Gastroenterologia Japonica Copyright 9 1990 by The Japanese Society of Gastroenterology
Vol. 25, No. 5 Printed in Japan
A case of coexisting malignant carcinoid tumor and adenocarcinoma in the papilla of vater Jun MISONOU 1, Makoto KANDA 1, Takashi KITAGAWA 2, Tomoaki OTA 2, Eiji MUTO 2, Masaaki NENOHI 3, and Tomoyoshi ATSUTA 3
Departments of 1Pathology, 21nternal Medicine, and 3Surgery, Asahikawa City General Hospital, Asahikawa 070, Japan. Summary: A 47-year-old Japanese woman in whom obstructive jaundice had already been diagnosed, was found to have a dome-shaped elevated tumor approximately 3 cm in diameter located in the area very close to the papilla of Vater on endoscopical and radiographical investigations. Histopathologicaily, the resected tumor was composed mainly of solid nests of atypical argyrophilic cells, and partially of an area of well differentiated tubular adenocarcinoma, showing mutual transition in the mucosal layer. Both immunohistochemical and ultrastructural analyses confirmed the difference in character of tumor cells between these two areas; neuroendocrine cell carcinoma and tubular adenocarcinoma of common type in the intestine. To the best of our knowledge, this is only the third case reported to be a coexisting malignant carcinoid tumor and adenocarcinoma arising in the periampullary region. Gastroenterol Jpn 1990;25:630-635 Key words:
carcinoid tumor; duodenal neoplasms; endocrine cell tumor; periampullary tumor
Introduction
Case Report
The occurrence of carcinoid t u m o r in the periampullary region is generally considered to be m u c h rarer I than that of adenocarcinoma. The present case is very unique in that both an area of malignant carcinoid tumor and one of tubular adenocarcinoma was observed within the same tumor, showing a histological transition with each other. Recently, similar cases of composite adenocarcinoma-carcinoid tumors have been reported at various sites in the gastrointestinal tract 2-7. However, the analyses of the histogenesis of such cases seems to be very controversial. A f t e r a detailed clinicopathological description of the present case, the histogenesis of such composite tumors is discussed.
A 47-year-old Japanese woman, who had suffered from continuous appetite loss and nausea, consulted the D e p a r t m e n t of Internal Medicine of Asahikawa City General Hospital in the beginning of March, 1989, because icterus had been pointed out. As shown in Table 1, laboratory data on admission indicated the presence of obstructive jaundice, slight iron deficiency anemia, and bleeding from gastrointestinal tract. O f all the tumor markers investigated, carbohydrate antigen (CA)19-9, CA-50, and D U P A N - 2 slightly exceeded the normal ranges. Percutaneous transhepatic cholangiography (PTC), echography, and computed t o m o g r a p h y (CT) d e m o n s t r a t e d the dilatation of the c o m m o n bile duct in the whole part and the enlargement of the gallbladder. A n d
Received January 11, 1990. Accepted March 16, 1990. Address for correspondence: Jun Misonou, M.D., The Department of Pathology, Asahikawa City General Hospital, Kinsei-chou 1, Asahikawa, Hokkaido 070, Japan. The authors wish to express their special thanks to M. Nakagawa, C.T. and K. Onagawa, C.T., both in the Department of Pathology of Asahikawa City General Hospital, for their technical assistance in the preparation of the present case report.
Periampullaty adenocarcinoid tumor
October 1990
631
Table 1 Laboratory data on her admission Urinalysis Protein ( - ) Sugar ( - ) Bilirubin ( + + ) Stool occult blood (+ +) CBC RBC 358x104/mm 3 Hb 10.6 g/dl Ht 33.8% Plat 42.6x104/mm3 WBC 7300/mm3 Chemistry T.P 7.6 g/dl T.Bil 14.2 mg/dl D.Bil 10.4 mg/dl GOT 234 IU/I GPT 175 IU/I
LDH AL-P y-GTP LAP T-Chol BUN CRE Na K CI Ca s-Amylase AFP CEA CA19-9 DUPAN-2 CA-50 ESR
545 IU/I 153.5 IU/I 514 IU/I 1006 G.R.U 178 mg/dl 16.4 mg/dl 0.6 mg/dl 127 mEq/I 4.8 mEq/I 90 mEq/I 4.6 mEq/I 78 IU/I 1.8 ng/ml 1.6 ng/ml 74.6 U/ml 300 U/ml 89 U/ml 95 mm/hr
Fig. 2 Gross and cut surface of the periampullary tumor. Tumor is located just above the papilla of Vater. On cut surface, solid white tumor nodule is observed mainly within submucosal layer, showing a protruding growth pattern.
