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Original Research: Diffuse Lung Disease |

Pulmonary Langerhans Cell HistiocytosisBRAF V600E and Langerhans Cell Histiocytosis: Profiling of Multifocal Tumors Using Next-Generation Sequencing Identifies Concordant Occurrence of BRAF V600E Mutations FREE TO VIEW

Samuel A. Yousem, MD, FCCP; Sanja Dacic, MD, PhD; Yuri E. Nikiforov, MD, PhD; Marina Nikiforova, MD
Author and Funding Information

From the Department of Pathology, UPMC Presbyterian, Pittsburgh, PA.

Correspondence to: Samuel A. Yousem, MD, FCCP, Department of Pathology, UPMC Presbyterian Campus-A610, 200 Lothrop St, Pittsburgh, PA 15213-2582; e-mail: yousemsa@upmc.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;143(6):1679-1684. doi:10.1378/chest.12-1917
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Background:  Pulmonary Langerhans cell histiocytosis is a localized proliferation of Langerhans cells in the lung that presents without systemic manifestations as bilateral nodular lung disease in adult cigarette smokers. The molecular basis for this proliferation is unknown.

Methods:  Twenty-two concurrent nodules in five patients were microdissected from formalin-fixed paraffin-embedded tissue and analyzed by next-generation sequencing for mutations in 46 cancer genes with the Ion AmpliSeq Cancer Panel on an Ion PGM (Personal Genome Machine) Sequencer (Life Technologies Corporation). Mutation confirmation was performed by conventional Sanger sequencing or by sensitive coamplification at lower denaturation polymerase chain reaction/fluorescence melting curve analysis.

Results:  Small amounts of DNA (10 ng) isolated from nodules were sufficient for successful interrogation of 740 mutational hot spots in 46 cancer genes by the Ion PGM Sequencer, with an average depth of coverage of 2,783 reads per hot spot and with uniformity of coverage of 92%. BRAF V600E mutation was detected in all concurrent nodules studied in two of the five patients, whereas in three of the five patients, no oncogene mutations were found.

Conclusions:  Pulmonary Langerhans cell histiocytosis appears to be a clonal proliferation that may or may not have BRAF V600E mutations. For those with BRAF V600E mutations, new targeted therapies, such as vemurafenib, may be used in progressive cases.

Figures in this Article

Pulmonary Langerhans cell histiocytosis (PLCH) is a disorder of Langerhans cells that represents a localized form of a spectrum of Langerhans cell proliferations. Although systemic manifestations of Langerhans cell histiocytosis (LCH) appear most often in childhood, PLCH is a distinct disease that presents as bilateral 1- to 2-cm nodules in middle-aged adult cigarette smokers who usually are without evidence of extrathoracic disease.15 PLCH has an unpredictable biologic course, with some cases progressing to honeycomb fibrosis, others remaining stable, and still others spontaneously regressing. Complicating this unpredictable biologic behavior is whether LCH, and specifically PLCH, represents a neoplastic or reactive condition, and the literature supports both arguments.617 Studies of LCH demonstrated clonality when LCH presents as a systemic disease or as a solitary mass.1820 PLCH represents a much different clinicopathologic syndrome because it occurs almost exclusively in adult smokers (termed tobacco-induced pneumoconiosis); has innumerable bilateral nodules; and has, for the most part, an indolent course.13

This study uses next-generation sequencing techniques examined over 46 cancer-associated genes for > 740 mutations and is the first to our knowledge to comprehensively analyze multiple PLCH nodules occurring in a single individual. The results indicate a significant influence of BRAF V600E transversions in the development of PLCH, affecting all nodules in an individual patient and raising intriguing questions about pathogenesis. The findings also provide a potential therapeutic option for progressive disease with Food and Drug Administration-approved medications, such as vemurafenib, for targeting Langerhans cells with the BRAF mutation.

Tumor Specimens and DNA Preparation

Five cases of PLCH from untreated patients with surgical lung biopsy specimens were obtained from the UPMC paraffin block archives and the consultation files of one of the authors (S.A.Y.) after obtaining institutional review board consent (UPMC IRB PRO 09010191) for a deidentified patient study. The diagnosis of PLCH in each case was confirmed by the presence of S100+ and CD1a+ LCH cells. No patient had evidence of extrapulmonary disease at presentation, and all patients had evidence of bilateral multinodular disease by high-resolution CT scan.

