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Cutaneous xanthoma consist of foam cells that originate from monocytes or macrophages and accumulate in perivascular areas of the skin. The main component of these cells is oxidized low-density lipoprotein (oxLDL). In this study, we show that mast cells surround the accumulated foam cells, suggesting their involvement in xanthoma formation. Coculture of THP-1 or U937 monocytes with the human mast cell line LUVA upregulated their uptake of oxLDL. Positive staining for intracellular cell adhesion molecule-1 (ICAM-1) at the borders between mast cells and foam cells was seen in pathological specimens of the most common cutaneous xanthoma, xanthelasma palpebrarum, and in cocultures. In the latter, ICAM1 messenger RNA levels were upregulated. The administration of anti-ICAM-1 blocking antibody inhibited the increase in oxLDL uptake by THP-1 or U937 monocytes cocultured with LUVA. Taken together, these results suggest a role for mast cells in the formation of xanthelasma palpebrarum and the involvement of ICAM-1 in this process., (© 2023 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

We elucidated clinicopathological characteristics of giant cell tumor of bone (GCTB) in Japan, and significant clinicopathological factors for predicting local recurrence. Clinicopathological profiles of 213 patients with GCTB (100 male, 113 female) involving extra-craniofacial bones were retrieved. Pathological slides obtained at the initial surgery were reviewed. Fourteen pathological and five clinical features were statistically analyzed to disclose prognostic significance. Patient age ranged from 12-80 years (Average 38.7). Long bones were most frequently affected (86.4%), especially around the knee (62.9%). Histological features are basically similar to those previously reported. Within a follow-up period (24-316 months, average 106.1 months), the local recurrence rate is 29.1%. Metastasis has occurred in 9 patients. Cox regression analysis of representative clinicopathological features shows that younger age, higher mitotic count, smaller zones of stromal hemorrhage, considerable vascular invasion and absence of ischemic necrosis are significant predictors for local recurrence. Initial operative method (curettage) is a significant risk factor in univariate analysis but not by multivariate analysis (P = 0.053). Denosumab administration increases risk but not significantly (P = 0.053). Histone 3.3 G34W immunopositivity is not significant for predicting local recurrence., (© 2021 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Desmoid-type fibromatosis (DF) is a locally aggressive but non-metastatic (myo)fibroblastic neoplasm. A hallmark of the tumor is nuclear positivity for beta-catenin in immunohistochemistry due mostly to CTNNB1 mutations. However, a recent study has reported that even beta-catenin 'nuclear-negative' DFs can harbor CTNNB1 mutations and that the positive ratio of nuclear beta-catenin in DF is different among antibodies. Here, we reviewed soft tissue lesions for which the possibility of DF was considered and compared the sensitivity and specificity of nuclear beta-catenin for the diagnosis of DF among commonly used anti-beta-catenin antibodies, i.e., clone beta-catenin 1, 17C2 and 14. We analyzed 26 cases of DF, 28 cases of benign fibroblastic lesions, and 27 cases of other soft tissue tumors. The sensitivity and specificity of nuclear beta-catenin for the diagnosis of DF were different among antibodies; 54% and 98% in clone beta-catenin 1, 85% and 84% in 17C2, and 96% and 62% in 14. IHC of LEF1 showed comparable results with IHC of beta-catenin, with a sensitivity of 88% and specificity of 76%. Additionally, when beta-catenin 1 was used, DFs showed characteristic dotted cytoplasmic staining, often appearing as rings. Our results might be helpful for making a correct diagnosis of DF., (© 2021 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

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.)

