福嶋 敬宜

Cancer-stromal interactions play important roles in the biology of various cancers, including lung adenocarcinoma. We aimed to comprehensively analyze the lung cancer interactome and identify the key ligand-receptor pairs involved in the aggressiveness of lung adenocarcinoma. Transcriptome data were obtained from xenografts of 11 lung cancer cell lines that represented the major driver mutations in lung adenocarcinomas. A quantitative dataset was constructed in both stroma-to-cancer and cancer-to-stroma directions using the cancer-stromal interactome analysis method. The prognostic value of each factor was evaluated using multiple datasets. Analysis of 24,250 stroma-derived mouse transcripts and 26,289 human cancer-derived transcripts identified 1150 cancer-stromal interactions, from which we selected 117 interactions based on the intensity score of ligand-stromal transcript levels. Further prognostic analysis using public databases led us to identify 21 ligand-receptor pairs, including well-known as well as less well-characterized ligand-receptor pairs. Therefore, we selected tumor necrosis factor superfamily member 12/tumor necrosis factor receptor superfamily member 12A as possible factors contributing to the aggressiveness of lung adenocarcinoma via cancer-stromal interactions; immunohistochemical analysis confirmed that these factors were expressed mainly in the stroma and cancer cells, respectively, in both xenografts and primary lung adenocarcinoma. In human clinical specimens, high tumor necrosis factor receptor superfamily member 12A expression significantly correlated with tumor size, invasive diameter, and stage. Thus, tumor necrosis factor superfamily member 12 and its receptor tumor necrosis factor receptor superfamily member 12A signaling axis may be potential candidates for therapeutic intervention for lung adenocarcinoma.

BACKGROUND/AIMS: Although endoscopic diagnosis of primary small intestinal lymphoma (PSIL) is important, the association between endoscopic findings and histologic types remains unclear. This study aimed to evaluate the diagnostic accuracy of endoscopic classifications and biopsies in PSIL. METHODS: We retrospectively reviewed 100 lesions from 49 patients with PSIL who underwent double-balloon enteroscopy between 2005 and 2020. Endoscopic findings were classified into six macroscopic types: polypoid, ulcerative, multiple nodules, diffuse, concentric stenosis, or unclassified. RESULTS: Of the 100 lesions, 47 were multiple nodules, 32 were ulcerative, 8 were polypoid, 7 were diffuse, 4 were concentric stenosis, and 2 were unclassified. Diffuse large B-cell lymphoma (DLBCL) was mainly ulcerative (72%) or polypoid (75%), whereas follicular lymphoma appeared as multiple nodules (98%) or concentric stenosis (100%) (p<0.001, Cramér's V=0.41). The ulcerative type was associated with DLBCL (sensitivity, 0.74; specificity, 0.87), and multiple-nodule type were associated with follicular lymphoma (sensitivity, 0.75; specificity, 0.97). The overall diagnostic yield of the biopsy was 95%. Interobserver agreement was substantial (κ=0.69; agreement, 78%). CONCLUSIONS: Endoscopic findings were significantly associated with histologic types. Endoscopic findings and biopsies provide a high diagnostic yield, supporting their central role in the diagnostic management of PSIL.

