Clinical Characteristics and Surgical Outcomes of Sinonasal Lesions Associated With Tumor-Induced Osteomalacia.

OBJECTIVE: To investigate the clinical characteristics and surgical outcomes of sinonasal tumors associated with tumor-induced osteomalacia (TIO). STUDY DESIGN: Retrospective case series. SETTING: Single tertiary center. METHODS: We studied the clinical characteristics and surgical outcomes of 43 patients (22 male, 21 female) who had lesions in the nasal cavity and paranasal sinus associated with TIO and underwent surgery between August 2006 and November 2019. RESULTS: The mean ± SD duration between the onset of symptoms and surgery was 3.9 ± 2.6 years. The most common tumor site was the ethmoid sinus (76.7%), and the skull base was involved in 12 cases. Phosphaturic mesenchymal tumors were diagnosed in 41 patients, among whom there was 1 multifocal case. Another 2 cases involved odontogenic fibroma and hemangiofibroma, respectively. Serum phosphorus normalized in 39 cases within 4.4 ± 2.3 days, and serum fibroblastic growth factor 23 normalized within 1 day; clinical symptoms, however, gradually improved within several months after the first operation. There was no significant difference in the recovery rate between endoscopic and open surgery (P = 0.639). Two patients with recurrent cases and 2 with nonremission cases recovered after a sinonasal reoperation. The patient with a multifocal case recovered after the resection of the tumors in the ethmoid sinus and mandible. The overall recovery rate was 97.7%. CONCLUSION: Most sinonasal tumors associated with TIO are located in the ethmoid sinus, and the skull base is involved in some cases. Complete excision of the tumor leads to recovery, and endoscopic surgery could achieve recovery rates similar to those of open surgery.

Efficacy of different regimens in nasal NK/T-cell lymphoma and analysis of serum inflammation and prognosis of patients.

PURPOSE: To explore the efficacy of different regimens in nasal natural killer (NK)/T-cell lymphoma (NNKTL) and their effects on the serum inflammation and prognosis of patients. METHODS: 146 NNKTL patients admitted to and treated in the Oncology Department of our hospital from January 2010 to December 2014 were randomly enrolled and divided into chemotherapy group (group A) and concurrent chemoradiotherapy group (group B). The expression levels of interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-α) before and after treatment were detected, the short-term efficacy was followed up and analyzed, and the correlation between the two was statistically analyzed. RESULTS: In group A and group B, the total short-term effective rate was 71.87% and 84.97%, the 5-year overall survival (OS) rate was 39.9% and 66.2%, and the progression-free survival (PFS) rate was 18.1% and 46.9%, respectively. Treatment regimens, clinical stage, the presence of B symptoms and lactate dehydrogenase (LDH) level were independent factors related to prognosis, and the remission rate after the first-course chemotherapy was an independent factor unrelated to prognosis. After treatment, there was no significant difference in the IL-2 level between the two groups of patients before and after treatment. The expression level of TNF-α after treatment was reduced compared with that before treatment, and the reduction was more obvious in group B. CONCLUSIONS: The short-term efficacy of concurrent chemoradiotherapy favors NNKTL, and the therapy can reduce the expression level of TNF-α.

Novel Biomarkers in Sinonasal Cancers: from Bench to Bedside.

PURPOSE OF REVIEW: Sinonasal cancers are a heterogenous group of rare cancers for which histopathological diagnosis can be very challenging and treatment options are limited for advanced disease in particular. Here, we review the candidacy of novel diagnostic and prognostic biomarkers, and therapeutic targets for sinonasal cancers. RECENT FINDINGS: Molecular multidimensional analyses of sinonasal cancers have been lagging behind other major cancers, but there are numerous publications describing the discovery of novel candidate biomarkers, e.g. the methylation classifier, originally developed for brain cancers, and gene expression panels for the prediction of response to induction chemotherapy in sinonasal undifferentiated carcinoma. The most promising biomarkers are summarized and discussed further with regard to their clinical applicability and future potential. Many of the described novel biomarkers for sinonasal cancers will eventually overcome the pitfalls associated with the frequently non-specific immunohistological tests. With comprehensive, multidimensional molecular testing of these tumours in collaborative consortia projects, our better understanding of the molecular mechanisms of sinonasal cancers and their carcinogenesis will determine the most useful diagnostic and prognostic biomarkers, allow stringent multi-institutional validation and guide trials on targeted therapies.

