Neuroendocrine Carcinoma of the Larynx and Pharynx: A Clinical and Histopathological Study

Neuroendocrine carcinomas (NECs) of the head and neck are rare and the experience scanty. The Cancer Registry of Slovenia database was used to identify cases of laryngeal and pharyngeal NECs diagnosed between 1995–2020. Biopsies were analyzed for the expression of standard neuroendocrine markers (synaptophysin, chromogranin, CD56), INSM1, Ki-67, p16, and PD-L1 (using the combined positive score, CPS). In situ hybridization for human papillomavirus (HPV) and Epstein–Barr virus (EBV) was performed. Twenty patients (larynx, 12; pharynx, 8) were identified. One tumor was well differentiated (WD), five were moderately differentiated (MD), and 14 were poorly differentiated (PD). Disease control was achieved solely by surgery in 4/4 MD/PD T1-2N0-1 tumors. Eight patients died of the disease, seven of which were due to distant metastases. All three traditional markers were positive in 11/17 NECs and the INSM1 marker in all 20 tumors. Two of fourteen p16-positive tumors were HPV-positive, but all three nasopharyngeal NECs were EBV-negative. Three tumors had CPSs ≥ 1. In conclusion, INSM1 was confirmed to be a reliable marker of neuroendocrine differentiation. Except in WD and early-stage MD/PD tumors, aggressive multimodal therapy is needed; the optimal systemic therapy remains to be determined. p16, HPV, and EBV seem to bear no prognostic information.

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Integrated Diagnostic Model That Incorporates Epstein-Barr Virus DNA, Imaging, and Nasal Endoscopy to Stratify Primary Tumor and Lymph Nodes in a Patient with N1 Nasopharyngeal Carcinoma: Multidisciplinary Management

Case Reports in Oncology ◽

10.1159/000489086 ◽

2018 ◽

Vol 11 (2) ◽

pp. 289-297 ◽

Cited By ~ 1

Author(s):

Paolo Gamba ◽

Luigina Rota ◽

C. Abeni ◽

Alessandra Huscher ◽

Gabriele Saldi ◽

...

Keyword(s):

Nasopharyngeal Carcinoma ◽

Epstein Barr Virus ◽

Early Stage ◽

Distant Metastases ◽

Disease Stage ◽

Diagnostic Model ◽

Barr Virus ◽

Ebv Dna ◽

Epstein Barr

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy, with a high metastatic potential. Epstein-Barr virus (EBV) infection plays a fundamental role, even if it is not well understood. The diagnosis of the disease in its early stage is infrequent. Imaging studies, positron emission tomography scans in addition to clinical examination, endoscopic examination, and biopsy provide information on the extent of the disease. The application of neoadjuvant chemotherapy followed by concomitant chemoradiation can improve the control of NPC. In March 2016, a 54-year-old male with NPC cT1 cN2 cM0, stage III (8th edition of American Joint Committee on Cancer (AJCC) staging system) underwent to a two-step treatment: induction chemotherapy by TPF regimen (docetaxel, cisplatin, 5-fluorouracil), followed by concomitant chemoradiotherapy (weekly cisplatin). The quantity of free plasma EBV-DNA can be related to the disease stage, and the detection of EBV-DNA during follow-up can be predictive of distant metastases. Especially, either plasma or serum EBV-DNA titer is estimated to reflect tumor volume. Biologically, such EBV-DNA reflects reproduced or released DNA from dead or dying tumor cells. On the other hand, EBV-specific DNA released as exosome may reflect the biological feature of the alive NPC tumor cell. The follow-up is ongoing after 21 months from a complete response.

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Prospective Study of Tailoring Whole-Body Dual-Modality [18F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography With Plasma Epstein-Barr Virus DNA for Detecting Distant Metastasis in Endemic Nasopharyngeal Carcinoma at Initial Staging

Journal of Clinical Oncology ◽

10.1200/jco.2012.46.0816 ◽

2013 ◽

Vol 31 (23) ◽

pp. 2861-2869 ◽

Cited By ~ 87

Author(s):

Lin-Quan Tang ◽

Qiu-Yan Chen ◽

Wei Fan ◽

Huai Liu ◽

Lu Zhang ◽

...

