Clinical characteristics, molecular aberrations, treatments, and outcomes of malignant histiocytosis.

Malignant histiocytosis (MH) is an extremely rare neoplasm of the macrophage-dendritic cell lineage. We report the clinical characteristics, molecular aberrations, treatments, and outcomes of patients with MH seen at two referral centers from January 2000 to May 2023. We identified 43 patients with MH, of which 26 had histiocytic sarcoma (MH-H), 9 interdigitating dendritic cell sarcoma (MH-IDC), and 8 Langerhans cell sarcoma (MH-LC). The median age at diagnosis was 61 years (range, 3-83). Thirty-three patients (77%) had multifocal disease, while 10 had unifocal involvement. Tumor specimens from 22 patients (51%) underwent targeted next generation sequencing, and 19 of 22 (86%) had at least one pathogenic mutation, including mutations in MAPK pathway genes (73%). The median overall survival (OS) among the entire cohort was 16 months (95% CI: 8-50). The outcomes of those with multifocal disease were significantly shorter than their unifocal counterpart: median OS of 10 months versus 50 months (p = .07). Patients with risk organ involvement (bone marrow, spleen, or liver) had significantly inferior outcomes. Chemotherapy and surgery were the most common first-line treatments for multifocal and unifocal disease, respectively. While the outcome for patients with multifocal disease was poor, there was a subset of patients who had durable responses to treatment. Our study highlights that MH has heterogeneous clinical presentation, frequent oncogenic mutations, and prognosis, which is strongly tied to disease extent and type of organ involvement.

Extranodal Rosai-Dorfman Disease: a rare presentation involving anterior chest wall in a middle-aged female.

Rosai-Dorfman Disease is a rare benign disorder involving overproduction of immune cells, causing swollen lymph nodes and, in rare cases, the sternum. The sternal involvement may cause chest pain and masses. Diagnosis is confirmed through clinical examination, biopsy, and imaging. Treatment options may include surgery, radiation, or steroids. In this case study, we present an unusual example of extranodal Rosai-Dorfman Disease involving the sternum, bilateral clavicles and first three ribs, and pectoral muscle with no associated lymphadenopathy or systemic symptoms in a 57-year-old female. The etiology, pathology, immunohistochemistry, imaging findings, and treatment options of this unique disease are discussed.

Long-term outcomes among adults with Langerhans cell histiocytosis.

Advances in the treatment of Langerhans cell histiocytosis (LCH) have resulted in a growing survivor population. There is a lack of data on long-term outcomes among adults with LCH. We conducted a retrospective record review of 219 adults (aged ≥18 years) with LCH. Most common presentation was multisystem (34.2%), followed by single-system pulmonary (32%), unifocal (28.3%), and single-system multifocal (5.5%) LCH. Risk organ involvement (the liver, spleen, or bone marrow) was seen in 8.7% of cases, and 40 of 88 (45.5%) tested cases were BRAFV600E. At a median follow-up of 74 months, 5-year progression-free survival (PFS) was 58.3% and estimated median PFS was 83 months. Median overall survival (OS) was not reached; 5- and 10-year OS rates were 88.7% and 74.5%, respectively. Risk organ involvement was associated with worse PFS (hazard ratio [HR], 4.5) and OS (HR, 10.8). BRAFV600E was not associated with risk organ involvement or survival. When compared with matched unaffected US population, individuals with LCH had a significantly higher risk of overall mortality (standardized mortality ratio [SMR], 2.66), specifically among those aged <55 years at diagnosis (SMR, 5.94) and those with multisystem disease (SMR, 4.12). Second cancers occurred in 16.4% cases, including diverse hematologic and solid organ malignancies. LCH-associated deaths constituted 36.1% of deaths and occurred within 5 years of diagnosis. After 5 years, non-LCH causes of death, including second cancers, chronic obstructive pulmonary disease, and cardiovascular diseases, predominated. Our study highlights, to our knowledge, for the first time, that adults with LCH experience early and late mortality from non-LCH causes and the need for development of targeted survivorship programs to improve outcomes.

BRAF V600E is associated with higher incidence of second cancers in adults with Langerhans cell histiocytosis.

In this retrospective study, BRAF mutation status did not correlate with disease extent or (event-free) survival in 156 adults with Langerhans cell histiocytosis. BRAFV600E was associated with an increased incidence of second malignancies, often comprising hematological cancers, which may be clonally related.

Malignant Histiocytosis Comprises a Phenotypic Spectrum That Parallels the Lineage Differentiation of Monocytes, Macrophages, Dendritic Cells, and Langerhans Cells.

