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BRAF V600E mutation-specific immunohistochemistry is a rare finding in dendritic cell- and histiocytederived tumors a
b
c
d
e
Yuri Fedoriw , Young S. Kim , Jo-Anne Vergilio , Z. Will Chen , Lawrence M. Weiss & Dennis P. O'Malley
ef
a
Department of Pathology and Laboratory Medicine, University of North Carolina, Wilmington, NC, USA
Click for updates
b
Department of Pathology, City of Hope National Medical Center, Monrovia, CA, USA
c
Department of Pathology, University of Michigan, Ann Arbor, MI, USA
d
Department of Pathology, University of Utah, Salt Lake City, UT, USA
e
Clarient/GE Healthcare, Aliso Viejo, CA, USA
f
M. D. Anderson Cancer Center, University of Texas, Houston, TX, USA Published online: 09 Jun 2015.
To cite this article: Yuri Fedoriw, Young S. Kim, Jo-Anne Vergilio, Z. Will Chen, Lawrence M. Weiss & Dennis P. O'Malley (2015) BRAF V600E mutation-specific immunohistochemistry is a rare finding in dendritic cell- and histiocyte-derived tumors, Leukemia & Lymphoma, 56:4, 1132-1133, DOI: 10.3109/10428194.2014.946028 To link to this article: http://dx.doi.org/10.3109/10428194.2014.946028
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Leukemia & Lymphoma, April 2015; 56(4): 1132–1133 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.946028
LETTER TO THE EDITOR
BRAF V600E mutation-specific immunohistochemistry is a rare finding in dendritic cell- and histiocyte-derived tumors Yuri Fedoriw1, Young S. Kim2, Jo-Anne Vergilio3, Z. Will Chen4, Lawrence M. Weiss5 & Dennis P. O’Malley5,6 1Department of Pathology and Laboratory Medicine, University of North Carolina, Wilmington, NC, USA, 2Department of
Downloaded by [University of Iowa Libraries] at 01:22 11 August 2015
Pathology, City of Hope National Medical Center, Monrovia, CA, USA, 3Department of Pathology, University of Michigan, Ann Arbor, MI, USA, 4Department of Pathology, University of Utah, Salt Lake City, UT, USA, 5Clarient/GE Healthcare, Aliso Viejo, CA, USA and 6M. D. Anderson Cancer Center, University of Texas, Houston, TX, USA
Mutations of the oncogene BRAF were identified in human cancers over a decade ago [1]. BRAF encodes a serine/ threonine protein kinase with an integral role in regulating extracellular-signal regulated kinase (ERK) with ultimate effects on cell division and differentiation [2]. Somatic mutations in BRAF are now known to occur in many malignancies, although the prevalence varies markedly depending on tumor type [3]. Early work demonstrated that over 80% of nevi [4] and half of metastatic melanomas [5] harbor mutations of BRAF, and the majority of these represent valine to glutamate substitutions in codon 600 (V600E). BRAF V600E mutations were subsequently identified in other carcinomas including those of thyroid, colon and lung origin [3]. More recently, mutated BRAF was found to be the driver mutation in all tested cases of hairy cell leukemia, expanding the spectrum of affected tumor types [6]. The development of mutation-specific antibodies provides a potentially powerful tool for identifying BRAF V600E mutations [7]. Such antibodies appear to have comparable sensitivity to allele-specific polymerase chain reaction (PCR) and can be readily applied to archived formalin-fixed and paraffin-embedded tissues, with the added advantage of in situ analysis. Moreover, identifying BRAF-mutated neoplasms is particularly relevant, as BRAF inhibitors have been recently approved for clinical use and show significant clinical promise. The ontogeny of histiocytic and dendritic cell disorders is poorly understood, and little is known about the molecular alterations underlying these rare neoplasms. Although primary tumors are likely more common, transformations between distinct classes of histiocytic/dendritic cell neoplasms and cases transdifferentiated from B cell lymphomas have been reported [8]. Recently, the BRAF V600E mutation has been identified in Langerhans cell histiocytosis (LCH) [9], Erdheim–Chester disease/disseminated juvenile xanthogranuloma (JXG) [10] and follicular dendritic cell sarcoma (FDCS) [11]. While the BRAF mutated subset of LCH
