Cutaneous Rosai-Dorfman disease: a systematic review and reappraisal of its treatment and prognosis.

Cutaneous Rosai Dorfman disease (CRDD) is a rare histiocytic disorder that shows distinctive clinical presentation and prognosis. Sufficient data is currently lacking regarding evidence-based management of CRDD. This systematic review aims to provide a comprehensive overview of CRDD, focusing on treatment approaches and outcomes. PubMed and Scopus databases were searched for studies on CRDD from June 1st, 2013 to May 31st, 2023. Articles describing cases of CRDD confirmed with histological examination were eligible for inclusion. All interventions for CRDD were analyzed. The primary outcome measure was the response of cutaneous lesions to treatment including complete response (CR), partial response (PR), and no response. The secondary outcome measures were mortality rate, relapse rate, and the occurrence of adverse events related to CRDD treatment. Eighty-seven articles describing 118 CRDD cases were included. The mean age was 48.2±16.8 years. The sex ratio (F/M) was 1.53. Nodular (46.6%) erythematous (45.3%) lesions, located on the face (38.1%) were the most prevalent presentations. Associated hematological malignancies were noted in 8 (6.8%) cases. Surgical excision was the most prevalent intervention (51 cases) with CR in 48 cases. Systemic corticosteroids were used in 32 cases with 20 CR/PR, retinoids in 10 cases with 4 CR/PR, thalidomide in 9 cases with 5 CR/PR, methotrexate in 8 cases with 7 CR/PR while observation was decided in 10 cases with 6 CR/PR. Factors independently associated with the absence of response to treatment were facial involvement (OR = 0.76, p = 0.014), and cutaneous lesion size (OR = 1.016, p = 0.03). This systematic review shows distinctive clinical characteristics of CRDD and provides insights into the appropriate management of the disease. It allowed a proposal of a treatment algorithm that should be interpreted in the context of current evidence and would help practitioners in treating this rare disease.

Investigating the correlation between small molecular inhibitor utilization, peripheral blood monocytes, and treatment outcomes in Rosai Dorfman disease.

Rosai Dorfman disease (RDD) is a non-Langerhans cell histiocytic neoplasm characterized by sinus histiocytosis with variable emperipolesis. There is a limited understanding of the factors that contribute to disease progression. Traditional management of RDD consists of local therapies (resection, radiation) for localized disease and myelosuppression for systemic disease; targeted medications have also recently been introduced into clinical practice as an additional therapeutic modality. The goals of this study are to compare the impact of targeted therapies to conventional management of RDD and identify trends in laboratory data that may provide insight into disease progression. A retrospective analysis was conducted at a single institution over a 20-year period in 35 adult patients with histopathologic evidence of RDD without confounding secondary malignancies. Clinical data points included laboratory evaluation, molecular diagnostics, imaging, and therapies rendered. Binary data was utilized for statistical analysis and comparison of outcomes by treatment type and utilization of targeted agents. Evaluation of treatment response varied based on anatomic disease sites and baseline imaging modality. To standardize the radiographic analysis, we included PERCIST (if PET was utilized) or RECIST assessments (in the cases of CT or MR imaging). Conventional therapies rendered included local treatment (surgery, radiation, intralesional injections), systemic corticosteroids, immunotherapy, and chemotherapy while targeted agents included only small molecule inhibitors. In this analysis, primary disease was identified in cutaneous, osseous, and CNS structures (17, 11, and 6/35 patients respectively). Management consisted of surgery (12/35 patients), steroid and myelosuppressive therapies (9/35 each), immunotherapy (5/35), and targeted molecular agents (5/35). In evaluating outcomes, the proportion of partial responses was substantially higher in recipients of molecular as compared to conventional therapy (4/5 patients compared to 6/29) while complete responses were more common in the conventional therapy cohort (12/29 compared to 1/5). Lastly, an evaluation of peripheral blood absolute monocytes in all patients who had progressed on therapy identified a significant decrease in pre-progression values as compared to values following therapy re-institution (averages of 0.70 and 0.27 K/µL, respectively; p = 0.0002, 95% CI 0.652-0.2360). Larger-scale studies are needed to further evaluate the relevance of the monocyte trends that were identified in terms of their relationship to disease status. This study is the largest analysis of Rosai Dorfman disease, that we are aware of, from a single institution. In this cohort, the utilization of small molecule inhibitors corresponded to a greater increase in partial responses than conventional therapies, although the opposite effect has been observed in complete responses. This finding can be attributed to the recent introduction of targeted agents and shorter follow-up. We anticipate higher complete response rates with the use of small molecule in ongoing analyses over a longer follow-up period. The recognition of relative monocyte elevation prior to disease progression is an intriguing and to our knowledge, novel finding in the field of Rosai Dorfman disease. Future studies aimed at elucidating the implications of this trend are in progress.

