Head and Neck Solitary Fibrous Tumor Presenting as Salivary Gland Tumor: Two Case Reports and Review of the Literature.

Solitary fibrous tumors (SFTs) are soft tumors (mesenchymal origin) that most likely develop from adult mesenchymal stem cells. SFTs are not common in the head and neck region, and the characteristics of tumors in this location are unclear. The present study describes the clinicopathological findings of 2 cases of SFTs arising in the parotid gland and buccal space, presenting as salivary gland tumors. The first case is a 76-year-old man presenting with a painless tumor on the right parotid gland who subsequently underwent partial superficial parotidectomy. According to the results of histopathological analysis, the tumor consisted of stellate and spindle-shaped cells proliferating on a mucous-like substrate. Immunohistochemical staining revealed that neoplastic cells were positive for CD34, vimentin, Bcl2, and STAT6. The second case is of a 64-year-old man presenting with a painless lump on his right cheek. Based on the findings of fine needle aspiration cytology, a tumor derived from myoepithelial cells of the minor salivary gland or a nonepithelial tumor was suspected. The patient underwent surgical resection via an intraoral approach. Histopathologically, the tumor consisted of spindle-shaped cells with rod-shaped or irregular nuclei. Immunohistochemical staining revealed that the neoplastic cells were positive for CD34, CD99, Bcl2, and STAT6. Briefly, SFT should be considered in the differential diagnosis of a well-marginalized lesion in the salivary gland and oral cavity. STAT6 immunohistochemistry is the most specific and sensitive method of diagnosing SFT. A thorough understanding of the morphological changes associated with SFT and their correlation with clinical, immunohistochemical, and molecular characteristics is important to avoid misdiagnosis.

The Landscape of MYB/MYBL1- and Peri-MYB/MYBL1-Associated Rearrangements in Adenoid Cystic Carcinoma.

Approximately 60% of adenoid cystic carcinoma (AdCC) cases are positive for MYB::NFIB or MYBL1::NFIB, whereas MYB/MYBL1 oncoprotein, a key driver of AdCC, is overexpressed in most cases. Juxtaposition of superenhancer regions in NFIB and other genes into the MYB/MYBL1 locus is an attractive oncogenic hypothesis for AdCC cases, either negative or positive for MYB/MYBL1::NFIB. However, evidence supporting this hypothesis is insufficient. We examined 160 salivary AdCC cases for rearrangements in MYB/MYBL1 loci and peri-MYB/MYBL1 areas (centromeric and telomeric areas of 10 Mb each) using formalin-fixed, paraffin-embedded tumor sections. For the detection of the rearrangements, we employed conventional fluorescence in situ hybridization split and fusion assays and a 5 Mb fluorescence in situ hybridization split assay. The latter is a novel assay that enabled us to detect any possible splits within a 5 Mb distance of a chromosome. We found MYB/MYBL1- and peri-MYB/MYBL1-associated rearrangements in 149/160 patients (93%). AdCC cases positive for rearrangements in MYB, MYBL1, the peri-MYB area, and the peri-MYBL1 area numbered 105 (66%), 20 (13%), 19 (12%), and 5 (3%), respectively. In 24 peri-MYB/MYBL1 rearrangement-positive cases, 14 (58%) were found to have a juxtaposition of the NFIB or RAD51B locus into the MYB/MYBL1 loci. On comparing with a tumor group positive for MYB::NFIB, a hallmark of AdCC, other genetically classified tumor groups had similar features of overexpression of the MYB transcript and MYB oncoprotein as detected by semiquantitative RT-qPCR and immunohistochemistry, respectively. In addition, clinicopathological and prognostic features were similar among these groups. Our study suggests that peri-MYB/MYBL1 rearrangements may be a frequent event in AdCC and may result in biological and clinicopathological consequences comparable to MYB/MYBL1 rearrangements. The landscape of MYB/MYBL1 and peri-MYB/MYBL1 rearrangements shown here strongly suggests that juxtaposition of superenhancers into MYB/MYBL1 or peri-MYB/MYBL1 loci is an alteration that acts as a key driver for AdCC oncogenesis and may unify MYB/MYBL1 rearrangement-positive and negative cases.

