Undifferentiated Nasopharyngeal Carcinoma Research Articles

Early intra-treatment diffusion weighted magnetic resonance imaging in patients with recurrent nasopharyngeal carcinoma treated with nivolumab

<p class="abstract">Immune check point inhibitors have demonstrated promising efficacy in patients with recurrent or metastatic nasopharyngeal carcinoma (NPC) in phase I and phase II trials. Early identification of treatment response is important in these patients. This report aimed to document the early intratreatment diffusion weighted magnetic resonance imaging (DW-MRI) findings in NPC patients following treatment with the programmed cell death-1 inhibitor, nivolumab. Two consecutive patients with histologically confirmed recurrent undifferentiated NPC treated with nivolumab were prospectively recruited. Nivolumab was administered at a dosage of 3 mg/kg intravenously every 2 weeks. Patients underwent magnetic resonance imaging examinations at baseline, and at 3 and 5 weeks after commencement of treatment. Intratreatment changes in tumour volume and apparent diffusion coefficient (ADC<sub>mean</sub>)were calculated. The endpoints were objective response by response evaluation criteria in solid tumors and survival. In patient 1, an intratreatment ADC increase at 5 weeks corresponded with anatomical tumour volume reduction and a better long-term survival outcome (progression free survival 1.3 years, overall survival 2.9 years). In patient 2, an intratreatment ADC decrease at 5 weeks corresponded to progressive disease and worse outcome (progression free survival 0.0 years, overall survival 0.9 years). Intratreatment ADC changes at 3 weeks were not associated with response outcome. These cases suggest that intratreatment changes in ADC at 5 weeks may potentially predict tumour response in patients treated with nivolumab. Dedicated studies are needed to clarify these findings and fully characterise patterns of treatment related ADC change.</p>

Nasopharyngeal Carcinoma Profile in dr. Cipto Mangunkusumo Hospital Year 2013

Background: Nasopharyngeal carcinoma (NPC) remains as a health burden in Indonesia. It is one of most common cancers in Indonesia, with an overall incidence estimated at 6.2/100,000 or 12,000 new cases per year. Unfortunately, many of these cases are unregistered due to several factors, such as lack of national cancer registry. In most developing countries, cancer registration often begins in hospitals. Hospital-Based Cancer Registry (HBCR) provides the initial and major source of information on patients that leads to the set-up of a population-based registry. Materials and Methods: This was a descriptive retrospective study of all registered NPC patient in HBCR, from January-December 2013. All registered NPC patients in HBCR in the year 2013 is included. Results: There were 299 NPC patients, with a male-to-female ratio of 2.4:1. Median age was 47 years old, with majority of age between 40-49 years old (27.4%). Most common type of histology was undifferentiated NPC (85%). Most patients presented with locally advanced disease, with majority of stage IVA (33.9%). Chemoradiation remained as standard treatment for locally advanced NPC (84.1%). Conclusion: Demographic data of patients, such as age and sex, are consistent with previous studies. Whereas racial distribution was not parallel with previous studies, maybe due to its lack of available data. Moreover, most common histopathology type and presentation was undifferentiated NPC and patients with Stage III to IV cancer.

Seroprevalence of human immunodeficiency virus, hepatitis B virus, and hepatitis C virus in patients undergoing nasopharyngeal biopsy

Objectives:We aimed to determine the seroprevalence of hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in patients undergoing nasopharyngeal biopsy (NPB). Materials and Methods: The medical records of patients who had undergone NPB under local anesthesia between 2009 and 2020 were retrospectively analyzed in our clinic. The hepatitis B surface antigen (HBsAg), HCV antibody (anti-HCV), and HIV antibody (anti-HCV) were recorded in all patients. Age, gender, and pathology result of the patients were also recorded. The patients were divided into two groups (benign and malignant) according to the pathology results. The study included 666 patients with a mean age of 38.5±17.2 years (range, 6-89 years). Serology positivity was detected in 18 patients (2.7%) for HBsAg, in 4 patients (0.6%) for anti-HCV, and in 2 patients (0.3%) for anti-HIV. All serology-positive patients were older than eighteen. The HBV seropositivity rate was significantly higher in males (p=0.003). No statistically significant difference was found between male and female genders for HCV and HIV seropositivity (p>0.05). Reactive lymphoid hyperplasia (70.7%) and chronic inflammation (27.8%) were the most common results in the benign group. Undifferentiated Nasopharyngeal Carcinoma (58.9%) and B-cell non-Hodgkin lymphoma (17.8%) were the most common subtypes in the malignant group. There was no statistically significant difference between benign and malignant groups for HBV, HCV, and HIV seropositivity rates (p>0.05). Preoperative serological testing in patients undergoing NPB is required for increasing awareness of HBV, HCV, and HIV infections among healthcare personnels. Otolaryngologists must have the highest awareness of occupational infections deriving from blood and body fluids. It is necessary to take precaution measures including personal protective equipment during procedures.

