Diffuse dermal angiomatosis associated with calciphylaxis: A 5-year retrospective institutional review.

BACKGROUND: Although diffuse dermal angiomatosis (DDA), a rare acquired reactive cutaneous vascular disorder, has been previously reported in association with calciphylaxis (CP), the clinical significance of this relationship has not yet been elucidated. METHODS: A total of 24 cases of CP diagnosed from 2013 to 2018 were retrospectively reviewed for the presence of associated DDA. Pertinent clinical information for each patient was also collected, and statistical analysis was performed using multivariable logistic regression, Student t test and Fisher exact test. RESULTS: African American race and comorbid congestive heart failure were the only variables that demonstrated independent, statistically significant association with the presence of DDA. End-stage renal failure, diabetes mellitus, immunosuppressive and hypercoagulable states, arrhythmia, body mass index, hypertension, coronary artery disease, patient age, duration of CP symptoms, gender, time interval from biopsy to death, anticoagulation therapy and sodium thiosulfate administration at the time of biopsy did not demonstrate a statistically significant association with DDA. CONCLUSION: DDA does not appear to be associated with disease severity or prognosis in cases of CP; however, in our population CP with concurrent DDA was more prevalent in African Americans and individuals with congestive heart failure.

Galactose-deficient IgA1 in skin and serum from patients with skin-limited and systemic IgA vasculitis.

BACKGROUND: IgA vasculitis (IgAV) encompasses a systemic form involving kidneys, gut, skin, or joints, and a skin-limited form. One characteristic feature of systemic IgAV is deposition of galactose-deficient IgA1 (GD-IgA1) in kidneys (as in IgA nephropathy). The relevance of GD-IgA1 for cutaneous vasculitis is unknown. OBJECTIVE: We investigated whether GD-IgA1 is deposited perivascularly in systemic and also skin-limited IgAV and whether its serum levels differ between both forms. METHODS: In a case-control study, deposition of GD-IgA1 was analyzed immunohistochemically by KM55 antibody in skin biopsy specimens from 12 patients with skin-limited IgAV and 4 with systemic IgAV. GD-IgA1 levels were compared by enzyme-linked immunosorbent assay in sera from 15 patients each with skin-limited and systemic IgAV and from 11 healthy individuals. RESULTS: All biopsy samples from systemic IgAV, and also from skin-limited IgAV, revealed perivascular GD-IgA1 deposition. The average GD-IgA1 concentration in serum was significantly higher in systemic IgAV than in skin-limited IgAV, despite overlap between the groups. LIMITATIONS: Although high GD-IgA1 levels may be predictive of systemic IgAV, patient numbers were too low to determine cutoff values for systemic versus skin-limited IgAV. CONCLUSION: Perivascular GD-IgA1 deposition is a prerequisite for systemic and skin-limited IgAV; however, high GD-IgA1 levels in some patients with systemic IgAV suggest a dose-dependent effect of GD-IgA1 in IgAV.

Cryptococcus-like changes in the setting of vasculitis.

Cutaneous vasculitis has many underlying causes, and the clinical and histological findings often overlap. Inflammatory vasculitis can mimic infection; however, distinction is critical for the timely institution of appropriate therapy. We present two patients who had generalized polymorphous eruptions whose cutaneous pathology showed vasculitis with unusual haloed yeast-like cells within the inflammatory infiltrate, mimicking Cryptococcus. The unusual cells stained negatively with Gomori methenamine silver and periodic acid-Schiff fungal stains, but positively for CD68 and had cytoplasmic reactivity with antibody to myeloperoxidase (MPO). Both patients had positive serum anti-MPO antibodies. The first patient experienced a rapidly fatal course, whereas the second patient improved with prompt initiation of systemic corticosteroids. Interestingly, the second case had prior biopsy showing Sweet syndrome with crypotoccoid-appearing cells. Cryptococcoid cells have been described previously in association with neutrophilic dermatoses, but not in the setting of vasculitis as was seen in our patients. Our cases add to the existing literature on crypotoccoid mimickers, and are the first to be reported in association with vasculitis.

Cutaneous collagenous vasculopathy: a new case series with clinicopathologic and ultrastructural correlation, literature review, and insight into the pathogenesis.

