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Synchronous occurrence of nasopharyngeal carcinoma and Hodgkin lymphoma
International Journal of Pediatric Otorhinolaryngology 78 (2014) 154–156
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Case report
Synchronous occurrence of nasopharyngeal carcinoma and Hodgkin lymphoma Janalee Stokken a, Ryan M. Manz a, Aron Flagg b, L. Kate Gowans b, Samantha Anne a,* a b
Cleveland Clinic, Head and Neck Institute, Cleveland, OH, USA Cleveland Clinic, Department of Pediatric Hematology and Oncology, Cleveland, OH, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 11 July 2013 Received in revised form 16 October 2013 Accepted 19 October 2013 Available online 14 November 2013
Latent Epstein–Barr virus infection is associated with several lymphoid and epithelial malignancies. This is the first reported case of a patient presenting with synchronous nasopharyngeal carcinoma and Hodgkin lymphoma associated with Epstein–Barr virus. A 17-year-old previously healthy African– American male presented with anterior mediastinal mass and a nasopharyngeal mass. Histology from biopsy of both lesions revealed evidence of Epstein–Barr virus. The patient successfully completed sequential therapies with chemo radiation with no evidence of active disease. Simultaneous occurrence of the two malignancies is undoubtedly a rare event, and their coexistence raises the question of a common etiologic factor. ß 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Nasopharyngeal carcinoma Hodgkin lymphoma Viral oncogenesis Epstein–Barr virus
Introduction Epstein–Barr virus is an omnipresent g-herpes virus, infecting the majority of the human population by adulthood [1,2]. Primary infection typically occurs by adolescence, and can be asymptomatic or result in infectious mononucleosis. It is transmitted through saliva, infecting oropharyngeal epithelial cells, and B-lymphocytes, and resulting in life-long persistence of the viral genome. The virus initially gives rise to the lytic form of infection and then, to the latent form of infection. Latent EBV infection is associated with lymphoid and epithelial malignancies, including Hodgkin lymphoma (HL), Burkitt lymphoma, nasopharyngeal carcinoma (NPC), and a spectrum of post-transplant lymphoproliferative disease (PTLD) [1,2]. There are two published case reports of patients with sequential development of NPC and HL, both separated by several years [3,4]. Here we describe the case of both EBV-related cancers presenting concurrently at diagnosis. To our knowledge, this is the first description of such an event occurring. Case report IRB was submitted; however the institution does not require IRB approval for single case reports. A 17-year-old previously
* Corresponding author at: Desk A71, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Tel.: +1 216 445 0075; fax: +1 216 444 9409. E-mail address: [email protected] (S. Anne). 0165-5876/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijporl.2013.10.055
healthy African–American male was presented to the emergency department with chest pain following a track meet. The patient initially underwent a chest radiograph followed by CT scan of the chest which detected the presence of a bulky anterior mediastinal mass. He was further evaluated by the hematology/oncology service and upon further questioning, described a six month history of right-sided nasal obstruction, recent epistaxis, and an eight pound weight loss. A PET-CT (Fig. 1) obtained the following day revealed multiple FDG-avid lesions including a nasopharyngeal mass, mediastinal mass, and multiple bilateral supraclavicular and sub-centimeter cervical lymph nodes. A CT sinus scan (Fig. 2) defined the right posterior nasopharyngeal mass with nearcomplete occlusion of the bilateral posterior nasal airways and an air-fluid level in the right maxillary sinus. An otolaryngology consultation was then attained. On examination of nasal cavity anteriorly, blood stained rhinorrhea was noted. The oropharyngeal and otoscopic exams revealed rightsided palate fullness and a serious middle ear effusion respectively. The neck exam was benign without appreciable lymphadenopathy. On nasal endoscopy, the mass and thick secretions obstructed the right nare and a large exophytic mass completely filled the right nasopharynx and extended into the right oropharynx. He was taken to the operating room for nasal endoscopy and biopsy; an exophytic, friable mass in the bilateral nasopharynx was examined and biopsied (Fig. 3). The morphology, immunoprofile, and EBV-encoded RNA (EBER) staining supported a diagnosis of undifferentiated, non-keratinizing nasopharyngeal carcinoma. Although lymphatic spread from the nasopharynx to the mediastinum was a possibility, the bulky disease appeared atypical in the
J. Stokken et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 154–156
155
Fig. 3. The Endoscopic view of the right nasopharyngeal mass.Fig. 3 Large exophytic mass filling nasopharynx and protruding through right choana into posterior nasal cavity as seen by endoscopic view.