Huge cervical lymphadenopathy revealing nasopharyngeal non-Hodgkin's lymphoma

Non-Hodgkin's lymphoma is a rare histological type of nasopharyngeal cancer. Most of these cancers are undifferentiated carcinomas or undifferentiated nasopharyngeal carcinomas (UNC). We report a case of nasopharyngeal non-Hodgkin's lymphoma. Immunohistochemical examination showed B-cell non-Hodgkin's lymphoma. The study involved a 47-year old patient with no particular past medical history presenting with right laterocervical swelling associated with right nasal obstruction and rhinorrhea that had persisted for 6 months. Clinical examination showed right voluminous painless adherent laterocervicale lymphadenopathy without signs of inflammation. Endoscopic examination of the nasopharynx showed enormous process extending to the posterior nares. Anatomo-pathologic study of the biopsy with immunohistochemical study showed B-cell non-Hodgkin's lymphoma. Patient's outcome was favorable under chemotherapy with no relapse during 6-month follow-up period. Primary non-Hodgkin's lymphoma of the nasopharynx is a rare localization of lymphomas. It occurs in less than 10% of patients with lymphoma of the head and of the neck. It often poses a problem in positive clinical and histological diagnosis. Symptoms are generally little specific. Peripheral lymphadenopathies occur in 50% of cases. Diagnosis is based on biopsy with immunohistochemical examination. Therapeutic progress have been achieved through the more frequent use of chemotherapy associated with radiotherapy.

Cancer-Associated Fibroblasts in Undifferentiated Nasopharyngeal Carcinoma: A Putative Role for the EBV-Encoded Oncoprotein, LMP1.

Undifferentiated nasopharyngeal carcinoma (NPC) is 100% associated with Epstein–Barr virus (EBV) infection, and biopsies display variable levels of expression of the viral oncoprotein, latent membrane protein 1 (LMP1). Emerging evidence suggests an important role for cancer-associated fibroblasts (CAFs) in the NPC tumour microenvironment, yet the interaction between the virus, its latent gene products and the recruitment and activation of CAFs in the NPC tumour stroma remains unclear. This short review will discuss the current evidence for the importance of CAFs in NPC pathogenesis and outline a putative role for the EBV-encoded oncoprotein, LMP1, in governing tumour–stromal interactions.

COMPARISON OF CYTHOCROME P450 FAMILY 2 SUBFAMILY A POLYPEPTYDE 6 (CYP2A6) GENE POLYMORPHISM PROPORTION ON EARLY AND ADVANCED STAGE OF UNDIFFERENTIATED TYPE NASOPHARYNGEAL CARCINOMA IN BALINESE

Introduction
 Nasopharyngeal carcinoma (NPC) is a malignancy derived from epithelial cells lining the nasopharynx. The etiology of nasopharyngeal carcinoma is multifactorial. One of the risk factors is CYP2A6 gene polymorphism which causes nitrosamines are not metabolized, leading to DNA change that could trigger cancer.
 Objectives
 The purpose of this study is to know the association of CYP2A6 gene polymorphism and clinical stage of undifferentiated type of NPC
 Material and Method
 This is a cross sectional analytic study. The sample in this study were 80 nasopharyngeal carcinoma patients whose treated in ENT-HN department of Sanglah General Hospital between 2017 - 2018. The collected data consist of subject’s characteristic and CYP2A6 gene polymorphisms identified by the PCR-RFLP technique.
 Results
 The probability of CYP2A6 gene polymorphism in the undifferentiated type of NPC in the Balinese tribe is 3.125 times greater in advanced stage than early stage. Based on multivariate analysis, there was a statistically significant association between CYP2A6 gene polymorphism and clinical stage of undifferentiated type NPC in Balinese with p value = 0,0048 (p < 0,05).
 Conclusion
 There is association between CYP2A6 gene polymorphism and clinical stage of undifferentiated type NPC in Balinese tribe.