represent clonal neoplasms, it remains unclear whether the BRAF unmutated cases represent reactive proliferations rather than true neoplasms of Langerhans cells. In addition to the biologic ramifications, clinical and therapeutic implications are significant. We evaluated 42 cases of histiocytic and dendritic cell proliferations using immunohistochemical staining to survey for the BRAF V600E mutation. This immunohistochemical stain has been shown to be both sensitive and specific for the presence of the mutant allele [7]. Appropriate immunohistochemical stains were performed on original cases to confirm the diagnosis. Immunohistochemical staining for BRAF V600E was performed using antibody clone VE1 (Spring BioScience, Pleasanton, CA) on a Ventana Benchmark Ultra (Tucson, AZ) with standard protocol. The cases identified for study included six FDCS, five interdigitating dendritic cell sarcoma (IDCS), 15 LCH, one Langerhans cell sarcoma (LCS), one indeterminate cell tumor, 12 Rosai–Dorfman disease (RDD), 11 hyaline-vascular Castleman disease (HV-CD), seven cutaneous JXG, four cases of hemophagocytic lymphohistiocytosis (HLH), two systemic JXG, two histiocytic sarcoma and two atypical histiocytic proliferation suspicious for histiocytic sarcoma, two cases of blastic plasmacytoid dendritic cell neoplasm (BPDCN), two cases of mastocytosis, two xanthelasma, one cutaneous fibrous histiocytoma, one case of Kikuchi–Fujimoto disease and one case each of Niemann–Pick disease and Gaucher disease. In keeping with the published literature, four of 15 cases (27%) of LCH were positive for BRAF V600E by immunohistochemistry [Figure 1(a), hematoxylin and eosin (H&E) and Figure 1(b), BRAF V600E] [12]. Notably, we also identified mutated BRAF V600E expression in histiocytic/dendritic disorders that have not previously been associated with this abnormality, including the single indeterminate cell tumor studied and one case of IDCS [Figure 1(c), H&E and Figure 1(d), BRAF V600E]. In all cases the intensity of staining was
Correspondence: Dennis P. O’Malley, MD, Clarient Pathology Services, 31 Columbia, Aliso Viejo, CA 92656, USA. Tel: 949-425-5832. Fax: 949-389-0371. E-mail: [email protected] Received 12 June 2014; revised 6 July 2014; accepted 12 July 2014
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independent events in IDCS, it is interesting to speculate whether BRAF mutations may represent preserved markers of transformation from Langerhans cells in rare cases. The lack of staining does not, of course, exclude the possibility that other non-V600E mutations are present in these proliferations, nor does it inherently suggest that the ERK pathway can be productively targeted in mutated cases. Although the number of cases for each individual entity is too small to draw biologic conclusions, collectively, these data would suggest that BRAF V600E mutations are present in rare cases of dendritic cell and histiocytic disorders, and their identification offers a potential therapeutic target for these neoplasms.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal. Figure 1. H&E staining (a) and BRAF V600E immunohistochemical staining (b) in Langerhans cell histiocytosis. H&E staining (c) and BRAF V600E immunohistochemical staining (d) in interdigitating dendritic cell sarcoma.