Keyword(s):

Odds Ratio ◽

Epstein Barr Virus ◽

Distant Metastases ◽

Emission Tomography ◽

Barr Virus ◽

Positron Emission ◽

Pet Ct ◽

Risk Patients ◽

Ebv Dna ◽

Epstein Barr

Purpose To evaluate which patients with nasopharyngeal carcinoma (NPC) obtained the greatest benefits from the detection of distant metastasis with [18F]fluorodeoxyglucose positron emission tomography and computed tomography (PET/CT) combined with plasma Epstein-Barr virus (EBV) DNA levels. Patients and Methods Consecutive patients with NPC were prospectively enrolled. PET/CT, conventional work-up (CWU), and quantification of plasma EBV DNA were performed before treatment. The accuracy of these strategies for distant metastases was assessed. The costs of the diagnostic strategies were compared. Results Eighty-six (14.8%) of the 583 eligible patients were found to have distant metastases; 71 patients (82.6%) by PET/CT and 31 patients (36.0%) by CWU. In the multivariable analysis, advanced N stage (odds ratio, 2.689; 95% CI, 1.894 to 3.818) and pretreatment EBV DNA level (odds ratio, 3.344; 95% CI, 1.825 to 6.126) were significant risk factors for distant metastases. PET/CT was not superior to CWU for detecting distant metastases in very low–risk patients (N0-1 with EBV DNA < 4,000 copies/mL; P = .062), but was superior for the low-risk patients (N0-1 with EBV DNA ≥ 4,000 copies/mL and N2-3 with EBV DNA < 4,000 copies/mL; P = .039) and intermediate-risk patients (N2-3 disease with EBV DNA ≥ 4,000 copies/mL; P < .001). The corresponding patient management changes based on PET/CT were 2.9%, 6.3%, and 16.5%, respectively. The costs per true-positive case detected by PET/CT among these groups were ¥324,138 (≈$47,458), ¥96,907 (≈$14,188), and ¥34,182 (≈$5,005), respectively. Conclusion PET/CT detects more distant metastases than conventional staging in patients with NPC. The largest benefit in terms of cost and patient management was observed in the subgroup with N2-3 disease and EBV DNA ≥ 4,000 copies/mL.

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Three Molecular Subtypes of Gastric Adenocarcinoma Have Distinct Histochemical Features Reflecting Epstein-Barr Virus Infection Status and Neuroendocrine Differentiation

Applied Immunohistochemistry & Molecular Morphology ◽

10.1097/pai.0000000000000122 ◽

2015 ◽

Vol 23 (9) ◽

pp. 633-645 ◽

Cited By ~ 5

Author(s):

Olga Speck ◽

Weihua Tang ◽

Douglas R. Morgan ◽

Pei Fen Kuan ◽

Michael O. Meyers ◽

...

Keyword(s):

Virus Infection ◽

Gastric Adenocarcinoma ◽

Epstein Barr Virus ◽

Molecular Subtypes ◽

Neuroendocrine Differentiation ◽

Epstein Barr Virus Infection ◽

Infection Status ◽

Barr Virus ◽

Epstein Barr ◽

Barr Virus Infection

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INSM1 Is a Highly Specific Marker of Neuroendocrine Differentiation in Primary Neoplasms of the Gastrointestinal Tract, Appendix, and Pancreas

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqaa014 ◽

2020 ◽

Vol 153 (6) ◽

pp. 811-820 ◽

Cited By ~ 6

Author(s):

Kelsey E McHugh ◽

Sanjay Mukhopadhyay ◽

Erika E Doxtader ◽

Christopher Lanigan ◽

Daniela S Allende

Keyword(s):