Cutaneous collagenous vasculopathy (CCV) is a rare distinct idiopathic microangiopathy of the superficial cutaneous vasculature. Seven new cases are reported (6 females and 1 male) ranging in age from 42 to 85 years, with some showing unusual clinical and histopathological findings. All presented with macular telangiectases starting on the lower extremities and spreading progressively in 5 cases and were suspected to have generalized essential telangiectasia. Two cases had a history of over 20 years. One case had lesions in the abdominal striae, and 1 was markedly ecchymotic. All skin biopsies showed the characteristic features of CCV with dilatation and marked thickening of the walls of superficial dermal blood vessels displaying reduplication of the basement membrane on periodic acid-Schiff-diastase stain and deposition of hyaline collagenous material immunostaining as collagen type IV, and showing decreased or absent actin staining. However, the changes were subtle and only seen focally in some biopsies. Few lymphoid cells were present around occasional vessels. Electron microscopy showed increased basement membrane lamellae with marked deposition of normal and some abnormal collagen (Luse-like bodies) and focal endothelial damage, suggesting reparative perivascular fibrosis resulting from repeated endothelial injury. These cases (and all 18 previously reported ones) are of a wide age range and no gender predilection. This disorder is underdiagnosed, and it is likely that some cases clinically suspected to be generalized essential telangiectasia may actually represent CCV. Better recognition by dermatologists may lead to more biopsies from patients with generalized telangiectasia and a further understanding of the pathogenesis of CCV and its relationship to other cutaneous vascular disorders.

Activated STING in a vascular and pulmonary syndrome.

BACKGROUND: The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation. METHODS: We analyzed the DNA of an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. We sequenced a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING), in this patient and in five unrelated children with similar clinical phenotypes. Four children were evaluated clinically and immunologically. With the STING ligand cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls, as well as commercially obtained endothelial cells, and then assayed transcription of IFNB1, the gene encoding interferon-ß, in the stimulated cells. We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs. Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1 (STAT1), so we tested the effect of Janus kinase (JAK) inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls. RESULTS: We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mononuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation. On stimulation with cGAMP, fibroblasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients' lymphocytes was reduced by JAK inhibitors. CONCLUSIONS: STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173. (Funded by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; ClinicalTrials.gov number, NCT00059748.).

Cutaneous collagenous vasculopathy associated with intravascular occlusive fibrin thrombi.

Cutaneous collagenous vasculopathy (CCV) is a rare cutaneous microangiopathy that clinically resembles generalized essential telangiectasia with only 12 cases reported to date. The perivascular fibrosis is thought to be due to production of abnormal collagen by veil cells in the outer vessel walls as a result of unknown factors. This report is of an 84-year-old male with progressive telangiectasia. Biopsies showed characteristic features of CCV. In addition, there were multiple intravascular fibrin thrombi, some organizing and associated with endothelial cell hyperplasia with recanalization reminiscent of glomeruloid bodies and simulating reactive angioendotheliomatosis (RAE). Histochemically and ultrastructurally fibrin was noted within the vessel walls integrating into the fibrous tissue around the vessels; however, the patient had no evidence of coagulation disorder, cryoglobulinemia or cold agglutinemia. Immunofluorescence showed fibrinogen within the vessel walls but no immunoglobulins or C3. As well, there were minimal inflammatory cells. This suggests pauci-inflammatory injury to the endothelial cells by unknown angiogenic factors causing local intravascular fibrin thrombi with fibrin leaking and incorporating into the vessel walls, eventually leading to reparative perivascular fibrosis. This case suggests that some cases of CCV are related to a primary local intravascular occlusive thrombotic microangiopathy. However, the primary triggering factor causing the endothelial cell damage has yet to be elucidated.

Widespread atypical vascular lesions of the skin after whole-body electron beam therapy: expanding the clinical spectrum.

