The Japanese Journal of Surgery (1992) 22:284-287
@
SURGEaYTOgA~
© Springer-Verlag 1992
A Case of Intraductal Papillary Adenocarcinoma of the Pancreas Associated with Mass Forming Chronic Pancreatitis NAOTAKAKADOYA,TAKUKAZUNAGAKAWA,TETSUOOHTA, WATARUFUKUSHIMA,KAZUHIROMORI, TATSUONAKANO, NOBUHIKOUEDA, MASATOKAYAHARA,TAKAYOSHIAKIYAMA,KEIICHIUENO, ICHIROKONISHI,and ITSUOMIYAZAKI Second Departmentof Surgery,KanazawaUniversitySchoolof Medicine,Kanazawa,Japan
Abstract: A case of intraductal papillary adenocarcinoma of the pancreas associated with mass forming chronic pancreatitis without calcifications is described. Pancreatolithiasis, or calcified pancreas, is recognized as a high risk factor f~r pancreatic cancer. However, epidemiologic studies have found that carcinoma of the pancreas associated with chronic pancreatits was rare. The question is whether chronic pancreatitis without calcifications is actually a precancerous background lesion or not. This case suggests that hyperplasia of the pancreatic ductal epithelium may be a precancerous lesion for pancreatic cancer in some patients with chronic pancreatitis.
Key .Words: intraductal papillary adenocarcinoma of the
pancreas, chronic pancreatitis, pancreatic ductal hyperplasia
Introduction
Pancreatolithiasis, or calcified pancreas, is recognized as a high risk factor for carcinoma of the pancreas,~'2 but pancreatolithiasis describes both chronic calcified pancreatitis, and pancreatic cancer with calcifications. In epidemiologic studies, the association between carcinoma of the pancreas and chronic pancreatitis has been rare. 3"4 To determine whether chronic pancreatitis without calcifications is in fact a risk factor for pancreatic cancer or not, 5 we describe a case of intraductal papillary adenocarcinoma of the pancreas associated with mass forming chronic pancreatitis without calcifications and present the detailed pathologic findings.
Reprint requests to: Naotaka Kadoya, MD, Second Department of Surgery, Kanazawa University, 13-1 Takaramachi, Kanazawa 920, Japan (Received for publication on Nov. 2, 1990)
Case Report
A 77-year-old man was transferred to Kanazawa University Hospital with a chief complaint of severe right hypochondralgia. He had been on medication for diabetes mellitus for 20 years, On physical examination, he appeared healthy without any signs of anemia or jaundice. A palpable mass was noted in the right hypochondrium, which was suspected of being a swollen gall bladder. The liver function tests were as follows: serum glutamic oxaloacetic transaminase (sGOT) 817IU/L, serum glutamic pyruvic transaminase (sGPT) 383IU/L, alkaline phosphatase 2581IU/L, and total bilirubin 1.4mg/dl. Carcinoembrionic antigen (CEA) was 3.4 ng/ml and carbohydrate antigen 1%9 (CA 19-9) was 48U/ml. Abdominal ultrasonography and computed tomography (CT) revealed a mass in the head of the pancreas 4cm in diameter, a dilated main pancreatic duct and a gall stone (Fig. 1A). Contrast-enhanced CT revealed a homogenous stain of the mass (Fig. 1B). On celiac angiography, some branches of the anterior superior pancreatoduodenal artery were observed to be serrated in the arterial phase, but no encasement or stenosis of any other branches was noted. A cholangiogram obtained through a percutaneous transhepatic cholangiodrainage (PTCD) catheter, and a pancreatogram by endoscopic retrograde pancreatography (ERP) revealed a smooth narrowing in the distal bile duct and a 3cm serration of the main pancreatic duct at the junction of the pancreatic head and neck (Fig. 2). Preoperatively, a mass forming chronic pancreatitis was suspected because the mass in the head of the pancreas stained homogenously on the contrast-enhanced CT, the main pancreatic duct was serrated but not completely obstracted, and the changes on celiac angiography were less marked than usually observed in pancreatic cancer. A pancreatoduodenectomy was performed because we could not rule out pancreatic
N. Kadoya et al.: Intraductal Papillary Adenocarcinoma
285
Fig. 3. Low power view of hyperplastic epithelium of the main pancreatic duct (H&E, x22)
Fig. 1. A Computed tomography (CT) revealed a mass in the head of the pancreas (arrow)4 cm in diameter, a dilated main pancreatic duct, and a gall stone. B Contrast-enhanced CT revealed homogenous stain of a mass in the head of the pancreas (arrow)
Fig. 4. High-power view of hyperplastic epithelium with papillomatous elements, which was confirmed as intraductal papillary adenocarcinoma of the pancreas (H&E, x55)
cancer completely, and the patient was extremely symptomatic.
