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Malignant Nasopharyngeal Tumors Workup

  • Author: Ho-Sheng Lin, MD, FACS; Chief Editor: Arlen D Meyers, MD, MBA  more...
 
Updated: Feb 03, 2016
 

Laboratory Studies

Many studies have shown that nasopharyngeal carcinoma (NPC) is closely associated with EBV. Elevated EBV titers may also be associated with other disease entities, such as sinonasal undifferentiated carcinoma (SNUC), sinonasal lymphoma, and tongue cancer.

Seroepidemiologic studies have demonstrated that 80-90% of patients with World Health Organization (WHO) type 2 NPC and WHO type 3 NPC have elevated levels of immunoglobulin A (IgA) antibodies to viral capsid antigen (VCA) and early antigen (EA). However, only 10-20% of patients with WHO type 1 NPC have elevated levels of IgA to VCA.

Low et al. examined the EBV serology in 111 patients with NPC and in 111 healthy patients.[11] In the patients with NPC, 80.2% tested positive for IgA to EA, and 97.3% tested positive for IgA to VCA. In the control group, 100% tested negative for IgA to EA, but only 46.8% tested negative for IgA to VCA. In other words, the positive predictive value (PPV) of the EA serology is 100%, while the negative predictive value (NPV) is 83.5%. For VCA serology, the PPV is 64.7%, while the NPV is 94.5%. Therefore, a patient who tested positive for EA serology has a 100% chance of having NPC. A patient who has negative VCA serology only has a 5.5% chance of having NPC. A difficult clinical situation arises if a patient has a negative EA serology test but has a positive VCA serology. This serology combination predicts a 37.8% chance of having NPC. See Tables 1-2.

Table 1. Diagnostic profiles of IgA to EA and IgA to VCA[11] (Open Table in a new window)

Serology Status Sensitivity Specificity PPV NPV
IgA to EA 80.2% 100% 100% 83.5%
IgA to VCA 97.3% 46.8% 64.7% 94.5%

 

Table 2. Predictive Value of Epstein-Barr Virus Serology Combinations (Open Table in a new window)

IgA Antibody to EA IgA Antibody to VCA Probability of NPC
+ + 100%
+ 100%
5.5%
+ 37.8%

 

Other serologic tests include IgA antibodies directed against EBV, EBV nuclear antigen (EBNA)–1 (found in about 90% of patients with NPC), and immunoglobulin G (IgG) antibodies to the EBV replication activator (ZEBRA) and BRLF1 transcription activator (Rta). Cai et al[12] investigated the diagnostic significance of 4 EBV antibodies in 211 NPC patients and 413 healthy controls and found similar sensitivity and specificity for IgA to EA and IgA to VCA (Table 3), as described by Low et al. (Table 2). They then determined the diagnostic accuracy based on different combinations of these 4 EBV antibody titers (Table 4).

The utility of using a combination of IgA to VCA and IgA to EBNA-1 as a screening tool in an endemic area of Southern China was reported by Liu et al.[13] In this study, 28,688 patients were screened and 862 patients were found to have positive serology. These patients underwent further diagnostic evaluation including fiberoptic nasopharyngoscopy and nasopharyngeal biopsy. Of these, 38 (4.4%) were eventually diagnosed with NPC, the majority of which was at early stages.

Table 3. Diagnostic Values of the 4 EBV Antibodies[12] (Open Table in a new window)

Serology Status Sensitivity Specificity Area Under ROC Curve (95% CI)
IgA to EA 89.1% 98.5% 0.94 (0.92-0.96)  
IgA to VCA 98.1% 82.8% 0.98 (0.96-0.99)    
IgG to Rta 90.5% 85.2% 0.92 (0.89-0.95)    
IgA to EBNA1 87.2% 84.2% 0.92 (0.89-0.95)    

 

Table 4. Diagnostic Accuracy based on Different Combination of the 4 EBV Antibodies (Open Table in a new window)