NASOPHARYNGEAL CARCINOMA CHARACTERISTIC AT ARIFIN ACHMAD HOSPITAL IN JANUARY-OCTOBER 2018

Introduction:
 Nasopharyngeal carcinoma is the most head and neck malignancy worldwide that is capable of performing distant metastasis and potentially to relapse. Indonesia prevalence of cancer estimate 1.4% or approximately 347.792 population and the highest found in D.I Yogyakarta, whereas Riau province counted 0.7% or around 4.301 population. This concludes the nasopharyngeal carcinoma stand as the 4th of the most malignancy in Indonesia after the mamae carcinoma, cervix carcinoma, and skin tumor.
 Objective:
 The purpose of this study is to asses the characteristic of NPC patient in Arifin Achmad Hospital Riau Province involving the incidence, gender, age, histopathology classification, distribution by the period and the therapy.
 Material and method:
 Retrospective cross-sectional approach with the descriptive presentation to assess the entire population of nasopharyngeal carcinoma based on gender, age, histopathology classification and treatment in January to October 2018. The data obtained from several data provide unit and process into a frequent and distribution table.
 Result: 
 The number of the cases obtained include the new case and old case was 137 cases sequently 62 new cases and 75 old cases. Men were most affected and the commonest occurring in range 40-60 years. All the most histopathology classification was the undifferentiated nasopharyngeal carcinoma. Most of the patient treated with chemotherapy.
 Conclusion: 
 NPC was the highest incidence of the head and neck malignancy commonly in men. All the most occurred in early elderly and the highest histopathology type was undifferentiated nasopharyngeal carcinoma (WHO Type III). Chemotherapy was the choice to treat the patient.

COMPARISON OF POLYMORPHISM rs3813865 CYTOCHROME P450 FAMILY 2 SUBFAMILY E POLYPEPTIDE 1 (CYP2E1) GENE IN VARIOUS CLINICAL STAGE OF UNDIFFERENTIATED TYPE NASOPHARYNGEAL CARCINOMA

Nasopharyngeal carcinoma is caused by interaction of Epstein-Barr virus chronic infection, environtment, and genetic factors. Epstein-Barr virus (EBV) infect nasopharyngeal ephitelial cell in latent period. This infection will cause mutation and further causing malignancy. This is a cross-sectional study in undifferentiated type NPC patients after hystopatological examination and were examined in RSUP Sanglah Denpasar from January 2017 to December 2018. This study is using 62 subjects who meets inclusion criteria. Univariate analysis was done to show subject characteristics which include age, gender, occupation, clinical stage, gene allele and rs3813865 polymorphism CYP2E1 gene. Mean age of subject is 48.05 years with standard deviation of 10.86 years. The youngest is 17 years old and the oldest is 73 years old. The most are men as many as 47 subjects (75.8%), and the most occupation are government employee as many as 17 subjects (27.4%). The most clinical stage of undifferentiated type NPC are stage II as many as 7 subjects (11.3%). Based on TNM, the most are T4 as many as 32 subjects (51.6%), N3 as many as 21 subjects (33.9%), and M0 as many as 60 subjects (96.8%).