2–4⫹/4 and was seen in the majority of tumor cells. To our knowledge, this is the first reported case of indeterminate cell tumor and IDCS with evidence of mutated BRAF. All evaluated cases of FDCS, LCS, JXG, HV-CD, RDD, HLH, BPDCN and histiocytic sarcoma were negative. In spite of their rarity, it is not entirely surprising that an indeterminate cell tumor would show expression of BRAF V600E. These tumors have significant overlap with LCH, and indeterminate cells are purported precursors of Langerhans cells. Our case showed histologic features that were not typical for LCH (lacking eosinophilic infiltrate and folded nuclei) but usual in indeterminate cell tumors (more ample eosinophilic cytoplasm than LCH). Our case also had a similar immunophenotype to LCH (CD1a positive, S100 positive, but langerin negative), and the presence of the coincident genetic abnormality may suggest a close ontological relationship of these tumors. More surprising is the identification of mutant BRAF expression in the one case of IDCS. These tumors, while rare, are not thought to be related to the same lineage as Langerhans cells. However, recent studies have shown significant plasticity in the cell lineage and differentiation of histiocytic and dendritic cells. In our experience, we have seen cases of LCH with differentiation toward interdigitating dendritic cells. These cases lacked BRAF expression. Although likely
References [1] Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–954. [2] Cantwell-Dorris ER, O’Leary JJ, Sheils OM. BRAFV600E: implications for carcinogenesis and molecular therapy. Mol Cancer Ther 2011;10:385–394. [3] Pakneshan S, Salajegheh A , Smith RA , et al. Clinicopathological relevance of BRAF mutations in human cancer. Pathology 2013;45: 346–356. [4] Kumar R, Angelini S, Snellman E, et al. BRAF mutations are common somatic events in melanocytic nevi. J Invest Dermatol 2004;122:342–348. [5] Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 2011;29:1239–1246. [6] Tiacci E, Schiavoni G, Forconi F, et al. Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation. Blood 2012;119:192–195. [7] Routhier CA , Mochel MC, Lynch K, et al. Comparison of 2 monoclonal antibodies for immunohistochemical detection of BRAF V600E mutation in malignant melanoma, pulmonary carcinoma, gastrointestinal carcinoma, thyroid carcinoma, and gliomas. Hum Pathol 2013;44:2563–2570. [8] Feldman AL, Arber DA , Pittaluga S, et al. Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone. Blood 2008; 111:5433–5439. [9] Badalian-Very G, Vergilio JA , Degar BA , et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 2010;116:1919–1923. [10] Haroche J, Charlotte F, Arnaud L, et al. High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other nonLangerhans cell histiocytoses. Blood 2012;120:2700–2703. [11] Go H, Jeon YK , Huh J, et al. Frequent detection of BRAF mutations in histiocytic and dendritic cell neoplasms. Histopathology 2014;65:261–272. [12] Roden AC, Hu X, Kip S, et al. BRAF V600E expression in Langerhans cell histiocytosis: clinical and immunohistochemical study on 25 pulmonary and 54 extrapulmonary cases. Am J Surg Pathol 2014;38:548–551.
Leukemia & Lymphoma Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ilal20
BRAF V600E mutation-specific immunohistochemistry is a rare finding in dendritic cell- and histiocytederived tumors a
b
c
d
e
Yuri Fedoriw , Young S. Kim , Jo-Anne Vergilio , Z. Will Chen , Lawrence M. Weiss & Dennis P. O'Malley
ef
a
Department of Pathology and Laboratory Medicine, University of North Carolina, Wilmington, NC, USA
Click for updates
b
Department of Pathology, City of Hope National Medical Center, Monrovia, CA, USA
c
Department of Pathology, University of Michigan, Ann Arbor, MI, USA
d
Department of Pathology, University of Utah, Salt Lake City, UT, USA
e
Clarient/GE Healthcare, Aliso Viejo, CA, USA
f
M. D. Anderson Cancer Center, University of Texas, Houston, TX, USA Published online: 09 Jun 2015.
To cite this article: Yuri Fedoriw, Young S. Kim, Jo-Anne Vergilio, Z. Will Chen, Lawrence M. Weiss & Dennis P. O'Malley (2015) BRAF V600E mutation-specific immunohistochemistry is a rare finding in dendritic cell- and histiocyte-derived tumors, Leukemia & Lymphoma, 56:4, 1132-1133, DOI: 10.3109/10428194.2014.946028 To link to this article: http://dx.doi.org/10.3109/10428194.2014.946028
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Leukemia & Lymphoma, April 2015; 56(4): 1132–1133 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.946028
LETTER TO THE EDITOR
BRAF V600E mutation-specific immunohistochemistry is a rare finding in dendritic cell- and histiocyte-derived tumors Yuri Fedoriw1, Young S. Kim2, Jo-Anne Vergilio3, Z. Will Chen4, Lawrence M. Weiss5 & Dennis P. O’Malley5,6 1Department of Pathology and Laboratory Medicine, University of North Carolina, Wilmington, NC, USA, 2Department of
Downloaded by [University of Iowa Libraries] at 01:22 11 August 2015
Pathology, City of Hope National Medical Center, Monrovia, CA, USA, 3Department of Pathology, University of Michigan, Ann Arbor, MI, USA, 4Department of Pathology, University of Utah, Salt Lake City, UT, USA, 5Clarient/GE Healthcare, Aliso Viejo, CA, USA and 6M. D. Anderson Cancer Center, University of Texas, Houston, TX, USA
