NCCN Guidelines Insights: Head and Neck Cancers, Version 1.2018.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the head and neck (H&N), and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding the increase in human papillomavirus-associated oropharyngeal cancer and the availability of immunotherapy agents for treatment of patients with recurrent or metastatic H&N cancer.

A prognostic scoring system for locoregional control in nasopharyngeal carcinoma following conformal radiotherapy

AGGRESSIVE CARCINOMA EX-MIXED TUMOR: CASE REPORT

The microbiology of ethmoid and maxillary sinuses in patients with chronic sinusitis

Objective: The main objective of this study is to study head and neck cancer among Yemenis to establish a reliable database, determine the common histopathological type, common site, and defined the relation of the type and size to the age and gender of patients. Material and Methods: This study design was a prospective descriptive hospital-based study, carried out atAl-Komori–Teaching Hospital in the Sana’aRepublic of Yemen (major referral center of oncology). The material of this study consisted of 633 patients with head and neck cancer referred for management at the department of oral and maxillofacial surgery and to the consultant unit of the head and neck surgery and who were diagnosed clinically, radiographically and histopathology as having head and neck cancer. A patient who presented with recurrent cancer, or who had previous treatment with radiation or chemotherapy were excluded. Datawerecollectedfrompatienthistory (using a questionnaire sheet), clinical examination of patients, radiograph examination and from the histopathology results of the biopsies. Data have entered the computer and analysis using Statistical Package for Social Science (SPSS) (version 24). Quantitative data were summarized using simple descriptive statistics of mean and standard deviation (SD). A Chi-square test was used to assess the association and the level of significance among categorical variables. A P-value of less than 0.05 is considered statistically significant. Results: During the study period, 633 cases of head and neck cancers were seen, 355 cases (55.9%) were males and 279 cases (44.1%) were females, male to female ratio was 1.3:1. The patient age was ranged from 3 to 95 years with a mean age of 59.05 years ±std=15.9 years. The majority of cases (94.9%) were carcinomas, followed by lymphoma 2.5% and sarcoma 1.4%. The less common types were malignant melanoma and malignant fibrous histiocytoma, accounting 0.9 %and 0.2% respectively. Squamous cell carcinoma was the most common type of head and neck carcinoma, accounting (72.9%). Of lymphoma, all cases were Burkitt's lymphoma. Osteosarcoma was the most common type of sarcoma, accounting 55.5% of all sarcoma. The most common affected sites were oral cavity and facial skin, accounting 66.0% and 21.8% respectively. The less affected sites were salivary glands, jawbones and maxillary sinus, accounting 4.4%, 4.1% and 3.6% respectively. Of the oral cavity, the gingiva was the most affected site, followed by the tongue, accounting (33.3%) and (31.0%). Naso-labial region, infra-orbital region were the most common affected sites of the facial skin, accounting (23.9%) and (18.8%) respectively. Basal cell carcinoma and squamous cell carcinoma were the most common types of accounting, 75.4% and 23.2% respectively. Conclusion: The present study demonstrated the distribution of the head and neck cancers among Yemenis, determine the common type, common site and the relationship between the type and site to the age and gender of patients. In Yemen as in all countries, head and neck cancers were remained the disease of elderly male patients with a male to female ratio of 1.3:1. Patient age was running from 3 to 95 years. The majority of patients (90.9 %) were over the age of 40 years. Carcinoma was the commonest type, followed by lymphoma and sarcoma, accounting, 94.9%, 2.5% and 1.4% respectively. The oral cavity (66.0%) was the most affected site, followed by the facial skin accounting 21.8 %. The less affected sites were salivary glands, jawbones and maxillary sinus, accounting 4.4%, 4.1% and 3.6%respectively.

Differences in urinary leukotriene E4 levels and distribution of eosinophils between chronic rhinosinusitis patients with aspirin-intolerant and -tolerant asthma.

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses. Occult primary cancer, salivary gland cancer, and mucosal melanoma (MM) are also addressed. The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding management of HPV-positive oropharynx cancer and ongoing research in this area.

Salivary function provides host protection, assists in the initiation of food and fluid intake, and enables communication through speech. Without adequate salivary output, oral and pharyngeal health declines along with a person’s quality of life. The complaint of a dry mouth (xerostomia) and the objective finding of salivary dysfunction are common occurrences in older individuals, producing transient and permanent oral and systemic problems. Salivary dysfunction, however, is not a normal consequence of growing older, and is due to systemic diseases, medications, and head and neck radiotherapy. Diagnosis of salivary disorders begins with a careful medical history, head, and neck examination. While complaints of xerostomia may be indicative of a salivary gland disorder, salivary diseases can present without symptoms. Therefore, routine examination of salivary function must be part of any head, neck, and oral examination. Therapies are designed to prevent the development of oral and pharyngeal sequelae of salivary hypofunction. Current xerostomia-based treatments include replacement therapies and gustatory, masticatory, and pharmacological stimulants. Healthcare professionals can play a vital role in identifying patients at risk for developing salivary dysfunction, and should provide appropriate preventative and interventive techniques that will help preserve a person’s health, function, and quality of life.

