- Email: [email protected]
Genomic analysis of metastatic rhabdomyosarcoma masquerading as acute leukemia
Pathology - Research and Practice xxx (xxxx) xxxx
Contents lists available at ScienceDirect
Pathology - Research and Practice journal homepage: www.elsevier.com/locate/prp
Case report
Genomic analysis of metastatic rhabdomyosarcoma masquerading as acute leukemia Oren Pasvolskya,b, Lucille Heimanb,c, Aron Popovtzerb,d, Yael Zimrab,e, Esther Rabizadehb,e, Iris Barshackb,f, Corine Mardoukhb,f, Pia Raanania,b, Uri Rozovskia,b,* a
Institute of Hematology, Davidoff Center, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel c Department of Pathology, Rabin Medical Center, Petah Tikva, Israel d Head and Neck Tumor Unit, Davidoff Cancer Center, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel e Hemato-Oncology Laboratory, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel f Department of Pathology, Sheba Medical Center, Israel b
A R T I C LE I N FO
A B S T R A C T
Keywords: Leukemia Rhabdomyosarcoma Metastases Genetics
Blast appearing cells in the peripheral blood and bone marrow may occasionally arise from non-hematopoietic tissues. We present a 58 year old female who presented at our emergency room with symptomatic pancytopenia. Several months earlier she was diagnosed and treated for rhabdomyosracoma of the nasopharynx and entered remission. When we examined the bone-marrow aspirate we estimated the number of blasts at 25 %. Based on this evaluation, a provisional diagnosis of acute leukemia was made. However, immunohistochemistry and flow cytometry analysis revealed that the cells presumed to be blasts were in fact rhabdomyosarcoma cells masquerading as leukemia. The mutational landscapes of the primary tumor and the bone marrow metastasis had similar yet distinct profiles. Annotation analysis suggested that the primary and metastatic tumors use alternate mutations to activate the RAS/AKT signaling pathways. In this case, looking beyond the mutational profiling revealed an additional layer of similarity between both the original and metastatic samples, exposing a common and possibly targetable pathway. Application of annotation tools in clinical practice could enable extraction of valuable information from somatic mutational gene panels.
1. Introduction When the bone-marrow is filled with blasts, the diagnosis of acute leukemia is usually straightforward. Rarely, the morphological findings might be misleading. Herein, we describe the pathological, molecular and genetic workup of metastatic embryonal rhabdomyosarcoma (RMS) that masqueraded as acute leukemia. 2. Case report A 58 years old woman presented to the emergency room with severe weakness. The initial blood work revealed pancytopenia, and "blast”appearing cells were seen in the peripheral blood smear. A provisional diagnosis of acute leukemia was made, and the patient was admitted. Nine months earlier she was diagnosed with embryonal RMS of the nasopharynx and received combination chemotherapy according to the
⁎
VAC (vincristine, cyclophosphamide and doxorubicin) protocol, as well as local radiation to affected areas. Positron Emission Tomography/ Computed Tomography (PET/CT) at end of treatment demonstrated a very good partial response with no evidence of systemic spread, and the blood counts returned to normal shortly after treatment was completed. Upon admission, the patient underwent bone marrow examination and the aspirate showed hypercellular marrow with 60 % blasts (Fig. 1). At this point our working diagnosis was therapy-related AML. Albeit rare, early therapy-related AML is sometimes reported and has been associated with cyclophosphamide [1]. To our surprise, the flow cytometry did not support the morphological diagnosis (Fig. 2). The blast-appearing cells were CD45 negative, indicating that they were not of hematopoietic origin. These cells stained positively for CD56, commonly expressed on skeletal and NK cells, and immune histochemical studies were positive for desmin, a typical staining for RMS. Taken together, these additional studies confirmed that the blast-appearing cells in the bone marrow were not actual blasts. These cells were in fact
Corresponding author at: Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, 39 Ze'ev Jabotinsky Rd, Petah-Tikva 49100, Israel. E-mail address: [email protected] (U. Rozovski).
https://doi.org/10.1016/j.prp.2019.152779 Received 31 October 2019; Received in revised form 1 December 2019; Accepted 1 December 2019 0344-0338/ © 2019 Elsevier GmbH. All rights reserved.