Large cell neuroendocrine carcinoma (LCNEC) is a neuroendocrine carcinoma (NEC) of the lung that is characterized by its heterogeneous morphology, diverse immunophenotypes, and complex genomic profiles. Among LCNECs, a subset expressing the transcription factor POU2F3 (LCNEC-P) has been suggested to share similarities with small cell lung carcinoma (SCLC)-P, a subtype of SCLC defined by POU2F3 expression. However, the specific characteristics of LCNEC-P have not been fully elucidated. Therefore, the aim of the present study is to clarify the clinicopathological, immunohistochemical, and genetic characteristics of LCNEC-P. Fifty-six LCNEC cases were analyzed, including 12 LCNEC-P and 44 LCNEC-non-P cases. Morphologically, LCNEC-P exhibited significantly lower cytomorphology scores, indicating a resemblance to SCLC. Immunohistochemically, LCNEC-P showed the lower expression of neuroendocrine markers (SYP, CHGA, and INSM1), but the higher expression of C-MYC than LCNEC-non-P. A strong mutually exclusive expression pattern was observed between POU2F3 and ASCL1/NEUROD1. Whole-genome sequencing of 20 cases revealed that LCNEC-P harbored RB1 mutations in 100 % of cases, which was significantly higher than in LCNEC-non-P (40 %). FGFR1 amplification was observed in 60 % of LCNEC-P cases, representing a higher prevalence than previously reported for LCNEC. In addition, LCNEC-P showed a distinct copy number alteration profile, including frequent 20q13 amplification, compared with LCNEC-non-P. These results demonstrate that LCNEC-P represents a distinct subgroup of LCNEC that is characterized by a specific morphological, immunohistochemical, and genetic profile, closely resembling SCLC-P. This study provides insights into the biology of LCNEC-P and supports its classification as a unique entity within LCNEC.

Acquired cystic kidney disease-associated renal cell carcinoma (ACKD-RCC) can develop in the kidneys of patients with chronic kidney disease, particularly those on long-term dialysis, and displays morphologic diversity. We present a 70-year-old man with acquired cystic disease who developed 3 discrete tumors, each with different morphology. The patient had been on hemodialysis for 22 years and underwent right nephrectomy for a newly detected kidney mass. Histopathology and immunohistochemistry revealed 3 discrete tumors: a superior polar tumor displaying classic ACKD-RCC architecture with PAX8, AMACR, and KRT7 expression; an inferior polar tumor displaying ACKD-RCC morphology combined with a high-grade sarcomatoid component with PAX8 expression without AMACR and KRT7, consistent with dedifferentiation; and a midkidney tumor consisting mainly of bland spindle cells in fascicles with PAX8 and focal KRT7 expression confirming its epithelial origin, and negative mesenchymal and melanocytic markers excluding mimics, leading to a diagnosis of renal cell carcinoma (RCC), not otherwise specified (NOS). The patient developed pulmonary and bone metastases postoperatively and died of the disease 3 months later. The synchronous occurrence of conventional ACKD-RCC, a dedifferentiated sarcomatoid form, and a spindle cell RCC, NOS demonstrate the marked morphological heterogeneity of neoplasia in ACKD. The presence of both sarcomatoid and spindle cell histologic patterns is associated with an aggressive clinical course, highlighting the importance of intensive surveillance and thorough pathological evaluation of kidney masses in patients on long-term dialysis.

Pathologic potassium (K+) deficiency causes kidney inflammation and injury, known as hypokalemic nephropathy (HN), the underlying pathogenesis of which is obscure. NLR family pyrin domain-containing 3 (NLRP3) inflammasomes are platforms that sense the reduction of intracellular K+, engaging inflammation and tissue injury. The present study investigated whether or not systemic K+ deficiency induces NLRP3 inflammasome activation in HN. Clinically diagnosed HN in humans manifested up-regulation of NLRP3 and apoptosis-associated speck-like protein-containing a CARD (ASC) in the kidney epithelia. A K+ depletion model in mice demonstrated that kidney-resident NLRP3 and ASC play key roles in triggering early inflammation in HN kidneys. Unexpectedly, the K+ depletion-induced kidney inflammation was not dependent on inflammasome activation. A single-cell RNA-sequencing analysis revealed ASC up-regulation, NF-κB activation, and an increased level of tumor necrosis factor-like weak inducer of apoptosis receptor fibroblast growth factor-inducible 14 (FN14) in the HN kidneys, primarily in the distal nephron/collecting duct epithelial cells. Although kidney epithelial cells did not drive NLRP3 inflammasomes, NLRP3 and ASC alternatively enhanced with-no-lysine kinase-dependent NF-κB signaling in response to tumor necrosis factor-like weak inducer of apoptosis under a low-K+ milieu. These findings indicate a unique proinflammatory cascade mediated by NLRP3 and ASC beyond the framework of inflammasomes, which broadens the understanding of electrolyte-associated immunity in the kidney.