Fig. 1 Duodenal fiberscopy showing a dome-shaped elevating mass with a hemorrhagic and irregular mucosal surface. Biopsied specimen from this lesion confirmed the malignant nature of the tumor.
PTC-drainage simultaneously performed successfully reduced her obstructive jaundice. By both hypotonic duodenography and endoscopical examination, a dome-shaped elevated mass of about 3 cm in diameter was found out in the area very close to the papilla of Vater (Fig. 1). Endoscopically, the center part of the tumor showed a reddish and irregular appearance, which was sus-
pected of ulceration. The histopathological diagnosis of the biopsied specimen confirmed the malignant nature of the t u m o r cells. After transfer to the D e p a r t m e n t of Surgery in our hospital, she underwent pancreatoduodenectomy on April 4th, 1989. She was discharged on May 20, 1989. No remarkable changes were found in her general conditions and laboratory data for a period. However, recent CT findings disclosed the presence of multiple low density areas in the liver. Moreover, the serum level of serotonin as well as that of neuron specific enolase has been gradually increasing. From these findings, recurrence of the tumor is highly suspected, at present, about 9 months after the initial surgery. Histopathological Findings As shown in Figure 2a, a tumor nodule 3 cm in
632
J. M i s o n o u et al.
Vol. 25, No. 5
Fig. 4 Photomicrograph of tumor cells with neuroendocrine cell differentiation. Tumor cells with atypical, rounded nuclei grow in solid or trabecular arrangement. More malignant potential of tumor cells can be suspected from these remarkable cellular atypia and frequent mitotic figures, compared with typical carcinoid tumors. (HE, •
Fig. 3 Photomicrograph at lower magnifications of a cut surface of the tumor (a) (HE x4), and its shematic figure (b). Most of tumor cells are composed of those with neuroendocrine cell differentiation, except small areas showing glandular differentiation within the mucosal layer. Tumor metastasis is observed within one regional lymph node around the pancreas (white arrow).
diameter was located just above the papilla of Vater, and showed a dome-shaped yellowish appearance. In the center of the mass, there was an area of ulceration with bleeding, however, most of the lesion was covered with duodenal mucosa on its surface. On cut surfaces, a yellowish-white nodule of 3.0 x 3.5 cm was observed, relatively sharply demarcated from surrounding tissue
(Fig. 2b). Microscopic observation revealed that the tumor nodule was composed of two loci of tumor cells with different histological features (Fig. 3).
Fig. 5 Photomicrograph of tumor cells with glandular differentiation. Tumor cells in this area are considered to be nonargyrophilic from special stains and immunohistochemistry. (HE, x280).
As shown in Figure 4, most tumor cells were composed of small atypical cells with rounded nuclei with remarkable atypia and frequent mitotic figures. These anaplastic tumor cells grew in various patterns; in a solid nest, in a trabecular or in an alveolar growth pattern. These tumor cells showed a strong positivity for argylophil with Fontana-Masson staining. No positive result was obtained for any staining for mucosubstances. Histopathological investigation disclosed the direct invasion of these anaplastic tumor cells beneath the propria muscle, but no infiltration of tu-
October 1990
Periampullary adenocarcinoid tumor
Fig. 6 Photomicrograph of a transitional zone of each component of tumor cells. (HE, x140).
