Kenichi Hirabayashi

Introduction: Signet-ring cells (SRCs) or SRC-like cells are a characteristic cytological feature observed in several malignancies. However, the diagnostic significance of SRC-like cells, including SRCs, in intraductal papillary mucinous neoplasms (IPMNs) remains unclear. Therefore, this study aimed to evaluate the diagnostic significance of SRC-like cells in pancreatic juice cytology (PJC) of patients with IPMN. Methods: We retrospectively analyzed the prevalence, quantity, and mucus coloration of SRC-like cells in PJC specimens from 63 patients with IPMN, categorized by the histological grade and subtype. Results: SRC-like cells were observed in 5.0% (1/20) of low-grade dysplasia, 26.9% (7/26) of high-grade dysplasia (HGD), and 47.1% (8/17) of invasive carcinoma (IC) cases. Based on receiver operating characteristic curve analysis, the presence of ≥30 SRC-like cells (termed the “SRC pattern”) was identified as the optimal threshold for diagnosing HGD/IC, demonstrating 100% specificity and positive predictive value. Among the 16 patients with SRC-like cells, the histological subtypes were gastric (n = 4) and intestinal (n = 12). Gastric-type IPMN cases showed <30 SRC-like cells with yellow to orange mucus, whereas intestinal-type IPMN cases showed ≥30 SRC-like cells with clear to pink mucus. Conclusions: SRC pattern, defined as the presence of ≥30 SRC-like cells in PJC, may be a supportive cytological finding for diagnosing IPMN with HGD/IC, particularly the intestinal subtype. Furthermore, the mucus coloration of SRC-like cells might reflect subtype-related morphological tendencies.

INTRODUCTION: Rhabdomyosarcoma (RMS) is the most common malignant soft tissue tumor in children, with the alveolar subtype associated with an aggressive clinical course and poor prognosis. Metastasis to the breast from RMS is extremely rare, particularly in preadolescent patients, and optimal local treatment strategies have not been established.CASE PRESENTATION: We report the case of a 9-year-old girl with alveolar RMS originating in the left lower extremity. The patient underwent wide resection of the primary tumor and dissection of the regional lymph node, followed by multimodal therapy, including chemotherapy and proton beam radiotherapy, and achieved complete remission. Three months after the completion of treatment, she developed a palpable mass in the right breast. Imaging studies revealed multiple breast lesions without evidence of local recurrence at the primary site. Histopathological examination confirmed the presence of metastatic RMS. Preoperative chemotherapy resulted in a limited tumor response, and local control was pursued. An endoscopic-assisted nipple–areola-sparing mastectomy with partial resection of the pectoralis major muscle was performed, followed by adjuvant chemotherapy and radiotherapy. Immunohistochemical findings supported the diagnosis of metastatic RMS. Comprehensive genomic profiling of the metastatic lesion identified a TP53 pathogenic variant. However, germline testing was not performed, and the clinical significance of this finding remains uncertain. Despite aggressive multidisciplinary treatment, the patient developed widespread metastatic disease and died approximately 4 years after the initial diagnosis.CONCLUSIONS: Breast metastasis from alveolar RMS is rare but should be considered in pediatric patients who present with breast masses after treatment. Surgical resection may contribute to local control and QOL in selected cases. Additional cases are needed to clarify the role of surgery and to establish optimal treatment strategies, particularly in patients with suspected hereditary cancer predisposition syndromes.