Microdissection of 22 nodules and paired reference lung tissue was performed in two to three 4-μm unstained histologic sections under stereomicroscopic visualization with an Olympus SZ61 microscope (Olympus Europa Holding GmbH). Microdissection was carefully performed to avoid the bronchial and bronchiolar epithelium. All nodules comprised predominantly LCH cells, a variable number of eosinophils, and other inflammatory cells (Figs 13). Cases showing advanced fibrosis were not included in the study. Microdissected areas of respiratory bronchiolitis were used as controls. Slides were poststained with hematoxylin and eosin to ensure accurate tissue sampling for genotypic analysis.

Figure Jump LinkFigure 1. The lesion of pulmonary Langerhans cell histiocytosis appears as a stellate centrilobular nodule with adjacent airspaces filled with smokers-type macrophages (hematoxylin-eosin, original magnification ×40).Grahic Jump Location
Figure Jump LinkFigure 2. Within the stellate nodule of pulmonary Langerhans cell histiocytosis are a mixture of cells dominated by the characteristic Langerhans cell with folded reniform nuclei and eosinophilic cytoplasm. In the background are smokers-type pigmented macrophages, bilobed eosinophils, lymphocytes, and stromal myofibroblasts. There were no distinctive histologic features that separated cases with and without BRAF V600E mutations (hematoxylin-eosin, original magnification ×600).Grahic Jump Location
Figure Jump LinkFigure 3. Microdissection allowed the entirety of each pulmonary Langerhans cell histiocytosis nodule to be analyzed with next-generation DNA sequencing (hematoxylin-eosin, original magnification ×40).Grahic Jump Location

DNA was isolated from each target with the DNeasy Blood & Tissue Kit on the automated QIAcube instrument (QIAGEN) according to the manufacturer’s instructions. The DNA was quantitated using the Invitrogen Qubit 2.0 Fluorometer (Life Technologies Corporation).21

Ion Torrent Next-Generation Sequencing

The Ion AmpliSeq Cancer Panel (Life Technologies Corporation) was used to generate target amplicon libraries. Briefly, 10 ng of DNA was amplified by polymerase chain reaction (PCR) with the Ion AmpliSeq Cancer Panel Primer Pool and Ion AmpliSeq HiFi Master Mix with the protocol recommended by the manufacturer. The multiplexed 190-amplicon library targets 46 cancer genes for > 740 mutations (Tables 1 and 2). Library concentration and amplicon size was determined with an Agilent High Sensitivity DNA Kit (Agilent Technologies, Inc). Samples were barcoded with the Ion Xpress Barcode Adapters 1-16 Kit according to the manufacturer’s instructions and multiplexed for emulsion PCR and sequencing on an Ion PGM (Personal Genome Machine) Sequencer. Sequencing was performed using the Ion PGM 200 Sequencing Kit according to the manufacturer’s instructions on Ion 316 and 318 Chips.

Table Graphic Jump Location
Table 1 —Clinicopathologic and Molecular Data on Cases of Pulmonary Langerhans Cell Histiocytosis

F = female; HRCT = high-resolution CT; M = male.

Table Graphic Jump Location
Table 2 —Cancer Genes on Ion AmpliSeq Cancer Panel (Life Technologies Corporation) Interrogated by Next-Generation Sequencing
Bioinformatic Analysis

Ion Torrent platform-specific pipeline software (Torrent Suite version 2.0; Life Technologies Corporation) was used to separate barcoded reads, generate sequence alignment with the hg19 human genome reference, perform target region coverage analysis, and filter and remove poor signal reads. Variant calling was performed with Ion Torrent Variant Caller version 2.0 software. For variant detection, a minimum coverage of 500 reads must be achieved, and at least 5% of mutant reads was selected for variant identification.

Mutation Confirmation

The presence of mutation detected by Ion Torrent next-generation sequencing was confirmed either by Sanger sequencing or by COLD-PCR (coamplification at lower denaturation PCR)/fluorescence melting curve analysis as previously reported.22

The results of the analysis are shown in Table 1. In cases 1 and 5, five and two individual and distinct nodules, respectively, revealed that each nodule had an identical BRAF V600E mutation, with a range of mutated Langerhans cells of 3% to 33% (average, 16%). In cases 2, 3, and 4, four, two, and nine distinct nodules were examined in each, and all lacked any mutation, including BRAF V600E. All nodules were negative for mutations in the other 46 cancer-related genes (Table 2).

