Molecular Profiling of Tumor Tissue and Plasma Cell-Free DNA from Patients with Non-Langerhans Cell Histiocytosis.

The BRAF V600E mutation and BRAF inhibitor responsiveness characterize ∼50% of patients with the non-Langerhans cell histiocytosis (non-LCH) Erdheim-Chester disease (ECD). We interrogated the non-LCH molecular landscape [ECD, n = 35; Rosai-Dorfman disease (RDD), n = 3; mixed ECD/RDD, n = 1] using BRAF V600E PCR and/or next-generation sequencing [tissue and cell-free DNA (cfDNA) of plasma and/or urine]. Of 34 evaluable patients, 17 (50%) had the BRAF V600E mutation. Of 31 patients evaluable for non-BRAF V600E alterations, 18 (58%) had ≥1 alteration and 12 putative non-BRAF V600E MAPK pathway alterations: atypical BRAF mutation; GNAS, MAP2K1, MAP2K2, NF1, and RAS mutations; RAF1 or ERBB2 amplifications; LMNA-NTRK1 (TRK inhibitor-sensitive) and CAPZA2-BRAF fusions. Four patients had JAK2, MPL ASXL1, U2AF1 alterations, which can correlate with myeloid neoplasms, a known ECD predisposition, and one developed myelofibrosis 13 months after cfDNA testing. Therefore, our multimodal comprehensive genomics reveals clinically relevant alterations and suggests that MAPK activation is a hallmark of non-LCH.

A case of rosai-dorfman disease with highly elevated serum ferritin.

Sinus histiocytosis with massive lymphadenopathy, also known as Rosai-Dorfman disease is a rare disorder characterized by proliferation of distinctive histiocytes within lymph node sinuses and lymphatics, sometimes involving extranodal sites. However, clinical suspicion is difficult and there is also a lack of useful diagnostic markers for this disorder prior to histological confirmation. High elevation of serum ferritin is known to be a useful diagnostic marker for various hematologic diseases, including hemophagocytic lymphohistiocytosis and lymphoma. Here, we report a case of fever of unknown origin that presented along with highly elevated serum ferritin (5,780 ng/mL), and was finally diagnosed as Rosai-Dorfman disease by lymph node biopsy.

Fever of unknown origin (FUO) due to Rosai-Dorfman disease with mediastinal adenopathy mimicking lymphoma: diagnostic importance of elevated serum ferritin levels and polyclonal gammopathy.

Fever of unknown origin (FUO) characterizes febrile disorders that are accompanied by prolonged fevers of 101 degrees F or greater for 3 weeks or more that remain undiagnosed after comprehensive inpatient and outpatient diagnostic testing. At the present time, malignancies are the most common cause of FUOs. Among malignant FUOs, lymphomas are the most common. We present the case of a non-Asian young adult man who presented with FUO. He had no peripheral adenopathy or splenomegaly but was found to have anterior/superior mediastinal adenopathy and right paratracheal adenopathy. His diagnostic workup was negative for rheumatic/inflammatory and infectious diseases. Laboratory test results were unremarkable except for a highly elevated erythrocyte sedimentation rate and highly elevated serum ferritin level. Otherwise unexplained highly elevated serum ferritin levels in patients with FUOs suggest rheumatic and inflammatory disorders, for example, systemic lupus erythematosus flare or malignancy. The findings of mediastinal adenopathy combined with a highly elevated ESR and highly elevated serum ferritin levels indicate lymphoma as the most likely diagnosis. He also had polyclonal gammopathy on serum protein electrophoresis (SPEP). In a patient with FUO, negative blood cultures, and a heart murmur, polyclonal gammopathy on SPEP suggests atrial myxoma. Lymphomas are often associated with elevated alpha(1)/alpha(2) globulins on SPEP. Lymph node biopsy of the mediastinal nodes was negative for lymphoma but did not show characteristic emperiopolesis, pathognomonic of Rosai-Dorfman disease, a benign lymphoproliferative disorder. Rosai-Dorfman disease usually presents with massive bilateral cervical adenopathy but may present with lymph node involvement in other sites, as in this case. In patients with lymphadenopathy and a negative FUO workup, clinicians should consider the possibility of Rosai-Dorfman disease, particularly if accompanied by an otherwise unexplained highly elevated serum ferritin levels and polyclonal gammopathy on SPEP.

