The role of radiotherapy in the treatment of sinonasal undifferentiated carcinoma: A population-based analysis.

BACKGROUND: Sinonasal undifferentiated carcinoma (SNUC) is a rare, aggressive disease with ambiguous management and poor prognosis. This study aimed to evaluate the role of radiation therapy (RT) and explore the optimal treatment sequence. METHODS: Retrospective analysis of survival trends of 410 SNUC patients between 1973 and 2015. RESULTS: The 5-year cancer-specific survival (CSS) rate (45.1%) and overall survival (OS) rates (38.1%) were reported in the 84-month median follow-up. Radiotherapy was a prognosticator for improving CSS (hazard ratio [HR] = 0.425, 95% confidence interval [CI]: 0.299-0.603, p = 0.000) and OS (HR = 0.415, 95% CI: 0.303-0.570, p = 0.000), either with surgery (p = 0.000) or without surgery (p = 0.000). However, in a combined therapy of surgery and RT, preoperative and postoperative RT (5-year OS rates were 47.1% and 45.6%, respectively, p = 0.486) were not significantly different. CONCLUSIONS: Radiotherapy plays a key role in improving SNUC survival rates. No significant difference in survival rates was observed in preoperative and postoperative RT treatment.

A case of high-grade non-intestinal paranasal sinus adenocarcinoma primary in the maxillary sinus: targeted therapy after postoperative immunocombination with chemotherapy.

BACKGROUND: High-grade non-intestinal-type sinonasal adenocarcinoma (non-ITAC) is a rare and aggressive form of adenocarcinoma with poor prognosis. The current standard treatment approach involves surgery combined with radiation therapy. However, there is a need for exploring additional treatment modalities to improve patient outcomes. CASE PRESENTATION: We present a case of a 65-year-old male patient who presented with pain in the right maxillary sinus and was diagnosed with high-grade non-ITAC following surgery. Postoperative pathology revealed tumor invasion into bone tissue and vascular invasion, necessitating further treatment. The patient underwent radiation therapy, followed by immunotherapy with carilizumab combined with chemotherapy. During the maintenance immunotherapy period, tumor progression was observed, and genetic testing identified EGFR and TP53 mutations. Consequently, the patient was treated with gefitinib, a targeted therapy drug. Notably, the patient's lung metastases showed a gradual reduction in size, indicating a favorable treatment response. The patient is currently undergoing oral treatment with gefitinib. CONCLUSIONS: This case report highlights the potential benefit of combining immunotherapy and targeted therapy in the treatment of high-grade non-ITAC. Despite the rarity of this cancer type, this approach may offer an alternative treatment strategy for patients with this aggressive disease. We hope that this case can contribute to a deeper understanding of high-grade non-ITAC and promote the application of immunotherapy and targeted therapy in improving survival rates for patients with this condition.

Sinonasal Carcinoma Presenting with Proptosis and Visual Impairment: A Case Report.

Sinonasal carcinoma is a rare but aggressive malignancy arising from the nasal cavity and paranasal sinuses. We present a case of a 40-year-old female who presented with a three-month history of headache, diminution of vision, and proptosis. Imaging studies revealed soft tissue density with bony erosion and extraconal extension in the left orbit. Histopathological examination confirmed sinonasal carcinoma with anaplastic changes. The patient underwent surgical excision of the tumor and received post-operative care in the neuro-ICU. Her visual acuity improved post-surgery, and she was discharged with stable neurological status. This case highlights the challenges in the diagnosis and management of sinonasal carcinoma and underscores the importance of multidisciplinary care for optimal outcomes. Early diagnosis and intervention are crucial in preventing complications and achieving favorable outcomes in patients with this aggressive malignancy.

Outcomes of SMARCB1-deficient sinonasal carcinoma: Largest single-center cross-sectional study.

