Analysis of the clinicopathological features of tailgut cyst with emphasis on the development of neoplastic lesions.

Tailgut cyst is a rare congenital cyst occurring in the retrorectal space and development of neoplastic lesions in tailgut cyst has been reported. Due to the rarity of the tumor, the histogenesis of neoplastic lesions in tailgut cyst has remained elusive. In the present study, the clinicopathological features of tailgut cyst were analyzed with a particular focus on the development of neoplastic lesions. The clinicopathological features of four patients with tailgut cyst (one female and three males) were retrospectively reviewed. No symptoms were present in two patients. Perineal discomfort, and constipation and urinary retention, were described in the other two patients, respectively. Magnetic resonance imaging showed that the cystic lesions were hypointense on T1- and hyperintense on T2-weigted images in all patients. Histopathological analysis revealed that all lesions were multilocular, and cystic walls were covered by squamous and ciliated epithelia without nuclear atypia. The development of neoplastic lesions was noted in two patients. Dysplastic change composed of piling-up proliferation of glandular cells with mild to moderate nuclear atypia was present in one patient, and invasive adenocarcinoma with a dysplasia component was observed in another patient. Dysplasia of the glandular cells, as seen in two patients in the present series, may be a precursor lesion of invasive adenocarcinoma; therefore, adenocarcinoma arsing in tailgut cyst may show a dysplasia-carcinoma sequence. While the reported incidence of neoplastic lesions in tailgut cysts is ~9% or less, their frequency remains to be accurately determined. Therefore, complete surgical resection is important for the management of patients with tailgut cyst. Additional clinicopathological and molecular studies with large cohorts may be required to clarify the histogenesis of neoplastic lesion in tailgut cyst.

Bronchogenic cysts in rare sites (retroperitoneum, skin, spinal cord and pericardial cavity): A case series and characterization of epithelial phenotypes.

Bronchogenic cysts are congenital malformations of the bronchial tree, detected as a cystic and/or mass lesion in the thoracic cavity. Although it occurs in distant locations, such as skin and retroperitoneum, to the best of our knowledge, little is known about the components and phenotypes of the epithelium that line a bronchogenic cyst in rare sites. The present study reviewed 34 bronchogenic cysts that were surgically resected at Osaka Medical and Pharmaceutical University Hospital (Osaka, Japan) from January 1998 to December 2020. Bronchogenic cysts in rare sites were detected and diagnosis was confirmed based on the presence of pseudostratified, ciliated and/or columnar epithelium together with at least one of the following: Cartilage, smooth muscle or seromucous glands. The phenotypes of epithelium lining the cyst were characterized using immunohistochemical analysis. A total of six bronchogenic cysts in rare sites (two cases each in the retroperitoneum and skin and one case each in the cervical spinal cord and pericardial cavity) met the criteria for confirmation of the diagnoses. The epithelium lining the cyst stained positive for cytokeratin CK7 and thyroid transcription factor 1 (a marker expressed in thyroid follicles and bronchial epithelium) and negative for CK20, indicating that the phenotypes were similar to those of the respiratory epithelium. The present study demonstrated that a bronchogenic cyst can occur in rare sites, such as the retroperitoneum, skin, spinal cord and pericardial cavity, suggesting that it should be considered as a differential diagnosis before surgical approach to implement relevant management modalities such as follow-up, simple or radical resection.

Expression of Preferentially Expressed Antigen in Melanoma, a Cancer/Testis Antigen, in Carcinoma In Situ of the Urinary Tract.

Carcinoma in situ (CIS) of the urinary tract comprises 1-3% of all urothelial malignancies and is often a precursor to muscle-invasive urothelial carcinoma (UC). This study aimed to examine the expression profiles of preferentially expressed antigen in melanoma (PRAME), a cancer/testis antigen, and assess its diagnostic and therapeutic applications in CIS, given that its expression in UC has been minimally studied and has not yet been analyzed in CIS. We selected consecutive patients with CIS who underwent biopsy and/or transurethral tumor resection at the Osaka Medical and Pharmaceutical University Hospital. Immunohistochemical staining for PRAME and p53 was performed. Overall, 53 patients with CIS (6 females and 47 males) were included. Notably, PRAME expression was observed in 23 of the 53 patients (43.4%), whereas it was absent in the non-neoplastic urothelial epithelium. Furthermore, no correlation was found between PRAME expression and aberrant p53 expression. Therefore, PRAME expression may serve as a useful marker for CIS of the urinary tract. Furthermore, PRAME may be a candidate for the novel therapeutic target for standard treatment-refractory CIS patients.

