Foamy Cells Research Articles

HPV-negative Gastric Type Adenocarcinoma In Situ of the Cervix: A Spectrum of Rare Lesions Exhibiting Gastric and Intestinal Differentiation.

In recent years, a number of benign and malignant cervical glandular lesions exhibiting gastric differentiation have been described but premalignant gastric-type lesions have not been well characterized. We report a series of 9 cases of a rare form of cervical adenocarcinoma in situ (AIS) distinguished by gastric and sometimes intestinal differentiation and lack of association with human papillomavirus (HPV) infection. The lesions occurred in women aged 25 to 73 years (mean age 51 y). All cases were located at (or just proximal to) the cervical transformation zone and there was extension to the lower uterine segment in 3 cases, 2 of which also involved the endometrium. In all cases, the normal cervical glandular architecture was largely preserved but in 5 cases there was a mild degree of increased intraglandular architectural complexity. The glandular epithelium ranged from almost purely gastric in type (4 cases) to mixed gastric and intestinal (5 cases), with varying proportions of intermixed goblet cells. In contrast to the basophilic cytoplasm of normal endocervical glands, the gastric-type epithelium was typically predominantly composed of cells with eosinophilic or pale pink cytoplasm, but conspicuous foamy or clear cell cytoplasm was present in some cases. Nuclear atypia was present in all cases but was considered low-grade in 8. High-grade features such as marked nuclear pleomorphism and hyperchromasia were evident in only 1 case. Mitotic activity and apoptotic bodies were present but both were noted to be less frequent than in usual type (HPV-related) AIS. Immunohistochemically, there was usually positive staining with CK 7 (7/7 cases) and MUC 6 (7/8 cases) and some cases were positive with CK 20 (3/7), CDX2 (5/9), PAX 8 (5/9) and CEA (2/6). Estrogen receptor and progesterone receptor were usually negative, although Estrogen receptor was positive in 3 of 9 cases. p16 was negative or exhibited mosaic-type staining (nonblock staining) in all cases and there was mutation-type p53 staining in 2 of 9 cases. HPV molecular testing was negative in all 4 cases tested. We believe this unusual subtype of AIS, which we term "gastric-type AIS (gAIS)," represents a precursor to gastric-type adenocarcinoma of the cervix and suggest that gAIS and so-called "atypical lobular endocervical glandular hyperplasia" are related entities within a spectrum of premalignant gastric-type lesions for which we propose the umbrella term gAIS. The malignant potential and optimal management of gAIS are currently unknown but in one of our cases a gastric-type adenocarcinoma developed 6 years after removal of a cervical polyp which contained gAIS. The introduction of HPV vaccination will result in a relative increase in incidence of premalignant and malignant cervical glandular lesions exhibiting gastric differentiation and these will not be detected by HPV-based screening programs.

Abstract 1851: A murine model of von Hippel-Lindau associated retinal hemangioblastoma

