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Papillary carcinoma with diffuse papillomatosis of gallbladder and cystic duct
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Annals of Diagnostic Pathology 15 (2011) 140 – 144
Papillary carcinoma with diffuse papillomatosis of gallbladder and cystic duct Kemal Kosemehmetoglu, MDa,⁎, Erhan Akpinar, MDb , Cenk Sokmensuer, MDa , Erhan Hamaloglu, MDc a
Department of Pathology, Hacettepe University, 06100 Ankara, Turkey Department of Radiology, Hacettepe University, 06100 Ankara, Turkey c Department of Surgery, Hacettepe University, 06100 Ankara, Turkey
b
Abstract
Keywords:
Biliary papillomatosis and papillary carcinoma are rare tumors of biliary tract; and because of their morphologic similarities, papillomatosis-papillary carcinoma sequel has been proposed. We report an unusual case of polypoid minimally invasive papillary carcinoma located at the junction between cystic and common bile ducts, complicated with biliary papillomatosis of gallbladder and cystic duct, showing focal areas of malignant change. Intrahepatic ducts, hepatic ducts, and distal common bile duct were spared. Both papillomatosis and papillary carcinoma showed areas of high p53 and p21 expression with high proliferative index. Patient is still alive for 4 years without evidence of disease after modified Whipple operation. Possible pathogenetic mechanisms are further discussed. © 2011 Elsevier Inc. All rights reserved. Papillomatosis; Gallbladder; Papillary carcinoma; p53; MDM2; p21; Ki67
1. Introduction
2. Case report
Biliary papillomatosis, characterized by papillary adenomas covering mucosal surface of extrahepatic and/or intrahepatic biliary system, is regarded as a premalignant condition; and focal malignant transformation is not so uncommon [1-3]. However, distinction of papillomatosis from noninvasive papillary carcinomas is sometimes difficult, especially when extensive malignant change in papillomatosis occurs [3-6]. Therefore, biliary papillomatosis-papillary carcinoma sequence is proposed by some authors [7]. Here we report a case with large solitary papillary carcinoma, located in common hepatic duct, arising in the background of diffuse malignant papillomatosis of gallbladder and cystic duct.
A 62-year-old woman presented with epigastric pain, jaundice, acholic gaita, and darkening in urine. She had epigastric pain for 10 years that became exaggerated in the last month. In this period, she had lost 4 to 5 kg. In physical examination, sclera was icteric and gallbladder was palpable. Laboratory studies detected anemia (hemoglobin, 12.3 mg/ dL) and elevations in alkaline phosphatase and γ-glutamyl transferase enzymes. Total bilirubin level was 5.78 mg/dL, with an indirect bilirubin level of 3.87 mg/dL. Radiological studies showed a thickened gallbladder wall, suggesting gallbladder carcinoma; a 3-cm mass filling the lower end of common bile duct; and secondary dilation of intra-extrahepatic bile ducts (Fig. 1A). Endoscopic retrograde cholangiopancreatography (ERCP) confirmed a 3-cm mass at distal one third of common bile duct. Modified Whipple operation was performed. No further therapy was given to patient, and patient recovered well without evidence of recurrence as yet (48 months of follow-up). Whipple specimen was dissected and fixed in 10% neutral buffered formalin. Whole bile duct system and representative
⁎ Corresponding author. Tel.: +90 312 305 1563; fax: +90 312 305 2621. E-mail address: [email protected] (K. Kosemehmetoglu). 1092-9134/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2010.02.004
K. Kosemehmetoglu et al. / Annals of Diagnostic Pathology 15 (2011) 140–144
141
Fig. 1. (A) Computed tomography showed thickening in gallbladder, a 3-cm mass filling the lower end of common bile duct, and secondary dilation of intra-extrahepatic bile ducts. (B) Dissected Whipple specimen. A 2-cm polypoid mass, obliterating cystic and common hepatic ducts with secondary dilatation, and diffuse papillary fronds on gallbladder and cystic duct mucosae are shown. Inset demonstrates cream-colored cut section of polypoid mass.
