Simultaneous Occurrence of Two Ectopic Extramammary Paget Disease Lesions: A Case Report.

Paget disease of the breast is a malignant tumor that occurs primarily on the skin of the nipple, whereas extramammary Paget disease occurs on the skin in regions other than the breast, such as the pubis, perianal area, and axilla. Paget disease can also arise outside these areas; this is referred to as ectopic extramammary Paget disease. In this study, we present a case of a Japanese woman in her 70s who experienced simultaneous occurrence of two ectopic extramammary Paget disease lesions on the skin of the anterior chest and left buttock. Both lesions, exceeding 5 cm in diameter, were surgically excised, and the histopathological examination led to a diagnosis of ectopic extramammary Paget disease without invasion. To the best of our knowledge, this is the third reported case of multiple simultaneous ectopic extramammary Paget disease. Clinically, diagnosis of a patient with ectopic extramammary Paget disease is challenging because of its unusual location; however, the disease may be considered a differential diagnosis for Bowen disease.

Expression pattern of Runt-related transcription factor (RUNX) family members and the role of RUNX1 during kidney development.

Runt-related transcription factor (RUNX) family members play critical roles in the development of multiple organs. Mammalian RUNX family members, consisting of RUNX1, RUNX2, and RUNX3, have distinct tissue-specific expression and function. In this study, we examined the spatiotemporal expression patterns of RUNX family members in developing kidneys and analyzed the role of RUNX1 during kidney development. In the developing mouse kidney, RUNX1 protein was strongly expressed in the ureteric bud (UB) tip and weakly expressed in the distal segment of the renal vesicle (RV), comma-shaped body (CSB), and S-shaped body (SSB). In contrast, RUNX2 protein was restricted to the stroma, and RUNX3 protein was only expressed in immune cells. We also analyzed the expression of RUNX family members in the cynomolgus monkey kidney. We found that expression patterns of RUNX2 and RUNX3 were conserved between rodents and primates, whereas RUNX1 was only expressed in the UB tip, not in the RV, CSB, or SSB of cynomolgus monkeys, suggesting a species differences. We further evaluated the roles of RUNX1 using two different conditional knockout mice: Runx1f/f:HoxB7-Cre and Runx1f/f:R26-CreERT2 and found no abnormalities in the kidney. Our findings showed that RUNX1, which is mainly expressed in the UB tip, is not essential for kidney development.

Macrophage-mediated extracellular matrix remodeling controls host Staphylococcus aureus susceptibility in the skin.

Hypodermis is the predominant site of Staphylococcus aureus infections that cause cellulitis. Given the importance of macrophages in tissue remodeling, we examined the hypodermal macrophages (HDMs) and their impact on host susceptibility to infection. Bulk and single-cell transcriptomics uncovered HDM subsets with CCR2-dichotomy. HDM homeostasis required the fibroblast-derived growth factor CSF1, ablation of which abrogated HDMs from the hypodermal adventitia. Loss of CCR2- HDMs resulted in accumulation of the extracellular matrix component, hyaluronic acid (HA). HDM-mediated HA clearance required sensing by the HA receptor, LYVE-1. Cell-autonomous IGF1 was required for accessibility of AP-1 transcription factor motifs that controlled LYVE-1 expression. Remarkably, loss of HDMs or IGF1 limited Staphylococcus aureus expansion via HA and conferred protection against cellulitis. Our findings reveal a function for macrophages in the regulation of HA with an impact on infection outcomes, which may be harnessed to limit the establishment of infection in the hypodermal niche.

cis interaction of CD153 with TCR/CD3 is crucial for the pathogenic activation of senescence-associated T cells.