mor cells into the pancreatic parenchyma was observed. A r o u n d the main tumor nodule, many tumor thrombi were observed both within lymphatics and within veins located in submucosal or in subserosal layer of the intestinal wall. Microscopically, metastases of tumor cells were observed within superior as well as inferior pancreaticoduodenal lymph nodes. On the other hand, as shown in the Figure 5, small areas with histological features of well differentiated tubular adenocarcinoma was observed, limited within intramucosal layer around the nodule (Fig. 3b). Tumor cells in this glandular area did not show positive result for argentaffin nor argylophil reaction. Within this glandular area, tumor cells showing differentiation into goblet cells were scatteringly observed. A n d special staining for mucosubstances confirmed the presence of both neutral as well as sialo mucins within the cytoplasm of these cells. A n d on microscopic observation, these two areas showed a transition each other in the mucosal layer, as shown in Figure 6. Immunohistochemical analyses were performed to determine the presence of the following antigens in the tumor cells in both anaplastic and glandular areas, respectively; C E A , CA-19-9, calcitonin, neuron specific enolase (NSE), glucagon, gastrin, insulin, somatostatin, serotonin, and chromogranin. Polyclonal antibodies for these antigens were commercially available from D A K O , D e n m a r k , and the immunohistochemi-
633
Fi 9. 7 Electronmicroscopic observation showing abundant secretory granules of neuroendocrine type within the cytoplasm of most tumor cells. (x 10,000).
cal reaction was examined with indirect P A P methods. T u m o r cells with anaplastic, carcinoid like appearances mostly showed positive staining for serotonin and NSE solely within the cytoplasm of tumor cells. On the other hand, those with glandular appearances showed no reaction for these two markers, but showed positive reaction for C E A and CA-19-9, mainly on the surface of the cytomembrane. These immunohistochemical results coincided well with the distribution of both types of tumor cells observed on light-microscopic observation. On ultrastructural study, it was demonstrated that these anaplastic tumor cells had prominent intracellular organellae such as mitochondria, rough endoplasmic reticulum, and Golgi apparati. Bundles of intermediate filaments were also observed within the cytoplasm. The most notable point in the electron-microscopic observations was the presence of many dense core granules of neurosecretory type within these tumor cells. These centrally-densed granules covered with 'halos' measured 160 nm on average diameter, and they were observed in most of the tumor cells, mainly along the cell membranes. Well developed desmosomes were observed between tumor cells, however, no microvilli, intracytoplasmic lumen, mucin vacuoles nor the development of tonofilament were observed (Fig. 7).
634
J. M i s o n o u et al.
Discussion
To the best of our knowledge, this is only the third case reported as composite carcinoid-adenocarcinoma arising from a peri-ampullary region 2'3. Recently, similar cases of composite tumors showing both glandular and neuroendocrine cell differentiation have also been described in other regions within gastrointestinal tract, such as the stomach 4-7, intestine 7-9, and gallbladder 1~ From the histopathological viewpoint, these reported cases of composite tumors seems to have relatively wide ranges in histological features as well as growth patterns, and they have been reported in several eubitie, such as stem cell carcinomas, composite tumors, argyrophil or argentaffin cell rich adenocarcinomas, glandular carcinoid tumors, and so on. Therefore, clinicopathological considerations of the histogenesis as well as spectrum of these 'mixed' tumors seem to be very controversial. The greatest problem in the present case is undoubtedly whether these two types of tumor cells arose independently, or from one totipotent stem cell. In other words, question may well be raised whether the present case should be considered as a collision tumor or a malignant tumor with bidirectional differentiation. In our case, as described above, two areas with different histological features were observed, showing mutual transition with each other. Based on this observation, we consider that the present tumor presumably arose from one totipotent stem cell, and subsequently showed bidirectional differentiations. In the present case, the results of special stains for argylophilic reactions and mucosubstances as well as those of immunohistochemical studies for several markers were completely different in these two areas. The reasons for these phenomen o m a seem to be unknown. However, it seems possible to explain the histogenesis as well as growth patterns of tumor cells in each area, granted that tumor cells with anaplastic features have a natural tendency to invade deeply into the intestinal wall, while the other rather tend to spread superficially and laterally within the surface mucosa. In fact, among cases reported as
