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Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is life-threatening without treatment, but aggressive immunosuppression increases the risk of exacerbating a coexisting infection. Finding the balance between efficacy and safety of immunosuppression is challenging. We describe a 74-year-old man who was diagnosed with AAV following the aggravation of chronic pulmonary aspergillosis that required an aggressive antifungal agent. The laboratory data on admission demonstrated severe kidney failure requiring hemodialysis. Due to the active infection, we chose intravenous immunoglobulin (IVIg) as a low-risk initial treatment, which remarkably improved renal dysfunction (serum creatinine; 16.7 mg/dL-3.7 mg/dL) and systemic inflammation. Renal biopsy that was performed after renal recovery revealed atypical ANCA-associated nephritis without cellular crescents but with massive arteritis with multiple vascular sizes and diffuse interstitial inflammation. Despite these active AAV findings, adding plasma exchange therapy (PE) and low-dose steroids were sufficient to induce remission. The main pathogenesis of severe renal impairment was probably the reduction of blood flow, resulting from occlusions of small arteries by inflammatory cell infiltration and vascular endothelial injury due to AAV. Combination treatment with antifungal agents, IVIg, PE, and low-dose steroid treatment led to complete resolution of vasculitis. The specific histological findings and the good response to treatments suggest that pulmonary aspergillosis might trigger vasculitis through induction of ANCA antigen expression. IVIg could be an important option especially for cases of AAV associated with pulmonary aspergillosis., (© 2022. The Author(s) under exclusive licence to The Japan Society of Nephrology.)

Background: Tuft cells are chemosensory epithelial cells playing a role in innate immunity. Recent studies revealed cancers with a tuft cell-like gene expression signature in the thorax. We wondered whether this signature might also occur in extrathoracic cancers., Methods: We examined mRNA expression of tuft cell markers (POU2F3, GFI1B, TRPM5, SOX9, CHAT, and AVIL) in 19 different types of cancers in multiple extrathoracic organs with The Cancer Genome Atlas (TCGA) (N = 6322). Four different extrathoracic cancers in our local archives (N = 909) were analysed by immunohistochemistry., Results: Twenty-two (0.35%) extrathoracic tumours with co-expression of POU2F3 and other tuft cell markers were identified in various TCGA datasets. Twelve of the 22 "tuft cell-like tumours" shared poor differentiation and a gene expression pattern, including KIT, anti-apoptotic BCL2, and ionocyte-associated genes. In our archival cases, eleven (1.21%) tumours co-expressing POU2F3, KIT, and BCL2 on immunohistochemistry, i.e., were presumable tuft cell-like cancers. In three among five TCGA cohorts, the tuft cell-like cancer subsets expressed SLFN11, a promising biomarker of PARP inhibitor susceptibility., Conclusions: Tuft cell-like carcinomas form distinct subsets in cancers of many organs. It appears warranted to investigate their shared gene expression signature as a predictive biomarker for novel therapeutic strategies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: To compare the diagnostic performance of dynamic contrast-enhanced-MR (DCE-MR) and delayed contrast-enhanced (CE)-MRI added to unenhanced MRI, including diffusion weighted image (DWI) for differentiating malignant adnexal tumors, conducting a retrospective blinded image interpretation study., Methods: Data of 80 patients suspected of having adnexal tumors by ultrasonography between April 2008 and August 2018 were used for the study. All patients had undergone preoperative MRI and surgical resection at our institution. Four radiologists (two specialized in gynecological radiology and two non-specialized) were enrolled for blinded review of the MR images. A 3-point scale was used: 0 = benign, 1 = indeterminate, and 2 = malignant. Three imaging sets were reviewed: Set A, unenhanced MRI including DWI; Set B, Set A and delayed CE-T1WI; and Set C, Set A and DCE-MRI. Imaging criteria for benign and malignant tumors were given in earlier reports. The diagnostic performance of the three imaging sets of the four readers was calculated. Their areas under the curve (AUCs) were compared using the DeLong method., Results: Accuracies of Set B were 81%-88%. Those of Set C were 81%-85%. The AUCs of Set B were 0.83 and 0.89. Those of Set C were 0.81-0.86. For two readers, Set A showed lower accuracy and AUC than Set B/Set C (less than 0.80), although those were equivalent in other readers. No significant difference in AUCs was found among the three sequence sets. Intrareader agreement was moderate to almost perfect in Sets A and B, and substantial to almost perfect in Set C., Conclusion: DCE-MR showed no superiority for differentiating malignant adnexal tumors from benign tumors compared to delayed CE-T1WI with conventional MR and DWI.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare pediatric brain tumor with abnormalities in SMARCB1 located in 22q11.2. We report a case of AT/RT associated with Phelan-McDermid syndrome (PMS) characterized by congenital developmental disorder, mental retardation, and ring chromosome 22 with 22q13.3-qter depletion, for which we performed whole-genome sequencing (WGS). A 4-year-old girl with a developmental disability was referred to our hospital due to dysphoria. Brain magnetic resonance imaging showed a 5-cm well-demarcated mass that extended bilaterally in the frontal lobes. G-banding was performed preoperatively due to a history of developmental retardation. Ring chromosome 22 and deletion of 22q13.3-qter were observed, and she was diagnosed with PMS. She underwent gross total resection of the tumor, and the pathological diagnosis was AT/RT. WGS showed somatic SMARCB1 mutation (p.R201X) and somatic loss of the entire chromosome 22 in the tumor, but not in the blood sample. WGS confirmed previously unreported BRCA2 mutations, 6q loss, and 14q acquisition during tumor progression, but no other significant findings associated with tumor progression. The present case is discussed with reference to a systematic review of previous reports of AT/RT associated with PMS. PMS patients with ring chromosome 22 should be carefully followed up for AT/RT occurrence., (© 2022. The Author(s), under exclusive licence to The Japan Society of Brain Tumor Pathology.)