Prognostic scores for patients with salivary adenoid cystic carcinoma without lymph node metastasis.

Adenoid cystic carcinoma (AdCC) of salivary gland grows relatively slowly, but occasionally develops distant metastasis. Although cervical lymph node metastasis (LNM) has been reported as a strong prognostic factor, most of AdCC do not have LNM. In this study, we investigated the prognostic factors to predict disease free survival (DFS), distant metastasis free survival (DMFS), and overall survival (OS) for 175 patients surgically treated for AdCC without LNM, and developed prognostic score (PS) determined as number of positive prognostic factors. The following emerged as significant prognostic factors: positive surgical margin in DFS, pT3/4 and positive surgical margin in DMFS, and positive surgical margin and high-histological grade in OS. 10-year DFS rates were 56.4% in PS0, and 19.1% in PS1 (p < 0.0001). 10-year DMFS rates were 86.3% in PS0, 56.4% in PS1, and 30.7% in PS2 (p < 0.0001). 10-year OS rates were 100% in PS0, 73.3% in PS1, and 38.8% in PS2 (p < 0.0001).

Carcinoma Cuniculatum of the Maxilla Arising From Oroantral Fistula: A Report of an Extremely Rare Case.

Carcinoma cuniculatum (CC) is extremely rare in the maxilla. Here, we report a case of CC arising from an oroantral fistula (OAF). The patient was a 70-year-old Japanese man who was followed up for a non-closing OAF. Although there were no findings based on an intraoral examination, follow-up contrast-enhanced computed tomography and magnetic resonance imaging showed a 22-mm mass in the maxilla close to the OAF. Histologically, cystic and endophytic papillary proliferation of squamous epithelium with abundant keratinization mimicking rabbit burrows occupied the alveolar bone. This tumor was directly connected to the atypical proliferation of the covering epithelium of the OAF. The tumor cells showed mild cytological atypia and a few mitoses. Finally, the patient was diagnosed with CC arising from an OAF. CC is often misdiagnosed; nonetheless, the unique endophytic, branching, and tunnel-like structure is a hallmark of this tumor. We present the first well-documented case of CC arising from an OAF, discuss its diagnostic features, and highlight its differences from other common benign and malignant pathological entities.

A symptomatic intercalated duct lesion of the parotid gland: a case report with immunohistochemical and genetic analyses.

Intercalated duct lesions (IDLs) are usually asymptomatic. We report a case of IDL, in which a palpable mass formed. The patient was a 45-year-old Japanese male, who noticed a mass in the left parotid region. The nodular lesion was well-circumscribed, but did not have a fibrous capsule or exhibit infiltrative growth. It contained a small cystic space and consisted of basaloid cells arranged in a cribriform pattern and inner ductal cells. It had some solid areas of nest-like proliferation displaying mild cellular atypia. Immunohistochemically, the luminal cells were positive for cytokeratin (CK)7 and epithelial membrane antigen, and the abluminal cells were positive for CK5/6, p63, and DOG1. S-100 protein-positive stromal cells were also seen. The lesion's cells were all positive for SOX10, and the nuclei of some basaloid cells were positive for ß-catenin. The Ki-67 labeling index was 3.8%. The ductal cells contained diastase-digestion-resistant, Periodic acid Schiff-positive zymogen granules. Genetically, the lesion harbored a missense mutation in the CTNNB1 gene. We diagnosed the lesion as an IDL. As IDLs are usually small non-neoplastic lesions, symptomatic cases are rare. Based on its common immunohistochemical and genetic features, IDL may be a precursor of basal cell adenoma/adenocarcinoma, such as intercalated duct adenoma.

Salivary gland polymorphous adenocarcinoma: Clinicopathological features and gene alterations in 36 Japanese patients.