With age, senescence-associated (SA) CD4+ T cells that are refractory to T cell receptor (TCR) stimulation are increased along with spontaneous germinal center (Spt-GC) development prone to autoantibody production. We demonstrate that CD153 and its receptor CD30 are expressed in SA-T and Spt-GC B cells, respectively, and deficiency of either CD153 or CD30 results in the compromised increase of both cell types. CD153 engagement on SA-T cells upon TCR stimulation causes association of CD153 with the TCR/CD3 complex and restores TCR signaling, whereas CD30 engagement on GC B cells induces their expansion. Administration of an anti-CD153 antibody blocking the interaction with CD30 suppresses the increase in both SA-T and Spt-GC B cells with age and ameliorates lupus in lupus-prone mice. These results suggest that the molecular interaction of CD153 and CD30 plays a central role in the reciprocal activation of SA-T and Spt-GC B cells, leading to immunosenescent phenotypes and autoimmunity.

What is the "washout" of hepatocellular carcinoma as observed on the equilibrium phase CT?: consideration based on the concept of extracellular volume fraction.

PURPOSE: To verify the hypothesis that extracellular volume fraction (ECV) and precontrast CT density are the main determinants of washout of hepatocellular carcinoma (HCC) at the equilibrium phase CT. MATERIALS AND METHODS: Between 2018 and 2020, patients with surgically resected HCC were recruited who had undergone preoperative 4-phase CT. Those larger than 6 cm were excluded to minimize the possibility of intratumoral hemorrhage or degeneration. Two radiologists reviewed the whole images in consensus and divided cases into washout positive and negative groups. Washout positive group at the equilibrium phase was defined as "HCC showing relatively low density as compared to the surrounding background liver (BGL), irrespective of the presence of early enhancement or fibrous capsule". Several clinico-pathological and radiological features, including ECV and precontrast CT density, were correlated to the presence of washout, using uni- and multi-variable analyses. RESULTS: 27 HCC in 24 patients met the inclusion criteria. 22 (82%) and five HCC belonged to washout positive and negative groups, respectively. Univariable analysis revealed ECV of HCC and BGL, ECV difference between HCC and BGL, and presence of fibrous capsule on the equilibrium phase CT were the significant factors. Multivariable analysis showed ECV of HCC and BGL, and precontrast CT density of BGL, were the independently significant factors related to washout, suggesting washout is more likely observed with lower HCC ECV, higher BGL ECV, and higher BGL precontrast CT density. CONCLUSION: Major determinants of washout of HCC may be ECV of HCC and BGL, and precontrast CT density of BGL.

A case of methotrexate-associated Epstein-Barr virus-positive mucocutaneous ulcer.

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a B-cell proliferative disorder that has been designated as a provisional entity in the 2017 World Health Organization classification for lymphoid neoplasms. While EBVMCU may contain varying numbers of cells with Hodgkin and Reed-Sternberg cells-like morphology, the clinical course is benign and must be distinguished from lymphomas. Patients who develop EBVMCU are commonly immunocompromised, with methotrexate (MTX) as the leading cause. Most previously reported cases of EBVMCU describe mucosal ulcers with very little documentation on skin lesions and its course. Here, we report a case of MTX-associated EBVMCU of the lower leg that underwent spontaneous regression after MTX withdrawal, during which negative conversion of local Epstein-Barr virus activation was confirmed.

Mucinous cystic neoplasm of the liver communicated with intrahepatic duct exhibiting peculiar chronological change in MR imaging appearances: a case report.

A 70-year-old woman has been followed up for chronic hepatitis C and hepatocellular carcinoma which had been successfully controlled by several sessions of radiofrequency ablation. A small cystic lesion in segment IV associated with adjacent intrahepatic duct dilatation was firstly noted 4 years before on MR imaging, which showed gradual increase in size and significant interval change in the MRI signal intensity of the cystic content on the follow-up examinations. The mass finally reached 4 cm in its largest dimension, associated with slightly enhancing thickened wall, suggesting its neoplastic nature. The mass was surgically resected and a final diagnosis of mucinous cystic neoplasm (MCN) of the liver was made. MCN is usually considered to have no communication with intrahepatic duct, but in this particular case, the communication with the biliary duct was suggested from its early stage of the lesion, which would be the cause of peculiar chronological change in MR appearance.

Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells showing intraductal growth and intratumoral hemorrhage: MRI features.

