Treatment of Cerebral Histiocytosis With Low Dose of Cobimetinib: A Report of 2 Cases.

OBJECTIVES: Histiocytic disorders are pathologic expansions of myeloid cells in multiple organs, including the CNS. They share activation of the MAP kinase pathway due to either BRAFV600E variant or other variants in the RAS-RAF-MEK-ERK pathway. The rarity and heterogeneity of the disease only enable therapy through pathophysiologic considerations. METHODS: We present 2 histiocytosis cases without BRAF sequence variants that affect the CNS, one with Erdheim-Chester disease and the other with an unspecified histiocytosis, and their diagnostic and therapeutic challenges. RESULTS: In both cases, comprehensive analysis of the RAS-RAF-MEK-ERK signaling pathway secured the diagnosis. Treatment with the MEK inhibitor cobimetinib brought the disease to a complete halt. However, side effects such as thrombosis and serous macular edema made it necessary to reduce cobimetinib dosage. Low-dose cobimetinib maintenance medication was successful in preventing recurrence of histiocytic disease. DISCUSSION: CNS involvement of histiocytic disorders can lead to detrimental neurologic symptoms. MEK inhibitors are effective treatment options for some of these patients. Since side effects are common, according to our cases we propose a low-dose treatment of 20 mg per day to balance treatment effects with side effects. CLASSIFICATION OF EVIDENCE: This case report provides Class IV evidence. This is a single observational study without controls.

H syndrome treated with Tocilizumab: two case reports and literature review.

H syndrome is a rare autosomal recessive genetic disorder characterized by the following clinical features: cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature, hallux valgus, hyperglycemia, fixed flexion contractures of the toe joints, and the proximal interphalangeal joints. In rare cases, autoinflammatory and lymphoproliferative manifestations have also been reported. This disorder is due to loss-of-function mutations in SLC29A3 gene, which encode the equilibrative nucleoside transporter ENT3. This deficiency leads to abnormal function and proliferation of histiocytes. H syndrome is part of the R-group of histiocytosis. We report two different cases, one was diagnosed in adulthood and the other in childhood. The first case reported is a 37-year-old woman suffering from H syndrome with an autoinflammatory systemic disease that begins in adulthood (fever and diffuse organ's infiltration) and with cutaneous, articular, auditory, and endocrinological manifestations since childhood. The second case reported is a 2-year-old girl with autoinflammatory, endocrine, and cutaneous symptoms (fever, lymphadenopathy, organomegaly, growth delay, and cutaneous hyperpigmentation). Homozygous mutations in SLC29A3 confirmed the diagnosis of H syndrome in both cases. Each patient was treated with Tocilizumab with a significant improvement for lymphoproliferative, autoinflammatory, and cutaneous manifestations. Both cases were reported to show the multiple characteristics of this rare syndrome, which can be diagnosed either in childhood or in adulthood. In addition, an overview of the literature suggested Tocilizumab efficiency.

Failure of crizotinib based systemic treatment in ALK positive histiocytosis involving the central nervous system: a case report and literature review.

BACKGROUND: Among the histiocytic disorders, anaplastic lymphoma kinase (ALK)-positive histiocytosis emerged in 2008. As more and more cases of the novel entity are reported, our understanding of it is deepened. However, only a few cases with central nervous system (CNS) involvement have been reported. Furthermore, the lesion in the suprasellar region has not been documented.  CASE PRESENTATION: We presented a case of ALK-positive histiocytosis involving the suprasellar region of a one-year-and-four-month-old boy. Through clinical, neuropathological, and genomic analyses, the patient was diagnosed with ALK-positive histiocytosis. After lesions were resected he started treatment with a combination of the three compounds vincristine, prednisolone, and crizotinib, but they did not work. Cytarabine was then added as an additional chemotherapy drug for him, and the lesions in the brain and lungs were shrunk by combining treatment of crizotinib, dexamethasone, vincristine, and cytarabine according to the RECIST (esponse Evaluation Criteria In Solid Tumours). CONCLUSIONS: Additional adjuvant chemotherapy drugs are needed when ALK-inhibitor treatment is ineffective.

Progressive nodular histiocytosis in a 9-year-old boy treated with cobimetinib.

Progressive nodular histiocytosis is a rare variant of non-Langerhans cell histiocytosis that affects the skin and mucous membranes and displays a progressive clinical course and poor response to treatment. We describe a case of severe progressive nodular histiocytosis harboring a KRAS p.G12S mutation in a 9-year-old boy, refractory to chemotherapy, who was successfully treated with the MEK inhibitor cobimetinib. This is the first report of the use of MEK inhibition for this histiocytosis subtype in a pediatric patient.

ALK-rearranged histiocytosis: Report of two cases with involvement of the central nervous system.