BACKGROUND: We evaluate outcomes of SMARCB1-deficient sinonasal carcinomas in the largest single-institution study. METHODS: Retrospective cross-sectional study of patients with SMARCB1-deficient sinonasal carcinoma between 1998 and 2024. Disease-specific survival (DSS) and recurrence-free probability (RFP) at 1 and 5 years were measured by Kaplan-Meier method. RESULTS: There were 47 patients with a median age of 53. Initial pathological diagnosis was altered in 33%. Twelve (34%) patients received neoadjuvant chemotherapy, with one partial response. Curative surgical approach was undertaken in 73%. Definitive chemoradiation was administered in 20%. DSS at 1 and 5 years was 93% and 45%, respectively. RFP at 1 and 5 years was 73% and 33%, respectively. On multivariate analysis, cranial nerve involvement (p = 0.01 for DSS) remained significantly worse for DSS and overall survival. CONCLUSIONS: SMARCB1-deficient tumors had limited response to neoadjuvant chemotherapy. Cranial nerve involvement was associated with worse prognosis. Optimal treatment is unclear. Surgery should be offered to patients with resectable disease.

Value of multiparametric magnetic resonance imaging in distinguishing sinonasal lymphoma from sinonasal carcinoma: a case control study.

BACKGROUND: The study aimed to evaluate the diagnostic efficacy of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) parameters in distinguishing sinonasal lymphoma from sinonasal carcinoma. METHODS: Forty-two participants with histologically confirmed sinonasal lymphomas and fifty-two cases of sinonasal carcinoma underwent imaging with a 3.0T MRI scanner. DCE-MRI and DWI were conducted, and various parameters including type of time-intensity curve(TIC), time to peak, peak enhancement, peak contrast enhancement, washout rate, apparent diffusion coefficient (ADC), and relative ADC were measured. Binary logistic regression and receiver operating characteristic (ROC) curve analysis were employed to assess the diagnostic capability of individual and combined indices for differentiating nasal sinus lymphoma from nasal sinus carcinoma. RESULTS: Sinonasal lymphoma predominantly exhibited type II TIC(n = 20), whereas sinonasal carcinoma predominantly exhibited type III TIC(n = 23). Significant differences were observed in all parameters except washout ratio (p < 0.05), and ADC value emerged as the most reliable diagnostic tool in single parameter. Combined DCE-MRI parameters demonstrated superior diagnostic efficacy compared to individual parameters, with the highest efficiency (area under curve = 0.945) achieved when combining all parameters of DCE-MRI and DWI. CONCLUSIONS: Multiparametric evaluation involving contrast-enhanced dynamic MRI and DWI holds considerable diagnostic value in distinguishing sinonasal lymphoma from sinonasal carcinoma.

Dry Crusty Nose: Not Just Rhinosinusitis! Hidden IgG4-related Disease Without IgG4 Level Rise.

IgG4-related disease (IgG4-RD) is a fibro-inflammatory condition that can affect various organs. Localized sinonasal IgG4-RD is a rare condition characterized by bone and soft-tissue invasion. In this report, we present a case of a patient initially diagnosed with chronic rhinosinusitis, who underwent endoscopic sinus surgery and was later found to have biopsy proven IgG4-related sinonasal disease despite having normal serum levels of IgG4, resulting in erosion of the right lamina papyracea.

Cerebritis, optic ischemia, and cavernous sinus thrombosis arising from sinonasal mucormycosis.

Brain and ocular infections can be the worst and fatal consequences of sinonasal infections in immunomodulated or immunocompromised patients. We report a case of a 35-year-old female who received an allogenic hematopoietic stem cell transplantation for acute myeloid leukemia, suffering from maxillo-spheno-ethmoidal rhinosinusitis which was complicated by cavernous sinus thrombosis, orbital cellulitis, optic ischemia and cerebritis.

Interferon alpha-2b treatment for exophytic nasal papillomas and human papillomavirus infection.

OBJECTIVES: Exophytic Sinonasal Papilloma (ESP) is a benign tumor of the sinonasal tract. Complete surgical excision by endoscopic surgery is the treatment of choice. However, a high recurrence rate (36% at 5-year follow-up) is associated with this method, which may indicate the presence of microorganisms such as Human Papillomavirus (HPV). It is important to note that the standard treatment for ESP does not include antiviral drugs. In our study, we are testing the effectiveness of an interferon-containing drug in reducing recurrence and postoperative reactions in patients with ESP. METHODS: We included 78 patients aged 23-83 years with a confirmed diagnosis of ESP by rhinoscopy and nasal endoscopy and a positive PCR test for HPV in nasal scrapings. To compare the results, we divided the patients into main and control groups. The main group received recombinant human interferon after surgery, while the control group did not receive the drug. We performed a statistical analysis to compare the proportion of patients without reactive manifestations at different stages of the postoperative period, as well as to compare the proportion of patients with recurrent ESP at certain stages of observation. RESULTS: The introduction of recombinant human interferon accelerated the resolution of postoperative reactions and promoted the healing of the nasal mucosa after surgical removal of the ESP. We also found a statistically significant association between treatment with recombinant interferon and a reduction in the recurrence rate of ESP. CONCLUSION: According to the results of the study, it was found that in the main group of patients who received rhIFN-α2b (recombinant human Interferon alpha 2b) in the postoperative period, the frequency of relapses of ESP and the time of postoperative recovery were significantly lower than in patients in the control group who did not take the drug. LEVEL OF EVIDENCE: Cohort Study.