Pathologic Findings
Fig. 2. A A cholangiogram revealed a smooth narrowing (arrow) in the distal bile duct. B A pancreatogram revealed a 3cm serration (arrow) of the main pancreatic duct at the junction of the pancreatic head and neck
The resected pancreas was hard, and the mass measured 6.0 x 4.5 x 3.5cm, with a smooth outer surface: The specimen was cut into serial section 5 m m in thickness, fixed in 10% neutral buffered formalin and e m b e d d e d in paraffin. Serial section 5 g thick were stained with hematoxylin-eosin ( H & E ) stain. Some sections were also used for histochemical staining of C E A and C A 19-9 by the peroxidase-antiperoxidase (PAP) method. 6 A control serum, instead of the primary specific antiserum, was used as the negative control. Sections of C A 19-9-producing panreatic
286
N. Kadoya et ai.: Intraductal Papillary Adenocarcinoma Discussion
Fig. 5. A Immunohistochemical staining with anti-CEA in intraductal papillary adenocarcinorna of the pancreas (× 110). B Immunohistochemical staining with anti-CA19-9 in intraductal papillary adenocarcinoma of the pancreas (× 110)
carcinoma and CEA-producing colonic carcinoma served as the positive controls. On histologic examination, the parenchyma of the pancreas was atrophic, while fibrosis and lymphocytic infiltration were observed throughout the stroma, and marked fibrotic changes of the stroma grossly formed a mass in the head of the pancreas. Fibrosis and lymphocytic infiltration were also observed around the main pancreatic duct, and the serrated change in the main pancreatic duct shown by ERP was mainly due to fibrosis around the main pancreatic duct. The epithelium of the main pancreatic duct showed hyperplastic changes and an intraductal spreading throughout the entire resected pancreas (Figs. 3, 4). In part of these hyperplastic epithelia with papillomatous elements, the nuclei showed severe atypia, with a loss of polarity, an increased nuclear-cytoplasmic ratio, hyperchromasia, and occasional mitotic figures, which we confirmed as intraductal papillary adenocarcinoma of the pancreas. No metastasis was noted in the regional lymph nodes or organs adjacent to the pancreas. Immunohistochemically, the loci of intraductal papillary adenocarcinoma of the pancreas showed a strong reactivity with anti-CEA and CA 19-9 staining as well as with the positive control. Namely, staining with antiCEA was observed markedly on the luminal surface of carcinoma cells and faintly in their cytoplasm (Fig. 5A). Staining with anti-CA19-9 was diffusely observed in the cytoplasm of carcinoma cells as well as on their luminal surface (Fig. 5B). The other foci of the hyperplastic epithelium only showed reactivity with anti-CA19-9. staining, which was observed restrictively on the luminal surface of these hyperplastic epithelium, but did not show any reactivity with anti-CEA staining.