Computed tomography imaging of the maxillary and ethmoid sinuses in children with short-duration purulent rhinorrhea

Radiotherapy (RT) has an unassailable track record as the backbone of treatment in nasopharyngeal carcinoma (NPC). Several reasons explain its dominance. Likewise to human papilloma virus-associated oropharyngeal squamous cell carcinoma, Epstein-Barr virus (EBV)-associated NPC is exquisitely sensitive to RT. Thus, huge leaps with technological advances in RT delivery over the past decades have led to substantial improvements in tumor control, while reducing debilitating late RT-induced complications [1, 2]. Innovations in this space continue to drive the enhancement of the therapeutic ratio of RT, with the goal of enhancing the quality of life (QoL) among long-term survivors [3]. Therefore, there has not been any compelling reason to disrupt this time-honored convention of employing RT as the standard of care in NPC. Currently, intensity-modulated RT (IMRT) is the standard RT modality for NPC and other head and neck cancers. High-quality level 1 evidence confirms its superiority to historical 2- and 3-dimensional techniques, particularly for the reduction of severe late RT adverse events such as xerostomia, hearing impairment, brain necrosis, and cranial nerve palsies [4]. However, patients continue to suffer from a high incidence of severe acute toxicities to RT. Interestingly, in a prospective observational study of reduced volume and dose IMRT in 103 NPC patients, all of whom had early-stage NPC (T1-2 and N0-1), the study investigators still observed grade 2 or worse acute xerostomia, mucositis, and dermatitis in about 40%-50% of patients [5]. Such data highlights the perennial limitations of RT and emphasizes the need for close supportive care to assist patients through the acute phase of RT. Additionally, apart from affecting the tolerability of RT, acute toxicities such as severe mucositis and xerostomia could harbor long-term consequences on QoL among the survivors [4]. These non-minuscule issues support the relentless pursuit of innovative strategies to de-intensify treatment, especially in patients with early-stage, curable NPC. In this regard, advances in RT modalities such as proton beam therapy and FLASH-RT (delivery of ultra-high dose rate of > 40 Gy/s) are being investigated as potential means to mitigate RT toxicities [6, 7]. To address this clinical unmet need, Chen and colleagues [8] presented the preliminary results of their prospective single-arm observational study on the outcomes following endoscopic nasopharyngectomy (ENPG) in a cohort of T1 NPC patients. The underlying rationale of this study was simple and intuitive: to explore the possibility of “replacing” IMRT with ENPG in early-stage NPC patients, so as to avoid potential acute and late toxicities due to RT, without compromising the excellent survival outcomes of these individuals. Patient selection was stringent, as judged by the enrolment criteria: (1) biopsy-confirmed T1 NPC and tumor size of ≤1.5cm as defined by magnetic resonance imaging (MRI); (2) no evidence of retropharyngeal and cervical lymph node metastasis (note that all patients were staged by MRI and/or 18F-fluorodeoxyglucose positron emission tomography [18F-FDG-PET]); and (3) ≥ 0.5 cm margin from the internal carotid artery for feasibility of ENPG. Briefly, the surgical procedure involved complete excision of the NP mucosa, with the surgical anatomical boundaries defined as such: the mucoperiosteum was dissected superiorly to posteriorly from the floor of sphenoid sinus to the clivus; the anterior margin was defined by the posterior nasal cavity; and the bilateral eustachian cartilage from the pharyngeal recess under the mucous membrane and foramen lacerum and the soft palate constitute the lateral and inferior margins, respectively. Finally, the nasal septum and floor mucosa were transposed to cover the surgical defect. Using this surgical technique, the median duration of ENPG was 92.5 min (range: 60-135 min), and the median quantity of blood loss was 20 mL (range: 10-100 mL). Recovery was quick, with flap re-epithelization occurring within 2-4 weeks post-EPNG. No severe EPNG-related complications or death was observed; information on hospital stay duration was not reported. Crucially, the authors did not observe any tumor recurrence and all patients remained alive at the time of analysis. Notably, while the reported median follow-up was 59.0 months, it must be cautioned that only half of the study cohort was monitored for longer than 5 years, and in fact, three patients had follow-up duration of less than 2 years (this can be inferred from the reported numbers at risk indicated in the Kaplan-Meier survival curves). Although the authors included an IMRT-treated cohort for comparison, one would be circumspect about such an analysis given the feasibility of “perfect matching” of clinical and tumor characteristics. Expectedly, none of the patients experienced acute and delayed toxicities of xerostomia and neuropathies, and all patients reported minimal deterioration in QoL post-EPNG. Finally, the authors presented a preliminary cost-effective analysis in favor of EPNG over IMRT in the treatment of these low-risk NPC patients. These are certainly impressive results. However, they have to be weighed against several caveats. Foremost, as with any surgical technique, there is an acute learning phase that will affect procedural quality, and this metric certainly corresponded to tumor control and toxicity outcomes [9, 10]. Therefore, while excellent results were achieved by the team at Sun Yat-sen University Cancer Centre (Guangzhou, Guangdong, China), it remains to be seen if similar quality can be attainable by lower volume centers [11]. Next, it must be emphasized that the present study cohort has been