We report a case of undifferentiated carcinoma of the pancreas with osteoclast-like giant cells ocalized within the main pancreatic duct (MPD). A 61-year-old woman was referred to our hospital for evaluation of dilatation of the MPD that was detected on screening sonogram. Preoperative MR imaging revealed a small hypervascular tumor within the dilated MPD, showing high signal on R2* map and signal reduction on in-phase as compared to out-of-phase. R2* hyperintensity and in-phase signal reduction may be a characteristic feature of undifferentiated carcinoma of the pancreas with osteoclast-like giant cells, which indicates intratumoral hemorrhage even if they are small.

Cell-autonomous FLT3L shedding via ADAM10 mediates conventional dendritic cell development in mouse spleen.

Conventional dendritic cells (cDCs) derive from bone marrow (BM) precursors that undergo cascades of developmental programs to terminally differentiate in peripheral tissues. Pre-cDC1s and pre-cDC2s commit in the BM to each differentiate into CD8α+/CD103+ cDC1s and CD11b+ cDC2s, respectively. Although both cDCs rely on the cytokine FLT3L during development, mechanisms that ensure cDC accessibility to FLT3L have yet to be elucidated. Here, we generated mice that lacked a disintegrin and metalloproteinase (ADAM) 10 in DCs (Itgax-cre × Adam10-fl/fl; ADAM10∆DC) and found that ADAM10 deletion markedly impacted splenic cDC2 development. Pre-cDC2s accumulated in the spleen with transcriptomic alterations that reflected their inability to differentiate and exhibited abrupt failure to survive as terminally differentiated cDC2s. Induced ADAM10 ablation also led to the reduction of terminally differentiated cDC2s, and restoration of Notch signaling, a major pathway downstream of ADAM10, only modestly rescued them. ADAM10∆DC BM failed to generate cDC2s in BM chimeric mice with or without cotransferred ADAM10-sufficient BM, indicating that cDC2 development required cell-autonomous ADAM10. We determined cDC2s to be sources of soluble FLT3L, as supported by decreased serum FLT3L concentration and the retention of membrane-bound FLT3L on cDC2 surfaces in ADAM10∆DC mice, and by demonstrating the release of soluble FLT3L by cDC2 in ex vivo culture supernatants. Through in vitro studies utilizing murine embryonic fibroblasts, we determined FLT3L to be a substrate for ADAM10. These data collectively reveal cDC2s as FLT3L sources and highlight a cell-autonomous mechanism that may enhance FLT3L accessibility for cDC2 development and survival.

Homeostatic Control of Sebaceous Glands by Innate Lymphoid Cells Regulates Commensal Bacteria Equilibrium.

Immune cells and epithelium form sophisticated barrier systems in symbiotic relationships with microbiota. Evidence suggests that immune cells can sense microbes through intact barriers, but regulation of microbial commensalism remain largely unexplored. Here, we uncovered spatial compartmentalization of skin-resident innate lymphoid cells (ILCs) and modulation of sebaceous glands by a subset of RORγt+ ILCs residing within hair follicles in close proximity to sebaceous glands. Their persistence in skin required IL-7 and thymic stromal lymphopoietin, and localization was dependent on the chemokine receptor CCR6. ILC subsets expressed TNF receptor ligands, which limited sebocyte growth by repressing Notch signaling pathway. Consequently, loss of ILCs resulted in sebaceous hyperplasia with increased production of antimicrobial lipids and restricted commensalism of Gram-positive bacterial communities. Thus, epithelia-derived signals maintain skin-resident ILCs that regulate microbial commensalism through sebaceous gland-mediated tuning of the barrier surface, highlighting an immune-epithelia circuitry that facilitates host-microbe symbiosis.

Disappearance of multiple hyperechoic liver nodules in sporadic porphyria cutanea tarda after treatment with ledipasvir/sofosbuvir for hepatitis C.