It has been reported that pancreatolithiasis, or calcified pancreas, is a high risk factor for carcinoma of the pancreas, ~'2 but on the other hand, several studies have found that carcinoma of the pancreas is rarely associated with chronic pancreatitis. 3'4'7'8 PaulinoNetto et al. 1 have reported that the incidence of pancreatic cancer associated with pancreatolithiasis was 25 per cent, while Johnson et al. 2 have reported that the incidence of pancreatic cancer associated with pancreatolithiasis was only 3.7 per cent. These reports impressed us with the fact that pancreatic cancer is closely associated with pancreatolithiasis. However the term pancreatolithiasis, is not limited to chronic calcified pancreatitis, but also includes pancreatic cancer with calcifications. Ishii et al. 4 and Wynder3 have reported in their epidemiologic studies that chronic pancreatitis is not likely to be a precancerous lesion. On the other hand, it is well known that squamous metaplasia or goblet cell metaplasia of the pancreatic duct often occurs, and papillary hyperplasia of pancreatic duct is sometimes present in the case of pancreatic cancer9'~° or in aging healthy adults. ~1 Cublilla et al. 12 found that the incidence of papillary hyperplasia of the pancreatic duct in 227 patients with pancreatic cancer was three times higher than in 100 healthy adult controls matched according to age and sex. They reported that marked atypical hyperplasia was associated in 20 per cent and carcinoma in situ in 18 per cent in the uninvolved area of the pancreatic duct of pancreatic cancer patients, while marked atypical hyperplasia or carcinoma in situ was not present in any of the controls. These authors thus speculated that hyperplasia of the pancreatic duct may be a precancerous lesion. Intraductal carcinomas, such as mucin-producing pancratic cancer or cystoadenocarcinoma of the pancreas have a better prognosis than invasive ductal carcinoma. Morohoshi et al. 13 have argued that intraductal papillary neoplasms of the pancreas should be considered as a single clinical entity because they are limited to the ductal system and, if these intraductal papillary tumors have malignant potential, it is extremely low because no case of metastatic spread has yet been reported. Our case was, of course, non invasive, so better prognosis should be expected. Pancreatic cancer associated with chronic pancreatitis is rare, but as our case suggests, the hyperplastic epithelium of the main pancreatic duct may indeed be a precancerous lesion for pancreatic cancer in some patients with chronic pancreatitis.
N. Kadoya et al.: Intraductal Papillary Adenocarcinoma
References
1. Paulino-Netto A, Dreiling DA, Boronofsky ID (1960) The relationship between pancreatic calcification and cancer of the pancreas. Ann Surg 151:530-537 2. Johnson JR, Zintel HA (1963) Pancreatic calcification and cancer of the pancreas. Surg Gynecol Obstet 117:585-588 3. Wynder EL (1975) An epidemiological evaluation of the cause of cancer of the pancreas. Cancer Res 35:2228-2233 4. Ishii K, Nakamura K, Takeuchi T (1973) Chronic calcifying pancreatitis and pancreatic cancer in Japan. Digestion 9:429-437 5. Becker V (1978) Carcinoma of the pancreas and chronic pancreatitis: A possible relationship. Hepato gastroenterology 25:257-259 6. Sternberger LA (1979) The unlabeled antibody peroxidase antiperoxidase (PAP) method. In: Sternberger LA (ed) Immunocytochemistry. John Wiley and Sons, New York, pp 104-109
287 7. Gambill EE, Baggenstoss AH, Priestley JT (1960) Chronic relapsing pancreatitis, fate of fifty-six patients first encountered in the years 1939 to 1943. Gastroenterology 39:404-413 8. Amman R (1980) Zur Klinik und Differentialdiagnose der chronischen Pankreatitis (in German). $chweiz Med Wochenschr 110:1322-1327 9. Kozuka S (1979) Relation of pancreatic duct hyperplasia to carcinoma. Cancer 43:1418-1428 10. Kloppel G (1980) Intraductai proliferation in the pancreas and its relationship to human and experimental carcinogenesis. Virchows Arch [A] 387:221-233 11. Feldman M (1955) The pancreas in the aged, an autopsy study. Geriatrics 10:373-374 12. Cubilla LA, Fitzgerald PJ (1976) Morphological lesions associated with human primary invasive nonendocrine pancreas cancer. Cancer Res 36:2690-2698 13. Morohoshi T, Kanda M, Asanuma K (1989) Intraductal papillary neoplasms of the pancreas, a clinicopathologic study of six patients. Cancer 64:1329-1335
@
SURGEaYTOgA~
© Springer-Verlag 1992
