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Published in: Virchows Archiv 5/2017

01-05-2017 | Original Article

In liver metastases from small intestinal neuroendocrine tumors, SSTR2A expression is heterogeneous

Authors: Mongkon Charoenpitakchai, Eric Liu, Zhiguo Zhao, Tatsuki Koyama, Won Jae Huh, Jordan Berlin, Kenneth Hande, Ronald Walker, Chanjuan Shi

Published in: Virchows Archiv | Issue 5/2017

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Abstract

We examined somatostatin receptor type 2A (SSTR2A) expression in primary and metastatic small intestinal neuroendocrine tumors (SI-NETs). We retrieved 156 liver metastases from 26 patients (10 males, 16 females) who had two or more liver lesions resected. A representative formalin-fixed paraffin-embedded section of tumor tissue from each liver metastasis and from the primary tumor, when available, were immunohistochemically stained for SSTR2A. SSTR2A expression was evaluated by the Her2/neu-scoring system and the scoring system proposed by Volante et al. Based on the Her2/neu-scoring system, moderate to strong SSTR2A expression was observed in 121 of 156 (78%) liver metastases. In 15 (58%) subjects, all liver metastases showed moderate to strong SSTR2A expression, whereas in 11 (42%) one or more liver tumors had weak or no expression. Of the 16 stained primaries, 11 (69%) showed heterogeneous SSTR2A expression. The corresponding liver metastases showed only weak to no expression in one, moderate to strong in five, and both weak to no and moderate to strong expression in five of the 11 cases. Using the Volante scoring system, no tumor was scored 0 (0%), two were scored 1 (1%), 38 were scored 2 (24%), and 116 were scored 3 (74%). No statistically significant association was observed between SSTR2A expression and Ki67 index (p = 0.56). Fifteen of 18 (83%) metastatic tumors with a Ki67 index >20% showed moderate to strong SSTR2A. Most liver tumors with weak SSTR2A expression or an IHC score of 2 were detected by OctreoScan. SSTR2A expression in liver metastases of SI-NETs can be variable, even between lesions in the same patient. Expression in metastatic lesions is not always similar to that in the primary tumor. SSTR2A expression is not associated with the Ki67 index.
Literature
1.
go back to reference Patel YC, Greenwood MT, Panetta R, Demchyshyn L, Niznik H, Srikant CB (1995) The somatostatin receptor family. Life Sci 57:1249–1265CrossRefPubMed Patel YC, Greenwood MT, Panetta R, Demchyshyn L, Niznik H, Srikant CB (1995) The somatostatin receptor family. Life Sci 57:1249–1265CrossRefPubMed
2.
go back to reference Jais P, Terris B, Ruszniewski P, LeRomancer M, Reyl-Desmars F, Vissuzaine C, Cadiot G, Mignon M, Lewin MJ (1997) Somatostatin receptor subtype gene expression in human endocrine gastroentero-pancreatic tumours. Eur J Clin Investig 27:639–644CrossRef Jais P, Terris B, Ruszniewski P, LeRomancer M, Reyl-Desmars F, Vissuzaine C, Cadiot G, Mignon M, Lewin MJ (1997) Somatostatin receptor subtype gene expression in human endocrine gastroentero-pancreatic tumours. Eur J Clin Investig 27:639–644CrossRef
3.
go back to reference Papotti M, Bongiovanni M, Volante M, Allia E, Landolfi S, Helboe L, Schindler M, Cole SL, Bussolati G (2002) Expression of somatostatin receptor types 1-5 in 81 cases of gastrointestinal and pancreatic endocrine tumors. A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis. Virchows Arch 440:461–475CrossRefPubMed Papotti M, Bongiovanni M, Volante M, Allia E, Landolfi S, Helboe L, Schindler M, Cole SL, Bussolati G (2002) Expression of somatostatin receptor types 1-5 in 81 cases of gastrointestinal and pancreatic endocrine tumors. A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis. Virchows Arch 440:461–475CrossRefPubMed
4.
