Advancements in the understanding and management of histiocytic neoplasms.

Histiocytic neoplasms are rare diseases involving macrophages, dendritic cells, and monocytes. They include Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), Rosai-Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and histiocytic sarcoma. Histiocytic neoplasms are characterized by varied clinical courses and prognoses, necessitating a nuanced understanding of their classification, epidemiology, and clinical manifestations. Genetic studies have revealed somatic mutations, predominantly in the MAPK pathway, suggesting a clonal neoplastic nature. This review covers the current understanding of histiocytic neoplasms, molecular pathophysiology, with a particular focus on mutations in genes such as BRAF, MAP2K1, and the PI3K-AKT signaling pathways, and evolving treatment strategies, especially focusing on LCH, ECD, RDD, and JXG. The treatment landscape has evolved with advancements in targeted therapies. BRAF inhibitors, such as vemurafenib and dabrafenib, have shown efficacy, especially in high-risk LCH cases; however, challenges remain, including relapse post-treatment discontinuation, and adverse effects. MEK inhibitors have also demonstrated effectiveness, and cobimetinib has recently been approved for use in adults. Further research is required to determine the optimal treatment duration and strategies for managing therapy interruptions. Advancements in molecular genetics and targeted therapies have revolutionized the management of histiocytic neoplasms. However, ongoing research is crucial for optimizing patient outcomes.

Orbital histiocytosis; From A to Z.

PURPOSE: Histiocytosis is one of the most challenging diseases in medical practice. Because of the broad spectrum of clinical manifestations, systemic involvements, unknown etiology, and complex management, different types of histiocytosis are still a big question mark for us. Orbital histiocytosis is characterized by the abnormal proliferation of histiocytes in orbital tissues. It could affect the orbit, eyelid, conjunctiva, and uveal tract. Orbital histiocytosis can cause limited eye movement, proptosis, decreased visual acuity, and epiphora. In this study, we review the novel findings regarding the pathophysiology, diagnosis, and treatment of different types of histiocytosis, focusing on their orbital manifestations. METHOD: This review was performed based on a search of the PubMed, Scopus, and Embase databases or relevant published papers regarding orbital histiocytosis on October 9th, 2023. No time restriction was proposed, and articles were excluded if they were not referenced in English. RESULTS: 391 articles were screened, most of them being case reports. The pathophysiology of histiocytosis is still unclear. However, different mutations are found to be prevalent in most of the patients. The diagnostic path can be different based on various factors such as age, lesion site, type of histiocytosis, and the stage of the disease. Some modalities, such as corticosteroids and surgery, are used widely for treatment. On the other hand, based on some specific etiological factors for each type, alternative treatments have been proposed. CONCLUSION: Significant progress has been made in the detection of somatic molecular changes. Many case studies describe various disease patterns influencing the biological perspectives on different types of histiocytosis. It is necessary to continue investigating and clustering data from a broad range of patients with histiocytosis in children and adults to define the best ways to diagnose and treat these patients.

Congenital isolated juvenile xanthogranuloma of the sole - a unique case report in a newborn.

Juvenile xanthogranuloma (JXG) is a rare, benign non-Langerhans cell histiocytosis that primarily affects the skin, with infrequent extracutaneous manifestations. Lesions typically emerge during early childhood and often resolve spontaneously, obviating the need for treatment. This paper details the case of a child diagnosed with a solitary JXG on the sole, necessitating surgical excision due to its functional impairment, specifically a delay in walking and weight bearing.

Congenital Juvenile Xanthogranuloma in the Perioral Region: A Case Image.

Juvenile xanthogranuloma (JXG) is the most common form of non-Langerhans cell histiocytosis in childhood. It often presents with cutaneous involvement and exhibits a predilection for the head and neck region. This article illustrates a case of congenital JXG in a 5-month-old boy, characterized by a solitary, well-circumscribed nodule above the left upper lip. Histopathologically, the lesion exhibited histiocytes with eosinophilic cytoplasm and Touton giant cells. Immunohistochemistry revealed histiocytes positive for CD68 and Factor XIIIa, while negative for S-100 protein. Clinicians should become familiar with the broad clinical spectrum of cutaneous JXG, particularly its congenital presentation, in order to ensure timely and accurate management.

