Supraglottic subepithelial benign mass lesions: Focus on clinical features of sialolipoma-like lesion

ObjectivesSialolipoma has been classified as a benign soft tissue lesion in the 2017 World Health Organization classification of head and neck tumors. To our knowledge, only one case of laryngeal sialolipoma has been reported in the English literature. We conducted a retrospective study to identify clinical characteristics of supraglottic sialolipoma-like lesion and differentiate it from other supraglottic subepithelial masses.MethodsMedical records of 16 patients with supraglottic subepithelial benign mass lesions who underwent histological evaluation between 2003 and 2019 were retrospectively analyzed. Sialolipoma-like lesion was defined as a local finding of a well-circumscribed gross mass with pathological presence of salivary gland-like parenchymal lobules with evenly interspersed adipose tissue.ResultsEight patients showed histological positivity for sialolipoma-like lesion, 3 for amyloidosis, 2 for hemangioma, and 1 each for cyst, lymphoid hyperplasia, and chondrometaplasia. Sialolipoma-like lesion tended to be predominant among men; those affected had a mean age of 52.8 (range, 39–74) years. By contrast, among patients with amyloidosis, the ratio of men to women was 1:2 (100% vs. 33%; p = 0.055). Fiberscopic examination of all patients with sialolipoma-like lesions identified well-circumscribed, yellowish masses, closely resembling local amyloidosis findings. Sialolipoma-like lesion was associated with a significantly higher body-mass index (BMI; 27.4 ± 2.8 kg/m²) than amyloidosis (21.6 ± 1.4 kg/m²; p = 0.014). The transoral approach was used for lesion resection in all patients with sialolipoma-like lesion. No patient experienced postoperative recurrence.ConclusionLaryngeal sialolipoma-like lesion might be more prevalent than was previously reported, and histological examination is important to differentiate it from amyloidosis. Supraglottic sialolipoma-like lesion must be differentially diagnosed in patients with high BMI presenting with well-circumscribed, yellowish supraglottic masses.     

Comprehensive mutational analysis of the VHL gene in sporadic renal cell carcinoma: relationship to clinicopathological parameters

To delineate more precisely the somatic von Hippel-Lindau disease (VHL) gene alteration as well as to elucidate its etiologic role in renal tumorigenesis, we examined a total of 240 sporadic renal cell carcinomas (RCCs) for somatic VHL gene alterations by DNA-SSCP followed by sequencing, methylation-specific PCR assay, microsatellite LOH study, and Southern blot analysis. Intragenic mutation of the VHL gene was found exclusively in clear-cell or variant-type RCCs at a frequency of 51% (104/202). Hypermethylation of the VHL promoter region was detected in an additional 11 clear-cell RCCs. Microsatellite analysis demonstrated that LOH of the VHL locus was found in 140/155 (90%) informative clear-cell RCCs. The VHL gene therefore seems to be inactivated in a two-hit manner by intragenic mutation or hypermethylation plus allelic loss in clear-cell RCC. Genomic rearrangement of the VHL gene detected by Southern analysis was not found (0/216 cases); this is in contrast to germ lines in which Southern aberrations consisted of 7-19% of the mutations. Clinicopathologic data demonstrated that VHL mutation/LOH did not vary according to tumor progression in clear-cell RCC, including tumor diameter, stage, grading, distant metastasis, and lymph node metastasis. Interestingly, VHL mutation was significantly less frequent in RCCs occurring in younger (< or = 55 years) than that in older (> or = 56 years) patients. These data suggested that the inactivation of the VHL tumor-suppressor gene is a specific genetic change in clear-cell RCC, and that it may occur at an early or first step in the clear-cell tumorigenic pathway rather than as a late event.     

Gastric juvenile polyposis associated with germline SMAD4 mutation

We treated a 39-year-old woman with hypoproteinemia and anemia who had profuse gastric polyposis. Radiographic and endoscopic examination showed numerous polyps restricted to the stomach. The patient had pulmonary arteriovenous malformations in the left lung. Histological examination of the resected stomach revealed the gastric polyposis to be composed of cystic dilatation of the glands with small areas of adenocarcinoma. These findings were compatible with gastric juvenile polyposis (GJP) accompanied by gastric cancer. Analysis of genomic DNA revealed that the patient had truncating mutation of SMAD4, a responsible gene for juvenile polyposis (JP). Our case suggests that SMAD4 is possibly a responsible gene for GJP.     

