Morphological and Molecular Characteristics of HER2 Amplified Urothelial Bladder Cancer

Overview

Journal Virchows Arch

Specialties Cell Biology
Molecular Biology
Pathology

Date 2015 Mar 27

PMID 25809292

Citations 24

Authors

J Tschui

E Vassella

N Bandi

U Baumgartner

V Genitsch

D Rotzer

R Seiler

G N Thalmann

A Fleischmann

Affiliations

Soon will be listed here.

Abstract

Several (pre-) clinical trials are currently investigating the benefit of HER2-targeted therapy in urothelial bladder cancer (UBC). Patients with HER2 amplified UBC could potentially profit from these therapies. However, little is known about histomorphology, HER2 protein expression patterns and occurrence of alterations in the HER2 gene in their tumors. Among 150 metastasizing primary UBC, 13 HER2 amplified tumors were identified. Their histopathological features were compared with 13 matched, non-amplified UBC. HER2 protein expression was determined by immunohistochemistry. The 26 tumors were screened for mutations in exons 19 and 20 of the HER2 gene. UBC with HER2 amplification presented with a broad variety of histological variants (median 2 vs. 1), frequently featured micropapillary tumor components (77 % vs. 8 %) and demonstrated a high amount of tumor associated inflammation. Immunohistochemically, 10 of 13 (77 %) HER2 amplified tumors were strongly HER2 protein positive. Three tumors (23 %) were scored as HER2 negative. One of the HER2 amplified tumors harbored a D769N mutation in exon 19 of the HER2 gene; all other tested tumors were wild type. In conclusion, HER2 amplified UBC feature specific morphological characteristics. They frequently express the HER2 protein diffusely and are, therefore, promising candidates for HER2 targeted therapies. The detection of mutations at the HER2 locus might add new aspects to molecular testing of UBC.

Citing Articles

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References

Jenkins M, Hayashi S, OShea A, Burgart L, Smyrk T, Shimizu D . Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology. 2007; 133(1):48-56. PMC: 2933045. DOI: 10.1053/j.gastro.2007.04.044. View

Schechter A, Stern D, Vaidyanathan L, Decker S, Drebin J, Greene M . The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature. 1984; 312(5994):513-6. DOI: 10.1038/312513a0. View

Tinoco G, Warsch S, Gluck S, Avancha K, Montero A . Treating breast cancer in the 21st century: emerging biological therapies. J Cancer. 2013; 4(2):117-32. PMC: 3563073. DOI: 10.7150/jca.4925. View

Fleischmann A, Rotzer D, Seiler R, Studer U, Thalmann G . Her2 amplification is significantly more frequent in lymph node metastases from urothelial bladder cancer than in the primary tumours. Eur Urol. 2011; 60(2):350-7. DOI: 10.1016/j.eururo.2011.05.035. View

Ching C, Amin M, Tubbs R, Elson P, Platt E, Dreicer R . HER2 gene amplification occurs frequently in the micropapillary variant of urothelial carcinoma: analysis by dual-color in situ hybridization. Mod Pathol. 2011; 24(8):1111-9. DOI: 10.1038/modpathol.2011.69. View

Coogan C, Estrada C, Kapur S, Bloom K . HER-2/neu protein overexpression and gene amplification in human transitional cell carcinoma of the bladder. Urology. 2004; 63(4):786-90. DOI: 10.1016/j.urology.2003.10.040. View

Lae M, Couturier J, Oudard S, Radvanyi F, Beuzeboc P, Vieillefond A . Assessing HER2 gene amplification as a potential target for therapy in invasive urothelial bladder cancer with a standardized methodology: results in 1005 patients. Ann Oncol. 2009; 21(4):815-819. PMC: 2844947. DOI: 10.1093/annonc/mdp488. View

Hansel D, Swain E, Dreicer R, Tubbs R . HER2 overexpression and amplification in urothelial carcinoma of the bladder is associated with MYC coamplification in a subset of cases. Am J Clin Pathol. 2008; 130(2):274-81. DOI: 10.1309/41VLTFX3YPP1HF6F. View

Buttitta F, Barassi F, Fresu G, Felicioni L, Chella A, Paolizzi D . Mutational analysis of the HER2 gene in lung tumors from Caucasian patients: mutations are mainly present in adenocarcinomas with bronchioloalveolar features. Int J Cancer. 2006; 119(11):2586-91. DOI: 10.1002/ijc.22143. View

10.

Slamon D, Clark G, Wong S, Levin W, Ullrich A, McGuire W . Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987; 235(4785):177-82. DOI: 10.1126/science.3798106. View

11.

Wolff A, Hammond M, Schwartz J, Hagerty K, Allred D, Cote R . American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2006; 25(1):118-45. DOI: 10.1200/JCO.2006.09.2775. View

12.

Shigematsu H, Takahashi T, Nomura M, Majmudar K, Suzuki M, Lee H . Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res. 2005; 65(5):1642-6. DOI: 10.1158/0008-5472.CAN-04-4235. View

13.

Nicholson R, Gee J, Harper M . EGFR and cancer prognosis. Eur J Cancer. 2001; 37 Suppl 4:S9-15. DOI: 10.1016/s0959-8049(01)00231-3. View

14.

Hartman Z, Yang X, Glass O, Lei G, Osada T, Dave S . HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis. Cancer Res. 2011; 71(13):4380-91. PMC: 3129398. DOI: 10.1158/0008-5472.CAN-11-0308. View

15.

Bose R, Kavuri S, Searleman A, Shen W, Shen D, Koboldt D . Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2012; 3(2):224-37. PMC: 3570596. DOI: 10.1158/2159-8290.CD-12-0349. View

16.

Amin M . Histological variants of urothelial carcinoma: diagnostic, therapeutic and prognostic implications. Mod Pathol. 2009; 22 Suppl 2:S96-S118. DOI: 10.1038/modpathol.2009.26. View

17.

Yarden Y, Sliwkowski M . Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001; 2(2):127-37. DOI: 10.1038/35052073. View

18.

Latif Z, Watters A, Dunn I, Grigor K, Underwood M, Bartlett J . HER2/neu gene amplification and protein overexpression in G3 pT2 transitional cell carcinoma of the bladder: a role for anti-HER2 therapy?. Eur J Cancer. 2003; 40(1):56-63. DOI: 10.1016/j.ejca.2003.08.027. View

19.

Zwick E, Bange J, Ullrich A . Receptor tyrosine kinase signalling as a target for cancer intervention strategies. Endocr Relat Cancer. 2001; 8(3):161-73. DOI: 10.1677/erc.0.0080161. View

20.

Caner V, Sen Turk N, Duzcan F, Satiroglu Tufan N, Kelten E, Zencir S . No strong association between HER-2/neu protein overexpression and gene amplification in high-grade invasive urothelial carcinomas. Pathol Oncol Res. 2008; 14(3):261-6. DOI: 10.1007/s12253-008-9027-y. View