Remission of necrobiotic xanthogranuloma after intravenous immunoglobulin interruption: A case report.

Necrobiotic xanthogranuloma is a rare non-Langerhans cell histiocytosis with the potential for multisystemic involvement. It's a challenging disease to treat and multiple treatments have been reported in the literature with variable results. We present the case of a 92-year-old woman with multiple orange-brown papules and plaques on her face progressing for several years. The biopsy showed dermal xanthogranulomatous infiltration with multinucleated giant cells and necrobiosis, and she was diagnosed with necrobiotic xanthogranuloma. A complete response was obtained with intravenous immunoglobulins and she remained in remission despite treatment discontinuation.

[28-year-old male patient with headaches on the left side and facial pain]. / 28-jähriger Patient mit in den Kiefer ausstrahlenden ­Kopfschmerzen temporal links.

INTRODUCTION: A 28-year-old male suffers for two weeks from new-onset very severe headache located on his left temple radiating to his jaw. He also complains about left sided retroorbital pain and chewing aggravated symptoms. In addition, nausea and emesis in the mornings during the past six months were reported. Clinical examination revealed tender swelling over the left temple, but laboratory results showed no signs of inflammation, normal electrolytes, kidney and liver values. A CT-scan revealed a circumscriptive osteolytic lesion in the left os temporale.

Diffuse Cystic Lung Disease: A Clinical Guide to Recognition and Management.

TOPIC IMPORTANCE: Diffuse cystic lung diseases (DCLDs) represent a group of pathophysiologically heterogeneous entities that share a common radiological phenotype of multiple thin-walled pulmonary cysts. DCLDs differ from the typical fibroinflammatory interstitial lung diseases in their epidemiology, clinical presentation, molecular pathogenesis, and therapeutic approaches, making them worthy of a distinct classification. The importance of timely and accurate identification of DCLDs is heightened by the impact on patient management including recent discoveries of targeted therapeutic approaches for some disorders. REVIEW FINDINGS: This article offers a practical framework for evaluating patients with DCLD indicating the most appropriate and current diagnostic and management approaches. We focus on the DCLDs that are most likely to be encountered by practicing pulmonologists: lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, Birt-Hogg-Dubé syndrome, and lymphoid interstitial pneumonia. Chest computed tomography is the most informative non-invasive diagnostic modality to identify DCLDs. Thereafter, instituting a structured approach to high-yield associated factors such as medical, social and family history, as well as renal and dermatological findings increases the likelihood of identifying DCLDs and achieving a diagnosis. SUMMARY: While the individual diseases that comprise the DCLD family are rare, taken together DCLDs can be encountered more frequently in clinical practice than commonly perceived. An increased eagerness among general pulmonary physicians to recognise these entities, coupled with a practical and systematic clinical approach to examinations and investigations is required to improve case finding, allow earlier intervention, and reduce morbidity and mortality.

Pulmonary Langerhans cell histiocytosis presenting as an uncommon mass in the lung: A rare case report and literature review.

A comprehensive diagnostic approach, including immunohistochemistry, is crucial for confirming pulmonary Langerhans cell histiocytosis in adults. Individualized treatment with dynamically adjusted chemotherapy based on therapeutic response leads to significant absorption of lesions and symptom alleviation. Regular follow-up and timely treatment adjustments according to the patient's condition are essential in managing this rare disease.

Pituitary Involvement in Langerhans Cell Histiocytosis: A Challenging Case.

Langerhans cell histiocytosis (LCH) is a rare disorder involving an abnormal clonal proliferation of precursor cells of the mononuclear phagocytic system. The hypothalamic-pituitary axis is commonly affected by central nervous system (CNS) involvement, with central diabetes insipidus being the most common endocrine abnormality observed. We report the case of a 55-year-old female presenting with vision changes and found to have a hypothalamic mass that was responsive to high-dose steroids. After an initial diagnostic dilemma, the surgical pathology eventually confirmed the diagnosis of LCH. She is being treated with hormone supplementation for panhypopituitarism and intensity-modulated radiation therapy (IMRT) for the LCH. Our case highlights that LCH can present as isolated hypothalamic-pituitary involvement. Early diagnosis is critical to prevent extensive progression of the disease, ultimately leading to permanent physical and endocrine abnormalities. More studies are required to develop specific guidelines and approaches for patients with isolated hypothalamic-pituitary involvement due to LCH.

Langerhans cell histiocytosis in sphenoid sinus with vision impairment: Case report and literature review.