The neonatal Fc receptor (FcRn) plays a role in trafficking IgG and albumin and is thought to mediate intravenous immunoglobulin (IVIG) therapy for certain diseases. IVIG can be used for the treatment of human Langerhans cell histiocytosis (LCH); however, the mechanism remains unclear. The expression and function of FcRn protein have not been studied in LCH, though the expression of FcRn messenger RNA (mRNA) have been reported. In this report, we confirmed the expression of FcRn in 26 of 30 pathological cases (86.7%) diagnosed immunohistochemically as LCH. The expression was independent of age, gender, location, multi- or single-system, and the status of BRAFV600E immunostaining. We also confirmed the expression of FcRn mRNA and protein in the human LCH-like cell line, ELD-1. FcRn suppressed albumin consumption and growth of IVIG preparation-treated ELD-1 cells, but not of IVIG preparation-untreated or FcRn-knockdown ELD-1 cells. In addition, FITC-conjugated albumin was taken into Rab11-positive recycle vesicles in mock ELD-1 cells but not in FcRn-knockdown ELD-1 cells. IVIG preparation prolonged this status in mock ELD-1 cells. Therefore, ELD-1 recycled albumin via FcRn and albumin was not used for metabolism. Our results increase our understanding of the molecular mechanism of IVIG treatment of LCH., (© 2021 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Kasai operation is widely performed for biliary atresia (BA), as it improves the prognosis. Biliary tract cancer has rarely been reported as a complication after Kasai operation. A 17-year-old man underwent liver transplantation for progressive jaundice and liver dysfunction after Kasai operation for BA. A macroscopic examination of the explanted liver revealed a 3.6-cm-diameter mass in the hilus of the explanted liver. The tumor consisted of an atypical proliferation of glandular cells in the collagenous stroma. The differential diagnosis included a florid ductular reaction and primary adenocarcinoma. Immunohistochemistry revealed that the glandular cells were diffusely positive for IGF2BP3 and S100P, but negative for CDX2. A diagnosis of extrahepatic cholangiocarcinoma arising from the liver hilus was made. To our knowledge, this is the third case of perihilar cholangiocarcinoma after Kasai operation for BA. The previously reported cases had a poor prognosis, but the current case did not recur during a 15-year follow-up. Cholangiocarcinoma and hepatocellular carcinoma can occur as a late complication of BA after Kasai operation, and early detection and liver transplantation may improve the prognosis., (© 2020 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Immunohistochemically p16 (CDKN2A)-negative uterine cervical squamous cell carcinoma (SCC) is uncommon, and there are few reports about its pathological features. This study explored the causes of p16 negativity in such cases. We analyzed diagnostic tissue samples of five cases of p16-negative cervical SCC among 107 patients who underwent hysterectomy at Kyoto University Hospital between January 2010 and December 2015. The samples were subjected to immunohistochemical staining, in situ hybridization and a genetic analysis. Two of five cases were positive for human papilloma virus (HPV) by genotyping. One was positive for HPV56 with promoter hypermethylation of CDKN2A and co-existing Epstein-Barr virus infection. Another was positive for HPV6 categorized as low-risk HPV with condylomatous morphology. Among the remaining three cases, one had amplification of the L1 gene of HPV with promoter hypermethylation of CDKN2A and TP53 mutation, and one of the other two HPV-negative cases had a homozygous CDKN2A deletion, while the other was positive for p53 and CK7. p16-negativity of cervical SCC is often associated with an unusual virus infection status and CDKN2A gene abnormality., (© 2020 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Renal cell carcinoma unclassified with medullary phenotype (RCCU-MP) is a rare variant of renal medullary carcinoma (RMC) characterized by loss of SMARCB1 (INI1 / SNF5 / BAF47) protein expression in patients without sickle cell trait. Here, we report a case of RCCU-MP in a Japanese patient who had experienced colon cancer 13 years ago, gastric cancer 11 years ago and lung cancer 9 years ago and had received hemodialysis for 15 years. This is the first report of RCCU-MP in Japan. The patient was not of African descent, and did not have SCT or any other hereditary blood abnormality typical of RMC. The tumor was located in the left kidney, and was composed histologically of rhabdoid cells with marked lymphocyte infiltration; it was immunohistochemically negative for SMARCB1. We were, however, unable to detect mutation in the SMARCB1 gene, reduced messengerRNA expression, or deletion or translocation of chromosome 22, where the SMARCB1 gene is located. These results suggest that RCCU-MP may not involve the hemizygous loss of this gene noted in typical RMC cases., (© 2019 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a rare but occasionally fatal limbic encephalitis that may be accompanied by ovarian teratoma. Since the neuroglial tissue within the teratoma may be involved in the pathogenesis of this encephalitis, we attempted morphological and immunohistochemical characterization of the neuroglial tissue in four cases of ovarian teratoma associated with anti-NMDA receptor encephalitis and 12 control cases, i.e., six consecutive cases of immature teratoma and six cases of mature teratoma with an abundant neuronal component, focusing mainly on NMDA receptor-expressing neurons. NMDA receptor-expressing neurons, being observed in all of the cases analyzed, were significantly densely aggregated (P = 0.030, Wilcoxon test) and relatively smaller in size in the encephalitis-associated cases than in the control cases, and the Ki-67 labeling index of neuroglial cells with these neurons was significantly higher in the encephalitis-associated cases (P = 0.004, Wilcoxon test). In the cases with encephalitis, aggregation of B-cells within or around the neuroglial tissue was also observed. Our present findings may be useful for more accurate diagnosis of anti-NMDA receptor encephalitis and contribute to a better understanding of the pathogenesis., (© 2018 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