Background: Central nervous system (CNS) mature teratoma is a rare disease with symptoms that can vary according to tumor location. Most lesions are benign; rarely, malignancy can develop in any of the somatic components. Elevated levels of tumor markers such as α-fetoprotein and β-human chorionic gonadotropin are not usually found in patients with CNS mature teratoma, and no reports have described an association with carbohydrate antigen 19-9 (CA19-9)., Observations: A 64-year-old woman with headache was found to have a mass lesion in the anterior cranial fossa. Magnetic resonance imaging of the brain suggested a mature teratoma. Serum and cerebrospinal fluid (CSF) tests showed significant CA19-9 elevations (2,770 U/mL and 4,387 U/mL, respectively). Other examinations, including whole-body 18F-fluorodeoxyglucose positron emission tomography, did not detect the origin of elevated CA19-9, suggesting that the high CA19-9 levels were caused by intracranial tumor. The patient underwent tumor removal. The histopathological diagnosis was mature teratoma with positive CA19-9 staining. CA19-9 levels in serum and CSF decreased significantly after tumor removal., Lessons: The histopathological findings and postoperative decreased CA19-9 levels established the diagnosis of CA19-9-producing CNS mature teratoma. CNS mature teratoma can cause elevations in CA19-9 in cases with absence of neoplasms in the trunk.

Background: The European Society for Medical Oncology Precision Medicine Working Group (ESMO-PMWG) published recommendations regarding confirmatory germline testing for presumed germline pathogenic variants (PGPVs) in tumor-only comprehensive genomic profiling (CGP). However, the clinical validity of these recommendations has not been investigated in a real-world practice., Methods: Medical records of 180 consecutive patients who obtained the results of a tumor-only CGP (FoundationOne ® CDx, Foundation Medicine, Inc, Cambridge, MA, USA) between October 2018 and March 2020, were retrospectively reviewed. After excluding patients with no reported variants in 45 actionable genes (n = 6), or no archived germline DNA samples (n = 31), 143 patients were investigated. The PGPVs were selected from the CGP report and germline sequencing were performed using DNA samples archived in Clinical Bioresource Center in Kyoto University Hospital (Kyoto, Japan)., Results: A total of 195 variants were classified as PGPV based on the conventional criteria. Germline sequencing disclosed that 12 variants (6.2%) were of germline origin. In contrast, after filtering these 195 variants through the ESMO-PMWG recommendation criteria for confirmatory germline testing, following seven PGPVs, BRCA2 (n = 2), BRIP1 (n = 1), BAP1 (n = 1), PMS2 (n = 1), MSH2 (n = 1), and SDHB (n = 1) remained and six variants (85.7%) were confirmed to be of germline origin., Conclusion: Our current data suggested that the application of ESMO-PMWG criteria is helpful in selecting PGPVs with a high likelihood of germline origin in a tumor-only CGP in daily clinical practice., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Polypoid endometriosis is a benign, rare variant of endometriosis that forms polypoid nodules mimicking malignant tumors. For three cases of polypoid endometriosis of female genital organs, this report presents characteristic MR imaging features reflecting the histopathological findings. The solid and microcystic pattern or the multilocular pattern both reflecting dilated endometrial glands, and characteristic morphology of the nodules, multilobulated or polypoid-shaped, were helpful diagnostic clues present in these three cases. Earlier reported MR findings were also recognized, including signal intensity similar to that of the endometrium on T2-weighted image and contrast enhanced T1-weighted image, hypointense rim on T2-weighted image, lack of diffusion restriction, and hyperintense foci on T1-weighted image. Two cases were diagnosed preoperatively based on MR imaging findings as polypoid endometriosis. Fertility-preserving treatment was administered for one patient. Preoperative inference of polypoid endometriosis from MR imaging can avoid overtreatment and lead to fertility preservation., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Tumor heterogeneity has been known to cause inter-assay discordance among next-generation sequencing (NGS) results. However, whether preclinical factors such as sample type, sample quality and analytical features of gene panel can affect the concordance between two different assays remains largely unexplored., Methods: Replicate sets of DNA samples extracted from formalin-fixed paraffin-embedded tissues (FFPE) (n = 20) and fresh frozen (FF) tissues (n = 10) were herein analyzed using a tumor-only (TO) and paired tumor-normal (TN) gene panel in laboratories certified by the Clinical Laboratory Improvement Amendment. Reported variants from the TO and TN panels were then compared. Furthermore, additional FFPE samples were sequentially sliced from the same FFPE block and submitted to another TN panel assay., Results: Substantial discordance (71.8%) was observed between the results of the two panels despite using identical DNA samples, with the discordance rate being significantly higher for FFPE samples (p < 0.05). Among the 99 variants reported only in the TO panel, 32.3% were consistent with germline variants, which were excluded in the TN panel, while 30.3% had an allele frequency of less than 5%, some of which were highly likely to be artificial calls. The comparison of two independent TN panel assay results from the same FFPE block also showed substantial discordance rate (55.3%)., Conclusions: In the context of clinical settings, our comparative analysis revealed that inter-NGS assay discordance commonly occurred due to sample types and the different analytical features of each panel., (© 2022. The Author(s).)

Decidualization of endometrial stromal cells and the presence of immunocompetent cells, including human mast cells, play important roles in the establishment of pregnancy. In the present study, the effects of decidualization of endometrial stromal cells on the function of decidual mast cells were elucidated. The in vitro assay revealed that decidualization of an endometrial stromal cell line, T HESCs, increased stem cell factor (SCF) mRNA expression. Decidualization of T HESCs enhanced the production of leukemia inhibitory factor (LIF), and the migration of LAD2 cells when co-cultured with T HESCs and LAD2 cells. In addition, decidualization of T HESCs enhanced cell migration in a human trophoblast cell line, HTR-8/SVneo, increased CD9 expression, a marker for extravillous trophoblast (EVT) differentiation, and decreased the secretion of β human chorionic gonadotropin (hCG), a marker for syncytiotrophoblast (ST) differentiation, when co-cultured with T HESCs, LAD2 cells, and HTR-8/SVneo cells, in a LIF-dependent manner. Histological samples from uterine pregnancies, including decidual stromal cells, showed increased SCF mRNA expression, mast cell numbers and LIF mRNA expression thereof compared with tubal pregnancy. SCF produced by decidual stromal cells enhanced the migration and LIF production of mast cells, and promoted the migration and differentiation of trophoblasts to increase the likelihood of successful human pregnancy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ueshima, Kataoka, Osakabe, Sugimoto, Ushirokawa, Shibata, Nakamura, Shibuya, Minamiguchi, Sugai and Haga.)

