Foamy Cell Histiocytosis Is a Diagnostic Pitfall: A Case Report of Xanthomatosis Secondary to Sitosterolemia Mimicking Progressive Nodular Histiocytosis.

ABSTRACT: We report a noteworthy case of a 10-year-old girl who presented with papular and nodular lesions on the skin that were clinically and histologically mistaken for progressive nodular histiocytosis. During the clinical management of the patient, the high lipid levels raised the suspicion of lipid metabolism disease and helped us to make the correct diagnosis of sitosterolemia. In sitosterolemia, proper management such as restriction of plant sterol intake and administration of cholesterol absorption inhibitor can improve prognosis.

HDL Cholesterol Efflux and Serum Cholesterol Loading Capacity Alterations Associate to Macrophage Cholesterol Accumulation in FH Patients with Achilles Tendon Xanthoma.

Achilles tendon xanthoma (ATX) formation involves macrophage cholesterol accumulation within the tendon, similar to that occurring in atheroma. Macrophage cholesterol homeostasis depends on serum lipoprotein functions, namely the high-density lipoprotein (HDL) capacity to promote cell cholesterol efflux (cholesterol efflux capacity, CEC) and the serum cholesterol loading capacity (CLC). We explored the HDL-CEC and serum CLC, comparing 16 FH patients with ATX to 29 FH patients without ATX. HDL-CEC through the main efflux mechanisms mediated by the transporters ATP binding cassette G1 (ABCG1) and A1 (ABCA1) and the aqueous diffusion (AD) process was determined by a cell-based radioisotopic technique and serum CLC fluorimetrically. Between the two groups, no significant differences were found in terms of plasma lipid profile. A trend toward reduction of cholesterol efflux via AD and a significant increase in ABCA1-mediated HDL-CEC (+18.6%) was observed in ATX compared to no ATX patients. In ATX-presenting patients, ABCG1-mediated HDL-CEC was lower (−11%) and serum CLC was higher (+14%) compared to patients without ATX. Considering all the patients together, ABCG1 HDL-CEC and serum CLC correlated with ATX thickness inversely (p = 0.013) and directly (p < 0.0001), respectively. In conclusion, lipoprotein dysfunctions seem to be involved in ATX physiopathology and progression in FH patients.

Topical Simvastatin Improves Lesions of Diffuse Normolipemic Plane Xanthoma by Inhibiting Foam Cell Pyroptosis.

Xanthoma pathogenesis is speculated to be associated with oxidized low-density lipoprotein (ox-LDL) deposition, although this remains unclear. Most patients with diffuse plane xanthomas present elevated blood lipid levels, and they benefit from treatment with oral lipid-lowering agents. However, there is no available treatment for diffuse normolipemic plane xanthoma (DNPX). In this study, for the first time, we used a topical simvastatin ointment to treat DNPX in three pediatric patients and observed favorable results. Immunofluorescence staining showed that the pyroptotic pathway was significantly attenuated after topical simvastatin application on the skin lesions of the patients. As ox-LDL deposition was observed in the lesions, we used ox-LDL to build a foam cell model in vitro. In the ox-LDL-induced foam cell formation, simvastatin consistently inhibited pyroptotic activation and inflammation in the macrophages. Additionally, the overexpression of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) or 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase (HMGCR), the known target of statins, reversed the effects of simvastatin. Moreover, gasdermin D (GSDMD) or HMGCR knockdown inhibited ox-LDL-induced pyroptosis. Furthermore, the immunoprecipitation results confirmed the interaction between NLRP3 and HMGCR, and this interaction was inhibited by simvastatin. In conclusion, we demonstrated that topical application of simvastatin ointment might be a promising treatment for DNPX skin lesions and that this therapeutic effect may be related to pyroptosis inhibition via HMGCR inhibition in foam cells. Moreover, xanthoma pathogenesis might be associated with ox-LDL deposition and inflammation.

Exploration of differentially-expressed exosomal mRNAs, lncRNAs and circRNAs from serum samples of gallbladder cancer and xantho-granulomatous cholecystitis patients.