Ultrasonography in a 60-year-old man with chronic hepatitis C (CHC) demonstrated multiple hyperechoic nodules. Radiological investigations did not reveal any signs of malignancy. However, magnetic resonance chemical shift imaging showed multiple focal fatty changes in the liver. Urinary levels of uroporphyrin and coproporphyrin were elevated, and we made a diagnosis of porphyria cutanea tarda. Direct-acting antivirals, ledipasvir/sofosbuvir, were initiated for CHC, which led to sustained viral response, resolution of the liver nodules, and normalization of urinary porphyrin. Hepatitis C virus infection can cause porphyria cutanea tarda with multiple hyperechoic liver nodules, which might be cured by direct-acting antivirals.

Hepatic Hodgkin lymphoma with delayed enhancement on CT and MRI.

Hepatic Hodgkin lymphoma is a rare disease, characterized by the presence of abundant granulofibrous stroma, and its radiological features have rarely been described. We report a 67-year-old man, who presented with liver masses that showed apparent delayed enhancement, along with systemic lymphadenopathy and musculoskeletal lesions. Repeated percutaneous needle biopsy, however, failed to confirm the diagnosis, and surgical biopsy finally revealed small amount of Hodgkin cells and Reed-Sternberg cells. In this report, the radiological features of hepatic Hodgkin lymphoma will be presented and discussed, in correlation with its histological findings.

A case of porphyria cutanea tarda of the liver exhibiting multifocal macrovesicular steatosis in the background of microvesicular steatosis, probably caused by uneven iron accumulation.

A 61-year-old man with chronic hepatitis B and a history of alcohol overconsumption was admitted to our hospital for the scrutiny of multiple echogenic liver nodules. CT and hepatobiliary phase of gadoxetate-enhanced MR imaging revealed no nodular lesions. Quantitative fat fraction images and R2* map of MR imaging suggested homogeneous steatosis and uneven iron deposition in the liver, namely moderately and severely elevated R2* values at the nodules and surrounding background liver, respectively. Biopsy specimens showed macrovesicular fatty liver and less iron deposition at the echogenic nodules, and microvesicular fatty change and more prominent iron deposition at the surrounding liver tissue. The patient's urinary uroporphyrin level was elevated, and the final diagnosis of porphyria cutanea tarda was made. In patients with history of excessive alcohol intake or viral hepatitis, echogenic nodules on ultrasonography along with radiological evidence of absence of space occupying lesions, and presence of excessive intrahepatic fat and iron, might suggest a possible diagnosis of porphyria cutanea tarda.

Osteopontin in Spontaneous Germinal Centers Inhibits Apoptotic Cell Engulfment and Promotes Anti-Nuclear Antibody Production in Lupus-Prone Mice.

Disposal of apoptotic cells is important for tissue homeostasis. Defects in this process in immune tissues may lead to breakdown of self-tolerance against intracellular molecules, including nuclear components. Development of diverse anti-nuclear Abs (ANAs) is a hallmark of lupus, which may arise, in part, due to impaired apoptotic cell clearance. In this work, we demonstrate that spontaneous germinal centers (GCs) in lupus-prone mice contain significantly elevated levels of unengulfed apoptotic cells, which are otherwise swiftly engulfed by tingible body macrophages. We indicate that osteopontin (OPN) secreted by CD153(+) senescence-associated T cells, which selectively accumulate in the GCs of lupus-prone mice, interferes with phagocytosis of apoptotic cells specifically captured via MFG-E8. OPN induced diffuse and prolonged Rac1 activation in phagocytes via integrin αvß3 and inhibited the dissolution of phagocytic actin cup, causing defective apoptotic cell engulfment. In wild-type B6 mice, administration of TLR7 ligand also caused spontaneous GC reactions with increasing unengulfed apoptotic cells and ANA production, whereas B6 mice deficient for Spp1 encoding OPN showed less apoptotic cells and developed significantly reduced ANAs in response to TLR7 ligand. Our results suggest that OPN secreted by follicular CD153(+) senescence-associated T cells in GCs promotes a continuous supply of intracellular autoantigens via apoptotic cells, thus playing a key role in the progression of the autoreactive GC reaction and leading to pathogenic autoantibody production in lupus-prone mice.

Homogeneously enhancing breast lesions on contrast enhanced US: differential diagnosis by conventional and contrast enhanced US findings.