The Impact of FGFR3 Alterations on the Tumor Microenvironment and the Efficacy of Immune Checkpoint Inhibitors in Bladder Cancer.

BACKGROUND: Currently, only limited knowledge is available regarding the phenotypic association between fibroblast growth factor receptor 3 (FGFR3) alterations and the tumor microenvironment (TME) in bladder cancer (BLCA). METHODS: A multi-omics analysis on 389 BLCA and 35 adjacent normal tissues from a cohort of OMPU-NCC Consortium Japan was retrospectively performed by integrating the whole-exome and RNA-sequence dataset and clinicopathological record. A median follow-up duration of all BLCA cohort was 31 months. RESULTS: FGFR3 alterations (aFGFR3), including recurrent mutations and fusions, accounted for 44% of non-muscle invasive bladder cancer (NMIBC) and 15% of muscle-invasive bladder cancer (MIBC). Within MIBC, the consensus subtypes LumP was significantly more prevalent in aFGFR3, whereas the Ba/Sq subtype exhibited similarity between intact FGFR3 (iFGFR3) and aFGFR3 cases. We revealed that basal markers were significantly increased in MIBC/aFGFR3 compared to MIBC/iFGFR3. Transcriptome analysis highlighted TIM3 as the most upregulated immune-related gene in iFGFR3, with differential immune cell compositions observed between iFGFR3 and aFGFR3. Using EcoTyper, TME heterogeneity was discerned even within aFGFR cases, suggesting potential variations in the response to checkpoint inhibitors (CPIs). Among 72 patients treated with CPIs, the objective response rate (ORR) was comparable between iFGFR3 and aFGFR3 (20% vs 31%; p = 0.467). Strikingly, a significantly higher ORR was noted in LumP/aFGFR3 compared to LumP/iFGFR3 (50% vs 5%; p = 0.022). This trend was validated using data from the IMvigor210 trial. Additionally, several immune-related genes, including IDO1, CCL24, IL1RL1, LGALS4, and NCAM (CD56) were upregulated in LumP/iFGFR3 compared to LumP/aFGFR3 cases. CONCLUSIONS: Differential pathways influenced by aFGFR3 were observed between NMIBC and MIBC, highlighting the upregulation of both luminal and basal markers in MIBC/aFGFR3. Heterogeneous TME was identified within MIBC/aFGFR3, leading to differential outcomes for CPIs. Specifically, a favorable ORR in LumP/aFGFR3 and a poor ORR in LumP/iFGFR3 were observed. We propose TIM3 as a potential target for iFGFR3 (ORR: 20%) and several immune checkpoint genes, including IDO1 and CCL24, for LumP/iFGFR3 (ORR: 5%), indicating promising avenues for precision immunotherapy for BLCA.

Impact of Trinal Histological Glandular Differentiation Grade on the Prognosis of Patients with Intrahepatic Cholangiocarcinoma: a Multicenter Retrospective Study.

INTRODUCTION: It is unclear whether the histological glandular differentiation (HGD) score that evaluates the tumor grade of two dominant components is prognostic for survival in patients with intrahepatic cholangiocarcinoma (ICC). METHOD: We retrospectively analyzed the clinical and histopathologic data of 235 consecutive patients with histologically confirmed ICC following hepatectomy at 5 university hospitals in the Kansai region of Japan. RESULTS: Survival was statistically significantly stratified by trinal HGD grade (p < 0.05). Median disease-free survival (DFS) of patients with high HGD grade was significantly shorter compared with moderate HGD grade (13.0 vs 31.2 months, respectively; p = 0.004). By Cox proportional hazards regression analysis, HGD grade had the fifth-highest hazard ratio (HR = 1.77, p = 0.002) for DFS after vascular and/or biliary invasion, extrahepatic invasion, lymph node metastasis and multiple tumors. Multivariate logistic regression analysis revealed four predictors of early recurrence after hepatectomy (lymph node metastasis: odds ratio [OR] = 3.74, p = 0.001; tumor size > 50 mm: OR = 2.80, p = 0.002; HGD grade, high: OR = 2.11, p = 0.012; and vascular or biliary tract invasion: OR = 2.11, p = 0.048). CONCLUSION: Trinal HGD grade had a significant prognostic impact on the survival of patients with ICC after radical hepatectomy.