Combination Sensitivity Specificity Area Under ROC Curve (95% CI)
IgG to Rta +



IgA to EBNA1



93.4% 90.6% 0.97 (0.95-0.98)  
IgA to VCA +



IgA to EA



92.4% 98.5% 0.98 (0.96-0.99)    
IgA to VCA +



IgA to EBNA1



94.3% 98.0% 0.98 (0.97-0.99)    
IgA to VCA +



IgG to Rta



94.8% 98.0% 0.99 (0.98-1.00)    
IgA to VCA +



IgA to EA +



IgA to EBNA1



97.2% 95.6% 0.98 (0.97-0.99)    
IgA to VCA +



IgA to EA +



IgG to Rta



92.9% 99.5% 0.99 (0.98-1.00)    
IgA to VCA +



IgG to Rta +



IgA to EBNA1



94.8% 98.5% 0.99 (0.98-1.00)    
IgA to VCA +



IgA to EA +



IgG to Rta +



IgA to EBNA1



96.7% 97.0% 0.99 (0.98-1.00)    

 

Recently, several authors also reported on the potential use of plasma EBV DNA as a screening tool either alone or in combination with other serological EBV antibodies.[14, 15]

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Imaging Studies

Assessment of locoregional disease

MRI with gadolinium and fat suppression is the radiologic modality of choice.[16] Determine if any intracranial extension of the tumor involves the brain parenchyma or the cavernous sinus. Intracranial spread can occur through several foramina that are in close proximity to the nasopharynx. These foramina include the foramen ovale, the foramen spinosum, the foramen lacerum, the carotid canal, and the jugular foramen.

Detect any tumor extension into the retropharyngeal, parapharyngeal, and pterygomaxillary spaces, as well as the infratemporal fossa and the sinuses.

Workup for metastatic disease

In a study involving 150 patients with untreated nasopharyngeal carcinoma (NPC), whole-body MRI and18 F-FDG positron emission tomography (PET)/CT showed similar diagnostic accuracy of 90.5% and 87.8% respectively in assessing distant site metastasis.[17]

In another study involving 78 patients, PET-CT scan was shown to be more sensitive and specific than CT scan in assessing for distant metastasis to lungs, liver, and bones.[18]

Detection of residual and/or recurrent nasopharyngeal carcinoma following definitive radiation with or without chemotherapy

Detection of residual and/or recurrent NPC following radiation treatment can be challenging because of radiation-induced scarring, fibrosis, and edema of the nasopharyngeal tissue. This treatment-related anatomic distortion may limit the role of anatomic-based imaging modalities such as MRI and CT. Function-based imaging modalities, such as18 F-FDG PET scan, are not affected by this anatomic distortion. In a systemic review of 21 articles, Liu et al found that18 F-FDG PET scan has an average sensitivity 95% in detection of local residual or recurrent disease, which is significantly higher compared with CT scan (76%) and MRI (78%).[19]

Function-based imaging modality, however, also has its limitations in cancer detection. The fact that both the cancer and the inflammatory tissues take up18 F-FDG limits the ability of the18 F-FDG PET-CT scan to distinguish viable tumor tissue from radionecrosis or osteomyelitis, resulting in high false-positive interpretation. Furthermore, because the hypermetabolic brain tissue provided a high background, recurrent/residual tumor located intracranially may be missed by18 F-FDG PET-CT scan, resulting in a high false-negative rate.

Another function-based imaging,201 TI single photon emission computed tomography (SPECT)/CT scan is based on thallium-201, which is a potassium analogue that competes with potassium for intracellular transport across the cell membrane via sodium-potassium-ATPase pump system in tumor cell membrane.[20] Because the necrotic tissue cell membrane lack the sodium-potassium-ATPase pump,201 TI does not accumulate in areas of osteoradionecrosis, and its uptake reflects the presence of viable tumor. This modality, however, is limited by spatial resolution and can miss tumors less than 1.5 cm in size.[21]

In a study comparing the use of201 TI SPECT/CT versus18 F-FDG PET-CT in detecting recurrent skull base nasopharyngeal carcinoma, Yen et al found the accuracy of these 2 modalities to be similar. The sensitivity and specificity for201 TI SPECT/CT were 66.7% and 100%, and those for18 F-FDG PET-CT were 86.7% and 75%.[21]