335P - PD-L1 profile of nasopharyngeal cancer patients in Indonesia

BackgroundMolecular and biological characterization of nasopharyngeal cancer (NPC) is scarce. Clinical trials of emerging treatment such as immunotherapy for NPC in endemic area is lacking. Currently the most extensively studied immune related molecule that potentially become the target for treatment is PD-1/PD-L1. PD-L1 profile of NPC patients in Indonesia has never been studied before. This study aimed to elucidate PD-L1 profile from NPC specimens in Indonesia. MethodsNasopharyngeal biopsy specimen was taken for PD-L1 protein examination with enzyme-linked immunosorbent assay (ELISA) method. Tissue specimen was homogenized and then ELISA test was conducted using ABCAM AB214565 kit. All protocols from the manufacturer kit was followed. Total protein concentration from homogenized tissue specimen was obtained through Bradford protein assay method. Then, PD-L1 concentration per mg protein of tissue specimen was calculated. ResultsTwenty-four nasopharyngeal biopsy specimens was obtained. The average age of all patients was 45 years old. Sixteen (66.67%) out of 24 specimens were confirmed histologically to be undifferentiated nasopharyngeal carcinoma. The rest, 8 other specimens have normal histology. Average PD-L1 concentration from NPC specimens was 2,186.67 ± 1,399.32 pg/mg protein (Range: 461.76 to 4,805.85 pg/mg protein). Average PD-L1 concentration from non NPC specimens was 612.43±314.04 pg/mg protein (Range: 326.87 to 1,155.19 pg/mg protein). ConclusionsFrom this preliminary result, PD-L1 protein (both in tumor cells and in immune cells) from NPC specimens has been shown to be elevated compared to normal nasopharyngeal epithelium. This finding indicate that further work is warranted to test anti PD-L1 drug for NPC patients that has failed all the standard treatment. Furthermore, our upcoming work would be exploring relationship between PD-L1, EBV, and tumor microenvironment from our NPC specimens. Legal entity responsible for the studyThe authors. FundingUniversity of Indonesia. DisclosureAll authors have declared no conflicts of interest.

EPIDERMAL GROWTH FACTOR RECEPTOR EXPRESSION IN NON-KERATINIZED NASOPHARYNGEAL CARCINOMA SUBTYPE AT PADANG

Introduction: 
 Patients with nasopharyngeal carcinoma have a poor prognosis, there are several factors that cause it to happen, one of the existing therapeutic response has been inadequate. Expression of Epidermal Growth Factor Receptor (EGFR) has been used as a biological marker targeted therapy in nasopharyngeal carcinoma. Histopathologic subtype tumors also determine the prognosis of patients with nasopharyngeal carcinoma.
 Objective: 
 The aim of the study to determine between the expression of epidermal growth factor receptor between non-keratinized differentiated and undifferentiated subtypes in nasopharyngeal carcinoma and correlation with their clinical stage. Study design, Cross-sectional comparative study. Place and duration study, Department of Otorhinolaryngology, Department of Pathology Anatomy in Dr. M. Djamil Hospital, Padang and Department of Pathology Anatomy in Gajah Mada University, between May 2015 until October 2015
 Material and methods: 
 We included 36 samples paraffin blocks of nasopharyngeal carcinoma biopsy, respectively 18 paraffin blocks are non-keratinized differentiated and 18 non-keratinized undifferentiated nasopharyngeal carcinoma subtypes. Each sample examined EGFR expression by immunohistochemical staining methods.
 Results: 
 There were positive EGFR expression results in all sample as 69.4%. Expression of EGFR positive non-keratinized differentiated subtypes in nasopharyngeal carcinoma as 77.8% and undifferentiated subtype as 61.6%. There are no significant differences of EGFR expression between non keratinized differentiated and undifferentiated subtypes nasopharyngeal carcinoma (P>0.05). There are no significant differences of EGFR expression between new and advanced stage nasopharyngeal carcinoma (P>0.05).
 Conclusion: 
 There were no significant differences of EGFR expression between non-keratinized differentiated and non-keratinized undifferentiated subtypes in nasopharyngeal carcinoma. Analysis of the study also showed no significant differences of EGFR expression based on the clinical stage nasopharyngeal carcinoma.