Clinicopathological characteristics of four major histological types of high-grade parotid carcinoma.

OBJECTIVE: High-grade parotid carcinoma generally has a poor prognosis, and the histological type is mucoepidermoid carcinoma (MEC), salivary duct carcinoma (SDC), carcinoma ex pleomorphic adenoma (CEPA), or adenoid cystic carcinoma (AdCC) in the majority of cases. METHODS: During the 23-year period from September 1999 to December 2022, 250 patients with parotid carcinoma underwent initial treatment and had the histopathological type of their carcinoma. Retrospective study evaluated 111 MEC, SDC, CEPA, or AdCC cases among 134 patients with high-grade parotid carcinoma. We examined pathological and clinical features and prognosis, evaluated factors associated with recurrence, and performed immunohistological examinations. RESULTS: Pathological and clinical features and factors associated with recurrence were different for each histological type. The 10-year disease-free survival rates were as follows: MEC, 34.9%; SDC, 22.6%; CEPA, 47.1%; and AdCC, 56.3%. Human epidermal growth factor receptor type-2 and androgen receptor were positive in 48% and 56% of patients with SDC, respectively, 38% and 25% of those with CEPA. CONCLUSION: Each histological type has its own pathological and clinical features, recurrence types, and tumor activities, suggesting that differentiating between high-grade parotid carcinomas according to histological type will improve diagnosis, and thus prognosis.

Intratumoral metabolic heterogeneity of colorectal cancer.

Although the metabolic phenotype within tumors is known to differ significantly from that of the surrounding normal tissue, the importance of this heterogeneity is just becoming widely recognized. Colorectal cancer (CRC) is often classified as the Warburg phenotype, a metabolic type in which the glycolytic system is predominant over oxidative phosphorylation (OXPHOS) in mitochondria for energy production. However, this dichotomy (glycolysis vs. OXPHOS) may be too simplistic and not accurately represent the metabolic characteristics of CRC. Therefore, in this review, we decompose metabolic phenomena into factors based on their source/origin and reclassify them into two categories: extrinsic and intrinsic. In the CRC context, extrinsic factors include those based on the environment, such as hypoxia, nutrient deprivation, and the tumor microenvironment, whereas intrinsic factors include those based on subpopulations, such as pathological subtypes and cancer stem cells. These factors form multiple layers inside and outside the tumor, affecting them additively, dominantly, or mutually exclusively. Consequently, the metabolic phenotype is a heterogeneous and fluid phenomenon reflecting the spatial distribution and temporal continuity of these factors. This allowed us to redefine the characteristics of specific metabolism-related factors in CRC and summarize and update our accumulated knowledge of their heterogeneity. Furthermore, we positioned tumor budding in CRC as an intrinsic factor and a novel form of metabolic heterogeneity, and predicted its metabolic dynamics, noting its similarity to circulating tumor cells and epithelial-mesenchymal transition. Finally, the possibilities and limitations of using human tumor tissue as research material to investigate and assess metabolic heterogeneity are discussed.

Tertiary lymphoid structure and neutrophil-lymphocyte ratio coordinately predict outcome of pembrolizumab.

Emerging evidence suggests that the presence of tertiary lymphoid structures (TLS) and neutrophil-lymphocyte ratio (NLR) in peripheral blood is associated with the treatment response to checkpoint inhibitors (CPIs), whereas there is limited knowledge regarding whether these factors reciprocally impact the treatment outcomes of CPIs in metastatic urothelial carcinoma (mUC). Herein, we investigated treatment outcomes of platinum-refractory mUC patients (50 cases with whole-exome and transcriptome sequencing) treated with pembrolizumab. The pathological review identified 24% of cases of TLS in the specimens. There was no significant difference in the NLR between the TLS- and TLS+ groups (p = 0.153). In the lower NLR group, both overall survival and progression-free survival were significantly longer in patients with TLS than in those without TLS, whereas the favorable outcomes associated with TLS were not observed in patients in the higher NLR group. We explored transcriptomic differences in UC with TLS. The TLS was comparably observed between luminal (20%) and basal (25%) tumor subtypes (p = 0.736). Exploring putative immune-checkpoint genes revealed that ICOSLG (B7-H2) was significantly increased in tumors with lower NLR. KRT expression levels exhibited higher basal cell markers (KRT5 and KRT17) in the higher NLR group and lower differentiated cell markers (KRT8 and KRT18) in patients with TLS. In conclusion, the improved outcomes of pembrolizumab treatment in mUC are restricted to patients with lower NLR. Our findings begin to elucidate a distinct molecular pattern for the presence of TLS according to the NLR in peripheral blood.