Atypical vascular lesion of the skin is an uncommon usually benign condition, thus far reported almost exclusively from mammary skin after radiotherapy for carcinoma of the breast. Some clinical and histological overlap exists with early angiosarcoma, which can also occur on irradiated skin. The lesions are divided into vascular and lymphatic types, the first representing a higher risk for development of angiosarcoma and the latter being more common. This article reports a rare case of widespread, progressive, vascular-type atypical vascular lesion after repeated whole-body electron beam irradiation administered as treatment for mycosis fungoides.

Cutaneous collagenous vasculopathy: a rare cutaneous microangiopathy.

Cutaneous collagenous vasculopathy is a rare microangiopathy of superficial dermal blood vessels. Patients present with telangiectatic macules, predominantly on the extremities. A skin biopsy specimen is necessary to distinguish cutaneous collagenous vasculopathy from generalized essential telangiectasia. Microscopically, cutaneous collagenous vasculopathy resembles the superficial telangiectasias of generalized essential telangiectasia but additionally shows hyaline material in thickened vessel walls. The amorphous pink material is periodic acid-Schiff-positive and resistant to diastase. We describe a series of four patients with cutaneous collagenous vasculopathy and highlight its clinical and histopathologic features.

Collagenous vasculopathy: a report of three cases.

Cutaneous collagenous vasculopathy (CCV) is an idiopathic microangiopathy involving the superficial blood vessels that was initially reported in a 54-year-old male. We recently have identified this rarely reported entity in three Caucasian males. The first patient was a 59-year-old male with diabetes, hypertension and hypercholesterolemia who presented with multiple, red, blanchable, asymptomatic telangiectasias covering the extensor surface of the forearms, the lower abdomen and parts of the chest. The second patient was a 62-year-old male with psoriasis and extensive arthritis who presented with prominent telangiectasias on the left lateral distal thigh with mild overlying epidermal atrophy. The third patient was an 80-year-old male with atrial fibrillation who presented with blanching, telangiectatic areas on the abdomen, thighs and back. Histologically, the skin lesions showed ectatic superficial small blood vessels with laminated, hyalinized concretions around vessels that were highlighted with periodic acid-Schiff staining following diastase digestion and reactive by immunohistochemical staining with an antibody to collagen type IV. CCV is a rare and poorly understood entity with distinct histopathological features that may clinically resemble generalized essential telangiectasia (GET), yet which may affect a different demographic population than GET. Awareness of this uncommon entity may further help to elucidate its etiology.

Increased serum levels of the chemokine CXCL13 and up-regulation of its gene expression are distinctive features of HCV-related cryoglobulinemia and correlate with active cutaneous vasculitis.

Chemokine CXCL13, also known as BCA-1 (B cell-attracting chemokine-1) or BLC (B-lymphocyte chemoattractant), is a major regulator of B-cell trafficking. Hepatitis C virus (HCV) infection may be associated with B-cell dysfunction and lymphoproliferative disorders, including mixed cryoglobulinemia (MC). This study evaluates circulating levels of CXCL13 protein and specific mRNA expression in chronically HCV-infected patients with and without MC. Compared with healthy controls and HCV-infected patients without MC, CXCL13 serum levels were significantly higher in MC patients. The highest CXCL13 levels strongly correlated with active cutaneous vasculitis. CXCL13 gene expression in portal tracts, isolated from liver biopsy tissues with laser capture microdissection, showed enhanced levels of specific mRNA in MC patients with active cutaneous vasculitis. Specific CXCL13 gene mRNA expression was also up-regulated in skin tissue of these patients. These findings paralleled specific deposits of CXCL13 protein both in the liver and in the skin. Our results indicate that up-regulation of CXCL13 gene expression is a distinctive feature of HCV-infected patients. Higher levels of this chemokine in the liver as well as in the skin of patients with active MC vasculitis suggest a possible interrelation between these biologic compartments.

Generalized livedo reticularis associated with monoclonal cryoglobulinemia and multiple myeloma.