Cardiac hemangioma is a rare benign tumor, and the cavernous type accounts for 50~60% of all cardiac hemangiomas. Although most cases are asymptomatic, the risk of serious complications, such as embolism, arrhythmia, tumor rupture, coronary artery obstruction, or sudden death, is high, and surgical resection should be considered. In a 60-year-old woman, follow-up imaging studies after a left breast cancer operation incidentally revealed a cardiac tumor in the right atrium. Transthoracic echocardiography showed a poorly mobile, highly echogenic 12×16 mm mass with clear margins, and contrast-enhanced computed tomography (CT) showed a round tumor with no obvious enhancement. The tumor was resected with an atrial wall and diagnosed as a cavernous hemangioma on histopathological examination. Cardiac hemangiomas are enhanced using contrast medium; however, some cases have no contrast enhancement. Histopathological examination confirmed this diagnosis. The patient was discharged on postoperative day 11 in a good condition.

PURPOSE: To examine magnetic resonance imaging (MRI) features of mesonephric-like adenocarcinoma (MLA) of the uterine corpus. METHOD: MRI features of 19 patients with pathologically proven MLA of the uterine corpus were retrospectively compared with those of 95 patients with endometrial endometrioid carcinoma (EEC). RESULTS: Most patients with MLA were postmenopausal. Advanced FIGO stages were more common in the MLA than in the EEC group (63.2 % vs. 18.9 %, p < 0.001). On MRI, endophytic growth into the myometrium were more frequent in the MLA than in the EEC group (68.4 % vs. 14.7 %, p = 0.005). The median maximum tumor diameter in the MLA group (52.4 mm) tended to be larger than that in the EEC group (38.9 mm), although the difference was not statistically significant (p = 0.374). The tumor-to-muscle signal intensity ratio (SIR) on fat-suppressed gadolinium-enhanced T1-weighted gradient-echo imaging was higher in the MLA group than in the EEC group. (1.67 vs. 1.36, p = 0.002). The SIR on diffusion-weighted imaging (DWI) was comparable between the two groups (8.35 vs. 6.72, p = 0.330). The apparent diffusion coefficient value was lower in the MLA than in the EEC group (0.69 10-3 mm2/s vs. 0.76 × 10-3 mm2/s, p = 0.003). Coexisting adenomyosis was more frequent in the MLA than in the EEC group (52.6 % vs. 21.1 %, p = 0.034). The concordance rate between MRI and pathology for adenomyosis coexistence was 84.2 % for MLA, 87.4 % for EEC, and 86.8 % overall. MLA of the uterine corpus was identified in two patients, characterized by development independent of and discontinuous from the endometrium, whereas EEC in all patients demonstrated continuity with the endometrium. CONCLUSIONS: MRI of MLA of the uterine corpus typically demonstrates large, diffuse, and endophytic growth into the myometrium, with strong contrast enhancement and more restricted diffusion compared to EEC, with coexisting adenomyosis present in over 50% of patients. Therefore, postmenopausal women with adenomyosis should be carefully evaluated for MLA on MRI, particularly using DWI.