Abstract Purpose: von Hippel-Lindau disease (VHL) is an autosomal dominant condition that features a constellation of cysts or highly vascularized tumors due to loss of heterozygosity (LOH) of the VHL gene, resulting in deregulated hypoxia-induced factors (HIFs). Clinical manifestations of VHL include hemangioblastomas in the central nervous system and retina. To date, no VHL animal model has reproduced retinal capillary hemangioblastomas (RCH), the hallmark lesion of ocular VHL. The RCHs may arise from arrested hemangioblast progenitor cells, with VHL LOH in the tumor stroma. The stem cell leukemia (SCL) gene encodes a basic helix-loop-helix (bHLH) transcription factor, a critical regulator of hematopoiesis and vasculogenesis. We aim to generate a murine model of VHL-associated RCH by conditionally inactivating Vhl in a hemangioblast progenitor population with the angioblast-specific Cre line, (SCL) Cre-ERt2. Methods: We established a genetic mouse model in which the inducible Vhl gene is specifically “knocked-out” in angioblast cells using the stem cell leukemia (SCL) Cre-ERt2 transgenic mice. Two-week-old SCL-CreERt2;Vhl-F/F mice were administrated tamoxifen (2mg/40g body weight) for 5 consecutive days to activate the Cre recombinase that induces Vhl deletion in angioblast-derived cells. Fundoscopy was done monthly to detect retinal lesions. Fluorescein angiography (FA) was performed on affected mice. All retinas were analyzed by histology at 4 months of age. Genome typing of the Vhl conditional KO allele was conducted in retinal lesions using microdissection, nest-PCR and Sanger sequencing. Results: About 64% (18/28) of the transgenic mice exhibited various retinal vascular defects following induction. Affected mice demonstrated retinal vascular lesions that were variably associated with prominent vessels, anomalous capillary networks, hemorrhage, exudates, and localized fibrosis. FA revealed vascular leakage from the lesions. Histological analyses showed RCH-like lesions of tortuous, dilated vessels surrounded by “tumorlet” cells, isolated foamy stromal cells, and glia, classically found in RCH. Vhl LOH was detected in the tumor-like area as verified by sequencing. Conclusion: This is the first demonstration of VHL-associated RCH in a transgenic mouse model. This model may be useful for studying RCH pathogenesis, including HIF-dependent and HIF-independent pathways, and for testing potential therapies. Citation Format: Herui Wang, Qi Zhang, Lijin Dong, Liliana Guedez, Stanley Park, Yujuan Wang, Shida Chen, Chun Gao, Wai T. Wong, Henry Wiley, Emily Chew, Chi-Chao Chan, Zhengping Zhuang. A murine model of von Hippel-Lindau associated retinal hemangioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1851. doi:10.1158/1538-7445.AM2017-1851

Mastitis Acuta in a Pure Breed Cane Corso female. A Case Report

Data regarding bitch mastitis is fairly scarce compared to the literature regarding ruminant mastitis. Neglecting clinical and subclinical cases of mastitis can be life threatening for both dam and puppies. The aim of this report is to present a case of Mastitis acuta complicated with a case of neonatal septicaemia in a Cane Corso (Canis lupus familiaris L.) pure breed female. Laboratory assays showed a milk pH value of 7.5, milk cytology revealed the presence of segmented neutrophils, while foamy cells, phagocytosis and highly pathogenic bacteria (i.e. Escherichia coli and Pseudomonas aeruginosa) were isolated from milk and puppy. To the author's knowledge, this is the first case of bitch mastitis linked to neonatal septicaemia with mixed E. coli and P. aeruginosa infection.

Chloroquine enhances the antimycobacterial activity of isoniazid and pyrazinamide by reversing inflammation-induced macrophage efflux

Mycobacterium tuberculosis (MTB) is notorious for persisting within host macrophages. Efflux pumps decrease intracellular drug levels, thus fostering persistence of MTB during therapy. Isoniazid (INH) and pyrazinamide (PZA) are substrates of the efflux pump breast cancer resistance protein-1 (BCRP-1), which is inhibited by chloroquine (CQ). In this study, BCRP-1 was found to be expressed on macrophages of human origin and on foamy giant cells at the site of MTB infection. In the current in vitro study, interferon-gamma (IFNγ) increased the expression of BCRP-1 in macrophages derived from the human monocytic leukaemia cell line THP-1. Using a BCRP-1-specific fluorescent dye and radioactively labelled INH, it was demonstrated that efflux from macrophages increased upon activation with IFNγ. CQ was able to inhibit active efflux and augmented the intracellular concentrations both of INH and the dye. In agreement, CQ and specific inhibition of BCRP-1 increased the antimycobacterial activity of INH against intracellular MTB. Although PZA behaved differently, CQ had comparable advantageous effects on the intracellular pharmacokinetics and activity of PZA. The adjunctive effects of CQ on intracellular killing of MTB were measurable at concentrations achievable in humans at approved therapeutic doses. Therefore, CQ, a widely used and worldwide available drug, may potentiate the efficacy of standard MTB therapy against bacteria in the intracellular compartment.

Hypervirulent Mycobacterium tuberculosis strain triggers necrotic lung pathology associated with enhanced recruitment of neutrophils in resistant C57BL/6 mice.