Gallbladder cancer (GBC) is the most common biliary tract malignancy worldwide. Although a growing number of studies have explored the mechanism of GBC, thus far, few molecules have been discovered that can be utilized as specific biomarkers for the early diagnosis and therapeutic treatment of GBC. Recent studies have shown that exosomes not only participate in the progression of tumors, but also carry specific information that can define multiple cancer types. The present study investigated the expression profiles of coding (or messenger) ribonucleic acids (mRNAs) and non-coding RNAs (ncRNAs, including long non-coding RNAs [lncRNAs] and circular RNAs [circRNAs]) in plasma-derived exosomes from GBC patients. Using high-throughput RNA sequencing and subsequent bioinformatic analysis, a number of differentially expressed (DE) mRNAs, lncRNAs, and circRNAs were identified in GBC exosomes, compared to their expressions in xantho-granulomatous cholecystitis (XGC) exosomes. Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) analyses were then conducted to investigate the potential functions of these DE RNAs. Furthermore, the interaction networks and competing endogenous RNA networks of these DE RNAs and their target genes were investigated, revealing a complex regulatory network among mRNAs and ncRNAs. In summary, this study demonstrates the diagnostic value of plasma-derived exosomes in GBC and provides a new perspective on the mechanism of GBC.

Clear Cell Proliferations of the Skin: A Histopathologic Review.

ABSTRACT: Cutaneous clear cell proliferations encompass a heterogenous group of several primary cutaneous neoplasms and metastatic tumors with different histogenesis. Many of these clear cell proliferations may seem strikingly similar under the microscope resulting in challenging diagnosis. In many of these clear cell lesions, the reason for the clear or pale appearance of proliferating cells is unknown, whereas in other ones, this clear cell appearance is due to intracytoplasmic accumulation of glycogen, mucin, or lipid. Artifacts of tissue processing and degenerative phenomenon may also be responsible for the clear cell appearance of proliferating cells. Awareness of the histopathologic findings as well as histochemical and immunohistochemical techniques are crucial to the accurate diagnosis. This review details the histopathologic features of clear cell cutaneous proliferations, classifying them according their type of differentiation and paying special attention to the histopathologic differential diagnosis among them.

Eruptive xanthoma model reveals endothelial cells internalize and metabolize chylomicrons, leading to extravascular triglyceride accumulation.

Although tissue uptake of fatty acids from chylomicrons is primarily via lipoprotein lipase (LpL) hydrolysis of triglycerides (TGs), studies of patients with genetic LpL deficiency suggest additional pathways deliver dietary lipids to tissues. Despite an intact endothelial cell (EC) barrier, hyperchylomicronemic patients accumulate chylomicron-derived lipids within skin macrophages, leading to the clinical finding eruptive xanthomas. We explored whether an LpL-independent pathway exists for transfer of circulating lipids across the EC barrier. We found that LpL-deficient mice had a marked increase in aortic EC lipid droplets before and after a fat gavage. Cultured ECs internalized chylomicrons, which were hydrolyzed within lysosomes. The products of this hydrolysis fueled lipid droplet biogenesis in ECs and triggered lipid accumulation in cocultured macrophages. EC chylomicron uptake was inhibited by competition with HDL and knockdown of the scavenger receptor-BI (SR-BI). In vivo, SR-BI knockdown reduced TG accumulation in aortic ECs and skin macrophages of LpL-deficient mice. Thus, ECs internalize chylomicrons, metabolize them in lysosomes, and either store or release their lipids. This latter process may allow accumulation of TGs within skin macrophages and illustrates a pathway that might be responsible for creation of eruptive xanthomas.

Immunohistochemical ALK Expression in Granular Cell Atypical Fibroxanthoma: A Diagnostic Pitfall for ALK-Rearranged Non-neural Granular Cell Tumor.