Please cite this article as: Oren Pasvolsky, et al., Pathology - Research and Practice, https://doi.org/10.1016/j.prp.2019.152779
Pathology - Research and Practice xxx (xxxx) xxxx
O. Pasvolsky, et al.
Fig. 1. Bone marrow aspirate, showing blast-like metastatic rhabdomyosarcoma cells, with abundant vacuole-containing cytoplasm and immature nuclei with several nucleoli. Image magnification X100.
RMS metastases.
3. Discussion Embryonal RMS of the nasopharynx is a mesenchymal tumor that arises from cells committed to the skeletal muscle lineage. It is extremely rare among adults and the prognosis is dismal, although combined modality with chemotherapy, radiotherapy and sometimes surgical interventions has significantly improved the clinical outcomes [2]. The tumor cells in embryonal RMS represent different stages of skeletal muscle differentiation ranging from highly differentiated "small round blue" cells to undifferentiated large "polygonal-shaped" cells (Fig. 3). The most common genetic alteration in RMS is the translocation t(2;13) (q35;q14) occurring in 60 % of patients. This translocation results in the fusion of the paired box3(PAX3) and the forkhead box O1 (FOXO1), two transcription-factors which are active during myocyte development [3]. The presence of this translocation is associated with poor prognosis [4,5] and increased rates of bone marrow metastasis [6]. RMS metastasizes to different organs, with a wide range of frequencies. Lung and bone being common sites [2,7]. Bone marrow metastases, mimicking leukemia blasts, have been previously described [8], even leading to erroneous treatment as acute leukemia [9]. The factors which promote metastasis of the primary tumor remain unknown. None of the known molecular and immune histochemical properties consistently distinguish metastatic from non-metastatic RMS. Yet, the presence CD56, a surface glycoprotein with adhesive properties in most cases of BM metastasis [10], might facilitate homing of the neoplastic cells to the BM. This case provided us an opportunity to explore the genomic landscape of a solid-tumor-derived bone marrow metastasis. In order to compare the genomic profile of the primary and metastatic specimen we performed deep coverage next-generation targeted sequencing of more than 400 cancer related gene using the FoundationOne assay (Cambridge, MA, USA) in the primary and metastatic specimens (Table 1). The primary specimen included 14 genetic alterations, 11 of which were shared by the metastatic tumor, including the driver PAX3FOXO1 fusion gene. This observation is expected, as the 2 specimens share common clonal origin. Nonetheless, since we did not have access to germline DNA, we cannot rule out that genetic changes that were observed in both specimens were already present in germline. In addition, some genetic changes were unique and detected only in one of the specimens. The primary tumor included 3 unique alterations including 8 copies of the FGF4, a receptor tyrosine kinase located upstream the RAS/AKT signaling pathway [11], and 2 additional variants of unknown significance (VUS). The metastatic specimen also included 3 unique alterations including 7 copies of NMYC, a transcription factor located downstream the RAS/AKT signaling pathway [12]. Together, these findings suggest that maintaining the RAS/AKT signaling pathway is imperative to RMS cells' survival. At least within the range of our panel, the genomic complexity of the primary and metastatic tumor was similar. Yet, our genomic
Fig. 2. Flow cytometry of the bone marrow aspirate, showing negative staining for CD45, and positive staining for CD56.
profiling suggested that the primary and metastatic tumors utilized 2 converging yet distinct strategies to activate the same pathway. While this may have therapeutic implications in selecting a more targeted approach for future patients, our patient was treated with 6 cycles of ifosfamide and etoposide and additional cycles of VAC. Unfortunately, 2