Vol. 25, No. 5
composite tumors in various gastrointestinal tract, similar distribution of t u m o r cells has been described 5"9'm. In the present case, we could not perform ultrastructual analyses of tumor cells in glandular areas. Therefore, we could not completely exclude the possibility that tumor cells in this area showed poor differentiation into neuroendocrine cells, which could be possibly found out only on the ultrastructual level. Jones et al. 2 disclosed the coexistence of cells with mucin vacuoles and those with neurosecretory granules in the same acinar structure, and claimed that the histoenesis of their cases should be considered as multidirectrional differentiation of tumor cells, in their case of composite t u m o r arising in the papilla of Vater. Soga et al 6 described that some cases of tubular adenocarcinomas of the stomach are partially composed of endocrine cells, even if they lack the histological features of typical carcinoid tumors. Similar results were reported in composite tumors in the gallbladder 1~ and in the intestine 7'9. Smith et al. 11reported that they found scattered argyrophilic c o m p o n e n t within tumor cells of adenocarcinoma of c o m m o n histological type of the colon in 52% (13/25) cases. On the other hand, Moyana et al. 8 described cases also categorized as those 'mixed tumor', which had been possibly cured by local resections and had been histopathologically considered to be benign, composite adenoma-carcinoid tumor consequently. Moreover, as for lung carcinomas, it has been widely accepted that there exists extreme histological heterogeneity, and that tumor cells show multidirectional differentiation by using immunohistochemical, ultrastructural, and cytological methods 12. On the other hand, Shimoyama et al 3 reported a case of periampullary tumor composed of tubular and carcinoidal components, which they had considered to originate independently, on the grounds of the absence of a transitional zone of both components. We expect that the histogenesis of such composite tumors will be clarified in the future, by making further clinicopathological consideration, with the increased number of reported cases. We also hope that the concept of neuroendocrine cell
October 199(I
Periampullal T adenocarcinoid tumor
tumors in the gastrointestinal tract will be further discussed.
References 1. Maruta S, Tashiro S, Akahoshi N, ct al: Carcinoid of papilla of Vater, Report of a case, Stomach and Intestine 1983 18:83-90, (in Japanese) 2. Jones MN, Griffith LM, West AB: Adenocarcinoid tumor of the periampullary lesion: A novel duodenal neoplasm presenting as biliary tract obstruction. H u m Pathol 1989 2(1:198-200, 3. Shimoyama T, Kitasato S, Takagi T, et al: Coexisting carcinoid and carcinoma in the papilla of Vater, Report of a case. Stomach and Intestine 1981 16:589-593 (in Japanese) 4. lshida M, Hosokawa M, Genba K, et al: A case of a gastric carcinoid tumor with a coexisting adenocarcinoma in the same tumor. G a n no Rinsho 1989 35:1687-1692 (in Japanese) 5. Miura K, Kanazawa M, Watanabe T, et al: A case of a gastric carcinoid with transient features of a tubular adenocarcinoma.: Gan no Rinsho 1989 35:1693-1698 (in Japanese)
635
6. Soga J, Tazawa K, Aizawa O, et al: Argentaffin cell adenocarcin o m a of the stomach: A n atypical carcinoid? Cancer 1971 28:999-1003 7. Klappenbach RS, K u r m a n RJ, Sinclair CF, et al: Composite carcinoma-carcinoid tumors of the gastrointestinal tract. A morphologic, histochemical, and immunohistochemical study. A m J Clin pathol 1984 84:137-143 8. Moyana TN, Oizilbash A H , Murphy F: Composite glandular carcinoid tumors of the colon and rectum. A m J Surg Pathol 1988 12:607-611 9. Bates H R , Belter LF: Composite carcinoid tumor (argentaffinomas-adenocarcinoma) of the colon: Report of two cases. Dis Colon Rectum 10:467-470, 1970 10. Y a m a m o t o M, Nakajo S, Miyoshi N, et al: Endocrine cell carcin o m a (carcinoid) of the gall bladder. A m J Surg Pathol 1989 13:292-302 11. Smith DM, Haggitt RC: T h e prevalence and prognostic significance of argyrophil cells in colorcctal carcinomas. A m J Surg Pathol 1984 8:123-128 12. Roggli VL, Vollmer RT, Greenberg SD, et al: Lung cancer heterogeneity: A blinded and randomized study of 100 consecutive cases. H u m Pathol 1985 16:569-579