Attachment-oriented endoscopic surgical management for inverted papillomas in the nasal cavity and paranasal sinuses.

OBJECTIVE: The treatment of all forms of sinonasal inverted papilloma (IP) is a complete, wide, local resection. The main surgical purpose is to remove all diseased mucosa and mucoperiosteum, together with a cuff of normal-looking mucosa at the attachment site, followed by drilling and/or coagulation. Our aim is to present our experiences in endoscopic surgical management of IP by using attachment-oriented excision. METHODS: We present 20 cases of sinonasal IP. The data collected includes the histopathological diagnosis, staging, extension of the tumor, tumor attachment site, approach to surgery, serum squamous cell carcinoma antigen (SCCA) level, and recurrences. RESULTS: All patients underwent endoscopic surgery. A Caldwell-Luc operation was required in addition to the endoscopic surgery in one case. There was one case of recurrence (5%). After the additional operation, there was no recurrence. The tumor attachment sites vary, and the case of recurrence had a wide attachment site at the primary surgery. No major intra- or post-operative complications were observed. CONCLUSION: The present study shows that attachment-oriented excision for IP is useful for complete resection of IP. Surgeons should choose the surgical approach according to the location of the tumor attachment site rather than the Krouse staging system.

The clinical value of serum squamous cell carcinoma antigens 1 and 2 in head and neck squamous cell carcinoma.

OBJECTIVE: The usefulness of pretreatment measurement of SCC antigen in patients with head and neck SCC is still controversial. Our aim of this study was to evaluate the clinical usefulness of serum SCC antigen, SCCA1 and SCCA2 in the management of patients with head and neck SCC. METHODS: Serum samples for the analysis of SCCA1, SCCA2 and SCC antigen were taken from head and neck SCC patients before treatment. Serum SCC antigen was assayed with a solid phase immunoradiometric assay. The SCCA1 and SCCA2 protein level was determined by a sandwich ELISA. RESULTS: Fifty-two of 96 cases (54%) showed evaluated serum SCC antigen levels above the upper limit. The serum SCCA2 level was significantly higher in the head and neck SCC patients than in control group, whereas there were no significant differences in the serum SCCA1 level between head and neck SCC patients and control group. 72% of head and neck SCC patients demonstrated SCCA2 levels higher than 0.15, whereas 68% of the control subjects had SCCA2 levels less than 0.15. CONCLUSION: The serum SCCA2 levels were increased during the progression of cancer and might be a useful tool for the management of head and neck SCC.

Combination of serum squamous cell carcinoma antigens 1 and 2 as potential diagnostic marker for sinonasal squamous cell carcinoma and inverted papilloma.

BACKGROUND: Differentiating inverted papilloma from squamous cell carcinoma (SCC) is sometimes difficult. We evaluated the clinical usefulness of serum SCCA1 and SCCA2 in the management of patients with inverted papilloma or SCC. METHODS: Serum and tissue samples for the analysis of SCCA1, SCCA2, and SCC antigen were taken from 18 patients with sinonasal inverted papilloma and 23 cases with sinonasal SCC. The SCCA1, SCCA2, and SCC antigen levels were determined. RESULTS: The serum SCCA1 concentration was significantly higher in the inverted papilloma group than in the SCC group, whereas the serum SCCA2 level was significantly higher in the SCC group than in the inverted papilloma group. CONCLUSION: Patients with sinonasal inverted papilloma predominantly express SCCA1 protein, whereas those with SCC predominantly express SCCA2. This suggests that combined measurements of both serum SCCA1 and SCCA2 concentrations can be very useful for distinguishing sinonasal inverted papilloma from SCC.

Development of new prognostic model based on pretreatment ßLRI and LLRI for stage IE/IIE upper aerodigestive tract ENKTL, nasal type.