From a small amount of DNA (10 ng), the Ion AmpliSeq Cancer Panel allowed for successful interrogation of multiple nodules in the five cases for 46 cancer genes and > 740 mutational hot spots (Table 2). The individual samples averaged 536,660 mapped sequence reads with a 72-bp mean read length. The distribution of reads across 190 amplicons was consistent among all samples tested; the average depth of coverage for mutational hot spots was 2,783 reads, and uniformity of coverage was 92%.

BRAF V600E mutation was identified by the Ion AmpliSeq Cancer Panel in seven nodules from two cases (Fig 4A). To confirm the presence of BRAF V600E using conventional technologies, these samples were sequenced by clinically validated Sanger sequencing assay and by sensitive COLD-PCR/fluorescence melting curve analysis assay. Both methods confirmed the presence of BRAF V600E mutation in all nodules (Fig 4 B and 4C).

Figure Jump LinkFigure 4. Detection of the BRAF c.1799T>A, p.V600E mutation by the Ion Personal Genome Machine (PGM) next-generation sequencing platform (Life Technologies Corporation), Sanger sequencing, and COLD-PCR (coamplification at lower denaturation polymerase chain reaction). A, BRAF mutation detected by the Ion PGM Sequencer visualized using the Integrative Genomics Viewer (Broad Institute). B, Sanger sequencing confirmed the presence of T-to-A substitution at codon 1799. C, The COLD-PCR/fluorescence melting curve analysis technique showed the presence of BRAF mutation in all positive samples. Melting curve analysis demonstrates the presence of a single peak for BRAF wild-type sequence (black) and the presence of a wild-type peak and mutant peak for BRAF high-positive control (50% mutation) (blue) and low-positive control (5% mutation) (red). BRAF-positive patient tumor sample is depicted in green.Grahic Jump Location

From a clinical perspective, all patients represented by these cases are alive with stable pulmonary function. No association of histology and BRAF mutations with clinical behavior was noted in this survey study.

BRAF is part of the intracellular Ras-Raf/mitogen-activated protein kinase signaling pathway that is responsible for several cell functions, primarily cell proliferation, differentiation, migration, and senescence/apoptosis. Mutations in BRAF have been associated with the development of aggressive neoplasms, including malignant melanoma, colonic adenocarcinoma, papillary thyroid carcinoma, and lung adenocarcinoma.2332BRAF mutations also have been described in myelomonocytic hematolymphoid proliferations most commonly in 60% of cases of LCH described by Badalian-Very et al18 and Satoh et al.20 Both studies focused on systemic forms of LCH, and both noted the clonal nature of the proliferations. Only Badalian-Very et al18 reported on the localized adult form of PLCH. They examined with a mass spectrometry approach a single nodule in five cases, finding as we did that 40% of the cases had BRAF V600E mutations. The present study was unique in that it examined multiple lung nodules in five patients who presented in adulthood with bilateral lung disease with innumerable nodules identified on high-resolution CT scans. Of note, we demonstrated that if a BRAF V600 mutation was present in one nodule, all the examined nodules had the identical mutation, and the same held true in 60% of the cases that did not have BRAF alterations. This concordance of BRAF mutation occurrence suggests that PLCH is a clonal process in which BRAF alterations occur as an early mutational event or that some PLCH proliferations may not require BRAF mutations at all but have a separate and distinct molecular evolution.

An interesting epidemiologic relationship exists between the development of PLCH and cigarette smoking, an association described in nearly all large series.15 It is challenging to explain this association of tobacco use with what appears to be a clonal proliferation arising in adulthood as bilateral multifocal nodular pulmonary disease. Although it is tempting to associate the inhalation of cigarette smoke into the lungs with locoregional stimulation of intrinsic Langerhans cells in the bronchovascular bundle, the observation that either all or none of the nodules have the identical BRAF V600E mutational status would be statistically rare (likelihood of all five independent tumors to have BRAF mutation is 0.031). One could speculate a germline predisposition to BRAF V600 transversion, which is activated by inhaled tobacco smoke, resulting in these multiclonal BRAF V600 proliferations. A more appealing and biologically reasonable possibility is that rather than having a local proliferative effect on preexistent in situ pulmonary Langerhans cells, cigarette smoke has a systemic effect, stimulating sensitized Langerhans cell precursors in the bone marrow. Once a mutational event occurs, the activated Langerhans cells would migrate selectively to the lung, producing the clonal pulmonary nodular disease.