AIMS: Histiocytoses are a heterogeneous group of localized or disseminated diseases. Clinical presentation and patients' outcome vary greatly, ranging from mild to life-threatening disorders. Rare cases of systemic or localized histiocytosis harboring ALK rearrangement have been reported. METHODS: Two cases of CNS histiocytosis were thoroughly investigated by implementing multiple molecular tests, i.e. FISH, RT-qPCR, NGS analysis. RESULTS: In a 10-month old girl (patient #1), MRI showed two left hemispheric lesions and a right fronto-mesial lesion histologically consisting of a moderately cellular infiltrative proliferation, composed by CD68(PGM1)+/CD163+ spindle cells. ALK 5'/3'-imbalance and a KIF5B(exon 24)-ALK(exon 20) fusion were documented by RT-qPCR and NGS analysis, respectively. A subsequent CT scan showed multiple hepatic and pulmonary lesions. The patient was started on chemotherapy (vinblastine) associated to an ALK-inhibitor (Alectinib) with remarkable response. In a 11-year-old girl (patient #2), MRI showed a right frontal 1.5 cm lesion. Neuropathological examination revealed a histiocytic proliferation composed by medium sized CD68(PGM1)+/HLA-DR+ cells, showing moderate ALK1 positivity. ALK rearrangement and a KIF5B(exon 24)-ALK(exon 20) fusion were demonstrated also in this case. Subsequent CT, 18F-FDG-PET and MRI scans showed the presence of a single right femoral lesion, proved to be a fibrous cortical defect. CONCLUSIONS: In ALK-histiocytoses, CNS involvement may occur as part of a systemic disease or, rarely, as its only primary disease localization, which could remain otherwise asymptomatic. The diagnosis often relies on neuropathological examination of brain biopsy, which may pose a diagnostic challenge due to the variable histopathological features. An integrated histological and molecular approach in such cases is recommended.

ALK-positive histiocytosis associated with chronic lymphocytic leukaemia/small lymphocytic lymphoma: a multitarget response under ibrutinib.

ALK-positive histiocytosis is a recently described entity with few reported cases in literature. Herein, we report an unusual case of ALK-positive histiocytosis showing an Erdheim-Chester disease (ECD)-like presentation, occurring in a 37-year-old woman with a 2-year history of chronic lymphocytic leukaemia (CLL). Our CLL patient relapsed 6 months after the end of fludarabine, cyclophosphamide and rituximab frontline therapy and complained of lower limb pains. A bone marrow biopsy was performed and showed concomitant CLL/small lymphocytic lymphoma and ALK-positive histiocytosis with an identical immunoglobulin heavy-chain gene rearrangement in both neoplasms, suggesting clonal relationship. After 4 years under ibrutinib therapy, our patient remains free of both diseases. This report extends the spectrum of composite hematolymphoid neoplasms and shows that ALK rearrangement should be considered in all histiocytosis subtypes. Moreover, both tumours eradication under ibrutinib suggests that BTK inhibitors may also be effective in histiocytic neoplasms.

The triptych of mixed histiocytosis: a systematic review of 105 cases and proposed clinical classification.

Histiocytoses are one of the ultimate diagnostic challenges that every physician face at least once in his/her life. Giving their protean manifestation and differentiated therapeutic needs, histiocytosis requires extensive characterization and multidisciplinary management. Mixed histiocytosis is an emerging group of syndromes defined by the overlap of Langerhans cell histiocytosis and another histiocytic disorder of different type. Despite rare, it may account for up to a fifth of systemic histiocytosis patients in some series. In this work, we comprehensively review for the first time the clinical, radiological, histopathological and molecular features of mixed histiocytosis in children and adults. Moreover, we propose a clinical classification in three groups that differentiate patients with systemic involvement and worse overall survival to other groups with more localized manifestations and indolent behavior, wanting to ease their recognition and treatment. Interestingly we also found that mixed histiocytosis harbor BRAFV600E mutations with a higher frequency comparing to all other histiocytoses, and may therefore benefit of specific inhibitory drugs.

Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms.

Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.

Efficacy of MEK inhibition in patients with histiocytic neoplasms.

Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway1,2. For the 50% of patients with histiocytosis who have BRAFV600 mutations3-5, RAF inhibition is highly efficacious and has markedly altered the natural history of the disease6,7. However, no standard therapy exists for the remaining 50% of patients who lack BRAFV600 mutations. Although ERK dependence has been hypothesized to be a consistent feature across histiocytic neoplasms, this remains clinically unproven and many of the kinase mutations that are found in patients who lack BRAFV600 mutations have not previously been biologically characterized. Here we show ERK dependency in histiocytoses through a proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, in patients with histiocytoses. Patients were enrolled regardless of their tumour genotype. In parallel, MAPK alterations that were identified in treated patients were characterized for their ability to activate ERK. In the 18 patients that we treated, the overall response rate was 89% (90% confidence interval of 73-100). Responses were durable, with no acquired resistance to date. At one year, 100% of responses were ongoing and 94% of patients remained progression-free. Cobimetinib treatment was efficacious regardless of genotype, and responses were observed in patients with ARAF, BRAF, RAF1, NRAS, KRAS, MEK1 (also known as MAP2K1) and MEK2 (also known as MAP2K2) mutations. Consistent with the observed responses, the characterization of the mutations that we identified in these patients confirmed that the MAPK-pathway mutations were activating. Collectively, these data demonstrate that histiocytic neoplasms are characterized by a notable dependence on MAPK signalling-and that they are consequently responsive to MEK inhibition. These results extend the benefits of molecularly targeted therapy to the entire spectrum of patients with histiocytosis.