SMARCB1-Retained and SMARCB1-Deficient SNUC are Genetically Distinct: A Pilot Study Using RNA Sequencing.

Background Understanding the genetic basis for the molecular classification of sinonasal undifferentiated carcinoma (SNUC) based on SMARCB1 may improve our understating regarding the nature of the disease. The objective of the study was to compare the genetic profile of SMARCB1-retained (SR-SNUC) and SMARCB1-deficient SNUC (SD-SNUC). Methods Formalin-fixed, paraffin-embedded tissue from treatment-naive patients with SNUC were selected. Three cases of SR-SNUC, four cases of SD-SNUC, and four samples of nontumor tissue (control samples) were selected. Ribonucleic acid (RNA) sequencing was performed. Results SR-SNUC had a higher number of variants (1 variant for every 15,000 bases) compared with SD-SNUC (1 variant every 29,000 bases). The ratio of missense to silent mutation ratio was higher for SR-SNUC (0.8) as compared with SD-SNUC (0.7). Approximately 1,500 genes were differentially expressed between SR-SNUC and SD-SNUC. The genes that had a higher expression in SR-SNUC included TPD52L1, B3GNT3, GFY, TJP3, ELL3, CYP4F3, ALDH3B2, CKMT1B, VIPR1, SLC7A5, PPP2R2C, UPK3B, MUC1, ELF5, STY7, and H2AC14. The gene that had a higher expression in SD-SNUC was ZFHX4. Most of these genes were related to either protein translation or immune regulation. The most common ( n = 3, 75%) mechanisms of loss of SMARCB1 gene in SD-SNUC was loss of heterozygosity. Conclusion RNA sequencing is a viable and informative approach for genomic profiling of archival SNUC samples. Both SR-SNUC and SD-SNUC were noted to have distinct genetic profiles underlying the molecular classification of these diseases.

Clinical Outcome in Patients with Large Sinonasal Tumors with Intracranial Extension.

Objectives Malignant tumors of the sinonasal cavities with extension to the frontal skull base are rare and challenging pathologies. Combined-approach surgery using a frontobasal craniotomy and endoscopic sinus surgery with reconstruction of the anterior skull base followed by adjuvant radiotherapy is a preferred treatment strategy in selected cases. Morbidity and mortality rates are high in this population. We aim to add our experience to the current literature. Design We performed a retrospective cross-sectional single center study of the long-term clinical outcome in a tertiary university referral hospital in the Netherlands between 2010 and 2021. Descriptive statistics and frequency distributions were performed Participants Patient, tumor, treatment, complications and survival characteristics of eighteen consecutive patients were extracted from the electronic health records. Main Outcome Measures The primary outcome measures are progression free survival, overall survival and complication rate. Results Eighteen consecutive patients were included with a mean age of 61 (SD ± 10) years (range 38-80); ten males and eight females. Gross total resection was achieved in 14 (77%) patients. Eleven (61%) patients underwent local radiotherapy, one (5%) chemotherapy and three (17%) a combination of both. Mean follow-up duration was 49 months (range 3 - 138). Three (17%) patients died in hospital due to post-operative complications. Six (33%) patients died during follow-up due to disease progression. Mean progression-free survival was 47 months (range 0 - 113). Conclusion In conclusion, the overall survival was 50% for this group of patients with large sinonasal tumors. Progressive disease affects survival rate severely. Surgical complications were seen in five (28%) patients. Radiotherapy is associated with high complication rates. Radiation necrosis was a serious complication in two patients and could be treated with high dose steroids.

Impact of Treatment Delay in Head and Neck Mucosal Melanoma on Overall Patient Survival.

