Somatic activating ARAF mutations in Langerhans cell histiocytosis

Nelson, David S.; Quispel, Willemijn T.; Badalian-Very, Gayane; Halteren, Astrid G. S. van; Bos, Cor van den; Bovée, Judith V.M.G.; Tian, Sara; Hummelen, Paul Van; Ducar, Matthew; MacConaill, Laura E.; Egeler, R. Maarten; Rollins, Barrett J.

doi:10.1182/blood-2013-06-511139

Cited by 158 publications

(111 citation statements)

References 23 publications

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“…8 In addition, several groups have noted that a larger proportion of LCH and ECD lesions have activation of ERK signaling than that demonstrated to have the BRAFV600E mutation. 3,8,9 Interestingly, Cangi et al recently identified that 18 of 18 ECD patients had a BRAFV600E mutation in DNA from whole lesional tissue if an ultrasensitive methodology was used, suggesting that current data underestimate the true mutational frequency of BRAFV600E mutations in ECD. 8 Concurrently, we recently identified an NRASQ61R mutation in an ECD patient who was definitively BRAF-wild-type.…”

Section: Introductionmentioning

confidence: 99%

Recurrent RAS and PIK3CA mutations in Erdheim-Chester disease

Émile

Diamond

Hélias‐Rodzewicz

et al. 2014

Blood

214

159

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Key Points• PIK3CA and NRAS mutations are recurrent in BRAFV600E wild-type ECD patients.• 57.5% (46/80) of ECD patients have a BRAFV600E mutation, and an additional 10.9% and 3.7% have PIK3CA and NRAS mutations, respectively.Erdheim-Chester disease (ECD) is a rare histiocytic disorder that is challenging to diagnose and treat. We performed molecular analysis of BRAF in the largest cohort of ECD patients studied to date followed by N/KRAS, PIK3CA, and AKT1 mutational analysis in BRAF wild-type patients. Forty-six of 80 (57.5%) of patients were BRAFV600E-mutant. NRAS mutations were detected in 3 of 17 ECD BRAFV600E wild-type patients. PIK3CA

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Section: Introductionmentioning

confidence: 99%

Recurrent RAS and PIK3CA mutations in Erdheim-Chester disease

Émile

Diamond

Hélias‐Rodzewicz

et al. 2014

Blood

214

159

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“…Table 1 summarizes the clinical and cytologic findings of LCH cases diagnosed in thyroid FNA specimens. In one of these cases, a diagnosis of PTC in a background suggestive of LCH was rendered [15]. In the other reported cases of thyroid LCH where FNA was performed, the cytologic findings were misinterpreted as ''atypical follicular epithelial cells'', ''epithelial neoplasm'' and papillary or medullary carcinoma, or were non-diagnostic [6,25].…”

Section: Fine Needle Aspiration and Biopsymentioning

confidence: 99%

“…It should be noted, however, that detection of the BRAF V600E mutation is not specific for LCH even among histiocytic disorders, as this mutation has been detected in 54 % cases of Erdheim-Chester disease [12] Whether the presence of BRAF V600E mutations reflects biologic relatedness of these types of histiocytoses remains to be determined [13]. More recent studies have uncovered a high frequency of MAP2K1 mutations (33-50 %) in LCH cases that have wild-type BRAF as well as occasional somatic mutations in other mitogen-activated protein kinase (MAPK) pathway genes, ARAF and ERBB3 [11,14,15].…”

Section: Fine Needle Aspiration and Biopsymentioning

confidence: 99%

Langerhans Cell Histiocytosis: Diagnosis on Thyroid Aspirate and Review of the Literature

Saqi

Ebner

Ausiello

et al. 2015

Head and Neck Pathol

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Thyroid gland involvement by Langerhans cell histiocytosis is extremely rare. A 35-year-old woman with a history of a suprasellar mass previously diagnosed as a ganglioglioma and complicated by diabetes insipidus, hypogonadotropic hypogonadism, and central hypothyroidism presented with acute onset of neck enlargement. On ultrasound examination, almost the entire thyroid appeared replaced by abnormal lobulated hypoechoic tissue with increased vascularity. Fine needle aspiration (FNA) of the thyroid was performed and revealed singly scattered and loosely cohesive large cells with abundant cytoplasm, including some with irregular nuclear contours and nuclear grooves. No thyroid follicular cells were noted. Based on the cytomorphologic findings and ancillary studies (immunohistochemistry and flow cytometry analysis) a cytological diagnosis of ''positive for neoplastic cells'' with features suggestive of monocytic/histiocytic origin, possibly Langerhans cell histiocytosis (LCH) was rendered. Following FNA, the patient underwent an incisional thyroid biopsy that confirmed the cytological impression of LCH. In light of the new diagnosis of LCH, the prior suprasellar mass biopsy slides were re-reviewed and rare cells suspicious for LCH were observed.Appropriate treatment for systemic LCH was initiated successfully. This case demonstrates that the presence of enlarged and loosely cohesive cells, especially those with irregular nuclear contours, in thyroid FNA specimens should raise suspicion for LCH. The diagnosis of LCH in FNA specimens is challenging. Additional material should be allocated for ancillary studies to confirm the morphological impression. In our case, not only was the thyroid FNA crucial in diagnosing LCH, but instrumental in initiating a thorough diagnostic work-up for multisystem involvement and thus unmasking the true etiology of the patient's suprasellar mass and associated endocrinopathies.Keywords Thyroid Á Langerhans cell histiocytosis Á Fine needle aspiration Á Cytology Á Cytopathology Clinical PresentationA 35-year-old woman with a history of a suprasellar mass, previously diagnosed as a ganglioglioma and complicated by diabetes insipidus (DI), hypogonadotropic hypogonadism, and central hypothyroidism, presented with acute onset of neck enlargement. On physical exam, she appeared euthyroid, and a bilaterally enlarged soft, nontender thyroid of about 60 g was palpated. Radiographic FeaturesOn thyroid ultrasound, the right lobe measured 7.3 9 2.9 9 3.4 cm, and the left lobe measured 5.8 9 2.3 9 2.5 cm; replacement of almost the entire thyroid with abnormal lobulated hypoechoic tissue with increased vascularity was identified (Fig. 1a, b). The rate of growth and the ultrasound

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“…As in our series, Nelson et al also described a very low overall rate of somatic mutations. 22 In summary, ϳ75% of LCH lesions have been shown to harbor mutually exclusive somatic MAPK pathway mutations resulting in ERK activation.…”

Section: Molecular Landscape Of Lch: Mapk Activationmentioning

confidence: 99%