As noted by Nezelof and Basset33,34 and highlighted by many other authors,9,12,16 the status of host immune surveillance and dysregulation plays a major role in LCH. This is obvious in the very histology of the Langerhans cell nodule, where the Langerhans cells can be obscured by eosinophils, macrophages, lymphocytes, and stromal mesenchymal cells. The impact of these secondary elements on the development, evolution, and persistence of Langerhans cell nodules or clones is unclear, although certainly individuals with impaired immunity are predisposed to both systemic LCH and PLCH disease.5,33 Additionally, the influence of these infiltrating cells on spontaneous involution of the lesions with or without BRAF V600E-predisposed cellular apoptosis is yet to be elucidated.

In malignant melanoma and lung, thyroid, and colonic adenocarcinoma, mutations of BRAF V600E in epithelial cells acts as a driver mutation for neoplastic transformation.2231 In these settings, targeted therapy with drugs against mutated BRAF has been shown to have provisional success. We are not aware of the use of such drugs in progressive systemic or pulmonary forms of LCH, but such studies would be worthwhile, especially because some of these drugs are approved by the Food and Drug Administration for disease nonresponsive to conventional therapy.25,26 This option needs to be investigated in progressive PLCH.

Author contributions: Dr Yousem had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Yousem: contributed to the clinical, pathologic, and immunohistochemical assessment, and writing and review of the manuscript.

Dr Dacic: contributed to the clinical, pathologic, and immunohistochemical assessment, and writing and review of the manuscript.

Dr Y. E. Nikiforov: contributed to the next-generation sequencing and writing and review of the manuscript.

Dr M. Nikiforova: contributed to the next-generation sequencing and writing and review of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: We thank Diana Winters for secretarial and technical assistance.

LCH

Langerhans cell histiocytosis

PCR

polymerase chain reaction

PLCH

pulmonary Langerhans cell histiocytosis

Aubry MC, Wright JL, Myers JL. The pathology of smoking-related lung diseases. Clin Chest Med. 2000;21(1):11-35. [CrossRef] [PubMed]
 
Desai SR, Ryan SM, Colby TV. Smoking-related interstitial lung diseases: histopathological and imaging perspectives. Clin Radiol. 2003;58(4):259-268. [CrossRef] [PubMed]
 
Hansell DM, Nicholson AG. Smoking-related diffuse parenchymal lung disease: HRCT-pathologic correlation. Semin Respir Crit Care Med. 2003;24(4):377-392. [CrossRef] [PubMed]
 
Travis WD, Borok Z, Roum JH, et al. Pulmonary Langerhans cell granulomatosis (histiocytosis X). A clinicopathologic study of 48 cases. Am J Surg Pathol. 1993;17(10):971-986. [CrossRef] [PubMed]
 
Vassallo R, Ryu JH, Colby TV, Hartman T, Limper AH. Pulmonary Langerhans’-cell histiocytosis. N Engl J Med. 2000;342(26):1969-1978. [CrossRef] [PubMed]
 
Betts DR, Leibundgut KE, Feldges A, Plüss HJ, Niggli FK. Cytogenetic abnormalities in Langerhans cell histiocytosis. Br J Cancer. 1998;77(4):552-555. [CrossRef] [PubMed]
 
Chikwava KR, Hunt JL, Mantha GS, Murphy JE, Jaffe R. Analysis of loss of heterozygosity in single-system and multisystem Langerhans’ cell histiocytosis. Pediatr Dev Pathol. 2007;10(1):18-24. [CrossRef] [PubMed]
 
Cotter FE, Pritchard J. Clonality in Langerhans’ cell histiocytosis. BMJ. 1995;310(6972):74-75. [CrossRef] [PubMed]
 
da Costa CET, Szuhai K, van Eijk R, et al. No genomic aberrations in Langerhans cell histiocytosis as assessed by diverse molecular technologies. Genes Chromosomes Cancer. 2009;48(3):239-249. [CrossRef] [PubMed]
 
Dacic S, Trusky C, Bakker A, Finkelstein SD, Yousem SA. Genotypic analysis of pulmonary Langerhans cell histiocytosis. Hum Pathol. 2003;34(12):1345-1349. [CrossRef] [PubMed]
 
De Filippi P, Badulli C, Cuccia M, et al. Specific polymorphisms of cytokine genes are associated with different risks to develop single-system or multi-system childhood Langerhans cell histiocytosis. Br J Haematol. 2006;132(6):784-787. [CrossRef] [PubMed]
 