BACKGROUND: Polymorphous adenocarcinoma is a common intraoral minor salivary gland carcinoma in Western countries but is extremely rare in Japan. The current study aimed to characterize the clinicopathological features and status of molecular alterations of polymorphous adenocarcinoma-associated genes, such as PRKD1/2/3, ARID1A, and DDX3X, in a large cohort of Japanese patients with polymorphous adenocarcinoma. METHODS: We examined the cases of 36 Japanese patients with salivary gland polymorphous adenocarcinoma and 26 cases involving histopathological mimics. To detect gene splits, fluorescence in situ hybridization was carried out for polymorphous adenocarcinoma-associated genes. Additionally, we applied a SNaPshot multiplex assay to identify PRKD1 hotspot mutations. RESULTS: This study revealed the indolent clinical course of polymorphous adenocarcinoma with a high 10-year overall survival rate (92.9%), accompanied by occasional local recurrences and cervical lymph node metastasis (23.3%). Twenty cases (55.6%) of polymorphous adenocarcinoma (but none of the mimics) exhibited alterations in at least one polymorphous adenocarcinoma-associated gene. Rearrangement of polymorphous adenocarcinoma-associated genes and PRKD1 E710D were identified in 17 (47.2%) and 4 (11.1%) cases, respectively; one case showed coexisting PRKD3 split and PRKD1 E710D. In the multivariate analysis, high clinical stage (p = 0.0005), the presence of prominent nucleoli (p = 0.0003), and ARID1A split positivity (p = 0.004) were independent risk factors for disease-free survival. CONCLUSION: Japanese patients with polymorphous adenocarcinoma showed clinicopathological features similar to those reported in Western countries. This study disclosed that polymorphous adenocarcinoma-associated genetic alterations were common and specific findings in polymorphous adenocarcinomas. The diagnostic role and possible prognostic significance of polymorphous adenocarcinoma-associated genetic alterations in polymorphous adenocarcinomas were suggested.

The implicated clinical factors for outcomes in 304 patients with salivary duct carcinoma: Multi-institutional retrospective analysis in Japan.

BACKGROUND: Salivary duct carcinoma (SDC) is a high-grade salivary malignancy that frequently occurs as the carcinomatous component of carcinoma ex pleomorphic adenoma. We herein examined the clinical factors affecting outcomes in a large cohort of SDC. METHODS: We selected 304 SDC cases and investigated clinical characteristics and the factors affecting outcomes. RESULTS: The median age of the cases examined was 68 years, the most common primary site was the parotid gland (238 cases), and there was a male predominance (M/F = 5:1). Outcomes were significantly worse when the primary tumor site was the minor salivary glands (SG) than when it was the major SG. Outcomes were also significantly worse in pN(+) cases (161 cases) than in pN0 cases, particularly those with a metastatic lymph node number ≥11. The cumulative incidence of relapse and distant metastases was significantly higher in stage IV cases than in stage 0-III cases. CONCLUSIONS: The absolute number of lymph node metastases, higher stages, and the minor SG as the primary tumor site were identified as factors affecting the outcome of SDC.

Salivary mucoepidermoid carcinoma: histological variants, grading systems, CRTC1/3-MAML2 fusions, and clinicopathological features.

AIMS: To investigate the histological diversity of salivary mucoepidermoid carcinoma (MEC), its clinicopathological features, and its associations with CRTC1/3-MAML2 fusions. METHODS AND RESULTS: Salivary MEC cases (n = 177) were examined for CRTC1/3-MAML2 fusions, histological variants were classified, and tumours were graded according to four different grading systems. Adverse histological features considered to be unusual in MEC were also investigated. Of the 177 MEC cases, 110 were positive for CRTC1/3-MAML2 fusions. The classical variant was the most frequent in the fusion-positive case group, the fusion-negative case group, and the total case group. The clear/oncocytic variant was the second most frequent in the fusion-positive and total case groups. Oncocytic, Warthin-like and spindle variants were seen in the fusion-positive case group only. Clear cell, sclerosing, mucinous and central variants were seen in both the fusion-positive case group and the fusion-negative case group. No case was classified as a ciliated variant, as a mucoacinar variant, or as a high-grade transformation. As compared with the classical variant, non-classical variants were characterised by frequent CRTC1/3-MAML2 fusions and a low clinical stage in all cases. Of the four histological features considered to be unusual in MEC, marked nuclear atypia, frequent mitoses (>10/10 high-power fields) and extensive necrosis were found independently of the fusion status, and were present in 3-5% of all cases. However, none of the cases showed overt keratinisation. On comparison, the Armed Forces Institute of Pathology and modified Healey grading systems downgraded tumours, the Brandwein system upgraded tumours, and the Memorial Sloan Kettering system provided a moderate means of assessment. CONCLUSION: Recognition of the histological diversity of MEC, its clinicopathological features and its associations with CRTC1/3-MAML2 fusions is helpful for an accurate diagnosis of this carcinoma.

