AB014. The accurate classification of high-grade glioma, IDH-wildtype, is based on methylation profiling: a case report.

BACKGROUND: The 2021 World Health Organization (WHO) classification has significantly enhanced the molecular diagnostics of diffuse gliomas, emphasizing the role of molecular features alongside histology. However, accurate classification remains challenging, particularly for high-grade gliomas, IDH-wildtype. DNA methylation profiling provides an unbiased diagnostic approach, offering valuable insights into tumor classification. Here, we present a case of a high-grade glioma, initially diagnosed as glioblastoma, IDH-wildtype based on histological and genetic analysis, but later reclassified as a diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (RTK2 subtype) through methylation profiling. CASE DESCRIPTION: A 7-year-old boy presenting with seizures was admitted to our hospital, where brain magnetic resonance imaging revealed a tumor in the right temporal lobe. Intraoperative histology indicated a high-grade glioma, prompting maximal resection. Diagnosis according to the 2021 WHO classification involved histological analysis, immunohistochemistry, testing for specific genetic alterations, and DNA methylation profiling. Histological and immunohistochemical assessment initially identified the tumor as a high-grade astrocytoma, IDH-wildtype. Specific genetic testing revealed IDH1-wildtype, IDH2-wildtype, and TERT promoter mutation, consistent with a diagnosis of glioblastoma, IDH-wildtype. However, methylation profiling yielded a classifier score of 0.99 for a diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (RTK2 subtype). CONCLUSIONS: Our case illustrated that conventional histological and genetic analysis classification can be reclassified according to the DNA methylation analysis, demonstrating that methylation profiling is useful to accurately classify high-grade gliomas, particularly those of the IDH-wildtype subtype.

Insulin-like growth factor II mRNA binding protein 3 is highly expressed in primary diffuse large B-cell lymphoma of the CNS.

Primary diffuse large B-cell lymphoma of the central nervous system (CNS-DLBCL) can be difficult to diagnose because of the limited amount of biopsy tissue. Here, we analyzed the utility of insulin-like growth factor II mRNA binding protein 3 (IMP3) immunohistochemistry (IHC) as an adjunctive diagnostic tool for CNS-DLBCL. IHC was performed on 57 biopsy samples (55 brain biopsy samples and two vitreous cell blocks) from 54 patients with CNS-DLBCL, including three biopsy samples initially diagnosed as negative or indeterminate for CNS-DLBCL. Additionally, IMP3 IHC was performed on 68 DLBCLs other than CNS-DLBCL and 12 inflammatory brain diseases. Cytoplasmic IMP3 expression was noted in ≥50% of tumor cells in 100% (57/57) of CNS-DLBCLs and 88.2% (60/68) of non-CNS-DLBCLs. In contrast, no IMP3-positive CD20-positive B cells were observed in the inflammatory brain disease (P < 0.0001). In conclusion, IMP3 is highly expressed in CNS-DLBCL. However, it is also expressed in other types of DLBCLs, making it less specific. Most CNS-DLBCL cases can be diagnosed without performing IHC for IMP3 expression, but it may be a useful adjunctive tool to differentiate from reactive lesions when tumor cells are few or deformed.

Genetic profiles and clinical features in subcutaneous panniculitis-like T-cell lymphomas.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare peripheral T-cell lymphoma characterized by cutaneous lesions and immunologic manifestations. The five-year survival rate of SPTCL has been reported to be over 80%, indicating a favorable prognosis. Recent studies have uncovered recurrent germline variants in HAVCR2, encoding an immunomodulator. In this study, we integrated whole-exome sequencing data from 60 samples collected from 36 SPTCL patients, encompassing six patients of our cohort and 30 patients of publicly available data. We identified 138 somatic mutations in skin tumors of 24 patients and HAVCR2 germline mutations in 23 of 29 patients. HAVCR2 p.Tyr82Cys mutations were identified in four of six Japanese patients. During the clinical courses of four patients, cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone were administered to all patients, but it resulted in incomplete responses in all four patients. However, disease conditions of all patients remained stable with additional treatment, including autologous peripheral blood stem cell transplantation. Over a 7.5-year median follow-up, one patient developed autoimmune-related diseases, while one developed other hematological malignancy, resulting in death. To our knowledge, this is the first report of recurrent HAVCR2 germline mutations in Japanese patients, suggesting the necessity for long-term follow-up.

