in the tail of the pancreas. It occurs predominantly in females. Distinction should be made from pseudocyst and retention cyst. The cystadenoma is spherical and varies from 2 to 15 cm. or more in diameter. A tense capsule surrounds the tumor, which is firm or rubbery and nodular. Visible on the cut surface are honeycombed cystic spaces ranging from microscopic to several centimeters in diameter and filled with viscous fluid (Fig. 9). Fibrous connective tissue stroma separates the individual cystic spaces. The fibrous capsule as we11 as the connective tissue septa may contain calcium, producing a stellate radiographic pattern. The epithelium that lines the cystic spaces varies from flat to tall columnar (Fig. 10). Occasionally, papillary areas are present; these may create difficulty in distinguishing microscopically benign from malignant lesions. The unusual cystadenocarcinoma presents many clinical radiographic and
PATHOLOGY
OF
THE
PANCREAS
225
surgical similarities to its benign counterpart. The course may be slowly progressive with a tendency for recurrent disease to remain localized.’ Even more rare neoplasms of the pancreas have been described. Lymphangioma may involve the pancreas, and leiomyoma and leiomyosarcoma have been reported. Carcinoid is difficult to distinguish from islet cell neoplasm. Primary neoplasm of the duodenum or stomach may invade the pancreas, and carcinoma of the lung or breast may metastasize to it.
Fig. 9.-Cystadenoma in the body of the pancreas. A. Outer surface is nodular and covered by a fibrous capsule. B. The cut surface shows multicystic and fibrous areas. The tumor is well circumscribed.
Fig. 10. - Cystadenoma. Same case as in Fig. 9. Note the thinwalled papillary projections. The lining epithelium is flat to cuboidal.
286
SPJUT
AND
ANDERSON
REFERENCES 1. Bank, S., Marks, I. N., Farman, J., and Immelman, E. J.: Further observations on calcified medullary bone lesions in chronic pancreatitis. Gastroenterology 51:224, 1966. 2. Becker, W. F., Welsh, R. A., and Pratt, H. S.: Cystadenoma and cystadenocarcinoma of the pancreas. Ann. Surg. 161: 845, 1965. 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, 1957. 4. di Sant’Agnese, P. A., and Lepore, M. J.: Involvement of abdominal organs in cystic fibrosis of the pancreas. Gastroenterology 40:64, 1961. 5. Drapiewski, J. F.: Carcinoma of the pancreas : A shady of neoplastic invasion of nerves and its possible clinical significance. Amer. J. Clin. Path. 14:549, 1944. 6. Ellison, E. H., and Wilson, S. D.: The Zollinger-Ellison syndrome: Re-appraisal and evaluation of 260 registered cases. Ann. Surg. 160: 152, 1964. 7. Frantz, V. K.: Tumors of the Pancreas. Armed Forces Institute of Pathology, 1959. 8. Grossman, H., Berdon, W. E., and Baker, D. H.: Gastrointestinal findings in cystic fibrosis. Amer. J. Roentgen. 97:227, 1966. 9. Harcourt, K. F., and Chandler, J. J.: Annular pancreas in the newborn. Northwest Med. 64:746, 1965.
10. Hermann, R. E.: Clinical aspects of pancreatitis: An analysis of 100 consecutive cases. Postgrad. Med. 36:135, 1964. 11. Howard, J. M., Moss, N. H., and Rhoads, J. E.: Hyperinsulinism and islet cell tumors of the pancreas: With 398 recorded tumors. Surg. Gynec. Obstet. 90:417, 1950. 12. Hyden, W. H.: The true nature of annular pancreas. Ann. Surg. 157:71, 1963. 13. Klintrup, H. E.: Carcinoma of the pancreas: A statistical, clinical and pathological study. Acta Chir. Stand. Suppl. 362: 1, 1966. 14. Lacy, P. E.: Pathology of the islets of Langerhans. In Sommers, S. C. (Ed.): Pathology Annual. New York, AppletonCentury-Crofts, 1966. 15. Laird, C. A,, and Clagett, 0. T.: Mediastinal pseudocyst of the pancreas in a child: Report of a case. Surgery 60:465, 1966. 16. Steedman, R. A., Doring, R., and Carter, R.: Surgical aspects of pancreatic abscess. Surg. Gynec. Obstet. 125:757, 1967. 17. Walker, L. G., Jr., Stone, H. H., and Apple, D. G.: Pseudocysts of the pancreas: A review of 59 cases. Southern Med. J. 60: 389, 1967. 18. Zollinger, R. M., and Ellison, E. H.: Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Arm. Surg. 142:709, 1955.