Protective effect of astaxanthin nanoemulsion on mammalian inner ear hair cells.

Background: Aminoglycoside antibiotics are used for treating certain acute infections. However, these drugs cause ototoxicity by inducing inner ear hair cell death. Aims/Objectives: We investigated the protective effect of a nanoemulsion of the carotenoid astaxanthin on mammalian inner ear hair cells against neomycin-induced ototoxicity. Material and Methods: Dose-response relationship, quantification of hair cell loss, and reactive oxygen species production were assayed in response to neomycin with and without astaxanthin in cultured utricles of CBA/N mice. In addition, auditory brain response (ABR) and hair cell loss after exposure to the nanoformulation and loud noise were examined in vivo in guinea pigs. Results: Astaxanthin suppressed neomycin-induced reduction of hair cells by reducing the production of hydroxy radicals. Furthermore, hair cell loss in the second rotation of the cochlea was significantly lower in the astaxanthin group than in the noise-only group. Conclusions and Significance: The blood-labyrinth barrier limits the successful delivery of drugs for inner ear complications. However, in the nanoemulsion form, astaxanthin can penetrate the round window (fenestra ovale) membrane, enabling topical administration. Thus, astaxanthin nanoemulsion could be useful in treating ototoxicity in individuals with inner ear complications.

Ocular and extraocular sebaceous carcinomas: A retrospective study with emphasis on the presence of in situ lesion and discussion and review of the histogenesis of extraocular sebaceous carcinoma.

Sebaceous carcinoma (SC) is a rare carcinoma classified as ocular or extraocular. Ocular SC is believed to arise from the meibomian glands or the glands of Zeis. However, the origin of extraocular SC is controversial because there is no evidence of carcinoma arising from pre-existing sebaceous glands. Several hypotheses about the origin of extraocular SC have been proposed, including one suggesting an origin from intraepidermal neoplastic cells. Although extraocular SCs have been shown to occasionally comprise intraepidermal neoplastic cells, no study has investigated whether intraepidermal neoplastic cells possess sebaceous differentiation. The present study analyzed the clinicopathological features of ocular and extraocular SC, with an emphasis on the presence of in situ (intraepithelial) lesions. It retrospectively reviewed the clinicopathological features of eight patients with ocular and three patients with extraocular SC (eight women and three men; median age, 72 years), respectively. In situ (intraepithelial) lesions were observed in four of the eight ocular SC cases and one of the three extraocular SC cases and an apocrine component was noted in one patient with ocular SC (seboapocrine carcinoma). In addition, immunohistochemical analyses showed that the androgen receptor (AR) was expressed in all ocular SCs and two of the three extraocular SC cases. Adipophilin expression was observed in all ocular and extraocular SC. In situ lesions of extraocular SC showed positive immunoreactivity for both AR and adipophilin. The present study is the first to demonstrate sebaceous differentiation in in situ lesions of extraocular SC. The possible origin of extraocular SC is speculated to be the progenitor cells present in the sebaceous duct or interfollicular epidermis. The results of the present study and reported cases of SC in situ indicate that extraocular SC also arises from intraepidermal neoplastic cells.

Management and outcome of adenoid cystic carcinoma of the major salivary glands: the 22-year experience of a single institution.