Fig. 1. Coronal PET-CT.Fig. 1 The Coronal PET-CT showing FDG-avid nasopharyngeal and bulky anterior mediastinal masses.
absence of substantial neck disease and metastatic disease is typically located in the bone, lung, and liver [5]. When nodal metastasis from NPC does occur, it is most commonly noted in the jugular chain and retrophyarngeal space. Ng et al. noted mediastinal adenopathy in only 4.5% (n = 89) of patients, in which all were associated with advanced nodal metastasis in the supraclavicular fossa [6]. The mediastinal mass was therefore biopsied in addition to the nasopharyngeal lesion. The mediastinal pathology demonstrated classical Hodgkin lymphoma, mixed cellularity type. All subsequent bone marrow biopsies were negative for disease. Serologic testing suggested remote EBV infection, and quantitative whole blood PCR revealed 45,000 EBV genome copies/ milliliter (mL). The quantitative EBV DNA PCRs are reported as copies/mL whole blood. The level of detection on the assay used is 500 copies/mL and the linear range of this assay is 500 copies/mL
to 5,000,000 copies/mL. Comparison of values is difficult between assays due to methodology used. For a typical immunocompetent person with a history of past EBV infection, the virus is usually undetectable in the blood. Of more importance is a trend in level of viremia over time. It is notable that the virus became undetectable along with clinical and radiographic evidence of remission. CD4 lymphocyte count was depressed at 435 cells/mL. HIV testing by enzyme immunoassay was non-reactive. Sequencing for autoimmune lymphoproliferative syndrome (FAS gene) and X-linked lymphoproliferative disorder (SH2D1A and BIRC4 genes) was normal. The patient completed sequential therapies, which included a single cycle of COPP (cyclophosphamide, vincristine, prednisone, procarbazine), and three cycles of ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide) for the Hodgkin lymphoma, and intensity modulated radiation therapy (70.2 Gy) with concomitant cisplatin to target the NPC. An additional 21 Gy mediastinal irradiation was then given to complete consolidation for HL. Doxorubicin was avoided initially due to uncertainty about radiation timing. PET-CT obtained after COPP showed dramatic improvement in both tumors, and end-oftherapy imaging demonstrated a complete metabolic response in both areas with no evidence of active disease. His treatment was
Fig. 2. (a) Axial CT image of right nasopharyngeal mass. (b) Coronal CT image of right nasopharyngeal mass.Fig. 2 (a) Mass in the posterior right nasopharynx with near complete occlusion of the posterior nasal airways bilaterally. Neither fossa of Rosenmueller is seen well. (b) Same mass seen in coronal view nearly occluding right nasal cavity and causing maxillary sinus opacification.
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J. Stokken et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 154–156
remarkably uncomplicated, with one admission for fever and expected oral mucositis with anorexia, aggressively managed with gastrostomy tube feeding and enteral narcotics. Discussion Review of the literature reveals just two cases of NPC and HL occurring in the same patients, both sequentially. The first describes a patient with HL followed by NPC two years later [3], and the second describes a patient with NPC followed by HL eight years later [4]. A retrospective study of 13 international cancer registries for second primaries occurring after NPC revealed none associated with EBV infection [7]. Here we report the first case, to our knowledge, of the simultaneous occurrence of these two cancers. The underlying pathogenesis for EBV-related cancers has not been completely defined, but appears to be mediated through activation of various cell signaling pathways by EBV nuclear antigens (EBNAs) and latent membrane proteins (LMPs) [2,8]. Indeed, an association has been found between the malignancies and the different types of latent EBV expression profiles in which they develop. A type I latency pattern is typical of Burkitt lymphoma, and type II is seen in NPC and HL, as well as PTLD [1,2]. There are two recognized subtypes of Epstein–Barr virus. EBV-A is the more common strain, and EBV-B appears predominantly in immunocompromised patients [1,9]. The possible influence of the virus subtype on disease development is unknown. In this patient, the serologic assessment for EBV included EBV Viral Capsid Antigen (VCA) IgM, EBV VCA IgG, EBV Early Antigen (EA) Antibody (Ab), and EBNA Ab. All values were over the upper limit of detection with the exception of EBV VCA IgM, which was undetectable. This