carefully selected. In addition to recruiting only small T1 tumors, patients were meticulously screened for occult retropharyngeal and cervical nodal metastases using both MRI and PET imaging, given the omission of nodal dissection/RT. Future prospective studies will inform us if high-resolution imaging alone is sufficient for the screening of suitability for EPNG or if additional biomarkers like EBV DNA are needed. Third, it is notable that ENPG in this study entailed the removal of the entire NP mucosa. This extent of resection contradicts the principle of target contouring in head and neck cancer, which ascribes to the 5+5 mm rule for the definition of high-risk and low-risk subclinical disease [12]. Fourth and most importantly, the authors had not actually outlined a detailed protocol in the instance when adjuvant/salvage treatment is required for margin-positive disease or local/nodal recurrence. These unresolved issues require consensus among the NPC expert community, ideally prior to the design and conduct of larger-scale clinical trials of ENPG in T1-2 NPC patients. To conclude, Liu and colleagues ought to be applauded for challenging the status quo in the treatment of NPC. Evidently, patients still suffer from RT-induced toxicities despite the phenomenal success of IMRT, and EPNG represents a disruptive innovation in this space. It is unlikely that these impressive results of zero recurrence will be replicated in future trials with larger cohorts, and thus begs the pertinent question of the measurable impact of disease relapse on a patient's QoL. Ultimately, how does the primary physician decide on the appropriate treatment recommendation for such a highly curable disease? The truth probably lies somewhere in the individual patient's tolerance for the cost of treatment toxicities versus the uncertainty of tumor recurrence. Meanwhile, it remains our responsibility to continue pushing the frontiers of innovation in the treatment of NPC. The authors thank members of the Soo's and Chua's lab for their critical comments. Study conception: Melvin L.K. Chua. Collection and assembly of data: Melvin L.K. Chua, Luo Huang. Administrative and funding support: Melvin L.K. Chua. Manuscript writing and approval of the final manuscript: All authors. MC is supported by the National Medical Research Council Singapore Clinician-Scientist Award - #NMRC/CSA/0027/2018 and the Duke-NUS Oncology Academic Program Proton Research Program. Not applicable Not applicable Not applicable The author declares no competing interests; Melvin L.K. Chua reports grants and personal fees from Ferring Singapore, personal fees from Janssen, personal fees from Astellas, personal fees from Merck, personal fees from Illumina, personal fees and non-financial support from Varian, non-financial support from PVMed Inc., non-financial support from Medlever Inc, non-financial support from Decipher Biosciences, outside the submitted work.

Objective To evaluate the clinical efficacy and safety of the hypofractionated three-dimensional conformal radiotherapy in the treatment of recurrent nasopharyngeal carcinoma. Methods Clinical data of 153 patients with recurrent nasopharyngeal carcinoma admitted to our hospital from 2008 to 2013 undergoing hypofractionated three-dimensional conformal radiotherapy (3 Gy for each time, 5 times a week, a total dose of 51-60 Gy, 17-20 times/4 weeks) were retrospectively analyzed. The short-and long-term radiation-induced injury, Karnofsky performance score (KPS), short-and long-term clinical efficacy were evaluated. Results For the short-term radiation-induced injury, the incidence of oral mucosa and fatigue significantly differed before and after treatment (both P<0.05). Regarding the long-term radiation-induced injury, the incidence of dry mouth (95.4%) and deafness (51.0%), difficulty in opening mouth (79.1%), maxillofacial fibrosis (33.3%) and radiation-induced encephalopathy (15.0%) significantly differed before and following treatment (all P<0.05). The actual long-term radiation-induced injury included dry mouth (91.5%), deafness (50.9%), difficulty in opening mouth (76.5%), maxillofacial fibrosis (32.0%) and radiation-induced encephalopathy (14.4%). The number of patients with changes in the KPS scores significantly differed between the end of treatment and 3 months after treatment (P<0.05). The local control rates were 29.4%, 68.6%, 79.1%, 83.7% and 86.9% at 1-, 3-, 6-, 9-and 12-month after corresponding treatment, respectively. The local control rate significantly differed between 1 and 3 months, and between 3 and 6 months after treatment (both P<0.05). The 1-, 2-, 3-, 4-and 5-year survival rates were calculated as 96.1%, 80.4%, 68.5%, 57.9% and 51.1%, respectively. Conclusions Hypofractionated three-dimensional conformal radiotherapy is an efficacious and safe treatment of recurrent nasopharyngeal nasopharyngeal carcinoma, which yields relatively high short-and long-term clinical efficacy, high local control rate and well tolerance by the patients. Key words: Nasopharyngeal neoplasm recurrence/three-dimensional conformal radiotherapy; Radiotherapy, hypofractionated; Radiation-induced injury; Treatment outcome