Pathology - Research and Practice xxx (xxxx) xxxx
O. Pasvolsky, et al.
References [1] H. Koklu, A. Tufan, Y. Erkul, N. Akyurek, R. Civelek, Secondary acute myeloid leukemia arising early after cyclophosphamide treatment, Int. J. Clin. Pharm. 37 (2015) 289–291. [2] A. Ferrari, P. Dileo, M. Casanova, R. Bertulli, C. Meazza, L. Gandola, P. Navarria, P. Collini, A. Gronchi, P. Olmi, F. Fossati-Bellani, P.G. Casali, Rhabdomyosarcoma in adults. A retrospective analysis of 171 patients treated at a single institution, Cancer 98 (2003) 571–580. [3] J.F. Shern, L. Chen, J. Chmielecki, J.S. Wei, R. Patidar, M. Rosenberg, L. Ambrogio, D. Auclair, J. Wang, Y.K. Song, C. Tolman, L. Hurd, H. Liao, S. Zhang, D. Bogen, A.S. Brohl, S. Sindiri, D. Catchpoole, T. Badgett, G. Getz, J. Mora, J.R. Anderson, S.X. Skapek, F.G. Barr, M. Meyerson, D.S. Hawkins, J. Khan, Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors, Cancer Discov. 4 (2014) 216–231. [4] D. Williamson, E. Missiaglia, A. de Reynies, G. Pierron, B. Thuille, G. Palenzuela, K. Thway, D. Orbach, M. Lae, P. Freneaux, K. Pritchard-Jones, O. Oberlin, J. Shipley, O. Delattre, Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma, J. Clin. Oncol. 28 (2010) 2151–2158. [5] T. Kubo, S. Shimose, J. Fujimori, T. Furuta, M. Ochi, Prognostic value of PAX3/7FOXO1 fusion status in alveolar rhabdomyosarcoma: Systematic review and metaanalysis, Crit. Rev. Oncol. Hematol. 96 (2015) 46–53. [6] A.D. Marshall, G.C. Grosveld, Alveolar rhabdomyosarcoma - the molecular drivers of PAX3/7-FOXO1-induced tumorigenesis, Skelet. Muscle 2 (2012) 25. [7] Y. Aida, T. Ueki, T. Kirihara, W. Takeda, T. Kurihara, K. Sato, I. Shimizu, Y. Hiroshima, M. Sumi, M. Ueno, N. Ichikawa, M. Watanabe, H. Kobayashi, Bone marrow metastasis of rhabdomyosarcoma mimicking acute leukemia: a case report and review of the literature, Intern. Med. 54 (2015) 643–650. [8] A.E. Quesada, R. Kanagal-Shamanna, Metastatic rhabdomyosarcoma initially diagnosed on the bone marrow, Blood 128 (2016) 2189. [9] U. Srinivas, L. Pillai, R. Kar, M. Mahapatra, S. Gujra, H.P. Pati, A case of rhabdomyosarcoma masquerading as acute leukemia at presentation: a case report, Indian J. Pathol. Microbiol. 50 (2007) 917–919. [10] F. Bozzi, P. Collini, A. Aiello, E. Barzano, F. Gambirasio, M. Podda, C. Meazza, A. Ferrari, R. Luksch, Flow cytometric phenotype of rhabdomyosarcoma bone marrow metastatic cells and its implication in differential diagnosis with neuroblastoma, Anticancer Res. 28 (2008) 1565–1569. [11] S. Tang, Y. Hao, Y. Yuan, R. Liu, Q. Chen, Role of fibroblast growth factor receptor 4 in cancer, Cancer Sci. 109 (2018) 3024–3031. [12] R. Tonelli, A. McIntyre, C. Camerin, Z.S. Walters, K. Di Leo, J. Selfe, S. Purgato, E. Missiaglia, A. Tortori, J. Renshaw, A. Astolfi, K.R. Taylor, S. Serravalle, R. Bishop, C. Nanni, L.J. Valentijn, A. Faccini, I. Leuschner, S. Formica, J.S. Reis-Filho, V. Ambrosini, K. Thway, M. Franzoni, B. Summersgill, R. Marchelli, P. Hrelia, G. Cantelli-Forti, S. Fanti, R. Corradini, A. Pession, J. Shipley, Antitumor activity of sustained N-myc reduction in rhabdomyosarcomas and transcriptional block by antigene therapy, Clin. Cancer Res. 18 (2012) 796–807.
Fig. 3. Nasopharyngeal biopsy specimen, showing characteristic spindle-like cells. Image magnification X20.
Table 1 Genetic analysis of the primary and metastatic tumor using the FoundationOne assay. Nasopharynx only
BM only
Nasopharynx and BM
FGFR4 amplification * PTCH1 splice site 1603-2A > G* PAX3 PAX3-FOXO1 fusion *
MycN amplification * FANCD2 N405S
BRCA2 P655R FBXO11 Q50P
WISP3 A119V
MLL3 I4674M MYO18A R144H NCOR2 A1076V NOD1 A554V SPEN A3327V PBRM1 Q779E PCLO E1953Q RELN G2300E SOCS3 Q42R
BM = bone marrow; *= potentially targetable genetic alteration.
the disease progressed, and the patient died 10 months after she relapsed. Research support None. Disclaimers None.