Langerhans cell histiocytosis (LCH) is a neoplastic disease characterized by aberrant proliferation of the mononuclear phagocyte system, predominantly affecting children under the age of 3 years. Although LCH can affect almost all organs, sinus involvement is rare. This case report documents a 9-year-old boy presented with vision impairment and intermittent headache on the right side. The CT scan and MRI examination revealed the presence of a soft mass in the right atrium of sphenoid sinus, which impacted the right optic canal. Biopsy results confirmed the presence of LCH. Considering the involvement of optic canal and vision impairment, meticulous debridement was performed followed by a 12-month standard chemotherapy. After 2 years of follow-up, the patient showed significant improvement, despite the presence of an encapsulated cyst in the right sphenoid sinus. This case highlights the importance of considering LCH when encountering an isolated soft mass accompanied by decreased vision in the sphenoid sinus. A thorough physical examination, laboratory tests, and imaging methods should be performed, with a biopsy being necessary to confirm the type of lesion and guide the appropriate treatment.

A Systematic Review of Clinical Features and Treatment Outcomes of Xanthoma Disseminatum.

Xanthoma disseminatum (XD) is a rare normolipidemic mucocutaneous xanthomatosis within the spectrum of cutaneous non-Langerhans histiocytosis. Managing XD poses substantial challenges, with limited available data. This study aims to comprehensively evaluate existing literature on clinical features of XD and treatment outcomes. A systematic search of MEDLINE, Embase, and PubMed was performed, using "xanthoma disseminatum" and "Montgomery syndrome" as search terms, without restrictions. Screening was performed in duplicate by 2 reviewers. One hundred fifty-one studies met the inclusion criteria, yielding 166 cases of XD (106 females, 60 males), mean age at diagnosis 35.3 years (range: 9 months-87 years). XD typically presented as yellow-to-brown coalescing papules/plaques and nodules. Distribution affects mainly the face (n = 116/166), flexures (n = 45/166), trunk (n = 65/166), and genitalia/inguinal areas (n = 63/166). Most cases (99.4%; n = 165/166) exhibited extracutaneous manifestations, including the pituitary gland and the oropharynx. Treatment options rendered low complete response rates (CRRs). Treatments with reported outcomes included surgical resection (n = 17/99), systemic steroids (n = 40/99), immunosuppressants/immunomodulators (n = 73/99), energy-based devices (n = 7/99), lipid-lowering agents (n = 24/99), cryotherapy (n = 6/99), lasers (n = 10/99), topical steroids (n = 6/99), oral retinoids (n = 2/99), and radiotherapy (n = 5/99), with CCRs of 23.5% (n = 4/17), 5.0% (n = 2/40), 9.6% (n = 7/73), 14.3% (n = 1/7), 4.2% (n = 1/24), 16.7% (n = 1/6), 10.0% (n = 1/10), 0% (n = 0/6), 0% (n = 0/2), and 0% (n = 0/5), respectively. The most promising therapy is cladribine, with the highest CRR of 27.1% (n = 6/22) and the lowest no response rate (9.1%; n = 2/22) of all reported treatments. This review confirms the high prevalence of systemic manifestations in XD. Treatment options vary widely; thus, further research is needed to establish management strategies for this challenging condition.

Circulating monocytes decrease significantly following disease-directed therapy and may reflect disease expansion in Langerhans Cell Histiocytosis.

We aimed to examine the association between relative monocytosis and the recurrence of pulmonary Langerhans Cell Histiocytosis. Clinical, laboratory, radiographic and treatment data for 86 patients with a histopathological diagnosis of Langerhans Cell Histiocytosis over a 20-year duration. Parameters such as biological sex, age at diagnosis, time to diagnosis, molecular diagnostic data and imaging were collected. Treatment responses were assessed predominantly through radiography, with RECIST 1.1 criteria applied to MRI or CT scans and PERCIST utilized for serial PET imaging. Investigators also assessed peripheral blood absolute monocyte count at various time points, including initial diagnosis and the most recently available value. While peripheral blood absolute monocyte count between the earliest assessed timepoint and latest value did not differ, the mean value on progression (0.94 K/µL), however, was significantly higher than that following re-institution of therapy (0.31, p = 0.000794. Our observation of relative monocytosis on LCH disease progression may be related to an increase in circulating LCH on disease progression or from increased monocyte production for later differentiation into mature dendritic cells that participate in MHC Class 1 upregulation. This trend is especially evident in pulmonary LCH which is incited by tissue trauma and irritation by environmental factors. The phenomena observed in our study parallel other non-LCH cohorts, specifically in published findings from our own group in patients with Rosai Dorfman and Erdheim Chester Disease. To further elucidate the molecular underpinnings of LCH and explore the etiology of this monocyte trend, expanded integrated genomic-transcriptomic sequencing analyses to evaluate the molecular character of LCH and ultimately clarify the origin of this monocyte trend are in progress. These studies are poised to offer invaluable insight to the molecular mechanisms underlying LCH, specifically as they pertain to monocyte signaling and differentiation.