go back to reference Kubota A, Yamada Y, Kagimoto S, Shimatsu A, Imamura M, Tsuda K, Imura H, Seino S, Seino Y (1994) Identification of somatostatin receptor subtypes and an implication for the efficacy of somatostatin analogue SMS 201-995 in treatment of human endocrine tumors. J Clin Invest 93:1321–1325CrossRefPubMedPubMedCentral Kubota A, Yamada Y, Kagimoto S, Shimatsu A, Imamura M, Tsuda K, Imura H, Seino S, Seino Y (1994) Identification of somatostatin receptor subtypes and an implication for the efficacy of somatostatin analogue SMS 201-995 in treatment of human endocrine tumors. J Clin Invest 93:1321–1325CrossRefPubMedPubMedCentral
5.
go back to reference Reubi JC, Schaer JC, Waser B, Mengod G (1994) Expression and localization of somatostatin receptor SSTR1, SSTR2, and SSTR3 messenger RNAs in primary human tumors using in situ hybridization. Cancer Res 54:3455–3459PubMed Reubi JC, Schaer JC, Waser B, Mengod G (1994) Expression and localization of somatostatin receptor SSTR1, SSTR2, and SSTR3 messenger RNAs in primary human tumors using in situ hybridization. Cancer Res 54:3455–3459PubMed
6.
go back to reference Kimura N, Pilichowska M, Date F, Kimura I, Schindler M (1999) Immunohistochemical expression of somatostatin type 2A receptor in neuroendocrine tumors. Clin Cancer Res 5:3483–3487PubMed Kimura N, Pilichowska M, Date F, Kimura I, Schindler M (1999) Immunohistochemical expression of somatostatin type 2A receptor in neuroendocrine tumors. Clin Cancer Res 5:3483–3487PubMed
7.
go back to reference Reubi JC, Waser B (2003) Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting. Eur J Nucl Med Mol Imaging 30:781–793CrossRefPubMed Reubi JC, Waser B (2003) Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting. Eur J Nucl Med Mol Imaging 30:781–793CrossRefPubMed
8.
go back to reference Kagimoto S, Yamada Y, Kubota A, Someya Y, Ihara Y, Yasuda K, Kozasa T, Imura H, Seino S, Seino Y (1994) Human somatostatin receptor, SSTR2, is coupled to adenylyl cyclase in the presence of Gi alpha 1 protein. Biochem Biophys Res Commun 202:1188–1195CrossRefPubMed Kagimoto S, Yamada Y, Kubota A, Someya Y, Ihara Y, Yasuda K, Kozasa T, Imura H, Seino S, Seino Y (1994) Human somatostatin receptor, SSTR2, is coupled to adenylyl cyclase in the presence of Gi alpha 1 protein. Biochem Biophys Res Commun 202:1188–1195CrossRefPubMed
9.
go back to reference Modlin IM, Lye KD, Kidd M (2003) A 5-decade analysis of 13,715 carcinoid tumors. Cancer 97:934–959CrossRefPubMed Modlin IM, Lye KD, Kidd M (2003) A 5-decade analysis of 13,715 carcinoid tumors. Cancer 97:934–959CrossRefPubMed
10.
go back to reference Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evan DB (2008) One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26:3063–3072CrossRefPubMed Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evan DB (2008) One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26:3063–3072CrossRefPubMed
11.
go back to reference Caplin ME, Pavel M, Ruszniewski P (2014) Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371:1556–1557CrossRefPubMed Caplin ME, Pavel M, Ruszniewski P (2014) Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371:1556–1557CrossRefPubMed
12.