Axial T2-weighted image shows a left-sided cervica Axial T2-weighted image shows a left-sided cervical nodal metastasis resulting from nasopharyngeal cancer.
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Diagnostic Procedures

See the list below:

  • Transnasal biopsy of nasopharyngeal mass
    • Obtain multiple biopsy samples of the primary site to accurately determine the WHO histologic type of the tumor; an accurate determination is important because the classification has a significant prognostic implication. Although most NPCs are homogenous, Shanmugaratnam found that 26.4% of NPCs had features of more than 1 histologic type.[22] Fee encountered similar findings in 35% of recurrent NPC cases.[23] These heterologous tumors are classified according to the predominant histologic type.
    • Because of a mixture of large numbers of lymphocytes, detecting NPC by routine histopathology may be difficult. Diagnosing NPC from biopsy samples obtained from previous irradiated tissue can also be challenging. Because the association between NPC and EBV is well established, EBV-specific molecules can be used as markers for the detection of NPC in biopsy specimens. One of the EBV-specific molecules is the EBV-encoded small RNA (EBER). In a study from Taiwan, in situ hybridization assay for EBV-encoded RNA 1 (EBER1) was reported to have a sensitivity of 96.4% in detecting primary NPC.[24] When divided into subtypes, the sensitivity is 80% for WHO type 1, 97.3% for WHO type 2, and 97.3% for WHO type 3.
    • Another useful marker is the EBV gene that encodes the latent membrane protein 1 (LMP1). Although the gene that encodes LMP1 (LMP1) is not expressed consistently in all NPC (only about 65%), LMP1 is detected in every NPC cell. With the advent of the polymerase chain reaction (PCR) technique, only a few NPC cells are needed for detection of LMP1. Therefore, swabbing of the nasopharynx and testing for LMP1 could theoretically be used as a screening tool for early detection of NPC in areas of high incidence. However, the inability of this test to detect submucosal tumors limits its usefulness. Hao et al reported using LMP1 as a potential marker to help differentiate recurrent NPC from osteoradionecrosis in sequestrectomy specimens.[25]
    • The normal nasopharynx is rich in lymphoid tissue, which makes this area a well-known target for EBV infection in conditions such as mononucleosis. A large amount of lymphocyte infiltration is also present in NPC. Therefore, obvious concern is raised because the EBV-specific molecules that are detected from the nasopharynx may come from previously EBV-infected cells and not from NPC cells. Chen et al address this issue and use immunohistochemistry to demonstrate that EBV-DNA is localized only within NPC cells and not in the lymphocytes surrounding the tumor cells or in the normal nasopharyngeal tissue.[24] Other investigators have also shown that latent EBV infection does not occur in normal nasopharyngeal epithelial cells.
    • Other malignancies, such as human T-cell leukemia virus type 1 (HTLV-1)–associated adult T-cell lymphoma, nasal lymphoma, tongue cancer, and some lethal midline granuloma, are also associated with EBV. Although these lesions are rare, they must be included in the differential diagnoses when a patient tests positive for EBV-specific molecules.
    • The histological diagnosis of persistent disease following radiotherapy may sometimes be misleading. Biopsies obtained immediately following radiation may reveal viable cancer cells, even those that eventually undergo cell death. Kwong et al studied 803 patients with NPC by obtaining serial postradiotherapy nasopharyngeal biopsies.[26] They found that cancer cells may take up to 10 weeks after the completion of radiation to undergo cell death. Thus, biopsies to exclude persistent disease should usually be obtained at least 10 weeks following completion of radiation treatment to avoid a false-positive diagnosis.
  • Fine-needle aspiration of a neck mass
    • Fine-needle aspiration of a neck mass may be useful for the detection of an occult nasopharyngeal primary tumor.
    • The PCR technique can be used to evaluate the aspirate for the presence of EBV-DNA, or in situ hybridization can be used to determine the presence of EBER (EBER1-ISH). The in situ assay was reported to have a sensitivity of 98.1% and a specificity of 100%, even in an area such as Taiwan, where a large proportion of the population is infected with EBV.[27] The PCR technique has a lower sensitivity of 90.7% and was positive in 7 out of 61 patients without NPC (specificity of 88.5%). Several publications from Western countries demonstrate the use of this test in nonendemic areas. Dictor et al reported a sensitivity of 88.9% and a specificity of 100% using EBER1-ISH on biopsy samples from cervical metastasis.[28] The 2 cases of false-negative results were cervical metastasis from keratinizing NPC.
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Histologic Findings