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb) that in most cases induces irreversible necrosis of lung tissue as a result of excessive inflammatory reactions. The murine model of TB in resistant C57BL/6 mice infected with reference Mtb strains is widely used in TB studies; however, these mice do not show a necrotic pathology, which restricts their use in studies of irreversible tissue damage. Recently, we demonstrated that necrotic lung lesions could be induced in the C57BL/6 mice by highly virulent Mtb strains belonging to the modern Beijing sublineage. However, the pathogenic mechanisms leading to necrosis in this model were not elucidated. In this study, we investigated the dynamics of lung lesions in mice infected with highly virulent Beijing Mtb strain M299, compared with those infected with laboratory Mtb strain H37Rv. The data demonstrate that necrotic lung lesions in mice infected by the strain M299 were associated with enhanced recruitment of myeloid cells, especially neutrophils, and increased levels of proinflammatory cytokines, consistent with exacerbated inflammation. High levels of IFN-γ production contributed to the control of bacterial growth. Further progression to chronic disease was associated with a reduction in the levels of inflammatory mediators in the lungs, the accumulation of foamy macrophages and partial healing of the necrotic tissue by fibrosis. At a late stage of disease, degradation of foamy cells resulted in the liberation of accumulated lipids and persisting bacilli and further activation of inflammation, which promoted lung consolidation. Overall, our studies show that C57BL/6 mice infected with highly virulent Mtb strain may serve as a TB model reproducing an exacerbated inflammatory response in a resistant host to hypervirulent mycobacteria, leading to irreversible necrotic lung lesions.

Clinicopathological study of 9 cases of prostate cancer involving the rectal wall

BackgroundProstate cancer involving the rectal wall is rare and may lead to diagnostic pitfalls.Case presentationOut of 9504 patients with rectal tumors between January 2003 and January 2015, 9 patients (elderly with a mean age of 74 years) with prostate cancer involving the rectal wall were clinically misdiagnosed with rectal cancer. The lesions were located in the rectum, and included 3 circumferential rectal masses, 1 ulceration lesion, 1 crater-like mass, and 4 protruding lesions. Specimens were acquired using biopsy, fine needle aspiration, or resection. The initial symptoms of these patients included rectal urgency, bowel obstruction, and lower gastrointestinal bleeding. Prostate-related symptoms were not obvious. Histologically, 2 cases showed cancer cell invasion in the mucosa, 1 showed transmural invasion from the mucosa to subserosal soft tissues, and 7 cases had submucosa and muscularis propria involvement. All the 9 cases had muscularis propria involvement. However, there were no intraepithelial neoplasias in the mucosal layer, which is reminiscent of rectal carcinoma. The tumors consisted of small-sized or foamy cells that formed acinus-like, duct-like, and cribriform-like structures. We conducted histological staining and an immunohistochemical analysis for CDX-2, prostate-specific antigen (PSA), P504s, villin, carcinoembryonic antigen, CK-pan, cytokeratin 20, and Ki-67. All tumors were PSA and CK-pan positive, 5 of 9 tumors were P504s-positive, and all tumors were negative for the other markers. All patients underwent standard therapy for prostate cancer after the definitive pathological diagnosis. As of March 31, 2015, 8 patients were alive and 1 had died of prostate cancer 6 months posttreatment.ConclusionsAdenocarcinoma appearing in the rectal wall is not always rectal carcinoma. It is necessary to perform a differential diagnosis for prostate cancer in cases of rectal malignant tumors in elderly male patients. Any treatment should be postponed until the final definitive diagnosis is reached.

A rare incidence of ganglion cyst in a indigenous cow

An 8 year old indigenous cow was presented with the history of swelling at the left lower mid cervical region. Aspiration of the swollen mass revealed thick, gelatinous, yellowish, honey like fluid. Direct smears prepared by the aspirated material were stained with Giemsa and Wright's stains. Cytological examination of the smear revealed dark blue staining mucoid material. The mucoid material had folding at the periphery and appeared like plastic sheath wrap. In addition, small number of histiocytes lying singly with foamy cytoplasm and abundant red blood cells were also observed. The case was diagnosed as Ganglion cyst based on anamnesis, ultrasound examination, and cytological findings.

Cholic Acid Enhances Visceral Adiposity, Atherosclerosis and Nonalcoholic Fatty Liver Disease in Microminipigs.