Hybrid Carcinoma of the Parotid Gland: An Extremely Rare Three Cases with an Immunohistochemical Analysis and a Review of the Literature.

Salivary hybrid carcinoma (HC) is defined as when two or more kinds of carcinoma exist at the same location in a single mass. We reestimated and examined three cases of salivary gland HC. Case 1 involved a 76-year-old male. Case 2 involved a 74-year-old female. Case 3 involved a 66-year-old male. Histologically, case 1 involved a combination of salivary duct carcinoma (SDC) and squamous cell carcinoma (SqCC). Immunohistochemically, the former was positive for gross cystic disease fluid protein (GCDFP)-15 and androgen receptor (AR). Case 2 involved a combination of SqCC and neuroendocrine carcinoma. Immunohistochemically the latter was positive for synaptophysin and neural cell adhesion molecule (NCAM). Case 3 involved a combination of SDC and epithelial-myoepithelial carcinoma (EMC). Immunohistochemically, the former was positive for GCDFP-15 and AR, whereas the inner cells of the latter were positive for cytokeratin 7, and the outer cells of the latter were positive for actin. Because of the transitional zone between SDC and EMC, it was speculated that high-grade SDC arose from low-grade EMC.

Carcinoma showing thymus-like differentiation (CASTLE) of the salivary gland: Report of 2 cases of a hitherto under-recognized extrathyroid counterpart.

Carcinoma showing thymus-like differentiation (CASTLE) outside the thyroid gland is extremely rare. Here we report two cases of CASTLE of the major salivary gland. The tumors occurred in the parotid gland of a 31-year-old female (Case 1) and in the submandibular gland of a 40-year-old female (Case 2). Both tumors showed a lobulated growth pattern, and were histologically composed of a nested or sheet-like proliferation of carcinoma cells with round- to oval-shaped nuclei, distinct nucleoli and pale eosinophilic cytoplasm, accompanied by various degrees of lymphocytic infiltration. Immunohistochemical staining revealed that the tumors were positive for pan-cytokeratin, p40, CD5, CD117 and bcl-2. In addition, PD-L1 expression was seen in 10-90% of tumor cells. After the initial surgery, Case 1 remained tumor-free for 20 months, while Case 2 suffered lymph node recurrence at 4 months, followed by lung metastasis, which was treated with chemoradiotherapy and anti-PD-1 immune checkpoint inhibitor, resulting in a partial response. The present findings indicate that an extrathyroid counterpart of CASTLE can occur as a primary salivary gland neoplasm. Salivary CASTLEs seem to show a wide range of biological behavior, and long-term follow-up may be needed. Immune checkpoint inhibitor targeting PD-1 might become a promising treatment option in patients with CASTLE; however, further study with a larger number of cases is necessary to establish the optimal therapeutic strategy and prognostic factors for this rare cancer.

Periostin expression and its supposed roles in benign and malignant thyroid nodules: an immunohistochemical study of 105 cases.

BACKGROUND: Thyroid tumors are often difficult to histopathologically diagnose, particularly follicular adenoma (FA) and follicular carcinoma (FC). Papillary carcinoma (PAC) has several histological subtypes. Periostin (PON), which is a non-collagenous extracellular matrix molecule, has been implicated in tumor invasiveness. We herein aimed to elucidate the expression status and localization of PON in thyroid tumors. METHOD: We collected 105 cases of thyroid nodules, which included cases of adenomatous goiter, FA, microcarcinoma (MIC), PAC, FC, poorly differentiated carcinoma (PDCa), and undifferentiated carcinoma (UCa), and immunohistochemically examined the PON expression patterns of these lesions. RESULTS: Stromal PON deposition was detected in PAC and MIC, particularly in the solid/sclerosing subtype, whereas FA and FC showed weak deposition on the fibrous capsule. However, the invasive and/or extracapsular regions of microinvasive FC showed quite strong PON expression. Except for it, we could not find any significant histopathological differences between FA and FC. There were no other significant histopathological differences between FA and FC. Although PDCa showed a similar PON expression pattern to PAC, UCa exhibited stromal PON deposition in its invasive portions and cytoplasmic expression in its carcinoma cells. Although there was only one case of UCa, it showed strong PON immunopositivity. PAC and MIC showed similar patterns of stromal PON deposition, particularly at the invasive front. CONCLUSIONS: PON may play a role in the invasion of thyroid carcinomas, particularly PAC and UCa, whereas it may act as a barrier to the growth of tumor cells in FA and minimally invasive FC.