Vol. 25, No. 5 Printed in Japan
A case of coexisting malignant carcinoid tumor and adenocarcinoma in the papilla of vater Jun MISONOU 1, Makoto KANDA 1, Takashi KITAGAWA 2, Tomoaki OTA 2, Eiji MUTO 2, Masaaki NENOHI 3, and Tomoyoshi ATSUTA 3
Departments of 1Pathology, 21nternal Medicine, and 3Surgery, Asahikawa City General Hospital, Asahikawa 070, Japan. Summary: A 47-year-old Japanese woman in whom obstructive jaundice had already been diagnosed, was found to have a dome-shaped elevated tumor approximately 3 cm in diameter located in the area very close to the papilla of Vater on endoscopical and radiographical investigations. Histopathologicaily, the resected tumor was composed mainly of solid nests of atypical argyrophilic cells, and partially of an area of well differentiated tubular adenocarcinoma, showing mutual transition in the mucosal layer. Both immunohistochemical and ultrastructural analyses confirmed the difference in character of tumor cells between these two areas; neuroendocrine cell carcinoma and tubular adenocarcinoma of common type in the intestine. To the best of our knowledge, this is only the third case reported to be a coexisting malignant carcinoid tumor and adenocarcinoma arising in the periampullary region. Gastroenterol Jpn 1990;25:630-635 Key words:
carcinoid tumor; duodenal neoplasms; endocrine cell tumor; periampullary tumor
Introduction
Case Report
The occurrence of carcinoid t u m o r in the periampullary region is generally considered to be m u c h rarer I than that of adenocarcinoma. The present case is very unique in that both an area of malignant carcinoid tumor and one of tubular adenocarcinoma was observed within the same tumor, showing a histological transition with each other. Recently, similar cases of composite adenocarcinoma-carcinoid tumors have been reported at various sites in the gastrointestinal tract 2-7. However, the analyses of the histogenesis of such cases seems to be very controversial. A f t e r a detailed clinicopathological description of the present case, the histogenesis of such composite tumors is discussed.
A 47-year-old Japanese woman, who had suffered from continuous appetite loss and nausea, consulted the D e p a r t m e n t of Internal Medicine of Asahikawa City General Hospital in the beginning of March, 1989, because icterus had been pointed out. As shown in Table 1, laboratory data on admission indicated the presence of obstructive jaundice, slight iron deficiency anemia, and bleeding from gastrointestinal tract. O f all the tumor markers investigated, carbohydrate antigen (CA)19-9, CA-50, and D U P A N - 2 slightly exceeded the normal ranges. Percutaneous transhepatic cholangiography (PTC), echography, and computed t o m o g r a p h y (CT) d e m o n s t r a t e d the dilatation of the c o m m o n bile duct in the whole part and the enlargement of the gallbladder. A n d
Received January 11, 1990. Accepted March 16, 1990. Address for correspondence: Jun Misonou, M.D., The Department of Pathology, Asahikawa City General Hospital, Kinsei-chou 1, Asahikawa, Hokkaido 070, Japan. The authors wish to express their special thanks to M. Nakagawa, C.T. and K. Onagawa, C.T., both in the Department of Pathology of Asahikawa City General Hospital, for their technical assistance in the preparation of the present case report.
Periampullaty adenocarcinoid tumor
October 1990
631
Table 1 Laboratory data on her admission Urinalysis Protein ( - ) Sugar ( - ) Bilirubin ( + + ) Stool occult blood (+ +) CBC RBC 358x104/mm 3 Hb 10.6 g/dl Ht 33.8% Plat 42.6x104/mm3 WBC 7300/mm3 Chemistry T.P 7.6 g/dl T.Bil 14.2 mg/dl D.Bil 10.4 mg/dl GOT 234 IU/I GPT 175 IU/I
LDH AL-P y-GTP LAP T-Chol BUN CRE Na K CI Ca s-Amylase AFP CEA CA19-9 DUPAN-2 CA-50 ESR
545 IU/I 153.5 IU/I 514 IU/I 1006 G.R.U 178 mg/dl 16.4 mg/dl 0.6 mg/dl 127 mEq/I 4.8 mEq/I 90 mEq/I 4.6 mEq/I 78 IU/I 1.8 ng/ml 1.6 ng/ml 74.6 U/ml 300 U/ml 89 U/ml 95 mm/hr
Fig. 2 Gross and cut surface of the periampullary tumor. Tumor is located just above the papilla of Vater. On cut surface, solid white tumor nodule is observed mainly within submucosal layer, showing a protruding growth pattern.