Juvenile xanthogranuloma manifesting with LCH-associated neurodegenerative disease-like radiological findings.

Here, we describe two patients with juvenile xanthogranuloma (JXG) manifesting with Langerhans cell histiocytosis (LCH)-associated neurodegenerative disease (ND)-like radiological findings. One patient showed typical radiological abnormalities at onset, which worsened with progressing central nervous system symptoms 7 years after LCH-oriented chemotherapy. Another showed spontaneous regression of clinical symptoms, with a transient radiological change 1 year after salvage chemotherapy for recurrence of JXG. These data regarding JXG-associated ND will facilitate future investigation of the disease, as well as development of therapeutic interventions.

Oral sirolimus for the treatment of juvenile xanthogranuloma: Report of two pediatric cases.

Juvenile xanthogranuloma (JXG) with extensive cutaneous or visceral organ involvement is often associated with high morbidity and treatment commonly involves surgical excision, radiotherapy, systemic steroids, or chemotherapy. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is an oral antitumor and immunosuppressive therapy used to treat various neoplastic disorders, including histiocytic disorders. We report two pediatric cases of JXG successfully treated with oral sirolimus monotherapy, and postulate that sirolimus may induce rapid disease resolution and long-term remission for patients with both skin-limited and multisystemic JXG. Our findings warrant further investigation of the relationship between the mTOR pathway and JXG.

Systemic xanthogranuloma involving bone marrow and skin in a case of B-Lymphoblastic Leukemia.

Juvenile xanthogranuloma is a benign self-limiting lesion commonly described in infants and young children. It most commonly involves the skin presenting as single or multiple yellowish-brown papules. Clinical scenario with the classic histomorphology showing histiocytic aggregates in the dermis with xanthomatous cytoplasm, toutan type giant cells, immunohistochemistry with positive CD68, CD163, factor XIIIa and negative CD1a and S-100 help in diagnosis. However, diagnosis becomes challenging with predominant systemic bone marrow involvement in post-B-lymphoblastic leukemia settings.

Histopathological maturation in juvenile xanthogranuloma: a blueberry muffin infant mimicking aleukemic leukemia cutis.

Juvenile xanthogranuloma (JXG) is usually identified by Touton giant cells, so their absence can complicate diagnosis. We encountered a case of non-typical neonatal JXG lacking Touton giant cells, which was difficult to differentiate from aleukemic leukemia cutis because of overlapping histopathological characteristics. A 1 month-old girl presented with a blueberry muffin rash and multiple 1-2 cm nodules within the subcutaneous and deeper soft tissues. Blood tests revealed pancytopenia. The initial nodule biopsy showed mononuclear cell infiltration, suggestive of mature monocytes or histiocytes, but no Touton giant cells. Bone marrow examination showed no evidence of leukemia. Despite worsening of the rash, pancytopenia, and weight gain over the following month, the results of the second biopsy remained consistent with the initial findings. Consequently, we provisionally diagnosed aleukemic leukemia cutis and initiated chemotherapy. After two courses of chemotherapy, the pancytopenia improved, but the nodules only partially regressed. A third biopsy of the nodule was performed to evaluate the histological response, and revealed Touton giant cells, confirming the diagnosis of JXG. In conclusion, distinguishing non-typical JXG from aleukemic leukemia cutis is challenging. This case highlights the importance of multiple biopsies and the potential for histopathological maturation.

Presentación clínica de patologías no malignas que simulan leucemia cutis: a propósito de dos casos / Clinical presentation of non-malignant diseases mimicking leukemia cutis: A report of two cases

La infiltración cutánea por células leucémicas conocida como leucemia cutis es una presentación infrecuente de esta patología y constituye un desafío diagnóstico. Los diagnósticos como infecciones, otras patologías neoplásicas con afectación cutánea y los trastornos histiocíticos, entre otros, constituyen los principales diagnósticos diferenciales, ya que configuran un escenario pronóstico y terapéutico diferente. Se presentan dos pacientes que fueron diagnosticados inicialmente como leucemia cutis, cuyo diagnóstico final fue de patologías no malignas.