pattern of antibody production is consistent with either ‘‘recent’’ or ‘‘past’’ infection with EBV, as the EBV VCA IgM tends to wane by 2–4 months after the intial infection. The EBV NA Ab is typically not seen until later in infection, weeks to months. The EBV EA Ab can persist for quite some time, perhaps 1,2 years. Once detectable, the EBV NA Ab and EBV VCA IgG typically remain elevated indefinitely. Accordingly, the timing of the initial EBV infection was likely at least several months prior to presentation, although it is difficult to narrow the window beyond that. The use of IgA antibodies directed against various EBV antigens has been reported in the literature primarily in the context of screening for NPC in high-risk patients, such as those from southeast Asia. This was not assayed for the patient described in our case report. While there may be prognostic importance to IgA anti-EBV antibodies, this has not yet been incorporated into clinical staging for children with NPC. In addition, a recent study has shown that plasma EBV DNA detection is a more sensitive and specific marker than serum IgA/VCA titers in both diagnosis and monitoring of patients with NPC [10]. For this reason, quantitative EBV viral loads in the blood were followed for post-therapy monitoring in this patient. Nasopharyngeal carcinoma presents as an epithelial cancer with histology that ranges from well-differentiated to undifferentiated squamous cell carcinoma, and includes both keratinizing and non-keratinizing forms. The disease is rare in the United States and Europe, but is endemic to parts of China and elsewhere in Asia [2,7]. The undifferentiated variant of NPC is universally associated with EBV; viral genomes within the tumor are clonal and exhibit EBV gene products typical of a type II latency pattern [1,2]. In children and adolescents, NPC is usually of the undifferentiated and non-keratinizing subtype, and lymphatic spread at presentation is common.
Hodgkin lymphoma is a malignant neoplasm of the lymphoreticular system with a bimodal age distribution, with peaks during adolescence and after the fifth decade. The disease is characterized histologically by the presence of the malignant Reed– Sternberg cells, multinucleated with large nucleoli surrounded by a clear ‘‘halo zone’’. Interestingly, Reed–Sternberg cells are rare amongst a background of reactive inflammatory infiltrate. About half of Hodgkin cases are EBER-positive by in situ hybridization (EBER-ISH) and contain clonal EBV genomes with a type II latency profile [2]. The pathological subtypes of Hodgkin lymphoma appear to have differing associations with EBV. Nodular sclerosing HL, the most common and with a superior prognosis, is EBVassociated in 20% of cases. Lymphocyte-depleted HL, which carries the poorest prognosis and makes up a minority of cases, almost always, occurs with evidence of EBV infection. Mixed cellularity HL occurs in the setting of EBV approximately 70% of the time [2]. While the two malignancies are both associated with a type II EBV latency profile, the development of both in the same patient is certainly rare. Despite both being associated with EBV, the cell signaling pathway activation may be different in NPC as compared with HL [2]. In the patient described by Ray et al., PCR amplification of the DNA found in each tumor revealed different EBV strains [3]. This suggests that the different subtypes may have lead to activation of different oncogenic pathways and the development of distinct malignancies. The simultaneous presentation with NPC and HL in this patient raises the question of perhaps dual EBV infection or a different oncogenic mechanism. Additionally, immune dysfunction in response to EBV latency is suggested, but without specific evidence of such. Further evaluation of EBV protein expression and cellular immune response in this patient could lend additional insight into the development EBV-associated neoplasia. Finally, an accurate pathologic diagnosis here would not have been made without performing multiple biopsies. This should be considered in future cases of EBV-related malignancies, especially when a pattern of metastatic spread is atypical. References [1] A.T. Deyrup, Epstein–Barr virus-associated epithelial and mesenchymal neoplasms, Hum. Pathol. 39 (4) (2008) 473–483. [2] J.A. Morrision, M.L. Gulley, R. Pathmanathan, N. Raab-Traub, Differential signaling pathways are activated in the Epstein–Barr virus-associated malignancies nasopharyngeal carcinoma and Hodgkin lymphoma, Cancer Res. 64 (15) (2004) 5251– 5260. [3] J.J. Viala, G. De The, F. Berger, P.A. Bryon, B. Coiffier, C. Dubreuil, et al., Nasopharyngeal carcinoma with positive Epstein–Barr virus serology in a Hodgkin’s disease patient. Viral reactivation? Presse Medicale. 