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.

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.

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.

Elevated Serum Lactate in Patients With Lymphoma: It Is Not Always Infection.

OBJECTIVE: To distinguish between sepsis only vs progressive lymphoma in patients with a history of lymphoma who present to the hospital with lactic acidosis. PATIENTS AND METHODS: We identified patients with non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma from January 2014 to December 2015. Patients were categorized into 2 groups: sepsis only or progressive lymphoma. Two-sided Wilcoxon rank sum test and χ1/Fisher exact test were used to compare the continuous and categorical variables, respectively. Kaplan-Meier analysis was used to estimate overall survival (OS). RESULTS: A total of 51 patients were identified; 33 (65%) patients were categorized into the sepsis only group, and 18 (35%), into the progressive lymphoma group. Values for serum lactate dehydrogenase (LDH) drawn during hospitalization were statistically different between the sepsis only and progressive lymphoma groups (median, 262 vs 665 U/L; P=.005), respectively. The sensitivity and specificity of serum LDH level 2 or more times the upper limit of normal for progressive lymphoma were 56% (95% CI, 33% to 79%) and 85% (95% CI, 73% to 97%), respectively. Serum LDH level was independently predictive of inferior OS (hazard ratio, 27.8; 95% CI, 4.0 to 160.1; P<.001), while serum albumin level (hazard ratio, 0.05; 95% CI, 0.01 to 0.27; P<.001) was independently predictive of improved OS. CONCLUSION: Serum LDH levels used in conjunction with serial serum lactate values may be reliable markers to differentiate patients with progressive lymphomatous disease from patients with lymphoma with sepsis only. The LDH levels should be obtained in all patients with lymphoma who present to the hospital with lactic acidosis.