Cryoglobulins are detected in a wide variety of diseases, including malignancies, infections and systemic autoimmune diseases. Classically, monoclonal cryoglobulinemia is associated with hematologic malignancies, whereas mixed cryoglobulinemias are reported in association with hepatitis C virus infections or autoimmune diseases. We present a patient with generalized livedo reticularis as the first manifestation of monoclonal cryoglobulinemia and multiple myeloma. Histopathology demonstrated that nearly all small blood vessels of the upper and deep dermis, as well as the capillaries of the fat lobule, were filled with homogeneous, eosinophilic material that corresponded to monoclonal cryoglobulin deposits within the vascular lumina. Our case of livedo reticularis associated with monoclonal cryoglobulinemia and multiple myeloma was exceptional, because the mottled cyanotic discoloration of the skin with a reticular pattern was generalized, covering most of the skin surface. We have not found previous report of similar cases. Therefore, we recommend that dermatologists be made aware of the significance of this diagnosis.

Increased expression of VEGF in glomeruloid reactive angioendotheliomatosis.

Reactive angioendotheliomatosis (RAE) is a very rare disorder characterized by marked proliferation of endothelial cells. It is often associated with infections, such as subacute bacterial endocarditis, but has also been described as an early sign of a developing hematological malignancy. We report the case of a 71-year-old Caucasian female who developed lupus-like RAE lesions. A thorough diagnostic workup and subsequent 3-year clinical follow-up revealed no sign of an underlying infectious or neoplastic disorder. Repetitive serum immunofixations were only once consistent with a monoclonal gammopathy of undetermined significance. In lesional skin, the pronounced bud-like endothelial cell formation was associated with an increased epidermal expression of vascular endothelial growth factor (VEGF), a potent angiogenic mediator. In accordance with the paracrine action of epidermally derived VEGF, vascular endothelial cells in lesional skin revealed increased expression of the VEGF receptor VEGFR-2 (KDR). This case suggests a possible role of epidermally derived VEGF in endothelial cell proliferation in RAE.

Bone morphogenic protein-4 expression in vascular lesions of calciphylaxis.

Calciphylaxis is characterized by an extensive media-calcification of cutaneous and subcutaneous arterioles and capillaries. Recent studies have provided evidence that vascular calcification is a process with similarities to bone metabolism. Bone morphogenic protein-4 (BMP-4) is physiologically involved in bone development and repair. The presence of BMP-4 in atherosclerosis and in sclerotic heart valves led us to suggest that BMP-4 is also involved in calciphylaxis. A 47-year-old male patient developed end-stage renal failure due to chronic glomerulonephritis. He has had two kidney transplants with an immunosuppressive regimen consisting of cyclosporine A and steroids. He was admitted to our hospital because of an increase in serum creatinine (Cr) and he subsequently developed progressive dermal ulcerations. A skin biopsy led to the diagnosis of calciphylaxis. Immunohistochemistry for BMP-4 of a skin specimen from our patient showed strong cytoplasmic immunoreactivity of intradermal cells with clear spatial association to arterioles and hair follicles. Whereas there are identified inhibitors and promoters of vascular calcification, the presence of BMP-4 has not been demonstrated in calcific uremic arteriolopathy. In contrast to atherosclerosis, BMP-4 in calciphylaxis cannot be found in vascular media, but in intradermal cells at the border of arterioles and hair follicles. Therefore, in calciphylaxis BMP-4 can play the role of a cytokine, a growth factor or a media-calcification promoter.

An immunohistopathologic study in cutaneous necrotizing vasculitis.

In order to investigate the importance of timing in the immunophenotypical characteristics of the inflammatory infiltrate and in the adhesion molecules expression in cutaneous necrotizing vasculitis (CNV) we carried on an immunohistopathologic study. An avidin-biotin-streptavidin peroxidase technique was performed on 21 lesional skin biopsy specimens obtained sequentially at 0 to 24, 72 and 120 hours from seven patients with a CNV presenting as palpable purpura. A panel of monoclonal antibodies specific for inflammatory cells (T lymphocytes, polymorphonuclear leukocytes, macrophages, dendritic cells) and different adhesion molecules (E-selectin, ICAM-1, VCAM-1, LFA-1, VLA-4) was used. Moreover, HECA-450 monoclonal antibody was used to identify cutaneous lymphocyte antigen (CLA) in the inflammatory infiltrate. In all cases, polymorphonuclear leukocytes predominated in the early phase of CNV and their number decreased significantly with time (p = 0.0001). The T lymphocytes were present from the beginning and their number remained stable or increased slightly in time (p = 0.1), thus becoming predominant in the perivascular infiltrate in older lesions. Macrophages were scattered on interstitium since the early phase and they showed a time-dependent increase (p = 0.0003). E-selectin (ELAM-1) expression was detected at the first biopsy and it decreased depending on the age of the evolving vasculitis (p = 0.0033). The expression of CLA decreased also with time in 5 of the 7 cases (p = 0.0001). Our study supports the existence of an unique histopathologic pattern in CNV, in which the inflammatory infiltrate varies with time at the expense of the number of polymorphonuclear cells and macrophages.