go back to reference Wynick D, Anderson JV, Williams SJ, Bloom SR (1989) Resistance of metastatic pancreatic endocrine tumours after long-term treatment with the somatostatin analogue octreotide (SMS 201-995). Clin Endocrinol 30:385–388CrossRef Wynick D, Anderson JV, Williams SJ, Bloom SR (1989) Resistance of metastatic pancreatic endocrine tumours after long-term treatment with the somatostatin analogue octreotide (SMS 201-995). Clin Endocrinol 30:385–388CrossRef
13.
go back to reference Reubi JC, Kvols LK, Waser B, Nagorney DM, Heitz PU, Charboneau JW, Reading CC, Moertel C (1990) Detection of somatostatin receptors in surgical and percutaneous needle biopsy samples of carcinoids and islet cell carcinomas. Cancer Res 50:5969–5977PubMed Reubi JC, Kvols LK, Waser B, Nagorney DM, Heitz PU, Charboneau JW, Reading CC, Moertel C (1990) Detection of somatostatin receptors in surgical and percutaneous needle biopsy samples of carcinoids and islet cell carcinomas. Cancer Res 50:5969–5977PubMed
14.
go back to reference Kvols LK, Buck M, Moertel CG, Schutt AJ, Rubin J, O'Connell MJ, Hahn RG (1987) Treatment of metastatic islet cell carcinoma with a somatostatin analogue (SMS 201-995). Ann Intern Med 107:162–168CrossRefPubMed Kvols LK, Buck M, Moertel CG, Schutt AJ, Rubin J, O'Connell MJ, Hahn RG (1987) Treatment of metastatic islet cell carcinoma with a somatostatin analogue (SMS 201-995). Ann Intern Med 107:162–168CrossRefPubMed
15.
go back to reference Kvols LK, Moertel CG, O'Connell MJ, Schutt AJ, Rubin J, Hahn RG (1986) Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med 315:663–666CrossRefPubMed Kvols LK, Moertel CG, O'Connell MJ, Schutt AJ, Rubin J, Hahn RG (1986) Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med 315:663–666CrossRefPubMed
16.
go back to reference Gardner-Roehnelt NM (2012) Update on the management of neuroendocrine tumors: focus on somatostatin antitumor effects. Clin J Oncol Nurs 16:56–64CrossRefPubMed Gardner-Roehnelt NM (2012) Update on the management of neuroendocrine tumors: focus on somatostatin antitumor effects. Clin J Oncol Nurs 16:56–64CrossRefPubMed
17.
go back to reference Laznicek M, Laznickova A, Maecke HR (2012) Receptor affinity and preclinical biodistribution of radiolabeled somatostatin analogs. Anticancer Res 32:761–766PubMed Laznicek M, Laznickova A, Maecke HR (2012) Receptor affinity and preclinical biodistribution of radiolabeled somatostatin analogs. Anticancer Res 32:761–766PubMed
18.
go back to reference Reubi JC, Schar JC, Waser B, Wenger S, Heppeler A, Schmitt JS, Macke HR (2000) Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med 27:273–282CrossRefPubMed Reubi JC, Schar JC, Waser B, Wenger S, Heppeler A, Schmitt JS, Macke HR (2000) Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med 27:273–282CrossRefPubMed
19.
go back to reference Janson ET, Gobl A, Kalkner KM, Oberg K (1996) A comparison between the efficacy of somatostatin receptor scintigraphy and that of in situ hybridization for somatostatin receptor subtype 2 messenger RNA to predict therapeutic outcome in carcinoid patients. Cancer Res 56:2561–2565PubMed Janson ET, Gobl A, Kalkner KM, Oberg K (1996) A comparison between the efficacy of somatostatin receptor scintigraphy and that of in situ hybridization for somatostatin receptor subtype 2 messenger RNA to predict therapeutic outcome in carcinoid patients. Cancer Res 56:2561–2565PubMed
20.