Treatment of benign cephalic histiocytosis with topical 1% rapamycin ointment.

We report a pediatric case of extensive, progressive benign cephalic histiocytosis (BCH) involving the face, trunk, and extremities with response of facial lesions to treatment with topical 1% rapamycin. A split-face model was used to demonstrate improvement on the treated side versus the untreated side. After physician and parental perception of effectiveness, based in part on photodocumentation, subsequently both cheeks were treated with continued improvement.

ALK-positive histiocytosis: an expanded clinicopathologic spectrum and frequent presence of KIF5B-ALK fusion.

In 2008, we presented three cases of ALK-positive histiocytosis as a novel systemic histiocytic proliferation of early infancy with hepatosplenomegaly and dramatic hematological disturbances. This series of 10 cases (including the original three cases) describes an expanded clinicopathological spectrum and the molecular findings of this histiocytic proliferation. Six patients had disseminated disease: five presented in early infancy with eventual disease resolution, and the sixth presented at 2 years of age and died of intestinal, bone marrow, and brain involvement. The other four patients had localized disease involving nasal skin, foot, breast, and intracranial cavernous sinus - the first three had no recurrence after surgical resection, while the cavernous sinus lesion showed complete resolution with crizotinib therapy. The lesional histiocytes were very large, with irregularly folded nuclei, fine chromatin, and abundant eosinophilic cytoplasm, sometimes with emperipolesis. There could be an increase in foamy histiocytes and Touton giant cells with time, resembling juvenile xanthogranuloma. Immunostaining showed that the histiocytes were positive for ALK, histiocytic markers (CD68, CD163) and variably S100, while being negative for CD1a, CD207, and BRAF-V600E. Next-generation sequencing-based anchored multiplex PCR (Archer® FusionPlex®) performed in six cases identified KIF5B-ALK gene fusion in five and COL1A2-ALK fusion in one. There was no correlation of gene fusion type with disease localization or dissemination. The clinicopathological spectrum of ALK-positive histiocytosis is broader than originally described, and this entity is characterized by frequent presence of KIF5B-ALK gene fusion. We recommend that every unusual histiocytic proliferative disorder, especially disseminated lesions, be tested for ALK expression because of the potential efficacy of ALK inhibitor therapy in unresectable or disseminated disease.

Reactive hemophagocytic syndrome in the setting of acute human immunodeficiency virus 1 infection: case report and review of the literature.

We report a case of reactive hemophagocytic syndrome (RHS) in the setting of acute human immunodeficiency virus type 1 infection (AHI). In addition, we review 11 previously reported cases of RHS precipitated by AHI and discuss strategies in the diagnosis and management of these overlapping clinical entities.

Rare childhood hybrid histiocytosis of the central nervous system-diagnosed by stereotactic brain biopsy with marked treatment response to clofarabine.

Histiocytosis is a heterogeneous group of disease entities, comprised by two main categories, namely Langerhans and non-Langerhans cell histiocytoses. Central nervous system involvement in histiocytosis is considered very rare and is often secondary to affection of anatomically related bone structures and/or multi-organ disease. We present a never-before described case of rare childhood histiocytosis with hybrid features of Langerhans cell histiocytosis and juvenile xanthogranuloma confined to the central nervous system in a 2- and a half-year-old boy with distinct treatment response to clofarabine. The case also emphasizes the diagnostic significance of stereotactic brain biopsy.

Intralymphatic histiocytosis treated with intralesional triamcinolone acetonide and pressure bandage.

Intralymphatic histiocytosis is a rare disorder associated with a variety of inflammatory conditions. We report the case of an 89-year-old woman with a history of a right knee replacement and a ruptured popliteal cyst who developed an erythematous indurated plaque over the surgical scar. Histopathology revealed fibrosis, chronic inflammation, and histiocytes within the lymphatics consistent with intralymphatic histiocytosis. The plaque flattened following intralesional injection of triamcinolone acetonide 10 mg/cc×1.6 cc once monthly for 2 consecutive months and application of a pressure bandage, with no recurrence after 4 months. This treatment may be useful for recalcitrant disease.

Intralymphatic Histiocytosis: A Report of 2 Cases. / Histiocitosis intralinfática, a propósito de 2 casos.

Intralymphatic histiocytosis is a benign condition characterized by poorly defined erythematous plaques (sometimes forming a reticular pattern) as well as the presence of nodules and vesicles. Its etiology and pathogenesis appear to be related to chronic inflammation in the affected area, prior surgery, or systemic disease, particularly rheumatoid arthritis. We report on 2 new cases, both associated with joint surgery in the affected area and osteoarticular disease (primary synovial osteochondromatosis and rheumatoid arthritis). This is a chronic disease and there is no specific treatment. Different treatment options were chosen in the 2 cases described. A spectacular response to treatment with oral pentoxifylline and topical tacrolimus was observed in 1 of the patients.