Fig. 1 Duodenal fiberscopy showing a dome-shaped elevating mass with a hemorrhagic and irregular mucosal surface. Biopsied specimen from this lesion confirmed the malignant nature of the tumor.
PTC-drainage simultaneously performed successfully reduced her obstructive jaundice. By both hypotonic duodenography and endoscopical examination, a dome-shaped elevated mass of about 3 cm in diameter was found out in the area very close to the papilla of Vater (Fig. 1). Endoscopically, the center part of the tumor showed a reddish and irregular appearance, which was sus-
pected of ulceration. The histopathological diagnosis of the biopsied specimen confirmed the malignant nature of the t u m o r cells. After transfer to the D e p a r t m e n t of Surgery in our hospital, she underwent pancreatoduodenectomy on April 4th, 1989. She was discharged on May 20, 1989. No remarkable changes were found in her general conditions and laboratory data for a period. However, recent CT findings disclosed the presence of multiple low density areas in the liver. Moreover, the serum level of serotonin as well as that of neuron specific enolase has been gradually increasing. From these findings, recurrence of the tumor is highly suspected, at present, about 9 months after the initial surgery. Histopathological Findings As shown in Figure 2a, a tumor nodule 3 cm in
632
J. M i s o n o u et al.
Vol. 25, No. 5
Fig. 4 Photomicrograph of tumor cells with neuroendocrine cell differentiation. Tumor cells with atypical, rounded nuclei grow in solid or trabecular arrangement. More malignant potential of tumor cells can be suspected from these remarkable cellular atypia and frequent mitotic figures, compared with typical carcinoid tumors. (HE, •
Fig. 3 Photomicrograph at lower magnifications of a cut surface of the tumor (a) (HE x4), and its shematic figure (b). Most of tumor cells are composed of those with neuroendocrine cell differentiation, except small areas showing glandular differentiation within the mucosal layer. Tumor metastasis is observed within one regional lymph node around the pancreas (white arrow).
diameter was located just above the papilla of Vater, and showed a dome-shaped yellowish appearance. In the center of the mass, there was an area of ulceration with bleeding, however, most of the lesion was covered with duodenal mucosa on its surface. On cut surfaces, a yellowish-white nodule of 3.0 x 3.5 cm was observed, relatively sharply demarcated from surrounding tissue
(Fig. 2b). Microscopic observation revealed that the tumor nodule was composed of two loci of tumor cells with different histological features (Fig. 3).
Fig. 5 Photomicrograph of tumor cells with glandular differentiation. Tumor cells in this area are considered to be nonargyrophilic from special stains and immunohistochemistry. (HE, x280).
As shown in Figure 4, most tumor cells were composed of small atypical cells with rounded nuclei with remarkable atypia and frequent mitotic figures. These anaplastic tumor cells grew in various patterns; in a solid nest, in a trabecular or in an alveolar growth pattern. These tumor cells showed a strong positivity for argylophil with Fontana-Masson staining. No positive result was obtained for any staining for mucosubstances. Histopathological investigation disclosed the direct invasion of these anaplastic tumor cells beneath the propria muscle, but no infiltration of tu-
October 1990
Periampullary adenocarcinoid tumor
Fig. 6 Photomicrograph of a transitional zone of each component of tumor cells. (HE, x140).