BACKGROUND: Prognostic factors and survival rate are difficult to determine for adenoid cystic carcinoma(AdCC) of salivary glands. AIMS/OBJECTIVES: To clarify the clinical characteristics of AdCC and examine factors associated with recurrence and prognosis by histopathological grade classification. MATERIALS AND METHODS: Twenty-five patients with AdCC of the parotid gland and 10 patients with AdCC of the submandibular gland were included. We classified AdCC histopathologically by the proportion of solid components. Clinical features, fine-needle aspiration cytology (FNAC), and patient outcomes were examined according to grade. Factors associated with local recurrence and distant metastases were examined. RESULTS: Age was significantly higher in the grade III group than in the grade I group. The grade III group had significantly higher proportions of patients with cN+, pN+, and perineural invasion. In FNAC, lower-grade groups showed higher rates of correct histopathological type. Five-year disease-specific survival and disease-free survival rates were significantly lower in the grade III than in the grade I. Distant metastases were more common among patients with high-stage and perineural invasion. CONCLUSIONS: Five-year survival is significantly worse in patients with grade III.

Significance of desmoplastic reactions on tumor deposits in patients with colorectal cancer.

It has been well recognized that the tumor microenvironment serves important roles in the progression and invasion of cancer. The desmoplastic reaction (DR) is a fibrous tissue reaction around tumor cells, and the prognostic significance of DR in colorectal cancer (CRC) has been established. Tumor deposits (TD) are also an important prognostic indicator of CRC. Notably, immature type DR has been linked to poor prognosis. In addition, immature type DR is significantly associated with a higher pT stage, presence of lymphovascular invasion and lymph node metastasis; however, to the best of our knowledge, the association between DR and TD has not yet been examined. The present study aimed to clarify this association. This study included 443 consecutive patients with pT3 or pT4 CRC who underwent surgical resection. The histopathological features, including DR and TD, were evaluated. Statistical analyses of the presence of TD, DR and other clinicopathological parameters were performed. The present cohort included 205 female and 238 male patients; 293 (66.1%) and 150 (33.9%) patients were classified as pT3 and pT4, respectively. Immature, intermediate and mature DR were noted in 282 (63.7%), 91 (20.5%) and 70 patients (15.8%), respectively. TD was observed in 93 (21.0%) patients. Immature type DR was significantly associated with a higher pT stage (P<0.0001), presence of lymph node metastasis (P<0.0001), lymphatic (P=0.0007), venous (P<0.0001) and perineural invasion (P<0.0001), and higher tumor budding (TB) (P<0.0001). Moreover, immature type DR was significantly associated with the presence of TD (P<0.0001). The present study demonstrated a significant association between immature type DR and the presence of TD, and suggested a close relationship between lymphovascular invasion, DR, TB and TD. Additional studies are required to analyze the detailed mechanism underlying the development of immature DR in CRC to define novel treatment strategies.

Examination of nailfold videocapillaroscopy findings in ANCA-associated vasculitis.

OBJECTIVE: The objective of this study was to evaluate nailfold videocapillaroscopy (NVC) as a useful tool for assessing the disease activity of ANCA-associated vasculitis (AAV). METHODS: This study enrolled 51 patients with AAV and 21 healthy controls. We scored NVC findings semiquantitatively, and compared them between AAV patients and controls. We examined the association of NVC findings with disease activity indicators, histopathological findings of skin biopsies, and high-resolution CT (HRCT) scores in AAV. Additionally, we repeatedly rated the NVC findings 3 months after immunosuppressive therapy. RESULTS: Of the 51 enrolled patients, 36 (70.6%) showed a microangiopathy pattern and 4 (7.8%) showed a scleroderma pattern in AAV. The scores for microhaemorrhage, capillary loss, neoangiogenesis, and tortuosity were significantly higher in the AAV group than in the control group. NVC abnormalities correlated with the severity of skin, lung and kidney involvement. The scores of giant capillaries significantly correlated with the total BVAS and the chest BVAS; the scores of capillary loss correlated with the chest BVAS and the renal BVAS. The scores of microhaemorrhage significantly correlated with perivascular inflammatory cell infiltrations in the upper dermis of the purpura and tended to correlate with the total ground-glass opacity and consolidation scores on HRCT. In addition, capillary loss scores had a significant positive correlation with serum creatinine levels. Additionally, the microhaemorrhage scores were significantly reduced after 3 months of immunosuppressive therapy. CONCLUSION: In AAV patients, NVC abnormalities are significantly associated with disease severity. This result suggests that NVC is a useful tool for assessing the disease activity and treatment response in AAV.