The infiltration of leukemia cells into the skin, known as leukemia cutis, is a rare presentation of this disease and accounts for a diagnostic challenge. The main differential diagnoses include infections, other neoplastic diseases with skin involvement and histiocytic disorders, among others, as they entail different prognostic and therapeutic approaches. Here we describe two patients who were initially diagnosed with leukemia cutis, whose final diagnosis was of non-malignant diseases.

Clinical and pathological evaluation of cladribine treatment response in a case series of patients with xanthoma disseminatum.

BACKGROUND: Xanthoma disseminatum (XD) is a rare form of non-Langerhans histiocytosis with extensive cutaneous involvement. There is a paucity of evidence-based recommendations for treatment decision-making. Previous case reports have established purine analogues, especially cladribine, as a hopeful first-line treatment option, but characterization of the clinical and pathological responses is lacking. OBJECTIVES: To characterize the clinical and pathological responses to cladribine monotherapy based on serial examinations in XD patients. MATERIALS & METHODS: We retrospectively studied the clinical, pathological and laboratory data in a cohort of five XD patients who received intravenous cladribine monotherapy with serial examinations in our hospital. Compared with baseline characteristics, changes in clinical features and pathological patterns were identified and analysed. We also conducted a literature review of reported cases of cladribine treatment in XD patients. RESULTS: Four male and one female patient were involved in the study. All patients demonstrated satisfactory clinical responses to cladribine monotherapy after 5 to 10 cycles. We observed a pathological shift in pattern from classic xanthogranuloma to transitional fibrohistiocytic infiltration during the treatment, and pathological responses heralded persistent clinical improvement. Other than afebrile neutropenia, no prominent adverse events were identified. Sustainable lesion clearance was achieved in all five patients during the follow-up period, ranging from 19 to 66 months. CONCLUSION: Cladribine monotherapy is an effective and well-tolerated therapeutic option for XD patients. Pathological transformation is a signature of the clinical response and possibly unveils the underlying histiocyte biology of diseases in the xanthogranuloma family.

Juvenile xanthogranuloma as a differential diagnosis for sellar and suprasellar lesions in child: Case report and review of literature.

Juvenile xanthogranuloma (JXG) is a rare type of non-Langerhans cell histiocytosis. Its systemic form affects 4% of patients. Lesions in the Central Nervous System (CNS) occur in 2% of systemic cases. Sellar JXG should be one of the differential diagnoses for sellar lesions in young. This is a 15-year-old patient with non-specific headache, progressive visual loss and magnetic resonance imaging showing sellar lesion with suprasellar extension. The patient underwent microsurgery by pterional craniotomy with partial resection of the tumor. Pathology evidenced JXG. It progressively evolved with impairment of neuroendocrine functions, new lesions in different CNS locations and death two years after diagnosis. Sellar JXG without cutaneous manifestations is rare. There are no specific findings of the disease. Diagnosis requires additional tests, being defined by pathological analysis. Total resection presents a greater potential control comparing to partial resection. Even so, some patients may have progressive disease with poor clinical outcome.

Unusual presentation of a vascularized iris lesion in an infant.

We report an unusual presentation of a 10-month-old girl with left eye (LE) redness and watering. Evaluation showed an iris vascular lesion and lens opacity in her LE. Child underwent USG B-scan and ultrasound biomicroscopy, by which an extensive mass lesion arising from iris and ciliary body with absent calcification was revealed. Following extensive evaluation, child underwent cataract extraction and trans-scleral total excision of the mass lesion. Histopathology proved it as juvenile xanthogranuloma (JXG) with vascular proliferation. JXG is a rare benign self-limiting dermatologic disorder affecting mainly infants and small children. Ocular lesions are the most common extracutaneous manifestation. Cataract in JXG is less frequently reported. This case is reported due to its rarity and as it presented solely as an intraocular lesion with combined diffuse infiltration into ciliary body and cataract which is unusual. Early recognition and systematic approach helped in sight saving and organ salvaging.

A Case of Multiple Self-Involuting, Mixed Presentation, Giant Congenital Juvenile Xanthogranuloma.

