Search

Competing Interests: The authors declare no conflicts of interest.

Abstract: Cutaneous perivascular hemophagocytosis (CH) is a histological manifestation that manifests as systemic hemophagocytic syndrome, also known as hemophagocytic lymphohistiocytosis, when accompanied by fever, hepatosplenomegaly, liver dysfunction, and cytopenia, and may rarely manifest independently of hemophagocytic lymphohistiocytosis. CH typically presents as purpuric or brownish macules and patches on the extremities, abdomen, and trunks. Histopathologically, the hallmark of CH includes extravasated erythrocytes and karyorrhectic debris phagocytized by histiocytes, associated with dermal capillary ectasia, perivascular infiltration of neutrophils, nuclear dust, and histiocytes without atypia. In this study, we report 2 cases of CH encountered in routine diagnostic practice and elucidate their significant clinical and histologic features. Our first patient had leukocytoclastic vasculitis with CH in the setting of Yersinia enterocolitis, and the second case represents CH in association with non-Hodgkin lymphoma. This study highlights the importance of considering CH as a potential indicator of underlying systemic pathology, including infectious and hematological disorders, in clinical practice., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Cutaneous leukocytoclastic vasculitis (CLV) is a vasculitis that involves mainly small blood vessels in the skin. CLV has different causes (drugs, infections, or neoplastic or systemic inflammatory diseases). Sporotrichosis has rarely been associated with CLV. We report a case of disseminated cutaneous sporotrichosis caused by microorganisms in the Sporothrix clade in a Chinese woman with a tuberculous peritonitis history. Her lesions included many ulcers with crusts on the limbs. A skin biopsy yielded a histologic diagnosis of leukocytoclastic vasculitis. Periodic acid-Schiff and Grocott methenamine silver stains revealed numerous round-to-oval, thick-walled yeast cells in the necrotic tissue of the dermis. Mycological cultures grew pure dark brown wrinkled and villous fungus colonies morphologically and microscopic characteristics suggestive of the pathogenic Sporothrix clade which was followed confirmed as Sporothrix globosa (S. globosa) by the PCR method and sequencing based on calmodulin gene. Although infrequently, Sporothrix clade may cause CLV and should be considered in its differential diagnosis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Leukocytoclastic vasculitis (LCV) is a small vessel inflammatory condition considered to be caused by circulating immune complexes and often occurs after an acute infection or exposure to a new medication, although it may be associated with an underlying systemic disease or be idiopathic in nature. It is important to determine the etiology, identify the extent of the disease for early intervention and appropriate management, and treat and/or eliminate the underlying cause. Here, we report cases of scurvy and tinea corporis that presented with histopathologic features of LCV and had significant clinical improvement with treatment of the underlying etiologies. These cases emphasize that histopathologic features of early evolving LCV may be seen in other settings including scurvy and tinea corporis. Appropriate treatment of the underlying condition is important for optimized patient management., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Urticarial vasculitis (UV) is a clinicopathologic entity characterized by persistent urticarial lesions with biopsy features of vasculitis. Currently, only certain clinical features such as arthralgia and serum complement concentrations are used to identify UV patients at risk for an underlying systemic disease. Hypocomplementemic urticarial vasculitis (HUV) is in contrast to normocomplementemic urticarial vasculitis (NUV), strongly associated with underlying systemic disease, especially systemic lupus erythematosus (SLE). The aim of this study was to find specific histopathological features associated with HUV and underlying systemic disease in UV. In addition, the use of complement C4d deposition in skin biopsies was evaluated as a diagnostic adjunct for HUV- and UV-associated systemic disease. In this retrospective study, the clinical, histopathological, and immunohistological (C4d) features of 43 patients with UV were compared between HUV and NUV and analyzed for association with UV-associated systemic disease. Eight of 43 patients with UV (19%) had hypocomplementemia. Patients with HUV showed a significantly higher number of perivascular neutrophils and lower number of eosinophils compared to NUV. Of all histopathological features, alignment of neutrophils along the dermal-epidermal junction (DEJ) and dermal granular C4d deposition were found to be strongly associated with HUV and underlying SLE. This study shows that both the alignment of neutrophils along the DEJ and dermal C4d deposition are strongly associated with HUV and SLE. Therefore, these (immuno)histopathological features can be used as an easy diagnostic adjunct for early detection of underlying systemic disease in UV.