Aim To analyse the target of Rhizoma Curcumae in nasopharyngeal carcinoma by using network pharmacological techniques and to explore the associated molecular mechanism. Methods The targets of nasopharyngeal carcinoma were retrieved from the GeneCards database. At the same time, the drug therapeutic targets of Rhizoma Curcumae were obtained from the TCMSP and SymMap databases. The data were imported into the STRING database and Cytoscape 3.7.1 to construct a network of “Chinese medicine component-target-disease” interactions; then, the intersection was screened as the core Rhizoma Curcumae antinasopharyngeal cancer targets. Through GO target function and KEGG pathway enrichment analyses of the core targets, we predicted the biological processes and key signalling pathways involved in the Rhizoma Curcumae treatment of nasopharyngeal carcinoma. Results Twenty-five core targets of Rhizoma Curcumae in nasopharyngeal carcinoma were mined: TP53, BCL2 ICAM1 RXRA, TLR3 and TLR9, TNF, PTGS2, IL-6, CTSD, MMP2, MMP9, MMP14, TIMP2, ABCC1, ABCB1, ABCG2, and so on. The results of visual analysis showed that the Rhizoma Curcumae treatment of nasopharyngeal carcinoma mainly involves leukocyte adhesion to vascular endothelial cells, positive regulation of NF-κB import into the nucleus, regulation of the reactive oxygen species biosynthetic and metabolic process, regulation of the chemokine biosynthetic and metabolic process, various cancer-related signalling pathways, and a variety of cytokine signal transduction pathways, such as the NF-κB, TLR, IL-17, and TNF signalling pathways. Conclusion The core targets predicted by our research can be used as molecular markers for the treatment and prediction of nasopharyngeal carcinoma. The mechanism of Rhizoma Curcumae treatment in NPC may be related to immune regulatory pathways, the inhibition of cancer cell proliferation, metastasis, and angiogenesis, as well as the regulation of tumour microenvironment. Combined with the prediction of its associated mechanism of action, the core targets can provide targeted reference value for subsequent drug development related to Curcuma.

Tumors of the salivary glands are rare and mainly affect young and middle-aged adults with an equal distribution between the genders 1. The majority of these tumors are of epithelial origin, but while benign tumors are the most common, the carcinomas pose a number of challenges and for some subtypes, namely adenoid cystic carcinoma (ACC), the prognosis may be grave 2. No other organ in the human organism gives rise to such a large spectrum of neoplasia, and the number of different entities has increased dramatically, from 7 carcinoma types in 1972 to 22 in 2017 3, 4. A quite unique feature for this group of tumors is the identification of a network of genes involved in the formation of a variety of fusion oncogenes, each being characteristic of particular tumor types 5. Although believed to be without prognostic significance, these fusion oncogenes have become valuable diagnostic markers and are instrumental in delineating the biology of salivary gland tumors 6. In 1974, Conley and Dingman recapitulate their experience of managing ACC with the following statement: 'Of all tumors in the head and neck region, the adenoid cystic carcinoma is one of the most biologically deceptive and frustrating in management' 7. ACC represents approximately 1% of head and neck malignancies and, in contrast to the rest of the world, it is the most frequent type of salivary gland carcinoma in Denmark 1. It is notorious for its unpredictable and often relentlessly progressive clinical course 2, 8. Although clinically slow growing, ACC is locally invasive and has a propensity for early invasion of peripheral nerves and blood vessels, resulting in a high incidence of local recurrence and distant metastases mainly to the lung, bone, and liver 2, 9. Interestingly, intraneural and not perineural invasion has recently been established to be associated with reduced overall and recurrence-free survival 10. Also, regional recurrence, mainly to the cervical lymph nodes, are highly dependent on the presence of high-grade transformation as well as on the T-site 11, 14, 13, 12. Further complicating the management of ACC patients is the continuing presentation of recurrences many years after primary treatment, causing ACC to constitute a disproportionate disease burden despite its low incidence 2. One reason for this is the shortage of prognostic factors beyond conventional cancer staging and classical histopathological parameters such as close or involved surgical margins and a special histological subset with a predominantly solid growth pattern 2. Metastatic disease is one of the main causes of ACC-related mortality as metastases are often surgically unresectable, are relatively resistant to radiotherapy, and lack effective chemotherapeutic regimens 15-17. Once metastatic disease is diagnosed, median survival is about 2 years but, especially for pulmonary metastases, patients can be asymptomatic for several years 2, 15. If inoperable, normal lung parenchyma is replaced by confluent metastatic masses and this evolution is inevitably fatal. Despite that metastatic disease is one of the main causes of ACC-related mortality, previous research on the biology of ACC has focused on exploring the biology of primary lesions 18-21. Adenoid cystic carcinoma is not a disease that is exclusive to the salivary gland, but is also found in the lacrimal gland and breast, as well as more rare locations including sweat gland, lung, and Bartholin's gland 22-26. Regardless of the site, ACC is characterized by recurrent fusion oncogenes and relatively few but diverse mutations 5, 18, 21, 24, 27-32. Lacrimal gland ACC shares the clinical characteristics of salivary gland ACC, with pronounced infiltrative growth and frequent recurrences in local as well as distant sites 29, 33. In contrast, ACC in the breast is a rare, indolent type of breast cancer, with recurrences and distant spread being vanishingly rare events 34. Also, breast ACC has phenotypic features in common with a subset of breast carcinomas with a very poor prognosis 28. This paradox in the clinical behavior of ACC depending on its origin in the salivary gland or breast has earned ACC the all but flattering title as the Dr. Jekyll and Mr. Hyde of exocrine gland carcinomas 35. But what makes this particular puzzling, besides the identical morphology of ACC in the breast and salivary glands, is that the