Malignant histiocytoses (MHs), or the 'M group' of the Histiocyte Society classification, are characterized by neoplastic histiocytes with large pleomorphic nuclei. MH encompasses the diagnoses of histiocytic sarcoma, interdigitating dendritic cell sarcoma, and Langerhans cell sarcoma. We aimed to define the phenotypic spectrum of MH and examine the genotypic features across this spectrum. Using immunohistochemistry, we arranged the 22 cases into 4 subtypes that correspond to the lines of differentiation from monocytic and dendritic cell precursors as follows: (1) macrophage (n = 5): CD68+, CD163+, CD14+, and Factor 13a+; (2) monocyte-macrophage (n = 5): CD68+, CD163+, CD14+, S100+, and OCT2+; (3) dendritic cell (n = 6): CD68+, CD11c+, S100+, lysozyme+, ZBTB46+, and CD1a/langerin < 5%; and (4) Langerhans cell (n = 6): CD68+, CD11c+, S100+, ZBTB46+, CD1a+, and langerin+. The phenotypic subtypes align with those seen in low-grade histiocytic neoplasms as follows: MH-macrophage type correlates with Erdheim-Chester disease phenotype; MH-monocyte-macrophage type with Rosai-Dorfman disease phenotype, and MH-Langerhans cell type with Langerhans cell histiocytosis. Activating mutations in MAPK-pathway genes were identified in 80% of MH cases; 29% had mutations in the PI3k-AKT-mTOR pathway and 59% had mutations in epigenetic modulating genes. Strong expression of cyclin D1 was present in all cases, whereas p-ERK and p-AKT were not uniformly expressed. Eight of 22 (36%) MH cases were proven to be clonally related to a prior B-cell lymphoma. Defining the phenotypic spectrum of MH provides a guide to diagnosis and allows further exploration into the potential biological and clinical significance.

BRAF testing modalities in histiocytic disorders: Comparative analysis and proposed testing algorithm.

OBJECTIVES: Understanding of histiocytic disorders has been revolutionized by demonstration of mitogen-activated protein kinase (MAPK) pathway mutations, most commonly BRAFV600E. The optimal testing strategy to assess BRAFV600E is unknown. We aimed to compare performance of testing modalities, to propose a framework for evaluation of BRAFV600E mutation status in histiocytic disorders. METHODS: We retrospectively reviewed patients with histiocytic disorders and BRAF mutation testing on a lesional tissue specimen. RESULTS: In 120 patients, BRAF assessment included immunohistochemistry (IHC) in 97 (80.2%), polymerase chain reaction (PCR) in 35 (28.9%), and next-generation sequencing (NGS) in 62 (51.2%). Forty-five underwent both NGS and IHC. With NGS as the gold standard, the sensitivity and specificity of IHC were 82.4% and 96.4%. Three false negatives were observed in biopsy specimens with low BRAFV600E variant allele frequency or decalcified tissue. One false-positive IHC was observed in a lung biopsy specimen, likely due to antibody cross-reactivity with respiratory cilia. Among 14 with successful NGS and PCR, a single discordance was observed. Two PCR-to-IHC discrepancies were observed, including one other false-positive IHC. CONCLUSIONS: Immunohistochemistry was highly specific for detection of BRAFV600E. Main caveats were false negatives and lack of detection of non-BRAFV600E mutations. We propose the use of IHC as initial screening in general practice with reflex molecular testing if negative.

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.

ALK-positive histiocytosis involving the cavernous sinus: A deceptive radiologic mimic of meningioma.

Anaplastic lymphoma kinase (ALK)-positive histiocytosis is an uncommon condition, recently considered a separate condition from other histiocytosis by WHO 5th edition. It can involve intracranial structures. This manuscript describes a case of ALK-positive histiocytosis of the cavernous sinus, focusing on the radiologic and pathologic presentation of the entity. Our case had MRI manifestations mimicking meningioma, metastasis, and Langerhans histiocytosis. On CT imaging, benign osseous remodeling of the cavernous sinus was detected, which can be helpful in differentiating it from more common meningioma.

Neurological Manifestations of Histiocytic Disorders.

PURPOSE OF REVIEW: Histiocytic disorders, including Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease (RDD), are rare neoplasms that may present with a spectrum of neurologic involvement. Diagnostic delay is common due to heterogeneity in presentation and challenging pathology. RECENT FINDINGS: Recent advances in the treatment of these diseases targeted towards mutations in the MAP kinase pathway have led to an improved prognosis in these patients with neurologic involvement. It is critical for clinicians to have a high index of suspicion to allow for early targeted treatment and optimize neurologic outcomes. A systematic approach to diagnosis is presented in this article to allow for accurate diagnosis of these rare diseases.