Erythema nodosum (EN) is considered to represent a septal panniculitis. In a period from January 2000 until June 2018, we clinically and histopathologically investigated 124 patients with EN, 13 (10.5%) of them in an early stage demonstrating features of a leukocytoclastic vasculitis (LCV) around postcapillary venules of the subcutaneous fat. Three of these patients presented with EN on the lower legs and Sweet syndrome on the head/neck, arms, or trunk. 19.3% and 70.2% of patients demonstrated "classic" features of subacute and chronic forms of EN, respectively. Histopathologically, in cases of early EN apart from septally accentuated vascular damage and neutrophils with nuclear dust, eosinophils were evident in 5 specimens as well, in one case even with flame figures as seen in Wells syndrome. The inflammation spilled over to the dermis and lobular panniculus in 12 and 10 specimens, respectively. From the same time period and for comparison, we investigated 497 cases of "classic" LCV. Depending on the degree of vascular damage and the presence of neutrophils and nuclear dust, 65.8% presented with acute, 18.9% with subacute, and 15.3% with late-stage disease. In the latter, only a few neutrophils but rather lymphocytes and macrophages were present. Four hundred forty patients revealed an involvement of the deep dermis; of those, in 342, a septal inflammation was present as well, whereas in 94, the process was purely dermal. The subcutis was missing for evaluation in 61 cases. These results indicate a closer relationship between EN and LCV than previously considered.

Skin is commonly affected by vasculitic process and often subjected to biopsy. Cutaneous vasculitis can be either primary or part of a systemic vasculitic process. This study was conducted to evaluate the diagnostic utility of direct immunofluorescence (DIF) in determination of etiology of cutaneous vasculitis. All histologically proven cases of cutaneous vasculitis over the past two and half years were retrospectively analyzed along with their clinical and DIF findings (IgG, IgA, IgM, and C3). Within this study period, a total of 198 cases of small-vessel vasculitis were diagnosed based on skin biopsy and DIF findings. The mean age of patients was 31.2 years (range 1-84 years) with slight male dominance (M:F ratio 1.06:1). Henoch-Schonlein purpura/IgA vasculitis was the commonest clinical diagnosis (31%), followed by urticarial vasculitis (11%) and others. Idiopathic vasculitis was suspected in 33% cases. Overall, DIF was positive in 60% (119/198) cases, with vascular deposition of IgA being commonest, followed by C3. The clinical diagnosis of Henoch-Schonlein purpura could be confirmed in 61.5% (40/65) cases by DIF, whereas another 20 unsuspected cases were picked up as IgA vasculitis based on DIF findings. DIF findings confirmed lupus vasculitis in 50% cases. Other cases showed variable nonspecific deposition of C3 and IgM in 42% cases. DIF can be highly useful to classify cutaneous vasculitis, with maximum efficacy for diagnosis of IgA vasculitis and lupus vasculitis. It can aid in the accurate diagnosis even when the histological changes are minimal. All cases of suspected cutaneous vasculitis should be subjected to DIF.

Erythema elevatum diutinum (EED) is a rare dermatosis with evolving histopathological features that vary according to the age of the lesions, with a variable fibrosis and a fascicled proliferation of spindle cells in late phases. The authors present an otherwise healthy 57-year-old woman with multiple indurated nodules on the inner aspect of both feet. Skin biopsy showed storiform interlacing bundles of spindled cells with plump nuclei and some areas with neutrophils and leukocytoclasia. CD34 and S100 were negative. This case is noteworthy clinically due to its location and its histopathological presentation that comprises a wide differential diagnosis, including inflammatory pseudotumor, dermatofibrosarcoma protuberans, superficial nodular fasciitis, hyalinized leiomyoma, sclerosing spindle cell perineuroma, and sclerotic fibroma. The authors have reviewed the main histopathological and immunohistochemical features that help in the differential diagnosis of this rare variant of EED. A careful search for leukocytoclasia and neutrophilic vasculitis is mandatory to establish the right diagnosis of nodular or late-stage EED and avoid the pitfall of considering this a neoplastic process.