Targeted Therapy With Vemurafenib in Brazilian Children With Refractory Langerhans Cell Histiocytosis: Two Case Reports and Review of Literature.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a clonal myeloid neoplasm with inflammatory component. Refractory disease is a challenge, but vemurafenib has emerged as a therapeutic option. We will delineate the cases of two Brazilian children suffering from refractory LCH with a positive response to vemurafenib. CASES: Both cases had a diagnosis of multisystem disease with involvement of organs at risk and had not responded to standard and second-line treatment. After refractoriness to classic treatment regimens, the BRAF mutation was investigated and found to be positive in both patients, and target therapy with vemurafenib was sought. The first case has been using vemurafenib for about 2 years and the second case has been using it for about 3 years, having had an attempt to suspend the medication after concomitant use with maintenance therapy. However, the disease returned 4 months after stopping the medication. Fortunately, the disease returned to remission status after the medication was reintroduced. CONCLUSION: These cases represent the first reported instances of off-label vemurafenib use in Brazil for the treatment of LCH and both patients have demonstrated excellent responses to the medication. However, the long-term side effects are unknown in children, and prospective studies are needed. In addition, there is a lack of epidemiological data on histiocytosis in Brazil and studies evaluating the budgetary impact of incorporating BRAF mutation research and the use of vemurafenib into the public health system. These reports could be a starting point.

Pulmonary involvement in children with Langerhans cell histiocytosis.

BACKGROUND: Pulmonary Langerhans cell histiocytosis (pLCH) is a rare disease, mostly a component of multisystemic LCH. We aimed to investigate the clinical features and treatment results in children with pLCH. METHODS: We retrospectively reviewed the clinical, radiological, and treatment data of 37 patients with pLCH, diagnosed from 1974 to 2022. RESULTS: 10% (n=37) of 367 patients with LCH had lung involvement. The median age was 1.8 years (range: 0.4 & 17.7) with a male-to-female ratio of 2.3. At admission 29.7% (n=11) presented with respiratory symptoms. Imaging showed a spectrum from nodular opacities to multiple cysts. All but one patient had multisystem disease. Twenty-nine received vinblastine-containing therapy. Ten-year event-free (EFS) and overall survival (OS) rates were 47.8% and 63.3%, respectively. In children younger and older than two years of age, the 10-year EFS was 53.3% vs. 40.2% and the 10-year OS was 58.7% vs. 68.8%, respectively. In children with and without risk organ involvement, 10-year EFS was 51.9% vs. 46.3% and 10-year OS was 51.9% vs. 73.7%. CONCLUSIONS: Lung and multisystem involvement are significant concerns in LCH, highlighting the need for careful management to reduce morbidity and mortality.

Pulmonary Langerhans Cell Histiocytosis: Diagnosis in Bronchoalveolar Lavage Liquid-Based Cytology Samples.

INTRODUCTION: Pulmonary Langerhans cell histiocytosis (PLCH) is a rare interstitial lung disease characterized by the accumulation of Langerhans cells within the lung tissue. The diagnosis of PLCH traditionally involves clinical, radiological, and lung biopsy histopathological evaluations. CASE PRESENTATION: We present 2 cases where the diagnosis of PLCH was confirmed through the analysis of bronchoalveolar lavage (BAL) fluid cytology using immunoperoxidase technique, highlighting the significance of this minimally invasive technique in the diagnostic process. Clinical and radiological examination suggested advanced interstitial lung disease characterized by a fibrocystic pattern in both cases. The cytologic analysis of the BAL fluid revealed typical histiocytes with longitudinal grooves and eosinophils, which was better seen on liquid-based cytology (LBC) smears. ICC with CD1a, Langerin, and S-100 confirmed the diagnosis of PLCH. CONCLUSION: Detecting PLCH through the examination of BAL cytology poses challenges, yet it is achievable, particularly with the assistance of LBC and ICC.

Liver involvement with Langerhans cell histiocytosis in adults.