Overlap of C3 Glomerulopathy and Thrombotic Microangiopathy: A Case Series.

Introduction: Dysregulation of alternative complement pathway underlies the pathogenesis of both C3 glomerulopathy (C3G) and thrombotic microangiopathy (TMA). In this study, we describe both disease entities occurring in 5 patients. Methods: We identified 114 patients at our institution from 2007 to 2016 with C3G in native kidney biopsies and those with concurrent TMA were included. Results: The median age at diagnosis was 58 years (range: 28-69); all were male. Median serum creatinine and proteinuria at presentation were 2.3 mg/dl and 2089 mg/d, respectively. Three cases presented with TMA-predominant phenotype and 2 with C3G-predominant phenotype. Immunofluorescence (IF) showed bright C3 staining in mesangium and/or capillary walls. Electron microscopy showed marked subendothelial expansion by fluffy material in the capillary loops without associated deposits. However, capillary wall deposits were present in other loops in 4 cases. Mesangial deposits were present in all cases. Four cases showed low C3, of which 2 showed low C4. Complement evaluation in 3 cases showed pathogenic CFH mutation in 1 case, and multiple variant of unknown significance along with factor B autoantibody and C4 nephritic factor in 1 case. One patient negative for complement abnormalities had a monoclonal gammopathy. Three cases were treated with steroids and/or immunosuppressants. One case progressed to end-stage renal disease (ESRD) at 38.3 months; the remaining showed median serum creatinine and proteinuria of 2.5 mg/dl and 1169 mg/d, respectively at median follow-up of 17.5 months. Conclusion: Overlap of C3G and TMA is rare and can clinically present as C3G-predominant or TMA-predominant phenotype. The significance of concurrent C3G/TMA findings on long-term renal survival remains to be explored.

Ophthalmologic Involvement in Adults with Histiocytic Disorders: Clinical Presentation and Treatment Outcomes.

PURPOSE: To evaluate the clinical presentation, treatment, and outcomes in adult patients with histiocytic disorders with ocular, orbital, optic nerve, or cavernous sinus involvement. DESIGN: Observational, retrospective chart review. PARTICIPANTS: Adult patients (age ≥ 18 years) at Mayo Clinic from January 1, 1996, to July 1, 2021, with histiocytic disorders. Inclusion criteria were (1) histiocytic disorder by biopsy and appropriate clinical phenotype; (2) available medical records; and (3) ocular, orbital, optic nerve, or cavernous sinus involvement. METHODS: Retrospective chart review. MAIN OUTCOME MEASURES: Response to therapy, measured in clinical and radiographic impact. RESULTS: Thirty-two patients were identified: 7 with Langerhans cell histiocytosis (LCH); 15 with Erdheim-Chester disease (ECD); 1 with mixed LCH/ECD phenotype; 8 with Rosai-Dorfman disease (RDD); and 1 with mixed RDD/ECD phenotype. Ophthalmologic involvement was part of the initial presentation in 69% of patients (22/32). Eyelid edema (13/32, 41%) and proptosis (12/32, 38%) were the most frequent presentations. Isolated orbital or cavernous sinus involvement was present in 3 of 7 patients with LCH and 1 of 8 patients with RDD. Optic nerve sheath involvement was present in 2 of 7 LCH patients, 14 of 15 ECD patients, and 1 RDD/ECD patient. Diffuse (> 75%) orbital involvement was seen in 12 of 15 ECD patients and 1 of 7 LCH patients. Ocular involvement was seen in 1 of 15 ECD patients, 6 of 8 RDD patients, and 1 of 1 mixed RDD/ECD patient. The cavernous sinuses were involved in 1 of 7 LCH patients, 5 of 15 ECD patients, and both mixed phenotype patients. Visual acuity was affected in 14 patients (14/24, 58%) with a median logarithm of the minimum angle of resolution visual acuity of 0.1 (range, -0.12 to 3). BRAF V600E mutations were found in 75% (3/4) of LCH patients and 91% (10/11) of ECD patients. Patients received a variety of treatment, and response was variable across disease types. CONCLUSIONS: Orbital involvement was more commonly seen in LCH and ECD, whereas ocular involvement was more common in RDD. Visual acuity may be impacted from ocular involvement or compression of the optic nerve with diffuse orbital involvement.

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.