One of the pathogenic causes of cutaneous inflammatory pseudotumors is chronic localized fibrosing leukocytoclastic vasculitis (CLFLCV), a vasculitic reaction pattern seen in granuloma faciale (GF), a localized vasculitis, and erythema elevatum diutinum (EED), a generalized vasculitis. Patients with myelodysplastic syndromes (MDSs) are at risk for a diverse spectrum of cutaneous neutrophilic dermatoses such as EED. Herein, we report a 74-year-old man who presented with a large ulcerative, fungating tumor affecting the right flexor ankle caused by CLFLCV. During his workup and management, MDS and Philadelphia chromosome-negative chronic myeloid leukemia was diagnosed. Surgical excision of the inflammatory mass promptly triggered tumor recurrence, whereas antineutrophil therapy (dapsone coupled with hydroxyurea, and prednisone) lead to tumor regression. Histopathologic examination revealed an eosinophilic-rich small-vessel neutrophilic vasculitis associated with storiform and angiocentric fibrosis (GF-like). In the regions of fibrosis, dilated lymphatic and vascular spaces were numerous, some of which were congested with small CD3-positive lymphocytes (intralymphatic and intravascular lymphocytosis). These findings indicate coexisting localized lymphedema. By direct immunofluorescence, IgM and C4d vessel deposits were detected. The pathogenesis of the fibrotic nodules and plaques of CLFLCV is suspected to be due to recurring bouts of immune-complex vasculitis, creating a cycle of vessel damage followed by reparative granulation tissue. Poor lymphatic drainage may be the underlying factor initiating and maintaining recurrent, localized episodes of immune-complex vasculitis and progressive fibrosis. Although his tumor histopathology resembled GF-eosinophilic rich CLFLCV-the clinical context points to a solitary and paraneoplastic case of EED.

Objective: To study the diagnostic utility and clinical associations of immunoglobulin deposition, determined by direct immunofluorescence (DIF) in cutaneous leukocytoclastic vasculitis (LCV)., Methods: We performed a retrospective study of all biopsy-proven LCV cases seen at Cleveland Clinic between 2007 and 2012. All LCV cases in which DIF was performed were included., Results: Of the 218 LCV cases, 106 cases had DIF performed and data from 88 cases were available: median (SD) age 53.3 (19.4), 52% male, 64.1% white, duration of rash 5.5 (20.8) months; follow-up 14 (19.7) months. DIF results showed any immunoglobulin and/or complement and/or fibrinogen in 70.5%, immunoglobulin A (IgA) in 36.4%, immunoglobulin M (IgM) in 21.6%, immunoglobulin G (IgG) in 11.4%. Patients with IgA deposition by DIF, compared with those without IgA, were younger, 44 (19) versus 56 (17) (P = 0.006), more likely to be white (P = 0.025) and had more organs affected by vasculitis (P = 0.002), higher incidence of gastrointestinal tract involvement (P = 0.0001) and renal disease (P = 0.006). No differences between rates of infection or malignancy were seen between DIF IgA, IgM, or IgG-positive versus negative patients., Conclusions: In patients with cutaneous LCV, IgA is the most common immunoglobulin found by DIF. IgA deposition, but not IgM or IgG, is predictive of associated renal and gastrointestinal organ involvement by vasculitis. No association between the type of immunoglobulin and preexisting infection or malignancy was found. DIF results add information that is clinically relevant to the diagnosis and management of LCV.

In 1964, Sweet described an acute febrile neutrophilic dermatosis. It is now widely accepted that Sweet syndrome is one of the associated neutrophilic dermatoses. Herein, we describe an unusual case of Sweet syndrome in a 5-year-old child who suffered from recurrent papules, plaques, and blisters on his face and trunk after the initial onset of fever without an obvious cause. Two skin biopsies were performed. The histopathological findings of the left arm biopsy showed a subepidermal blister with dense infiltrating neutrophils within the blister that were superficial to the middle layer of the dermis. The biopsy from a plaque on the left leg showed a dense infiltrate of neutrophils and a large number of infiltrating histiocytes superficial to the middle layer of the dermis. Direct immunofluorescence of a skin biopsy from the left arm confirmed that immunoglobulin M (IgM), IgG, IgA, and C3 expression were negative.