sections from gallbladder and pancreas were taken and embedded in paraffin. Four-micrometer–thick sections were prepared from each and stained with routine hematoxylin and eosin. An immunohistochemical study was performed with a standard streptavidin-biotin-peroxidase complex technique using a SkyTek (Tokyo, Japan) according to the manufacturer's instructions. Antigen retrieval was performed by a heatinduced epitope retrieval method. Monoclonal antibodies against Ki67 (Neomarkers, Fremont, CA; clone SP6, 1:200 dilution), p53 (Neomarkers, clone DO-7, 1:100 dilution), MDM2 (Neomarkers, polyconal, 1:25), and p21 (Neomarkers, clone DCS-60.2, 1:50), were used.
3. Results Macroscopic examination revealed a 2 × 1.5 × 1-cm pedunculated polypoid mass located at the conjunction
between common hepatic duct and cystic duct, obliterating whole proximal biliary tree (Fig. 1B). Gallbladder was hydropic and full of mucinous material with floating fragments of tumor papillae. Mucosae of gallbladder and cystic duct proximal to polypoid mass were covered with fine papillary tumoral structures. Rest of biliary tract was normal macroscopically. Whole biliary duct and representative parts from gallbladder were sectioned and examined. In histologic examination, papillomatous proliferation of atypical epithelial cells on the wall of gallbladder and cystic duct was seen. Delicate fibrovascular cores were surrounded by 3 to 4 layered columnar cells with hyperchromatic nuclei. Frequent mitotic figures and areas with malignant cellular features were encountered (Fig. 2). Despite cells with malignant morphology being confined above basal membrane in most of the sections of tumor, superficial infiltration was seen in some areas (Fig. 2). Polyp was composed of noninvasive papillary fronds that
142
K. Kosemehmetoglu et al. / Annals of Diagnostic Pathology 15 (2011) 140–144
Fig. 2. Morphologic characteristics of papillomatosis and polypoid papillary carcinoma.
share the same morphologic features as those of gallbladder and cystic duct (Fig. 2). Ki67, p53, p21, and MDM2 expressions were shown in Fig. 3. No sign of primary biliary sclerosis, Caroli disease, Clonorchis sinensis
infestation, and cholelithiasis was seen. Lymph node or distant metastasis was not detected. Diagnosis of papillary carcinoma with diffuse malignant papillomatosis of gallbladder and cystic duct was given.
Fig. 3. Immunohistochemical studies showing high Ki67 proliferation index, diffuse nuclear p53 and p21 expression, and negative MDM2 staining in both gallbladder (papillomatosis) and polyp (papillary carcinoma).
K. Kosemehmetoglu et al. / Annals of Diagnostic Pathology 15 (2011) 140–144
4. Discussion Biliary papillomatosis is a rare disease. In a large series, Lee et al [1] studied 58 patients and Yeung et al [2] reviewed English literature and presented 50 cases with biliary papillomatosis, yielding a total 108 cases. According to both studies, characteristic presentation is an elderly male patient with abdominal pain and jaundice, or acute cholangitis. Radiological and cholangioscopic studies are usually successful in detecting those papillary adenomas. In terms of prognosis, results are controversial; and it depends on the extent and location of tumor. Nevertheless, extensive resection is recommended to prevent local recurrences. Either clinical presentation or treatment of our case was consistent with literature, except for the female sex, diffuse malignant morphology, and sole extrahepatic involvement. The literature has opposing data about localization of papillomatosis. Exclusive extrahepatic involvement without intrahepatic involvement was previously reported in 20% to 27% of cases [2,8]; however, in the largest series [1], only intrahepatic or diffuse intra- and extrahepatic involvement was present. Because patients diagnosed as extrahepatic papillomatosis have recurrences intrahepatically [5], this difference may be due to underestimation of the extent of tumor by radiological and endoscopic techniques. Sole extrahepatic involvement may have better prognosis because whole tumor can be excised surgically. Presented case yielded 4 years of disease-free survival, like other cases in the literature [6-9]. Biliary papillomatosis was known to be a premalignant condition with a low malignant potential, as focal malignant change is rarely encountered [6]. However, the frequency of malignant change has recently been found to be much more than expected. In