A Case of Intraductal Papillary Adenocarcinoma of the Pancreas Associated with Mass Forming Chronic Pancreatitis NAOTAKAKADOYA,TAKUKAZUNAGAKAWA,TETSUOOHTA, WATARUFUKUSHIMA,KAZUHIROMORI, TATSUONAKANO, NOBUHIKOUEDA, MASATOKAYAHARA,TAKAYOSHIAKIYAMA,KEIICHIUENO, ICHIROKONISHI,and ITSUOMIYAZAKI Second Departmentof Surgery,KanazawaUniversitySchoolof Medicine,Kanazawa,Japan
Abstract: A case of intraductal papillary adenocarcinoma of the pancreas associated with mass forming chronic pancreatitis without calcifications is described. Pancreatolithiasis, or calcified pancreas, is recognized as a high risk factor f~r pancreatic cancer. However, epidemiologic studies have found that carcinoma of the pancreas associated with chronic pancreatits was rare. The question is whether chronic pancreatitis without calcifications is actually a precancerous background lesion or not. This case suggests that hyperplasia of the pancreatic ductal epithelium may be a precancerous lesion for pancreatic cancer in some patients with chronic pancreatitis.
Key .Words: intraductal papillary adenocarcinoma of the
pancreas, chronic pancreatitis, pancreatic ductal hyperplasia
Introduction
Pancreatolithiasis, or calcified pancreas, is recognized as a high risk factor for carcinoma of the pancreas,~'2 but pancreatolithiasis describes both chronic calcified pancreatitis, and pancreatic cancer with calcifications. In epidemiologic studies, the association between carcinoma of the pancreas and chronic pancreatitis has been rare. 3"4 To determine whether chronic pancreatitis without calcifications is in fact a risk factor for pancreatic cancer or not, 5 we describe a case of intraductal papillary adenocarcinoma of the pancreas associated with mass forming chronic pancreatitis without calcifications and present the detailed pathologic findings.
Reprint requests to: Naotaka Kadoya, MD, Second Department of Surgery, Kanazawa University, 13-1 Takaramachi, Kanazawa 920, Japan (Received for publication on Nov. 2, 1990)
Case Report
A 77-year-old man was transferred to Kanazawa University Hospital with a chief complaint of severe right hypochondralgia. He had been on medication for diabetes mellitus for 20 years, On physical examination, he appeared healthy without any signs of anemia or jaundice. A palpable mass was noted in the right hypochondrium, which was suspected of being a swollen gall bladder. The liver function tests were as follows: serum glutamic oxaloacetic transaminase (sGOT) 817IU/L, serum glutamic pyruvic transaminase (sGPT) 383IU/L, alkaline phosphatase 2581IU/L, and total bilirubin 1.4mg/dl. Carcinoembrionic antigen (CEA) was 3.4 ng/ml and carbohydrate antigen 1%9 (CA 19-9) was 48U/ml. Abdominal ultrasonography and computed tomography (CT) revealed a mass in the head of the pancreas 4cm in diameter, a dilated main pancreatic duct and a gall stone (Fig. 1A). Contrast-enhanced CT revealed a homogenous stain of the mass (Fig. 1B). On celiac angiography, some branches of the anterior superior pancreatoduodenal artery were observed to be serrated in the arterial phase, but no encasement or stenosis of any other branches was noted. A cholangiogram obtained through a percutaneous transhepatic cholangiodrainage (PTCD) catheter, and a pancreatogram by endoscopic retrograde pancreatography (ERP) revealed a smooth narrowing in the distal bile duct and a 3cm serration of the main pancreatic duct at the junction of the pancreatic head and neck (Fig. 2). Preoperatively, a mass forming chronic pancreatitis was suspected because the mass in the head of the pancreas stained homogenously on the contrast-enhanced CT, the main pancreatic duct was serrated but not completely obstracted, and the changes on celiac angiography were less marked than usually observed in pancreatic cancer. A pancreatoduodenectomy was performed because we could not rule out pancreatic
N. Kadoya et al.: Intraductal Papillary Adenocarcinoma
285
Fig. 3. Low power view of hyperplastic epithelium of the main pancreatic duct (H&E, x22)
Fig. 1. A Computed tomography (CT) revealed a mass in the head of the pancreas (arrow)4 cm in diameter, a dilated main pancreatic duct, and a gall stone. B Contrast-enhanced CT revealed homogenous stain of a mass in the head of the pancreas (arrow)
Fig. 4. High-power view of hyperplastic epithelium with papillomatous elements, which was confirmed as intraductal papillary adenocarcinoma of the pancreas (H&E, x55)
cancer completely, and the patient was extremely symptomatic.