Aim: We have recently established a novel swine model for studies of atherosclerosis using Microminipigs™ (µMPs) fed a high-fat/high-cholesterol diet (HcD). Using this swine model, we re-evaluated the effects of dietary cholic acid (CA) on serum lipid profile, atherosclerosis and hepatic injuries.Methods: The µMPs were fed HcD supplemented with 0.7% CA (HcD+CA) for eight weeks, and the effect of CA on serum lipoprotein levels, expression of oxidative stress markers, adiposity and lesion formation in the aorta, liver, and other organs was investigated.Results: The HcD+CA-fed group exhibited more visceral adiposity, progression of atherosclerosis and higher serum levels of oxidative stress markers than the HcD-fed group, even though they showed similar serum lipid levels. The liver demonstrated increased lipid accumulation, higher expression of oxidative stress markers, accelerated activation of foamy Kupffer cells and stellate cells, and increased hepatocyte apoptosis, indicating non-alcoholic fatty liver disease (NAFLD). Intriguingly, foamy macrophage mobilization was observed in various organs, including the reticuloendothelial system, pulmonary capillary vessels and skin very often in HcD+CA-fed µMPs.Conclusion: To our knowledge, this is the first large animal model, in which visceral obesity, NAFLD and atherosclerosis are concomitantly induced by dietary manipulation. These data suggest the detrimental effects of CA, potentially through local and systemic activation of oxidative stress-induced signaling to macrophage mobilization, on the acceleration of visceral adiposity, atherosclerosis and NAFLD.

Diagnosis of alpha mannosidosis after incidental finding of foamy cells on surgical specimen

Diagnosis of alpha mannosidosis after incidental finding of foamy cells on surgical specimen

Cytology pulmonary in horses (Equus caballus) maintained the field or stabled

Tracheobronchial secretion was collected by endoscopy (Welch-AllynÒ, 200cm long and 9mm diameter), from equines with different ages, races and sex, for posterior cytological analysis. Thirty-six equines were divided into two groups (Group I = stabled, n = 18; Group II = field regimen, n = 18). Animals of Group I (age = 3.5 years) were lodged in the Tarumã´s Jockey Club in Curitiba, Parana State. The equines of Group II always were maintained at field condition (never were stabled), in the farm located in Jacarezinho, Paraná State. Following endoscopic exams, tracheobronchial secretion smears were stained by Pappenhein´s method and submitted to cytological analysis. Group I had higher frequency of tracheal discharge than Group II. The cytological analysis showed more presence of macrophages (58.8%), foamy cells (2.3%), body giant cells (0.2%), neutrophils (4.57%), eosinophils (0.7%) and Curshmann´s spirals (0.04%) on 3 of the 18 animals. The cytological analysis of Group II showed higher frequency of ciliated epithelial cells than Group I, and no Curshmann´s spirals were observed. In conclusion, data showed that horses stabled had more cytological alterations than the animals maintained at field, therefore more tracheobronchial complications. Thus, the care of place where horse are stabled have influence on development of respiratory diseases, may predispose to affections as Chronic Obstructive Pulmonary Disease and Exercise-Induced Pulmonary Hemorrhage, as well athletic horses may be never reach their full respiratory potential.

Admixed foamy cell and signet ring cell change in a cutaneous angiosarcoma – A diagnostic pitfall

Cutaneous epithelioid angiosarcomas are known to exhibit various morphological variations. The present case is first of its own kind describing admixture of foamy cell and signet ring cell morphological patterns in a case of cutaneous angiosarcoma occurring in a 64-year-old female. The initial incisional biopsy revealed predominantly cytoplasmic vacuolations in the tumor cells with only focal presence of typical angiosarcomatous component, while in subsequent resection specimen, these variations were present only focally with predominant classical angiosarcomatous areas. This case highlights the importance of awareness of such morphological variations in angiosarcomas as these can be easily missed or misdiagnosed in small biopsies due to sample selection.

Eruptive Xanthoma with Acute Pancreatitis in a Patient with Hypertriglyceridemia and Diabetes.