Background: Craniopharyngioma (CP) often arises in the sellar and suprasellar areas; ectopic CP in the posterior fossa is rare. Familial adenomatous polyposis (FAP) is a genetic disorder involving the formation of numerous adenomatous polyps in the gastrointestinal tract, and it is associated with other extraintestinal manifestations., Observations: The authors reported the case of a 63-year-old woman with FAP who presented with headache and harbored a growing mass in the fourth ventricle. Magnetic resonance imaging (MRI) findings revealed a well-circumscribed mass with high intensity on T1-weighted images and low intensity on T2-weighted images and exhibited no contrast enhancement. Gross total resection was performed and histopathology revealed an adamantinomatous CP (aCP). The authors also reviewed the previous reports of ectopic CP in the posterior fossa and found a high percentage of FAP cases among the ectopic CP group, thus suggesting a possible association between the two diseases., Lessons: An ectopic CP may be reasonably included in the differential diagnosis in patients with FAP who present with well-circumscribed tumors in the posterior fossa.

Purpose: To evaluate radiomic machine learning (ML) classifiers based on multiparametric magnetic resonance images (MRI) in pretreatment assessment of endometrial cancer (EC) risk factors and to examine effects on radiologists' interpretation of deep myometrial invasion (dMI)., Methods: This retrospective study examined 200 consecutive patients with EC during January 2004 -March 2017, divided randomly to Discovery (n = 150) and Test (n = 50) datasets. Radiomic features of tumors were extracted from T2-weighted images, apparent diffusion coefficient map, and contrast enhanced T1-weighed images. Using the Discovery dataset, feature selection and hyperparameter tuning for XGBoost were performed. Ten classifiers were built to predict dMI, histological grade, lymphovascular invasion (LVI), and pelvic/paraaortic lymph node metastasis (PLNM/PALNM), respectively. Using the Test dataset, the diagnostic performances of ten classifiers were assessed by the area under the receiver operator characteristic curve (AUC). Next, four radiologists assessed dMI independently using MRI with a Likert scale before and after referring to inference of the ML classifier for the Test dataset. Then, AUCs obtained before and after reference were compared., Results: In the Test dataset, mean AUC of ML classifiers for dMI, histological grade, LVI, PLNM, and PALNM were 0.83, 0.77, 0.81, 0.72, and 0.82. AUCs of all radiologists for dMI (0.83-0.88) were better than or equal to mean AUC of the ML classifier, which showed no statistically significant difference before and after the reference., Conclusion: Radiomic classifiers showed promise for pretreatment assessment of EC risk factors. Radiologists' inferences outperformed the ML classifier for dMI and showed no improvement by review., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Despite the recommendations of the latest guidelines, the practical efficacy of universal screening for identifying Lynch syndrome (LS) among patients with colorectal cancer (CRC) may be limited in the real world due to infrequent referrals and the difficulties of genetic testing. Thus, the present study aimed to retrospectively analyze the results of universal screening of patients with CRC at a referral hospital in Japan. Immunohistochemistry was performed for mismatch repair proteins [including DNA mismatch repair protein MSH6 (MSH6), mismatch repair endonuclease PMS2 (PMS2), DNA mismatch repair protein Msh2 (MSH2) and DNA mismatch repair protein Mlh1 (MLH1)] and BRAF V600E mutation. Tumors that showed the following were considered to indicate LS and patients with such tumors were designated as genetic testing candidates (GTCs): i) Loss of MSH6/MSH2; ii) loss of MSH6 alone; iii) loss of PMS2 alone; and iv) loss of PMS2/MLH1 with negative BRAF V600E. MLH1 methylation and BRAF V600E mutation were analyzed in deficient mismatch repair (dMMR) tumors retrospectively. The frequency of dMMR and GTCs in an independent cohort of patients with young-onset CRC were also investigated. Universal screening revealed dMMR tumors, GTCs and LS probands in 7.3, 3.9 and 0.4%, respectively, of 463 patients with CRC. Although dMMR tumors were observed in both younger (<50 years) and older (≥60 years) patients, the GTCs were enriched in younger individuals. Evaluation of mismatch repair status in an independent cohort confirmed the high rate of GTCs in patients with young-onset CRC. The low detection rate of LS demonstrated in this study questions the implementation of routine universal screening in regions with low prevalence of LS. Considering the enrichment of GTCs in young-onset CRCs, age-restricted strategies may be simple and efficient practical alternatives to universal screening in the real world., (Copyright © 2020, Spandidos Publications.)