Goblet Cell ◽

Neuroendocrine Differentiation ◽

Neuroendocrine Neoplasms ◽

Specific Marker ◽

Low Grade ◽

Ki 67 ◽

Neuroendocrine Markers ◽

Primary Neoplasms ◽

Poorly Differentiated ◽

Well Differentiated

Abstract Objectives INSM1 has been described as a sensitive and specific neuroendocrine marker. This study aims to compare INSM1 with traditional neuroendocrine markers in gastrointestinal neuroendocrine neoplasms. Methods Retrospective review (2008-2018) was used to retrieve paraffin-embedded tissue from 110 gastrointestinal neuroendocrine neoplasms and controls that was subsequently stained with INSM1, synaptophysin, chromogranin, CD56, and Ki-67. Results INSM1 was positive in 16 of 17 (94.1%) gastric, 17 of 18 (94.4%) pancreatic, 13 of 18 (72.2%) small bowel, 17 of 21 (81.0%) colonic, and 26 of 36 (72.2%) appendiceal tumors. INSM1 was positive in 58 of 70 (82.9%) well-differentiated neuroendocrine tumors, 17 of 20 (85.0%) poorly differentiated neuroendocrine carcinomas, 8 of 11 (72.7%) low-grade goblet cell adenocarcinomas (grade 1), and 6 of 9 (66.7%) high-grade goblet cell adenocarcinomas (grade 2/3). INSM1 sensitivity for neuroendocrine neoplasms (80.9%) was less than that of synaptophysin (99.1%), chromogranin (88%), and CD56 (95.3%); specificity was higher (95.7% vs 86.0%, 87.3%, and 86.0%, respectively). Conclusions INSM1 is a useful marker of neuroendocrine differentiation in gastrointestinal neuroendocrine and mixed neuroendocrine neoplasms. Compared with traditional neuroendocrine markers, INSM1 is less sensitive but more specific.

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Clinical implications of plasma Epstein-Barr virus DNA in early-stage extranodal nasal-type NK/T-cell lymphoma patients receiving primary radiotherapy

Blood ◽

10.1182/blood-2012-06-435024 ◽

2012 ◽

Vol 120 (10) ◽

pp. 2003-2010 ◽

Cited By ~ 55

Author(s):

Zhao-Yang Wang ◽

Qing-Feng Liu ◽

Hua Wang ◽

Jing Jin ◽

Wei-Hu Wang ◽

...

Keyword(s):

Epstein Barr Virus ◽

Cell Lymphoma ◽

Early Stage ◽

Stage I ◽

Nasal Type ◽

Barr Virus ◽

Tumor Load ◽

Primary Radiotherapy ◽

Ebv Dna ◽

Epstein Barr

Abstract The clinical value of plasma Epstein-Barr virus (EBV) DNA has not been evaluated in patients with early-stage extranodal nasal-type NK/T-cell lymphoma (NKTCL) receiving primary radiotherapy. Fifty-eight patients with stage I disease and 11 with stage II disease were recruited. High pretreatment EBV-DNA concentrations were associated with B-symptoms, elevated lactate dehydrogenase levels, and a high International Prognostic Index score. EBV-DNA levels significantly decreased after treatment. The 3-year overall survival (OS) rate was 82.6% for all patients. Stage I or II patients with a pretreatment EBV-DNA level of ≤ 500 copies/mL had 3-year OS and progression-free survival (PFS) rates of 97.1% and 79.0%, respectively, compared with 66.3% (P = .002) and 52.2% (P = .045) in patients with EBV-DNA levels of > 500 copies/mL. The 3-year OS and PFS rates for patients with undetectable EBV-DNA after treatment was significantly higher than patients with detectable EBV-DNA (OS, 92.0% vs 69.8%, P = .031; PFS, 77.5% vs 50.7%, P = .028). Similar results were observed in stage I patients. EBV-DNA levels correlate with tumor load and a poorer prognosis in early-stage NKTCL. The circulating EBV-DNA level could serve both as a valuable biomarker of tumor load for the accurate classification of early-stage NKTCL and as a prognostic factor.

