Successful treatment of xanthoma disseminatum with pulsed dye laser: A case report.

Xanthoma disseminatum is a rare form of non-Langerhans cell histiocytosis with limited treatment options due to its unknown aetiology and diffuse skin lesions. This case report presents the successful treatment of a 31-year-old male with severe pan-facial xanthoma disseminatum lesions following a facial burn and traumatic brain injury resulting from a car accident. After 5 sessions of monthly pulsed dye laser treatment, there was a clinically significant reduction in the lesions. Over the course of 3 years, the patient underwent a series of monthly pulsed dye laser treatments, and the lesions were almost cleared. These findings suggest that pulsed dye laser therapy may offer an effective treatment option for managing xanthoma disseminatum. This is the first report on use of the pulsed dye laser for treatment of xanthoma disseminatum.

Novel ANKRD26 and PDGFRB gene mutations in pediatric case of non-Langerhans cell histiocytosis: Case report and literature review.

Cutaneous non-Langerhans cell histiocytosis (NLCH) is a rare and biologically benign entity that can be broadly classified into two categories: xanthogranuloma and non-xanthogranuloma. The xanthogranuloma family is characterized by a proliferation of histiocytes with both macrophage and dendritic cell differentiation, negative BRAF mutation, and rare Touton-type giant cells. Molecular studies have reported that mutations involved in the MAPK signaling pathways are implicated in the pathophysiology of histiocytoses. While LCH is associated with the somatic mutation of BRAF v600e, however, mutations and gene fusions in NLCH cases are undefined. We hereby present a 19-month-old female with recalcitrant nodular rashes diagnosed as NLCH with associated novel genetic mutation involving ANKRD26 and PDGFRB genes, as well as PDGFRB::CD74 fusion mRNA. Immunohistochemical staining showed strong and diffuse CD68 and CD163 positivity, and negative CD1a, CD207, ALK D5F3, S100 protein, and BRAF V600E (VE1). Albeit unknown significance, this case of an ANKRD26 and PDGFRB gene mutation in cutaneous NLCH has not been reported prior in the literature. Our case highlights the advantage of pathology and genetic studies in cutaneous NLCH to increase the understanding of this heterogeneous enigmatic disorder and identify further options in management.

Histiocytoid melanoma: Diagnostic pitfall and mimicker of non-Langerhans cell histiocytoses including reticulohistiocytoma.

Melanoma and benign histiocytic proliferations can sometimes show considerable clinical and histopathologic overlap. Recently, cases of melanomas resembling xanthogranuloma and Rosai-Dorfman disease have been reported, and herein we report a case of melanoma closely mimicking reticulohistiocytoma. An 84-year-old man presented with a 1 cm purple-red nodule on his arm concerning for squamous cell carcinoma. While the biopsy findings resembled reticulohistiocytoma, the clinical context and regression changes at the lesion perimeter raised stronger concern for melanoma, which was confirmed with immunohistochemistry. We review prior rare reports of melanomas resembling non-Langerhans cell histiocytic proliferations and summarize helpful clinical and histopathologic clues to avoid a diagnostic pitfall when confronted with this unusual quandary.

Therapy of necrobiotic xanthogranuloma - case series and review of the literature.

Necrobiotic xanthogranuloma is a rare disease that is part of the non-Langerhans cell histiocytoses. It is characterized by yellowish skin lesions, which are typically periorbitally localized. Extracutaneous manifestations of all organs are possible and can cause potentially life-threatening complications. The disease also belongs to the facultative paraneoplasias and is often associated with paraproteinemia. These aspects should be considered regarding further diagnostics. Due to the rarity of the disease, there are no standardized guidelines for therapy so far. The combination of prednisolone and chlorambucil as well as intravenous immunoglobulins seem to be effective therapeutic options. We present four cases from our clinic as well as the current results of the literature in this mini-review and would like to highlight the therapeutic challenge as well as the need for the development of guidelines.

Reddish-brown, papulonodular skin lesions in the periungual region.