Objective: This study aimed to investigate the most accurate magnetic resonance (MR) sequence for tumor detection, maximal tumor diameter, and parametrial invasion compared with histopathologic diagnoses., Methods: Fifty-one patients with International Federation of Gynecology and Obstetrics 2018 IB1 to IIB cervical cancer underwent preoperative MR imaging and surgical resection. Two radiologists independently evaluated the tumor detection, parametrial invasion, and tumor size in each of T2-weighted image, diffusion-weighted image, and contrast-enhanced T1-weighted image. Results obtained for squamous cell carcinoma (SCC) and adenocarcinoma were also compared., Results: Neither the tumor detection rate nor parametrial invasion was found to be significantly different among sequences. Tumor size assessment using MR imaging with pathology showed good correlation: r = 0.63-0.72. The adenocarcinoma size tended to be more underestimated than SCC in comparison with the pathologic specimen., Conclusions: Cervical cancer staging by MR images showed no significant difference among T2-weighted image, diffusion-weighted image, and contrast-enhanced T1-weighted image. Adenocarcinoma was prone to be measured as smaller than the pathologic specimen compared with SCC., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The most recurrent fusion of central nervous system high-grade neuroepithelial tumor with MN1 alteration (HGNET-MN1) is MN1 rearrangement. Here, we report the case of a 36-year-old man with spinal cord astroblastoma showing Ewing Sarcoma breakpoint region 1/EWS RNA-binding protein 1 (EWSR1)-BEN domain-containing 2 (BEND2) fusion. The patient presented with back pain, gait disturbance and dysesthesia in the lower extremities and trunk. Magnetic resonance imaging showed an intramedullary tumor at the T3-5 level, displaying homogeneous gadolinium enhancement. Partial tumor removal was performed with laminectomy. Histological examinations demonstrated solid growth of epithelioid tumor cells showing high cellularity, a pseudopapillary structure, intervening hyalinized fibrous stroma, and some mitoses. Astroblastoma was diagnosed, classified as HGNET-MN1 by the German Cancer Research Center methylation classifier. MN1 alteration was not detected by fluorescence in situ hybridization (FISH), but EWSR1-BEND2 fusion was detected by FISH and RNA sequencing. Previously, a child with EWSR1-BEND2 fusion-positive spinal astroblastoma classified as HGNET-MN1 was reported. In conjunction with that, the present case provides evidence that EWSR1-BEND2 fusion is identified in the entity of HGNET-MN1. Taken together, the BEND2 alteration rather than MN1 may determine the biology of a subset of the central nervous system HGNET-MN1 subclass., (© 2021. The Japan Society of Brain Tumor Pathology.)

The purpose of this study is to evaluate utility of MRI in differentiation of uterine low-grade endometrial stromal sarcoma (LGESS) from rare leiomyoma variants. This multi-center retrospective study included consecutive 25 patients with uterine LGESS and 42 patients with rare leiomyoma variants who had pretreatment MRI. Two radiologists (R1/R2) independently evaluated MRI features, which were analyzed statistically using Fisher's exact test or Student's t-test. Subsequently, using a five-point Likert scale, the two radiologists evaluated the diagnostic performance of a pre-defined MRI system using features reported as characteristics of LGESS in previous case series: uterine tumor with high signal intensity (SI) on diffusion-weighted images and with either worm-like nodular extension, intra-tumoral low SI bands, or low SI rim on T2-weighted images. Area under the receiver operating characteristic curve (AUC), sensitivity, and specificity of the two readers' Likert scales were analyzed. Intra-tumoral low SI bands (p < 0.001), cystic/necrotic change (p ≤ 0.02), absence of speckled appearance (p < 0.001) on T2-weighted images, and a low apparent diffusion coefficient value (p ≤ 0.02) were significantly associated with LGESS. The pre-defined MRI system showed very good diagnostic performance: AUC 0.86/0.89, sensitivity 0.95/0.95, and specificity 0.67/0.69 for R1/R2. MRI can be useful to differentiate uterine LGESS from rare leiomyoma variants., (© 2021. The Author(s).)

Background: Mutations in driver genes such as IDH and BRAF have been identified in gliomas. Meanwhile, dysregulations in the p53, RB1, and MAPK and/or PI3K pathways are involved in the molecular pathogenesis of glioblastoma. RAS family genes activate MAPK through activation of RAF and PI3K to promote cell proliferation. RAS mutations are a well-known driver of mutation in many types of cancers, but knowledge of their significance for glioma is insufficient. The purpose of this study was to reveal the frequency and the clinical phenotype of RAS mutant in gliomas., Methods: This study analysed RAS mutations and their clinical significance in 242 gliomas that were stored as unfixed or cryopreserved specimens removed at Kyoto University and Osaka National Hospital between May 2006 and October 2017. The hot spots mutation of IDH1/2, H3F3A, HIST1H3B, and TERT promoter and exon 2 and exon 3 of KRAS, HRAS, and NRAS were analysed with Sanger sequencing method, and 1p/19q codeletion was analysed with multiplex ligation-dependent probe amplification. DNA methylation array was performed in some RAS mutant tumours to improve accuracy of diagnosis., Results: RAS mutations were identified in four gliomas with three KRAS mutations and one NRAS mutation in one anaplastic oligodendroglioma, two anaplastic astrocytomas (IDH wild-type in each), and one ganglioglioma. RAS-mutant gliomas were identified with various types of glioma histology., Conclusion: RAS mutation appears infrequent, and it is not associated with any specific histological phenotype of glioma., (© 2021. The Author(s).)

