SUN-278 Isolated Hypothalamic Langerhans Cell Histiocytosis in an Adult Manifesting as Panhypopituitarism

Abstract Background: Langerhans Cell Histiocytosis (LCH) is a rare disease characterized by abnormal proliferation of bone marrow derived histiocytes. Although predominantly a childhood disease, LCH can occur at any age and has an incidence of one to two cases per million in adults. LCH can involve a single organ or present as disseminated disease. Sites most commonly affected are bone, skin, bone marrow and pituitary. Isolated hypothalamic LCH is a rare entity. A few reports of LCH presenting as a hypothalamic mass exist but mainly in children. Treatment of adult LCH is derived from pediatric studies, and no standard of care exists. We report a unique case of an adult with panhypopituitarism secondary to a hypothalamic mass found to be biopsy proven isolated LCH treated with Vemurafenib, a BRAF V600E inhibitor. Clinical Case: A 66-year-old previously healthy man presented with progressively increasing confusion, cognitive decline and generalized weakness requiring hospital admission. Laboratory evaluation revealed an 8AM cortisol of 2.5 ug/dL (reference [ref] 7.0–25.0 ug/dL), ACTH of 9.3 pg/mL (ref 8–42 pg/mL), TSH of 0.106 uIU/mL (ref 0.35–5.5 uIU/mL), free T4 of 0.67 ug/dL (ref 0.7–1.25 ng/dL), LH <0.2 IU/L (ref 0.5–11 IU/L), FSH 0.6 IU/mL (ref 1–12 IU/L), total testosterone <12 ng/dL (ref 193 - 824 ng/dL), free testosterone <3.3 pg mL (ref 41.7 - 180.2 pg/mL), IGF1 41 ng/mL (ref 33–220 ng/mL) and prolactin of 31.5 ng/mL (ref 3.5–15 ng/mL). Findings were consistent with panhypopituitarism, and he was started on glucocorticoid and levothyroxine replacement therapy. MRI pituitary revealed an 18.1 x 13.8 x 15.8 mm hypothalamic mass with signal intensity alteration in the optic pathway. Patient developed polyuria with a serum sodium of 148 mmol/L (ref 136–145 mmol/L), elevated serum osmolality and low urine osmolality consistent with central DI and was started on oral DDAVP. The patient underwent right sided neuroendoscopic intraventricular biopsy of hypothalamic mass. Pathology was consistent with LCH with immunohistochemistry staining for CD1a, Langerin and BRAFV600E, with occasional cells staining for CD68, CD163 and S100. Bone marrow biopsy was normal. A NM PET scan revealed a hypermetabolic hypothalamic mass compatible with LCH without evidence of involvement of other sites including the skeletal system. Given histopathologically confirmed BRAF-mutated LCH, treatment with Vemurafenib was initiated. Behavioral changes gradually improved, and repeat MRI brain three months after treatment revealed decrease in size of hypothalamic mass. Conclusion: Isolated hypothalamic LCH is exceedingly rare. No clear guidelines exist for treatment of LCH in adults. BRAFV600E mutations are found in more than fifty percent of LCH cases and are associated with worse outcomes. This case demonstrates the successful use of targeted BRAF inhibitor therapy in an adult patient with BRAF mutated hypothalamic LCH.

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BRAF-V600E–mutated Rosai-Dorfman-Destombes disease and Langerhans cell histiocytosis with response to BRAF inhibitor

Blood Advances ◽

10.1182/bloodadvances.2019000093 ◽

2019 ◽

Vol 3 (12) ◽

pp. 1848-1853 ◽

Cited By ~ 8

Author(s):

Rosemarie Mastropolo ◽

Allison Close ◽

Steven W. Allen ◽

Kenneth L. McClain ◽

Scott Maurer ◽

...

Keyword(s):

Langerhans Cell Histiocytosis ◽

Braf Inhibitor ◽

Langerhans Cell ◽

Braf V600e ◽

Disease Monitoring ◽

Blood Testing ◽

Molecular Assays ◽

Key Points ◽

Treatment Plans ◽

Inhibitor Treatment

Key Points Demonstration of BRAF-V600E in Rosai-Dorfman-Destombes disease requires sensitive molecular assays and molecular-based tissue immunostain. BRAF-V600E blood testing is important for disease-monitoring BRAF-mutated histiocytosis and can guide inhibitor treatment plans.