Decorative tattoos are associated with a variety of adverse cutaneous reactions. We describe a unique fibrosing vasculitic reaction to red tattoo ink. The histopathology was similar to that in localized chronic fibrosing vasculitis (LCFV), but sharply limited to sites of red tattoo ink injection and associated with florid verrucoid epidermal hyperplasia. LCFV has been described in a broad variety of slowly progressive disorders with a firm consistency such as erythema elevatum diutinum, plasma cell granuloma, granuloma faciale, and IgG4-associated sclerosing diseases. It has been hypothesized that LCFV is the result of maladaptive immune reaction with failure to clear the causative antigen. To the best of our knowledge, this is the first case of LCFV associated with tattoo. We speculate on the implications our case holds for the pathogenesis of LCFV.

Background: Conidiobolomycosis (also known as rhinoentomophthoramycosis) is a rare cutaneous/mucosal fungal infection seen mainly in the tropical rain forest regions of the world that can be associated with disfiguring facial elephantiasis, and rarely, death., Objective: To present an exemplary case report and perform a systematic review of the world's literature to more accurately describe the natural history and the effect of therapy on outcome in conidiobolomycosis., Methods: Case report and meta-analysis of published case reports and series of conidiobolomycosis to determine which clinical, pathologic, mycologic, and treatment factors impact on prognosis., Results: We document delay in diagnosis of conidiobolomycosis in a young Malaysian woman, whose biopsy showed pathognomonic features-massive tissue eosinophilia and Splendore-Hoeppli phenomenon surrounding broad hyphae. These findings coexisted with granuloma faciale-like changes (fibrosing leukocytoclastic vasculitis) and lymphedema. Treatment with multiple antifungals was followed by complete resolution. For the meta-analysis, pooled data from 199 cases (162 with full outcome data) from 120 reports revealed a similar course for most cases: a disease affecting healthy young adults who present with progressive nasal symptoms (eg, nasal obstruction) and central facial swelling and show improvement or cure after surgical excision and/or treatment with one or more antifungal agents in 83%. Persistent-progressive facial disease occurred in 11%, and 6% died rapidly of fungal infection. Presentation with facial elephantiasis correlated with persistent-progressive rhinoentomophthoramycosis and a longer duration of disease before diagnosis (P = 0.02). Lethal infections were significantly associated with nonstereotypical presentation (eg, orbital cellulitis), visceral infection, absence of the Splendore-Hoeppli phenomenon, presence of comorbidities (eg, immunosuppression, hematolymphoid malignancy), infection with Conidiobolus incongruus or Conidiobolus lamprauges (not Conidiobolus coronatus), lack of response to amphotericin B, and female sex (all P ≤ 0.002). The few sensitivity studies performed demonstrated in vitro multidrug resistance of Conidiobolus species to most available antifungal agents., Limitations: Publication bias, reporting heterogeneity, and data deficits may affect results., Conclusions: Conidiobolomycosis should be included in the differential diagnosis of patients who present with nasal symptoms and painless centrofacial swelling. Massive tissue eosinophilia and Splendore-Hoeppli material coating thin-walled hyphae confirms the clinical diagnosis. The granuloma faciale-like histology found in this case can explain the onset of facial lymphedema by fibroinflammatory destruction of lymphatic vessels; the duration of disease and severity of inflammation likely predicts whether the lymphedema is reversible or not. Although rhinoentomophthoramycosis ostensibly responds in vivo to most available antifungal agents, routine culture and susceptibility testing is recommended to better define the efficacy of these therapeutic agents.