THE RELATION OF EBNA-1 AND EGFR EXPRESSION SCREENING FROM ADVANCED STAGE UNDIFFERENTIATED NASOPHARYNGEAL CANCER

Introduction:
 Nasopharyngeal carcinoma (NPC) is a lymphoepithelial malignancy of the nasopharynx, one of the etiologies is the infection of Epstein–Barr virus in undifferentiated type of nasopharyngeal carcinoma. The Epstein-Barr virus Nucleus Antigen-1 (EBNA-1) is Epstein–Barr virus-encoded proteins as regulatory virus transcription. Epithelial Growth Factor Receptor (EGFR) consist of a single polypeptide chain of amino acid, ErbB members, tyrosine kinase receptor, a transmembrane glycoprotein encoded by gen location in the short arms of a chromosome and overexpression in epithelial tumors. EGFR plays a central role in signal transduction pathways which regulate key cellular functions in epithelial malignancies. and may also present in NPC.
 Objective:
 To investigate this relation of expression patterns of EBNA-1 and EGFR in a histological type of undifferentiated nasopharyngeal carcinoma.
 Method:
 Observational, analytical study with a cross-sectional method of 34 formalin-fixed within inclusion criteria are EBNA-1 and positive staining of EGFR expression (30 patients) and exclusion criteria of negative staining of EGFR (4 patients). All biopsy samples work with paraffin embedded and resulted in hematoxylin-eosin undifferentiated histological types of the advanced stage in nasopharyngeal carcinoma. EBNA-1 and EGFR expression used immunohistochemistry staining.
 Result:
 EBNA-1 and EGFR expression level were detection and correlated with the advanced stadium of nasopharyngeal undifferentiated carcinoma.
 Conclusion: 
 EBNA-1 is significantly related to EGFR expression in the advanced stadium of undifferentiated nasopharyngeal carcinoma. Overexpression of EGFR is mostly found in advanced NPC but not in all ages. Male is dominated and overall age below 55 years old. Screening of EGFR with immunohistochemistry is highly considered before anti-EGFR treatment

PPARβ/δ Agonist GW501516 Inhibits Tumorigenesis and Promotes Apoptosis of the Undifferentiated Nasopharyngeal Carcinoma C666-1 Cells by Regulating miR-206.

In previous investigations, we reported that peroxisome proliferator-activated receptor β/δ (PPARβ/δ) activation by GW501516 inhibits proliferation and promotes apoptosis in the undifferentiated C666-1 nasopharyngeal carcinoma (NPC) cells by modulating caspase-dependent apoptotic pathway. In the present study, the mechanism by which GW501516 induces apoptosis was explored from the perspective of microRNA (miRNA) expression. Among the assayed miRNAs that were involved in regulating the expression of antiapoptotic protein Bcl-2, miR-206 was increased significantly and specifically by GW501516 in C666-1 cells at both the in vitro level and at the in vivo xenograft samples. The induction on miR-206 expression caused by GW501516 was capable of being antagonized by the PPARβ/δ antagonist GSK3787 and AMPK antagonist dorsomorphin in C666-1 cells. GW501516’s suppression on the growth and apoptosis of C666-1 cells was found to be dependent on the presence of miR-206. miR-206 overexpression resulted in suppressed proliferation and colony formation ability, and further triggered increased apoptosis in C666-1 cells in a caspase-dependent manner. The expression of cleaved caspase 3 and caspase 9, and the ratio of Bax to Bcl-2 were elevated remarkably by miR-206. Consistent with the in vitro result, miR-206 was corroborated to suppress the ectopic NPC xenograft tumorigenesis that derived from the C666-1 cells in BALB/c nu/nu mice. Taken together, the current data demonstrated that miR-206 plays a critical role in the direct apoptosis-promoting effect induced by GW501516 in C666-1 cells. Furthermore, the emphasized tumor-suppressive role of miR-206 in the C666-1 cells indicates that it has the potential to provide a new therapeutic approach for the undifferentiated NPC.

Update in pediatric nasopharyngeal undifferentiated carcinoma.

Many of the principles established in adults with undifferentiated nasopharyngeal carcinoma (NPC) apply to children, adolescents and young adults. However, NPC in young patients should be distinguished from the adult form by several points. This review focuses mainly on differences between adult and pediatric NPC. The role of biology and genetics in pediatric NPC is discussed. Systemic treatment modalities including type of chemotherapy induction, timing of treatment, role of immunotherapy as adjuvant treatment, or in relapsing/ metastatic diseases are reported. Radiation modalities (doses, techniques…) in children are also reviewed. Long-term effects including secondary cancers are finally be discussed in this young NPC population.