IMPORTANCE: The lack of multidisciplinary workflow guidelines and clear definitions and classifications for neoplasms in and around the ampulla of Vater results in inconsistencies affecting patient care and research. OBJECTIVE: The PERIPAN international multidisciplinary consensus group aimed to standardize the multidisciplinary diagnostic workflow and achieve consensus on definitions and classifications in order to ensure proper classification and optimal diagnostic assessment and consequently to improve patient care and future research. DESIGN: An international team of 43 experts (pathologists, surgeons, radiologists, gastroenterologists, oncologists) from 12 countries identified knowledge gaps, reviewed 37061 articles, and proposed recommendations using the Scottish Intercollegiate Guidelines Network methodology (SIGN), including the Delphi methodology and the AGREEII tool for quality assessment and external validation. RESULTS: The 38 consensus questions and 51 recommendations provide guidance on the following key aspects: I. More specific anatomic criteria for the definition of what qualifies as "ampullary" neoplasms, their distinction from duodenal and common bile duct tumors, and clinicopathologic characteristics of anatomic subsets; II. Avoidance of the confusing term "periampullary" for final classification; III. Refined definitions of intestinal, pancreatobiliary and mixed subtypes, and introduction of rare histologic subtypes; IV. The use and limitations of immunohistochemical and molecular profiling; V. Biopsy acquisition; VI. Clinical information required for accurate pathology assessment of biopsies and ampullectomy specimens; VII. Key items to be included in pathology reports of endoscopic specimens. CONCLUSIONS AND RELEVANCE: Recognition of the Brescia PERIPAN guidelines will allow a more accurate classification of true ampullary cancers and their differentiation from other "periampullary" tumors. This will have significant implications for endoscopic interpretation and management, staging, pathologic diagnosis and therapeutic evaluation as well as oncologic treatment of various anatomic and histologic subsets of ampullary tumors. This will enhance the quality of both clinical care and future research in this complex medical field.

BACKGROUND/AIM: The Hippo signaling pathway comprises mammalian sterile 20-like kinase 1/2, large tumor suppressor 1/2, and Yes-associated protein 1 (YAP1). This study investigated phosphorylated YAP (pYAP, Ser 127) protein expression in oral squamous cell carcinoma (OSCC). PATIENTS AND METHODS: Tissues from patients with oral epithelial dysplasia (OED, n=7), carcinoma in situ (CIS, n=14), and OSCC (n=109) were analyzed. RESULTS: Cytoplasmic expression of pYAP was low in OED, CIS, and OSCC tissues. The expression of pYAP was correlated with differentiation, and the expression of low levels of YAP was significantly more common in well-differentiated to moderately differentiated OSCC than in poorly differentiated OSCC. High pYAP expression correlates with characteristics of epithelial-to-mesenchymal transition (EMT), e.g., loss of E-cadherin and increased expression of vimentin and laminin 5 (p<0.0001). Additionally, the protein arginine methyltransferase 1, a positive modulatory factor of YAP activity, was found to be correlated with elevated levels of pYAP expression (p<0.0007). CONCLUSION: The presence of elevated pYAP expression may serve as a prognostic indicator of an aggressive OSCC with EMT during the invasive stage.

A 76-year-old Japanese man was incidentally diagnosed with a pancreatic head tumor on computed tomography after surgery for colon cancer. He underwent pancreatoduodenectomy and was diagnosed with IgG4-related autoimmune pancreatitis. Concurrent chronic kidney disease gradually progressed and chronic hemodialysis was introduced 2 years later. Six months after the introduction of hemodialysis, follow-up abdominal computed tomography revealed marked enlargement of bilateral kidneys compared with previous images. Blood tests revealed persistent high IgG and IgG4 levels, and IgG4-related kidney disease was suspected. Thus, percutaneous kidney biopsy was performed. No evidence of IgG4-related kidney disease was detected, and a diagnosis of diffuse large B-cell lymphoma was made. Six courses of combination chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone was effective, and the patient achieved and maintained complete remission for five years. This case highlights the need to consider the possible development of malignant lymphoma within several years after IgG4-related disease, especially in cases of autoimmune pancreatitis.