the 2 largest studies [1,2], 74% to 83% of cases showed malignant change; and those malignant changes occur focally in the background of benign biliary papillary adenomas. Interestingly, in our case, most of the papillary structures showed malignant morphology with focal invasive areas; and a 2-cm polypoid mass is found to be noninvasive papillary carcinoma. In the literature, to our knowledge, only 2 cases share similar pathologic features, namely, extrahepatic involvement and diffuse malignant morphology [3,7]. Among many others, activating mutations of K-ras and cyclin-dependent kinase inhibitor p21, TP53 gene mutation associated accumulation of p53, and inactivation of p16 play important roles in the pathogenesis of usual gallbladder carcinoma [10]. In the presented case, both malignant papillomatosis and papillary adenocarcinoma areas showed similar morphologic and immunohistochemical properties: p53 and p21 were both expressed in papillary carcinoma and papillomatosis of gallbladder. Ki67 proliferation indices were high in both areas. MDM2 was negative. p21, a cyclindependent kinase inhibitor mediated by p53, regulates the activity of Rb and subsequently cell entry into S phase [11,12]. p53 is also known to interact with the tumor
143
progression factor MDM2, which is a promoter in p53 degradation and inhibitor of its transactivation [13]. p53 is overexpressed in biliary precancerous proliferations such as dysplasia and carcinoma in situ; therefore, p53 overexpression is thought to be an early event in biliary carcinogenesis [14]. Albores-Saavedra et al [4] reported p53 positivity in 3 papillary carcinomas out of 7, and there was no correlation between survival and p53 positivity. Nearly half of invasive adenocarcinomas, including well-differentiated ones, also express p53 [14,15]. Moreover, it has been shown that among the patients who had gallbladder carcinoma with p53 mutation, the patients with concomitant p21 mutation had worse prognosis than the patients with wild-type p21 [16]. Strong p53 expression was also reported in malignant biliary papillomatosis [7]. Although diffuse p53 expression in papillomatosis component of the presented case supports malignant morphology, expression of p53 and p21 in both papillary carcinoma and papillomatosis may suggest similar origin. Biliary papillomatosis cases show extensive involvement of biliary tree, especially intrahepatic ducts, with worse prognosis, whereas noninvasive papillary carcinomas tend to be solitary. Some papillary structures may be seen in base of papillary adenocarcinoma, but extensive involvement is consistent with papillomatosis. Regarding the histopathologic and immunohistochemical properties, it can be speculated that noninvasive papillary carcinoma developed as an initiating event; and consequently, papillomatosis of gallbladder and cystic duct occurred as a seeding process because of biliary blockade and backflow. On the contrary, noninvasive papillary carcinoma might have developed in the background of papillomatosis; but exclusive involvement of mucosa proximal to largest polypoid mass and normal intrahepatic biliary ducts favor the first probability. References [1] Lee SS, Kim MH, Lee SK, et al. Clinicopathologic review of 58 patients with biliary papillomatosis. Cancer 2004;100(4):783-93. [2] Yeung YP, AhChong K, Chung CK, et al. Biliary papillomatosis: report of seven cases and review of English literature. J Hepatobiliary Pancreat Surg 2003;10(5):390-5. [3] Tetikkurt S, Şahan E, İğdem-Akyıldız A. Gallbladder adenocarcinoma arising from papillomatosis. Turkish J Pathol 2000;16:113-5. [4] Albores-Saavedra J, Murakata L, Krueger JE, et al. Noninvasive and minimally invasive papillary carcinomas of the extrahepatic bile ducts. Cancer 2000;89(3):508-15. [5] Lam CM, Yuen ST, Yuen WK, et al. Biliary papillomatosis. Br J Surg 1996;83(12):1715-6. [6] Taguchi J, Yasunaga M, Kojiro M, et al. Intrahepatic and extrahepatic biliary papillomatosis. Arch Pathol Lab Med 1993;117(9):944-7. [7] Ahaouche M, Cazals-Hatem D, Watrin T, et al. Malignant biliary papillomatosis: analysis of p53 expression. Ann Pathol 2004;24 (4):364-7. [8] Sotiropoulos GC, Lang H, Nadalin S, et al. Papillomatosis confined to the distal biliary tract–a rare cause of obstructive jaundice: report of a case. Surg Today 2003;33(10):781-4. [9] Holtkamp W, Reis HE. Papillomatosis of the bile ducts: papillomacarcinoma sequence. Am J Gastroenterol 1994;89(12):2253-5.