14 (46) (1985, Dec 28.) 2349. [4] J. Rey, L. Xerri, R. Bouabdallah, M. Keuppens, et al., Detection of different clonal EBV strains in Hodgkin lymphoma and nasopharyngeal carcinoma tissues from the same patient, Br. J. Haematol. 142 (1) (2008) 79–81. [5] E.P. Hui, S.F. Leung, J.S. Au, et al., Lung metastasis alone in nansopharyngeal carcinoma: a relatively favorable prognostic group, Cancer 101 (2) (2004) 300– 306. [6] S.H. Ng, J.T. Chang, S.C. Chan, et al., Nodal metastases of nasopharyngeal carcinoma: patterns of disease on MRI and FDG PET, Eur. J. Nucl. Med. Mol. Imaging 31 (8) (2004) 1073–1080. [7] G. Sce´lo, P. Boffetta, M. Corbex, et al., Second primary cancers in patients with nasopharyngeal carcinoma: a pooled analysis of 13 cancer registries, Cancer Cause Control 18 (3) (2007) 269–278. [8] C.P. Kung, D.G. Meckes, N. Raab-Traub, Epstein–Barr virus LMP1 activates EGFR, STAT3, and ERK through effects on PKCd, J. Virol. 85 (9) (2011) 4399–4408. [9] S.C. Peh, L.H. Kim, S. Poppema, Frequent presence of subtype A virus in Epstein– Barr virus-associated malignancies, Pathology 34 (5) (2002) 446–450. [10] J.Y. Shao, Y.H. Li, H.Y. Gao, Q.L. Wu, N.J. Cui, L. Zhang, G. Cheng, L.F. Hu, I. Ernberg, Y.X. Zeng, Comparison of plasma Epstein–Barr virus (EBV) DNA levels and serum EBV immunoglobulin A/virus capsid antigen antibody titers in patients with nasopharyngeal carcinoma, Cancer 100 (6) (2004) 1162–1170.
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Case report
Synchronous occurrence of nasopharyngeal carcinoma and Hodgkin lymphoma Janalee Stokken a, Ryan M. Manz a, Aron Flagg b, L. Kate Gowans b, Samantha Anne a,* a b
Cleveland Clinic, Head and Neck Institute, Cleveland, OH, USA Cleveland Clinic, Department of Pediatric Hematology and Oncology, Cleveland, OH, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 11 July 2013 Received in revised form 16 October 2013 Accepted 19 October 2013 Available online 14 November 2013
Latent Epstein–Barr virus infection is associated with several lymphoid and epithelial malignancies. This is the first reported case of a patient presenting with synchronous nasopharyngeal carcinoma and Hodgkin lymphoma associated with Epstein–Barr virus. A 17-year-old previously healthy African– American male presented with anterior mediastinal mass and a nasopharyngeal mass. Histology from biopsy of both lesions revealed evidence of Epstein–Barr virus. The patient successfully completed sequential therapies with chemo radiation with no evidence of active disease. Simultaneous occurrence of the two malignancies is undoubtedly a rare event, and their coexistence raises the question of a common etiologic factor. ß 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Nasopharyngeal carcinoma Hodgkin lymphoma Viral oncogenesis Epstein–Barr virus
Introduction Epstein–Barr virus is an omnipresent g-herpes virus, infecting the majority of the human population by adulthood [1,2]. Primary infection typically occurs by adolescence, and can be asymptomatic or result in infectious mononucleosis. It is transmitted through saliva, infecting oropharyngeal epithelial cells, and B-lymphocytes, and resulting in life-long persistence of the viral genome. The virus initially gives rise to the lytic form of infection and then, to the latent form of infection. Latent EBV infection is associated with lymphoid and epithelial malignancies, including Hodgkin lymphoma (HL), Burkitt lymphoma, nasopharyngeal carcinoma (NPC), and a spectrum of post-transplant lymphoproliferative disease (PTLD) [1,2]. There are two published case reports of patients with sequential development of NPC and HL, both separated by several years [3,4]. Here we describe the case of both EBV-related cancers presenting concurrently at diagnosis. To our knowledge, this is the first description of such an event occurring. Case report IRB was submitted; however the institution does not require IRB approval for single case reports. A 17-year-old previously
* Corresponding author at: Desk A71, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Tel.: +1 216 445 0075; fax: +1 216 444 9409. E-mail address: [email protected] (S. Anne). 0165-5876/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijporl.2013.10.055