Antioxidative role of urinary trypsin inhibitor in acute lung injury induced by lipopolysaccharide

We have previously demonstrated the protective role of urinary trypsin inhibitor (UTI) against acute inflammatory lung injury induced by lipopolysaccharide (LPS) using UTI-deficient (-/-) mice and corresponding wild-type (WT) mice. The protection was mediated, at least partly, through inhibition of the enhanced local expression of proinflammatory cytokines, chemokines, and intercellular adhesion molecule-1. In the present study, we addressed whether UTI regulates oxidative stress generated by LPS challenge in the lung. UTI (-/-) and WT mice were treated intratracheally with vehicle or LPS (125 microg/kg). After LPS challenge in both genotypes of mice, the lung levels of mRNA for inducible nitric oxide synthase and hemo oxygenase-1 were elevated, but to a greater extent in UTI (-/-) mice than in WT mice. Immunohistochemistry showed that the formations of 8-hydroxy-2'-deoxyguanosine and nitrotyrosine in the lung were more intense in UTI (-/-) mice than in WT mice after LPS challenge. These results indicate that endogenous UTI is protective against acute lung injury induced by bacterial endotoxin, at least partly, via the antioxidative properties.     

Protein kinase D1 and the beta 1 integrin cytoplasmic domain control beta 1 integrin function via regulation of Rap1 activation

The functional activity of integrins is dynamically regulated by T cell receptor stimulation and by protein kinase C (PKC). We report a novel function for the PKC effector protein kinase D1 (PKD1) in integrin activation. Constitutively active and kinase-inactive PKD1 mutants lacking the PKD1 pleckstrin homology (PH) domain block phorbol ester- and TCR-mediated activation and clustering of beta1 integrins. The PH domain of PKD1 mediates the association of PKD1 with the GTPase Rap1 and is central to Rap1 activation and membrane translocation in T cells. Furthermore, PKD1 and Rap1 associate with beta1 integrins in a manner that is dependent on the carboxy-terminal end of the beta1 integrin subunit cytoplasmic domain. beta1 integrin expression is required for Rap1 activation and membrane localization of the PKD1-Rap1 complex. Therefore, PKD1 promotes integrin activation in T cells by regulating Rap1 activation and membrane translocation via interactions with the beta1 integrin subunit cytoplasmic domain.     

SIRPα on CD11c+ cells induces Th17 cell differentiation and subsequent inflammation in the CNS in experimental autoimmune encephalomyelitis

Signal regulatory protein α (SIRPα) is expressed predominantly on type 2 conventional dendritic cells (cDC2s) and macrophages. We previously showed that mice systemically lacking SIRPα were resistant to experimental autoimmune encephalomyelitis (EAE). Here, we showed that deletion of SIRPα in CD11c⁺ cells of mice (Sirpa^ΔDC mice) also markedly ameliorated the development of EAE. The frequency of cDCs and migratory DCs (mDCs), as well as that of Th17 cells, were significantly reduced in draining lymph nodes of Sirpa^ΔDC mice at the onset of EAE. In addition, we found the marked reduction in the number of Th17 cells and DCs in the CNS of Sirpa^ΔDC mice at the peak of EAE. Whereas inducible systemic ablation of SIRPα before the induction of EAE prevented disease development, that after EAE onset did not ameliorate the clinical signs of disease. We also found that EAE development was partially attenuated in mice with CD11c⁺ cell-specific ablation of CD47, a ligand of SIRPα. Collectively, our results suggest that SIRPα expressed on CD11c⁺ cells, such as cDC2s and mDCs, is indispensable for the development of EAE, being required for the priming of self-reactive Th17 cells in the periphery as well as for the inflammation in the CNS.     