Nasopharyngeal carcinoma (NPC) can be grouped into the following 3 categories according to the WHO classification system:

  • WHO type 1 – Keratinizing squamous cell carcinoma (10% frequency)
  • WHO type 2 - Nonkeratinizing squamous cell carcinoma (20% frequency)
  • WHO type 3 – Undifferentiated carcinoma or lymphoepithelioma (70% frequency)
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Staging

The American Joint Committee on Cancer-Union Internationale Contre le Cancer (AJCC-UICC) 2002 Classification is as follows:

  • Primary tumor
    • TX - Primary tumor cannot be assessed.
    • T0 - No evidence of primary tumor
    • Tis - Carcinoma in situ
    • T1 - Tumor confined to the nasopharynx
    • T2 - Tumor extends to the soft tissues of the oropharynx and/or the nasal fossa.
      • T2a - Without parapharyngeal extension
      • T2b - With parapharyngeal extension
    • T3 - Tumor invades the bony structures and/or the paranasal sinuses.
    • T4 - Tumor with intracranial extension and/or involvement of cranial nerves, infratemporal fossa, hypopharynx, orbit, or masticator space
  • Regional lymph nodes
    • NX - Regional lymph nodes cannot be assessed.
    • N0 - No regional lymph node metastasis
    • N1 - Unilateral metastasis in lymph node(s), 6 cm or less in greatest dimension, above the supraclavicular fossa
    • N2 - Bilateral metastasis in lymph node(s), 6 cm or less in greatest dimension, above the supraclavicular fossa
    • N3 - Metastasis in lymph node(s)
      • N3a - Greater than 6 cm in dimension
      • N3b - Extension to the supraclavicular fossa
  • Distant metastasis
    • MX - Distant metastasis cannot be assessed.
    • M0 - No distant metastasis
    • M1 - Distant metastasis
  • Stage
    • Stage I - T1, N0, M0
    • Stage IIA - T2a, N0, M0
    • Stage IIB - T1/T2a, N1, M0; T2b, N0/N1, M0
    • Stage III - T1/T2a/T2b, N2, M0; T3, N0/N1/N2, M0
    • Stage IVA - T4, N0/N1/N2, M0
    • Stage IVB - Any T, N3, M0
    • Stage IVC - Any T, any N, M1
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Contributor Information and Disclosures
Author

Ho-Sheng Lin, MD, FACS Professor and Interim Chair, Department of Otolaryngology-Head and Neck Surgery, Faculty, Sleep Fellowship Program, Divison of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Wayne State University School of Medicine; Chief, Section of Otolaryngology, Department of Surgery, John D Dingell Veterans Affairs Medical Center

Ho-Sheng Lin, MD, FACS is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American Association of University Professors, American College of Surgeons, American Head and Neck Society, Association of VA Surgeons, Chinese American Medical Society, SWOG, American Academy of Sleep Medicine, Triological Society

Disclosure: Received consulting fee from Intuitive Surgical for proctoring; consultant for Checkpoint Surgical.