Multicentric reticulohistiocytosis is a rare, non-Langerhans cell histiocytosis that most commonly presents in women in their fourth or fifth decades of life. Cutaneous involvement, characterized by reddish-brown papules in a "string of pearls" or "coral bead" linear formation, and joint involvement are the two most common manifestations at presentation. Histopathology demonstrates dermal proliferation of epithelioid histiocytic-appearing cells with ground glass cytoplasm. We report a 51-year-old woman who presented with ruddy, periungual papules and bilateral joint pain in the hands, consistent with multicentric reticulohistiocytosis. We describe the clinical and histopathologic presentation, therapeutic options, and differential diagnosis of this rare condition.

Multicentric reticulohistiocytosis with dermatomyositis-like features: A case report with dermoscopy and reflectance confocal microscopy findings.

Multicentric reticulohistiocytosis (MRH) is an insidious-onset, non-Langerhans-cell histiocytosis (NLCH) affecting the joints and skin. Early diagnosis is important to prevent destructive arthritis and disease-related complications. Reflectance confocal microscopy (RCM) is a technique that allows the visualization of the epidermis and superficial dermis noninvasively on a horizontal plane with quasi-histologic images of the skin. RCM features of NLCH including Rosai-Dorfman disease, adult xanthogranuloma (AXG), and juvenile xanthogranuloma (JXG) have been reported. However, RCM features of MRH have not been described previously. Here we present the RCM features of a case of MRH with dermoscopic and histopathologic features.

A novel GAB2::BRAF fusion in cutaneous non-Langerhans-cell histiocytosis with systemic involvement.

Several mutations and gene fusions involved in the mitogen-activated protein kinase (MAPK) pathway have been reported in histiocytic neoplasms including Langerhans cell histiocytosis and non-Langerhans-cell histiocytosis (NLCH). We identified a GAB2::BRAF fusion in a cutaneous lesion from a 22-year-old woman who presented with central diabetes insipidus and red/brown papules on her face, oral mucosa, axilla, and groin. Skin biopsy showed a CD68+, S100-, and CD1a- histiocytic proliferation consistent with NLCH, best clinically classified as xanthoma disseminatum. Next-generation sequencing identified a GAB2::BRAF fusion involving exon 2 of GAB and exon 10 of BRAF. This case implicates a novel fusion in the MAPK signaling pathway, not previously reported in histiocytic neoplasms, as a possible driver of NLCH. Our findings underscore the utility of performing molecular studies on skin biopsy specimens with NLCH to help identify potential targets for therapy.

A Rare Case of Pediatric Xanthoma Disseminatum With Diabetes Insipidus and BRAF p.V600E Mutation.

ABSTRACT: Xanthoma disseminatum (XD) is a rare non-Langerhans cell histiocytosis characterized by xanthomatous lesions in the absence of hyperlipidemia. XD usually develops in young adults, and there are rare cases among children. BRAF mutations are frequent in Langerhans cell histiocytosis and Erdheim-Chester disease but absent or only rarely detected in other histiocytosis. Herein, we described a 6-year-old Chinese girl presented with generalized skin lesions and diabetes insipidus for 5 months. There were multiple periorbital xanthelasma with histopathological features of foamy histiocytes infiltration with Touton cells. Pituitary magnetic resonance imaging showed pituitary enlargement and pituitary stalk thickening. The presence of BRAF p.V600E mutation makes this case distinctive and also offers a potential therapeutic target. According to our review of the literature, this is the first pediatric XD with diabetes insipidus and BRAF mutation.

An Atypical Myelomonocytic Cell Infiltrate: Use of Next-Generation Sequencing to Diagnose Indeterminate Cell Histiocytosis.

ABSTRACT: Indeterminant cell histiocytosis (ICH) is a rare lymphoproliferative disorder that demonstrates features of Langerhans and non-Langerhans cell histiocytoses and diagnosis can be challenging. We present a case of a 62 year old woman with a generalized eruption of erythematous papules on the face, trunk and extremities. Skin biopsies demonstrated a dermal mononuclear cell infiltrate with monocytic (CD4, CD33), histiocytic (CD68, CD163), and dendritic cell (CD1a) immunophenotype but negative for Langerhans' cell marker (CD207). The differential diagnosis included leukemia cutis and ICH, and further workup revealed a normal bone marrow biopsy. To confirm the diagnosis of ICH, next generation sequencing with ETV3-NCOA2 gene fusion was performed and was positive. The patient's condition improved with methotrexate and narrow band UVB phototherapy. Our case adds to the existing literature supporting the use of next-generation sequencing to test for ETV3-NCOA2 gene fusion in suspected cases of ICH.