3
Contents lists available at ScienceDirect
Pathology - Research and Practice journal homepage: www.elsevier.com/locate/prp
Case report
Genomic analysis of metastatic rhabdomyosarcoma masquerading as acute leukemia Oren Pasvolskya,b, Lucille Heimanb,c, Aron Popovtzerb,d, Yael Zimrab,e, Esther Rabizadehb,e, Iris Barshackb,f, Corine Mardoukhb,f, Pia Raanania,b, Uri Rozovskia,b,* a
Institute of Hematology, Davidoff Center, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel c Department of Pathology, Rabin Medical Center, Petah Tikva, Israel d Head and Neck Tumor Unit, Davidoff Cancer Center, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel e Hemato-Oncology Laboratory, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel f Department of Pathology, Sheba Medical Center, Israel b
A R T I C LE I N FO
A B S T R A C T
Keywords: Leukemia Rhabdomyosarcoma Metastases Genetics
Blast appearing cells in the peripheral blood and bone marrow may occasionally arise from non-hematopoietic tissues. We present a 58 year old female who presented at our emergency room with symptomatic pancytopenia. Several months earlier she was diagnosed and treated for rhabdomyosracoma of the nasopharynx and entered remission. When we examined the bone-marrow aspirate we estimated the number of blasts at 25 %. Based on this evaluation, a provisional diagnosis of acute leukemia was made. However, immunohistochemistry and flow cytometry analysis revealed that the cells presumed to be blasts were in fact rhabdomyosarcoma cells masquerading as leukemia. The mutational landscapes of the primary tumor and the bone marrow metastasis had similar yet distinct profiles. Annotation analysis suggested that the primary and metastatic tumors use alternate mutations to activate the RAS/AKT signaling pathways. In this case, looking beyond the mutational profiling revealed an additional layer of similarity between both the original and metastatic samples, exposing a common and possibly targetable pathway. Application of annotation tools in clinical practice could enable extraction of valuable information from somatic mutational gene panels.
1. Introduction When the bone-marrow is filled with blasts, the diagnosis of acute leukemia is usually straightforward. Rarely, the morphological findings might be misleading. Herein, we describe the pathological, molecular and genetic workup of metastatic embryonal rhabdomyosarcoma (RMS) that masqueraded as acute leukemia. 2. Case report A 58 years old woman presented to the emergency room with severe weakness. The initial blood work revealed pancytopenia, and "blast”appearing cells were seen in the peripheral blood smear. A provisional diagnosis of acute leukemia was made, and the patient was admitted. Nine months earlier she was diagnosed with embryonal RMS of the nasopharynx and received combination chemotherapy according to the
⁎
VAC (vincristine, cyclophosphamide and doxorubicin) protocol, as well as local radiation to affected areas. Positron Emission Tomography/ Computed Tomography (PET/CT) at end of treatment demonstrated a very good partial response with no evidence of systemic spread, and the blood counts returned to normal shortly after treatment was completed. Upon admission, the patient underwent bone marrow examination and the aspirate showed hypercellular marrow with 60 % blasts (Fig. 1). At this point our working diagnosis was therapy-related AML. Albeit rare, early therapy-related AML is sometimes reported and has been associated with cyclophosphamide [1]. To our surprise, the flow cytometry did not support the morphological diagnosis (Fig. 2). The blast-appearing cells were CD45 negative, indicating that they were not of hematopoietic origin. These cells stained positively for CD56, commonly expressed on skeletal and NK cells, and immune histochemical studies were positive for desmin, a typical staining for RMS. Taken together, these additional studies confirmed that the blast-appearing cells in the bone marrow were not actual blasts. These cells were in fact
Corresponding author at: Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, 39 Ze'ev Jabotinsky Rd, Petah-Tikva 49100, Israel. E-mail address: [email protected] (U. Rozovski).
https://doi.org/10.1016/j.prp.2019.152779 Received 31 October 2019; Received in revised form 1 December 2019; Accepted 1 December 2019 0344-0338/ © 2019 Elsevier GmbH. All rights reserved.