mor cells into the pancreatic parenchyma was observed. A r o u n d the main tumor nodule, many tumor thrombi were observed both within lymphatics and within veins located in submucosal or in subserosal layer of the intestinal wall. Microscopically, metastases of tumor cells were observed within superior as well as inferior pancreaticoduodenal lymph nodes. On the other hand, as shown in the Figure 5, small areas with histological features of well differentiated tubular adenocarcinoma was observed, limited within intramucosal layer around the nodule (Fig. 3b). Tumor cells in this glandular area did not show positive result for argentaffin nor argylophil reaction. Within this glandular area, tumor cells showing differentiation into goblet cells were scatteringly observed. A n d special staining for mucosubstances confirmed the presence of both neutral as well as sialo mucins within the cytoplasm of these cells. A n d on microscopic observation, these two areas showed a transition each other in the mucosal layer, as shown in Figure 6. Immunohistochemical analyses were performed to determine the presence of the following antigens in the tumor cells in both anaplastic and glandular areas, respectively; C E A , CA-19-9, calcitonin, neuron specific enolase (NSE), glucagon, gastrin, insulin, somatostatin, serotonin, and chromogranin. Polyclonal antibodies for these antigens were commercially available from D A K O , D e n m a r k , and the immunohistochemi-
633
Fi 9. 7 Electronmicroscopic observation showing abundant secretory granules of neuroendocrine type within the cytoplasm of most tumor cells. (x 10,000).
cal reaction was examined with indirect P A P methods. T u m o r cells with anaplastic, carcinoid like appearances mostly showed positive staining for serotonin and NSE solely within the cytoplasm of tumor cells. On the other hand, those with glandular appearances showed no reaction for these two markers, but showed positive reaction for C E A and CA-19-9, mainly on the surface of the cytomembrane. These immunohistochemical results coincided well with the distribution of both types of tumor cells observed on light-microscopic observation. On ultrastructural study, it was demonstrated that these anaplastic tumor cells had prominent intracellular organellae such as mitochondria, rough endoplasmic reticulum, and Golgi apparati. Bundles of intermediate filaments were also observed within the cytoplasm. The most notable point in the electron-microscopic observations was the presence of many dense core granules of neurosecretory type within these tumor cells. These centrally-densed granules covered with 'halos' measured 160 nm on average diameter, and they were observed in most of the tumor cells, mainly along the cell membranes. Well developed desmosomes were observed between tumor cells, however, no microvilli, intracytoplasmic lumen, mucin vacuoles nor the development of tonofilament were observed (Fig. 7).
634
J. M i s o n o u et al.
Discussion
To the best of our knowledge, this is only the third case reported as composite carcinoid-adenocarcinoma arising from a peri-ampullary region 2'3. Recently, similar cases of composite tumors showing both glandular and neuroendocrine cell differentiation have also been described in other regions within gastrointestinal tract, such as the stomach 4-7, intestine 7-9, and gallbladder 1~ From the histopathological viewpoint, these reported cases of composite tumors seems to have relatively wide ranges in histological features as well as growth patterns, and they have been reported in several eubitie, such as stem cell carcinomas, composite tumors, argyrophil or argentaffin cell rich adenocarcinomas, glandular carcinoid tumors, and so on. Therefore, clinicopathological considerations of the histogenesis as well as spectrum of these 'mixed' tumors seem to be very controversial. The greatest problem in the present case is undoubtedly whether these two types of tumor cells arose independently, or from one totipotent stem cell. In other words, question may well be raised whether the present case should be considered as a collision tumor or a malignant tumor with bidirectional differentiation. In our case, as described above, two areas with different histological features were observed, showing mutual transition with each other. Based on this observation, we consider that the present tumor presumably arose from one totipotent stem cell, and subsequently showed bidirectional differentiations. In the present case, the results of special stains for argylophilic reactions and mucosubstances as well as those of immunohistochemical studies for several markers were completely different in these two areas. The reasons for these phenomen o m a seem to be unknown. However, it seems possible to explain the histogenesis as well as growth patterns of tumor cells in each area, granted that tumor cells with anaplastic features have a natural tendency to invade deeply into the intestinal wall, while the other rather tend to spread superficially and laterally within the surface mucosa. In fact, among cases reported as