Hypofractionated radiotherapy combined with bevacizumab plus low-dose ifosfamide, carboplatin, and etoposide as second-line chemoradiotherapy for progressing spinal diffuse midline glioma, H3K27-altered: illustrative case.

BACKGROUND: Spinal cord diffuse midline glioma (DMG) is a relatively rare disease with a poor prognosis and no effective treatment. OBSERVATIONS: A 45-year-old man presented with rapidly progressive paraplegia in both lower extremities, along with bladder and bowel disturbance. Spinal magnetic resonance imaging (MRI) showed a heterogeneously contrast-enhanced mass at the T1-4 levels. A biopsy via T1-4 decompressive laminectomy with expansive duraplasty was performed. The histopathological diagnosis was DMG, H3K27-altered, World Health Organization grade 4. Radiation plus concomitant temozolomide was started; however, follow-up MRI showed tumor progression. Additional hypofractionated radiotherapy (HFRT; 24 Gy/5 fractions) was performed, with bevacizumab (BEV) plus low-dose ifosfamide-carboplatin-etoposide (ICE) as second-line treatment. One month later, MRI showed tumor regression with significant improvement in the peritumoral edema. The chemotherapy regimen was repeated every 4-6 weeks, and the patient remained stable. After 13 courses of chemotherapy, the size of the spinal DMG increased markedly, with dissemination to the temporal lobe. The patient died approximately 21 months after the initial diagnosis. LESSONS: Spinal DMG is a malignant tumor with a poor prognosis. However, treatment with additional HFRT combined with BEV plus low-dose ICE may inhibit tumor progression to prolong the progression-free period and survival. https://thejns.org/doi/10.3171/CASE2464.

Trochlear nerve schwannoma with concomitant osimertinib-responsive stage IV lung adenocarcinoma: illustrative case.

BACKGROUND: The prognosis for cancer patients has been improved because of the development of molecularly targeted drugs. Treatment of intracranial tumors must be personalized while prioritizing the treatment of comorbid cancers. OBSERVATIONS: A 38-year-old man presented with bloody sputum, bilateral multiple nodules, and a mass in the lower lobe of his right lung. Bronchoscopy revealed stage IV lung adenocarcinoma with an epidermal growth factor receptor (EGFR) mutation. Screening head magnetic resonance imaging revealed a 38-mm-diameter mass in the left petroclival area. Because the patient was neurologically intact, the treatment of lung adenocarcinoma was prioritized, and the third-generation EGFR-tyrosine kinase inhibitor osimertinib was used. Although nodules in the lung began to shrink, the intracranial lesion expanded and caused hydrocephalus, necessitating a ventriculoperitoneal shunt. The tumor also caused diplopia, dysarthria, and gait abnormalities. A left anterior transpetrosal approach was used to remove the tumor derived from the trochlear nerve. The pathological examination revealed schwannoma. Neurological symptoms improved following surgery. Osimertinib was continued during the perioperative period. LESSONS: Osimertinib was effective for lung adenocarcinoma but not for trochlear nerve schwannoma, which required surgical intervention. It is necessary to tailor the treatment of benign brain tumors in patients with concurrent malignant cancers. https://thejns.org/doi/10.3171/CASE24144.

Intra-patient spatial comparison of non-metastatic and metastatic lymph nodes reveals the reduction of CD169+ macrophages by metastatic breast cancers.