To identify simple non-invasive prognostic factors for extranodal natural killer/T cell lymphoma (ENKTL), we have investigated the prognostic value of pretreatment ß2-microglobin to lymphocytes ratio index (ßLRI) or lactate dehydrogenase to lymphocytes ratio index (LLRI), by analyzing the retrospective data from 211 ENKTL patients. Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off value of pretreatment ßLRI and LLRI. The univariate analysis indicated that Ann Arbor Stage (p = 0.008), Eastern Cooperative Oncology Group score (ECOG) (p = 0.009), International Prognostic Index (IPI) (p = 0.023), ßLRI (p = 0.003), LLRI (p = 0.04), neutrophil-lymphocyte ratio index (p = 0.025) and monocyte/granulocyte to lymphocyte ratio (p = 0.030) were significantly associated with overall survival (OS) in ENKTL patients. However, multivariate analysis demonstrated that only Ann Arbor Stage (p = 0.028), ßLRI (p < 0.001) and LLRI (p = 0.006) were only correlated independently with OS. Furthermore, ßLRI and LLRI based new prognostic model showed improved discrimination for stage IE/IIE upper aerodigestive tract in ENKTL patients than IPI and Korean Prognostic Index. Overall, our study concluded that new ßLRI-based prognosis model is useful to stratify ENKTL patients and higher ßLRI and LLRI can act as independent prognostic predictor candidates in early stage ENKTL.

Postoperative value of serum squamous cell carcinoma antigen as a predictor of recurrence in sinonasal inverted papilloma.

OBJECTIVES: Sinonasal inverted papilloma (IP) has several unfavourable characteristics and therefore requires careful monitoring. The goal of this study was to identify whether serum squamous cell carcinoma antigen (SCCa) could predict IP recurrence. DESIGN: A retrospective cohort study. SETTING: Department of otolaryngology/head and neck surgery, Erasmus Medical Centre, Rotterdam, the Netherlands. PARTICIPANTS: One hundred and thirty patients with IP treated at our centre with SCCa measurements available were included. MAIN OUTCOME MEASUREMENTS: Follow-up of patients with IP since 2005, recurrence was defined as new disease within primary localisation at least 3 months after adequate surgical removal. We analysed the association between IP recurrence and serum SCCa values measured preoperatively, postoperatively and during follow-up. RESULTS: Preoperative SCCa values or values measured during follow-up were not associated with risk of recurrence. Postoperative SCCa was positively associated with the risk of recurrence (P < 0.001). Postoperative SCCa had a good discriminative ability for the identification of recurrence with an area under the curve of 80.9%. CONCLUSION: Postoperative SCCa is strongly associated with risk of recurrence. This might help the surgeon in the postoperative setting by identifying high-risk patients and planning follow-up strategy tailored to the individual patient.

[The significance of peripheral blood natural killer cell surface CD107a, NKG2D and serum sMICA in patients with extranodal NK/T cell lymphoma, nasal type].

The expression of CD107a, NKG2D on the surface of natural killer (NK) cells and serum soluble major histocompatibility complex class Ⅰ chain-related A (sMICA) level in patients with extranodal NK/T cell lymphoma, nasal type (ENKL) were detected.We found that CD107a expression was reduced on the surface of NK cells, suggesting impaired NK cell activity in ENKL patients, which may result from decreased NKG2D expression.

Seroconversion of sheep experimentally infected with enzootic nasal tumor virus.