CHARACTERISTIC OF NASOPHARYNGEAL CARSINOMA IN ACEH 2016-2017

Introduction
 Nasopharyngeal carcinoma is among five major malignancies in Indonesia and the primary malignant tumor in men. Among all head and neck (H&N) cancers, nasopharyngeal carcinoma (NPC) is endemic in certain regions of the world, especially in Southeast Asia, and has a poor prognosis. In Indonesia, the recorded mean prevalence is 13 000 yearly new NPC cases, but otherwise little is documented on NPC in Indonesia.
 Objectives
 We collected all cases of nasopharyngeal carcinoma diagnosed by histopathological examination during the period of 2016-2017 from archives of the registry in the Ear, Nose, and Throat department and Patologi Anatomy laboratory Dr. Zainoel Abidin General Hospital. We did this research to presenting the basic data of NPC in Aceh according to gender, age, geographic site and WHO histopathology criteria.
 Method
 All the data we counted by using Microsoft Excel 2016 by grouping it according to the variable that we want to grade. We made it into a table and graphic presentation to explain each item of the variable.
 Result
 Here, in Aceh, we reported 46 cases in the year 2016 and 26 cases in the year 2017, a total of 72 patients during 2 years. We studied NPC incidence in Aceh among all H&N cancer cases focusing on age, gender, the ethnic background, and the disease histopathology. In this study population, from a total of 72 patient we found 44 male (61.1%) and 28 female (38.9%), with a male to female ratio is 1.57:1. According to the geographic site, NPC in Aceh was the most endemic in the Banda Aceh population (15.3%) followed by Southwest Aceh (12.5%) as a second one. From the age range, NPC most frequent to affect patients at the age range 41-60 years (44.44%), besides that we found 8 (11.11%) cases NPC in Aceh at the age 0- 20 years with 13 years old patient was the younger one. Here, we found that Undifferentiated NPC is the most frequent histological type (44.4%). We continued the study by analyzed NPC patient according to WHO criteria, type I WHO most frequent from the Great Aceh. Type II and Type III WHO we found most frequent from Banda Aceh.
 Conclusion: Our data NPC incidence did not differ significantly among the literature. Mostly NPC patients over the world at the old adult age, even all of the age range can be affected by NPC. There are similar histopathological features results here compare to the Southeast Asian country.

Genomic profiling of pulmonary lymphoepithelioma-like carcinoma (PLELC).

1572 Background: PLELC, a rare and distinct type of primary lung cancer, is characterized by Epstein-Barr virus (EBV) infection. Histologically, it resembles undifferentiated nasopharyngeal carcinomas (NPC). Only a few hundred cases have been reported since its discovery. Due to the extreme rareness, its genomic landscape remains elusive. Methods: Tissue samples of 27 PLELC patients (13 males and 14 females) with various stages (Ib to IV) were subjected to targeted sequencing using a panel consisting of 520 cancer-related genes, spanning 1.6Mb of human genome. Results: Collectively, we identified 184 somatic mutations spanning 109 genes, including 107 SNVs, 12 insertions or deletions (INDELs) and 65 copy-number amplifications (CNAs). Approximately, 50% of patients had CNAs. One patient had no mutation detected from this panel. Except for 2 patients, 1 with HER2 amplification and another with KRAS mutation, no other classic NSCLC driver genes were detected. The most frequently mutated genes were CCND1, TP53, DAXX and NF kBIA, occurring in 30%, 26%, 22% and 22% of patients, respectively. Interestingly, 78% (21/27) patients had mutations in epigenetic regulators. Of the 184 mutations identified, 51 occurred in epigenetics-related genes. Pathway analysis also revealed an enrichment of genes participating in chromatin remodeling and organization. Next, we compared the genomic profile of PLELC with lung adenocarcinoma and EBV positive NPC. The frequency of TP53 mutations was significantly higher in lung adenocarcinoma (68% vs 26%, p = 0.021). Comparing to NPC, PLELC had significantly more mutations in epigenetic regulators. TMB analysis revealed a median TMB of 1.6/Mb, significantly lowered than lung adenocarcinomas (p < 0.01). We also assessed PD-L1expression and revealed that 67% had an overexpression of PD-L1. Interestingly, TP53-mutant patients were more likely to associated low PD-L1 expression (p < 0.01). Conclusions: In this study, we elucidated a distinct genomic landscape associated with PLELC with no classic NSCLC driver mutation but an enrichment of mutations in epigenetic regulators. The observation of high expression of PD-L1 and lack of canonical druggable driver mutation raises the potential of immunocheckpoint blockade therapy for PLELC.