Mutations of the oncogene BRAF were identified in human cancers over a decade ago [1]. BRAF encodes a serine/ threonine protein kinase with an integral role in regulating extracellular-signal regulated kinase (ERK) with ultimate effects on cell division and differentiation [2]. Somatic mutations in BRAF are now known to occur in many malignancies, although the prevalence varies markedly depending on tumor type [3]. Early work demonstrated that over 80% of nevi [4] and half of metastatic melanomas [5] harbor mutations of BRAF, and the majority of these represent valine to glutamate substitutions in codon 600 (V600E). BRAF V600E mutations were subsequently identified in other carcinomas including those of thyroid, colon and lung origin [3]. More recently, mutated BRAF was found to be the driver mutation in all tested cases of hairy cell leukemia, expanding the spectrum of affected tumor types [6]. The development of mutation-specific antibodies provides a potentially powerful tool for identifying BRAF V600E mutations [7]. Such antibodies appear to have comparable sensitivity to allele-specific polymerase chain reaction (PCR) and can be readily applied to archived formalin-fixed and paraffin-embedded tissues, with the added advantage of in situ analysis. Moreover, identifying BRAF-mutated neoplasms is particularly relevant, as BRAF inhibitors have been recently approved for clinical use and show significant clinical promise. The ontogeny of histiocytic and dendritic cell disorders is poorly understood, and little is known about the molecular alterations underlying these rare neoplasms. Although primary tumors are likely more common, transformations between distinct classes of histiocytic/dendritic cell neoplasms and cases transdifferentiated from B cell lymphomas have been reported [8]. Recently, the BRAF V600E mutation has been identified in Langerhans cell histiocytosis (LCH) [9], Erdheim–Chester disease/disseminated juvenile xanthogranuloma (JXG) [10] and follicular dendritic cell sarcoma (FDCS) [11]. While the BRAF mutated subset of LCH
represent clonal neoplasms, it remains unclear whether the BRAF unmutated cases represent reactive proliferations rather than true neoplasms of Langerhans cells. In addition to the biologic ramifications, clinical and therapeutic implications are significant. We evaluated 42 cases of histiocytic and dendritic cell proliferations using immunohistochemical staining to survey for the BRAF V600E mutation. This immunohistochemical stain has been shown to be both sensitive and specific for the presence of the mutant allele [7]. Appropriate immunohistochemical stains were performed on original cases to confirm the diagnosis. Immunohistochemical staining for BRAF V600E was performed using antibody clone VE1 (Spring BioScience, Pleasanton, CA) on a Ventana Benchmark Ultra (Tucson, AZ) with standard protocol. The cases identified for study included six FDCS, five interdigitating dendritic cell sarcoma (IDCS), 15 LCH, one Langerhans cell sarcoma (LCS), one indeterminate cell tumor, 12 Rosai–Dorfman disease (RDD), 11 hyaline-vascular Castleman disease (HV-CD), seven cutaneous JXG, four cases of hemophagocytic lymphohistiocytosis (HLH), two systemic JXG, two histiocytic sarcoma and two atypical histiocytic proliferation suspicious for histiocytic sarcoma, two cases of blastic plasmacytoid dendritic cell neoplasm (BPDCN), two cases of mastocytosis, two xanthelasma, one cutaneous fibrous histiocytoma, one case of Kikuchi–Fujimoto disease and one case each of Niemann–Pick disease and Gaucher disease. In keeping with the published literature, four of 15 cases (27%) of LCH were positive for BRAF V600E by immunohistochemistry [Figure 1(a), hematoxylin and eosin (H&E) and Figure 1(b), BRAF V600E] [12]. Notably, we also identified mutated BRAF V600E expression in histiocytic/dendritic disorders that have not previously been associated with this abnormality, including the single indeterminate cell tumor studied and one case of IDCS [Figure 1(c), H&E and Figure 1(d), BRAF V600E]. In all cases the intensity of staining was
Correspondence: Dennis P. O’Malley, MD, Clarient Pathology Services, 31 Columbia, Aliso Viejo, CA 92656, USA. Tel: 949-425-5832. Fax: 949-389-0371. E-mail: [email protected] Received 12 June 2014; revised 6 July 2014; accepted 12 July 2014
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BRAF immunohistochemistry
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Downloaded by [University of Iowa Libraries] at 01:22 11 August 2015
independent events in IDCS, it is interesting to speculate whether BRAF mutations may represent preserved markers of transformation from Langerhans cells in rare cases. The lack of staining does not, of course, exclude the possibility that other non-V600E mutations are present in these proliferations, nor does it inherently suggest that the ERK pathway can be productively targeted in mutated cases. Although the number of cases for each individual entity is too small to draw biologic conclusions, collectively, these data would suggest that BRAF V600E mutations are present in rare cases of dendritic cell and histiocytic disorders, and their identification offers a potential therapeutic target for these neoplasms.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal. Figure 1. H&E staining (a) and BRAF V600E immunohistochemical staining (b) in Langerhans cell histiocytosis. H&E staining (c) and BRAF V600E immunohistochemical staining (d) in interdigitating dendritic cell sarcoma.