Coauthor(s)

Willard E Fee, Jr, MD Edward C and Amy H Sewall Professor Emeritus, Chairman Emeritus, Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine

Willard E Fee, Jr, MD is a member of the following medical societies: American College of Surgeons, American Laryngological Association, American Medical Association, California Medical Association, The Triological Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Nader Sadeghi, MD, FRCSC Professor, Otolaryngology-Head and Neck Surgery, Director of Head and Neck Surgery, George Washington University School of Medicine and Health Sciences

Nader Sadeghi, MD, FRCSC is a member of the following medical societies: American Head and Neck Society, American Thyroid Association, American Academy of Otolaryngology-Head and Neck Surgery, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Chief Editor

Arlen D Meyers, MD, MBA Professor of Otolaryngology, Dentistry, and Engineering, University of Colorado School of Medicine

Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American Head and Neck Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cerescan;RxRevu;SymbiaAllergySolutions<br/>Received income in an amount equal to or greater than $250 from: Symbia<br/>Received from Allergy Solutions, Inc for board membership; Received honoraria from RxRevu for chief medical editor; Received salary from Medvoy for founder and president; Received consulting fee from Corvectra for senior medical advisor; Received ownership interest from Cerescan for consulting; Received consulting fee from Essiahealth for advisor; Received consulting fee from Carespan for advisor; Received consulting fee from Covidien for consulting.

Additional Contributors

Benoit J Gosselin, MD, FRCSC Associate Professor of Surgery, Dartmouth Medical School; Director, Comprehensive Head and Neck Oncology Program, Norris Cotton Cancer Center; Staff Otolaryngologist, Division of Otolaryngology-Head and Neck Surgery, Dartmouth-Hitchcock Medical Center

Benoit J Gosselin, MD, FRCSC is a member of the following medical societies: American Head and Neck Society, American Academy of Facial Plastic and Reconstructive Surgery, North American Skull Base Society, American Academy of Otolaryngology-Head and Neck Surgery, American Medical Association, American Rhinologic Society, Canadian Medical Association, Canadian Society of Otolaryngology-Head & Neck Surgery, College of Physicians and Surgeons of Ontario, New Hampshire Medical Society, Ontario Medical Association

Disclosure: Nothing to disclose.

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Axial T2-weighted image shows a left-sided cervical nodal metastasis resulting from nasopharyngeal cancer.
Table 1. Diagnostic profiles of IgA to EA and IgA to VCA [11]
Serology Status Sensitivity Specificity PPV NPV
IgA to EA 80.2% 100% 100% 83.5%
IgA to VCA 97.3% 46.8% 64.7% 94.5%
Table 2. Predictive Value of Epstein-Barr Virus Serology Combinations
IgA Antibody to EA IgA Antibody to VCA Probability of NPC
+ + 100%
+ 100%
5.5%
+ 37.8%
Table 3. Diagnostic Values of the 4 EBV Antibodies [12]
Serology Status Sensitivity Specificity Area Under ROC Curve (95% CI)
IgA to EA 89.1% 98.5% 0.94 (0.92-0.96)  
IgA to VCA 98.1% 82.8% 0.98 (0.96-0.99)    
IgG to Rta 90.5% 85.2% 0.92 (0.89-0.95)    
IgA to EBNA1 87.2% 84.2% 0.92 (0.89-0.95)    
Table 4. Diagnostic Accuracy based on Different Combination of the 4 EBV Antibodies
Combination Sensitivity Specificity Area Under ROC Curve (95% CI)
IgG to Rta +



IgA to EBNA1



93.4% 90.6% 0.97 (0.95-0.98)  
IgA to VCA +



IgA to EA



92.4% 98.5% 0.98 (0.96-0.99)    
IgA to VCA +



IgA to EBNA1



94.3% 98.0% 0.98 (0.97-0.99)    
IgA to VCA +



IgG to Rta



94.8% 98.0% 0.99 (0.98-1.00)    
IgA to VCA +



IgA to EA +



IgA to EBNA1



97.2% 95.6% 0.98 (0.97-0.99)    
IgA to VCA +



IgA to EA +



IgG to Rta



92.9% 99.5% 0.99 (0.98-1.00)    
IgA to VCA +



IgG to Rta +



IgA to EBNA1



94.8% 98.5% 0.99 (0.98-1.00)    
IgA to VCA +



IgA to EA +



IgG to Rta +



IgA to EBNA1



96.7% 97.0% 0.99 (0.98-1.00)    
Table 5. Prospective Randomized Clinical Trials of Chemoradiation Versus Radiation Alone in the Treatment of Locally Advanced NPC
 