ABSTRACT: Atypical fibroxanthoma (AFX) is a neoplasm that most commonly occurs on sun-damaged skin of the head and neck in elderly patients and that usually exhibits indolent clinical behavior with complete excision. The granular cell variant of AFX demonstrates overlapping histopathologic features with dermal non-neural granular cell tumor (NNGCT), which typically arises on the extremities of young to middle aged adults with rare reports of regional metastasis. A subset of NNGCT harbors ALK rearrangements and expresses ALK by immunohistochemistry. Here, we present 2 cases of granular cell AFX occurring on the scalp of males aged 73 and 87 with ALK expression by immunohistochemistry and no evidence of an ALK rearrangement on fluorescence in situ hybridization, representing a diagnostic pitfall for NNGCT.

Preferentially expressed antigen in melanoma expression in nonmelanoma skin cancers and melanocytes in surrounding skin.

BACKGROUND: Immunohistochemistry for preferentially expressed antigen in melanoma (PRAME) has been studied in melanocytic lesions but not nonmelanoma skin cancers (NMSCs). This study evaluated PRAME expression in NMSCs and dermoepidermal junction (DEJ) melanocytes in the surrounding skin. METHODS: Ninety-nine NMSCs were studied: 23 Merkel cell carcinomas (MCCs), 25 well to poorly differentiated squamous cell carcinomas (SCCs), 14 basal cell carcinomas (BCCs), five basosquamous carcinomas, four sebaceous carcinomas, ten atypical fibroxanthomas, 11 dermatofibrosarcoma protuberans, and seven leiomyosarcomas. Staining quality was considered low or high intensity. Staining quantity was reported as negative 0%, 1% to 24%, 25% to 50%, and >50%. DEJ melanocyte PRAME expression was recorded. RESULTS: Forty-eight percent of NMSCs showed PRAME expression, mostly low intensity in fewer than 25% of cells. High-intensity expression was noted in one poorly differentiated SCC, six BCCs, and seven MCCs. Only MCCs showed expression in greater than 25% of tumor cells. Focal DEJ melanocytes expressed high-intensity PRAME in 18% of cases, most commonly SCCs (11/23). CONCLUSIONS: PRAME is negative or expressed with low intensity in a small percentage of NMSCs, with the exception of some MCC showing high-intensity and diffuse staining. Focal DEJ melanocytes showed high-intensity PRAME reactivity in the skin surrounding some NMSCs.

Lipodystrophies-Disorders of the Fatty Tissue.

Lipodystrophies are a heterogeneous group of physiological changes characterized by a selective loss of fatty tissue. Here, no fat cells are present, either through lack of differentiation, loss of function or premature apoptosis. As a consequence, lipids can only be stored ectopically in non-adipocytes with the major health consequences as fatty liver and insulin resistance. This is a crucial difference to being slim where the fat cells are present and store lipids if needed. A simple clinical classification of lipodystrophies is based on congenital vs. acquired and generalized vs. partial disturbance of fat distribution. Complications in patients with lipodystrophy depend on the clinical manifestations. For example, in diabetes mellitus microangiopathic complications such as nephropathy, retinopathy and neuropathy may develop. In addition, due to ectopic lipid accumulation in the liver, fatty liver hepatitis may also develop, possibly with cirrhosis. The consequences of extreme hypertriglyceridemia are typically acute pancreatitis or eruptive xanthomas. The combination of severe hyperglycemia with dyslipidemia and signs of insulin resistance can lead to premature atherosclerosis with its associated complications of coronary heart disease, peripheral vascular disease and cerebrovascular changes. Overall, lipodystrophy is rare with an estimated incidence for congenital (<1/1.000.000) and acquired (1-9/100.000) forms. Due to the rarity of the syndrome and the phenotypic range of metabolic complications, only studies with limited patient numbers can be considered. Experimental animal models are therefore useful to understand the molecular mechanisms in lipodystrophy and to identify possible therapeutic approaches.

Verruciform xanthoma accompanying a cystic growth: A case report.