BACKGROUND AND AIMS: Liver involvement portends poor prognosis in adults. We aimed to characterize the clinical features, liver function tests, radiologic findings, molecular profiles, therapeutic approaches and outcomes of adults patients with Langerhans cell histiocytosis (LCH) with liver involvement. METHODS: We conducted a retrospective analysis of all adults with LCH (≥ 18 years) seen at Peking Union Medical College Hospital (Beijing, China) between January 2001 and December 2022. RESULTS: Among the 445 newly diagnosed adults with LCH, 90 patients had liver involvement at diagnosis and 22 patients at relapse. The median age was 32 years (range, 18-66 years). Of 112 evaluable patients, 108 had full liver function testing, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), and total bilirubin and albumin. Elevated ALP was seen in 63.0% and GGT in 86.1%; 14.8% had elevated bilirubin. Next-generation sequencing of 54 patients revealed frequent BRAFN486_P490 (29.6%), BRAFV600E (18.5%), and MAP2K1 (14.8%). OUTCOMES: After a median 40 months' follow-up (range 1-168 months), 3-year progression-free survival (PFS) and overall survival were 49.7% and 86.6% respectively. In multivariable analyses, ≥3 abnormal liver function tests (HR 3.384, 95% CI 1.550-7.388, P = .002) associated with inferior PFS; immunomodulatory drug therapy (HR 0.073, 95% CI, 0.010-0.541, P = .010) correlated with superior PFS versus chemotherapy. CONCLUSIONS: In summary, elevated GGT and ALP were common in adults with LCH liver involvement. Greater than equal to 3 abnormal liver function tests predicted poor outcomes. Immunomodulatory drug therapy was associated with favorable progression-free survival compared to chemotherapy.

Case report: Uncommon manifestations of Rosai-Dorfman disease in the liver mimicking HCC.

Rosai-Dorfman-Destombes disease (RDD) is a rare non-Langerhans cell histiocytosis (LCH) disorder characterized by systemic extranodal lesions. Common cases include skin lesions, whereas liver lesions are rare. This study presents a case of a 66-year-old woman with a solitary extranodal liver lesion who underwent successful surgical treatment followed by glucocorticoid therapy. The patient did not experience any symptoms before surgery. The liver lesion was incidentally discovered during a routine ultrasound examination. Enhanced CT scan revealed the lesion with the characteristic of washout, similar to primary hepatic cancer (HCC). CT scans of the head, neck, chest, and abdominal pelvis revealed no lymph node or other organ lesions. After surgery, the liver lesion was diagnosed as RDD, and subsequent whole-body examinations did not reveal any skin lesions. The definitive diagnosis was solid liver RDD in adults. Although there were no typical cases of bilateral cervical lymph node lesions, ultrasound and CT examinations promptly detected liver lesions, leading to the correct diagnosis through surgical resection. The findings from this case indicate that RDD can occur in rare extrasegmental areas, and the imaging characteristics of liver lesions are not specific, indicating the importance of avoiding delayed diagnosis.

A challenging diagnosis of Langerhans' cell histiocytosis with hypothalamic-pituitary and mandibular involvement: case report and literature review.

Background: Langerhans cell histiocytosis (LCH) is a rare bone marrow derived neoplasm that mainly affects children. It is a multiorgan disorder and hypothalamic-pituitary involvement is uncommon. LCH reveals a wide spectrum of indications; thus, the diagnosis and treatment are usually challenging. Case Report: A 22-year-old male presented with polydipsia, polyuria with nonspecific radiological findings, later on, developed a mandibular lesion and a biopsy was conducted which led to LCH diagnosis. After many improper treatments due to unclear diagnosis, the patient was finally placed on chemotherapy and is now under surveillance. Discussion: LCH is a rare disease with diverse clinical manifestations affecting various organs. Associated mutations, such as BRAF V600E, contribute to its complexity. In adults, initial symptoms include pain, weight loss, and fever, with potential pituitary involvement leading to Arginine vasopressin (AVP) deficiency. Commonly affected organs include bone, skin, and the pituitary gland. The disease can be categorized into single-system and multisystem. Pathological diagnosis involves electron microscopy or immunohistochemical staining. Treatment options vary; the presented case utilized Desmopressin acetate and prednisolone before transitioning to cyclophosphamide for multisystemic LCH. Conclusion: AVP deficiency can suggest hypothalamic-pituitary LCH, and a biopsy, if possible, is recommended to confirm the diagnosis.

Cladribine Use in Xanthoma Disseminatum: A Rare Case Presentation and Brief Updated Literature Review.