Background: Tumor immunity is involved in the progression of malignant tumors. However, there are few reports on the relationship between the immunological environment and the efficacy of immune checkpoint inhibitors in small cell lung cancer (SCLC). We analyzed the relationship between tumor‐infiltrating immune cells and protein expression and survival in patients with SCLC treated with combined therapy with immune checkpoint inhibitors plus chemotherapy. Methods: Patients with SCLC who received combined therapy with immune checkpoint inhibitors plus chemotherapy between 2019 and 2023 were enrolled. Immune cell infiltration levels, including CD4, CD8, FOXP3, CD163‐positive cells and expression levels of TGFβ1 and SMAD3 proteins in tumor tissue were evaluated by immunohistochemistry. Progression‐free survival (PFS) and overall survival (OS) were evaluated as endpoints. Results: Data from 22 patients were analyzed. The high CD4‐positive T lymphocyte ( p = 0.008, log‐rank test) and the high CD8‐positive T lymphocyte infiltration group ( p = 0.031, log‐rank test) showed statistically significantly longer OS than the low infiltration group. On the other hand, the low TGFβ1 expression group showed significantly longer PFS ( p = 0.026, log‐rank test) and the low SMAD3 expression group showed significantly longer OS ( p = 0.042, log‐rank test) than the high expression group. Conclusion: In conclusion, it is suggested that infiltration of T lymphocytes and expression of TGFβ1 and SMAD3 may be related to the efficacy of the combined therapy with immune checkpoint inhibitors plus chemotherapy in patients with SCLC.

With advancements in multidisciplinary treatments such as chemotherapy and radiation therapy, there have been an increasing number of recent reports regarding surgical interventions for unresectable pancreatic ductal adenocarcinoma with metastasis (UR-M PDAC), known as “conversion surgery”. Olaparib, which is one of the treatment options, has been approved as a maintenance treatment in patients with UR-M PDAC and germline BRCA mutations who achieve disease control after a platinum-based regimen such as modified FOLFIRINOX (mFFX). A 49-year-old male patient was diagnosed with PDAC in the pancreatic body-tail. The 1st staging laparoscopy (SL) revealed hepatic metastases in both lobes and positive peritoneal lavage cytology. A germline BRCA2 mutation was considered, and mFFX was introduced and continued for 8 courses, followed by 8 months of olaparib. The initially elevated levels of duke pancreatic monoclonal antigen type 2 and carcinoembryonic antigen subsequently returned to normal, and CT revealed more than 60% shrinkage of the primary tumor. The 2nd SL revealed the disappearance of multiple hepatic metastases and negative conversion of peritoneal lavage cytology, so we performed chemoradiotherapy with olaparib to ensure an antitumor effect and surgical margin negativity, followed by distal pancreatectomy with celiac axis resection. Histopathological findings revealed R0 resection and a pathological complete response (pCR). Adjuvant olaparib treatment was administered for 10 months starting 2 months after surgery, and the patient has remained alive without recurrence for 2 years after surgery. We report the very rare case of a patient with BRCA-positive PDAC with multiple liver metastases who underwent conversion surgery after treatment with mFFX and olaparib, achieved a pCR, and has remained recurrence-free for 2 years.

Cytology is a useful method for diagnosing pancreatic neoplasms. Although endoscopic ultrasound‐guided fine‐needle aspiration has recently become the mainstream method for the diagnosis of pancreatic neoplasms, pancreatic juice and pancreatic duct brushing cytology continue to be useful diagnostic methods for the investigation of pancreatic neoplasms. Diagnoses using pancreatic cytology are primarily based on the features related to tumor cells; however, evaluation of the background features provides important information that could further aid the diagnosis. Pancreatic neoplasms show various histological types, each of which is associated with its own characteristic background features. The necrotic background, desmoplastic stroma, and presence of cancer‐associated fibroblasts are background features of pancreatic ductal adenocarcinoma, a mucinous background is associated with intraductal papillary mucinous neoplasms and mucinous cystic neoplasms, and hyaline globules are observed in solid pseudopapillary neoplasms. However, some background features are associated with more than one histological type of pancreatic neoplasm, highlighting the importance to base a diagnosis on the results of a comprehensive analysis of not only the background features but also the tumor cells. Here, we provide a review of the key background cytological features of pancreatic neoplasms, which can serve as a guide to improve diagnosis and research.