Pathologic Findings
Fig. 2. A A cholangiogram revealed a smooth narrowing (arrow) in the distal bile duct. B A pancreatogram revealed a 3cm serration (arrow) of the main pancreatic duct at the junction of the pancreatic head and neck
The resected pancreas was hard, and the mass measured 6.0 x 4.5 x 3.5cm, with a smooth outer surface: The specimen was cut into serial section 5 m m in thickness, fixed in 10% neutral buffered formalin and e m b e d d e d in paraffin. Serial section 5 g thick were stained with hematoxylin-eosin ( H & E ) stain. Some sections were also used for histochemical staining of C E A and C A 19-9 by the peroxidase-antiperoxidase (PAP) method. 6 A control serum, instead of the primary specific antiserum, was used as the negative control. Sections of C A 19-9-producing panreatic
286
N. Kadoya et ai.: Intraductal Papillary Adenocarcinoma Discussion
Fig. 5. A Immunohistochemical staining with anti-CEA in intraductal papillary adenocarcinorna of the pancreas (× 110). B Immunohistochemical staining with anti-CA19-9 in intraductal papillary adenocarcinoma of the pancreas (× 110)
carcinoma and CEA-producing colonic carcinoma served as the positive controls. On histologic examination, the parenchyma of the pancreas was atrophic, while fibrosis and lymphocytic infiltration were observed throughout the stroma, and marked fibrotic changes of the stroma grossly formed a mass in the head of the pancreas. Fibrosis and lymphocytic infiltration were also observed around the main pancreatic duct, and the serrated change in the main pancreatic duct shown by ERP was mainly due to fibrosis around the main pancreatic duct. The epithelium of the main pancreatic duct showed hyperplastic changes and an intraductal spreading throughout the entire resected pancreas (Figs. 3, 4). In part of these hyperplastic epithelia with papillomatous elements, the nuclei showed severe atypia, with a loss of polarity, an increased nuclear-cytoplasmic ratio, hyperchromasia, and occasional mitotic figures, which we confirmed as intraductal papillary adenocarcinoma of the pancreas. No metastasis was noted in the regional lymph nodes or organs adjacent to the pancreas. Immunohistochemically, the loci of intraductal papillary adenocarcinoma of the pancreas showed a strong reactivity with anti-CEA and CA 19-9 staining as well as with the positive control. Namely, staining with antiCEA was observed markedly on the luminal surface of carcinoma cells and faintly in their cytoplasm (Fig. 5A). Staining with anti-CA19-9 was diffusely observed in the cytoplasm of carcinoma cells as well as on their luminal surface (Fig. 5B). The other foci of the hyperplastic epithelium only showed reactivity with anti-CA19-9. staining, which was observed restrictively on the luminal surface of these hyperplastic epithelium, but did not show any reactivity with anti-CEA staining.