Dear Editor: A 41-year-old Japanese man presented in October 2013 with a 2-week history of pruritic, erythematous papules. He had diabetes mellitus, hyperlipidemia, and hypertriglyceridemia, but had stopped treatment 5 years prior to this visit. He also suffered from acute pancreatitis, and was admitted to the Department of Medicine, Japan Community Healthcare Organization Osaka Hospital, 1 day prior. Topical steroid ointment prescribed during a previous visit to another clinic was ineffective for the treatment of the papules. At the time of consultation, he presented with multiple, approximately 5-mm, pruritic, yellowish, erythematous papules on the trunk and extensor surfaces of the extremities (Fig. 1A). Dermoscopic examination of the papules clearly revealed granular yellowish characteristics (Fig. 1B). The laboratory findings (normal values are in parentheses) were: white blood cell count, 13.3×103 (4.0×103~8.5×103)/µl; neutrophils, 83.5% (38%~58%); alkaline phosphatase, 369 (115~359) U/L; C reactive protein, 5.91 (<0.3) mg/dl; hemoglobin A1c, 9.2% (4.6%~6.2%); amylase, 340 (40~130) IU/L; lipase, 960 (11~53) U/L; triglyceride, 6,784 (30~150) mg/dl; total cholesterol, 803 (130/219) mg/dl; high density lipoprotein cholesterol, 12 (42~74) mg/dl; low density lipoprotein cholesterol, 23 (70~140) mg/dl; remnant-like lipoprotein particle cholesterol, 84.4 (<7.5) mg/dl; apolipoprotein (Apo) A-I, 89 (119~155) mg/dl; Apo A-II, 12.6 (25.9~35.7) mg/dl; Apo B, 135 (73~109) mg/dl; Apo E, 11.0 (2.7~4.3) mg/dl; Apo C-II, 16.5 (1.8~4.6) mg/dl; Apo C-III, 28.3 (5.8~10.0) mg/dl. A skin biopsy sample obtained from papules on the waist revealed foamy cells that infiltrated the dermis. At higher magnification, foamy cells and extracellular lipids were present (Fig. 2). Therefore, we diagnosed the patient as having eruptive xanthoma with type V hyperlipoproteinemia according to Fredrickson's classification of hyperlipoproteinemias. We treated the acute pancreatitis with fasting, nafamostat mesilate, and ulinastatin, and the hypercholesterolemia with bezafibrate. The acute pancreatitis improved 16 days after admission. Serum triglyceride and total cholesterol values decreased to within normal range 1.5 months after the initiation of treatment. The eruptive xanthoma lesions rapidly resolved as the hyperlipidemia improved. Fig. 1 (A) Clinical appearance and (B) dermoscopic appearance of multiple yellowish erythematous papules on the patient's back in October 2013. Fig. 2 Skin biopsy from the erythematous papules present on the patient's waist. (A) At lower magnification, numerous pale areas containing foamy cells infiltrate the dermis, especially the upper dermis and perivascular areas (H&E, ×40). (B) ... Hyperlipidemia is divided into six subgroups. Cutaneous xanthomatous lesions can occur in all six types of hyperlipidemia1. Cutaneous xanthomas can be divided into subgroups, including eruptive xanthomas, tuberous xanthomas, tendon xanthomas, xanthelasmata, and plane xanthomas2. Eruptive xanthomas can be associated with hypertriglyceridemia (Type I, IV, or V hypercholesterolemia), particularly when diabetes is poorly controlled2,3. Eruptive xanthomas contain more triglycerides and fewer cholesteryl esters than other types of xanthomas, and lipids present in xanthomas are derived from circulating plasma lipoproteins. Triglyceride is mobilized more rapidly than cholesterol, so resolving eruptive xanthomas are rich in cholesterol4. Hypertriglyceridemia also increases the risk of acute pancreatitis, and the risk of eruptive xanthoma and pancreatitis increases when the serum triglyceride concentration reaches the thousands5. Eruptive xanthomas manifested in this patient 2 weeks before his visit, followed by acute pancreatitis. Dermatologists should carefully consider the possibility of acute pancreatitis with hypertriglyceridemia in eruptive xanthoma patients.

Cutaneous lesions in colorectal carcinoma: a rare presentation.

nodular painless lesions all over his body since 2 months. He had undergone emergency colostomy 1 year previously for intestinal obstruction due to an ulceroinfiltrative mass in the descending colon. Histopathology showed a mucinous adenocarcinoma (signet-ring type). The patient underwent left hemi-colectomy and received 6 sessions of 5-fluorouraciland oxaliplatin-based adjuvant chemotherapy for the tumor (T3N2M0). On physical examination, the patient was pale and had firm-to-hard non-tender nodules of varying sizes over the scalp, face, abdomen, back, and arms (Fig. A, B); the maximum nodule size was 8×8 mm. On microscopic examination, the nodules showed a basket-weave pattern of the stratum corneum, with follicular plugging and increased basal layer melanization. The dermis was infiltrated, showing a narrow green zone and foamy cells with a mucin-like substance (Fig. C, D; alcian blue staining, C: ×40, D: ×10). Imaging did not show any metastatic lesions in the liver or lungs. What is the diagnosis for this lesion?