Treatment of cutaneous Rosai-Dorfman disease with ALA-PDT combined with low-dose oral corticosteroids: A case report.

Cutaneous Rosai-Dorfman Disease (CRDD), a rare form of Rosai-Dorfman Disease (RDD), lacks established treatment guidelines. In this case report, we detailed a successful case of CRDD management in a 50-year-old woman with facial lesions. Our treatment included 5-aminolevulinic acid photodynamic therapy (ALA-PDT) and low-dose oral corticosteroids. Remarkable improvement was evident after six ALA-PDT courses, and a one-year follow-up confirmed sustained remission. This case highlights the potential of combining ALA-PDT with low-dose corticosteroids as a promising therapeutic strategy for CRDD. Further research is necessary to fully elucidate its mechanisms and effectiveness.

Rosai-Dorfman Disease in a Pediatric Patient: Imaging Findings and Pathology with a brief review of the Literature.

Rosai-Dorfman Disease, otherwise known as sinus histiocytosis with massive lymphadenopathy, is a rare form of non-Langerhans cell histiocytosis with an estimated incidence of 100 cases per year in the United States. Due to its variable presentation and nonspecific clinical findings, it is particularly difficult to diagnose in pediatric patients. We report a case of an 11-month-old male who presented with a 4-day history of a right groin mass. Ultrasound of the groin and pelvis demonstrated, and MRI of the abdomen and pelvis confirmed an inguinal mass with surrounding lymphadenopathy. Pathology confirmed Rosai-Dorfman Disease and the patient improved after starting oral steroid therapy. To the best of our knowledge, this is the first case of Rosai-Dorfman Disease involving the inguinal region in an infant under 1 year of age reported in the literature. In this case report, we discuss the imaging and histology findings as well as provide a brief literature review for this diagnosis.

Fractional laser combined with 5-Aminolevulinic acid photodynamic therapy for the treatment of Cutaneous Rosai-Dorfman Disease: A case report.

Rosai-Dorfman disease(RDD) is a rare benign histiocytic proliferative disorder. Cutaneous Rosai-Dorfman disease(CRDD)is a rare variant of RDD with lesions localized to the skin. We report a case of patients with CRDD who was refractory to methotrexate, thalidomide, cyclosporine, glucocorticoid for local injection and external use, but resolved with fractional laser combined with 5-aminolevulinic acid photodynamic therapy (ALA-PDT). We believe that fractional laser technology combined with ALA-PDT for CRDD is a minimally invasive, effective and satisfactory treatment.

How I Diagnose Rosai-Dorfman Disease.