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[10] Goldin RD, Roa JC. Gallbladder cancer: a morphological and molecular update. Histopathology 2009;55(2):218-29. [11] el-Deiry WS, Harper JW, O'Connor PM, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 1994;54(5):1169-74. [12] Reed SI, Bailly E, Dulic V, et al. G1 control in mammalian cells. J Cell Sci Suppl 1994;18:69-73. [13] Chen CY, Oliner JD, Zhan Q, et al. Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway. Proc Natl Acad Sci U S A 1994;91(7):2684-8.
[14] Wistuba II, Gazdar AF, Roa I, et al. p53 protein overexpression in gallbladder carcinoma and its precursor lesions: an immunohistochemical study. Hum Pathol 1996;27(4):360-5. [15] Teh M, Wee A, Raju GC. An immunohistochemical study of p53 protein in gallbladder and extrahepatic bile duct/ampullary carcinomas. Cancer 1994;74(5):1542-5. [16] Puhalla H, Wrba F, Kandioler D, et al. Expression of p21(Wafl/Cip1), p57(Kip2) and HER2/neu in patients with gallbladder cancer. Anticancer Res 2007;27(3B):1679-84.
Annals of Diagnostic Pathology 15 (2011) 140 – 144
Papillary carcinoma with diffuse papillomatosis of gallbladder and cystic duct Kemal Kosemehmetoglu, MDa,⁎, Erhan Akpinar, MDb , Cenk Sokmensuer, MDa , Erhan Hamaloglu, MDc a
Department of Pathology, Hacettepe University, 06100 Ankara, Turkey Department of Radiology, Hacettepe University, 06100 Ankara, Turkey c Department of Surgery, Hacettepe University, 06100 Ankara, Turkey
b
Abstract
Keywords:
Biliary papillomatosis and papillary carcinoma are rare tumors of biliary tract; and because of their morphologic similarities, papillomatosis-papillary carcinoma sequel has been proposed. We report an unusual case of polypoid minimally invasive papillary carcinoma located at the junction between cystic and common bile ducts, complicated with biliary papillomatosis of gallbladder and cystic duct, showing focal areas of malignant change. Intrahepatic ducts, hepatic ducts, and distal common bile duct were spared. Both papillomatosis and papillary carcinoma showed areas of high p53 and p21 expression with high proliferative index. Patient is still alive for 4 years without evidence of disease after modified Whipple operation. Possible pathogenetic mechanisms are further discussed. © 2011 Elsevier Inc. All rights reserved. Papillomatosis; Gallbladder; Papillary carcinoma; p53; MDM2; p21; Ki67
1. Introduction
2. Case report
Biliary papillomatosis, characterized by papillary adenomas covering mucosal surface of extrahepatic and/or intrahepatic biliary system, is regarded as a premalignant condition; and focal malignant transformation is not so uncommon [1-3]. However, distinction of papillomatosis from noninvasive papillary carcinomas is sometimes difficult, especially when extensive malignant change in papillomatosis occurs [3-6]. Therefore, biliary papillomatosis-papillary carcinoma sequence is proposed by some authors [7]. Here we report a case with large solitary papillary carcinoma, located in common hepatic duct, arising in the background of diffuse malignant papillomatosis of gallbladder and cystic duct.