go back to reference Bakker WH, Krenning EP, Reubi JC, Breeman WA, Setyono-Han B, de Jong M, Kooij PP, Bruns C, van Hagen PM, Marbach P et al (1991) In vivo application of [111In-DTPA-D-Phe1]-octreotide for detection of somatostatin receptor-positive tumors in rats. Life Sci 49:1593–1601CrossRefPubMed Bakker WH, Krenning EP, Reubi JC, Breeman WA, Setyono-Han B, de Jong M, Kooij PP, Bruns C, van Hagen PM, Marbach P et al (1991) In vivo application of [111In-DTPA-D-Phe1]-octreotide for detection of somatostatin receptor-positive tumors in rats. Life Sci 49:1593–1601CrossRefPubMed
21.
go back to reference Krenning EP, Kwekkeboom DJ, Bakker WH, Breeman WA, Kooij PP, Oei HY, van Hagen M, Postema PT, de Jong M, Reubi JC et al (1993) Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 20:716–731CrossRefPubMed Krenning EP, Kwekkeboom DJ, Bakker WH, Breeman WA, Kooij PP, Oei HY, van Hagen M, Postema PT, de Jong M, Reubi JC et al (1993) Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 20:716–731CrossRefPubMed
22.
go back to reference Maecke HR, Reubi JC (2011) Somatostatin receptors as targets for nuclear medicine imaging and radionuclide treatment. J Nucl Med 52:841–844CrossRefPubMed Maecke HR, Reubi JC (2011) Somatostatin receptors as targets for nuclear medicine imaging and radionuclide treatment. J Nucl Med 52:841–844CrossRefPubMed
23.
go back to reference Ambrosini V, Fani M, Fanti S, Forrer F, Maecke HR (2011) Radiopeptide imaging and therapy in Europe. J Nucl Med 52(Suppl 2):42S–55SCrossRefPubMed Ambrosini V, Fani M, Fanti S, Forrer F, Maecke HR (2011) Radiopeptide imaging and therapy in Europe. J Nucl Med 52(Suppl 2):42S–55SCrossRefPubMed
24.
go back to reference Treglia G, Castaldi P, Rindi G, Giordano A, Rufini V (2012) Diagnostic performance of gallium-68 somatostatin receptor PET and PET/CT in patients with thoracic and gastroenteropancreatic neuroendocrine tumours: a meta-analysis. Endocrine 42:80–87CrossRefPubMed Treglia G, Castaldi P, Rindi G, Giordano A, Rufini V (2012) Diagnostic performance of gallium-68 somatostatin receptor PET and PET/CT in patients with thoracic and gastroenteropancreatic neuroendocrine tumours: a meta-analysis. Endocrine 42:80–87CrossRefPubMed
25.
go back to reference Sharma N, Naraev BG, Engelman EG, Zimmerman MB, Bushnell DL, Jr., O'Dorisio TM, O'Dorisio MS, Menda Y, Muller-Brand J, Howe JR et al. (2016) Peptide receptor radionuclide therapy outcomes in a North American cohort with metastatic well-differentiated neuroendocrine tumors. Pancreas. Sharma N, Naraev BG, Engelman EG, Zimmerman MB, Bushnell DL, Jr., O'Dorisio TM, O'Dorisio MS, Menda Y, Muller-Brand J, Howe JR et al. (2016) Peptide receptor radionuclide therapy outcomes in a North American cohort with metastatic well-differentiated neuroendocrine tumors. Pancreas.
26.
go back to reference Yalchin M, Oliveira A, Theocharidou E, Pencharz D, Navalkissoor S, Quigley AM, Walker M, Caplin M, Toumpanakis C (2016) The impact of radiological response to peptide receptor radionuclide therapy on overall survival in patients with metastatic midgut neuroendocrine tumors. Clin Nucl Med. Yalchin M, Oliveira A, Theocharidou E, Pencharz D, Navalkissoor S, Quigley AM, Walker M, Caplin M, Toumpanakis C (2016) The impact of radiological response to peptide receptor radionuclide therapy on overall survival in patients with metastatic midgut neuroendocrine tumors. Clin Nucl Med.