Generalized Eruptive Histiocytoma With S100 Protein-Positive Histiocytes and Prominent Eosinophilic Infiltration: A Rare Case Report.

ABSTRACT: Generalized eruptive histiocytoma (GEH) is a very rare benign disorder belonging to the group of non-Langerhans cell histiocytosis (non-LCH). GEH is characterized by a nearly uniform infiltrate of histiocytes with classic immunological phenotype (CD68+, S-100- and CD1a-). Prominent eosinophilic infiltration and S100-positive histiocytes are rarely associated in GEH. In this article, we reported a middle-age man presented with disseminated reddish papules distributed on the trunk and proximal extremities. A skin biopsy of the papule showed a dense histiocytic infiltration with prominent eosinophils. By immunohistochemistry, the histiocytes revealed strongly positive for CD68 and S100 protein and negative for CD1a and Langerin (CD207). Based on clinical and histopathological criteria, the diagnosis of GEH was established. We presented this rare case of GEH with such distinctive features to strengthen the awareness of this uncommon form of non-LCH. Classical histopathological and immunological features cannot reliably distinguish GEH from other non-LCH.

Juvenile Xanthogranuloma: A Comparative Immunohistochemical Study of Factor XIIIa, CD11c, and CD4.

ABSTRACT: Juvenile xanthogranuloma is a group C and L non-Langerhans cell histiocytosis, and its cell of origin is still debatable. The expression of CD11c, a more recently described macrophage marker, and CD4 have not been studied comprehensively. This study aimed to expand immunophenotypic profile and hence our understanding of the origin of these lesions. The surgical pathology archive was searched for the cases with the pathologic diagnosis of "xanthogranuloma" from 1995 to 2019. Immunohistochemical (IHC) stains were performed for factor XIIIa, CD11c, and CD4. Morphologically, each lesion was classified into early classic, classic, or transitional subtypes. Seventy-seven cases were included with the median age of 7.8 years (male:female 1.3:1). Uniform positivity was noticed for CD4 (n = 77), CD68 (n = 37), CD163 (n = 5), and vimentin (n = 4) stains. Other stains included CD11c 75/77 (97.4%), factor XIIIa 71/76 (93.4%), S-100 protein 4/23 (17.4%), and CD1a 0/18 (0%). Despite insignificant association between morphologic subtype and main studied IHC stains, factor XIIIa reactivity was highest in transitional lesions and CD11c showed higher reactivity in early classic lesions. CD11c and CD4 are sensitive markers and showed promising results in the diagnosis of juvenile xanthogranuloma compared with factor XIIIa. Despite different reactivity of factor XIIIa and CD11c in various morphologic subtypes, such association was statistically insignificant.

Skin Manifestation Associated With Multicentric Reticulohistiocytosis.

ABSTRACT: Multicentric reticulohistiocytosis (MRH) is a rare multisystem disorder, primarily affecting the skin and joints. As severe joint damage is a possible symptom, early diagnosis and therapeutic intervention are required. Cutaneous lesions present with characteristic features such as discrete reddish nodules, especially on acral locations. Additionally, the face, scalp, trunk and extremities are also affected. Xanthomatous plaques are also seen on the face. The cutaneous manifestations of MRH are various, which therefore should be differentiated from several diseases. In particular, MRH has been reported to assume clinical appearances resembling Gottron papules, periungual erythema, V-neck erythema, shawl sign, and poikiloderma associated with dermatomyositis. Histopathologic features show proliferation of multinucleated giant cells with abundant eosinophilic granular ground glass-like cytoplasm in the dermis. Multicentric reticulohistiocytosis is occasionally paraneoplastic and is associated with internal malignancies. The appropriate therapies are still challenging, and oral prednisolone, immunosuppressants, and recent biologics are used. In this article, cutaneous lesions, histopathology, and pathogenesis of MRH are mainly discussed from a dermatological perspective. It is important, not only for dermatologists but also for rheumatologists and orthopedists, to be able to distinguish between the various types of skin lesions brought on by MRH. Cutaneous signs are important diagnostic clues and assessment tools for therapeutic efficacy.