BACKGROUND: Breast cancer cells suppress the host immune system to efficiently invade the lymph nodes; however, the underlying mechanism remains incompletely understood. Here, we aimed to comprehensively characterise the effects of breast cancers on immune cells in the lymph nodes. METHODS: We collected non-metastatic and metastatic lymph node samples from 6 patients with breast cancer with lymph node metastasis. We performed bulk transcriptomics, spatial transcriptomics, and imaging mass cytometry to analyse the obtained lymph nodes. Furthermore, we conducted histological analyses against a larger patient cohort (474 slices from 58 patients). FINDINGS: The comparison between paired lymph nodes with and without metastasis from the same patients demonstrated that the number of CD169+ lymph node sinus macrophages, an initiator of anti-cancer immunity, was reduced in metastatic lymph nodes (36.7 ± 21.1 vs 7.3 ± 7.0 cells/mm2, p = 0.0087), whereas the numbers of other major immune cell types were unaltered. We also detected that the infiltration of CD169+ macrophages into metastasised cancer tissues differed by section location within tumours, suggesting that CD169+ macrophages were gradually decreased after anti-cancer reactions. Furthermore, CD169+ macrophage elimination was prevalent in major breast cancer subtypes and correlated with breast cancer staging (p = 0.022). INTERPRETATION: We concluded that lymph nodes with breast cancer metastases have fewer CD169+ macrophages, which may be detrimental to the activity of anti-cancer immunity. FUNDING: JSPS KAKENHI (16H06279, 20H03451, 20H04842, 22H04925, 19K16770, and 21K15530, 24K02236), JSPS Fellows (JP22KJ1822), AMED (JP21ck0106698), JST FOREST (JPMJFR2062), Caravel, Co., Ltd, Japan Foundation for Applied Enzymology, and Sumitomo Pharma Co., Ltd. under SKIPS.

Predicting invasive disease-free survival in ER-positive, HER2-negative early breast cancer using the PAM50 risk-of-recurrence score: a retrospective analysis using single-center long-term follow-up data of postmenopausal Japanese patients.

BACKGROUND: The prognostic value of the risk-of-recurrence (ROR) score calculated using PAM50 has been validated using clinical trials and patient cohorts. This study aimed to investigate the prognostic value of the PAM50 ROR score in Japanese patients with early breast cancer using long-term follow-up data. METHODS: We enrolled postmenopausal patients with ER-positive, HER2-negative, stage I-II breast cancer who had undergone surgery at the Kyoto University Hospital between 2008 and 2014. The intrinsic subtype and ROR score were calculated using PAM50. The primary endpoint was invasive disease-free survival (IDFS). RESULTS: We enrolled 146 patients, of whom 47 (32%) patients had node-positive disease, and 36 (25%) had received neoadjuvant or adjuvant chemotherapy. The proportions of intrinsic subtypes for luminal A, luminal B, HER2-enriched, and basal-like subtypes were 67%, 27%, 3%, and 2%, respectively. The median follow-up duration was 8.4 (range 6.3-10.0) years, and 21 IDFS events were observed. Based on the ROR score, 37%, 33%, and 30% of the patients were classified as low, intermediate, and high risks, respectively. Patients in the high-risk group had a significantly worse 8-year IDFS rate than those in the low-to-intermediate-risk groups (75.1% vs. 91.6%, p = 0.04). The same trend was observed in patients with and without neoadjuvant or adjuvant chemotherapy. CONCLUSIONS: Using long-term follow-up data, this study showed that the ROR score can predict the prognosis of ER-positive, HER2-negative early breast cancer in Japanese postmenopausal patients. Further investigations are required to confirm the prognostic value of the ROR score in Asian populations.

Adenoma mimicking intraductal papillary neoplasm of the bile duct arising in an intrahepatic biliary duplication cyst.

We report a case of a cystic liver tumour in a 47-year-old man with Peutz-Jeghers syndrome (PJS) who had undergone sclerotherapy at another hospital for a cyst in hepatic segment IV (S4) 7 years earlier. Based on the preoperative imaging findings, the patient was diagnosed with an intraductal papillary neoplasm of the bile duct. Percutaneous transhepatic portal vein embolization was performed to increase the residual liver volume, followed by resection of the three right hepatic lobes and the caudate lobe, biliary reconstruction, and portal vein reconstruction. Pathological examination revealed an adenoma arising in an intrahepatic biliary duplication cyst. Retrospectively, the preoperative diagnosis was difficult, but it aligned with previous reports of biliary duplication cysts due to its continuity with the bile duct. Additionally, intrahepatic biliary duplication cysts with tumour lesions or cases in which 18F-fluorodeoxyglucose positron emission tomography was performed have not been previously reported. Therefore, preoperatively listing this disease as a differential diagnosis was difficult. PJS and chronic inflammation associated with cyst sclerotherapy may have contributed to tumour development in the intrahepatic biliary duplication cyst.