We elucidated clinicopathological characteristics of chondroblastoma (CB) in Japan, and reliable clinicopathologic parameters predicting local recurrence and/or metastasis. Clinicopathological profiles of 103 CB (80 male, 23 female) in extra-craniofacial bones were retrieved. Numerical scoring of nine pathological and five radiological features was statistically analyzed to determine prognostic significance. Age ranged 8-61 years (average 19.6 years). Frequently involved sites were femur, tibia, calcaneus, patella and humerus. Radiologically, tumors were 2-80 mm (average 31.1 mm) in size. Marginal sclerosis and calcification were common. Histologically, pink cartilage, mitoses, and chicken-wire calcification were often seen. Within a follow-up period [2-260 months (average 53.5 months)], the local recurrence rate was 15.5%. No patient had metastasis. Recurrence was most frequently observed at the femur. By log-rank analysis, only cyst formation in images was significant for predicting recurrence free survival (RFS). By Cox hazard analysis with representative clinico-radiological and pathological features, only age (≥16 years) and cyst formation were significant predictors for RFS. Pathological features were not significant in both uni- and multivariate analyses., (© 2017 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

The hepatocyte paraffin 1 (Hep Par 1) antibody is widely used as a hepatocyte marker, recognizing carbamoyl phosphate synthetase 1 (CPS1), an essential component of the urea cycle. Various missense, nonsense, and frameshift mutations occur in the CPS1 gene. In neonatal patients with homozygous CPS1 deficiency (CPS1D), urea cycle defects with resulting severe hyperammonemia can be fatal, though liver transplantation provides a complete cure for CPS1D. We performed Hep Par 1 immunostaining in the explanted livers of 10 liver transplant patients with CPS1D. Seven were negative for Hep Par 1 in the hepatocytes and the other three showed normal diffuse granular cytoplasmic staining. As expected, all three Hep Par 1-positive patients had at least one missense mutation, and all four patients who had only nonsense or frameshift mutations were Hep Par 1-negative. The other three patients were unexpectedly negative for Hep Par 1, even though each had one missense mutation. These results suggest that CPS1D can be related to the loss of Hep Par 1 reactivity due to the loss of protein production, a one amino acid substitution resulting in an abortive protein product, or both. Hep Par 1 immunohistochemistry can be used as a simple method to confirm CPS1D., (© 2016 The Authors Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

The aims of this study were: (i) to elucidate clinicopathological characteristics of pcCHS of long bones (L), limb girdles (LG) and trunk (T) in Japan; (ii) to investigate predictive pathological findings for outcome of pcCHS of L, LG and T, objectively; and (iii) to elucidate a discrepancy of grade between biopsy and resected specimens. Clinicopathological profiles of 174 pcCHS (79 male, 95 female), of L, LG, and T were retrieved. For each case, a numerical score was given to 18 pathological findings. The average age was 50.5 years (15-80 years). Frequently involved sites were femur, humerus, pelvis and rib. The 5-year and 10-year disease-specific survival (DSS) rates [follow-up: 1-258 months (average 65.5)] were 87.0% and 80.4%, respectively. By Cox hazards analysis on pathological findings, age, sex and location, histologically higher grade and older age were unfavorable predictors, and calcification was a favorable predictor in DSS. The histological grade of resected specimen was higher than that of biopsy in 37.7% (26/69 cases). In conclusion, higher histological grade and older age were predictors for poor, but calcification was for good prognosis. Because there was a discrepancy in grade between biopsy and resected specimens, comprehensive evaluation is necessary before definitive operation for pcCHS., (© 2015 The Authors. Pathology International published by Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

BCOR-CCNB3 sarcoma is a recently recognized tumor morphologically and clinically simulating Ewing sarcoma. We herein retrospectively collected clinicopathologic data on BCOR-CCNB3 sarcoma in the Kyoto University Hospital over the last 10 years. Three (20%) bone sarcomas were revealed to be diffusely positive for CCNB3 immunohistochemistry among 15 pediatric cases of undifferentiated sarcoma morphologically similar to Ewing sarcoma, while the other cases showed completely negative staining. The three patients with immunohistochemically CCNB3-positive tumors were all male, aged between 11 and 17, and confirmed to have the BCOR-CCNB3 fusion transcript by RT-PCR. Radiologically, all cases had well-demarcated solid masses with bone destruction. Although the tumors were basically small round cell tumors, less monomorphic histological patterns such as short spindle cells, a myxoid matrix, and hemangiopericytoma-like pattern were also observed in both biopsy and resected specimens. Two patients achieved a complete response after chemotherapy for Ewing sarcoma and osteosarcoma, respectively. These results demonstrated that the application of CCNB3 immunostaining was useful for differentiating BCOR-CCNB3 from a group of 'Ewing-like sarcomas' and may contribute to the evaluation of treatment strategies for bone sarcomas., (© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

