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HPV found in nonendemic areas has been identified to be another viral cause of NPC. 1592 According to the 5th edition of the WHO Classification of Head and Neck Tumors, NPC is classified into three major histological cat egories: keratinizing, nonkeratinizing, and basaloid SCC (Table XXV.1). 17 Traditionally, undifferentiated SCC was separately classified but is now grouped under nonkera tinizing tumors. Keratinizing SCC of the nasopharynx, which involves overt squamous differentiation in the form of keratiniza tion and intercellular bridges, appears similar to conven tional SCCs of the other head and neck sites. Despite some debate, keratinizing SCC is usually considered more radioresistant and has a worse prognosis than the nonker atinizing type. 1589,1593–1598 Different studies have reported varying results on the correlation between EBV and kera tinizing SCC, with a positive association more commonly found in endemic areas. 1599,1600 Nonkeratinizing SCC can be further divided into undif ferentiated and differentiated subtypes. The undifferenti ated subtype typically exhibits a syncytium of tumor cells with large and vesicular nuclei, prominent nucleoli, and indistinct cell borders. By contrast, tumor cells of the differ entiated subtype have relatively well-defined cell borders and usually present as a plexiform pattern that resem bles urothelial carcinoma of the genitourinary tract. Both subtypes are strongly associated with EBV. Additionally, it is not uncommon to observe a mix of differentiated and undifferentiated components. Although some studies have reported better survival rates for patients with tumors of the undifferentiated subtype, 1601–1603 the morphological separation of the two subtypes is regarded as being more of academic interest than clinical importance because of their similar etiology and prognosis. 1595,1596,1604,1605 Basaloid SCC of the nasopharynx, the rarest of the three histological categories of NPC, shares an identical morphology with that of basaloid SCC of other primary sites. It is characterized by large round basaloid tumor nests with comedo-type necrosis as well as an occasional cribriform-like pattern and stromal hyalinization, resem bling a solid-type ACC. Some cases have been reported to be associated with EBV. 1606 Patients with this type of tumor have been found to have good 1- and 5-year survival com parable to patients with the nonkeratinizing type, but have similar sharply decreased 10-year survival as that observed with the keratinizing type. 1607 Aggregate grade of evidence : B (Level 4: nine studies) 2 The role of EBV in NPC NPC has long been proven to be associated with EBV. Previously, NPC had no reliable tumor markers in clini

cal practice. Since 1970, various anti-EBV antibodies have been evaluated as diagnostic and prognostic markers of NPC. 1608–1611 After more than 30 years of studies, serologi cal antibody tests have been shown to be of little help in the clinical management of NPC and have rarely been inves tigated in recent years. The major reason for this may be that the antibody titer remains persistently high in most patients in remission after treatment 1612,1613 and has no significant impact on survival. 1614 In addition, there is no reliable cutoff value for differentiating between recurrence and remission. With recent advances in molecular biology, PCR-based techniques make it possible to detect trace amounts of biomolecules in a wide array of biological samples. In 1999, Lo et al. first successfully developed real-time quan titative PCR to quantify circulating EBV DNA in patients with NPC. 1615 Their series of studies 1615–1621 and another comprehensive study 1622 prompted routine use in the man agement of these patients. Since then, many subsequent reports have shown higher sensitivity and specificity for detecting cell-free EBV DNA in the plasma and serum of NPC patients. In addition, the quantification of circulating EBV DNA has been demonstrated to be highly corre lated with tumor burden and patient survival, differential diagnosis of recurrence/remission, and early prediction of treatment response. 1618,1623 EBV DNA serum testing is now accepted as a use ful tool in real-world practice. Table XXV.2 lists the application values of EBV DNA serum tests in clini cal practice. First, the presence of circulating EBV DNA can serve as a diagnostic marker for the detection of NPC in healthy controls and patients without NPC. Five meta-analysis studies showed a pooled sensitivity of 0.69–0.89, specificity of 0.84–0.96, positive likelihood of 4.81–14.66, and a negative likelihood of 0.12–0.25. 1624–1628 Second, serum EBV DNA can provide useful information to guide NPC treatment, including aiding in treatment outcome prediction and risk grouping, 1629–1633 supple menting the TNM staging system, 1634–1640 determining adjuvant therapy for post-RT patients with residually detectable lab values, 1641,1642 and early prediction of treat ment response in recurrent/metastatic 1643–1645 and locally advanced patients. 1645 Finally, EBV DNA can replace various anti-EBV antibodies as a screening marker for NPC in the general population. A large prospective study conducted in Hong Kong enrolled 20,174 asymptomatic persons using the serum EBV DNA test for NPC screen ing between July 2013 and February 2016. 1646 Thirty-four new cases of NPC were diagnosed among 309 partici pants (1.5%) who were persistently positive for circulating EBV DNA. These patients with NPC had a significantly higher proportion in the early stage than those in the his torical cohort (71% vs. 20%, p < 0.001) and superior PFS