A 62-year-old woman presented with epigastric pain, jaundice, acholic gaita, and darkening in urine. She had epigastric pain for 10 years that became exaggerated in the last month. In this period, she had lost 4 to 5 kg. In physical examination, sclera was icteric and gallbladder was palpable. Laboratory studies detected anemia (hemoglobin, 12.3 mg/ dL) and elevations in alkaline phosphatase and γ-glutamyl transferase enzymes. Total bilirubin level was 5.78 mg/dL, with an indirect bilirubin level of 3.87 mg/dL. Radiological studies showed a thickened gallbladder wall, suggesting gallbladder carcinoma; a 3-cm mass filling the lower end of common bile duct; and secondary dilation of intra-extrahepatic bile ducts (Fig. 1A). Endoscopic retrograde cholangiopancreatography (ERCP) confirmed a 3-cm mass at distal one third of common bile duct. Modified Whipple operation was performed. No further therapy was given to patient, and patient recovered well without evidence of recurrence as yet (48 months of follow-up). Whipple specimen was dissected and fixed in 10% neutral buffered formalin. Whole bile duct system and representative
⁎ Corresponding author. Tel.: +90 312 305 1563; fax: +90 312 305 2621. E-mail address: [email protected] (K. Kosemehmetoglu). 1092-9134/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2010.02.004
K. Kosemehmetoglu et al. / Annals of Diagnostic Pathology 15 (2011) 140–144
141
Fig. 1. (A) Computed tomography showed thickening in gallbladder, a 3-cm mass filling the lower end of common bile duct, and secondary dilation of intra-extrahepatic bile ducts. (B) Dissected Whipple specimen. A 2-cm polypoid mass, obliterating cystic and common hepatic ducts with secondary dilatation, and diffuse papillary fronds on gallbladder and cystic duct mucosae are shown. Inset demonstrates cream-colored cut section of polypoid mass.
sections from gallbladder and pancreas were taken and embedded in paraffin. Four-micrometer–thick sections were prepared from each and stained with routine hematoxylin and eosin. An immunohistochemical study was performed with a standard streptavidin-biotin-peroxidase complex technique using a SkyTek (Tokyo, Japan) according to the manufacturer's instructions. Antigen retrieval was performed by a heatinduced epitope retrieval method. Monoclonal antibodies against Ki67 (Neomarkers, Fremont, CA; clone SP6, 1:200 dilution), p53 (Neomarkers, clone DO-7, 1:100 dilution), MDM2 (Neomarkers, polyconal, 1:25), and p21 (Neomarkers, clone DCS-60.2, 1:50), were used.
3. Results Macroscopic examination revealed a 2 × 1.5 × 1-cm pedunculated polypoid mass located at the conjunction
between common hepatic duct and cystic duct, obliterating whole proximal biliary tree (Fig. 1B). Gallbladder was hydropic and full of mucinous material with floating fragments of tumor papillae. Mucosae of gallbladder and cystic duct proximal to polypoid mass were covered with fine papillary tumoral structures. Rest of biliary tract was normal macroscopically. Whole biliary duct and representative parts from gallbladder were sectioned and examined. In histologic examination, papillomatous proliferation of atypical epithelial cells on the wall of gallbladder and cystic duct was seen. Delicate fibrovascular cores were surrounded by 3 to 4 layered columnar cells with hyperchromatic nuclei. Frequent mitotic figures and areas with malignant cellular features were encountered (Fig. 2). Despite cells with malignant morphology being confined above basal membrane in most of the sections of tumor, superficial infiltration was seen in some areas (Fig. 2). Polyp was composed of noninvasive papillary fronds that
142
K. Kosemehmetoglu et al. / Annals of Diagnostic Pathology 15 (2011) 140–144
Fig. 2. Morphologic characteristics of papillomatosis and polypoid papillary carcinoma.
share the same morphologic features as those of gallbladder and cystic duct (Fig. 2). Ki67, p53, p21, and MDM2 expressions were shown in Fig. 3. No sign of primary biliary sclerosis, Caroli disease, Clonorchis sinensis
infestation, and cholelithiasis was seen. Lymph node or distant metastasis was not detected. Diagnosis of papillary carcinoma with diffuse malignant papillomatosis of gallbladder and cystic duct was given.