BACKGROUND: The aim of this study was to elucidate the association of pancreatic fluid cytology with intrapancreatic recurrence of intraductal papillary mucinous neoplasms (IPMNs). MATERIALS AND METHODS: A total of 68 patients with IPMN who underwent pancreatectomy and obtained cytologic analysis of pancreatic fluid at Jichi Medical University Hospital were included in this study. Computed tomography scan and magnetic resonance cholangiopancreatography were performed preoperatively. Endoscopic retrograde cholangiopancreatography was used to obtain pancreatic fluid. The association of recurrence with variables was determined by logistic regression multivariate analysis. RESULTS: Class V cytology was found in 7/68 patients preoperatively. Metachronous intrapancreatic recurrences occurred in 6/68 patients, including one branched type, main pancreatic duct type in two and mixed pancreatic duct type in three. Four of seven patients with class V cytology developed intra-pancreatic recurrences as a new lesion. Class V cytology was significantly associated with intrapancreatic recurrence, compared to those with class IV or lower cytology. In univariate analysis, patients with pathological findings with high-grade dysplasia or adenocarcinoma (P = 0.0392, odds ratio (OR) 10.2, 95 % confidence interval (CI) 1.12-93.6) and class V pancreatic fluid cytology (P = 0.0005, OR 38.7, 95 % CI 4.94-302) were significant risk factors. In multivariate analysis, class V pancreatic fluid cytology was significantly associated with developing intrapancreatic recurrence (P = 0.0149, OR 22.7, 95 % CI 1.83-279). CONCLUSION: Preoperative class V pancreatic fluid cytology is associated with intra-pancreatic recurrence after resection of IPMN.

The tumor microenvironment is highly heterogeneous and consists of neoplastic cells and diverse stromal components, including fibroblasts, endothelial cells, pericytes, immune cells, local and bone marrow-derived stromal stem and progenitor cells, and the surrounding extracellular matrix. Although the significance of p16 and p53 has been reported in various tumor types, their involvement in the stromal cells of oral squamous cell carcinoma (OSCC) remains unclear. We performed immunohistochemical analyses of p16 and p53 expression in OSCC samples, Of the 116 samples, 74 showed p16-positive stromal cells, and 33 showed p53-positive stromal cells. Both p16 and p53 positivity were associated with an increased histological grade, lymphovascular invasion, an immature stromal pattern with abundant amorphous extracellular matrix material, infiltrative invasion patterns (Yamamoto Kohama classification-4C and 4D), and poor prognosis. Multivariate analyses identified p16 and p53 positivity in the stroma as independent prognostic factors for overall survival (P = 0.032 and P = 0.020, respectively); moreover, stromal p16 positivity correlated with stromal p53 positivity. These findings indicated that p16 and p53 stroma positivity may regulate OSCC tumor aggressiveness.

INTRODUCTION: Neoadjuvant gemcitabine plus S-1 (GS) therapy for resectable pancreatic cancer has been shown to prolong overall survival significantly compared with upfront surgery. Herein, we report two opposite cases of patients with resectable pancreatic cancer who underwent distal pancreatectomy after neoadjuvant GS therapy. CASE PRESENTATION: In Case 1, a 49-year-old female with a 12 mm tumor in the pancreatic body (cT1N0M0, cStage IA, union for international cancer control [UICC] 8th edition) underwent two courses of neoadjuvant GS therapy followed by an open distal pancreatectomy. Pathological examination revealed no residual cancer and the patient was diagnosed with a pathological complete response (pCR) without recurrence 31 months after surgery. However, in Case 2, a 74-year-old male with a 12 mm tumor in the pancreatic body (cT1N0M0, cStage IA, UICC 8th edition) also underwent two courses of neoadjuvant GS therapy, and then a laparoscopic distal pancreatectomy was performed. Pathological examination showed invasive pancreatic ductal adenocarcinoma with a 20 mm tumor. The tumor exhibited invasion into the lumen of the splenic vein and retroperitoneal tissue (ypT1N0M0, ypStage IA, UICC 8th edition). Adjuvant chemotherapy with S-1 was started, but 4 months postoperatively, a significant rise in serum CA19-9 levels was observed with multiple hepatic metastases and portal venous tumor thrombus. Gemcitabine plus nab-paclitaxel (GnP) therapy was started, however, the tumor progressed rapidly. The patient died 6 months after surgery. CONCLUSIONS: Neoadjuvant GS therapy is potentially expected to have a significant therapeutic effect as the pCR. Nevertheless, even after surgical resection, some patients still exhibit extremely poor prognosis. Therefore, it is necessary to clarify their clinical characteristics.