A glucocorticoid-receptor agonist ameliorates bleomycin-induced alveolar simplification in newborn rats.

BACKGROUND: Glucocorticoids (GCs) are highly effective yet problematic agents against bronchopulmonary dysplasia (BPD). The dimeric trans-activation of GCs induces unfavorable effects, while monomeric trans-repression suppresses inflammation-related genes. Recently, non-steroidal-selective glucocorticoid-receptor agonists and modulators (SEGRAMs) with only the trans-repressive action have been designed. METHODS: Using a bleomycin (Bleo)-induced alveolar simplification newborn rat model (recapitulating arrested alveolarization during BPD), we evaluated the therapeutic effects of compound-A (CpdA), a SEGRAM. Sprague-Dawley rats were administered Bleo from postnatal day (PD) 0 to 10 and treated with dexamethasone (Dex) or CpdA from PD 0 to 13. The morphological changes and mRNA expression of inflammatory mediators, including interleukin (IL)-1ß, C-X-C motif chemokine ligand 1 (CXCL1), and C-C motif chemokine 2 (CCL2) were investigated. RESULTS: Similar to the effects of Dex, CpdA exerted protective effects on morphological derangements and inhibited macrophage infiltration and production of pro-inflammatory mediators in Bleo-treated animals. The effects of CpdA were probably mediated by GC receptor (GR)-dependent trans-repression, because unlike the Dex-treated group, anti-inflammatory genes specifically induced by GR-dependent trans-activation (such as "glucocorticoid-induced leucine zipper, GILZ") were not upregulated. CONCLUSIONS: CpdA improved lung inflammation, inhibited the arrest of alveolar maturation, and restored histological and biochemical changes in a Bleo-induced alveolar simplification model. IMPACT: SEGRAMs have attracted widespread attention because they are expected to not exhibit unfavorable effects of GCs. Compound A, one of the SEGRAMs, improved lung morphometric changes and decreased lung inflammation in a bleomycin-induced arrested alveolarization, a newborn rat model representing one of the main features of BPD pathology. Compound A did not elicit bleomycin-induced poor weight gain, in contrast to dexamethasone treatment. SEGRAMs, including compound A, may be promising candidates for the therapy of BPD with less adverse effects compared with GCs.

Prospective registration study of diagnostic yield and sample size in forceps biopsy using a novel device under digital cholangioscopy guidance with macroscopic on-site evaluation.

BACKGROUND: Although the SpyGlass Direct Visualization System can be clinically useful for diagnosing indeterminate biliary stricture, it employs SpyBite forceps, which typically obtain only a small amount of tissue and have a low sampling rate. An improved forceps biopsy device for SpyGlass DS has recently been released (SpyBite MAX). The aim of this prospective registration study was to assess the diagnostic yield and efficacy of histological biopsy tissue obtained with SpyBite MAX forceps compared with SpyBite forceps in patients with indeterminate biliary stricture. METHODS: The primary outcome of the study was the diagnostic accuracy of biopsy specimens obtained by SpyBite MAX forceps. The secondary outcomes were tissue size, number of forceps biopsies, rate of obtaining adequate tissue, and adverse events in the SpyBite MAX forceps group compared with the SpyBite group. RESULTS: Forceps biopsies using SpyBite MAX (n = 47) and SpyBite (n = 50) were performed successfully in all patients. The number of biopsies performed before visible core tissue was obtained was significantly lower in the SpyBite (mean, 1.5 ± 0.7) than in the SpyBite forceps group (mean, 2.3 ± 1.1 mm; P < .001). Tissue sample size was larger in the SpyBite MAX group (mean, 1.8 ± 1.6 mm2 ) than in the SpyBite group (mean, 1.0 ± 0.9 mm2 ; P = .004) but there was no significant difference in diagnostic accuracy. CONCLUSION: Improvements in dedicated forceps for biopsy in SpyGlass DS may contribute to improving the rates of adequate tissue and tissue sample size obtained, and to reducing the number of forceps biopsies required.

Breast neuroendocrine tumor arising in the axilla of a man: a case report.