Clinical and imaging characteristics of supratentorial glioma with IDH2 mutation.

PURPOSE: The rarity of IDH2 mutations in supratentorial gliomas has led to gaps in understanding their radiological characteristics, potentially resulting in misdiagnosis based solely on negative IDH1 immunohistochemical staining. We aimed to investigate the clinical and imaging characteristics of IDH2-mutant gliomas. METHODS: We analyzed imaging data from adult patients with pathologically confirmed diffuse lower-grade gliomas and known IDH1/2 alteration and 1p/19q codeletion statuses obtained from the records of our institute (January 2011 to August 2022, Cohort 1) and The Cancer Imaging Archive (TCIA, Cohort 2). Two radiologists evaluated clinical information and radiological findings using standardized methods. Furthermore, we compared the data for IDH2-mutant and IDH-wildtype gliomas. Multivariate logistic regression was used to identify the predictors of IDH2 mutation status, and receiver operating characteristic curve analysis was employed to assess the predictive performance of the model. RESULTS: Of the 20 IDH2-mutant supratentorial gliomas, 95% were in the frontal lobes, with 75% classified as oligodendrogliomas. Age and the T2-FLAIR discordance were independent predictors of IDH2 mutations. Receiver operating characteristic curve analysis for the model using age and T2-FLAIR discordance demonstrated a strong potential for discriminating between IDH2-mutant and IDH-wildtype gliomas, with an area under the curve of 0.96 (95% CI, 0.91-0.98, P = .02). CONCLUSION: A high frequency of oligodendrogliomas with 1p/19q codeletion was observed in IDH2-mutated gliomas. Younger age and the presence of the T2-FLAIR discordance were associated with IDH2 mutations and these findings may help with precise diagnoses and treatment decisions in clinical practice.

Response to capmatinib in a patient with neuroendocrine carcinoma of the gallbladder origin harboring MET amplification.

Neuroendocrine carcinoma (NEC) of the gallbladder origin is particularly rare, accounting for only 0.38% of primary malignancies of the gallbladder, and standard therapies are limited. The MET gene encodes the tyrosine kinase receptor, c-Met. Pathogenic variants of MET, such as MET exon 14 skipping and MET amplification, result in excessive downstream signaling that promotes tumor progression. A MET inhibitor, capmatinib, blocks signaling of c-Met and has been approved by the Food and Drug Administration for non-small cell lung cancer with MET exon 14 skipping. The effectiveness of capmatinib has been reported in other cancers with MET amplification, but NEC with MET variants has not been reported. Here, we present a case of a 72-year-old woman with NEC of the gallbladder with multiple liver and lymph node metastases, who was resistant to conventional chemotherapy including carboplatin plus etoposide as first-line treatment and irinotecan as second-line treatment, but she responded to capmatinib. After 6 weeks of treatment, CT scan showed a partial response (80% reduction in size), but after 13 weeks, regrowth of liver metastasis was observed. Herein, we report a meaningful efficacy of capmatinib to the patient of NEC of the gallbladder origin with MET amplification.

Expression of FOXI1 and POU2F3 varies among different salivary gland neoplasms and is higher in Warthin tumor.