Author, Year



Stage Number



of



Patients



Treatment Arms Survival Rate P Value
Neoadjuvant Chemotherapy Followed by Radiation
VUMCA, 1996[48] IV n=171 Bleomycin/epirubicin/cisplatin X 3



Radiation



60% (3 yr OS) P > .05
n=168 Radiation alone 54% (3 y OS)
Hareyama, 2002[49] I-IV n=40 Cisplatin/5-FU X 2



Radiation



60% (5 y OS) P > .05
n=40 Radiation alone 45% (5 y OS)
Chua, 1998[33] T3



N2-3



n=167 Cisplatin/epirubicin X 2-3



Radiation



78% (3 y OS) P = .57
n=167 Radiation alone 71% (3 y OS)
Ma, 2001[34] III-IV n=224 Cisplatin/bleomycin/5-FU X 2-3



Radiation



63% (5 y OS) P = .11
n=225 Radiation alone 56% (5 y OS)
Concurrent Chemotherapy and Radiation
Lin, 2003[36] III-IV n=141 Cisplatin/5-FU X 2 +



Radiation



72.3% (5 y OS) P = .002
n=143 Radiation alone 54.2% (5 y OS)
Chan, 2005[35] II-IV n=174 Cisplatin weekly and



Radiation



70.3% (5 y OS) P = .048
n=176 Radiation alone 58.6% (5 y OS)
Radiation Followed by Adjuvant Chemotherapy
Rossi, 1988[50] I-IV n=113 Radiation



Vincristine/cyclophosphamide/Adriamycin X 6



59% (4 y OS) P > .05
n=116 Radiation alone 67% (4 y OS)
Chi, 2002[32] IV n=77 Radiation



Cisplatin/5-FU/leucovorin X 9



61% (5 y OS) P = .5
n=77 Radiation alone 55% (5 y OS)
Neoadjuvant Chemotherapy Followed by Radiation Followed by Adjuvant Chemotherapy
Chan, 1995[35]   n=34 Cisplatin/5-FU X 2



Radiation



Cisplatin/5-FU X 4



80% (5 y OS) P = .1
n=40 Radiation alone 81% (5 y OS)
Concurrent Chemotherapy and Radiation Followed by Adjuvant Chemotherapy
Al-Sarraf, 1998[29] III-IV n=93 Cisplatin X 3 +



Radiation



Cisplatin/5-FU X 3



78% (3 y OS) P < 0.001
n=92 Radiation alone 47% (3 y OS)
Al-Sarraf, 2002[31] ; 2001[51] III-IV n=93 Cisplatin X 3 +



Radiation



Cisplatin/5-FU X 3



67% (5 y OS) P < 0.001
n=92 Radiation alone 37% (5 y OS)
Wee, 2004[37, 38] III-IV n=111 Cisplatin X 3 +



Radiation



Cisplatin/5-FU X 3



67% (5 y OS) P = 0.008
n=110 Radiation alone 49% (5 y OS)
Lee, 2005[39] ; 2010[40] T1-4



N2-3



n=172 Cisplatin X 3 +



Radiation



Cisplatin/5-FU X 3



68% (5 y OS) P = 0.22
n=176 Radiation alone 64% (5 y OS)
Chen, 2013[42] III-IV n=158 1) Cisplatin weekly + radiation



2) Cisplatin/5-FU X 3



72% (5 y OS) P = 0.043
n=158 Radiation alone
62% (5 y OS)
Table 6. Intergroup Study 0099. Subgroup Analysis of 5-Year Overall Survival Based on WHO Types [29]
Treatment WHO I, II, III



(n=147) OS, %



WHO II and III



(n=111, 75) OS, %



WHO I



(n=36, 25%) OS, %



Radiation 37 45 14
Chemoradiation 67 70 59
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