genetic background, including mutations, copy-number alterations, and gene fusions, is identical 18-21, 32. In this series of studies, we compare the phenotypes, genetics, and microRNA (miRNA) expression profiles of ACC in the salivary gland, lacrimal gland, and breast in order to explore the differences between these seemingly identical tumors with markedly differing prognoses (I). Next, we sought to investigate the genetic and miRNA expressional evolution of salivary gland ACC by comparing paired samples of primary and metastatic lesions (II). Lastly, we performed global miRNA expressional profiling of a large cohort of salivary gland ACC with long-term follow-up to investigate the prognostic value of miRNA (III). In early fetal life, the major salivary glands arise from ectodermal proliferations invading the underlying mesenchyme (Fig. 1) 36. Through a carefully regulated process, these initially solid proliferations develop to form tubuloacinar units consisting of acinar cells, a segmental ductal tree, and myoepithelial cells (Fig. 1). Distinct tumor types arise from each of these compartments, with ACC arising from the intercalated duct segment 37. The salivary glands are divided into (i) major salivary glands, namely the paired parotid-, submandibular-, and sublingual glands, and (ii) minor salivary glands located throughout the mucosal membrane of the upper aerodigestive tract (Fig. 2). The acini form the secretory unit and are composed of inner luminal acinar cells and an outer myoepithelial layer, with the composition of the secretion depending on the site of the acinus producing it. The parotid gland contains almost exclusively serous acinar cells, whereas the palatal minor salivary glands are predominantly of mucous type. Saliva produced by the major and intraoral minor salivary glands facilitates mastication and swallowing and provides lubrication and protection of the mucous membranes and teeth. In addition, saliva contains amylase that initiates digestion of starch, but saliva also plays an essential role in preventing dental caries and infection by direct cleansing of foreign bodies and by an anti-bacterial activity mediated through multiple factors (e.g., IgA and histatins) 38. In contrast, the secretion of the minor salivary glands lining the sinonasal tract is devoid of amylase but mainly functions in lubrication and innate immune defense. Carcinomas of the salivary glands are rare, with an incidence of 1.1/100 000/year in Denmark which has been stable since at least 1990 1. Salivary gland malignancies constitute 0.3% of human cancers and 6% of head and neck cancers in the United States and are predominantly of epithelial origin, with the remaining tumors represented by lymphomas, sarcomas, and metastases mainly to parotid lymph nodes from cutaneous squamous cell carcinomas 39-43. Epithelial salivary gland tumors comprise one of the most diverse groups of tumors in the human organism, with 11 benign and 22 malignant entities listed in the current WHO classification 4. The distribution between benign and malignant tumors varies tremendously according to the gland of origin, with an inverse relationship between the proportion of malignant tumors and the size of the major salivary gland of origin. Accordingly, 17% of parotid gland tumors are malignant, increasing to 38% of submandibular gland tumors and 96% of sublingual gland tumors 44, 45. With the notable exception of the palate, minor salivary gland tumors are malignant in the majority of cases 46, 47. In all surveys on the distribution of different histological types of salivary gland carcinomas, mucoepidermoid carcinoma has been identified as the most frequent 48. However, Denmark is an exception to this, as a nationwide study on Danish salivary gland carcinomas convincingly demonstrated a relatively high incidence of 11 salivary gland carcinomas/1,000,000 Danes/year as well as ACC being the by far the most frequent, constituting more than 25% of all salivary gland carcinomas 1. The reason for this uniquely high proportion of ACC among salivary gland carcinomas in Danes is unknown. Although it is well-known that the Inuit in Greenland (part of the Danish Kingdom) contribute with a high incidence of EBV-related lymphoepithelial carcinoma in salivary glands, these relatively few cases cannot itself explain the higher incidence of salivary gland carcinomas in Danes 1, 49, 50). Epithelial salivary gland tumors are rare in children and adolescents and are, as in adults, predominantly benign 51. In early adulthood, the incidence of benign tumors increases, especially in females, but carcinomas are equally distributed between the genders in Denmark, whereas foreign studies have found a higher incidence of salivary gland carcinomas in males 1, 52, 53. With the exceptions of a markedly increased risk of extranodal marginal zone lymphomas in patients with Sjögren syndrome and salivary gland carcinoma in patients exposed to ionizing radiation, risk factors for and etiology of salivary gland carcinogenesis have not been identified, including in ACC 54, 55. As with all rare diseases, identifying disease-causing factors is complicated due to several factors: First, their rarity makes the accumulation of large patient populations difficult; second, there are no known stages of premalignancy; and third, there has only been identified very few cases of familial accumulation of salivary gland carcinoma that have been identified and no genetic disposition was found in the single case of ACC that underwent genetic testing 56-59. Notable exceptions to the lack of hereditability in salivary gland tumors are the rare hereditary syndromes Muir Torre syndrome (OMIM: 158320), with an increased risk of sebaceous carcinoma, Brooke-Spiegler syndrome (OMIM: 605041), with an increased risk of basal cell adenoma, and