healthy African–American male was presented to the emergency department with chest pain following a track meet. The patient initially underwent a chest radiograph followed by CT scan of the chest which detected the presence of a bulky anterior mediastinal mass. He was further evaluated by the hematology/oncology service and upon further questioning, described a six month history of right-sided nasal obstruction, recent epistaxis, and an eight pound weight loss. A PET-CT (Fig. 1) obtained the following day revealed multiple FDG-avid lesions including a nasopharyngeal mass, mediastinal mass, and multiple bilateral supraclavicular and sub-centimeter cervical lymph nodes. A CT sinus scan (Fig. 2) defined the right posterior nasopharyngeal mass with nearcomplete occlusion of the bilateral posterior nasal airways and an air-fluid level in the right maxillary sinus. An otolaryngology consultation was then attained. On examination of nasal cavity anteriorly, blood stained rhinorrhea was noted. The oropharyngeal and otoscopic exams revealed rightsided palate fullness and a serious middle ear effusion respectively. The neck exam was benign without appreciable lymphadenopathy. On nasal endoscopy, the mass and thick secretions obstructed the right nare and a large exophytic mass completely filled the right nasopharynx and extended into the right oropharynx. He was taken to the operating room for nasal endoscopy and biopsy; an exophytic, friable mass in the bilateral nasopharynx was examined and biopsied (Fig. 3). The morphology, immunoprofile, and EBV-encoded RNA (EBER) staining supported a diagnosis of undifferentiated, non-keratinizing nasopharyngeal carcinoma. Although lymphatic spread from the nasopharynx to the mediastinum was a possibility, the bulky disease appeared atypical in the
J. Stokken et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 154–156
155
Fig. 3. The Endoscopic view of the right nasopharyngeal mass.Fig. 3 Large exophytic mass filling nasopharynx and protruding through right choana into posterior nasal cavity as seen by endoscopic view.
Fig. 1. Coronal PET-CT.Fig. 1 The Coronal PET-CT showing FDG-avid nasopharyngeal and bulky anterior mediastinal masses.
absence of substantial neck disease and metastatic disease is typically located in the bone, lung, and liver [5]. When nodal metastasis from NPC does occur, it is most commonly noted in the jugular chain and retrophyarngeal space. Ng et al. noted mediastinal adenopathy in only 4.5% (n = 89) of patients, in which all were associated with advanced nodal metastasis in the supraclavicular fossa [6]. The mediastinal mass was therefore biopsied in addition to the nasopharyngeal lesion. The mediastinal pathology demonstrated classical Hodgkin lymphoma, mixed cellularity type. All subsequent bone marrow biopsies were negative for disease. Serologic testing suggested remote EBV infection, and quantitative whole blood PCR revealed 45,000 EBV genome copies/ milliliter (mL). The quantitative EBV DNA PCRs are reported as copies/mL whole blood. The level of detection on the assay used is 500 copies/mL and the linear range of this assay is 500 copies/mL
to 5,000,000 copies/mL. Comparison of values is difficult between assays due to methodology used. For a typical immunocompetent person with a history of past EBV infection, the virus is usually undetectable in the blood. Of more importance is a trend in level of viremia over time. It is notable that the virus became undetectable along with clinical and radiographic evidence of remission. CD4 lymphocyte count was depressed at 435 cells/mL. HIV testing by enzyme immunoassay was non-reactive. Sequencing for autoimmune lymphoproliferative syndrome (FAS gene) and X-linked lymphoproliferative disorder (SH2D1A and BIRC4 genes) was normal. The patient completed sequential therapies, which included a single cycle of COPP (cyclophosphamide, vincristine, prednisone, procarbazine), and three cycles of ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide) for the Hodgkin lymphoma, and intensity modulated radiation therapy (70.2 Gy) with concomitant cisplatin to target the NPC. An additional 21 Gy mediastinal irradiation was then given to complete consolidation for HL. Doxorubicin was avoided initially due to uncertainty about radiation timing. PET-CT obtained after COPP showed dramatic improvement in both tumors, and end-oftherapy imaging demonstrated a complete metabolic response in both areas with no evidence of active disease. His treatment was
Fig. 2. (a) Axial CT image of right nasopharyngeal mass. (b) Coronal CT image of right nasopharyngeal mass.Fig. 2 (a) Mass in the posterior right nasopharynx with near complete occlusion of the posterior nasal airways bilaterally. Neither fossa of Rosenmueller is seen well. (b) Same mass seen in coronal view nearly occluding right nasal cavity and causing maxillary sinus opacification.