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Treatment of a Patient with Refractory Non-Langerhans-Cell-Histiocytosis with the Tyrosine Kinase Inhibitor Sorafenib: Clinical and Genetic Implications

Blood ◽

10.1182/blood.v116.21.4715.4715 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4715-4715

Author(s):

Andreas Viardot ◽

Frank Stegelmann ◽

Thorsten Zenz ◽

Peter Möller ◽

Konstanze Döhner

Keyword(s):

Bone Marrow ◽

Tyrosine Kinase ◽

Langerhans Cell Histiocytosis ◽

Kinase Inhibitor ◽

Langerhans Cell ◽

Braf V600e ◽

Off Label Use ◽

Off Label ◽

Hands And Feet ◽

Label Use

Abstract Abstract 4715 Non-Langerhans-cell-histiocytosis (Non-LCH) represents a rare disorder with a broad spectrum of clinical features and various outcome. We here report on a 61 years old man with Non-LCH with severe skin and bone marrow involvement. At the time of diagnosis in 2006, the patient presented with up to four centimeter large cutaneous papules involving face, stem, hands and feet. Since two years, the patient also developed an increasing tricytopenia due to an extensive bone marrow infiltration of histiocytes (80%). Since diagnosis, the patient received a large number of various therapies including daily glucocorticoids at different dosages (continuously since diagnosis), low-dose methotrexate (10-40mg s.c. per week; from may to september 2007), experimental treatment with lenalidomide (5-10mg per day; from february to june 2008), continous oral trofosfamide (100mg per day; from july to august 2008), cladribine monotherapy (2,1mg/m2 d1-5; 4 cycles; from December 2008 to march 2009) and the combination of cladribine (2.1mg/m2 d1-5) and cytarabine (40 mg s.c. d1-7; 3 cycles; from january to march 2010). The patient did not respond to any of these therapies. Due to the persistent distinctive clinical symptoms (massive skin involvement, tricytopenia), we started in July 2010 an experimental therapy with sorafenib at a dosage of 200mg per day for four days, followed by 400mg per day for another four days, and subsequently increased the dosage to 800mg daily. After four weeks, the marked skin papules flattened to skin level at all preferential sites. Small skin ulcers at the cheeks healed up. In parallel, there was a significant improvement of hematopoiesis since start of therapy with haemoglobin levels raising from 8,6g/dl to 12,2g/dl and normalization of leukocyte count (from 3.1/nl to 5.2/nl). Bone marrow rebiopsy is intended after three month of therapy, data on the actual grade of infiltration will be presented at the meeting. Based on the impressive clinical improvement under sorafenib, we analyzed selected target genes of the multityrosine kinase inhibitor: mutation screening was performed on the FLT3 (internal tandem duplication, point mutations of the tyrosine kinase domain) and KIT genes (exon 8 and exon 17) as well as for the recently described BRAF V600E mutation found in a significant number of patients with LCH (G. Badalian-Very et al., Blood prepublished online June 2, 2010; DOI 10.1182/blood-2010-04-279083). However, in none of these genes, mutations were found and further molecular analysis of the patient's bone marrow is currently under investigation. To our knowledge, this is the first report on the efficacy of sorafenib in a case of histiocytosis. However, the underlying genetic mechanisms of Non-LCH still have to be elucidated. Disclosures: Off Label Use: Sorafenib is approved for unresectable hepatocellular carcinoma and advanced renal cancer. We present an off-label use of sorafenib in a case of a severe orphan disease refractory to all standard therapies. Zenz:Roche: Honoraria; Boehringer: Honoraria; GSK: Honoraria; Celgene: Honoraria.

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Isolated Langerhans cell histiocytosis in the hypothalamic-pituitary region: a case report

BMC Endocrine Disorders ◽

10.1186/s12902-019-0474-0 ◽

2019 ◽

Vol 19 (1) ◽

Author(s):

Weibin Zhou ◽

Jia Rao ◽

Chengjiang Li

Keyword(s):