BACKGROUND: Accessory breast carcinomas of the axilla of males are rare, and primary breast neuroendocrine tumors (BNETs) are rare as well. We present a case of a BNET arising in the axilla of a man. CASE PRESENTATION: A 64-year-old Japanese man presented with a hard 15-mm mass in the axilla and axillary lymph node swelling. Histopathological examination of the incisional biopsy specimen revealed a neuroendocrine carcinoma. Therefore, wide radical excision of the axillary tumor and axillary lymph node dissection were performed. Hematoxylin and eosin staining showed that the solid tumor was mainly located in the subcutaneous adipose tissues and appeared to invade the skin. The tumor phenotypes were positive for CAM 5.2, synaptophysin, estrogen receptor, progesterone receptor, and GATA-binding protein 3; they were negative for human epidermal growth receptor 2. The neuroendocrine component comprised more than 90% of the tumor, and the Ki-67 index was 21%. These results indicated that the tumor was a BNET. This patient underwent adjuvant chemotherapy, endocrine therapy, and radiotherapy. CONCLUSIONS: BNET cases in males are rare. The clinical and histological criteria as well as treatment for these rare cases are discussed.

Management and outcome of parotid mucoepidermoid carcinoma by histological grade: A 21-year review.

Objective: Mucoepidermoid carcinoma (MEC) is the most common malignancy of the parotid gland, but the outcome depends on the histological grade. Therefore, the aim of this study was to evaluate MEC on the basis of histological grade. Study Design: Retrospective analysis. Methods: We performed a retrospective analysis of data from patients whose initial treatment for MEC of the parotid gland was performed at our department between 1999 and 2021. We examined the association between the Armed Forces Institute of Pathology (AFIP) grade and outcome. Results: The AFIP grades were as follows: low, 26 cases; intermediate, 9 cases; and high, 31 cases. About 50% of cases were correctly diagnosed as malignant, and both grade and histology were accurately determined by fine-needle aspiration cytology in 20% of cases. The 5-year disease-free survival rate was 95.5% and 53.8% in the low-/intermediate- and high-grade cases, respectively. In the high-grade group, cases with recurrence were found to have a higher rate of lymph nodes metastasis than cases without recurrence. Furthermore, in this high-grade group, total sacrifice of the facial nerve did not reduce local recurrence. However, radical resection in the cases without tumor invasion to the nerve has decreased the local recurrence rate. The CRTC1-MAML2 fusion gene was expressed in 42.3% of low-/intermediate- and 14.3% of high-grade cases. Conclusions: The survival rate in MEC was quite different between the low-/intermediate- and high-grade cases. However, the rate of correct assessment of the grade by fine-needle aspiration cytology was poor. In high-grade cases, total sacrifice of the facial nerve may improve the rate of local recurrence in cases without invasion of the main trunk of the nerve. Expression of the CRTC1-MAML2 fusion gene could be helpful in not only the assessment of grade but the prediction of recurrence. Level of Evidence: 4.

Association of M2 Macrophages, Th2, and B Cells With Pathomechanism in Microscopic Polyangiitis Complicated by Interstitial Lung Disease.

OBJECTIVE: To address the pathomechanism of microscopic polyangiitis (MPA) complicated by interstitial lung disease (ILD) using serum biomarker profile and pulmonary histopathology. METHODS: Serum biomarkers from patients with MPA-ILD (n = 32), MPA without ILD (n = 17), and healthy controls (n = 10) were examined. Based on the biomarker profiles, principal component analysis (PCA) and cluster analysis were performed to classify patients with MPA-ILD into subgroups. Clinical characteristics and prognosis were assessed for each subgroup. Two lung biopsies were examined following H&E staining and immunostaining. RESULTS: T cell and macrophage polarization was skewed toward the T helper (Th) 2 cells and M2 macrophages in the MPA-ILD group relative to that in MPA without ILD group. The PCA allowed classification of the 19 biomarker profiles into 3 groups: (1) B cell- and neutrophil-related cytokines, vascular angiogenesis-related factors, extracellular matrix-producing factors; (2) Th1-driven cytokines, M1 macrophage-driven cytokines, and Th2-driven cytokines; and (3) M2 macrophage-induced and driven cytokines. The cluster analysis stratified the patients with MPA-ILD into clinically fibrotic-dominant (CFD) and clinically inflammatory-dominant (CID) groups. Notably, severe infections were significantly higher in the CFD group than in the CID group. Immunohistochemical staining demonstrated intense CXC motif chemokine ligand 13 staining in B cells and Th2 cells in the interstitium of the lungs of patients with MPA-ILD. CONCLUSION: The activation of M2 macrophages, Th2 cells, and B cells plays a key role in the pathomechanism of MPA-ILD. Classification of MPA-ILD based on serum biomarker profile would be useful in predicting the disease activity and the complications of severe infection in MPA-ILD.