Verruciform xanthoma, an uncommon, benign lesion with characteristic histopathological features, usually develops on the oral mucosa or genital area. We present an unusual case of verruciform xanthoma observed on the inguinal skin of a 52-year-old healthy man along with an underlying cystic component. The superficial lesion was a pedunculated nodule with a fissured surface and an 18-mm mound-like pigmented tumor underneath it. The histopathologically deep lesion was continuously attached to the superficial lesion. It was composed of fistula or sinus-like spaces and covered with acanthotic epithelium. The epidermis and upper dermis of both lesions showed identical histopathological findings: varying degrees of acanthosis, elongation of rete ridges, eosinophilic parakeratotic layer extending toward the dermis, and densely infiltrating foam cells confined to the papillary layer of the dermis. This finding of a cystic component in the deep dermis expands the histopathologic features of verruciform xanthoma.

Multiple tuberous and tendinous xanthomas diagnosed on fine-needle aspiration cytology-report of a rare case.

Xanthomas are papulonodular skin lesions present in lipoprotein metabolism disorders, which result in cholesterol deposits in subcutaneous tissue, tendons, ligaments, periosteum, etc. A 11-year-old male presented with multiple soft tissue swellings, prominently over joints. Fine-needle aspiration (FNA) from multiple sites had similar appearance with foamy histocytes and giant cells. Oil Red O and polarized microscopy were also positive for fat. We describe an unusual case of tendinous and tuberous xanthoma diagnosed by cytology. Acquaintance with fine-needle aspiration cytology findings in xanthomas can help to avoid the need of surgical biopsy, as xanthomas can regress on medical therapy alone.

Plexiform Xanthomatous Tumor, Variety of Xanthoma or Subtype of Fibrohistiocytic Tumors?

Plexiform xanthomatous tumor was proposed as an independent neoplasm within fibrohistiocytic tumor group a few years ago. The arguments were based on their different clinical features as well as their own morphological and immunohistochemical findings. Nevertheless, it has not been widely studied yet, and there are few reports about this entity. Regarding a case, we reviewed the diagnostic characteristics of this underdiagnosed tumor.

Expression of proton-sensing G-protein-coupled receptors in selected skin tumors.

BACKGROUND: In humans, there are four known proton-sensing G-Protein-coupled receptors (pH-GPCRs): GPR4 (GPR19), TDAG8 (GPR65, T-cell death-associated gene 8), OGR1 (GPR68, ovarian cancer GPCR1) and G2A (GPR132, G2 accumulation protein). They are known to be involved in sensing changes of extracellular proton concentrations in the acidic microenvironment of tumors, which leads to altered cell proliferation, migration, metastasis, immune cell function and inflammation. However, little is known about the expression of pH-GPCRs in the skin and especially skin cancers. AIM: We studied the expression of pH-GPCRs in selected skin cancers, that is Merkel cell carcinoma (MCC), dermatofibrosarcoma protuberans (DFSP), atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS). METHODS: We did immunohistochemistry and immunofluorescence to analyse the expression of GPR4, TDAG8, OGR1 and G2A using paraffin-embedded tissue samples (n = 4, exceptions: PDS GPR4/GPR65 n = 5, AFX GPR132 n = 3) from patients suffering from MCC, DFSP, AFX and PDS. RESULTS: (a) GPR4 was expressed on all AFX and PDS specimens. All AFX and MCC showed a positive expression of G2A. All PDS exhibited a strong positive expression of G2A. (b) MCCs neither expressed GPR4 nor TDAG8. All DFSP showed no expression of TDAG8. (c) For any other combination of GPCR and skin disease, we found positive/negative mixed results. CONCLUSIONS: These are the first results on pH-GPCRs in selected skin cancers. We provide evidence that these GPCRs are differentially expressed on the various types of skin cancers and that they can potentially be addressed as a therapeutic target in extensive disease.

Verruciform xanthoma overlying inflammatory linear verrucous epidermal nevus and in broad segmental distribution.

A 17-year-old woman presented with moderately itchy, non-progressive, linearly arranged verrucous plaques over dorsum of left foot since early childhood. Two years ago, she developed slowly increasing, verrucous exophytic growth in posterior most aspect of linear verrucous plaque. One year ago, she also developed multiple, linearly arranged, fleshy plaques with surface crusting over lateral aspect of right leg extending to thigh. Biopsy from both verrucous lesion on left foot and fleshy plaque on right leg showed an exophytic growth with significant papillomatosis, neutrophils in stratum corneum, acanthosis and infiltration of papillary dermis with foamy macrophages that were CD 68 positive, features compatible with verruciform xanthoma (VX). Biopsy from linear verrucous plaque over left foot was consistent with inflammatory linear verrucous epidermal nevus (ILVEN). A diagnosis of segmental VX and VX overlying ILVEN was made.