27.
go back to reference Shi C, Gonzalez RS, Zhao Z, Koyama T, Cornish TC, Hande KR, Walker R, Sandler M, Berlin J, Liu EH (2015) Liver metastases of small intestine neuroendocrine tumors: Ki-67 heterogeneity and World Health Organization grade discordance with primary tumors. Am J Clin Pathol 143:398–404CrossRefPubMedPubMedCentral Shi C, Gonzalez RS, Zhao Z, Koyama T, Cornish TC, Hande KR, Walker R, Sandler M, Berlin J, Liu EH (2015) Liver metastases of small intestine neuroendocrine tumors: Ki-67 heterogeneity and World Health Organization grade discordance with primary tumors. Am J Clin Pathol 143:398–404CrossRefPubMedPubMedCentral
28.
go back to reference Kaemmerer D, Peter L, Lupp A, Schulz S, Sanger J, Baum RP, Prasad V, Hommann M (2013) Comparing of IRS and Her2 as immunohistochemical scoring schemes in gastroenteropancreatic neuroendocrine tumors. Int J Clin Exp Pathol 5:187–194 Kaemmerer D, Peter L, Lupp A, Schulz S, Sanger J, Baum RP, Prasad V, Hommann M (2013) Comparing of IRS and Her2 as immunohistochemical scoring schemes in gastroenteropancreatic neuroendocrine tumors. Int J Clin Exp Pathol 5:187–194
29.
go back to reference Daniel K, Maria A, Amelie L, Isabell L, Stefan S, Luisa P, Merten H, Vikas P, Gerd B, Paul BR (2014) Somatostatin receptor immunohistochemistry in neuroendocrine tumors: comparison between manual and automated evaluation. Int J Clin Exp Pathol 7:4971–4980PubMedCentral Daniel K, Maria A, Amelie L, Isabell L, Stefan S, Luisa P, Merten H, Vikas P, Gerd B, Paul BR (2014) Somatostatin receptor immunohistochemistry in neuroendocrine tumors: comparison between manual and automated evaluation. Int J Clin Exp Pathol 7:4971–4980PubMedCentral
30.
go back to reference Volante M, Brizzi MP, Faggiano A, La Rosa S, Rapa I, Ferrero A, Mansueto G, Righi L, Garancini S, Capella C et al (2007) Somatostatin receptor type 2A immunohistochemistry in neuroendocrine tumors: a proposal of scoring system correlated with somatostatin receptor scintigraphy. Mod Pathol 20:1172–1182CrossRefPubMed Volante M, Brizzi MP, Faggiano A, La Rosa S, Rapa I, Ferrero A, Mansueto G, Righi L, Garancini S, Capella C et al (2007) Somatostatin receptor type 2A immunohistochemistry in neuroendocrine tumors: a proposal of scoring system correlated with somatostatin receptor scintigraphy. Mod Pathol 20:1172–1182CrossRefPubMed
31.
go back to reference Team R R: A language and environment for statistical computing. (3.3):Vienna, Austria. Team R R: A language and environment for statistical computing. (3.3):Vienna, Austria.
32.
go back to reference Kloppel G (2011) Classification and pathology of gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer 18(Suppl 1):S1–16CrossRefPubMed Kloppel G (2011) Classification and pathology of gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer 18(Suppl 1):S1–16CrossRefPubMed
33.
go back to reference Heidari P, Wehrenberg-Klee E, Habibollahi P, Yokell D, Kulke M, Mahmood U (2013) Free somatostatin receptor fraction predicts the antiproliferative effect of octreotide in a neuroendocrine tumor model: implications for dose optimization. Cancer Res 73:6865–6873CrossRefPubMed Heidari P, Wehrenberg-Klee E, Habibollahi P, Yokell D, Kulke M, Mahmood U (2013) Free somatostatin receptor fraction predicts the antiproliferative effect of octreotide in a neuroendocrine tumor model: implications for dose optimization. Cancer Res 73:6865–6873CrossRefPubMed
34.