Egeler RM, Annels NE, Hogendoorn PC. Langerhans cell histiocytosis: a pathologic combination of oncogenesis and immune dysregulation. Pediatr Blood Cancer. 2004;42(5):401-403. [CrossRef] [PubMed]
 
Murakami I, Gogusev J, Fournet JC, Glorion C, Jaubert F. Detection of molecular cytogenetic aberrations in Langerhans cell histiocytosis of bone. Hum Pathol. 2002;33(5):555-560. [CrossRef] [PubMed]
 
Rodig SJ, Payne EG, Degar BA, et al. Aggressive Langerhans cell histiocytosis following T-ALL: clonally related neoplasms with persistent expression of constitutively active NOTCH1. Am J Hematol. 2008;83(2):116-121. [CrossRef] [PubMed]
 
Weintraub M, Bhatia KG, Chandra RS, Magrath IT, Ladisch S. p53 expression in Langerhans cell histiocytosis. J Pediatr Hematol Oncol. 1998;20(1):12-17. [CrossRef] [PubMed]
 
Wu WS, McClain KL. DNA polymorphisms and mutations of the tumor necrosis factor-alpha (TNF-alpha) promoter in Langerhans cell histiocytosis (LCH). J Interferon Cytokine Res. 1997;17(10):631-635. [CrossRef] [PubMed]
 
Yousem SA, Colby TV, Chen YY, Chen WG, Weiss LM. Pulmonary Langerhans’ cell histiocytosis: molecular analysis of clonality. Am J Surg Pathol. 2001;25(5):630-636. [CrossRef] [PubMed]
 
Badalian-Very G, Vergilio JA, Degar BA, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010;116(11):1919-1923. [CrossRef] [PubMed]
 
Kamionek M, Welch M, Tomaszewicz K, et al. BRAF mutation analysis in pulmonary Langerhans cell histiocytosis [abstract]. Mod Pathol. 2012;25(suppl 2):479A.
 
Satoh T, Smith A, Sarde A, et al. B-RAF mutant alleles associated with Langerhans cell histiocytosis, a granulomatous pediatric disease [published correction in.PLoS One. 2012;7(6)]. PLoS ONE. 2012;7(4):e33891. [CrossRef] [PubMed]
 
Nikiforov YE, Ohori NP, Hodak SP, et al. Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules: a prospective analysis of 1056 FNA samples. J Clin Endocrinol Metab. 2011;96(11):3390-3397. [CrossRef] [PubMed]
 
De Oliveira Duarte Achcar R, Nikiforova MN, Yousem SA. Micropapillary lung adenocarcinoma: EGFR, K-ras, and BRAF mutational profile. Am J Clin Pathol. 2009;131(5):694-700. [CrossRef] [PubMed]
 
Amaria RN, Lewis KD, Jimeno A. Vemurafenib: the road to personalized medicine in melanoma. Drugs Today (Barc). 2012;48(2):109-118. [PubMed]
 
Chang DT, Pai RK, Rybicki LA, et al. Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features. Mod Pathol. 2012;25(8):1128-1139. [CrossRef] [PubMed]
 
Finn L, Markovic SN, Joseph RW. Therapy for metastatic melanoma: the past, present, and future. BMC Med. 2012;10:23. [CrossRef] [PubMed]
 
Kudchadkar R, Paraiso KH, Smalley KS. Targeting mutant BRAF in melanoma: current status and future development of combination therapy strategies. Cancer J. 2012;18(2):124-131. [CrossRef] [PubMed]
 
Nikiforov YE. Molecular diagnostics of thyroid tumors. Arch Pathol Lab Med. 2011;135(5):569-577. [PubMed]
 
Pai RK, Jayachandran P, Koong AC, et al. BRAF-mutated, microsatellite-stable adenocarcinoma of the proximal colon: an aggressive adenocarcinoma with poor survival, mucinous differentiation, and adverse morphologic features. Am J Surg Pathol. 2012;36(5):744-752. [CrossRef] [PubMed]
 
Paik PK, Arcila ME, Fara M, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol. 2011;29(15):2046-2051. [CrossRef] [PubMed]
 
Yokota T, Ura T, Shibata N, et al. BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer. Br J Cancer. 2011;104(5):856-862. [CrossRef] [PubMed]
 