Amyloid and hyaline globules in undifferentiated nasopharyngeal carcinoma

We characterize the clinicopathological features of two patients (one 38 year old woman and one 42 year old man, both of Chinese ethnicity) with Epstein Barr Virus positive non-keratinizing nasopharyngeal carcinoma from an endemic region with prominent presence of amyloid and one case with both amyloid and abundant intracytoplasmic hyaline globules. The amyloid material was positive for Congo red and showed apple green birefringence when examined under polarized light. The amyloid was immunoreactive for cytokeratins and was located both intra- and extracellularly. Frequently the amyloid had a light microscopical spherical appearance and displayed peripheral radiating fibrils from a central homogenous core. One of the patients had a unique presentation of nasopharyngeal carcinoma with perceived hemoptysis and coughing up two pieces of tumor tissue. In reality, the nasopharyngeal tumor was polypoid and the two fragments were pinched of from the main tumor mass.

Epstein-Barr Virus-Associated Pulmonary Carcinoma: Proposing an Alternative Term and Expanding the Histologic Spectrum of Lymphoepithelioma-like Carcinoma of the Lung.

Lymphoepithelioma-like carcinoma (LELC) of the lung is a rare Epstein-Barr virus (EBV)-associated carcinoma. It is histologically characterized by a syncytial growth pattern with marked lymphocytic infiltration that is indistinguishable from the histology observed in undifferentiated nasopharyngeal carcinomas. However, it has been noted that LELC can display nonclassic morphology and lack significant lymphocytic infiltration. In this study, we conducted a comprehensive clinicopathologic analysis of 61 patients with pulmonary LELC and performed automatic quantification of the lymphocytic infiltrate using the IHC Profiler software. We demonstrated that pulmonary LELCs have a morphologically continuous spectrum, ranging from classic poorly differentiated tumors with intense lymphocytic infiltration to nonclassic morphology with little lymphocytic infiltration. These EBV-associated tumors represent a distinct entity and usually occur in female and nonsmoking patients. Tumors with low lymphocytic infiltration can closely resemble nonkeratinizing squamous cell carcinoma and tend to be larger in size, have higher maximum standardized uptake values on radiography, and exhibit shorter times to recurrence than those with high lymphocytic infiltration. Through detailed pathologic examination, we observed several distinct morphologic features in pulmonary LELCs, including granulomatous inflammation, focal keratinization, spread through alveolar spaces, and lepidic spreading pattern. We also found that patients with tumors exhibiting granulomatous inflammation have favorable outcomes; however, spread through alveolar spaces did not significantly correlate with prognosis. As many of these "LELCs" do not resemble undifferentiated nasopharyngeal carcinoma or lymphoepithelioma, we propose using an alternative term, EBV-associated pulmonary carcinoma, to encompass the entire morphologic spectrum of this distinct disease entity.

The Role of a Minimum Immunohistochemical Antibody Panel in Confirming Undifferentiated Nasopharyngeal Carcinoma: A Cross-Sectional Study at the Muhimbili National Hospital, Dar-es-Salaam, Tanzania.

Introduction:Nasopharyngeal carcinoma (NPC) is a malignant epithelial neoplasm arising in the nasopharyngeal mucosa that shows light microscopic and/or ultrastructural evidence of squamous differentiation. Immunohistochemistry (IHC) can be used to reliably distinguish undifferentiated NPC from other malignant tumors, and the technique may be a necessary tool toward the arrival of a definitive diagnosis, particularly when dealing with challenging cases.Materials and Methods:This was a cross-sectional hospital-based study which was conducted at Muhimbili National Hospital. The study involved 120 patients with NPC who were diagnosed on histopathological basis between 2009 and 2013.Results:The sensitivity and specificity of hematoxylin and eosin (H and E) stain in diagnosing NPC were 99% and 30.4%, respectively. The accuracy of H and E stain to diagnose NPC and lymphoma was 94.2% and 30.4%, respectively. CD45 antibody helped to confirm 16 cases which were diagnosed as NPC on H and E stain to be lymphoma. Further, AE1/AE3 antibody helped to confirm one case who was diagnosed as rhabdomyosarcoma on H and E stain to be NPC.Conclusions:The sensitivity and accuracy of H and E stains to diagnose NPC were very high whereas the specificity was very low. A significant proportion of previously diagnosed NPC cases by routine H and E stains were confirmed not to be so by a minimal IHC antibody panel of pan-cytokeratin cocktail (AE1/AE3) and leukocyte common antigen (CD45). This highlights the paramount importance of a minimum IHC panel in assisting to obtain a definitive diagnosis in challenging cases of NPC.