2–4⫹/4 and was seen in the majority of tumor cells. To our knowledge, this is the first reported case of indeterminate cell tumor and IDCS with evidence of mutated BRAF. All evaluated cases of FDCS, LCS, JXG, HV-CD, RDD, HLH, BPDCN and histiocytic sarcoma were negative. In spite of their rarity, it is not entirely surprising that an indeterminate cell tumor would show expression of BRAF V600E. These tumors have significant overlap with LCH, and indeterminate cells are purported precursors of Langerhans cells. Our case showed histologic features that were not typical for LCH (lacking eosinophilic infiltrate and folded nuclei) but usual in indeterminate cell tumors (more ample eosinophilic cytoplasm than LCH). Our case also had a similar immunophenotype to LCH (CD1a positive, S100 positive, but langerin negative), and the presence of the coincident genetic abnormality may suggest a close ontological relationship of these tumors. More surprising is the identification of mutant BRAF expression in the one case of IDCS. These tumors, while rare, are not thought to be related to the same lineage as Langerhans cells. However, recent studies have shown significant plasticity in the cell lineage and differentiation of histiocytic and dendritic cells. In our experience, we have seen cases of LCH with differentiation toward interdigitating dendritic cells. These cases lacked BRAF expression. Although likely
References [1] Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–954. [2] Cantwell-Dorris ER, O’Leary JJ, Sheils OM. BRAFV600E: implications for carcinogenesis and molecular therapy. Mol Cancer Ther 2011;10:385–394. [3] Pakneshan S, Salajegheh A , Smith RA , et al. Clinicopathological relevance of BRAF mutations in human cancer. Pathology 2013;45: 346–356. [4] Kumar R, Angelini S, Snellman E, et al. BRAF mutations are common somatic events in melanocytic nevi. J Invest Dermatol 2004;122:342–348. [5] Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 2011;29:1239–1246. [6] Tiacci E, Schiavoni G, Forconi F, et al. Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation. Blood 2012;119:192–195. [7] Routhier CA , Mochel MC, Lynch K, et al. Comparison of 2 monoclonal antibodies for immunohistochemical detection of BRAF V600E mutation in malignant melanoma, pulmonary carcinoma, gastrointestinal carcinoma, thyroid carcinoma, and gliomas. Hum Pathol 2013;44:2563–2570. [8] Feldman AL, Arber DA , Pittaluga S, et al. Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone. Blood 2008; 111:5433–5439. [9] Badalian-Very G, Vergilio JA , Degar BA , et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 2010;116:1919–1923. [10] Haroche J, Charlotte F, Arnaud L, et al. High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other nonLangerhans cell histiocytoses. Blood 2012;120:2700–2703. [11] Go H, Jeon YK , Huh J, et al. Frequent detection of BRAF mutations in histiocytic and dendritic cell neoplasms. Histopathology 2014;65:261–272. [12] Roden AC, Hu X, Kip S, et al. BRAF V600E expression in Langerhans cell histiocytosis: clinical and immunohistochemical study on 25 pulmonary and 54 extrapulmonary cases. Am J Surg Pathol 2014;38:548–551.