Please cite this article as: Oren Pasvolsky, et al., Pathology - Research and Practice, https://doi.org/10.1016/j.prp.2019.152779
Pathology - Research and Practice xxx (xxxx) xxxx
O. Pasvolsky, et al.
Fig. 1. Bone marrow aspirate, showing blast-like metastatic rhabdomyosarcoma cells, with abundant vacuole-containing cytoplasm and immature nuclei with several nucleoli. Image magnification X100.
RMS metastases.
3. Discussion Embryonal RMS of the nasopharynx is a mesenchymal tumor that arises from cells committed to the skeletal muscle lineage. It is extremely rare among adults and the prognosis is dismal, although combined modality with chemotherapy, radiotherapy and sometimes surgical interventions has significantly improved the clinical outcomes [2]. The tumor cells in embryonal RMS represent different stages of skeletal muscle differentiation ranging from highly differentiated "small round blue" cells to undifferentiated large "polygonal-shaped" cells (Fig. 3). The most common genetic alteration in RMS is the translocation t(2;13) (q35;q14) occurring in 60 % of patients. This translocation results in the fusion of the paired box3(PAX3) and the forkhead box O1 (FOXO1), two transcription-factors which are active during myocyte development [3]. The presence of this translocation is associated with poor prognosis [4,5] and increased rates of bone marrow metastasis [6]. RMS metastasizes to different organs, with a wide range of frequencies. Lung and bone being common sites [2,7]. Bone marrow metastases, mimicking leukemia blasts, have been previously described [8], even leading to erroneous treatment as acute leukemia [9]. The factors which promote metastasis of the primary tumor remain unknown. None of the known molecular and immune histochemical properties consistently distinguish metastatic from non-metastatic RMS. Yet, the presence CD56, a surface glycoprotein with adhesive properties in most cases of BM metastasis [10], might facilitate homing of the neoplastic cells to the BM. This case provided us an opportunity to explore the genomic landscape of a solid-tumor-derived bone marrow metastasis. In order to compare the genomic profile of the primary and metastatic specimen we performed deep coverage next-generation targeted sequencing of more than 400 cancer related gene using the FoundationOne assay (Cambridge, MA, USA) in the primary and metastatic specimens (Table 1). The primary specimen included 14 genetic alterations, 11 of which were shared by the metastatic tumor, including the driver PAX3FOXO1 fusion gene. This observation is expected, as the 2 specimens share common clonal origin. Nonetheless, since we did not have access to germline DNA, we cannot rule out that genetic changes that were observed in both specimens were already present in germline. In addition, some genetic changes were unique and detected only in one of the specimens. The primary tumor included 3 unique alterations including 8 copies of the FGF4, a receptor tyrosine kinase located upstream the RAS/AKT signaling pathway [11], and 2 additional variants of unknown significance (VUS). The metastatic specimen also included 3 unique alterations including 7 copies of NMYC, a transcription factor located downstream the RAS/AKT signaling pathway [12]. Together, these findings suggest that maintaining the RAS/AKT signaling pathway is imperative to RMS cells' survival. At least within the range of our panel, the genomic complexity of the primary and metastatic tumor was similar. Yet, our genomic
Fig. 2. Flow cytometry of the bone marrow aspirate, showing negative staining for CD45, and positive staining for CD56.
profiling suggested that the primary and metastatic tumors utilized 2 converging yet distinct strategies to activate the same pathway. While this may have therapeutic implications in selecting a more targeted approach for future patients, our patient was treated with 6 cycles of ifosfamide and etoposide and additional cycles of VAC. Unfortunately, 2