Angiomatosis of skin with local intravascular immunoglobulin deposits, associated with monoclonal gammopathy. A potential cutaneous marker for B-chronic lymphocytic leukemia. A report of unusual case with immunohistochemical and immunofluorescence correlation and review of the literature.

Reactive cutaneous vascular proliferation or angiomatosis is associated with various conditions, but is rarely seen secondary to vascular occlusion. We report an unusual case of a 79-year-old female who presented with 8 month history of purpuric facial plaques, with painful crusted ulceration of the nose, later developing similar eruptions on hands, thighs and trunk. Biopsies showed marked angioproliferation, with intravascular (IV) hyaline deposits (PAS+, fibrin+/-; IgM+, fibrinogen+, and C3+), associated with endothelial hyperplasia (Factor VIII+, Vimentin+). Immunofluorescence showed IV IgM, fibrinogen, and granular C3 deposits within vessel walls. Initially, extensive investigations only showed minimal monoclonal gammopathy of undetermined significance (MGUS) and repeatedly negative cryoglobulins. After a 3-year follow-up, the patient developed chronic lymphocytic leukemia (B-CLL). This case illustrates a difficult diagnostic challenge. Although this condition resembles other forms of reactive angiomatosis, it shows distinct features and should be considered in the differential diagnosis of unusual vascular proliferations of the skin. The cutaneous lesions are also considered a potential marker for an underlying systemic condition, which may require prolonged clinical follow-up. We believe this condition to be related to other rare cutaneous vascular proliferations associated with plasma cell and lymphoproliferative disorders. Furthermore, we suggest a common pathogenetic pathway resulting from the IV immunoglobulin deposits causing vascular injury, finally leading to the angiomatosis.

In situ labelling of fragmented DNA in cutaneous necrotizing vasculitis.

Apoptosis is a biochemically and morphologically gene-regulated distinctive form of cell death playing a pivotal role in tissue homeostatic, viral infections and clearance of damaged cells. The process is initiated by a cascade of intercellular and intracellular signals through an intrinsic cell suicide program resulting in early DNA fragmentation characterized by nuclear and cytoplasmic condensation. Recently some authors have reported apoptosis to occur in several inflammatory skin diseases, such as lichenoid reactions and cutaneous lymphomas. The aim of our study is to investigate the apoptotic phenomenon in two different forms of cutaneous necrotizing vasculitis (CNV) affecting the postcapillary venules such as leukocytoclastic and lymphocytic cutaneous vasculitis. For this purpose, the in situ nick end labelling of fragmented DNA technique has been performed on lesional skin biopsies from patients with acute phase of the disease. In both leukocytoclastic and lymphocytic forms apoptotic bodies were detected, evidencing two different characteristic patterns of distribution, probably related to the different nature of cellular inflammatory infiltrate. Our results seem to account for the involvement of apoptotic phenomena in cutaneous vasculitis; furthermore, the evaluation of in situ DNA fragmentation could be a useful tool to discriminate different forms of the disease.

Recurrent juvenile dermatomyositis and cutaneous necrotizing arteritis with molecular mimicry between streptococcal type 5 M protein and human skeletal myosin.

An adult patient had a syndrome associating the features of juvenile dermatomyositis and cutaneous polyarteritis nodosa that followed a cyclic course from childhood; recurrences were always associated with a rise of serum antistreptococcal antibodies. Regions of homology between streptococcal type 5 M protein and skeletal myosin were found. These findings suggest that streptococcal infection, possibly through a molecular mimicry mechanism, played a role in the pathogenesis of the disease in our patient.