Birt–Hogg–Dubé syndrome (OMIM:135150), with an increased risk of oncocytomas 60-62. ACC is considered a sporadic disease. The symptoms caused by salivary gland tumors are very similar across the different histological subtypes and vary according to the anatomical site (Figs 3 and 4). Usually, they are slow growing and fixated to the surrounding tissues. More than 30% of ACCs arise in the parotid gland, and the presenting features for this location are an often painless lump with occasional affection of facial muscle function due to facial nerve invasion 1. The intraoral minor salivary glands constitute the second most frequent site, with more than 25% of ACCs, and this location, along with ACCs in the sinonasal tract and sublingual gland, more frequently cause pain as the presenting symptom due to the propensity of ACC for neural invasion (Fig. 3) 1, 45, 63. Other symptoms of sinonasal ACC include obstructive symptoms, epistaxis, and/or auditory symptoms 64. Ulceration of overlaying mucosa can be seen in oral sites 45, 63. Metastases to bones often cause pain, whereas metachronous pulmonary metastases are often an incidental finding due to chest imaging performed for unrelated reasons. As with other lesions located to the major salivary glands, the preoperative diagnosis is based on the clinical history, imaging, and fine-needle aspiration (FNA) (Fig. 3). FNA has an excellent specificity and good sensitivity in separating benign from malignant lesions in both the major and oral minor salivary glands 65. However, ACC shows occasional cytological overlap with pleomorphic adenoma, basal cell adenocarcinoma, and polymorphous adenocarcinoma 66. For sinonasal lesions, the diagnosis is made by incisional biopsy. The final diagnosis is made by histopathological evaluation of the resected lesion. For diagnostic purposes and for surgical planning, preoperative imaging includes contrast-enhanced computerized tomography (CT) for the identification of bone invasion and/or magnetic resonance imaging (MRI) in assessing soft-tissue extension and the extent of perineural invasion (Fig. 4) 67, 68. The use of fluorodeoxyglucose positron emission tomography (18F-FDG PET) in combination with CT can be employed for the initial staging, and although not all ACCs are PET-positive, the physiological high uptake of the major salivary glands can obscure assessment of the primary lesions (Fig. 4) 69. Of note, caution must be taken in using 18F-FDG PET-CT to exclude distant metastases, especially if the primary tumor does not show enhanced 18F-FDG uptake, which is not uncommon in ACC 69. In a seminal paper published by Robin and Laboulbene in 1853, a tumor of the salivary glands with 'cylindrical' histology and a pronounced tendency to grow along nerves was described for the first time 70. In 1859, Billroth designated this entity as 'cylindroma', a term since modified to adenoid cystic carcinoma by Spies in 1930 71, 72. Regardless of whether it originates in the salivary gland, lacrimal gland, or breast, ACC is a biphasic tumor consisting of relatively uniform ductal and modified myoepithelial cells (Fig. 5). The ductal component is the minor of the two, and the small true lumens formed by these are easily overlooked, as the majority of luminae in ACC are pseudoluminae formed by the dominant myoepithelial component (Fig. 5). The myoepithelial cells lining pseudoluminae produce excess amounts of basophilic, eosinophilic, and occasionally hyalinized extracellular material, often both types varying within a tumor (Fig. 5). The name cylindroma recapitulates the characteristic and most frequent cribriform ('Swiss cheese') growth pattern of ACC, one of the three architectural patterns seen in this malignancy. Tubular and solid patterns are usually seen intermingled with cribriform areas, but often in varying proportions within a single tumor. Especially tubular and cribriform areas usually occur together in the same specimen, and also, in the least frequent of the three, the solid type, minor foci of tubular or cribriform growth are usually present (Fig. 5). Solid ACC, defined as solid growth in >30% of the tumor, is known to have a particularly aggressive clinical course 73. The value of distinguishing tubular and cribriform types is debated, and the WHO defines only the solid type as prognostically relevant, thereby also recognizing the substantial subjectivity in assessing proportions of tubular and cribriform areas in a specimen 74, 75. Invasion of peripheral nerves is a frequent but not specific or universally found hallmark of ACC (Fig. 3). This particular feature enables ACC to invade a significantly larger area than the clinically apparent lesion, with only intraneural invasion being associated with overall and recurrence-free survival (Fig. 3) 10. The immunohistochemical profile of ACC is identical irrespective of anatomical location, with ductal cells being positive for CD117 and the myoepithelial component being positive for p63 and smooth-muscle actin. The proliferation marker ki-67 is positive in a variable proportion of tumor cells and is highest in ACC with solid histology 76. Steroid hormone receptors (estrogen receptor [ER], progesterone receptor [PR], androgen receptor [AR]) and human epidermal growth factor receptor 2 [HER2] are negative, whereas cytokeratin 5/6 (CK5/6) and/or epidermal growth factor receptor [EGFR] have been reported in varying proportions 77-80. Despite its indolent nature, breast ACC belongs to the otherwise aggressive basal-like (estrogen receptor and human epidermal growth factor receptor 2 [HER2] negative, CK5/6 and/or epidermal growth factor receptor [EGFR] positive) and triple-negative (negative for estrogen receptor, progesterone receptor, and HER2) subtypes of breast cancer 35. The phenotypic classification of breast carcinoma (i.e., luminal, basal-like, and