Conjunctival epithelial hyperplasia in a patient with a nodular lesion in the palpebral conjunctiva: A case report.

The conjunctiva is a thin and delicate mucous membrane lining the inner eyelid and the anterior surface of the eyeball. Although hyperplastic changes can occur due to nonspecific chronic inflammation, 'conjunctival epithelial hyperplasia' has not been sufficiently established as a pathological entity. Additionally, the immunohistochemical (IHC) features of both the intact conjunctiva epithelium and conjunctival epithelial hyperplasia have not been sufficiently evaluated. The present report describes the case of an 86-year-old man who consulted with an ophthalmologist for a 6-month-old nodular lesion on his left eye. Located in the medial aspect of the left lower palpebral conjunctiva, the lesion was slightly erythematous and smooth. An excisional biopsy of the lesion was performed to obtain a pathological diagnosis. The hematoxylin and eosin sections revealed a thickened conjunctival epithelium composed of hyperplastic cuboidal epithelial cells and goblet cells, indicating conjunctival epithelial hyperplasia. Atypia, increased mitosis and a papillomatous architecture, indicative of neoplastic changes, were not observed. This resulted in conjunctival squamous intraepithelial neoplasia and squamous cell papilloma being ruled out. IHC analysis was performed to further characterize the lesion as well as the intact conjunctival epithelium. The thick conjunctival epithelium was composed of epithelial cells that stained positive for cytokeratin [AE1/AE3 (intensity: +), CK5/6 (intensity: ++), and CK7 (intensity: +)] and p63-positive basal cells (intensity: +) whose presence in the conjunctiva has received insufficient recognition. Moreover, squamous metaplasia was found in a segment of the thick conjunctiva, which exhibited IHC features similar to those of hyperplasia. CK5/6 was positive, indicating endogenous squamous differentiation of the conjunctival epithelial hyperplasia. These findings led to the diagnosis of conjunctival epithelial hyperplasia as a pathological entity. Further collection and analysis of several cases of conjunctival epithelial hyperplasia may lead the development of preventative methods and drug treatments for this lesion, and additional prognostic data, such as the recurrence rate.

Surgical resection of intraorbital metastasis of a gastrointestinal stromal tumor resistant to chemotherapy.

PURPOSE: We present a case of a gastrointestinal stromal tumor (GIST) metastasis of the rectal primary resisting chemotherapy to the right orbit 15 years after excision of the primary lesion. OBSERVATIONS: A 79-year-old man was diagnosed with rectal GIST at the age of 65 years and underwent rectal amputation. He underwent hepatectomy for GIST liver metastases at the age of 69 years and pericardiectomy for GIST pericardial metastases at 72 years of age. At the age of 79 years, positron emission tomography-computed tomography revealed the possibility of liver metastasis and metastasis to the right orbit of 10 mm in size. Magnetic resonance imaging revealed a well-circumscribed mass of 10 mm × 12 mm in the deep medial rectus muscle of the right orbit, which was referred to our department for ophthalmic examination. The latter revealed only mild abduction disorder in the right eye. Although chemotherapy was initiated, the tumor gradually increased, causing exophthalmos in the right eye, visual field impairment due to optic nerve exclusion, and decreased visual acuity. Due to repeated multiple metastases, the patient underwent right orbital exenteration and free flap reconstruction at the age of 83 years for radical cure. Pathological examination revealed c-Kit positive, CD34 positive, S100 protein minority positive, MIB-1 positive rate of 10% or more, and α-SMA negative, and the diagnosis was intraorbital metastasis of GIST. CONCLUSIONS AND IMPORTANCE: Orbital metastases in GISTs are extremely rare, and there is no established standard treatment. Therefore, a comprehensive decision must be made based on the final treatment goal and the patient's background when selecting treatment.