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J. Stokken et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 154–156
remarkably uncomplicated, with one admission for fever and expected oral mucositis with anorexia, aggressively managed with gastrostomy tube feeding and enteral narcotics. Discussion Review of the literature reveals just two cases of NPC and HL occurring in the same patients, both sequentially. The first describes a patient with HL followed by NPC two years later [3], and the second describes a patient with NPC followed by HL eight years later [4]. A retrospective study of 13 international cancer registries for second primaries occurring after NPC revealed none associated with EBV infection [7]. Here we report the first case, to our knowledge, of the simultaneous occurrence of these two cancers. The underlying pathogenesis for EBV-related cancers has not been completely defined, but appears to be mediated through activation of various cell signaling pathways by EBV nuclear antigens (EBNAs) and latent membrane proteins (LMPs) [2,8]. Indeed, an association has been found between the malignancies and the different types of latent EBV expression profiles in which they develop. A type I latency pattern is typical of Burkitt lymphoma, and type II is seen in NPC and HL, as well as PTLD [1,2]. There are two recognized subtypes of Epstein–Barr virus. EBV-A is the more common strain, and EBV-B appears predominantly in immunocompromised patients [1,9]. The possible influence of the virus subtype on disease development is unknown. In this patient, the serologic assessment for EBV included EBV Viral Capsid Antigen (VCA) IgM, EBV VCA IgG, EBV Early Antigen (EA) Antibody (Ab), and EBNA Ab. All values were over the upper limit of detection with the exception of EBV VCA IgM, which was undetectable. This pattern of antibody production is consistent with either ‘‘recent’’ or ‘‘past’’ infection with EBV, as the EBV VCA IgM tends to wane by 2–4 months after the intial infection. The EBV NA Ab is typically not seen until later in infection, weeks to months. The EBV EA Ab can persist for quite some time, perhaps 1,2 years. Once detectable, the EBV NA Ab and EBV VCA IgG typically remain elevated indefinitely. Accordingly, the timing of the initial EBV infection was likely at least several months prior to presentation, although it is difficult to narrow the window beyond that. The use of IgA antibodies directed against various EBV antigens has been reported in the literature primarily in the context of screening for NPC in high-risk patients, such as those from southeast Asia. This was not assayed for the patient described in our case report. While there may be prognostic importance to IgA anti-EBV antibodies, this has not yet been incorporated into clinical staging for children with NPC. In addition, a recent study has shown that plasma EBV DNA detection is a more sensitive and specific marker than serum IgA/VCA titers in both diagnosis and monitoring of patients with NPC [10]. For this reason, quantitative EBV viral loads in the blood were followed for post-therapy monitoring in this patient. Nasopharyngeal carcinoma presents as an epithelial cancer with histology that ranges from well-differentiated to undifferentiated squamous cell carcinoma, and includes both keratinizing and non-keratinizing forms. The disease is rare in the United States and Europe, but is endemic to parts of China and elsewhere in Asia [2,7]. The undifferentiated variant of NPC is universally associated with EBV; viral genomes within the tumor are clonal and exhibit EBV gene products typical of a type II latency pattern [1,2]. In children and adolescents, NPC is usually of the undifferentiated and non-keratinizing subtype, and lymphatic spread at presentation is common.