Fig. 3. Immunohistochemical studies showing high Ki67 proliferation index, diffuse nuclear p53 and p21 expression, and negative MDM2 staining in both gallbladder (papillomatosis) and polyp (papillary carcinoma).
K. Kosemehmetoglu et al. / Annals of Diagnostic Pathology 15 (2011) 140–144
4. Discussion Biliary papillomatosis is a rare disease. In a large series, Lee et al [1] studied 58 patients and Yeung et al [2] reviewed English literature and presented 50 cases with biliary papillomatosis, yielding a total 108 cases. According to both studies, characteristic presentation is an elderly male patient with abdominal pain and jaundice, or acute cholangitis. Radiological and cholangioscopic studies are usually successful in detecting those papillary adenomas. In terms of prognosis, results are controversial; and it depends on the extent and location of tumor. Nevertheless, extensive resection is recommended to prevent local recurrences. Either clinical presentation or treatment of our case was consistent with literature, except for the female sex, diffuse malignant morphology, and sole extrahepatic involvement. The literature has opposing data about localization of papillomatosis. Exclusive extrahepatic involvement without intrahepatic involvement was previously reported in 20% to 27% of cases [2,8]; however, in the largest series [1], only intrahepatic or diffuse intra- and extrahepatic involvement was present. Because patients diagnosed as extrahepatic papillomatosis have recurrences intrahepatically [5], this difference may be due to underestimation of the extent of tumor by radiological and endoscopic techniques. Sole extrahepatic involvement may have better prognosis because whole tumor can be excised surgically. Presented case yielded 4 years of disease-free survival, like other cases in the literature [6-9]. Biliary papillomatosis was known to be a premalignant condition with a low malignant potential, as focal malignant change is rarely encountered [6]. However, the frequency of malignant change has recently been found to be much more than expected. In the 2 largest studies [1,2], 74% to 83% of cases showed malignant change; and those malignant changes occur focally in the background of benign biliary papillary adenomas. Interestingly, in our case, most of the papillary structures showed malignant morphology with focal invasive areas; and a 2-cm polypoid mass is found to be noninvasive papillary carcinoma. In the literature, to our knowledge, only 2 cases share similar pathologic features, namely, extrahepatic involvement and diffuse malignant morphology [3,7]. Among many others, activating mutations of K-ras and cyclin-dependent kinase inhibitor p21, TP53 gene mutation associated accumulation of p53, and inactivation of p16 play important roles in the pathogenesis of usual gallbladder carcinoma [10]. In the presented case, both malignant papillomatosis and papillary adenocarcinoma areas showed similar morphologic and immunohistochemical properties: p53 and p21 were both expressed in papillary carcinoma and papillomatosis of gallbladder. Ki67 proliferation indices were high in both areas. MDM2 was negative. p21, a cyclindependent kinase inhibitor mediated by p53, regulates the activity of Rb and subsequently cell entry into S phase [11,12]. p53 is also known to interact with the tumor
143