Xanthoma disseminatum (XD) is a rare, non-Langerhans cell histiocytosis. While treatment is notoriously difficult, 2-chlorodeoxyadenosine (cladribine) has recently emerged as a potential effective therapeutic option. Here, we describe the case of a 65-year-old male with XD who experienced significant cutaneous improvement after cladribine treatment. We also provide an updated literature review on cladribine use in patients with XD in light of reported adverse effects (AEs). While the efficacy of cladribine in XD is clear, no consensus exists for treatment duration and AE management. Hence, we strongly encourage interdisciplinary discourse involving dermatology and oncology in these cases.

Potential indication of chemotherapy for hypodipsia and arginine vasopressin deficiency secondary to hypothalamic-pituitary Langerhans cell histiocytosis: a case report and literature review.

Hypothalamic-pituitary Langerhans cell histiocytosis (HP-LCH) is often associated with arginine vasopressin deficiency (AVD). Patients with AVD caused by HP-LCH rarely develop an impaired osmotic threshold for thirst (OTT). Improvement in OTT among such patients has not been reported in the literature. To our knowledge, here we report the first case of AVD due to HP-LCH in which hypodipsia resolved during chemotherapy. A nine-year-old Japanese girl presented with polydipsia, polyuria, anorexia, and hypernatremia (149.8 mEq/L) and was diagnosed with AVD secondary to HP-LCH. Visual analog scale examination showed a reduced OTT following the water deprivation test. During chemotherapy for Langerhans cell histiocytosis (LCH), serum sodium concentrations became stable between 138.9 and 142.9 mEq/L under the replacement of desmopressin. Repeated visual analog scale examinations showed that she experienced a sense of thirst at a serum sodium concentration of 142.3-144.6 mEq/L, at which she did not experience any thirst prior to the initiation of chemotherapy. These data suggest that chemotherapy directly improved the OTT in our patient. Improved mechanical compression or infiltration of the hypothalamus related to OTT may lead to the recovery of the sense of thirst. This report highlights the potential role of chemotherapy for solitary HP-LCH in patients with hypodipsia and AVD.

Living-donor lobar lung transplantation for pulmonary Langerhans cell histiocytosis complicated by extensive thrombi in central pulmonary arteries.

BACKGROUND: Pulmonary Langerhans cell histiocytosis (PLCH) is a rare disorder characterized by the proliferation of Langerhans cells along the small airways, which causes nodular and cystic changes in the lung parenchyma. Lung transplantation can be a life-saving option for patients with severe respiratory failure or pulmonary hypertension. Herein, we present a case of successful lung transplantation in a patient with PLCH who developed unusually large thrombi in the central pulmonary artery. CASE PRESENTATION: A 47-year-old woman with 16-year history of PLCH with rapidly developing respiratory failure was admitted to our hospital for the evaluation of a lung transplant. Enhanced computed tomography revealed large thrombi in dilated central pulmonary arteries. Right heart catheterization revealed severe pulmonary hypertension, with a mean pulmonary artery pressure of 48 mmHg. The thrombi shrank markedly after 3 months of anticoagulation therapy. However, the respiratory status of the patient did not improve. We performed bilateral living-donor lobar lung transplantation with thrombectomy under extracorporeal membrane oxygenation for the remaining thrombi in the main pulmonary arteries. The dilated main pulmonary arteries of the recipient required direct plication for size mismatch. The patient survived in good condition for more than 2 years with no recurrence of thrombosis. CONCLUSION: Preoperative anticoagulation therapy for massive thrombi in the pulmonary arteries was effective and led to safe lung transplantation.

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.

Multisystemic recurrent Langerhans cell histiocytosis misdiagnosed with chronic inflammation at the first diagnosis: A case report.

BACKGROUND: Langerhans cell histiocytosis (LCH) is characterized by diabetes insipidus and is an uncommon occurrence. Pathological biopsies still have a certain degree of diagnostic probability. We present a case in which LCH initially affected the pituitary gland. This resulted in a misdiagnosis of chronic inflammation upon pathological examination. CASE SUMMARY: A 25-year-old female exhibited symptoms of diabetes insipidus. Magnetic resonance imaging revealed an enhanced foci in the pituitary gland. After surgical resection of the pituitary lesion, the pathological diagnosis was chronic inflammation. However, the patient later experienced bone destruction in the skull and lower limb bones. After the lower limb bone lesion was compared with the initial pituitary lesion, the final diagnosis was modified to LCH. The patient was treated with multiple chemotherapy courses. However, the patient's condition gradually worsened, and she eventually passed away at home. CONCLUSION: LCH should be considered when patients exhibit diabetes insipidus and absence of high signal intensity in the pituitary gland on sagittal T1-weighted image and abnormal enhancement in the pituitary region.