Objectives Head and neck mucosal melanoma (HNMM) is a rare malignancy with high mortality. This study evaluates the impact of treatment delays on overall survival in HNMM. Design/Setting/Participants A retrospective review of patients with surgically managed HNMM treated with adjuvant radiation was performed from the 2004-2016 National Cancer Database. Main Outcome Measures Durations of diagnosis-to-treatment initiation (DTI), surgery-to-radiotherapy initiation (SRT), duration of radiotherapy (RTD), surgery-to-immunotherapy initiation (SIT), diagnosis-to-treatment end (DTE), and total treatment package (TTP) were calculated. Results A total of 1,011 patients (50.7% female, 90.5% Caucasian) met inclusion criteria. Median DTI, SRT, RTD, SIT, DTE, and TTP were 30, 49, 41, 102, 119, and 87 days, respectively. Only longer DTE was associated with decreased mortality (hazard ratio, 0.720; 95% confidence interval, 0.536-0.965; p = 0.028). Conclusion DTI, SRT, RTD, SIT, and TTP do not significantly affect overall survival in patients with HNMM who undergo surgery and adjuvant radiation. Longer DTE is associated with improved survival in this population. Level of Evidence 4.

Sinonasal Malignancy Following Cranial Irradiation: A Scoping Review and Case Report of Sinonasal Teratocarcinosarcoma.

Background Radiation therapy is a mainstay of treatment for brain tumors, but delayed complications include secondary malignancy which may occur months to years after treatment completion. Methods We reviewed the medical records of a 41-year-old female treated with 60 Gy of radiation for a recurrent astrocytoma, who 6 years later developed a locally advanced sinonasal teratocarcinosarcoma. We searched MEDLINE, Embase, and Web of Science to conduct a scoping review of biopsy-proven sinonasal malignancy in patients who previously received cranial irradiation for a brain tumor. Results To our knowledge, this is the first report of a patient to present with a sinonasal teratocarcinosarcoma after receiving irradiation for a brain tumor. Our scoping review of 1,907 studies produced 14 similar cases of secondary sinonasal malignancy. Median age of primary cancer diagnosis was 39.5 years old (standard deviation [SD]: 21.9), and median radiation dose was 54 Gy (SD: 20.3). Median latency time between the primary cancer and secondary sinonasal cancer was 9.5 years (SD: 5.8). Olfactory neuroblastoma was the most common sinonasal cancer ( n = 4). Fifty percent of patients died from their sinonasal cancer within 1.5 years. Conclusion Patients who receive radiation exposure to the sinonasal region for treatment of a primary brain tumor, including low doses or scatter radiation, may be at risk of a secondary sinonasal malignancy later in life. Physicians who monitor at-risk patients must be vigilant of symptoms which may suggest sinonasal malignancy, and surveillance should include radiographic review with careful monitoring for a secondary malignancy throughout the entire irradiated field.

Endoscopic-assisted transorbital extended orbital exenteration: A multi-institutional preclinical study.

BACKGROUND: Sinonasal malignancies with orbital invasion have dismal prognosis even when treated with orbital exenteration (OE). Sugawara et al. developed a surgical strategy called "extended-OE (EOE)," showing encouraging outcomes. We hypothesized that a similar resection is achievable under endoscopic guidance through the exenterated orbit (endoscopic-EOE). METHODS: The study was conducted in three institutions: University of Vienna; Mayo Clinic; University of Insubria; 48 orbital dissections were performed. A questionnaire was developed to evaluate feasibility and safety of each step, scoring from 1 to 10, ("impossible" to "easy," and "high risk" to "low risk," respectively), most likely complication(s) were hypothesized. RESULTS: The step-by-step technique is thoroughly described. The questionnaire was answered by 25 anterior skull base surgeons from six countries. Mean, median, range, and interquartile range of both feasibility and safety scores are reported. CONCLUSIONS: Endoscopic-EOE is a challenging but feasible procedure. Clinical validation is required to assess real-life outcomes.

Rare and common manifestation of musculoskeletal and sinonasal sarcoidosis: A case report.