Langerhans Cell Histiocytosis ◽

Clinical Symptoms ◽

Elevated Serum ◽

Urine Osmolality ◽

Langerhans Cell ◽

Lymphocytic Hypophysitis ◽

Pituitary Stalk ◽

High Signal ◽

Cns Disorders ◽

Hormonal Evaluation

Abstract Background Langerhans cell histiocytosis (LCH) is a rare disease that mainly affects children, but this disease is significantly rarer in patients who are older than 15 years. In this disease, any organ can be involved. The skeleton, skin and lung are commonly affected, and isolated hypothalamic-pituitary (HP) involvement is relatively rare. Here we report a 17-year-old adolescent with isolated HP-LCH of enlarged pituitary stalk presented with central diabetes insipidus (CDI). Case presentation A 17-year-old male adolescent with polydipsia and polyuria accompanied with elevated serum sodium level and low urine osmolality for 3 weeks was referred to our hospital. After admission, hormonal evaluation showed that his growth hormone (GH) was slightly elevated, and serum osmolality and glucose were normal. The fluid deprivation-vasopressin test demonstrated CDI. Imaging examination showed an obvious thickening of the pituitary stalk. Lymphocytic hypophysitis, sarcoidosis and granulation tissue lesions were suspected. After oral 1-deamino-8-Darginine vasopressin (DDAVP) and prednisone were administered for 2 months, symptoms were relieved, and he discontinued taking the drugs by himself. On reexamination, imaging revealed changes in the size and shape of the pituitary stalk, with thickened nodules. Then, a diagnostic biopsy of the pituitary stalk lesion was performed. Immunohistochemistry confirmed the definitive diagnosis of LCH. The clinical symptoms subsided with oral hormone replacements. Conclusion CDI is a rare symptom in children and adolescents. Most of the causes are idiopathic, while others are caused by central nervous system (CNS) disorders. Meanwhile, lymphocytic hypophysitis, germinoma, LCH and other CNS disorders can all present as thickening of the pituitary stalk, diffuse enlargement of the pituitary gland, and weakening of high signal intensity in the neurohypophysis on magnetic resonance imaging (MRI). The differential diagnosis among these diseases depends on immunohistochemistry evidence.

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Efficacy of BRAF‐Inhibitor Therapy in BRAF V600E ‐Mutated Adult Langerhans Cell Histiocytosis

The Oncologist ◽

10.1002/onco.13541 ◽

2020 ◽

Vol 25 (12) ◽

pp. 1001-1004

Author(s):

Antonious Z. Hazim ◽

Gordon J. Ruan ◽

Aishwarya Ravindran ◽

Jithma P. Abeykoon ◽

Caleb Scheckel ◽

...

Keyword(s):

Langerhans Cell Histiocytosis ◽

Braf Inhibitor ◽

Langerhans Cell ◽

Inhibitor Therapy ◽

Braf V600e

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High-Risk Langerhans Cell Histiocytosis in Infants Exhibits Malignant Features in a Xenograft Model but Responds Durably to Targeted Therapy

Blood ◽

10.1182/blood-2018-99-119383 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4323-4323

Author(s):

Lynn Lee ◽

Mary Christa Krupski ◽

Jason Clark ◽

Robert B. Lorsbach ◽

Michael Grimley ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Targeted Therapy ◽

Langerhans Cell Histiocytosis ◽

Conflicts Of Interest ◽

Clinical Care ◽

Interleukin 2 ◽

Langerhans Cell ◽

Braf V600e ◽

Markers Of Inflammation

Abstract Background: Langerhans cell histiocytosis (LCH) is a rare hematologic neoplasm primarily of childhood, characterized by a neoplastic proliferation of Langerhans-like cells. The clinical presentation of LCH is highly variable, and while some children are cured with combination chemotherapy, many will relapse and experience irreversible morbidity. Genomic profiling of LCH has identified recurrent somatic activating mutations in BRAF and MAP2K1, all of which culminate in activation of the mitogen-activated protein kinase pathway. However, key mechanistic and clinical questions such as the curative potential of targeted therapy and the cell of origin remain unanswered. Methods: Four infants with risk-organ positive (RO+) multisystem BRAF V600E-mutant LCH and secondary hemophagocytosis were treated at our institution with the BRAF V600E-inhibitor dabrafenib after failing chemotherapy, or up front at the discretion of the treating physician. Response assessment was performed as indicated for good clinical care. Excess bone marrow obtained during routine clinical evaluation was collected under an IRB-approved protocol, and transplanted into busulfan-conditioned NOD/LtSz-SCID interleukin-2(IL2)RG-/- (NSG) or NSG-SGM3 (NSGS) mice. Donor chimerism was assessed by flow cytometry for mouse and human CD45 and lineage reconstitution was determined with standard human markers. BRAF V600E detection was performed on extracted DNA from xenografts using a TaqMan Mutation Detection RTPCR assay. Results: At presentation, all patients exhibited features of HLH (hemophagocytic lymphohistiocytosis) with fever, splenomegaly, pancytopenia, elevated markers of inflammation, hypofibrinogenemia, and hemophagocytosis on bone marrow examination. All patients displayed marked and rapid improvement following initiation of dabrafenib. With a median follow up of 21 months, all patients remain in complete clinical remission, and are thriving. None of the patients experienced significant adverse effects classically associated with dabrafenib. In two patients, despite clinical disease resolution, BRAF V600E was still detectable in bone marrow by RTPCR at 23 and 26 months respectively post initiation of dabrafenib. Remarkably, the other two patients who were treated upfront with dabrafenib achieved molecular remissions (defined as undetectable BRAF V600E allele in a previously positive patient) after 11 and 12 months respectively of therapy. Among mice transplanted with patient bone marrow cells, the median survival was 9.6 weeks. A comparison arm consisting of mice transplanted with bone marrow from a low-risk LCH patient did not develop evidence of disease during the observation period. At necropsy, animals exhibited splenomegaly, thrombocytopenia and anemia. Flow cytometry of both bone marrow and spleens from mice demonstrated robust engraftment of human hematopoietic cells, and the BRAF V600E allele was detected from marrow and splenocytes in all mice. Frequent hemophagocytic forms were visible on bone marrow cytospins, and on histologic examination, bone marrow exhibited an abundance of CD1a-negative, CD163+ histiocytes, similar to findings observed in human disease. Bone marrow and splenocytes from primary NSG xenograft recipients were transplanted into secondary NSGS mice, and two out of three animals examined similarly became ill with comparable disease latency, and achieved engraftment of human cells with detectable BRAF V600E in bone marrow and splenocytes. Conclusions: For patients with LCH with hematologic involvement and secondary HLH, disease-initiating cells are present in the bone marrow and can engraft and recapitulate disease following primary and secondary transplant into immunodeficient mice. Targeted therapy with the BRAF V600E-specific inhibitor dabrafenib leads to durable, sustained remissions. Furthermore, we demonstrate that certain patients can achieve molecular remission with BRAF V600E-specific monotherapy alone. However, in at least a subset of patients with RO+ LCH, the persistence of mutated BRAF despite prolonged targeted therapy suggests that while quiescent, transformed disease-initiating cells are not eliminated by BRAF inhibition alone. Based on these results, we hypothesize that first-line therapy with BRAF inhibitors may be more likely to induce molecular remissions. Disclosures No relevant conflicts of interest to declare.