Hodgkin lymphoma is a malignant neoplasm of the lymphoreticular system with a bimodal age distribution, with peaks during adolescence and after the fifth decade. The disease is characterized histologically by the presence of the malignant Reed– Sternberg cells, multinucleated with large nucleoli surrounded by a clear ‘‘halo zone’’. Interestingly, Reed–Sternberg cells are rare amongst a background of reactive inflammatory infiltrate. About half of Hodgkin cases are EBER-positive by in situ hybridization (EBER-ISH) and contain clonal EBV genomes with a type II latency profile [2]. The pathological subtypes of Hodgkin lymphoma appear to have differing associations with EBV. Nodular sclerosing HL, the most common and with a superior prognosis, is EBVassociated in 20% of cases. Lymphocyte-depleted HL, which carries the poorest prognosis and makes up a minority of cases, almost always, occurs with evidence of EBV infection. Mixed cellularity HL occurs in the setting of EBV approximately 70% of the time [2]. While the two malignancies are both associated with a type II EBV latency profile, the development of both in the same patient is certainly rare. Despite both being associated with EBV, the cell signaling pathway activation may be different in NPC as compared with HL [2]. In the patient described by Ray et al., PCR amplification of the DNA found in each tumor revealed different EBV strains [3]. This suggests that the different subtypes may have lead to activation of different oncogenic pathways and the development of distinct malignancies. The simultaneous presentation with NPC and HL in this patient raises the question of perhaps dual EBV infection or a different oncogenic mechanism. Additionally, immune dysfunction in response to EBV latency is suggested, but without specific evidence of such. Further evaluation of EBV protein expression and cellular immune response in this patient could lend additional insight into the development EBV-associated neoplasia. Finally, an accurate pathologic diagnosis here would not have been made without performing multiple biopsies. This should be considered in future cases of EBV-related malignancies, especially when a pattern of metastatic spread is atypical. References [1] A.T. Deyrup, Epstein–Barr virus-associated epithelial and mesenchymal neoplasms, Hum. Pathol. 39 (4) (2008) 473–483. [2] J.A. Morrision, M.L. Gulley, R. Pathmanathan, N. Raab-Traub, Differential signaling pathways are activated in the Epstein–Barr virus-associated malignancies nasopharyngeal carcinoma and Hodgkin lymphoma, Cancer Res. 64 (15) (2004) 5251– 5260. [3] J.J. Viala, G. De The, F. Berger, P.A. Bryon, B. Coiffier, C. Dubreuil, et al., Nasopharyngeal carcinoma with positive Epstein–Barr virus serology in a Hodgkin’s disease patient. Viral reactivation? Presse Medicale. 14 (46) (1985, Dec 28.) 2349. [4] J. Rey, L. Xerri, R. Bouabdallah, M. Keuppens, et al., Detection of different clonal EBV strains in Hodgkin lymphoma and nasopharyngeal carcinoma tissues from the same patient, Br. J. Haematol. 142 (1) (2008) 79–81. [5] E.P. Hui, S.F. Leung, J.S. Au, et al., Lung metastasis alone in nansopharyngeal carcinoma: a relatively favorable prognostic group, Cancer 101 (2) (2004) 300– 306. [6] S.H. Ng, J.T. Chang, S.C. Chan, et al., Nodal metastases of nasopharyngeal carcinoma: patterns of disease on MRI and FDG PET, Eur. J. Nucl. Med. Mol. Imaging 31 (8) (2004) 1073–1080. [7] G. Sce´lo, P. Boffetta, M. Corbex, et al., Second primary cancers in patients with nasopharyngeal carcinoma: a pooled analysis of 13 cancer registries, Cancer Cause Control 18 (3) (2007) 269–278. [8] C.P. Kung, D.G. Meckes, N. Raab-Traub, Epstein–Barr virus LMP1 activates EGFR, STAT3, and ERK through effects on PKCd, J. Virol. 85 (9) (2011) 4399–4408. [9] S.C. Peh, L.H. Kim, S. Poppema, Frequent presence of subtype A virus in Epstein– Barr virus-associated malignancies, Pathology 34 (5) (2002) 446–450. [10] J.Y. Shao, Y.H. Li, H.Y. Gao, Q.L. Wu, N.J. Cui, L. Zhang, G. Cheng, L.F. Hu, I. Ernberg, Y.X. Zeng, Comparison of plasma Epstein–Barr virus (EBV) DNA levels and serum EBV immunoglobulin A/virus capsid antigen antibody titers in patients with nasopharyngeal carcinoma, Cancer 100 (6) (2004) 1162–1170.