Sarcoidosis is a systemic granulomatous disease that can affect multiple organ systems. Although many sarcoidosis patients are asymptomatic, the variable clinical progression of symptomatic patients and the nonspecific presentation make diagnosis difficult in certain cases. Musculoskeletal and sinonasal involvement of sarcoidosis are uncommon manifestations, and they are often only seen in patients with widespread disease. Diagnosis of osseous sarcoidosis, sarcoid arthropathy, and sarcoid rhinosinusitis are typically based on a combination of clinical history, radiological findings, and pathologic specimens. Although there are classic image findings, such as lacelike honeycomb appearance of small bones of the hands or hilar/mediastinal lymphadenopathy, sole reliance on image findings for the diagnosis of sarcoidosis is unreasonable as many findings are nonspecific. However, failure to include sarcoidosis in the differential diagnosis often leads to a delay in recognition of musculoskeletal or sinonasal involvement and results in ineffective treatment plan. Even in patients with biopsy-proven sarcoidosis, some image findings in isolation that may represent granulomatous infiltrates are disregarded as nonspecific without raising the possibility of sarcoidosis due to its rare occurrence. Here we discuss a case of multisystemic sarcoidosis in a 42-year-old female with a constellation of classic and rare findings of biopsy-proven sarcoidosis.

Surgical and regenerative treatment options for empty nose syndrome: A systematic review.

Objectives: Patients with empty nose syndrome usually suffer from paradoxical nasal congestion, nasal dryness, epistaxis and suffocation. Conservative management is general option for the empty nose syndrome. However, there are several patients who continually complain of symptoms. If symptoms persist, surgical options are considered. Therefore, we reviewed surgical and regenerative treatment options of empty nose syndrome. Methods: PubMed, Embase, Scopus, Cochrane Register of Controlled Trials, and Google Scholar were searched from the earliest date provided in the database until December 2022. In the studies, treatment outcomes were measured by patient symptom scores such as Sino-Nasal Outcome Test (SNOT-20, 22, and 25), and Empty Nose Syndrome 6-Item Questionnaire (ENS6Q) along with various clinical examiniations. Results: Twenty-eight studies were analyzed. Submucosal injectable materials, allografts/xenografts/cadaveric implants, autologous implants, and synthetic implants were used. Among them, polyethylene implant was most commonly used (23.3%), followed by autologous, homologous, or cadaveric costal cartilage (20%). The most common administration site was the anterior-inferior lateral nasal wall. Most of the studies showed that surgical intervention brought significant improvements in clinical findings including endoscopic exam, acoustic rhinometry, and CT, as well as patients reporting nasal symptom-, psychological-, or overall health-related quality of life questionnaires. However, several studies did not confirm improvement effects in some psychological-related questionnaires or saccharin transit time. The average follow-up duration was 12.0 (2.0-27.6) months. Postoperative adverse effects were reported in only two studies. Conclusion: Several surgical options and recent tissue regeneration techniques have shown its positive efficacy in treating empty nose syndrome. However more detailed investigations with a larger number and a randomized control study are needed to establish a standardized protocol in treating empty nose syndrome patients.

Long-term outcomes in advanced anterior skull base malignancy: a single quaternary institution experience.

BACKGROUND: Advanced skull base malignancies are a heterogenous subset of head and neck cancers, and management is often complex. In recent times, there has been a paradigm shift in surgical technique and the advent of novel systemic options. Our goal was to analyse the long-term outcomes of a single quaternary head and neck and skull base service. METHODS: A retrospective review of 127 patients with advanced anterior skull base malignancies that were treated at our institution between 1999 and 2015 was performed. Multiple variables were investigated to assess their significance on 5 and 10-year outcomes. RESULTS: The mean age was 60.9 (± 12.6 SD). Sixty-four percent were males and 36% were females. Ninety percent of patients had T4 disease. Median survival time was 133 months. The 5-year overall survival (OS) was 66.2%, disease-specific survival (DSS) was 74.7%, and recurrence-free survival (RFS) was 65.0%. The 10-year OS was 55.1%, DSS was 72.1%, and RFS was 53.4%. Histological type and margin status significantly affected OS & DSS. CONCLUSION: Surgical management of advanced skull base tumours has evolved over the last few decades at our institution with acceptable survival outcomes and complication rates. Histological diagnosis and margin status are the main predictors of survival. The addition of neoadjuvant systemic agents in current trials may improve outcomes.

Surgical therapy in advanced sinonasal carcinomas - retrospective study.