go back to reference Nicolas G, Giovacchini G, Muller-Brand J, Forrer F (2011) Targeted radiotherapy with radiolabeled somatostatin analogs. Endocrinol Metab Clin N Am 40:187–204 ix-xCrossRef Nicolas G, Giovacchini G, Muller-Brand J, Forrer F (2011) Targeted radiotherapy with radiolabeled somatostatin analogs. Endocrinol Metab Clin N Am 40:187–204 ix-xCrossRef
35.
go back to reference Oksuz MO, Winter L, Pfannenberg C, Reischl G, Mussig K, Bares R, Dittmann H (2014) Peptide receptor radionuclide therapy of neuroendocrine tumors with (90)Y-DOTATOC: is treatment response predictable by pre-therapeutic uptake of (68)Ga-DOTATOC? Diagn Interv Imaging 95:289–300CrossRefPubMed Oksuz MO, Winter L, Pfannenberg C, Reischl G, Mussig K, Bares R, Dittmann H (2014) Peptide receptor radionuclide therapy of neuroendocrine tumors with (90)Y-DOTATOC: is treatment response predictable by pre-therapeutic uptake of (68)Ga-DOTATOC? Diagn Interv Imaging 95:289–300CrossRefPubMed
36.
go back to reference Kwekkeboom DJ, de Herder WW, van Eijck CH, Kam BL, van Essen M, Teunissen JJ, Krenning EP (2010) Peptide receptor radionuclide therapy in patients with gastroenteropancreatic neuroendocrine tumors. Semin Nucl Med 40:78–88CrossRefPubMed Kwekkeboom DJ, de Herder WW, van Eijck CH, Kam BL, van Essen M, Teunissen JJ, Krenning EP (2010) Peptide receptor radionuclide therapy in patients with gastroenteropancreatic neuroendocrine tumors. Semin Nucl Med 40:78–88CrossRefPubMed
37.
go back to reference Frilling A, Clift AK (2015) Therapeutic strategies for neuroendocrine liver metastases. Cancer 121:1172–1186CrossRefPubMed Frilling A, Clift AK (2015) Therapeutic strategies for neuroendocrine liver metastases. Cancer 121:1172–1186CrossRefPubMed
38.
go back to reference Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Horsch D, O'Dorisio MS, O'Dorisio TM, Howe JR, Cremonesi M, Kwekkeboom DJ et al (2013) The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging 40:800–816CrossRefPubMedPubMedCentral Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Horsch D, O'Dorisio MS, O'Dorisio TM, Howe JR, Cremonesi M, Kwekkeboom DJ et al (2013) The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging 40:800–816CrossRefPubMedPubMedCentral
39.
go back to reference Korner M, Waser B, Reubi JC (2015) Does somatostatin or gastric inhibitory peptide receptor expression correlate with tumor grade and stage in gut neuroendocrine tumors? Neuroendocrinology 101:45–57CrossRefPubMed Korner M, Waser B, Reubi JC (2015) Does somatostatin or gastric inhibitory peptide receptor expression correlate with tumor grade and stage in gut neuroendocrine tumors? Neuroendocrinology 101:45–57CrossRefPubMed
Metadata
Title
In liver metastases from small intestinal neuroendocrine tumors, SSTR2A expression is heterogeneous
Authors
Mongkon Charoenpitakchai
Eric Liu
Zhiguo Zhao
Tatsuki Koyama
Won Jae Huh
Jordan Berlin
Kenneth Hande
Ronald Walker
Chanjuan Shi
Publication date
01-05-2017
Publisher
Springer Berlin Heidelberg
Published in
Virchows Archiv / Issue 5/2017
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI
https://doi.org/10.1007/s00428-017-2093-3

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