OBJECTIVES: Rosai-Dorfman disease (RDD) is one of 3 major types of histiocytosis, along with Erdheim-Chester disease and Langerhans cell histiocytosis. While historically, RDD was considered a benign self-limited condition, current data show MAPK/ERK pathway mutations in 30% to 50% of cases, indicative of a clonal process. Rosai-Dorfman disease was incorporated as a histiocytic neoplasm in the fifth edition of the World Health Organization classification of hematopoietic tumors and the International Consensus Classification. METHODS: We discuss the diagnosis of RDD using 2 illustrative cases, interpretative challenges, and a diagnostic algorithm. RESULTS: Rosai-Dorfman disease involves nodal and extranodal sites, including skin, sinuses, salivary gland, orbit, central nervous system, kidney, and bone. In a subset, RDD can coexist with other neoplasms (lymphomas, other histiocytosis) or autoimmune disease. Morphologically, RDD histiocytes are characterized by enlarged round to oval nuclei, distinct nucleoli, and voluminous cytoplasm with engulfment of inflammatory cells (emperipolesis). By immunohistochemistry, they express CD68, CD163 (majority), S100, OCT2, and cyclin D1. Appropriate use of ancillary studies is important to support the diagnosis of RDD while excluding other histiocytic neoplasms and reactive histiocytic proliferations. CONCLUSIONS: Management of RDD is dependent on the extent of organ involvement and clinical symptoms. In patients who require therapy, next-generation sequencing is recommended to identify MAPK/ERK pathway mutations for targeted therapy.

Erdheim-Chester disease with Rosai-Dorfman-like lesions: treatment with methotrexate, anakinra and upadacitinib.

Erdheim-Chester disease (ECD) is a non-Langerhans cell histiocytosis characterised by clonal expansion of histiocytes in various organs. These induce an inflammatory environment, which leads to damage of the affected areas. Recently, a new disease entity was proposed encompassing key features of ECD but also of Rosai-Dorfman-Destombes disease, another histiocytosis. Mitogen-activated protein kinase kinase 1 (MAP2K1) mutations seem to present a specific genetic lesion for this subtype.Here, we describe a case of this new disease entity with clinical, radiological and genetic findings compatible with ECD but histological findings compatible with Rosai-Dorfman-Destombes disease. In particular, there were intraabdominal and retroperitoneal lesions, which tested positive for a (c.167A>C; p.Q56P) mutation of the MAP2K1 gene. On histological examination, S100-positive, giant histiocytes with focal emperipolesis of haematological cells in addition to infiltration by lymphocytes and granulocytes were seen.As described for this rare variant of ECD, there was also bilateral testicular infiltration. We also describe a manifestation of oligoarthritis in this patient with ECD.The patient was treated with methotrexate and prednisolone. While radiological response to this regime was excellent, arthritis persisted. We added anakinra, which induced a response of the arthritis for more than a year. Due to treatment failure therapy was switched to upadacitinib, which induced a remission of the arthritis as well.This case adds a rare phenotype to an already rare presentation of ECD. The patient responded to immunosuppressive therapy.

Coexistent Rosai Dorfman disease and Langerhans cell histiocytosis in an Orbital mass: A Case Report.

INTRODUCTION: Rosai Dorfman disease (RDD) is a rare benign histiocytic proliferative disorder of lymph node sinuses. Langerhans cell histiocytosis (LCH) is a solitary or multisystem clonal proliferation of abnormal dendritic cells (Langerhans cells) with varied presentations. The co-occurrence of these two entities is quite rare. CASE DESCRIPTION: A six-year-old boy presented with multiple mass lesions in the neck since two years and a nodular lesion in right upper eyelid for the past 4 months. He was diagnosed with tubercular lymphadenitis 2 years back, and was given a course of anti-tubercular therapy (ATT) elsewhere. No improvement was seen. Fine needle aspiration cytology (FNAC) of the cervical lymph nodes revealed reactive lymphadenitis while lymph node biopsy showed features of RDD. Excision biopsy of the orbital mass showed features of both RDD and LCH. The patient was started on tablet prednisolone. Six months later, complete resolution of lymph node enlargement and remaining orbital mass was noted. Post operative contrast enhanced Magnetic Resonance Imaging of head and neck was normal. CONCLUSION: The coexistence of RDD and LCH may be a result of divergent differentiation from a common lineage or a de novo phenotypic evolution.

Outcomes After Treatment With Cobimetinib in Patients With Rosai-Dorfman Disease Based on KRAS and MEK Alteration Status.