BACKGROUND AND AIM: Sinonasal tumors are a rare and heterogeneous group of malignant tumors with different histopathological characteristics and clinical presentation. These tumors are usually treated through surgery. The aim of this study is to present our results of surgical therapy in patients with an advanced sinonasal tumor. METHODS: This retrospective study included patients with an advanced sinonasal tumor who were surgically treated. The surgical technique combined both a frontal transbasal approach together with an endoscopic endonasal approach. The parameters used for evaluation were the histological type of tumor, the radicality of resection (complete vs. incomplete), the frequency of recurrence, the surgical and postoperative complications, the type of subsequent oncological therapy and the overall survival. RESULTS: The group consisted of ten patients seven were men and three were women. Complete resection (defined as R0) was achieved in 8 (80%) of the cases, subcomplete resection was achieved in 2 (20%) of the cases. The overall survival period was 28.7 months (95% confidence interval 15.9-41.6). CONCLUSION: The combination of the frontal transbasal approach with the endoscopic endonasal approach is a suitable surgical strategy that enables easier achievement of complete tumor resection, reconstruction of the anterior skull base and reduces the need for extensive surgical approaches.

Outcomes of SWI/SNF complex-deficient sinonasal carcinomas in a Southeast Asian cohort.

BACKGROUND: SWI/SNF complex-deficient sinonasal carcinomas are rare, genetically distinct, and aggressive entities. METHODS: SMARCB1 and SMARCA4 immunohistochemistry was retrospectively performed on a cohort of undifferentiated, poorly differentiated, and poorly defined sinonasal carcinomas. Survival outcomes were compared between SMARCB1/SMARCA4 (SWI/SNF complex)-deficient and -retained groups. RESULTS: Eight SWI/SNF complex-deficient (six SMARCB1-deficient, two SMARCA4-deficient) cases were identified among 47 patients over 12 years. Triple-modality treatment was more frequently utilized in SWI/SNF complex-deficient carcinomas than in SWI/SNF complex-retained carcinomas (71.4% vs. 11.8%, p = 0.001). After a median follow-up of 21.3 (IQR 9.9-56.0) months, SWI/SNF complex-deficient sinonasal carcinomas showed comparable recurrence rates (57.1% vs. 52.9%, p = 0.839), time-to-recurrence (7.3 [IQR 6.6-8.3] vs. 9.1 [IQR 3.9-17.4] months, p = 0.531), and overall survival (17.7 [IQR 11.8-67.0] vs. 21.6 [IQR 8.9-56.0] months, p = 0.835) compared to SWI/SNF complex-retained sinonasal carcinomas. CONCLUSION: Triple-modality treatment may improve survival in SWI/SNF complex-deficient sinonasal carcinomas.

Expression of immune checkpoint molecules TIGIT and TIM-3 by tumor-infiltrating lymphocytes predicts poor outcome in sinonasal mucosal melanoma.

BACKGROUND: Sinonasal mucosal melanoma (SNMM) is a rare but aggressive tumor with a poor prognosis. The co-inhibitory receptors T cell immunoglobulin and mucinodomain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3) and T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) are promising new targets in anti-cancer immunotherapy. The expression profiles of these immune checkpoint molecules (ICMs) and potential prognostic implications have not been characterized in SNMM yet. METHODS: Immunohistochemical staining for TIGIT, LAG-3 and TIM-3 was performed on tumor tissue samples from 27 patients with primary SNMM. Associations between ICM expression and demographic parameters, AJCC tumor stage, overall survival, and recurrence-free survival were retrospectively analyzed. RESULTS: SNMM patients with low numbers of TIGIT+ and TIM-3+ tumor infiltrating lymphocytes (TILs) in the primary tumor survived significantly longer than patients with a high degree of TIGIT+ and TIM-3+ TILs. High infiltration with TIM-3+ or TIGIT+ lymphocytes was associated with the higher T4 stage and decreased 5-year survival. CONCLUSION: We identified high densities of TIM-3+ and TIGIT+ TILs as strong negative prognostic biomarkers in SNMM. This suggests that TIM-3 and TIGIT contribute to immunosuppression in SNMM and provides a rationale for novel treatment strategies based on this next generation of immune checkpoint inhibitors. Prospective studies with larger case numbers are warranted to confirm our findings and their implications for immunotherapy.