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Frequency detection of BRAF V600E mutation in a cohort of pediatric langerhans cell histiocytosis patients by next-generation sequencing

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01912-3 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Shunqiao Feng ◽

Lin Han ◽

Mei Yue ◽

Dixiao Zhong ◽

Jing Cao ◽

...

Keyword(s):

Next Generation Sequencing ◽

Langerhans Cell Histiocytosis ◽

Mutation Screening ◽

Langerhans Cell ◽

Braf V600e ◽

P Value ◽

Type I ◽

Next Generation ◽

Mutation Status ◽

Generation Sequencing

Abstract Background Langerhans cell histiocytosis (LCH) is a rare neoplastic disease that occurs in both children and adults, and BRAF V600E is detected in up to 64% of the patients. Several studies have discussed the associations between BRAF V600E mutation and clinicopathological manifestations, but no clear conclusions have been drawn regarding the clinical significance of the mutation in pediatric patients. Results We retrieved the clinical information for 148 pediatric LCH patients and investigated the BRAF V600E mutation using next-generation sequencing alone or with droplet digital PCR. The overall positive rate of BRAF V600E was 60/148 (41%). The type of sample (peripheral blood and formalin-fixed paraffin-embedded tissue) used for testing was significantly associated with the BRAF V600E mutation status (p-value = 0.000 and 0.000). The risk of recurrence declined in patients who received targeted therapy (p-value = 0.006; hazard ratio 0.164, 95%CI: 0.046 to 0.583). However, no correlation was found between the BRAF V600E status and gender, age, stage, specific organ affected, TP53 mutation status, masses close to the lesion or recurrence. Conclusions This is the largest pediatric LCH study conducted with a Chinese population to date. BRAF V600E in LCH may occur less in East Asian populations than in other ethnic groups, regardless of age. Biopsy tissue is a more sensitive sample for BRAF mutation screening because not all of circulating DNA is tumoral. Approaches with low limit of detection or high sensitivity are recommended for mutation screening to avoid type I and II errors.

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High prevalence of somatic MAP2K1 mutations in BRAF V600E–negative Langerhans cell histiocytosis

Blood ◽

10.1182/blood-2014-05-577361 ◽

2014 ◽

Vol 124 (10) ◽

pp. 1655-1658 ◽

Cited By ~ 203

Author(s):

Noah A. Brown ◽

Larissa V. Furtado ◽

Bryan L. Betz ◽

Mark J. Kiel ◽

Helmut C. Weigelin ◽

...

Keyword(s):

Targeted Therapy ◽

Genome Sequencing ◽

High Frequency ◽

Langerhans Cell Histiocytosis ◽

Langerhans Cell ◽

Braf V600e ◽

Braf Mutations ◽

Key Points ◽

High Prevalence

Key Points Targeted genome sequencing reveals high-frequency somatic MAP2K1 mutations in Langerhans cell histiocytosis. MAP2K1 mutations are mutually exclusive with BRAF mutations and may have implications for the use of BRAF and MEK targeted therapy.

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