Background: In Helicobacter pylori (Hp)-uninfected individuals, diffuse-type gastric cancer (DGC) was reported as the most common type of cancer. However, the carcinogenic mechanism of Hp-uninfected sporadic DGC is largely unknown., Methods: We performed whole-exome sequencing of Hp-uninfected DGCs and Hp-uninfected normal gastric mucosa. For advanced DGCs, external datasets were also analyzed., Results: Eighteen patients (aged 29-78 years) with DGCs and nine normal subjects (28-77 years) were examined. The mutation burden in intramucosal DGCs (10-66 mutations per exome) from individuals aged 29-73 years was not very different from that in the normal gastric glands, which showed a constant mutation accumulation rate (0.33 mutations/exome/year). Unbiased dN/dS analysis showed that CDH1 somatic mutation was a driver mutation for intramucosal DGC. CDH1 mutation was more frequent in intramucosal DGCs (67%) than in advanced DGCs (27%). In contrast, TP53 mutation was more frequent in advanced DGCs (52%) than in intramucosal DGCs (0%). This discrepancy in mutations suggests that CDH1-mutated intramucosal DGCs make a relatively small contribution to advanced DGC formation. Among the 16 intramucosal DGCs (median size, 6.5 mm), 15 DGCs were pure signet ring cell carcinoma (SRCC) with reduced E-cadherin expression and a low proliferative capacity (median Ki-67 index, 2.4%). Five SRCCs reviewed endoscopically over 2-5 years showed no progression., Conclusions: Impaired E-cadherin function due to CDH1 mutation was considered as an early carcinogenic event of Hp-uninfected intramucosal SRCC. Genetic and clinical analyses suggest that Hp-uninfected intramucosal SRCCs may be less likely to develop into advanced DGCs., (© 2021. The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Purpose: To evaluate the diagnostic performance of MRI findings for differentiating uterine leiomyoma with intraligamentous growth, or broad ligament fibroid, from subserosal leiomyoma., Methods: This study included 37 patients with surgically confirmed uterine smooth muscle tumors (36 leiomyomas and one smooth muscle tumor of uncertain malignant potential) with intraligamentous growth (IL) and size-matched control of 37 patients with subserosal leiomyoma (SS). Two radiologists independently evaluated eight preoperative MRI findings: tumor shape, degeneration, attachment to uterus, ovary elevation, ureter displacement, bladder deformation, rectal displacement, and separation of round ligament (RL) and uterine artery (UA). The diagnostic values of these findings and interobserver agreement were assessed. Receiver-operating characteristic (ROC) analysis of the number of positive MRI findings for diagnosing IL was performed. Clinical outcomes including surgical method, operation time, intraoperative blood loss, perioperative complications, and postoperative hospital stay of the two groups were compared., Results: Significant differences in tumor shape, attachment to uterus, ovary elevation, ureter displacement, and separation of RL and UA were found between IL and SS. Four of these findings, excluding ureter displacement, showed moderate to substantial interobserver agreement. When two or more of these four findings were positive, sensitivity, specificity, and area under the ROC curve were 91%, 77%, 0.90 in reader 1 and 82%, 89%, 0.91 in reader 2. The operation time was significantly longer for IL than for SS., Conclusion: Tumor shape, attachment to uterus, ovary elevation, and separation of RL and UA are useful MRI findings for differentiating intraligamentous leiomyoma from subserosal leiomyoma., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Langerhans cell histiocytosis (LCH) with primary involvement of the upper gastrointestinal (GI) tract is rare. We report 2 adult cases of localized LCH in the upper-GI tract, including the second reported adult case of esophageal LCH and review 11 previously reported cases. Case 1 involved the esophagus of a 61-year-old man; histiocytosis was detected when endoscopy was performed for an examination of epigastric pain. Case 2 involved the stomach of a 56-year-old woman wherein the lesion was detected during a follow-up endoscopy after Helicobacter pylori infection. Both biopsy specimens exhibited diffuse proliferation of mononuclear cells with nuclear convolution and a background of eosinophilic infiltrate. The cells were immunohistochemically positive for CD1a and langerin, and BRAF V600E mutation was detected in Case 2. Follow-up endoscopy for both cases revealed that the lesions disappeared without any treatment. It is important to avoid misdiagnosing LCH of the upper-GI tract as a malignant neoplasm.

Endometrial cancer (EC) is the most common gynecological tumor in developed countries, and preoperative risk stratification is essential for personalized medicine. There have been several radiomics studies for noninvasive risk stratification of EC using MRI. Although tumor segmentation is usually necessary for these studies, manual segmentation is not only labor-intensive but may also be subjective. Therefore, our study aimed to perform the automatic segmentation of EC on MRI with a convolutional neural network. The effect of the input image sequence and batch size on the segmentation performance was also investigated. Of 200 patients with EC, 180 patients were used for training the modified U-net model; 20 patients for testing the segmentation performance and the robustness of automatically extracted radiomics features. Using multi-sequence images and larger batch size was effective for improving segmentation accuracy. The mean Dice similarity coefficient, sensitivity, and positive predictive value of our model for the test set were 0.806, 0.816, and 0.834, respectively. The robustness of automatically extracted first-order and shape-based features was high (median ICC = 0.86 and 0.96, respectively). Other high-order features presented moderate-high robustness (median ICC = 0.57-0.93). Our model could automatically segment EC on MRI and extract radiomics features with high reliability., (© 2021. The Author(s).)

Introduction: Evaluating histopathology via machine learning has gained research and clinical interest, and the performance of supervised learning tasks has been described in various areas of medicine. Unsupervised learning of histological images has the advantage of reproducibility for labeling; however, the relationship between unsupervised evaluation and clinical information remains unclear in nephrology., Methods: We propose an unsupervised approach combining convolutional neural networks (CNNs) and a visualization algorithm to cluster the histological images and calculate the score for patients. We applied the approach to the entire images or patched images of the glomerulus of kidney biopsy samples stained with hematoxylin and eosin obtained from 68 patients with immunoglobulin A nephropathy. We assessed the relationship between the obtained scores and clinical variables of urinary occult blood, urinary protein, serum creatinine (SCr), systolic blood pressure, and age., Results: The glomeruli of the patients were classified into 12 distinct classes and 10 patches. The output of the fine-tuned CNN, which we defined as the histological scores, had significant relationships with assessed clinical variables. In addition, the clustering and visualization results suggested that the defined clusters captured important findings when evaluating renal histopathology. For the score of the patch-based cluster containing crescentic glomeruli, SCr (coefficient = 0.09, P  = 0.019) had a significant relationship., Conclusion: The proposed approach could successfully extract features that were related to the clinical variables from the kidney biopsy images along with the visualization for interpretability. The approach could aid in the quantified evaluation of renal histopathology., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