progression factor MDM2, which is a promoter in p53 degradation and inhibitor of its transactivation [13]. p53 is overexpressed in biliary precancerous proliferations such as dysplasia and carcinoma in situ; therefore, p53 overexpression is thought to be an early event in biliary carcinogenesis [14]. Albores-Saavedra et al [4] reported p53 positivity in 3 papillary carcinomas out of 7, and there was no correlation between survival and p53 positivity. Nearly half of invasive adenocarcinomas, including well-differentiated ones, also express p53 [14,15]. Moreover, it has been shown that among the patients who had gallbladder carcinoma with p53 mutation, the patients with concomitant p21 mutation had worse prognosis than the patients with wild-type p21 [16]. Strong p53 expression was also reported in malignant biliary papillomatosis [7]. Although diffuse p53 expression in papillomatosis component of the presented case supports malignant morphology, expression of p53 and p21 in both papillary carcinoma and papillomatosis may suggest similar origin. Biliary papillomatosis cases show extensive involvement of biliary tree, especially intrahepatic ducts, with worse prognosis, whereas noninvasive papillary carcinomas tend to be solitary. Some papillary structures may be seen in base of papillary adenocarcinoma, but extensive involvement is consistent with papillomatosis. Regarding the histopathologic and immunohistochemical properties, it can be speculated that noninvasive papillary carcinoma developed as an initiating event; and consequently, papillomatosis of gallbladder and cystic duct occurred as a seeding process because of biliary blockade and backflow. On the contrary, noninvasive papillary carcinoma might have developed in the background of papillomatosis; but exclusive involvement of mucosa proximal to largest polypoid mass and normal intrahepatic biliary ducts favor the first probability. References [1] Lee SS, Kim MH, Lee SK, et al. Clinicopathologic review of 58 patients with biliary papillomatosis. Cancer 2004;100(4):783-93. [2] Yeung YP, AhChong K, Chung CK, et al. Biliary papillomatosis: report of seven cases and review of English literature. J Hepatobiliary Pancreat Surg 2003;10(5):390-5. [3] Tetikkurt S, Şahan E, İğdem-Akyıldız A. Gallbladder adenocarcinoma arising from papillomatosis. Turkish J Pathol 2000;16:113-5. [4] Albores-Saavedra J, Murakata L, Krueger JE, et al. Noninvasive and minimally invasive papillary carcinomas of the extrahepatic bile ducts. Cancer 2000;89(3):508-15. [5] Lam CM, Yuen ST, Yuen WK, et al. Biliary papillomatosis. Br J Surg 1996;83(12):1715-6. [6] Taguchi J, Yasunaga M, Kojiro M, et al. Intrahepatic and extrahepatic biliary papillomatosis. Arch Pathol Lab Med 1993;117(9):944-7. [7] Ahaouche M, Cazals-Hatem D, Watrin T, et al. Malignant biliary papillomatosis: analysis of p53 expression. Ann Pathol 2004;24 (4):364-7. [8] Sotiropoulos GC, Lang H, Nadalin S, et al. Papillomatosis confined to the distal biliary tract–a rare cause of obstructive jaundice: report of a case. Surg Today 2003;33(10):781-4. [9] Holtkamp W, Reis HE. Papillomatosis of the bile ducts: papillomacarcinoma sequence. Am J Gastroenterol 1994;89(12):2253-5.
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[10] Goldin RD, Roa JC. Gallbladder cancer: a morphological and molecular update. Histopathology 2009;55(2):218-29. [11] el-Deiry WS, Harper JW, O'Connor PM, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 1994;54(5):1169-74. [12] Reed SI, Bailly E, Dulic V, et al. G1 control in mammalian cells. J Cell Sci Suppl 1994;18:69-73. [13] Chen CY, Oliner JD, Zhan Q, et al. Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway. Proc Natl Acad Sci U S A 1994;91(7):2684-8.
[14] Wistuba II, Gazdar AF, Roa I, et al. p53 protein overexpression in gallbladder carcinoma and its precursor lesions: an immunohistochemical study. Hum Pathol 1996;27(4):360-5. [15] Teh M, Wee A, Raju GC. An immunohistochemical study of p53 protein in gallbladder and extrahepatic bile duct/ampullary carcinomas. Cancer 1994;74(5):1542-5. [16] Puhalla H, Wrba F, Kandioler D, et al. Expression of p21(Wafl/Cip1), p57(Kip2) and HER2/neu in patients with gallbladder cancer. Anticancer Res 2007;27(3B):1679-84.