PURPOSE: Salivary gland tumors are histologically diverse. Ionocytes and tuft cells, rare epithelial cells found in normal salivary glands, might be associated with salivary tumors. Here, we explored the expression of FOXI1 and POU2F3, master regulators of ionocytes and tuft cells, respectively, for common salivary neoplasms using immunohistochemistry. METHODS: We analyzed normal salivary tissues and nine salivary gland tumors; Warthin tumors (WT), pleomorphic adenomas (PA), basal cell adenomas, and oncocytomas were benign, whereas mucoepidermoid, adenoid cystic, acinic cell, salivary duct carcinomas, and polymorphous adenocarcinomas were malignant. RESULTS: Normal salivary glands contained a few FOXI1- and POU2F3-positive cells in the ducts instead of the acini, consistent with ionocytes and tuft cells, respectively. Among the benign tumors, only WTs and PAs consistently expressed FOXI1 (10/10 and 9/10, respectively). The median H-score of WTs was significantly higher than that of PAs (17.5 vs. 4, P = 0.01). While WTs and PAs harbored POU2F3-positive cells (10/10 and 9/10, respectively), the median H-score was higher in WTs than in PAs (10.5 vs 4, respectively). Furthermore, WTs exhibited a unique staining pattern of FOXI1- and POU2F3-positive cells, which were present in luminal and abluminal locations, respectively. Whereas none of the malignant tumors expressed FOXI1, only adenoid cystic carcinoma consistently expressed POU2F3 (5/5), with a median H-score of 4. CONCLUSION: The expression patterns of the characteristic transcription factors found in ionocytes and tuft cells vary among salivary gland tumor types and are higher in WT, which might be relevant for understanding and diagnosing salivary gland neoplasms.

Successful Management of Malignant Pericarditis Using Nivolumab for Metastatic Esophageal Squamous Cell Carcinoma.

Esophageal cancer is a malignant disease with a poor prognosis and is one of the most common causes of cardiac metastasis. Malignant pericarditis may cause the repetitive accumulation of pericardial effusion, which can occasionally pose a clinical challenge. We herein report a case of malignant pericarditis in a patient with metastatic esophageal squamous cell carcinoma with cardiac tamponade, which was successfully managed with single pericardial drainage and systemic nivolumab monotherapy. This is the first case report to suggest that systemic therapy with nivolumab is a promising option for the management of malignant pericarditis.

Genetic Characterization of Primary Mediastinal B-Cell Lymphoma: Pathogenesis and Patient Outcomes.

PURPOSE: Primary mediastinal large B-cell lymphoma (PMBCL) is a rare aggressive lymphoma predominantly affecting young female patients. Large-scale genomic investigations and genetic markers for risk stratification are lacking. PATIENTS AND METHODS: To elucidate the full spectrum of genomic alterations, samples from 340 patients with previously untreated PMBCL were investigated by whole-genome (n = 20), whole-exome (n = 78), and targeted (n = 308) sequencing. Statistically significant prognostic variables were identified using a multivariable Cox regression model and confirmed by L1/L2 regularized regressions. RESULTS: Whole-genome sequencing revealed a commonly disrupted p53 pathway with nonredundant somatic structural variations (SVs) in TP53-related genes (TP63, TP73, and WWOX) and identified novel SVs facilitating immune evasion (DOCK8 and CD83). Integration of mutation and copy-number data expanded the repertoire of known PMBCL alterations (eg, ARID1A, P2RY8, and PLXNC1) with a previously unrecognized role for epigenetic/chromatin modifiers. Multivariable analysis identified six genetic lesions with significant prognostic impact. CD58 mutations (31%) showed the strongest association with worse PFS (hazard ratio [HR], 2.52 [95% CI, 1.50 to 4.21]; P < .001) and overall survival (HR, 2.33 [95% CI, 1.14 to 4.76]; P = .02). IPI high-risk patients with mutated CD58 demonstrated a particularly poor prognosis, with 5-year PFS and OS rates of 41% and 58%, respectively. The adverse prognostic significance of the CD58 mutation status was predominantly observed in patients treated with nonintensified regimens, indicating that dose intensification may, to some extent, mitigate the impact of this high-risk marker. By contrast, DUSP2-mutated patients (24%) displayed durable responses (PFS: HR, 0.2 [95% CI, 0.07 to 0.55]; P = .002) and prolonged OS (HR, 0.11 [95% CI, 0.01 to 0.78]; P = .028). Upon CHOP-like treatment, these patients had very favorable outcome, with 5-year PFS and OS rates of 93% and 98%, respectively. CONCLUSION: This large-scale genomic characterization of PMBCL identified novel treatment targets and genetic lesions for refined risk stratification. DUSP2 and CD58 mutation analyses may guide treatment decisions between rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab.

Circularity of islets is a distinct marker for the pathological diagnosis of adult non-neoplastic hyperinsulinemic hypoglycemia using surgical specimens.