The combination of exocrine and neuroendocrine neoplasms is rarely found in the pancreas. These combined lesions vary from a clonal tumor with mixed differentiation to the incidental co-existence of two or more independent tumors, but the differential diagnosis is sometimes difficult. Here we report a case of multiple endocrine neoplasia type 1 (MEN1) with extensive ductal and neuroendocrine neoplastic changes. These two types of tumors admixed markedly in some parts, which made it difficult to determine the pathological diagnosis based on histological findings. Cytogenetic analysis showed that loss of heterozygosity (LOH) of the MEN1 locus exists in neuroendocrine but not in exocrine neoplasms, indicating that independent mechanisms of tumorigenesis may occur in these two types of tumors. This case shows the usefulness of cytogenetic analysis for the diagnosis of combined tumors of the pancreas. Extensive exocrine neoplastic change, including pancreatic intraepithelial neoplasia (PanIN) in virtually all pancreatic ducts and a focus of intraductal papillary mucinous neoplasm (IPMN) with focal invasion, was a distinguishing feature of the present case. The possible association of ductal tumorigenesis and a MEN1 background is discussed., (© 2013 The Authors. Pathology International © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Systemic lupus erythematosus (SLE) and pregnancy-induced hypertension (PIH) are related to premature delivery and intrauterine growth restriction (IUGR), and share histological findings of the placenta. Association with complement dysregulation has been reported in pregnancy for both disorders. The purpose of this study was to investigate the utility of C4d immunohistochemistry for placentas with SLE- and PIH-associated pregnancy. C4d staining was performed on paraffin-embedded tissue of placentas from 26 patients with SLE, 26 with PIH, and 25 control cases. We used the H-score with a range of 0-300 for the evaluation of C4d immunoreactivity. Placentas of SLE and PIH cases showed a higher H-score than control cases (average, SLE, 38.3 (P < 0.05); PIH, 17.8; control, 1.68), with linear staining on the membrane of syncytiotrophoblast. C4d-high groups comprised 50% (12/26) of SLE and 35% (9/26) of PIH cases, with H-scores ranging 14-270 and 15-170. C4d-high groups were significantly associated with low-placental weights and low birth weight in both SLE and PIH (P < 0.05), and lower gestational age (P < 0.05) in PIH cases. These results suggest that C4d might be utilized as a biomarker evaluating the subsequent risk for IUGR and disease control during the gestation period in these patients., (© 2013 The Authors. Pathology International © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Recently the authors proposed a new staging and grading system for primary biliary cirrhosis (PBC) that takes into account necroinflammatory activity and histological heterogeneity. Herein is proposed a convenient version of this system. Scores for fibrosis, bile duct loss, and chronic cholestasis were combined for staging: stage 1, total score of 0; stage 2, score 1-3; stage 3, score 4-6; and stage 4, score 7-9. Cholangitis activity (CA) and hepatitis activity (HA) were graded as CA0-3, and HA0-3, respectively. Analysis of interobserver agreement was then conducted. Digital images of 62 needle liver biopsy specimens of PBC were recorded as virtual slides on DVDs that were sent to 28 pathologists, including five located overseas. All participants were able to apply this version in all 62 cases. For staging, kappa was 0.385 (fair agreement) and the concordance rate was 63.9%. For necroinflammatory activity, the kappa and concordance rate were 0.110 (slight agreement) and 36.9% for CA, and 0.197 (slight agreement) and 47% for HA, respectively. In conclusion, this new staging and grading system for PBC seems to be more convenient and practical than those used at present, but more instruction and guidance are recommended for the grading of necroinflammatory activity in practice.