Successful treatment of congenital systemic juvenile xanthogranulomatosis with pulmonary involvement.

Juvenile xanthogranuloma (JXG) is a common form of non-Langerhans cell histiocytosis, which usually presents with spontaneously regressing skin lesions. Systemic involvement is rare and mostly seen in patients with multiple skin nodules. It can spontaneously regress, but sometimes systemic involvement can cause life-threatening symptoms and can be fatal. Herein, we report a case of congenital systemic JXG with multiple skin nodules, soft tissue and pulmonary involvement. She was successfully treated with chemotherapy according to Langerhans cell histiocytosis treatment protocol IV of the Histiocyte Society (LCH-IV).

Progressive nodular histiocytosis: an unusual disorder.

Progressive nodular histiocytosis (PNH) is a rare type of non-Langerhans cell histiocytosis of the xanthogranuloma group. Less than 20 cases have been reported. We report here a novel case of PNH with dermoscopic description and post-surgical outcome. Our patient presented with pruritic papules and nodules with progression over two years. Dermoscopic examination of large lesions showed multiple telangiectases without ulceration. There was no mucosal involvement. Histopathological analysis of a papule showed a dermal infiltrate composed of histiocytes and many Touton giant cells; a nodule revealed a dermis occupied by spindle cells arranged in a storiform pattern. The nodules were resected and the largest surgical defect, on the forehead, was corrected with A-T advancement flap. The papules were treated with cryosurgery achieving adequate cosmetic outcome without recurrence.

Multicentric reticulohistiocytosis masquerading as cutaneous connective tissue disease.

Multicentric reticulohistiocytosis (MRH) is a rare type of non-Langerhans cell histiocytosis characterized by coral-toned papules with predilection for dorsal surfaces in addition to severe arthropathy. It sometimes proves difficult to differentiate these joint and skin findings clinically from certain rheumatologic diseases, primarily dermatomyositis. Herein, we present an 82-year-old woman who presented with the clinical findings described above and was subsequently diagnosed with MRH after biopsy and review of relevant clinical history. Because about 25% of patients diagnosed with MRH have an underlying occult malignancy, our patient underwent a complete malignancy workup that was negative. She was treated with systemic corticosteroids and methotrexate, which resulted in an improvement of the arthritis and constitutional symptoms. This case demonstrates that in patients with both rheumatologic and dermatologic symptoms, particularly on acral surfaces, MRH must be a diagnostic consideration. Identifying this disease early in its course can prevent negative consequences for the patients, specifically arthritis mutilans and upper airway involvement.

Multicentric reticulohistiocytosis: the Mayo Clinic experience (1980-2017).

OBJECTIVES: Multicentric reticulohistiocytosis (MRH), a rare histiocytic disease that can mimic other rheumatic conditions, may be associated with cancer and other autoimmune disorders. To better understand the disorder and its other associations, we aimed to evaluate clinical correlates and outcomes of all patients with MRH seen at Mayo Clinic, Rochester between 1980 and 2017. METHODS: A retrospective medical record review was conducted to identify all patients with MRH between 1 January 1980 and 30 April 2017. RESULTS: We identified 24 patients with biopsy-proven MRH (58% female, 75% Caucasian, median age at diagnosis 52 years, median follow-up of 2.3 years). All patients had cutaneous and articular involvement; 23 (96%) patients had papulonodular skin lesions (87% periungual and dorsal hand) and seven (30%) mucosal nodules; and 22 (92%) patients had arthralgias, 21 (88%) joint effusions and 13 (54%) synovitis. Most frequently used therapies included corticosteroids, cyclophosphamide, methotrexate and bisphosphonates. Biologics were used in four patients. Nine patients had symptomatic resolution at 1 year and 12 partial improvement. Radiological findings included erosive changes in three (60%) patients and arthritis mutilans in two patients (40%). Twenty-nine per cent of patients had a concomitant autoimmune disease and 25% malignancy including melanoma, endometrial, peritoneal and lung carcinoma. The 5-year survival rate was 85% (95% CI: 74, 100%). CONCLUSION: To our knowledge, this is the largest single-centre series of patients with MRH highlighting the rarity of the condition and an unmet need for treatment options that can allow sustained disease remission. It also highlights the need for a high vigilance for malignancy and autoimmune diseases.