BACKGROUND: Adult non-neoplastic hyperinsulinemic hypoglycemia (ANHH), also known as adult-onset nesidioblastosis, is a rare cause of endogenous hyperinsulinemic hypoglycemia in adults. This disease is characterized by diffuse hyperplasia of pancreatic endocrine cells and is diagnosed by a pathological examination. While diagnostic criteria for this disease have already been proposed, we established more quantitative criteria for evaluating islet morphology. METHODS: We measured the number, maximum diameter, total area, and circularity (representing how closely islets resemble perfect spheres) of islets contained in representative sections of ANHH (n = 4) and control cases (n = 5) using the NIS-Elements software program. We also measured the average cell size, percentage of cells with enlarged nuclei, and percentage of cells with recognizable nucleoli for each of three representative islets. We also assessed the interobserver diagnostic concordance of ANHH between five experienced and seven less-experienced pathologists. RESULTS: There was no significant difference in the number, maximum diameter, or total area of islets between the two groups, even after correcting for these parameters per unit area. However, the number of islets with low circularity (< 0.71) per total area of the pancreatic parenchyma was significantly larger in ANHH specimens than in controls. We also found that the percentage of cells with recognizable nucleoli was significantly higher in the ANHH group than in the controls. There were no significant differences in the average cell size or the number of cells with enlarged nuclei between the groups. The correct diagnosis rate with the blind test was 47.5% ± 6.12% for experienced pathologists and 50.0% ± 8.63% for less-experienced pathologists, with no significant differences noted. CONCLUSIONS: Low circularity, which indicates an irregular islet shape, referred to as "irregular shape and occasional enlargement of islets" and "lobulated islet structure" in a previous report, is a useful marker for diagnosing ANHH. An increased percentage of recognizable nucleoli, corresponding to "macronucleoli in ß-cells," has potential diagnostic value.

Evolutionary histories of breast cancer and related clones.

Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1-3. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.

Deep Infantile Hemangioma in the Involuting Phase That Was Difficult to Diagnose before Surgery.

Infantile hemangioma (IH) is a common pediatric vascular tumor and is easily diagnosed in most cases based on the clinical course and appearance, but deep IHs are difficult to diagnose based on external appearance alone. Clinical and imaging findings are therefore important clues to the diagnosis of soft tissue tumors; however, a definitive diagnosis is decided based on the pathological examination of biopsy or resection specimens. A 1-year-old girl with a subcutaneous mass on her glabella was referred to our hospital. At 3 months of age, her mother noticed a tumor that swelled when she cried. It gradually enlarged, and ultrasonography and magnetic resonance imaging were performed at 12 months of age. Doppler ultrasonography showed a hypo-vascular mass. Magnetic resonance imaging revealed a subcutaneous mass with low-intensity on T1-weighted image and slightly high-intensity on T2-weighted image, with tiny flow voids. Computed tomography showed no frontal bone defect. The soft tissue tumor could not be diagnosed based on these imaging findings; thus, we decided to perform total resection under general anesthesia. A histopathological examination showed a highly cellular tumor with capillaries with opened small vascular channels and glucose transporter 1 positivity. Thus, it was diagnosed as deep IH transitioning from the proliferative phase to the involuting phase. Deep IHs are difficult to diagnose because characteristic imaging findings disappear during the involuting phase. We emphasize the importance of performing Doppler ultrasonography in the early phase (eg, at 6 months of age) for soft tissue tumors of infancy.

An exploratory study for tuft cells in the breast and their relevance in triple-negative breast cancer: the possible relationship of SOX9.