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Characterization of the Epstein–Barr virus BALF2 promoter

Journal of General Virology ◽

10.1099/0022-1317-80-10-2747 ◽

1999 ◽

Vol 80 (10) ◽

pp. 2747-2750 ◽

Cited By ~ 23

Author(s):

Chien-Hui Hung ◽

Shih-Tung Liu

Keyword(s):

Transcription Factors ◽

Epstein Barr Virus ◽

Early Stage ◽

Lytic Cycle ◽

Mobility Shift ◽

Response Elements ◽

Barr Virus ◽

Epstein Barr ◽

Mobility Shift Assay

BALF2, which encodes the major DNA-binding protein of Epstein–Barr virus (EBV), is expressed during the early stage of the lytic cycle. The location of the BALF2 promoter was identified by primer extension, which indicated that the transcription start is located at nucleotide 164,782 of the EBV genome. Transfection analyses revealed that, similar to other EBV early promoters, the BALF2 promoter is activated by the EBV-encoded transcription factors Rta and Zta. The promoter is also synergistically activated if both transcription factors are present in B lymphocytes and in epithelial cells. Deletion analysis and electrophoretic mobility-shift assay revealed that the region between nucleotides −134 and −64 contains Zta- response elements and the region between nucleotides −287 and −254 contains Rta-response elements. This study demonstrates the importance of Rta and Zta in regulating the transcription of EBV early genes.

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Diagnostic and Prognostic Indications of Nasopharyngeal Carcinoma

Diagnostics ◽

10.3390/diagnostics10090611 ◽

2020 ◽

Vol 10 (9) ◽

pp. 611

Author(s):

Engku Nur Syafirah E. A. R. ◽

Ahmad Adebayo Irekeola ◽

Chan Yean Yean

Keyword(s):

Nasopharyngeal Carcinoma ◽

Tumor Suppressors ◽

Early Stage ◽

Clinical Signs ◽

Barr Virus ◽

Diagnosis And Prognosis ◽

Specific Pcr ◽

Pcr Multiplex ◽

Life Threatening ◽

Epstein Barr

Nasopharyngeal carcinoma (NPC) is a disease that is highly associated with the latent infection of Epstein–Barr virus. The absence of obvious clinical signs at the early stage of the disease has made early diagnosis practically impossible, thereby promoting the establishment and progression of the disease. To enhance the stride for a reliable and less invasive tool for the diagnosis and prognosis of NPC, we synopsize biomarkers belonging to the two most implicated biological domains (oncogenes and tumor suppressors) in NPC disease. Since no single biomarker is sufficient for diagnosis and prognosis, coupled with the fact that the known established methods such as methylation-specific polymerase chain reaction (PCR), multiplex methylation-specific PCR, microarray assays, etc., can only accommodate a few biomarkers, we propose a 10-biomarker panel (KIT, LMP1, PIKC3A, miR-141, and miR-18a/b (oncogenic) and p16, RASSF1A, DAP-kinase, miR-9, and miR-26a (tumor suppressors)) based on their diagnostic and prognostic values. This marker set could be explored in a multilevel or single unified assay for the diagnosis and prognosis of NPC. If carefully harnessed and standardized, it is hoped that the proposed marker set would help transform the diagnostic and prognostic realm of NPC, and ultimately, help prevent the life-threatening late-stage NPC disease.

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An EBV+ lymphoepithelioma-like cholangiocarcinoma in a young woman with chronic hepatitis B

BMJ Case Reports ◽

10.1136/bcr-2019-229520 ◽

2019 ◽

Vol 12 (7) ◽

pp. e229520 ◽

Cited By ~ 3

Author(s):

Sofia V Gearty ◽

Ayman Al Jurdi ◽

Meredith E Pittman ◽

Renuka Gupta

Keyword(s):

Chronic Hepatitis ◽

Nasopharyngeal Carcinoma ◽

Epstein Barr Virus ◽

Systemic Chemotherapy ◽

Early Stage ◽

Treatment Options ◽

Rare Type ◽

Barr Virus ◽

Epstein Barr ◽

Almost All

Epstein-Barr virus (EBV) is implicated in the tumorigenesis of a variety of malignancies, including Burkitt’s lymphoma, Hodgkin’s disease and nasopharyngeal carcinoma (NPC). EBV+ lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare type of intrahepatic cholangiocarcinoma with a distinct pathology and poorly understood treatment options. Morphologically, this neoplasm resembles undifferentiated NPC, a commonly EBV+ tumour with a prominent lymphoid infiltrate. Almost all of the current literature regarding LELCC describes early stage tumours that are treated surgically and achieve good outcomes. In contrast, this report documents a late stage LELCC treated unsuccessfully with systemic chemotherapy.

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