Importance: Rosai-Dorfman disease (RDD) is a rare histiocytic neoplasm with recent studies showing alterations in the MAPK pathway, most commonly in the KRAS and MEK genes in about 40% of patients. Reports on the use of MEK-inhibitor therapy in RDD have been limited to small case studies. There are no approved treatments for this neoplasm, and therefore patients with RDD need efficacious treatments. Objective: To study the outcomes after treatment with cobimetinib based on MAPK pathway alterations in patients with RDD. Design, Setting, and Participants: This retrospective cohort study conducted at 2 tertiary care centers included patients with RDD who underwent treatment with cobimetinib between January 1, 2013, and December 1, 2021. Cobimetinib was administered at a dosage of 20 to 60 mg orally once daily as a single agent for 21 days in a 28-day cycle. Pathology was centrally reviewed. Response assessment was centrally conducted and was based on the established positron emission radiography response criteria used for clinical trials of targeted therapies in histiocytosis. Main Outcomes and Measures: Main outcomes were overall response rate (ORR), progression-free survival (PFS), adverse events (AEs) of cobimetinib in the entire cohort, and ORRs and PFS based on MAPK pathway alterations in patients with RDD. Results: A total of 16 patients (median [range] age at cobimetinib initiation, 57 [31-74] years; 11 [69%] women) were included in the study. The median follow-up duration was 19.0 months (95% CI, 8.4-27.8 months). The ORR was 63% (n = 10), including 5 complete responses and 5 partial responses. Somatic alterations in the KRAS or MEK genes were detected in 8 (50%) patients. Patients with KRAS or MEK alterations had significantly higher ORR (88% vs 38%; P = .03), deeper responses (complete responses among responders: 71% vs 0%; P = .002), and better PFS (at 1 year, 100% vs 29% were free from progression or death, respectively; P < .001) compared with those without such alterations. Grade 2 or higher AEs occurred in 12 (75%) patients, and 9 (56%) required dose reduction or temporary/permanent treatment discontinuation due to AEs. Conclusions and Relevance: In this cohort study, treatment with cobimetinib was associated with positive outcomes in KRAS- or MEK-variant RDD. However, AEs requiring dose modifications were common.

Intermediate-dose cytarabine is an effective therapy for adults with non-Langerhans cell histiocytosis.

BACKGROUND: Non-Langerhans cell histiocytosis, including Erdheim-Chester disease (ECD), Rosai-Dorfman disease (RDD), indeterminate cell histiocytosis (ICH), and unclassified histiocytosis, is a rare disorder lacking a standard treatment strategy. We report our experience using intermediate-dose cytarabine as the first or subsequent therapy in non-Langerhans cell histiocytosis. RESULTS: Nine ECD patients, 5 RDD patients, 1 ICH patient and 1 unclassified histiocytosis patient were enrolled. Intermediate-dose cytarabine therapy was administered as 0.5-1.0 g/m2 of intravenous cytarabine every 12 h for 3 days every 5 weeks. The median age at cytarabine initiation was 47.5 years (range 18-70 years). The median number of cycles of cytarabine administered was 5.5 (range 2-6). The overall response rate (ORR) was 87.5% in the overall cohort, including 12.5% with complete response and 75.0% with partial response. One patient experienced disease recurrence 19 months after cytarabine therapy. The median follow-up duration for the entire cohort was 15.5 months (range 6-68 months). The estimated 2-year progression-free survival and overall survival rates were 85.6% and 92.3%, respectively. The most common toxicity was haematological adverse events, including grade 4 neutropenia and grade 3-4 thrombocytopenia. No treatment-related deaths occurred. CONCLUSIONS: Intermediate-dose cytarabine is an efficient treatment option for non-Langerhans cell histiocytosis patients, especially for those with CNS involvement.

Long-term Management of Panuveitis and Choroidal Mass Associated with Rosai Dorfman Disease with Pegylated Interferon.