Xanthogranulomatous endometritis presenting as pyometra and mimicking carcinoma on imaging

Xanthogranulomatous endometritis (XGE) is an uncommon but well-established histopathological entity seen affecting the kidney and gallbladder. Involvement of the endometrium is very rare, with only a few case reports in world literature till date. Histologically, it is characterized by the replacement of the endometrium by sheets of foamy histiocytes, plasma cells, lymphocytes, giant cells, and siderophages. We present a case of a 74-year-old female who presented with foul-smelling discharge and postmenopausal bleeding of a short duration. Clinical examination and imaging studies revealed a pyometra, cervical stenosis. A suspicion of carcinoma was raised. Since XGE may mimic an endometrial carcinoma clinically and pathologically, knowledge of this unusual and rare inflammatory pathology is important for both the gynecologists and the pathologists.

Xanthoma of the Duodenum.

A 55-year-old Japanese man without dyslipidemia underwent esophagogastroduodenoscopy screening. He was diagnosed with reflux esophagitis, atrophic gastritis, and multiple gastric ulcers. In addition, scattered white villi were seen in the superior duodenal angle. No white villi were seen in any other parts of the duodenum. Esophagogastroduodenoscopy performed three months after Helicobacter pylori eradication showed the white villi to still be present in the duodenum (Picture A and B). Close-up observation with narrow-band imaging revealed the presence of slightly swollen, white villi (Picture C). The margin of each white villus could be clearly visualized. A histological examination showed foamy cells in the duodenal mucosa (Picture D, ×20, arrow; Picture E, ×40) that were positive for CD68 (Picture F, ×20, arrows), suggesting they were histiocytes. As a result, a diagnosis of duodenal xanthoma was made.

Pitfall in immunohistochemical staining for thyroglobulin in case of thyroid metastasis from lung carcinoma.

A 73-year-old female presented with an enlarging neck mass over the last 2 years. She then started experiencing hoarseness, dysphagia, and weight loss for 5 months. Physical examination showed an irregular and hard consistency mass with a diameter of 4 cm occupying the left lobe and isthmus of the thyroid gland. Fine-needle aspiration biopsy (FNAB) was performed and the cytology specimen revealed sheets of neoplastic cells with enlarged, hyperchromatic, slightly pleomorphic nuclei, prominent nucleoli, and brownish pigment inside the tumor cells [Figure 1a]. The definitive diagnosis could not be made from cytology alone. Immunohistochemical staining was requested with positive results for thyroglobulin [Figure 1b], thyroid transcription factor 1 (TTF-1) [Figure 1c], but negative for calcitonin. Figure 1 (a) Fine-needle aspiration thyroid showed a background of cystic lesion (foamy cells) with few of neoplastic cells and a sheet of degenerative follicular cells (Papanicolaou stain, ×400), (b) cell block preparation showed the immunoreactivity ...

Gastric xanthalesmas: Report of five cases and review of the literature

Xanthalesmas are incidental lesions that are rarely encountered during upper gastrointestinal (GI) endoscopy. The most frequent location of xanthelasma in the upper GI tract is the stomach. The reported incidence of gastric xanthelasma is quite variable: it rangs from 0.018% to 0.8%. Upper GI xanthelasmas have a typical endoscopic appearance of yellow-white well-demarcated single or multiple nodules or plaques, with a size varying from 1 to 10 mm in diameter. Xanthelasmas are composed of large foamy cells containing lipids. In this report; five patients who attended hospital with nonspesific symptoms and xanthelasma-like lesions were incidentally found on their endoscopic examination.