BACKGROUND : Accurate preoperative assessment of the longitudinal extension of perihilar cholangiocarcinoma (PHCC) is essential for treatment planning. Mapping biopsies for PHCC remain challenging owing to technical difficulties and insufficient sample amounts. The aim of this study was to investigate the usefulness of a novel technique for mapping biopsies of PHCC. METHODS : Our novel method focused on a biliary stent delivery system for mapping biopsies. Fifty patients with PHCC undergoing endoscopic transpapillary mapping biopsy using the novel method were reviewed from August 2015 to June 2019. RESULTS : The median number of biopsy samples was six (range 1 - 17), and the rate of adequate sampling was 91.4 % (266 /291). Biopsy from the intrahepatic bile duct was possible in 82.0 % of patients (41 /50), and negative margins were confirmed in the resected specimens from 34 /39 patients who underwent surgery (87.2 %). None of the patients had post-endoscopic retrograde cholangiopancreatography pancreatitis. CONCLUSIONS : With our novel method, accurate assessment of the longitudinal extension of PHCC might be expected with minimal trauma to the duodenal papilla., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Secretory carcinoma or mammary analog secretory carcinoma is an entity of salivary gland carcinoma that is characterized by the ETV6-NTRK3 gene fusion. Although it is generally considered to be a low-grade malignancy, some cases of secretory carcinoma with high-grade transformation (SCHG) have been reported. We herein describe a case of SCHG composed almost exclusively of the high-grade component. The patient presented with a growing mass in the buccal mucosa and underwent surgery. Tumor cells showing high-grade nuclear atypia were arranged in solid or cribriform nests with comedo-like necrosis. A differential diagnosis included high-grade salivary gland carcinoma, such as salivary duct carcinoma. Immunohistochemically, tumor cells were focally positive for S-100 and negative for mammaglobin and showed nuclear positivity for pan-Trk. A reverse transcription polymerase chain reaction assay showed that the tumor harbored the ETV6-NTRK3 gene fusion. A histological review of microscopic slides of the tumor did not reveal a typical secretory carcinoma component, except for a very focal area. We ultimately diagnosed this tumor as SCHG. This case underscores the importance of recognizing the histological spectrum of SCHG and the utility of pan-Trk immunohistochemistry to detect secretory carcinoma, which may be targeted by tyrosine kinase inhibitors., (© 2021 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Background: Cryopyrin-associated periodic syndrome (CAPS) is a life-long, autoinflammatory disease associated with a gain-of-function mutation in the nucleotide-binding domain, leucine-rich repeat family, pyrin domain containing 3 (NLRP3) gene, which result in uncontrolled production of IL-1β and chronic inflammation. Chronic infantile neurologic cutaneous and articular (CINCA) syndrome/neonatal-Onset multisystem inflammatory disease (NOMID) is the most severe form of CAPS. Although the first symptoms may be presented at birth, there are few reports on the involvement of the placenta and umbilical cord in the disease. Therefore, we present herein a preterm case of CINCA/NOMID syndrome and confirms intrauterine-onset inflammation with conclusive evidence by using fetal and placental histopathological examination., Case Presentation: The female patient was born at 33weeks of gestation by emergency caesarean section and weighted at 1,514 g. The most common manifestations of CINCA/NOMID syndrome including recurrent fever, urticarial rash, and ventriculomegaly due to aseptic meningitis were presented. She also exhibited atypical symptoms such as severe hepatosplenomegaly with cholestasis. The genetic analysis of NLRP3 revealed a heterozygous c.1698 C > G (p.Phe566Leu) mutation, and she was diagnosed with CINCA/NOMID syndrome. Further, a histopathological examination revealed necrotizing funisitis, mainly inflammation of the umbilical artery, along with focal neutrophilic and lymphocytic villitis., Conclusions: The necrotizing funisitis, which only involved the artery, was an unusual observation for chorioamnionitis. These evidences suggest that foetal inflammation, probably due to overproduction of IL-1β, caused tissue damage in utero, and the first symptom of a newborn with CINCA/NOMID.

Recently, several malignant peritoneal mesotheliomas (MPMs), occurring in young women without asbestos exposure and with fusion genes such as anaplastic lymphoma kinase (ALK) and Ewing sarcoma breakpoint region 1, have been reported. In the present case, we encountered MPM with STRN-ALK fusion in a 17-year-old female adolescent. The case did not respond to chemotherapy and is currently in a clinical trial of alectinib. This is the fourth reported case of MPM with STRN-ALK fusion. Of the 45 cancer cases with STRN-ALK fusion in which the fusion partners were examined, all cases except for the current case showed fusion of exon 3 of STRN and exon 20 of ALK. This is the first case with fusion of exon 2 of STRN and exon 20 of ALK. Further advances in cancer genomic medicine may help clarify the clinical significance of this new fusion. KEY POINTS: Malignant peritoneal mesotheliomas (MPMs) can occur in young women without asbestos exposure and show fusion genes that activate anaplastic lymphoma kinase (ALK) by gene rearrangement. ALK rearrangement and the fusion partner can be detected by companion diagnostics and by next generation sequencing. Patients with MPMs with ALK rearrangement may benefit from target therapy., (© 2021 AlphaMed Press.)

Poor trastuzumab (Tmab) response of patients with human epidermal growth factor receptor 2-overexpressing gastric or gastroesophageal junction adenocarcinoma (HER2-GEA) is associated with the inhibition of phosphatase and tensin homolog (PTEN) expression. In this multicenter, retrospective observational study, pathological samples of patients with HER2-GEA receiving Tmab-combined chemotherapy were immunohistochemically analyzed for PTEN expression. The primary endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). We assessed the effect of conventional chemotherapy and Tmab alone or combined with PI3K pathway inhibitors in vitro in HER2-GEA cells with or without PTEN expression. Twenty-nine and 116 patients were in the PTEN-loss and PTEN-positive groups, respectively. In patients with the target region, DCR was significantly lower in PTEN-loss patients than in PTEN-positive patients (67% and 87%, respectively, p = 0.049). The multivariate analysis demonstrated that PTEN loss was significantly associated with shorter PFS (HR = 1.63, p = 0.035) and OS (HR = 1.83, p = 0.022). PTEN knockdown did not affect the cytostatic effect of 5-FU and cisplatin, whereas Tmab combined with the PI3K/mTOR inhibitor NPV-BEZ235 suppressed PTEN-knockdown cell proliferation. In patients with HER2-GEA, PTEN loss is a predictive biomarker of Tmab resistance and prognostic factor. Molecular-targeted therapy with a PI3K/mTOR inhibitor would be effective for HER2-GEA with PTEN loss.