In the course of daily sign-out, the diagnoses within a histopathologist's armamentarium are limited by the scope of the histopathologist's knowledge, that is, one cannot diagnose what one does not know. The subject of homogeneous intravascular eosinophilic deposits is used to illustrate this point. A histopathologist unaware that a tick bite reaction can induce intravascular eosinophilic deposits may misdiagnose the specimen as representing a manifestation of cryoglobulinemia. Furthermore, conventional teaching imparts that monoclonal cryoglobulinemia shows intravascular eosinophilic deposits (cryoprecipitates) histopathologically, whereas mixed cryoglobulinemia is histopathologically manifested as leukocytoclastic vasculitis. Although it is not well known, this is not always the case because mixed cryoglobulinemia may histopathologically present itself as intravascular eosinophilic deposits without leukocytoclastic vasculitis. In addition, it is not common knowledge that intravascular cryoprecipitates, when present, may be associated with an increased number of blood vessels. Examples of these phenomena are presented in conjunction with a discussion of relevant issues/lessons learned from such cases.

Hemophagocytic syndrome includes fever, hepatosplenomegaly, cytopenias, coagulopathy, and abnormal liver function tests, with some patients developing lymphadenopathy and cutaneous eruptions. Herein we report two cases of dermal perivascular hemophagocytosis identified in skin biopsies of two patients with no additional symptoms attributable to hemophagocytic syndrome. Biopsies showed capillary ectasia with dermal perivascular infiltrates. The overlying epidermis and adjacent subcutaneous fat was unremarkable. The infiltrate consisted of perivascular neutrophils and benign histiocytes with predominately phagocytized erythrocytes and occasional engulfed karyorrhectic debris. Perivascular nuclear dust (leukocytoclasia) and extravasated erythrocytes were present, but other factors typically found in leukocytoclastic vasculitis were absent, namely fibrin deposition and endothelial hypertrophy and/or necrosis. This appears to be hemophagocytosis, possibly associated with late lesions of leukocytoclastic vasculitis. Both hemophagocytosis and leukocytoclastic vasculitis are associated with activated immunity with increased cytokines and/or immune complexes. It is important to consider this uncommon finding in the evaluation of indeterminate cutaneous eruptions.

Sweet syndrome is a neutrophilic dermatosis defined by diagnostic criteria that include the lack of evidence for leukocytoclastic vasculitis. Because of the clinicopathological similarities on the one hand and the strict exclusion on the other hand, we were interested in a systematic evaluation of the relationship between these two diseases. We investigated the clinical and histopathological characteristics of 31 patients with Sweet syndrome, comparing our cases with 32 cases of leukocytoclastic vasculitis (including seven cases of urticarial vasculitis) and tried to place them in the background of published cases. There is a close relationship between Sweet syndrome and leukocytoclastic vasculitis in terms of clinical appearance, histopathological pattern, triggers, disease course, and response to treatment. The majority of the cases (23/31; 74%) showed histologic evidence of vasculitis, including nuclear dust, extravasation of erythrocytes, fibrin in and around vessel walls, and degeneration of collagen. Although one original criterion for Sweet syndrome is the absence of vasculitis, we propose that vasculitic changes should not exclude the diagnosis of Sweet syndrome. In contrast, Sweet syndrome can demonstrate vasculitis and may, similarly to urticarial vasculitis, be regarded a variant of leukocytoclastic vasculitis. Clinicopathologic characteristics with acute onset of juicy papules, plaques mostly on the face, shoulder, and trunk, and prominent edema probably reflect modifications of the pathogenetic process based on location and disease acuity.

A broad and diverse spectrum of vasculitic syndromes exists. These syndromes affect the skin with varying levels of associated systemic manifestations, running the gamut from a self-limited, localized, cutaneous phenomenon to rapidly progressive, multiorgan disease. The majority of cases of cutaneous vasculitis will show a neutrophilic small vessel vasculitis that can be either a primary (idiopathic) disorder (eg, cutaneous leukocytoclastic angiitis) or a secondary disorder that is associated with drugs, infection (eg, streptococcal infection, viral hepatitis), or underlying disease (eg, connective tissue disease, malignancy). Biopsy is the gold standard for the diagnosis of cutaneous vasculitis and also necessary for the detection of cutaneous vascular immune complexes by direct immunofluorescence. Based on the type of vessel disrupted by inflammation (small and/or muscular), the distribution of vasculitis in the dermis and subcutis, and predominate inflammatory cell-type mediating vessel wall damage, a list of relevant differential diagnoses can be generated. This histologic information coupled with extravascular findings such as tissue eosinophilia, tissue neutrophilia, and/or granulomas, plus pathophysiologic markers such as direct immunofluorescent examination for immune complexes and serologic evaluation for antineutrophil cytoplasmic antibodies allows for more accurate diagnosis of specific vasculitic entities. Herein, we review both primary and secondary vasculitic syndromes that affect the skin and show a small vessel neutrophilic mediated vasculitis.