INTRODUCTION: Acinar cell carcinomas are rare pancreatic neoplasms, accounting for approximately 1% of all exocrine pancreatic tumors. We describe a case of a cystic variant with intracystic hemorrhaging that was difficult to differentiate from a pseudocyst due to its morphology. CASE PRESENTATION: A 54-year-old man was admitted with severe left upper quadrant abdominal pain. Imaging studies showed a 7.0-cm internal heterogeneous cystic lesion with a splenic artery pseudoaneurysm near the lesion. Transarterial embolization of the splenic artery was performed, but rebleeding occurred 1 month later. Distal pancreatectomy with partial resection of the stomach revealed internal nodular lesions on the resected specimen. Microscopically, the cystic mass was composed of neoplastic tissue with papillary and tubular structures. The tumor was diagnosed as acinar cell carcinoma since immunohistochemical examination showed tumor cells positive for BCL10, lipase, and trypsin. The patient experienced local recurrence 6 months postoperatively, received chemotherapy with gemcitabine followed by S-1, underwent a 2nd resection at 18 months, and has remained recurrence-free for 15 years. CONCLUSIONS: Acinar cell carcinoma rarely presents with a cystic structure and may be accompanied by a pseudoaneurysm, which can complicate differentiation from a pancreatic pseudocyst, highlighting the importance of careful differential diagnosis for appropriate treatment.

INTRODUCTION: Follicular lymphoma is an indolent B-cell lymphoma that can involve the gastrointestinal tract, most commonly the small intestine. Although rituximab-based therapy is effective, transformation to diffuse large B-cell lymphoma (DLBCL) can occur and becomes difficult to diagnose after CD20 loss. CASE PRESENTATION: We report the case of a 64-year-old woman initially diagnosed with primary small intestinal follicular lymphoma who subsequently developed transformation to DLBCL 2 years after rituximab therapy. Double-balloon enteroscopy revealed progression of mucosal lesions, raising suspicion of histologic transformation. However, endoscopic biopsy was inconclusive because of the loss of CD20 expression, likely resulting from prior rituximab therapy. Surgical resection was performed to relieve intestinal obstruction and to establish a definitive diagnosis. Histopathological examination confirmed transformation to CD20-negative DLBCL. CONCLUSION: This case highlights the diagnostic limitation of endoscopic biopsy following rituximab therapy. Therefore, clinicians should be cautious in relying solely on endoscopic findings and remain open to surgical intervention to achieve a timely and accurate diagnosis.

INTRODUCTION: Moderately differentiated neuroendocrine tumors of the larynx are rare malignant tumors that arise from the submucosa of the larynx, for which surgery is the first-line treatment. PRESENTATION OF CASE: We report a case of moderately differentiated neuroendocrine tumor of the larynx, in which the patient, a 74-year-old man, experienced long-term palliation but an unfortunate outcome of death owing to metastasis. Laryngeal endoscopic examination revealed an elevated submucosal lesion on the laryngeal surface of the epiglottis. Computed tomography and magnetic resonance imaging showed a tumor-like lesion demonstrating a contrasting effect in the submucosa of the epiglottis. A biopsy revealed a moderately differentiated neuroendocrine tumor (formerly called an atypical carcinoid), and a horizontal partial laryngectomy was performed. The patient had a good postoperative course; however, three years and ten months after surgery, he experienced recurrence in the upper gastrointestinal tract and carcinoid syndrome and died four years and three months after the surgery. DISCUSSION: The prognosis of laryngeal neuroendocrine tumors remains poor. In this case, local control was possible without irradiation because the resection margins were negative on pathological examination. This case report has been reported in line with the SCARE Criteria. CONCLUSION: Long-term follow-up of this type of tumor is necessary, as distant metastasis is likely to affect prognosis. In addition to surgery, effective adjuvant therapies, including molecular targeted therapies, should be established.