PURPOSE: To present a patient with Rosai-Dorfman Disease (RDD), a histiocytic proliferative disorder typified by lymphadenopathy with rare ocular manifestations, who developed panuveitis that responded to pegylated interferon. METHODS: Descriptive case report of a patient with RDD with multi-organ involvement including ocular manifestations including bilateral panuveitis with choroidal masses. RESULTS: A 54-year-old African American woman with known systemic RDD of the breast, lung, and gastrointestinal tract presented with panuveitis with choroidal masses in both eyes. Her systemic and ocular disease initially responded well to oral and topical steroid therapy. Later, however, her systemic disease progressed with multiple muscular and bony lesions. Systemic therapy was switched to pegylated interferon, a cytokine with antiviral, antitumor and immunomodulatory activity. After 14 months of therapy with pegylated interferon, the patient's systemic and ocular disease stabilized. CONCLUSION: Rosai-Dorfman disease may be complicated by panuveitis and choroidal masses that may respond to pegylated interferon with stabilization of systemic and ocular manifestations. A multi-disciplinary approach is essential given the unique diagnostic and management challenges of RDD.

Thalidomide as treatment of refractory thoracic Rosai-Dorfman disease.

WHAT IS KNOWN AND OBJECTIVE: Rosai-Dorfman disease (RDD) is an infrequent entity of unknown aetiology. Currently, there is no clear consensus on the treatment, and nothing has shown definitive safety and efficacy. We describe the case of a woman diagnosed with pulmonary RDD, who responded to thalidomide treatment after failure of four previous lines of systemic chemotherapy. CASE DESCRIPTION: We present the case of a 74-year-old woman diagnosed with pulmonary RDD and autoimmune complications. We decided to use thalidomide as a rescue treatment after the failure of corticosteroids and several chemotherapies. Our patient achieved remission of the disease and remained stable for years. WHAT IS NEW AND CONCLUSION: To the authors' knowledge, this is the first reported case in which thalidomide treatment induced remission in refractory pulmonary RDD. Thalidomide showed a rapid onset of action, with lasting responses, which could make it an exciting option for treating this life-threatening.

5-Aminolevulinic acid photodynamic therapy combined with CO2 laser therapy for the treatment of cutaneous Rosai-Dorfman disease: A case report.

We report the case of a patient diagnosed with cutaneous Rosai-Dorfman disease (CRDD) who was treated successfully with 5-aminolevulinic acid photodynamic therapy (ALA-PDT) combined with carbon dioxide (CO2) laser therapy. CRDD is a rare form of Rosai-Dorfman disease that has various clinical presentations and multiple possible therapies with varying efficacies. ALA-PDT combined with CO2 laser therapy was safe and effective for treating CRDD in the current patient, with no recurrence during the 3 months of follow-up medical examinations. This case suggests that ALA-PDT combined with CO2 laser can be used to treat patients with CRDD.

Histiocytic Neoplasms, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Histiocytic neoplasms are rare hematologic disorders accounting for less than 1% of cancers of the soft tissue and lymph nodes. Clinical presentation and prognosis of these disorders can be highly variable, leading to challenges for diagnosis and optimal management of these patients. Treatment often consists of systemic therapy, and recent studies support use of targeted therapies for patients with these disorders. Observation ("watch and wait") may be sufficient for select patients with mild disease. These NCCN Guidelines for Histiocytic Neoplasms include recommendations for diagnosis and treatment of adults with the most common histiocytic disorders: Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease.

Regression of Intraocular Rosai- Dorfman Disease Following Treatment with Photodynamic Therapy.

Rosai-Dorfman disease (RDD), a rare form of histiocytosis, has been reported to cause choroidal masses and subsequent serous retinal detachments. We present a case of RDD associated with a choroidal mass and retinal detachment that did not respond to corticosteroid treatment and regressed after treatment with photodynamic therapy (PDT). Following treatment, the patient had a successful anatomic and clinical outcome, with no recurrence of serous detachment and 20/25 visual acuity. This is the first report of choroidal RDD successfully treated with PDT. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:568-571.].