Erythema elevatum diutinum (EED) is a chronic cutaneous vasculitis occurring in association with a variety of conditions including autoimmunity, infectious disease, and hematological abnormalities. The role of associated medical problems is controversial, and the exact pathogenesis of EED is unknown. A series of six cases is reported. The typical clinical presentation was that of erythematous papules and plaques involving the extensor surfaces of the extremities. Histologically, a spectrum from leukocytoclastic vasculitis to vessel occlusion and dermal fibrosis was seen. The lesions of EED have many mimics clinically and histologically. Establishing the diagnosis of EED is important so appropriate screening for associated conditions can ensue. The vascular endothelium of EED stains positive for CD31, CD34, VEGF, and factor VIIIa and negative for factor XIIIa, TGFB, and LANA, a reaction pattern that does not distinguish it from similar appearing lesions. Thus, the chronic and recurrent nature of EED is the primary means of distinguishing it from entities that are clinically and histologically similar.

Leukocytoclastic vasculitis is defined by histologic features and can be observed in a wide range of entities. Independent of the causative disease, extracutaneous complications are frequent, mainly in the kidneys and gastrointestinal tract. It has been suggested that the severity of histological changes could correlate with the clinical course of the disease. We have therefore compared the severity of histological changes of leukocytoclastic vasculitis to clinical and laboratory findings indicative of extracutaneous involvement in a large group of patients. Among 289 patients followed for cutaneous vasculitis, we included 184 patients with purpuric papules and proven leukocytoclastic vasculitis who all had standardized investigations. A cutaneous biopsy was performed early and standardized laboratory investigations were carried out. The slides were retrospectively randomized and the depth of vasculitis and severity of vascular necrosis were determined according to a semiquantitative scale. These data were compared to the renal, gastrointestinal and articular symptoms using Fischer's exact test, Chi-square test and variance analysis. The intensity of vascular necrosis and the depth of vasculitis were no more severe in patients having renal changes, gastrointestinal involvement or articular symptoms. Both variance analysis and Chi-square tests failed to show a significant increase in the severity score in patients having extracutaneous complications. In this study, the severity of histopathological changes was not predictive of extracutaneous involvement. Thus it appears that the degree of involvement of the cutaneous vessels probably does not correlate with that of vessels in visceral organs.

Lymphomatoid papulosis and cutaneous CD30+ lymphoma are closely related conditions in which large atypical lymphocytes that have similar immunophenotypic features occur. In lymphomatoid papulosis, the lesions are papules and nodules that spontaneously involute. There are two polar histologic patterns, type A and B, in which the large atypical cells resemble those of Hodgkin's disease and mycosis fungoides, respectively, but in many cases, features of both types are present, either separately or in the same lesions. Variants of lymphomatoid papulosis include cases with a perifollicular distribution and those with lymphocytic vasculitis or dermal mucin deposits. Clinical lesions that tend to be stable, a monomorphous cellular composition, and in the case of immunocompromised patients, the presence of Epstein-Barr viral genome characterize cutaneous CD30+ lymphoma. A loss of response to transforming growth factor-beta, which normally dampens cellular proliferation, may differentiate CD30+ lymphoma from lymphomatoid papulosis.

Cutaneous Acanthamoeba infection is a rare complication of immunocompromised individuals including those having acquired immunodeficiency syndrome (AIDS), who often have concurrent central nervous system involvement. Acanthamoeba typically involves the skin and central nervous system by disseminating from a primary focus in the lungs or sinuses. We report an unusual patient with AIDS who developed cutaneous infection with Acanthamoeba, apparently without CNS infection but with sinus involvement. Histologically, the purpuric lesions showed prominent leukocytoclastic vasculitis as well as myriads of organisms.