OBJECTIVE: To clarify the details of homogeneously enhancing lesions on contrast-enhanced ultrasonography (CEUS) and also to elucidate whether their differential diagnosis is possible. METHODS: Seventy-three homogeneously enhancing lesions on CEUS were retrospectively selected. Two radiologists first assessed conventional US findings alone in consensus to differentiate malignant vs. benign lesions. Then, qualitative and quantitative CEUS findings were analyzed to determine the useful findings for the differential diagnosis. Determined CEUS findings were applied to the indeterminate lesions based on conventional US findings to see whether CEUS can improve the diagnostic performance. RESULTS: There were 42 cancers (58 %) out of 73. Sensitivity and specificity using conventional US findings alone were 91 and 55 %, respectively. Among the CEUS findings tested, multivariate analysis revealed only the type 3 enhancement pattern, which indicates a larger enhancing area than the precontrast hypoechoic lesion, was related to malignancy (p < 0.05). By adding this information, however, no improvement was achieved in the diagnostic performance as determined by conventional US findings. CONCLUSIONS: Approximately half of the homogeneously enhancing lesions on CEUS are malignant, and differentiation of malignant from benign lesions may be possible, at least to some extent, by meticulous assessment of the conventional US rather than CEUS findings.

A CD153+CD4+ T follicular cell population with cell-senescence features plays a crucial role in lupus pathogenesis via osteopontin production.

Immune aging results in diminished adaptive immunity and increased risk for autoimmunity. We previously reported a unique PD-1(+) CD44(high)CD4(+) T cell population that increases with age in normal mice. In this study, we indicate that the age-dependent PD-1(+) CD44(high)CD4(+) T cells develop as unique T follicular (TF) cells in a B cell-dependent manner and consist of two subpopulations, as follows: CD153(+) cells preferentially secreting abundant osteopontin on TCR stimulation and CD153(-) cells that are apparently TCR anergic. These unique TF cells with essentially similar features increase much earlier and are accumulated in the spontaneous germinal centers (GCs) in lupus-prone female BWF1 (f-BWF1) mice. These TF cells showed characteristic cell-senescence features and developed in association with extensive CD4(+) T cell proliferation in vivo, suggesting replicative senescence. Although the CD153(+) TF cells were defective in proliferation capacity, they were quite stable and specifically responded to self GC-B cells to secret abundant osteopontin, which inhibited B cell receptor-induced GC-B cell apoptosis in f-BWF1 mice. Transfer of CD153(+) PD-1(+) CD4(+) T cells promoted the growth of spontaneous GCs, whereas administration of anti-osteopontin Ab suppressed GC enlargement and anti-nuclear Ab production and ameliorated clinical lupus nephritis of f-BWF1 mice. Current results suggest that senescent CD153(+) TF cells generated as a consequence of extensive endogenous CD4(+) T cell proliferation play an essential, if not sufficient, role in lupus pathogenesis in lupus-prone genetic background and may also contribute to an increased autoimmunity risk with age.

Preferential expression of OVOL1 in inner root sheath of hair, sebaceous gland, eccrine duct and their neoplasms in human skin.

OVOL1 is an important transcription factor for epidermal keratinization, which suppresses proliferation and switches on the differentiation of keratinocytes. A recent genome-wide association study has revealed that OVOL1 is one of the genes associated with susceptibility to atopic dermatitis. Although it is known to be expressed in murine skin and hair follicles, no investigations have focused on its localization in human skin. In the present study, we thus immunolocalized the expression of OVOL1 in normal and diseased human skin. In normal human skin, OVOL1 was preferentially expressed in the suprabasal layer of the epidermis, inner root sheath of hair, mature sebocytes and the ductal portion of the eccrine glands. Compared to this, no remarkable change in the expression of OVOL1 was observed among inflammatory skin diseases. The expression of OVOL1 was evident in eccrine poroma and hidradenoma. Moreover, it was overexpressed in Bowen's disease and sebaceous adenoma, in sharp contrast to its downregulation in their more malignant counterparts, squamous cell carcinoma and sebaceous carcinoma. OVOL1 may play an important role in human skin morphogenesis and tumorigenesis.