Follicular dendritic cell sarcoma (FDCS) is an uncommon neoplasia usually occurring in lymphoid tissue. Herein is presented a case of FDCS of the small intestine with positivity for T-cell antigen, simulating T-cell lymphoma. An 82-year-old man consulted a doctor for a 1 week history of epigastric pain. Imaging indicated a mass in the small intestine. Malignant lymphoma was suspected because of high serum levels of soluble interleukin-2 receptor, and resection of the tumor was performed. Microscopically the tumor consisted of large pleomorphic cells with reactive small lymphocytes. Most of the nuclei of the tumor cells were round or ovoid, and some of the tumor cells also had spindle-shaped nuclei. Although the tumor cells were diffusely positive for CD45RO and CD4 on immunohistochemistry, negativity for pan-T-cell markers and CD56 was unusual for T-cell lymphoma of intestinal origin. Additional immunohistochemistry demonstrated that the tumor cells were positive for follicular dendritic cell markers including CD23, CD35 and CAN.42, and diagnosis of FDCS was made. To the authors' knowledge this is the first case of FDCS aberrantly expressing CD45RO; FDCS expressing T-cell markers can be a pitfall for diagnosis of FDCS.

Schwannoma arising within brain parenchyma is a rare lesion, usually found in children. Reported herein is a case of intracerebral schwannoma in a 5-year-old boy, with a review of the English-language literature on the subject, in which 47 cases were found. Few detailed histological reviews of intracerebral schwannoma exist. The tumor had a distinctive plexiform growth pattern, and small aggregates of Schwann cells spread extensively into the surrounding brain tissue along perivascular spaces adjacent to the tumor nodule. Histological differential diagnoses included perivascular schwannosis and meningioangiomatosis. A few intratumoral axons, seen on immunostaining for neurofilament protein, were trapped at the periphery of the main lesion, but there was no evidence of intralesional axons in the multiple nodules of Schwann cell proliferations that extended into the perivascular spaces, suggesting that the lesions are neoplastic. Because Schwann cells are not a natural component of the central nervous system, the origin of intracerebral schwannomas remains unknown. The histology suggests that Schwann cells of the perivascular nerve plexus are a likely site of origin.

In Japan, most cases of malignant lymphoma arising in the thorax are pyothorax-associated lymphoma, which develops in patients who have undergone artificial pneumothorax, used in the past as surgical therapy for pulmonary tuberculosis. Pyothorax-associated lymphoma consist mostly of diffuse large B-cell lymphoma and have a strong association with EBV. Herein is reported the case of a diffuse large B-cell lymphoma arising in the left thoracic wall after left lung resection for squamous cell carcinoma and chest wall reconstruction with polyethylene terephthalate (PET) surgical mesh. The tumor was found 20 years after the operation and was confined to the chest wall adjacent to the PET mesh. The patient did not have a clinical history of pyothorax after surgery. The lymphoma cells were of the large cell type and were positive for CD20, EBV-encoded small RNA--in situ hybridization, LMP-1 and EBNA-2. The present case demonstrates that EBV-related B-cell lymphoma can occur after surgery other than artificial pneumothorax. In the present case, long-standing chronic inflammation induced by PET mesh may have been associated with the development of lymphoma.

Fibrous tumor of the breast is a rare, benign stromal proliferation with atrophy of the epithelial component. Almost all patients who develop fibrous tumors are premenopausal. An unusual example of fibrous tumor of the breast is reported in a 62-year-old postmenopausal woman. The mass, first noted 1 year previously, progressively enlarged over the year. The patient noted a history of taking exogenous estrogens for 10 years. Intense estrogen administration during the year of enlargement may be associated with accelerated growth of the tumor. In addition, positive nuclear staining for estrogen receptor antibodies in stromal cells was demonstrated by immunohistochemical methods.

Three cases of salivary duct carcinoma are presented. They occurred in a 60 year old man, a 66 year old man and a 57 year old woman. All of the lesions were located in the parotid gland. The tumor size ranged from 3 to 5 cm across the largest diameter. Facial paralysis was observed in two cases. Histologically, intraductal and invasive adenocarcinoma showing papillary, cribriform, and solid patterns with comedolike necrosis was observed. Immunohistochemically, the tumor cells were positive for keratin and epithelial membrane antigen. No myoepithelial cells were demonstrated within the tumor by staining for S-100 protein, alpha-smooth muscle actin or muscle specific actin. Ultrastructurally, intracytoplasmic lumina with microvilli, a moderate number of mitochrondria, lysosomes, and tight junctions were found. Regional lymph node metastasis was observed in one case, and distant metastasis developed in two cases. All of the patients were treated with adjuvant postoperative irradiation. One patient died of disease at 11 months after the initial diagnosis, another was alive with disease at 8 months, and the third patient was alive without disease at 2 years and 3 months. Salivary duct carcinoma should be differentiated from low-grade salivary gland carcinomas using morphologic and clinical criteria because of its poor prognosis even with aggressive therapy.