HER2 phenotypes) carries significant prognostic and therapeutic implications and has been shown to apply to at least a subset of salivary and lacrimal gland carcinomas 35, 81-83. Interestingly, triple-negative breast carcinoma is generally regarded as a clinically aggressive group of malignancies, in sharp contrast to the case for breast ACC 85, 84. The large number of different types of salivary gland carcinomas are broadly separated into two types: high-risk and low-risk types 86. ACCs, solid as well as tubulocribriform types, are high-grade malignancies, and consequently, the treatment of choice is radical surgical resection and almost always followed by adjuvant radiotherapy (Fig. 4) 8, 87. The surgical approach depends on tumor location and stage at diagnosis, with the objective of tumor-free margins being a compromise between functional outcome and therapeutic benefit 2, 88. The highly infiltrative nature of ACC makes this a complex task to preserve vital structures, speech, and masticatory function, as well as an acceptable cosmetic outcome. There is universal agreement about performing therapeutic neck dissection in the case of either clinically or radiologically detectable involvement of cervical lymph nodes. However, the reported low incidence of occult lymph node metastases has made management of the neck in ACC patients without detectable nodal involvement a matter of controversy 8. While high-grade transformation makes neck dissection mandatory due to a high rate of nodal involvement, recent international collaborations have identified occult lymph node metastases in 17% of clinically node-negative patients, with the highest frequencies found in ACC of the oral cavity (22%) and the lowest in the major salivary glands (12%) 11, 89. Importantly, nodal stage was shown to be an independent prognostic factor for overall and disease-specific survival 89. In head and neck squamous cell carcinoma, the rationale for elective neck dissection in clinically node-negative patients is justified in case of a > 15% risk of occult lymph node metastases 90, 91. Hence, the recommendation of selective neck dissection of levels I–III in clinically node-negative patients, especially if the tumor is located to the oral cavity, now seems justified for therapeutic and staging purposes 2, 92, 89. The effect of radiotherapy in the management of ACC has been a matter of debate. No direct survival benefit is seen in patients receiving adjuvant radiotherapy, but it does improve locoregional control 2, 93. As no data from randomized clinical trials are available, Danish guidelines currently includes adjuvant radiotherapy to all patients with salivary gland ACC 87. Similarly, evidence for the use of chemotherapy, conventional cytotoxic agents, and targeted therapies is heavily lacking. One of the main in these data is the rarity of the the of clinical trials no evidence for treatment, and one must that of the in A approach has shown in other types of salivary gland carcinomas, and recent of to the in patients with ACC to this approach 5, has a in the management of salivary gland ACC to be but this approach has in lacrimal gland ACC asymptomatic patients with disease be the of symptoms and this treatment is to be for patients with symptoms or in the 15. or of the disease may be ACC was first as an its malignant was not due to the course but was regarded as a of the benign pleomorphic due to its to This with the by and in which reported a rate of and distant metastases in of all ACC patients The term for ACC is earned by its relatively good but with recurrences and at least years following primary treatment 93. In a of salivary gland ACCs in Denmark, the and recurrence-free survival was and 2. Similarly, the and overall survival was and 2. factors for salivary gland carcinomas include close or involved surgical and high histological 1. is found between these parameters and shown to have prognostic value in ACC, which also include high close or involved surgical solid histology (i.e., high histological and invasion 2, 10. Importantly, while perineural invasion has been associated with involved surgical it is not associated with prognosis 2, 10. The factors associated with prognosis are not since these features are universally characteristics across human cancer types But while these features are of prognostic across different types of salivary gland carcinoma as well as within there are in based on these features in close or involved margins are found in approximately of patients, invasion is found only in only and a substantial proportion of patients with disease experience and/or distant recurrence 2, Also, the majority of patients metastatic spread are initially with surgical margins are only in of patients, and only have ACC 2, 15. more to a larger proportion of patients are highly The of cancer as a of genetic in a single cell was first by in a that has since been The initially described by in is a term to the of genetic in a including the of genetic from to or from to the early cancer research has identified a of genes that are frequently in cancer, resulting in (i) or (i.e., or (ii) or (i.e., tumor of a growth by mutations, in cancer of these types of genes are and include and which are involved in several cancer In contrast, tumor genes the normal of function, and of these types of genes carries the same effect as of that include the and known to be involved in a variety of different cancer A third, more recently of genes is the of which causes an increased rate of mutations throughout the increasing the risk of mutations in oncogenes and tumor and thereby resulting in cancer formation In the of salivary gland ACC, for mutations has identified only few and diverse mutations in primary tumors as well as the few metastatic lesions 18-21, Regardless of which type of