Immunohistochemical expression of melanocytic and myofibroblastic markers and their molecular correlation in atypical fibroxanthomas and pleomorphic dermal sarcomas.

BACKGROUND: Atypical fibroxanthomas (AFXs) and pleomorphic dermal sarcomas (PDSs) are UV-induced pleomorphic skin tumors with a non-specific immunoprofile. For that reason, exclusion of other dedifferentiated tumor entities by immunohistochemistry is still mandatory to avoid misdiagnosis. METHODS: We determined the expression frequency of several melanocytic and myofibroblastic markers investigating 50 AFXs and PDSs.. Next-generation-sequencing (NGS) was performed in microphthalmia-associated transcription factor (MiTF)-expressing cases. RESULTS: We identified one MiTF-expressing AFX and PDS, and two PDSs harboring single S100-positive dendritic cells whereas Melan A, HMB45, and SOX10 were negative. Calponin was moderately expressed by tumor giant cells in one PDS whereas h-caldesmon, desmin, and myogenin were not expressed in any of the AFXs or PDSs. The MiTF-positive AFX presented CDKN2A, OXA1L, and PDGFRA mutations whereas the PDS harbored a typical TP53 mutation. Both patients have not shown any tumor progression over the last 16 and 30 months. CONCLUSION: Rarely, AFX and PDS express the melanocytic marker MiTF and/or the myofibroblastic marker calponin. In doubtful cases, using a panel of immunohistochemical markers helps to avoid misdiagnosis.

Metastatic melanoma with balloon/histiocytoid cytomorphology after treatment with immunotherapy: A histologic mimic and diagnostic pitfall.

Epithelioid cells with foamy cytoplasm (histiocytoid features) are typical histopathologic findings among benign and malignant histiocytic neoplasms such as xanthoma and atypical fibroxanthoma. However, these changes are unusual in melanoma, which is typically composed of nested and variably pigmented atypical epithelioid cells. Here, we report a patient with metastatic melanoma in lymph nodes presenting with prominent balloon cell/histiocytoid features expressing melanocytic markers, after treatment with nivolumab. This report suggests that the spectrum of neoplasms with histiocytoid features should be expanded to include melanoma, a pattern that, to the best of our knowledge, is uncommon, especially in the setting of post-neoadjuvant therapy.

A tale of two clones: Caldesmon staining in the differentiation of cutaneous spindle cell neoplasms.

BACKGROUND: We sought to compare the sensitivity and specificity of 2 different caldesmon antibodies in differentiating leiomyosarcoma from other cutaneous spindle cell neoplasms. METHODS: Representative cutaneous spindle cell neoplasms were identified, including leiomyosarcoma, atypical fibroxanthoma, dermatomyofibroma and spindle cell squamous cell carcinoma. Immunohistochemistry was performed with antibodies directed toward caldesmon, smooth-muscle actin (SMA) and desmin. Sensitivity and specificity were calculated using grades from 3 independent observers. RESULTS: The sensitivity of caldesmon (Ventana) was 100% (95% CI 78.2%-100%) and the specificity was 8.3% (2.8%-18.4%). Because this stain appeared to be non-specific, additional testing was performed on the same set of specimens using a second caldesmon clone (H-caldesmon, Dako), which had a sensitivity of 53.9% (25.1%-80.8%) and specificity of 96.6% (88.1%-99.6%). The sensitivity and specificity of SMA were 85.7% (57.2%-98.2%) and 84.5% (72.6%-92.7%), respectively. The sensitivity of desmin was 53.3% (26.6%-78.7%) with a specificity of 100% (94.0%-100%). CONCLUSIONS: The Ventana caldesmon clone is not specific to smooth muscle, a potential pitfall to laboratories using this clone. The staining pattern, sensitivity and specificity of the Dako H-caldesmon antibody clone are similar to results from prior studies. The sensitivity and specificity of the Dako clone support its use in smooth muscle identification as an additional marker in challenging cases.