BACKGROUND: Enzootic nasal tumor virus (ENTV-1) is an exogenous betaretrovirus of sheep that transforms epithelial cells lining the ethmoid turbinates leading to a disease called enzootic nasal adenocarcinoma (ENA). A unique feature of ENA is the apparent absence of a specific humoral immune response to the virus, despite the highly productive infection in nasal tumors. The sheep genome contains approximately 27 copies of endogenous ovine betaretroviral sequences (enJSRVs) and expression of enJSRVs in the ovine placenta and uterine endometrium throughout gestation is thought to induce immunological tolerance to exogenous ovine betaretroviruses, a factor that may influence the likelihood of exogenous ENTV infection and disease outcome. Nevertheless, we recently demonstrated the presence of neutralizing antibodies directed against the ENTV-1 envelope glycoprotein in sheep naturally exposed to ENTV-1. FINDINGS: Here, we employed an ENTV-1 envelope glycoprotein surface subunit specific ELISA and a virus neutralization assay to monitor serum antibody responses to ENTV-1 in a group of lambs experimentally infected with ENTV-1 virus containing filtered ENA tumor homogenate. Seroconversion and development of neutralizing antibodies was detected in one of six experimentally infected lambs. CONCLUSIONS: Our results demonstrate that sheep can respond immunologically and seroconvert following ENTV-1 infection suggesting that anti-viral immune responses may play a role in the development of ENA.

High numbers of CD68+ tumor-associated macrophages correlate with poor prognosis in extranodal NK/T-cell lymphoma, nasal type.

Many studies have demonstrated that tumor-associated macrophages (TAMs) were a prognostic indicator in patients with B cell lymphoma. But, we know little about the clinical significance of TAMs in extranodal natural killer/T cell lymphoma(ENKTL), nasal type. CD68 expression was detected using immunohistochemistry to determine the numbers of TAMs in 70 ENKTL patients, and the data were used to evaluate its relationship with clinicopathological features, treatment response, and prognosis. Patients with high number of infiltrated CD68+ TAMs (>60/hpf) at diagnosis tended to have more adverse clinical characteristics. Patients with low CD68+ TAM content (<60/hpf) at diagnosis had better overall survival (P = 0.003) and progression-free survival (P = 0.002) and achieved higher complete remission rates (P = 0.008). Multivariate analysis revealed that CD68 + TAM content, Ki-67 index, and stage III and IV were independent prognostic factors for both OS and PFS. Using the International Prognostic Index or Korean Prognostic Index for extranodal NK/T cell lymphoma, nasal type, the majority of patients were in the low-risk category. CD68 + TAM content was helpful to differentiate the low-risk patients with different survival outcomes. Our data suggest that CD68+ TAM content at diagnosis is a powerful predictor of prognosis for ENKTL, which suggests a role for TAMs in the pathogenesis of this disease and offers new insight into potential therapeutic strategies.

A prognostic model based on pretreatment platelet lymphocyte ratio for stage IE/IIE upper aerodigestive tract extranodal NK/T cell lymphoma, nasal type.

Patients with stage IE/IIE natural killer T (NK/T) cell lymphomas have discrepant survival outcome. This study aims to establish a prognostic model based on the pretreatment platelet lymphocyte ratio (PLR) specifically for localized extranodal NK/T cell lymphoma to guide the therapy. We retrospectively analyzed the data of 252 patients with early-stage upper aerodigestive tract NK/T cell lymphoma. The 5-year overall survival rate in 252 patients was 67.1%. Prognostic factors for survival were female (P = 0.025; relative risk, 0.51; 95% CI 0.28-0.92), older age (P = 0.000; relative risk, 3.34; 95% CI 1.94-5.75), stage II(P = 0.020; relative risk, 1.79; 95% CI 1.10-2.91), lactate dehydrogenase (LDH) level (P = 0.009; relative risk, 2.00; 95% CI 1.19-3.35), and PLR (P = 0.020; relative risk, 1.77; 95% CI 1.10-2.87). Based on these five parameters, we identified three different risk groups: group 1(106 cases, 43.4%), no or one adverse factor; group 2(85 cases, 34.8%), two factors; group 3(53 cases, 21.7%), three to five factors. Five-year overall survival was 83.3% for group 1, 62.2% for group 2, and 43.1% for group 3 (P = 0.000). Compared with International Prognostic Index and Korean Prognostic Index, the new model has a better prognostic discrimination for the patients of stage IE/IIE upper aerodigestive tract NK/T cell lymphoma. The PLR-based prognosis model is useful to stratify patients with localized extranodal NK/T cell lymphoma into different risk groups and guide the treatment modalities selection.

Serum ferritin level is prognostic of patient outcome in extranodal NK/T cell lymphoma, nasal type.