gene is the malignant is the of a variety of by and in as the of cancer being to include cancer is the characteristic namely (i) (ii) growth invasion and of and immune mutations, there are two types of that cause and include and tumor include and and all three of these can in the of fusion genes (Fig. genes their as a of the of two genes by one of two In gene and fusion occur in the of one or both of the involved a fusion gene (Fig. In the gene occur the of both resulting in of the which in increased expression of a normal (Fig. The first fusion described is the arising with formation of the in This fusion gene is formed by the of both the and which is the direct cause of the disease due to the formation of a This the identification of a specific of the fusion which has the prognosis for this patient group types of recurrent fusion genes have been identified across a spectrum of different tumor types, a large proportion of which are whereas are more involved in malignancies fusion genes to be predominantly found in malignancies, but they have since been shown to be frequent in and carcinomas Hence, although gene are not for specific they have in tumor and as for the of targeted therapies 5. In salivary gland carcinomas, the most well-known with direct therapeutic is the of HER2 in salivary duct carcinoma, in which treatment has shown some effect in a subset of patients However, resulting in the formation of recurrent fusion genes have been shown to occur in a larger number of different types of salivary gland carcinomas 5, the prognostic value has been for some of especially the in mucoepidermoid carcinoma, but namely the in secretory carcinoma and in a subset of salivary duct carcinoma, are with good reported In ACC, the most frequent fusion gene of the of the to the of the factor which in most cases is the primary in ACC formation (Figs and to and different in both multiple have been with most the first of and from 11 of 21, very few have been described (Fig. Interestingly, a substantial proportion of ACCs without also the which is due to the of expression an fusion between the and was shown to occur in a substantial proportion of ACCs without fusion The and genes substantial in their functional and the fusion includes the first of similar to the involvement of in the fusion However, while identification of these gene are valuable diagnostic for ACC, only very few of these cases have been reported and the prognostic value is 21, no targeted therapies are for gene fusion found in plays a role in the formation of human and this has to to many in However, the of in biology was more than years and since several gene expression have been identified, including by of and gene by especially by miRNA to the involvement of these genes in cancer is that genes involved in these are frequently in human cancer In the of it is that miRNA genes are frequently located at sites and frequently involved in cancer, a

The NCCN Head and Neck Cancers guidelines address tumors arising in the lip, oral cavity, oropharynx, hypopharynx, glottic and supraglottic larynx, paranasal (ethmoid and maxillary) sinuses, nasopharynx, and salivary glands, as well as occult primary cancer. Approximately 39,250 new cases of oral cavity, pharyngeal, and laryngeal cancers will occur in 2005, which accounts for about 3% of new cancer cases in the United States. An estimated 11,090 deaths from head and neck (H&amp;N) cancers will occur in 2005. Alcohol and tobacco abuse are common etiologic factors in cancers of the oral cavity, oropharynx, hypopharynx, and larynx. Moreover, because the entire aerodigestive tract epithelium may be exposed to these carcinogens, patients with H&amp;N cancer are at risk for developing second primary neoplasms of the H&amp;N, lung, and esophagus. For the most recent version of the guidelines, please visit NCCN.org

A retrospective study was performed to evaluate the contribution of intracavitary hyperthermia in patients with nasopharyngeal carcinoma who received radiation therapy. Patients with nasopharyngeal carcinoma were treated with radiotherapy alone or with radiotherapy plus hyperthermia of the primary tumor. All patients were treated in a uniform fashion by definitive-intent radiotherapy in both groups. In the radiotherapy plus hyperthermia group, patients were treated with microwave heating hyperthermia delivered twice a week in combination with radiation. Between November 1992 to September 1994, 225 patients were recruited, with 98 patients matched to the criteria of either treatment group (49 in the radiotherapy and 49 in the radiotherapy plus hyperthermia group). Ninety-eight patients were included in the treatment response and 87 patients in the survival analysis according to the intent-to-treat principle (11 patients were lost to follow-up). Overall survival did not show a significant difference between the two groups (81 vs 86 months of median survival time, respectively, P = 0.068). However, there were significant differences not only in progression-free survival (median months, 60 vs 100, respectively, P = 0.036), but also in local progression-free survival (median months, 54 vs 111, respectively, P = 0.029) between the radiotherapy and radiotherapy plus hyperthermia groups. No statistical difference was noted in the cumulative incidence of grade 3 adverse events or late radiation morbidity during follow-up between the two study groups. The retrospective study showed that hyperthermia combined with radiation therapy can improve progression-free survival and local progression-free survival, although no increase in overall survival was observed. Thus, the inclusion of hyperthermia in the treatment of nasopharyngeal carcinoma using radiation offers no survival benefit but may help to improve the current standard of care consisting of radiation and chemotherapy.