Juvenile xanthogranuloma (JXG) is an uncommon benign skin disorder of infants and young children characterized by dermal proliferation and infiltration of dendrocytes. We present a unique case of giant congenital JXG with a mixed presentation of macules, papules, nodules, and ulcerations in a neonatal male who was observed until the age of 23 months, by which time all lesions had spontaneously self-involuted. Prior to complete resolution, some lesions took the form of pedunculated protrusions. To our knowledge, this is the first of this atypical case to be presented in the literature.

A Multifaceted Approach to Treatment of Recalcitrant Cutaneous Periorbital Juvenile Xanthogranuloma.

Purpose: To demonstrate novel treatments for patients with high juvenile xanthogranuloma (JXG) eyelid lesion burden. Case Report: A 14-year-old girl was referred to the oculoplastic surgery service for management of worsening extensive bilateral eyelid and adnexal lesions in the setting of JXG. The patient underwent intra-lesional steroid injections, serial excisions, and reconstruction with skin grafts. She was subsequently treated with CO 2 laser-assisted topical steroid application, which resulted in lesion regression. Conclusion: A novel multimodal approach to treatment of severe periocular JXG, incorporating surgical debulking, skin autograft, CO2 laser, and intra-lesional steroids, can be effective for lesion control.

Solitary juvenile xanthogranuloma in the parotid gland.

Juvenile xanthogranuloma (JX) is a non-Langerhans cell histiocytosis. Although precipitating factors remain unclear, it has been described mainly in infancy and early childhood. The giant variant of JX is a rare form that presents in infancy, measures over 2 cm and tends to involute only partly. Herein, we report a very rare localization of a giant JX in the parotid gland, discovered at age 1 month in an infant of a twin pregnancy and studied with ultrasound and magnetic resonance imaging.

Clinical presentation of non-malignant diseases mimicking leukemia cutis: A report of two cases. / Presentación clínica de patologías no malignas que simulan leucemia cutis: a propósito de dos casos.

The infiltration of leukemia cells into the skin, known as leukemia cutis, is a rare presentation of this disease and accounts for a diagnostic challenge. The main differential diagnoses include infections, other neoplastic diseases with skin involvement and histiocytic disorders, among others, as they entail different prognostic and therapeutic approaches. Here we describe two patients who were initially diagnosed with leukemia cutis, whose final diagnosis was of non-malignant diseases.

La infiltración cutánea por células leucémicas conocida como leucemia cutis es una presentación infrecuente de esta patología y constituye un desafío diagnóstico. Los diagnósticos como infecciones, otras patologías neoplásicas con afectación cutánea y los trastornos histiocíticos, entre otros, constituyen los principales diagnósticos diferenciales, ya que configuran un escenario pronóstico y terapéutico diferente. Se presentan dos pacientes que fueron diagnosticados inicialmente como leucemia cutis, cuyo diagnóstico final fue de patologías no malignas.

Disseminated Juvenile Xanthogranuloma with a Novel MYH9-FLT3 Fusion Presenting as a Blueberry Muffin Rash in a Neonate.

Juvenile xanthogranuloma (JXG) is a benign proliferative histiocytic disorder of the dendritic cell phenotype. It mostly presents in the pediatric age group as a solitary skin lesion. We describe a rare case of an infant born with disseminated JXG who presented with a blueberry muffin rash at birth. A term infant was noted to have multiple petechiae, purple nodules, and macules (1 mm-2 cm in diameter) and hepatosplenomegaly, at the time of birth. Further investigations revealed thrombocytopenia and direct hyperbilirubinemia and a magnetic resonance imaging showed scattered tiny foci of restricted diffusion in multiple areas of the brain. Patient received multiple platelet transfusions in the first few weeks with gradual improvement in thrombocytopenia. Ultimately, a biopsy of one of the lesions revealed the diagnosis of disseminated JXG with notable atypical features. Somatic mutation analysis showed a novel MYH9-FLT3 fusion, but a bone marrow biopsy was negative. The lesions faded over time, relative to patient's growth and normal neurodevelopment was noted at 18 months of age. JXG should be considered in the differentials of blueberry muffin rash in an infant. Although, JXG is mostly a self-limited condition, congenital disseminated JXG may be associated with significant morbidity and mortality.