The objective of the current study was to assess the prognostic factors in patients with extranodal natural killer (NK)/T cell lymphoma, nasal type (ENKL). We retrospectively analyzed 35 patients who were diagnosed with ENKL between 1998 and 2011. The median patient age was 63 years, and the male/female ratio was 22:13; twenty patients had localized ENKL, and 26 had a good Eastern Cooperative Oncology Group performance status (score 0 or 1). B symptoms were present in 17 patients. Twenty-five patients presented with nasal or paranasal lesions, or both. With a median follow-up duration among patients still alive at their last follow-up of 47 months (range 8-93 months), the 3-year overall survival (OS) rate was 44.5 %. Multivariate analysis revealed that advanced disease stage (P = 0.002), the presence of extranasal disease (P = 0.013), and serum ferritin levels greater than 300 ng/ml (P < 0.001) were significant and independent (negative) prognostic factors. High serum ferritin levels were associated with the presence of B symptoms, elevated lactate dehydrogenase levels, and high soluble interleukin-2 receptor levels, but not with clinical stage. Patients with high ferritin levels had a remarkably low remission rate (23 %) and a short OS time (median: 4 months). Serum ferritin level at the time of diagnosis of ENKL was a useful prognostic factor.

Prognostic impact of beta-2 microglobulin in patients with extranodal natural killer/T cell lymphoma.

Although serum beta-2 microglobulin (B2M) has been suggested as an independent prognostic factor for several lymphoproliferative diseases, it has rarely been investigated in extranodal natural killer/T cell lymphoma (ENKTL). From a prospectively collected database, 145 patients with ENKTL were identified. Among them, a total of 101 patients were included in the analysis, with exclusion of patients without baseline serum B2M level and those did not receive anticancer therapy. Serum B2M (<3.0 vs. ≥3.0 mg/L) was analyzed for association with overall survival (OS). Seventy-nine (78 %) patients had nasal ENKTL, and 22 (22 %) had extranasal ENKTL. In overall patients, median OS was 26.7 months (95 % confidence interval (CI), not assessable), with a median follow-up of 32.4 months (range, 0.9-155.2 months). While median OS was not reached in patients with nasal ENKTL, extranasal ENKTL group had median OS of 5.1 months (95 % CI, 1.2-8.9 months; p < 0.001). Baseline serum B2M was significantly associated with OS in patients with nasal ENKTL (p < 0.001). This was consistent in limited (stages I and II) nasal ENKTL (p = 0.002) and disseminated (stages III and IV) nasal ENKTL (p = 0.02). However, there was no difference of OS in extranasal ENKTL patients (p = 0.69). In multivariate analysis including other prognostic factors, elevated serum B2M was significantly associated with poor OS (hazard ratio (HR) = 3.8, 95 % CI 1.7-8.2, p = 0.001, in a model including Korean Prognostic Index, and HR = 3.6, 95 % CI 1.6-8.2, p = 0.002, in a model including International Prognostic Index). In patients with nasal ENKTL, baseline serum B2M is a powerful prognostic factor. The prognostic value of B2M was independent of previously established prognostic models. Further investigations are necessary to validate the role of B2M in ENKTL.

Squamous cell carcinoma antigen as a marker of sinonasal inverted papilloma.

This prospective study aimed to evaluate the usefulness of squamous cell carcinoma antigen (SCCA) as a clinical marker of sinonasal inverted papilloma (IP). The potential benefit of SCCA in the diagnosis of unilateral nasal pathology and as a marker of hidden recurrence was evaluated as well. Blood samples from patients with sinonasal IP were examined to determine serum SCCA levels before surgery, the day after surgery, and every 6 months during follow-up. Preoperative and postoperative levels of SCCA were compared. Twenty consecutive patients with histologically confirmed IP were included in the study, conducted between 2000 and 2011. The mean age of the patients was 54.2 years (range 35-72). The mean serum SCCA level before surgery was 3.885 µg/l (range 0.7-7.6). A decrease of the SCCA level to 0.885 µg/l (range 0.1-1.9) was observed on the 1 day after a radical surgical procedure. A statistically significant difference between the preoperative and postoperative levels was observed (P < 0.001). Elevated levels of SCCA during long-term follow-up were observed in three patients. All of them had a recurrence of IP. We conclude that the serum level of SCCA is a useful clinical marker of the presence of sinonasal IP. The level of SCC antigen was significantly lower in patients after IP was completely removed. According to our results, SCCA level also appears to be useful for long-term follow-up (hidden recurrence diagnosis).