Determination of the primary tumor in periampullary region carcinomas can be difficult, and the pathological assessment and clinicopathological characteristics remain elusive. In this study, we investigated the current recognition and practices for periampullary region adenocarcinoma with an indeterminable origin among expert pathologists through a cognitive survey. Simultaneously, we analyzed a prospective collection of cases with an indeterminable primary tumor diagnosed from 2008 to 2018 to elucidate their clinicopathological features. All cases with pathological indeterminable primary tumors were reported and discussed in a clinicopathological conference to elucidate if it was possible to distinguish the primary tumor clinically and pathologically. From the cognitive survey, over 85% of the pathologists had experienced cases with indeterminable primary tumors; however, 70% of the cases was reported as pancreatic cancer without definitive grounds. Interpretation of the main tumor mass varied, and no standardized method was developed to determine the primary tumor. During a prospective study, 42 of the 392 periampullary carcinoma cases (10.7%) were considered as tumors with a pathological indeterminable origin. After the clinicopathological conferences, 21 (5.4%) remained indeterminable and were considered final indeterminable cases. Histological studies showed that the tumors spread along both the bile duct and main pancreatic duct; this was the most representative finding of the final indeterminable cases. This study is the first to elucidate and recognize the current clinicopathological features of periampullary region adenocarcinomas with an indeterminable origin. Adequate assessment of primary tumors in periampullary region carcinomas will help to optimize epidemiological data of pancreatic and bile duct cancer.

Aims Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies. Hence, there is a need for new markers and treatment strategies. P68/DEAD box protein 5 (DDX5) is an ATP-dependent RNA helicase of the DEAD box protein family. It is a prognostic marker for several cancers. In this study, we aimed to evaluate the expression and clinical relevance of DDX5 in PDAC. Methods DDX5 expression in tissue microarray blocks containing 230 PDAC samples was examined using immunohistochemical analysis. DDX5 expression was considered high when more than 50% of the cells were stained and low when less than 50% of the cells were stained. We investigated the association between DDX5 expression and clinicopathological parameters, including patient survival. Results The nuclei of normal pancreatic ducts, normal acinar cells and PDAC cells were stained positive for DDX5 although the intensity and distribution of DDX5 expression varied. Islet cells showed strong and diffuse staining of DDX5. DDX5 expression was low and high in 148 (64.3%) and 82 cases (35.7%), respectively. Low DDX5 expression was significantly associated with an advanced pT factor (pT2–pT3: tumour size,>20 mm), lymphatic involvement, advanced tumour-node-metastasis (TNM) stage (stages IIB, III, and IV), and venous involvement. In addition, the multivariate analysis revealed that DDX5 expression is an independent prognostic factor for PDAC. Conclusion These results suggest that DDX5 plays an important role in tumour invasiveness and PDAC prognosis.

The biopsy‐based diagnosis of autoimmune pancreatitis (AIP) is difficult but is becoming imperative for pathologists due to the increased amount of endoscopic ultrasound‐guided biopsy tissue. To cope with this challenge, we propose guidance for the biopsy diagnosis of type 1 AIP. This guidance is for pathologists and comprises three main parts. The first part includes basic issues on tissue acquisition, staining, and final diagnosis, and is intended for gastroenterologists as well. The second part is a practical guide for diagnosing type 1 AIP based on the AIP clinical diagnostic criteria 2018. Inconsistent histological findings, tips for evaluating IgG4 immunostaining and key histological features including the ductal lesion and others are explained. Storiform fibrosis and obliterative phlebitis are diagnostic hallmarks but are sometimes equivocal. Storiform fibrosis is defined as spindle‐shaped cells, inflammatory cells and fine collagen fibers forming a flowing arrangement. Obliterative phlebitis is defined as fibrous venous obliteration with inflammatory cells. Examples of each are provided. The third part describes the differentiation of AIP from pancreatic ductal adenocarcinoma (PDAC), focusing on histological features of acinar‐ductal metaplasia in AIP, which is an important mimicker of PDAC. This guidance will help standardize pathology reports of pancreatic biopsies for diagnosing type 1 AIP.