Pathology - Research and Practice xxx (xxxx) xxxx
O. Pasvolsky, et al.
References [1] H. Koklu, A. Tufan, Y. Erkul, N. Akyurek, R. Civelek, Secondary acute myeloid leukemia arising early after cyclophosphamide treatment, Int. J. Clin. Pharm. 37 (2015) 289–291. [2] A. Ferrari, P. Dileo, M. Casanova, R. Bertulli, C. Meazza, L. Gandola, P. Navarria, P. Collini, A. Gronchi, P. Olmi, F. Fossati-Bellani, P.G. Casali, Rhabdomyosarcoma in adults. A retrospective analysis of 171 patients treated at a single institution, Cancer 98 (2003) 571–580. [3] J.F. Shern, L. Chen, J. Chmielecki, J.S. Wei, R. Patidar, M. Rosenberg, L. Ambrogio, D. Auclair, J. Wang, Y.K. Song, C. Tolman, L. Hurd, H. Liao, S. Zhang, D. Bogen, A.S. Brohl, S. Sindiri, D. Catchpoole, T. Badgett, G. Getz, J. Mora, J.R. Anderson, S.X. Skapek, F.G. Barr, M. Meyerson, D.S. Hawkins, J. Khan, Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors, Cancer Discov. 4 (2014) 216–231. [4] D. Williamson, E. Missiaglia, A. de Reynies, G. Pierron, B. Thuille, G. Palenzuela, K. Thway, D. Orbach, M. Lae, P. Freneaux, K. Pritchard-Jones, O. Oberlin, J. Shipley, O. Delattre, Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma, J. Clin. Oncol. 28 (2010) 2151–2158. [5] T. Kubo, S. Shimose, J. Fujimori, T. Furuta, M. Ochi, Prognostic value of PAX3/7FOXO1 fusion status in alveolar rhabdomyosarcoma: Systematic review and metaanalysis, Crit. Rev. Oncol. Hematol. 96 (2015) 46–53. [6] A.D. Marshall, G.C. Grosveld, Alveolar rhabdomyosarcoma - the molecular drivers of PAX3/7-FOXO1-induced tumorigenesis, Skelet. Muscle 2 (2012) 25. [7] Y. Aida, T. Ueki, T. Kirihara, W. Takeda, T. Kurihara, K. Sato, I. Shimizu, Y. Hiroshima, M. Sumi, M. Ueno, N. Ichikawa, M. Watanabe, H. Kobayashi, Bone marrow metastasis of rhabdomyosarcoma mimicking acute leukemia: a case report and review of the literature, Intern. Med. 54 (2015) 643–650. [8] A.E. Quesada, R. Kanagal-Shamanna, Metastatic rhabdomyosarcoma initially diagnosed on the bone marrow, Blood 128 (2016) 2189. [9] U. Srinivas, L. Pillai, R. Kar, M. Mahapatra, S. Gujra, H.P. Pati, A case of rhabdomyosarcoma masquerading as acute leukemia at presentation: a case report, Indian J. Pathol. Microbiol. 50 (2007) 917–919. [10] F. Bozzi, P. Collini, A. Aiello, E. Barzano, F. Gambirasio, M. Podda, C. Meazza, A. Ferrari, R. Luksch, Flow cytometric phenotype of rhabdomyosarcoma bone marrow metastatic cells and its implication in differential diagnosis with neuroblastoma, Anticancer Res. 28 (2008) 1565–1569. [11] S. Tang, Y. Hao, Y. Yuan, R. Liu, Q. Chen, Role of fibroblast growth factor receptor 4 in cancer, Cancer Sci. 109 (2018) 3024–3031. [12] R. Tonelli, A. McIntyre, C. Camerin, Z.S. Walters, K. Di Leo, J. Selfe, S. Purgato, E. Missiaglia, A. Tortori, J. Renshaw, A. Astolfi, K.R. Taylor, S. Serravalle, R. Bishop, C. Nanni, L.J. Valentijn, A. Faccini, I. Leuschner, S. Formica, J.S. Reis-Filho, V. Ambrosini, K. Thway, M. Franzoni, B. Summersgill, R. Marchelli, P. Hrelia, G. Cantelli-Forti, S. Fanti, R. Corradini, A. Pession, J. Shipley, Antitumor activity of sustained N-myc reduction in rhabdomyosarcomas and transcriptional block by antigene therapy, Clin. Cancer Res. 18 (2012) 796–807.
Fig. 3. Nasopharyngeal biopsy specimen, showing characteristic spindle-like cells. Image magnification X20.
Table 1 Genetic analysis of the primary and metastatic tumor using the FoundationOne assay. Nasopharynx only
BM only
Nasopharynx and BM
FGFR4 amplification * PTCH1 splice site 1603-2A > G* PAX3 PAX3-FOXO1 fusion *
MycN amplification * FANCD2 N405S
BRCA2 P655R FBXO11 Q50P
WISP3 A119V
MLL3 I4674M MYO18A R144H NCOR2 A1076V NOD1 A554V SPEN A3327V PBRM1 Q779E PCLO E1953Q RELN G2300E SOCS3 Q42R
BM = bone marrow; *= potentially targetable genetic alteration.
the disease progressed, and the patient died 10 months after she relapsed. Research support None. Disclaimers None.
3