Dramatic clinical efficacy of cladribine in Rosai-Dorfman disease and evolution of the cytokine profile: towards a new therapeutic approach.

Rosai-Dorfman disease (RDD) is a rare disorder, often benign but with possible life-threatening prognosis. In most cases, specific treatment is not necessary; when required, the management of RDD is not codified to date, and various chemotherapies have been shown to be ineffective. Here, we report a patient with RDD who presented a dramatic and sustained response with cladribine. Analysis of the cytokine profile evolution shows a clear correlation between serum levels of TNF-alpha and IL-6 and disease activity. Our findings show the promising efficacy of cladribine and suggest that therapies targeting specifically cytokines might be useful in some cases of active RDD.

Cutaneous Destombes-Rosai-Dorfman disease: absence of detection of HHV-6 and HHV-8 in skin.

BACKGROUND: We report three new cases of cutaneous Destombes-Rosai-Dorfman disease (DRDD). Two were skin-limited, and one was associated with systemic involvement. In all cases typical large S100 positive macrophages with emperipolesis were present, but different patterns were seen. A viral etiology has long been suspected in DRDD. METHODS: Thus, all cases were investigated for presence of HHV-6 major capsid protein gene by polymerase chain reaction (PCR), and for presence of HHV-8 latency-associated nuclear antigen 1 by immunohistochemistry. RESULTS: All results were negative. HHV-6 antibody tests were positive for IgG but not for IgM in one case. With regard to HHV-6, previous studies supplied inconclusive results while, to our knowledge, HHV-8 has never been investigated in DRDD. CONCLUSION: This study suggests that HHV-8 is not involved in the pathogenesis of cutaneous DRDD. However, this should be confirmed by further studies. We can postulate three hypotheses in regard to HHV-6 role in DRDD pathogenesis: 1) its presence in lesionnal tissues is fortuitous, 2) HHV-6 plays a role in promoting more aggressive diseases and 3) various causes, including HHV-6, are implicated in the pathogenesis of DRDD.

Sinus histiocytosis with massive lymphadenopathy.

Sinus histiocytosis with massive lymphadenopathy is a well recognised, but rare cause of lymphadenopathy in the first decade of life. Three cases presenting with nodal disease are described. The eyelids were involved in one case. The clinical, laboratory, and biopsy findings are discussed and compared with previously reported cases.

Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) in a patient with elevated Epstein-Barr virus titers.

Sinus histiocytosis with massive lymphadenopathy (SHML) is a newly recognized disorder. The etiology of this disease is unknown. An exaggerated response to an offending agent such as the Epstein-Barr virus or Klebsiella bacteria has been postulated. Its course is usually benign. Cervical adenopathy is seen in 97% of the patients, while 30% of patients have nodal involvement in other sites, and 30% have extranodal involvement. There is a 7% mortality rate that occurs primarily in patients with immunologic defects. Corticosteroids ameliorate the constitutional symptoms, but cyclophosphamide appears to have the most beneficial effect. This article presents the case of a patient with SHML who demonstrated elevated Epstein-Barr virus titers.

Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity.

This report reviews the clinical and pathologic features of 423 examples of sinus histiocytosis with massive lymphadenopathy (SHML) entered in a case registry, with special emphasis on extranodal manifestations of the disease. The most common sites of extranodal involvement in this population are skin, upper respiratory tract, and bone. However, SHML also can occur in a variety of other sites, including the genitourinary system, lower respiratory tract, oral cavity, and soft tissues. Involvement of kidney, lower respiratory tract, or liver was found to be a poor prognostic sign, and patients with associated immunologic disease often fared poorly. In general, prognosis has been found to correlate both with the number of nodal groups and with the number of extranodal systems involved by SHML. A complete bibliography of publications describing patients with SHML is included, and illustrations of the clinical, histopathologic, and radiographic features of the disease are provided.