Inflammatory Mediators in Xanthelasma Palpebrarum: Histopathologic and Immunohistochemical Study.

PURPOSE: To evaluate the expression of inflammatory mediators in xanthelasma palpebrarum. METHODS: In this retrospective histopathologic case-control study, xanthelasma specimens obtained from the private practice and pathology archives of 1 author (R.Z.S.) were analyzed and compared with the blepharoplasty tissues from age- and sex-matched controls. Paraffin-embedded tissue sections were stained with hematoxylin-eosin and CD3, CD20, CD163, cyclooxygenase-1, inducible nitric oxide synthase, matrix metallopeptidase-9, and myeloperoxidase antibodies. Immunostaining was quantified by light microscopy and with a computerized image analysis system of scanned images. RESULTS: Hematoxylin-eosin-stained preparations of xanthelasma specimens demonstrated significantly more intense chronic lymphocytic infiltrate when compared with the control blepharoplasty tissues (p < 0.001). Immunohistochemical studies revealed more intense CD3+ T cell and CD163+ histiocytic infiltrate (11% vs. 5%; p = 0.02 and 28% vs. 5%; p = 0.003, respectively) and increased expression of cyclooxygenase-1 (44% vs. 20% expressing cells; p < 0.001 and 21% vs. 9% strongly expressing cells; p = 0.008) and inducible nitric oxide synthase (43% vs. 26% expressing cells; p = 0.03 and 42% vs. 25% strongly expressing cells; p = 0.02) in xanthelasma specimens compared with control tissues. CONCLUSIONS: The inflammatory milieu in xanthelasma appears to be analogous to descriptions of the early stages of cardiac atherosclerotic plaque formation. These findings may contribute to the understanding of xanthelasma pathogenesis and to the development of potential targeted therapies.

[The disturbance of unification of coupled biochemical reactions in synthesis of endogenous ω-9 oleic acid. The resistance to insulin, stearic triglycerides and pathogenesis of eruptive xanthomata].

The eruptive xanthomata are formed in vivo under realization of biological function of endoecology. The xanthomata are formed in tissues by early in phylogenesis resident macrophages at absorption of secreted by hepatocytes aphysiological stearic lipoproteins of very low density with high content of the same name triglycerides down to tristearate. In these lipoproteins of very low density, by force of aphysiologically high hydrophobicity, stearic triglycerides are not hydrolyzed by post-heparin lipoproteinlipase. They both do not associate apoE and form apoE/B-J00 ligands. The formation of stearic lipoproteins of very low density occurred at impairment of function of coupled biochemical reactions in synthesis of physiological ω-9 oleic mono unsaturated fatty acid in hepatocytes. To synthesize endogenous oleic mono unsaturated fatty acid the late in phylogenesis insulin expresses two enzymes of coupled biochemical reactions: palmitoyl-KoA-elongase andstearyl-KoA-desaturase, activating synthesis of fatty acids following the path glucose-endogenous palmitic unsaturated fatty acid-stearic unsaturated fatty acid-oleic mono unsaturated fatty acid. The uncoupling of enzymes of coupling synthesis forms in hepatocytes surplus of stearic mono unsaturated fatty acid, stearic triglycerides and of the same name aphysiologic lipoproteins of very low density. During inhibition of the second enzyme the first one continues to actively produce stearic unsaturated fatty acid which the second enzyme, already uncoupled, does not convert into oleic unsaturated fatty acid. By absorbing aphysiologic ligand-free stearic lipoproteins of very low density in biologic reaction of endoecology, phylogenetically early macrophages convert into foam cells initiating aphysiologic biological reaction of transcytosis, biologic reaction of inflammation, biologic reaction of apoptosis and formation of eruptive xanthomata. The lipids of eruptive xanthomata: such endogenous stearic triglycerides as tristearate, tripalmitate, exogenous carotenoids, phospholipids and unesterified cholesterol.