It has been reported that pancreatolithiasis, or calcified pancreas, is a high risk factor for carcinoma of the pancreas, ~'2 but on the other hand, several studies have found that carcinoma of the pancreas is rarely associated with chronic pancreatitis. 3'4'7'8 PaulinoNetto et al. 1 have reported that the incidence of pancreatic cancer associated with pancreatolithiasis was 25 per cent, while Johnson et al. 2 have reported that the incidence of pancreatic cancer associated with pancreatolithiasis was only 3.7 per cent. These reports impressed us with the fact that pancreatic cancer is closely associated with pancreatolithiasis. However the term pancreatolithiasis, is not limited to chronic calcified pancreatitis, but also includes pancreatic cancer with calcifications. Ishii et al. 4 and Wynder3 have reported in their epidemiologic studies that chronic pancreatitis is not likely to be a precancerous lesion. On the other hand, it is well known that squamous metaplasia or goblet cell metaplasia of the pancreatic duct often occurs, and papillary hyperplasia of pancreatic duct is sometimes present in the case of pancreatic cancer9'~° or in aging healthy adults. ~1 Cublilla et al. 12 found that the incidence of papillary hyperplasia of the pancreatic duct in 227 patients with pancreatic cancer was three times higher than in 100 healthy adult controls matched according to age and sex. They reported that marked atypical hyperplasia was associated in 20 per cent and carcinoma in situ in 18 per cent in the uninvolved area of the pancreatic duct of pancreatic cancer patients, while marked atypical hyperplasia or carcinoma in situ was not present in any of the controls. These authors thus speculated that hyperplasia of the pancreatic duct may be a precancerous lesion. Intraductal carcinomas, such as mucin-producing pancratic cancer or cystoadenocarcinoma of the pancreas have a better prognosis than invasive ductal carcinoma. Morohoshi et al. 13 have argued that intraductal papillary neoplasms of the pancreas should be considered as a single clinical entity because they are limited to the ductal system and, if these intraductal papillary tumors have malignant potential, it is extremely low because no case of metastatic spread has yet been reported. Our case was, of course, non invasive, so better prognosis should be expected. Pancreatic cancer associated with chronic pancreatitis is rare, but as our case suggests, the hyperplastic epithelium of the main pancreatic duct may indeed be a precancerous lesion for pancreatic cancer in some patients with chronic pancreatitis.
N. Kadoya et al.: Intraductal Papillary Adenocarcinoma
References
1. Paulino-Netto A, Dreiling DA, Boronofsky ID (1960) The relationship between pancreatic calcification and cancer of the pancreas. Ann Surg 151:530-537 2. Johnson JR, Zintel HA (1963) Pancreatic calcification and cancer of the pancreas. Surg Gynecol Obstet 117:585-588 3. Wynder EL (1975) An epidemiological evaluation of the cause of cancer of the pancreas. Cancer Res 35:2228-2233 4. Ishii K, Nakamura K, Takeuchi T (1973) Chronic calcifying pancreatitis and pancreatic cancer in Japan. Digestion 9:429-437 5. Becker V (1978) Carcinoma of the pancreas and chronic pancreatitis: A possible relationship. Hepato gastroenterology 25:257-259 6. Sternberger LA (1979) The unlabeled antibody peroxidase antiperoxidase (PAP) method. In: Sternberger LA (ed) Immunocytochemistry. John Wiley and Sons, New York, pp 104-109
287 7. Gambill EE, Baggenstoss AH, Priestley JT (1960) Chronic relapsing pancreatitis, fate of fifty-six patients first encountered in the years 1939 to 1943. Gastroenterology 39:404-413 8. Amman R (1980) Zur Klinik und Differentialdiagnose der chronischen Pankreatitis (in German). $chweiz Med Wochenschr 110:1322-1327 9. Kozuka S (1979) Relation of pancreatic duct hyperplasia to carcinoma. Cancer 43:1418-1428 10. Kloppel G (1980) Intraductai proliferation in the pancreas and its relationship to human and experimental carcinogenesis. Virchows Arch [A] 387:221-233 11. Feldman M (1955) The pancreas in the aged, an autopsy study. Geriatrics 10:373-374 12. Cubilla LA, Fitzgerald PJ (1976) Morphological lesions associated with human primary invasive nonendocrine pancreas cancer. Cancer Res 36:2690-2698 13. Morohoshi T, Kanda M, Asanuma K (1989) Intraductal papillary neoplasms of the pancreas, a clinicopathologic study of six patients. Cancer 64:1329-1335