Identification and characterization of primary cilia-positive salivary gland tumours exhibiting basaloid/myoepithelial differentiation.

Primary cilia (PC) are non-motile, antenna-like structures on the cell surface. Many types of neoplasms exhibit PC loss, whereas in some neoplasms PC are retained and involved in tumourigenesis. To elucidate the PC status and characteristics of major salivary gland tumours (SGTs), we examined 100 major SGTs encompassing eight histopathological types by immunohistochemical analysis. PC were present in all (100%) of the pleomorphic adenomas (PAs), basal cell adenomas (BCAs), adenoid cystic carcinomas (AdCCs), and basal cell adenocarcinomas (BCAcs) examined, but absent in all (0%) of the Warthin tumours, salivary duct carcinomas, mucoepidermoid carcinomas, and acinic cell carcinomas examined. PC were also detected by electron-microscopic analysis using the NanoSuit method. It is worthy of note that the former category and latter category of tumours contained and did not contain a basaloid/myoepithelial differentiation component, respectively. The four types of PC-positive SGTs showed longer PC than normal and exhibited a characteristic distribution pattern of the PC in the ductal and basaloid/neoplastic myoepithelial components. Two PC-positive carcinomas (AdCC and BCAc) still possessed PC in their recurrent/metastatic sites. Interestingly, activation of the Hedgehog signalling pathway, shown by predominantly nuclear GLI1 expression, was significantly more frequently observed in PC-positive SGTs. Finally, we identified tau tubulin kinase 2 (TTBK2) as being possibly involved in the production of PC in SGTs. Taken together, our findings indicate that SGTs that exhibit basaloid/myoepithelial differentiation (PA, BCA, AdCC, and BCAc) are ciliated, and their PC exhibit tumour-specific characteristics, are involved in activation of the Hedgehog pathway, and are associated with TTBK2 upregulation, providing a significant and important link between SGT tumourigenesis and PC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A rare case of high-grade intraductal carcinoma of the upper lip: immunohistochemical and genetic analyses.

Although intraductal carcinoma (IDC) of the salivary glands was previously called low-grade cribriform cystadenocarcinoma, it was newly categorized in the 4th version of the World Health Organization classification. We report a case of IDC of the upper lip and examined it immunohistochemically and genetically. The patient was a 48-year-old Japanese female, who noticed a tiny nodule on her left upper lip. Histologically, the tumor cells, which had eosinophilic cytoplasm, exhibited papillary and solid growth patterns, and regions of suspected microinvasion or intraductal spread were also seen at the periphery of the tumor. Small necrotic foci were noted. Immunohistochemically, the tumor cells were diffusely positive for the androgen receptor, CK19, CK5/6, EGFR, and SOX10, whereas they were focally positive for GCDFP-15, S-100 protein, and mammaglobin. The tumor nests were surrounded by alpha-smooth muscle actin-p63-/calponin-/CK14-positive myoepithelial cells. The Ki-67 labeling index was 51.2%. Genetic analysis showed no evidence of the TRIM27-RET or NCOA4-RET fusion gene. We finally diagnosed the tumor as a high-grade mixed intercalated duct/apocrine-type IDC of the upper lip. IDC of the minor salivary glands is exceedingly rare. We discuss diagnostic problems associated with minor salivary gland lesions, and the "basal-like" phenotype of this case.

Salivary Duct Carcinoma With Rhabdoid Features-No or Aberrant Expression of E-cadherin and Genetic Changes in CDH1: Immunohistochemical and Genetic Analyses of 17 Cases.