Vol. 25, No. 5
composite tumors in various gastrointestinal tract, similar distribution of t u m o r cells has been described 5"9'm. In the present case, we could not perform ultrastructual analyses of tumor cells in glandular areas. Therefore, we could not completely exclude the possibility that tumor cells in this area showed poor differentiation into neuroendocrine cells, which could be possibly found out only on the ultrastructual level. Jones et al. 2 disclosed the coexistence of cells with mucin vacuoles and those with neurosecretory granules in the same acinar structure, and claimed that the histoenesis of their cases should be considered as multidirectrional differentiation of tumor cells, in their case of composite t u m o r arising in the papilla of Vater. Soga et al 6 described that some cases of tubular adenocarcinomas of the stomach are partially composed of endocrine cells, even if they lack the histological features of typical carcinoid tumors. Similar results were reported in composite tumors in the gallbladder 1~ and in the intestine 7'9. Smith et al. 11reported that they found scattered argyrophilic c o m p o n e n t within tumor cells of adenocarcinoma of c o m m o n histological type of the colon in 52% (13/25) cases. On the other hand, Moyana et al. 8 described cases also categorized as those 'mixed tumor', which had been possibly cured by local resections and had been histopathologically considered to be benign, composite adenoma-carcinoid tumor consequently. Moreover, as for lung carcinomas, it has been widely accepted that there exists extreme histological heterogeneity, and that tumor cells show multidirectional differentiation by using immunohistochemical, ultrastructural, and cytological methods 12. On the other hand, Shimoyama et al 3 reported a case of periampullary tumor composed of tubular and carcinoidal components, which they had considered to originate independently, on the grounds of the absence of a transitional zone of both components. We expect that the histogenesis of such composite tumors will be clarified in the future, by making further clinicopathological consideration, with the increased number of reported cases. We also hope that the concept of neuroendocrine cell
October 199(I
Periampullal T adenocarcinoid tumor
tumors in the gastrointestinal tract will be further discussed.
References 1. Maruta S, Tashiro S, Akahoshi N, ct al: Carcinoid of papilla of Vater, Report of a case, Stomach and Intestine 1983 18:83-90, (in Japanese) 2. Jones MN, Griffith LM, West AB: Adenocarcinoid tumor of the periampullary lesion: A novel duodenal neoplasm presenting as biliary tract obstruction. H u m Pathol 1989 2(1:198-200, 3. Shimoyama T, Kitasato S, Takagi T, et al: Coexisting carcinoid and carcinoma in the papilla of Vater, Report of a case. Stomach and Intestine 1981 16:589-593 (in Japanese) 4. lshida M, Hosokawa M, Genba K, et al: A case of a gastric carcinoid tumor with a coexisting adenocarcinoma in the same tumor. G a n no Rinsho 1989 35:1687-1692 (in Japanese) 5. Miura K, Kanazawa M, Watanabe T, et al: A case of a gastric carcinoid with transient features of a tubular adenocarcinoma.: Gan no Rinsho 1989 35:1693-1698 (in Japanese)
635
6. Soga J, Tazawa K, Aizawa O, et al: Argentaffin cell adenocarcin o m a of the stomach: A n atypical carcinoid? Cancer 1971 28:999-1003 7. Klappenbach RS, K u r m a n RJ, Sinclair CF, et al: Composite carcinoma-carcinoid tumors of the gastrointestinal tract. A morphologic, histochemical, and immunohistochemical study. A m J Clin pathol 1984 84:137-143 8. Moyana TN, Oizilbash A H , Murphy F: Composite glandular carcinoid tumors of the colon and rectum. A m J Surg Pathol 1988 12:607-611 9. Bates H R , Belter LF: Composite carcinoid tumor (argentaffinomas-adenocarcinoma) of the colon: Report of two cases. Dis Colon Rectum 10:467-470, 1970 10. Y a m a m o t o M, Nakajo S, Miyoshi N, et al: Endocrine cell carcin o m a (carcinoid) of the gall bladder. A m J Surg Pathol 1989 13:292-302 11. Smith DM, Haggitt RC: T h e prevalence and prognostic significance of argyrophil cells in colorcctal carcinomas. A m J Surg Pathol 1984 8:123-128 12. Roggli VL, Vollmer RT, Greenberg SD, et al: Lung cancer heterogeneity: A blinded and randomized study of 100 consecutive cases. H u m Pathol 1985 16:569-579