Novel and simple prognostic index for nasal natural killer/T-cell lymphoma.

BACKGROUND: Few studies have investigated the prognostic factors for nasal natural killer (NK)/T-cell lymphoma. METHODS: This was a retrospective multicenter clinical study. The clinical records of 36 patients with nasal NK/T-cell lymphoma who had been first treated between 1996 and 2011 were collected from 12 hospitals. RESULTS: High serum levels of C-reactive protein (≥1.0 mg/dL), lactate dehydrogenase (≥350 IU/L), and soluble interleukin-2 receptor (sIL-2R; ≥600 U/mL) were associated with worse prognosis. A prognostic score was devised by totaling the number of these 3 predictors: 0 or 1 = score 0; and 2 or 3 = score 1. As for tumor invasion, local invasion beyond the nasal cavity was associated with poor prognosis, and a prognostic score was devised as: tumor restricted to nasal cavity, yes = score 0; no = score 1. A novel prognostic index (NPI) was established based on these scores from 0 to 2. Disease-specific survival rates at 5 years were: 90.0% for NPI = 0; 29.3% for NPI = 1; and 0.0% for NPI = 2. CONCLUSION: Our NPI is valid for anticipating prognosis of nasal NK/T-cell lymphoma.

Hypercortisolaemia due to ectopic adrenocorticotropic hormone secretion by a nasal paraganglioma: a case report and review of the literature.

BACKGROUND: Adrenocorticotropic hormone-producing extraadrenal paragangliomas are extremely rare. We present a case of severe hypercortisolemia due to ectopic adrenocorticotropic hormone secretion by a nasal paraganglioma. CASE PRESENTATION: A 70-year-old Caucasian woman, was emergently admitted to our department with supraventricular tachycardia, oedema of face and extremities and hypertensive crisis. Initial laboratory evaluation revealed severe hypokalemia and hyperglycemia without ketoacidosis, although no diabetes mellitus was previously known. Computed tomography revealed a large tumor obliterating the left paranasal sinus and a left-sided adrenal mass. After cardiovascular stabilisation, a thorough hormonal assessment was performed revealing marked adrenocorticotropic hormone-dependent hypercortisolism. Due to the presence of a cardiac pacemaker magnetic resonance imaging of the hypophysis was not possible. [68Ga-DOTA]-TATE-Positron-Emission-Tomography was performed, showing somatostatin-receptor expression of the paranasal lesion but not of the adrenal lesion or the hypophysis. The paranasal tumor was resected and found to be an adrenocorticotropic hormone-producing paraganglioma of low-proliferative rate. Postoperatively the patient became normokaliaemic, normoglycemic and normotensive without further need for medication. Genetic testing showed no mutation of the succinatdehydrogenase subunit B- and D genes, thus excluding hereditary paragangliosis. CONCLUSION: Detection of the adrenocorticotropic hormone source in Cushing's syndrome can prove extremely challenging, especially when commonly used imaging modalities are unavailable or inconclusive. The present case was further complicated by the simultaneous detection of two tumorous lesions of initially unclear biochemical behaviour. In such cases, novel diagnostic tools - such as somatostatin-receptor imaging - can prove useful in localising hormonally active neuroendocrine tissue. The clinical aspects of the case are discussed and relevant literature is reviewed.

Nasal hemophilic pseudotumor: favorable response to radiotherapy.

Hemophilic pseudotumors are rare but dangerous complications of Hemophilia. We hereby report a 3-year-old boy with Hemophilia B, presenting with nasal pseudotumor, showing favorable response to radiotherapy after unsuccessful treatment with factor IX replacement therapy. The diagnosis and treatment of this rare condition is also reviewed.