Salivary duct carcinoma is a relatively uncommon malignancy of the salivary glands; however, it frequently occurs as a carcinomatous component of carcinoma ex pleomorphic adenoma. We previously reported salivary duct carcinoma with rhabdoid features (SDCRF) as an extremely rare subtype of salivary duct carcinoma, and that it occurred as a salivary counterpart of pleomorphic lobular carcinoma of the breast (PLCB). We collected new cases of SDCRF for this study, in which we examined a total of 17 cases immunohistochemically and genetically. As it is known that PLCB exhibits loss of or aberrant E-cadherin expression and carries nonsense/missense mutations in or deletion of the CDH1 gene, we examined the CDH1 gene status of our SDCRF cases. All of the examined SDCRF cases involved the diffuse proliferation of large ovoid cells with eosinophilic cytoplasm and eccentric nuclei, which displayed reduced cell-cell adhesion. Most cases were positive for pan-cytokeratin, androgen receptor, gross cystic disease fluid protein-15, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1, and WI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4, whereas they were negative for vimentin. No and decreased/cytoplasmic E-cadherin expression was observed in 11 and 4 of 17 cases, respectively, whereas no and decreased/cytoplasmic ß-catenin expression were observed in 10 and 5 of 17 cases, respectively. Among the 11 cases that could be genetically analyzed, a nonsense mutation (1 case), missense mutations (6 cases), and insertions (1 case) were detected in the CDH1 gene. In conclusion, we propose that SDCRF is the salivary counterpart of PLCB due to its morphology and immunophenotype, and the genetic status of CDH1.

Epithelial-myoepithelial carcinoma ex-pleomorphic adenoma of the parotid gland: report of a rare case with immunohistochemical and genetic analyses.

Epithelial-myoepithelial carcinoma (EMCa) is a rare low-grade salivary malignancy. It is rare for EMCa to occur as the carcinomatous component of carcinoma ex-pleomorphic adenoma (PA). We examined one additional case of EMCa ex-PA, immunohistochemically and genetically. The patient was an 83-year-old female, who suffered from swelling of the right parotid region. Histologically, the tumor contained a hyalinized nodule, which displayed elastosis. The main tumor exhibited a bi-layered structure, involving inner ductal cells and clear outer myoepithelial cells. Immunostaining indicated that the inner cells were positive for epithelial membrane antigen, whereas the outer cells were positive for p40. On the genetic level, the carcinoma harbored no HRAS gene mutations, whereas fluorescence in situ hybridization (FISH) of the Pleomorphic Adenoma Gene1 showed splitting signals in the carcinomatous component. We diagnosed this case as EMCa ex-PA. It is necessary to differentiate EMCa ex-PA from myoepithelial carcinoma and clear cell carcinoma, and FISH is useful for such purposes.

Pathological evaluation of tumor grade for salivary adenoid cystic carcinoma: A proposal of an objective grading system.

Three pathological grading systems advocated by Perzin/Szanto, Spiro, and van Weert are currently used for adenoid cystic carcinoma (AdCC). In these systems, the amount or presence of the solid tumor component in AdCC specimens is an important index. However, the "solid tumor component" has not been well defined. Salivary AdCC cases (N = 195) were collected after a central pathology review. We introduced a novel criterion for solid tumor component, minAmax (minor axis maximum). The largest solid tumor nest in each AdCC case was histologically screened, the maximum oval fitting the solid nest was estimated, and the length of the minor axis of the oval (minAmax) was measured. The prognostic cutoff for the minAmax was determined using training and validation cohorts. All cases were evaluated for the four grading systems, and their prognostic impact and interobserver variability were examined. The cutoff value for the minAmax was set at 0.20 mm. Multivariate prognostic analyses showed the minAmax and van Weert systems to be independent prognostic tools for overall, disease-free, and distant metastasis-free survival while the Perzin/Szanto and Spiro systems were selected for overall survival but not for disease-free or distant metastasis-free survival. The highest hazard ratio for overall survival (11.9) was obtained with the minAmax system. The reproducibility of the minAmax system (kappa coefficient of 0.81) was scored as very good while those of the other three systems were scored as moderate. In conclusion, the minAmax is a simple, objective, and highly reproducible grading system useful for prognostic stratification for salivary AdCC.

Extra-nodal metastasis should be classified separately from lymph node metastasis in gastric cancer.