BACKGROUND: Breast cancer is highly heterogeneous, suggesting that small but relevant subsets have been under-recognized. Rare and mainly triple-negative breast cancers (TNBCs) were recently found to exhibit tuft cell-like expression profiles, including POU2F3, the tuft cell master regulator. In addition, immunohistochemistry (IHC) has identified POU2F3-positive cells in the normal human breast, suggesting the presence of tuft cells in this organ. METHODS: Here, we (i) reviewed previously identified POU2F3-positive invasive breast cancers (n = 4) for POU2F3 expression in intraductal cancer components, (ii) investigated a new cohort of invasive breast cancers (n = 1853) by POU2F3-IHC, (iii) explored POU2F3-expressing cells in non-neoplastic breast tissues obtained from women with or without BRCA1 mutations (n = 15), and (iv) reanalyzed publicly available single-cell RNA sequencing (scRNA-seq) data from normal breast cells. RESULTS: Two TNBCs of the four previously reported invasive POU2F3-positive breast cancers contained POU2F3-positive ductal carcinoma in situ (DCIS). In the new cohort of invasive breast cancers, IHC revealed four POU2F3-positive cases, two of which were triple-negative, one luminal-type, and one triple-positive. In addition, another new POU2F3-positive tumor with a triple-negative phenotype was found in daily practice. All non-neoplastic breast tissues contained POU2F3-positive cells, irrespective of BRCA1 status. The scRNA-seq reanalysis confirmed POU2F3-expressing epithelial cells (3.3% of all epithelial cells) and the 17% that co-expressed the other two tuft cell-related markers (SOX9/AVIL or SOX9/GFI1B), which suggested they were bona fide tuft cells. Of note, SOX9 is also known as the "master regulator" of TNBCs. CONCLUSIONS: POU2F3 expression defines small subsets in various breast cancer subtypes, which can be accompanied by DCIS. The mechanistic relationship between POU2F3 and SOX9 in the breast warrants further analysis to enhance our understanding of normal breast physiology and to clarify the significance of the tuft cell-like phenotype for TNBCs.

On the origin of gastric tumours: analysis of a case with intramucosal gastric carcinoma and oxyntic gland adenoma.

Most gastric cancers develop in inflamed gastric mucosa due to Helicobacter pylori infection, typically with metaplastic changes. However, the origins of gastric cancer remain unknown. Here, we present a case of intramucosal gastric carcinoma (IGC) and oxyntic gland adenoma (OGA) derived from spasmolytic polypeptide-expressing metaplasia (SPEM). Early gastric cancer adjacent to a polyp was found in the upper corpus of a 71-year-old woman without H. pylori infection and was endoscopically resected. Histological examination showed IGC and OGA, both of which had predominant MUC6 expression. Interestingly, gastric glands with enriched MUC6-positive mucous cells, referred to as SPEM, expanded between them. Whole-exome sequencing analysis revealed a truncating KRAS(G12D) mutation in IGC, OGA, and SPEM. In addition, TP53 and CDKN2A mutations and a loss of chromosome 17p were found in the IGC, whereas a GNAS mutation was observed in the OGA. These results indicated that IGC and OGA originated from the KRAS-mutated SPEM. © 2023 The Pathological Society of Great Britain and Ireland.

Evaluation of breast lesions based on modified BI-RADS using high-resolution readout-segmented diffusion-weighted echo-planar imaging and T2/T1-weighted image.

PURPOSE: To evaluate the diagnostic performance of a non-contrast magnetic resonance imaging (MRI) protocol combining high-resolution diffusion-weighted images (HR-DWI) using readout-segmented echo planar imaging, T1-weighted imaging (T1WI), and T2-weighted imaging (T2WI), using our modified Breast Imaging-Reporting and Data System (modified BI-RADS). METHODS: Two experienced radiologists, blinded to the final pathological diagnosis, categorized a total of 108 breast lesions (61 malignant and 47 benign) acquired with the above protocol using the modified BI-RADS with a diagnostic decision tree. The decision tree included subcategories of category 4, as in mammography (categories 2, 3, 4A, 4B, 4C, and 5). These results were compared with the pathological diagnoses. RESULTS: The area under the ROC curve (AUC) was 0.89 (95% confidence interval [CI]: 0.83-0.95) for reader 1, and 0.89 (95% CI: 0.82-0.96) for reader 2. When categories 4C and above were classified as malignant, the sensitivity, specificity, and accuracy were 73.8%, 93.6%, and 82.4%, for reader 1; and 82.0%, 89.4%, and 85.2% for reader 2, respectively. CONCLUSION: Our results suggest that using HR-DWI, T1WI/T2WI analyzed with a modified BI-RADS and a decision tree showed promising diagnostic performance in breast lesions, and is worthy of further study.