Long-term outcomes of children with extracutaneous juvenile xanthogranulomas in Japan.

BACKGROUND: Juvenile xanthogranuloma (JXG) is the most common non-Langerhans cell histiocytosis in children. The mortality and morbidity of JXG with extracutaneous lesions remain unclear. METHODS: Data of patients aged < 18 years who were diagnosed with JXG between 2001 and 2010 were retrospectively collected through a nationwide survey. RESULTS: Twenty patients (11 male and nine female) had extracutaneous lesions. The median observation time was 10 years (range, 0-17). Six patients presented with symptoms at birth. The median age at diagnosis was 8.5 months (range, 0 month-13 years). Fifteen patients underwent treatment for JXG, including chemotherapy (n = 11), and five did not receive treatment. All patients except one survived; 17 were disease-free and two survived with disease. One newborn-onset patient with liver, spleen, and bone marrow involvement died of the disease. Permanent sequelae included central diabetes insipidus, growth hormone deficiency, and panhypopituitarism detected at diagnosis in three, one, and two patients, respectively. Four patients had visual impairment (optic nerve compression and intraocular invasion in two each), three had epilepsy, one had mental retardation, and one had a skin scar. Eight patients who had intracranial lesions were older at diagnosis, and had a higher frequency of disease-related comorbidities and permanent sequelae than those without intracranial involvement. CONCLUSIONS: Patients with extracutaneous JXG had good outcomes, although those with intracranial lesions had serious permanent sequelae. Effective and safe treatment regimens for patients with intracranial JXG need to be developed.

Reticulohistiocytoses: a revision of the full spectrum.

Reticulohistiocytoses (RH) are rare and clinically heterogeneous histiocytic disorders of dermatological interest. Three clinical entities with superimposable histopathological features are currently considered, namely solitary reticulohistiocytoma, diffuse/generalized reticulohistiocytosis and multicentric reticulohistiocytosis. Although in the last decade, RH studies have only minimally progressed, histiocytosis research has advanced considerably: the prognostic and therapeutic importance of the clinical subclassification of histiocytosis patients as well as of the detection of genetic alterations in the genes of the ERK pathway has been highlighted. According to these insights, we previously reported the presence of molecular alteration RH and described a subset of patients with disseminated multisystem involvement lacking arthritis. In the present review, we aim to update and revise the knowledge regarding RH. We first reviewed their histopathological, immunophenotypical and ultrastructural features, discussed their histopathological differential diagnosis with other conditions characterized by infiltrates made of oncocytic or epithelioid cells (with special regard to Destombes-Rosai-Dorfman disease) and finally summarized the molecular landscape of RH. We therefore tried to adjust the clinical subclassification of Langerhans cell histiocytosis to the clinical phenotypes of RH, outlining five clinically different groups of patients. Finally, we reconsidered the clinical workflow to the evaluation of RH patients, in light of the 5 different clinical groups and discussed the different therapeutic approaches and the possible role of target inhibitors.

Juvenile xanthogranulomas: Examining single, multiple, and extracutaneous presentations.

BACKGROUND: Juvenile xanthogranuloma (JXG) is a non-Langerhans cell histiocytosis characterized by yellowish papules in the skin. JXGs most often occur in infancy or early childhood and are typically solitary and asymptomatic, often regressing after several years. While JXGs predominantly occur on the skin, extracutaneous JXGs also exist. AIMS: In this paper, we review the literature on single, multiple, and visceral JXGs and provide recommendations on monitoring and work-up. MATERIALS & METHODS: A literature review was conducted with the PubMed database using selective search terms for single, multiple, ocular, and visceral lesions as well as NF1/JMML. RESULTS / DISCUSSION: JXG is typically a self-limited disorder if lesions are cutaneous and singular. While rare, JXGs may manifest as multiple and extracutaneous lesions. Further screening and referral to specialists may be warranted in these cases based on age and extent of involvement. CONCLUSION: Our review demonstrates common presentations of single, multiple, and extracutaneous lesions in addition to those that occur with NF1 and JMML. We suggest patients be evaluated on a case-by-case basis by a dermatologist and referred to specialists as appropriate.