The Primary Tumor and Regional Lymph Node Clinical Status of Distant Metastasis in Nasopharyngeal Carcinoma

Background: Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma derived from nasopharyngeal epithelium. NPC characteristic is highly invasive and can metastasize rapidly. The presence of distant metastasis is a major factor in determining the patient’s management and prognosis. The magnitude of radiologic and molecular costs encouraging the need to know the clinical variables associated with distant metastasis of NPC. Methods: Cross-sectional analytical retrospective studies of undifferentiated NPC (WHO type III) patients at initial diagnosis in the ORL-HNS Department of Dr. Sardjito Hospital Yogyakarta from January 2014 to December 2016. Results: At 276 NPC patients with the ratio of 197 men (71.4%) and 79 women (28.6%) was 2.5:1, mean age 48.5 years, distant metastasis was found in 37 patients (13.4%). There was no significant difference in the frequency of sex (p = 0.346), age (p = 0.784), and primary tumor clinical status (p = 0.297) between NPC with distant metastasis and without distant metastasis. There was significant difference in the frequency of regional lymph node clinical status between NPC with distant metastasis and without distant metastasis (p = 0.004; PR = 3.866). Conclusions: There is no statistically significant difference of primary tumor clinical status between NPC with and without distant metastasis. There is statistically significant difference of lymph node clinical status between NPC with and without distant metastasis.

Prognostic Significance of Immune Microenvironmental Factors in Undifferentiated Nasopharyngeal Carcinoma Patients Treated with Chemoradiotherapy

EBV-associated UNPC is characterized by an abundant immune infiltrate, which may have a prognostic relevance, considering EBV-specific immune response and microenvironmental immunesuppression. Our primary aim was to retrospectively assess the significance of immunesuppression in the UNPC microenvironment as prognostic biomarker of treatment failure in a non-endemic area population. As secondary aim we investigated the immunomodulating effects of chemoradiotherapy (CRT) monitoring the variation of EBV-specific immunity before and after treatment. We reviewed 63 consecutive patients (pts) with EBV-associated stage II-IVB UNPC undergoing radical CRT. Our policy was of administering concurrent CRT in pts with stage II disease, and sequential therapy in pts with advanced stages. The number of relapsed pts was 11 (cases), while 52 pts (controls) were free from treatment failure at a minimum follow-up of 2 years. DNA and RNA were extracted from tumor (T) and adjacent normal mucosa (M) frozen biopsies at diagnosis. We verified the expression of EBV-derived Barf1 gene in T versus M samples. We investigated the expression of the immune-related genes PD-L1, CD8, FoxP3 and IFN-g in T and M tissues by quantitative RealTime PCR, and their methylation status through quantitative methylation specific PCR. Quantitative RT-PCR analyses showed significantly higher expression levels of several immune-related genes (i.e. BARF1, CD8, IFN-g, IDO, PD-L1, and PD-1) in UNPC samples respect to healthy tissues. Interestingly, CD8 expression was significantly reduced in both tumor and healthy tissues in UNPC patients who relapsed within two years (P<0.001). Similarly, quantitative methylation-specific PCR analyses identified a hypomethylated FOXP3 intron 1 exclusively in relapsed UNPC patients. Finally, we quantified the amount of EBV- and BARF1-specific T-cells in the peripheral blood of 14 patients (7 relapses) through IFN-g ELISPOT assay, and observed a significant decrease after CRT only in relapsing patients. Altogether, our data suggest that a high level of immunosuppression (low CD8, hypomethylated FoxP3) in UNPC microenvironment may predict treatment failure and early identify those patients who could benefit from the addition of an immunotherapy improving first line CRT.