Purpose: To investigate the influence of microcystic, elongated and fragmented (MELF) pattern invasion on preoperative evaluation of lymph node (LN) metastasis and myometrial invasion in patients with low-grade endometrial carcinoma., Methods: The study included 192 consecutive patients with low-grade endometrial carcinoma who underwent preoperative computed tomography (CT) and magnetic resonance imaging (MRI), followed by surgery. One hundred sixty one of 192 patients underwent LN dissection and were analyzed for LN metastasis. All patients were analyzed for myometrial invasion. Presence of enlarged LN was evaluated by using size criteria on CT. Depth of myometrial invasion was evaluated on MRI using T 2 -weighted imaging, diffusion-weighted imaging and contrast-enhanced T 1 -weighted imaging comprehensively. Sensitivity and specificity for LN metastasis and deep myometrial invasion were evaluated for MELF group and non-MELF group. The difference of sensitivity between two groups was compared using Chi-square and Fisher's exact test., Results: MELF pattern invasion was identified in 43/192 patients (22%). LN metastases were observed in 18/39 patients in MELF group and 6/122 patients in non-MELF group for pelvic LN and 11/29 patients in MELF group and 4/57 patients in non-MELF group for para-aortic LN. Sensitivity for the detection of pelvic LN metastasis in MELF group was significantly lower than in non-MELF group (16.7% vs 66.7%). As for the assessment of the deep myometiral invasion, pathological deep myometrial invasion were found in 31/43 patients in MELF group and 32/149 patients in non-MELF group. Sensitivity in MELF group showed lower values than in non-MELF group (54.8% vs 78.1% for reader 1, 54.8% vs 62.5% for reader 2), although there was no statistically significant difference (P = 0.09 for reader 1 and P = 0.72 for reader 2)., Conclusion: In case of low-grade endometrial carcinoma with MELF pattern invasion, preoperative staging by CT and MRI have a risk for underestimation.

Aim: To elucidate correlation between signal intensity on diffusion-weighted images (SI-DWI) and clinical backgrounds for uterine adenomyosis and to compare SI-DWI of adenomyosis and malignant uterine tumors., Methods: This study examined 46 adenomyosis patients diagnosed using magnetic resonance imaging and 25 patients with surgically confirmed malignant uterine myometrial tumor. First, adenomyosis cases were classified visually into high-intensity and low-intensity groups based on the SI-DWI compared with that of normal uterine myometrium. Secondly, correlation was assessed between SI-DWI of adenomyosis and patient clinical background information such as age, menopausal status, menstrual cycle and dysmenorrhea severity. Third, quantitative comparison was made of low-intensity adenomyosis (LIA), high-intensity adenomyosis (HIA) and malignant tumor groups for the signal intensity ratio (SIR) on DWI and the apparent diffusion coefficient (ADC). Their diagnostic performance was evaluated using logistic regression analysis and receiver operating characteristic (ROC) analysis., Results: The 46 adenomyosis cases were classified as 26 low-intensity and 20 high-intensity cases. Significant correlation was found only for menstrual cycle phases. HIA had significantly lower SIR and higher ADC than malignant tumor. The ADC of HIA was significantly higher than that of LIA. The combination of SIR and ADC showed excellent diagnostic performance (area under ROC curve, 0.99)., Conclusion: There is a variation in signal intensity on DWI of uterine adenomyosis and it is associated with menstrual cycle phase. Adenomyosis with high signal intensity on DWI can be differentiated from malignant lesions by its lower signal intensity on DWI and higher ADC than that found for malignant uterine tumors, however overlaps exist., (© 2021 Japan Society of Obstetrics and Gynecology.)

Background: Lately, monoclonal gammopathy of renal significance (MGRS) has been defined as a group of renal disorders that are strongly associated with monoclonal protein, including amyloid immunoglobulin light chain (AL) amyloidosis. Amyloid myopathy is rare (1.5% of all patients with amyloidosis) and the prognosis is poor. Furthermore, only approximately 20% of patients with amyloid myopathy are reported to have renal involvement, indicating a lack of data in the literature., Case Presentation: Here, we report a rare case of MGRS-related AL amyloidosis complicated by amyloid myopathy that presented with muscle weakness in the upper and lower limbs, neck and fingers, and nephrotic syndrome. Blood, urine, and bone marrow examination revealed monoclonal gammopathy of undetermined significance (MGUS) (Bence Jones protein-lambda). Muscle biopsy of the vastus lateralis muscle demonstrated amyloid proteins in the sarcolemma and in the blood vessel walls on Congo red staining, suggesting amyloid myopathy, and tiny inclusions in fibers on modified Gomori trichrome stain. Although we thought they were reminiscent of nemaline bodies, we could not confirm the nature of this structure. Renal biopsy demonstrated amyloid proteins in the mesangial region, part of the capillary walls, and the blood vessel walls on direct fast scarlet staining. As these amyloid proteins were positive for p-component staining and negative for amyloid A staining, β2-microglobulin, and pre-albumin, and as lambda light chains were positive in the mesangial region, we diagnosed the patient with MGRS-related AL amyloidosis. Although he was treated with melphalan and dexamethasone, his symptoms did not improve., Conclusions: AL amyloidosis involving the kidneys and muscles has a poor prognosis, and a delayed diagnosis of amyloid myopathy is common because of its rarity and frequent misdiagnosis, which increases organ function deterioration. Therefore, early detection, therapeutic intervention, and careful follow-up are crucial.

The diagnosis and management of borderline ovarian tumors during pregnancy are still not standardized, because these tumors are rarely encountered. We report the case of a 27-year-old pregnant woman who presented with an ovarian mass in her first trimester. Magnetic resonance imaging revealed a multilocular cystic component with papillary lesions in the background of endometriosis, suggesting a seromucinous borderline tumor or ovarian cancer. A right salpingo-oophorectomy and partial omentectomy were performed at 7 weeks of gestation. Pathological examination demonstrated a serous borderline tumor. The subsequent pregnancy course was uneventful, and she gave birth to a healthy baby at 39 weeks of gestation. She wanted to retain fertility, and close follow-up was performed. Four years later, she became pregnant, and a lesion suggesting recurrence in the left ovary was detected. An abdominal left ovarian cystectomy was performed at 13 weeks of gestation, which demonstrated recurrence of the serous borderline tumor. She gave birth to a healthy baby at 39 weeks of gestation. Two months after delivery, she underwent total abdominal hysterectomy with left salpingo-oophorectomy, which revealed no malignant findings. We also reviewed 10 reports that included 58 cases of borderline ovarian tumors diagnosed during pregnancy. The borderline ovarian tumors diagnosed during pregnancy exhibited different characteristics according to each subtype, suggesting the importance of diagnosing borderline ovarian tumor subtypes preoperatively., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Japan Society of Clinical Oncology 2021.)