Negative regulation by SHPS-1 of Toll-like receptor-dependent proinflammatory cytokine production in macrophages

SHPS-1 is a transmembrane protein predominantly expressed in macrophages. The possible role of SHPS-1 in regulation of Toll-like receptor (TLR)-dependent production of proinflammatory cytokines by macrophages has remained unknown, however. We now show that expression either of a mutant version of mouse SHPS-1 (SHPS-1–4F) in which the four tyrosine phosphorylation sites in the cytoplasmic region are replaced by phenylalanine or of a chimeric protein comprising the extracellular and transmembrane regions of human CD8 fused to the cytoplasmic region of SHPS-1–4F (CD8–4F) markedly promoted the production of tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6) induced by lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid [poly(I : C)] in RAW264.7 macrophages. In contrast, expression of a mutant form of SHPS-1 that lacks most of the cytoplasmic region did not promote such responses. Expression of SHPS-1–4F promoted the LPS- or poly(I : C)-induced activation of NF-κB. LPS and poly(I : C) each induced the tyrosine phosphorylation of SHPS-1 through a Src family kinase and the association of SHPS-1 with SHP-1 and SHP-2. These results suggest that LPS or poly(I : C) induces tyrosine phosphorylation of SHPS-1 and the association of SHPS-1 with SHP-1 and SHP-2 in a manner dependent on a Src family kinase. SHPS-1 then negatively regulates TLR4- or TLR3-dependent cytokine production through inhibition of NF-κB-dependent signaling.     

Collecting duct carcinoma of the kidney: an immunohistochemical evaluation of the use of antibodies for differential diagnosis

Collecting duct carcinoma is a highly aggressive renal epithelial malignancy, although it accounts for less than 1% of the incidence of renal epithelial neoplasms. Differential diagnoses between collecting duct carcinoma, pelvic urothelial carcinoma with marked invasion to the renal parenchyma (invasive urothelial carcinoma), and papillary renal cell carcinoma is often challenging. In our current study, we examined the utility of using commercially available antibodies, in conjunction with lectin histochemistry, for such differential diagnoses. We examined 17 cases of collecting duct carcinoma, 10 cases of invasive urothelial carcinoma and 15 cases of papillary renal cell carcinoma (type 1, 6 cases; type 2, 9 cases) in these evaluations. Our results indicated that Ulex europaeus agglutinin 1, E-cadherin, and c-KIT were frequently positive in collecting duct carcinoma and invasive urothelial carcinoma, in comparison with papillary renal cell carcinoma, which had negative results for CD10 and α-methylacyl CoA racemase. We found, however, that collecting duct carcinoma showed positivity for high-molecular-weight cytokeratin and low-molecular-weight cytokeratin at a low frequency compared with invasive urothelial carcinoma, and that these distinctions need further careful evaluation. In addition, high-molecular-weight cytokeratin positivity was not a reliable marker for collecting duct carcinoma. We conclude that Ulex europaeus agglutinin 1 reactivity and positivity for E-cadherin and c-KIT are effective in distinguishing collecting duct carcinoma from papillary renal cell carcinoma, and that negative results for α-methylacyl CoA racemase and CD10 are potentially useful hallmarks of this distinction also. In contrast, a differential diagnosis for collecting duct carcinoma and invasive urothelial carcinoma will require careful examination of multiple routinely stained specimens, particularly in cases of in situ neoplastic lesions in the pelvic mucosa.     

Clinicopathologic Characteristics and Prognosis of Gastric Cancer in Young Patients

To determine the clinicopathologic characteristics and prognosis of gastric cancer in young patients, a total of 1985 gastric cancer patients who had undergone gastrectomy at our hospital were reviewed. The male-to-female ratio was significantly lower in the young patients than in either the middle-aged (P < 0.0001) or elderly patients (P < 0.0001). Undifferentiated carcinoma was observed more frequently in the young patients compared with either the middle-aged (P < 0.0001) or elderly patients (P < 0.0001). Furthermore, peritoneal metastasis was observed more frequently in the young patients than in either the middle-aged (P < 0.005) or elderly patients (P < 0.005). Five-year survival rates were 61.0, 73.6 and 68.1% in the young, middle-aged and elderly patients, respectively. The prognosis of the middle-aged patients was significantly better than that of either the young or the elderly patients (P < 0.05). Multivariate analysis indicated that age was an independent prognostic factor. Peritoneal recurrence was more frequently observed in the young patients than either the middle-aged or the elderly patients (P < 0.05). Gastric cancer in young patients has unique characteristics, namely, a predominance of female patients and a high frequency of undifferentiated cancer and peritoneal metastasis and recurrence.