ATG16L1 expression in carotid atherosclerotic plaques is associated with plaque vulnerability

Objective— Autophagy has emerged as a cell survival mechanism critical for cellular homeostasis, which may play a protective role in atherosclerosis. ATG16L1, a protein essential for early stages of autophagy, has been implicated in the pathogenesis of Crohn’s disease. However, it is unknown whether ATG16L1 is involved in atherosclerosis. Our aim was to analyze ATG16L1 expression in carotid atherosclerotic plaques in relation to markers of plaque vulnerability. Approach and Results— Histological analysis of 143 endarterectomized human carotid atherosclerotic plaques revealed that ATG16L1 was expressed in areas surrounding the necrotic core and the shoulder regions. Double immunofluorescence labeling revealed that ATG16L1 was abundantly expressed in phagocytic cells (CD68), endothelial cells (CD31), and mast cells (tryptase) in human advanced plaques. ATG16L1 immunogold labeling was predominantly observed in endothelial cells and foamy smooth muscle cells of the plaques. ATG16L1 protein expression correlated with plaque content of proinflammatory cytokines and matrix metalloproteinases. Analysis of Atg16L1 at 2 distinct stages of the atherothrombotic process in a murine model of plaque vulnerability by incomplete ligation and cuff placement in carotid arteries of apolipoprotein-E-deficient mice revealed a strong colocalization of Atg16L1 and smooth muscle cells only in early atherosclerotic lesions. An increase in ATG16L1 expression and autophagy flux was observed during foam cell formation in human macrophages using oxidized-LDL. Conclusions— Taken together, this study shows that ATG16L1 protein expression is associated with foam cell formation and inflamed plaque phenotype and could contribute to the development of plaque vulnerability at earlier stages of the atherogenic process.

Oral verruciform xanthoma: a clinicopathologic and immunohistochemical study of 20 cases.

Verruciform xanthoma of the oral cavity is an uncommon benign lesion that usually affects the palate and gingiva mainly as a well-circumscribed solitary yellowish to whitish plaque or nodule, which is promptly recognized microscopically by identification of sub-epithelial foamy macrophages. The aim of this study was to evaluate the clinicopathologic and immunohistochemical features of 20 cases of oral verruciform xanthoma. All cases were evaluated by conventional hematoxylin/eosin staining and six of those were submitted to immunohistochemical reactions for CD68, CD63, CD163, syndecan-1 (CD138), S-100 protein and cytokeratins (CK) 8, 14 and 19. Oral verruciform xanthoma presented as yellowish papillary nodules affecting mainly the palate (30%), buccal mucosa (30%) and gingiva (25%) of middle-aged male patients. Most cases presented papillary epithelial hyperplasia and sub-epithelial foamy cells, which were immunopositive for CD68, CD63 and CD163 in all cases. The orange parakeratin superficial layer was negative for CK14 and presented a distinct granular membrane pattern of positivity for CD138. S-100 protein, CK8, and CK19 were negative.

Human monocyte-derived dendritic cells turn into foamy dendritic cells with IL-17A

Interleukin 17A (IL-17A) is a proinflammatory cytokine involved in the pathogenesis of chronic inflammatory diseases. In the field of immunometabolism, we have studied the impact of IL-17A on the lipid metabolism of human in vitro-generated monocyte-derived dendritic cells (DCs). Microarrays and lipidomic analysis revealed an intense remodeling of lipid metabolism induced by IL-17A in DCs. IL-17A increased 2-12 times the amounts of phospholipids, cholesterol, triglycerides, and cholesteryl esters in DCs. Palmitic (16:0), stearic (18:0), and oleic (18:ln-9c) acid were the main fatty acid chains present in DCs. They were strongly increased in response to IL-17A while their relative proportion remained unchanged. Capture of extracellular lipids was the major mechanism of lipid droplet accumulation, visualized by electron microscopy and Oil Red O staining. Besides this foamy phenotype, IL-17A induced a mixed macrophage-DC phenotype and expression of the nuclear receptor NR1H3/liver X receptor-α, previously identified in the context of atherosclerosis as the master regulator of cholesterol homeostasis in macrophages. These IL-17A-treated DCs were as competent as untreated DCs to stimulate allogeneic naive T-cell proliferation. Following this first characterization of lipid-rich DCs, we propose to call these IL-17A-dependent cells "foamy DCs" and discuss the possible existence of foamy DCs in atherosclerosis, a metabolic and inflammatory disorder involving IL-17A.