Introduction: Chronic abruption oligohydramnios sequence (CAOS) is histologically characterized by diffuse chorioamniotic hemosiderosis (DCH). However, the criteria for the histological evaluation of the extent of CAOS-related hemosiderin deposition (HD) of the membranes and the difference in HD between the chorionic plate (CP) and fetal membrane (FM) are not well studied. This case control study compared the degree and distribution pattern of HD on CP and FM to present the histological features of DCH and the criteria for histological evaluation., Methods: From the medical records of Kyoto University Hospital (2010-2019), we selected 20 CAOS cases that were clinically diagnosed by Elliot's criteria. Twenty non-CAOS cases matched to the CAOS group by gestational age were selected as controls. We compared the clinical data and pathological features in the two groups. We performed iron staining in all the cases and analyzed HD in CP and FM according to the histological score (H-Score: 0-12), which was determined as the density (0-3) multiplied by the extent of staining (0-4)., Results: HD was found in 100% (20/20) of CAOS and 15% (3/20) of control cases. In both the FM and CP, CAOS cases showed a significantly higher HS than control cases (CAOS, HS = 4-12; Control, HS = 0-1, p < 0.0001). Three CAOS patients presented HD alone in the CP. The HS of the CP was significantly higher than that of the FM (p = 0.0003)., Discussion: CAOS presented DCH with HS ≥ 4. This study showed that the CP might be more suitable for evaluating DCH than the FM., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Umbilical vein varix is associated with a high incidence of fetal anomalies and perinatal complications. There are two types of umbilical vein varix: fetal intra-abdominal and extra-abdominal. Herein, a case is reported of severe fetal anemia with extra-abdominal umbilical vein varix. A 33-year-old primigravida was referred to our hospital for fetal growth restriction, fetal cardiomegaly, and decreased fetal movements at 26 weeks' gestation. A Doppler assessment showed an elevated middle cerebral artery peak systolic velocity at 2.2 MoM, suggesting fetal anemia. Umbilical vein varix had caused intermittent turbulent flow, provoking hemolytic anemia. Intrauterine transfusion improved fetal circulatory failure and anemia and prolonged gestational period. At 33 weeks' gestation, the patient underwent cesarean delivery due to nonreassuring fetal status. Pathological analysis revealed focal loss of vascular smooth muscle of the umbilical vein. Extra-abdominal umbilical vein varix has been reported in 14 cases including this case. The antenatal diagnosis rate is reported to be 79%; fetal heartbeat abnormalities and fetal deaths were reported as 50% and 14%, respectively. Eighty-six percent of patients had intra-umbilical cord thrombosis, but currently this is the only case of hemolytic anemia. Furthermore, extra-abdominal umbilical vein varix may present as fetal hydrops with anemia. During ultrasound examination of fetal anemia, umbilical cord screening should be performed with caution., (© 2020 Japanese Teratology Society.)

Comprehensive genomic profiling (CGP) testing by next-generation sequencing has been introduced into clinical practice as part of precision cancer medicine to select effective targeted therapies. However, whether CGP testing at the time of first-line chemotherapy could be clinically useful is not clear. We conducted this single-center, prospective, observational study to investigate the feasibility of CGP testing for chemotherapy-naïve patients with stage III/IV gastrointestinal cancer, rare cancer, and cancer of unknown primary, using the FoundationOne ® companion diagnostic (F1CDx) assay. The primary outcome was the detection rate of at least one actionable/druggable cancer genomic alteration. Actionable/druggable cancer genomic alterations were determined by the F1CDx report. An institutional molecular tumor board determined the molecular-based recommended therapies. A total of 197 patients were enrolled from October 2018 to June 2019. CGP success rate was 76.6% (151 of 197 patients), and median turnaround time was 19 days (range: 10-329 days). Actionable and druggable cancer genomic alterations were reported in 145 (73.6%) and 124 (62.9%) patients, respectively. The highest detection rate of druggable genomic alterations in gastrointestinal cancers was 80% in colorectal cancer (48 of 60 patients). Molecular-based recommended therapies were determined in 46 patients (23.4%). CGP testing would be a useful tool for the identification of a potentially effective first-line chemotherapy., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objective: Additional surgery is considered for patients at high risk for lymph node metastasis (LNM) after local resection for early rectal cancer. Several factors are considered as indications for additional surgery, although there are currently no definitive criteria. This study aimed to clarify the need for additional surgery based on the number of risk factors for LNM and to evaluate the significance of submucosal invasion on recurrence., Methods: Patients with early rectal cancer harboring risk factors for LNM who underwent local resection between March 2005 and December 2016 were retrospectively analyzed. Associations among the number of risk factors, prognosis, and additional treatment after local resection were investigated., Results: A total of 29 eligible patients were classified into the surgery (n = 10), chemoradiotherapy (n = 7), and no-additional-treatment (NAT, n = 12) groups. Among the 29 patients, 15 patients (52%) with only one risk factor did not relapse. The NAT group harbored fewer risk factors for LNM, and 8 of the 12 patients (67%) had only deep submucosal invasion. Local recurrence occurred in one patient in the chemoradiotherapy group. The estimated 5-year overall survival rates were 88.9%, 75.0%, and 81.5% in the surgery, chemoradiotherapy, and NAT groups, respectively. There were no disease-specific deaths in the overall cohort., Conclusions: In the present study, no recurrence occurred in patients who did not receive additional surgery with deep submucosal invasion as the only risk factor. A multicenter investigation is necessary to confirm the safety of nonsurgical options., Competing Interests: Conflicts of Interest There are no conflicts of interest., (Copyright © 2020 by The Japan Society of Coloproctology.)