INTRODUCTION: Extra-nodal metastasis (ENM) is defined as a tumor nodule without histological evidence of a lymph node structure. Although ENM has pathological features distinct from those of metastatic lymph nodes, both ENM and metastatic lymph nodes are considered within the same category in the pathological nodal (pN) classification. This study aimed to clarify the clinicopathological characteristics and prognostic relevance of ENM in gastric cancer patients who underwent curative gastrectomy. MATERIALS AND METHODS: We retrospectively evaluated 1207 Japanese patients who underwent curative gastrectomy at a single center between January 2009 and December 2013. All resected specimens were fixed in 10% formalin, processed, and stained using hematoxylin and eosin, and subsequently reviewed by two pathologists. Survival times were analyzed using the Kaplan-Meier method, and independent prognostic factors were identified using a Cox proportional hazards regression model. RESULTS: Patients who were ENM-positive had significantly poorer overall survival; multivariable analysis revealed that independent prognostic factors were older age (hazard ratio [HR]: 3.68, 95% confidence interval [CI]: 2.60-5.20), higher pathological tumor classification (HR: 2.28, 95% CI: 1.43-3.62), presence of metastatic lymph nodes (HR: 1.57, 95% CI: 1.0-2.36), and ENM-positive status (HR: 2.33, 95% CI: 1.48-3.66). ENM-positive patients had similar survival outcomes to those of ENM-negative patients with ≥16 metastatic lymph nodes. CONCLUSIONS: Among Japanese patients with gastric cancer who underwent curative gastrectomy, ENM was an independent prognostic factor with a prognostic significance different from that of lymph node metastasis. These results suggest that ENM and lymph node metastasis should be classified separately.

Eosinophilic airway inflammation and eosinophilic chronic rhinosinusitis during nivolumab and ipilimumab.

Immune-related adverse events (irAEs) are induced by immune checkpoint inhibitors (ICIs) which are administered for many cancers. There are many irAEs such as endocrine abnormalities, interstitial lung disease, and colitis. However, irAEs associated with type 2 (T2) inflammation are less known. We herein report a 71-year-old woman who developed eosinophilic airway inflammation and eosinophilic chronic rhinosinusitis (ECRS) simultaneously during combination therapy with nivolumab and ipilimumab for renal cell carcinoma. After two cycles of therapy, she developed cough and nasal congestion with high level of fractioned exhaled nitric oxide and blood eosinophil count, and nasal polyps with eosinophil infiltration in bilateral nasal cavities. She was diagnosed with eosinophilic airway inflammation and ECRS, and treated with corticosteroid inhalation, steroid nasal spray, and nasal irrigation, resulting in symptom reduction. Although they are relatively rare irAEs of ICIs, clinicians should consider these diseases associated with T2 inflammation and treat appropriately.

Prognostic impact of CRTC1/3-MAML2 fusions in salivary gland mucoepidermoid carcinoma: A multiinstitutional retrospective study.

Mucoepidermoid carcinoma (MEC) is rare, but the most common primary malignancy of the salivary gland and not infrequent in young individuals. CRTC1/3-MAML2 fusions are frequently detected in MEC and are useful as a diagnostic biomarker. However, there has been debate as to whether the fusions have prognostic significance. In this study, we retrospectively collected 153 salivary gland MEC cases from 11 tertiary hospitals in Japan. As inclusion criteria, the MEC patients in this study had curative surgery as the initial treatment, received no preoperative treatment, and had no distant metastasis at the time of the initial surgery. The MEC diagnosis was validated by a central pathology review by five expert salivary gland pathologists. The CRTC1/3-MAML2 fusions were detected using FISH and RT-PCR. In 153 MEC cases, 90 (58.8%) were positive for CRTC1/3-MAML2 fusions. During the follow-up period, 28 (18.3%) patients showed tumor recurrence and 12 (7.8%) patients died. The presence of the fusions was associated with favorable tumor features. Of note, none of the fusion-positive patients died during the follow-up period. Statistical analysis showed that the presence of the fusions was a prognostic indicator of a better overall survival in the total and advanced-stage MEC cohorts, but not in the early-stage MEC cohort. In conclusion, CRTC1/3-MAML2 fusions are an excellent biomarker for favorable overall survival of patients with salivary gland MEC.