Yousem SA, Nikiforova M, Nikiforov Y. The histopathology of BRAF-V600E-mutated lung adenocarcinoma. Am J Surg Pathol. 2008;32(9):1317-1321. [CrossRef] [PubMed]
 
Nikiforov YE, Nikiforova MN. Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol. 2011;7(10):569-580. [CrossRef] [PubMed]
 
Nezelof C, Basset F. Langerhans cell histiocytosis research. Past, present, and future. Hematol Oncol Clin North Am. 1998;12(2):385-406. [CrossRef] [PubMed]
 
Nezelof C, Basset F. An hypothesis Langerhans cell histiocytosis: the failure of the immune system to switch from an innate to an adaptive mode. Pediatr Blood Cancer. 2004;42(5):398-400. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. The lesion of pulmonary Langerhans cell histiocytosis appears as a stellate centrilobular nodule with adjacent airspaces filled with smokers-type macrophages (hematoxylin-eosin, original magnification ×40).Grahic Jump Location
Figure Jump LinkFigure 2. Within the stellate nodule of pulmonary Langerhans cell histiocytosis are a mixture of cells dominated by the characteristic Langerhans cell with folded reniform nuclei and eosinophilic cytoplasm. In the background are smokers-type pigmented macrophages, bilobed eosinophils, lymphocytes, and stromal myofibroblasts. There were no distinctive histologic features that separated cases with and without BRAF V600E mutations (hematoxylin-eosin, original magnification ×600).Grahic Jump Location
Figure Jump LinkFigure 3. Microdissection allowed the entirety of each pulmonary Langerhans cell histiocytosis nodule to be analyzed with next-generation DNA sequencing (hematoxylin-eosin, original magnification ×40).Grahic Jump Location
Figure Jump LinkFigure 4. Detection of the BRAF c.1799T>A, p.V600E mutation by the Ion Personal Genome Machine (PGM) next-generation sequencing platform (Life Technologies Corporation), Sanger sequencing, and COLD-PCR (coamplification at lower denaturation polymerase chain reaction). A, BRAF mutation detected by the Ion PGM Sequencer visualized using the Integrative Genomics Viewer (Broad Institute). B, Sanger sequencing confirmed the presence of T-to-A substitution at codon 1799. C, The COLD-PCR/fluorescence melting curve analysis technique showed the presence of BRAF mutation in all positive samples. Melting curve analysis demonstrates the presence of a single peak for BRAF wild-type sequence (black) and the presence of a wild-type peak and mutant peak for BRAF high-positive control (50% mutation) (blue) and low-positive control (5% mutation) (red). BRAF-positive patient tumor sample is depicted in green.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Clinicopathologic and Molecular Data on Cases of Pulmonary Langerhans Cell Histiocytosis

F = female; HRCT = high-resolution CT; M = male.

Table Graphic Jump Location
Table 2 —Cancer Genes on Ion AmpliSeq Cancer Panel (Life Technologies Corporation) Interrogated by Next-Generation Sequencing

References

Aubry MC, Wright JL, Myers JL. The pathology of smoking-related lung diseases. Clin Chest Med. 2000;21(1):11-35. [CrossRef] [PubMed]
 
Desai SR, Ryan SM, Colby TV. Smoking-related interstitial lung diseases: histopathological and imaging perspectives. Clin Radiol. 2003;58(4):259-268. [CrossRef] [PubMed]
 
Hansell DM, Nicholson AG. Smoking-related diffuse parenchymal lung disease: HRCT-pathologic correlation. Semin Respir Crit Care Med. 2003;24(4):377-392. [CrossRef] [PubMed]
 
Travis WD, Borok Z, Roum JH, et al. Pulmonary Langerhans cell granulomatosis (histiocytosis X). A clinicopathologic study of 48 cases. Am J Surg Pathol. 1993;17(10):971-986. [CrossRef] [PubMed]
 
Vassallo R, Ryu JH, Colby TV, Hartman T, Limper AH. Pulmonary Langerhans’-cell histiocytosis. N Engl J Med. 2000;342(26):1969-1978. [CrossRef] [PubMed]
 
Betts DR, Leibundgut KE, Feldges A, Plüss HJ, Niggli FK. Cytogenetic abnormalities in Langerhans cell histiocytosis. Br J Cancer. 1998;77(4):552-555. [CrossRef] [PubMed]
 
Chikwava KR, Hunt JL, Mantha GS, Murphy JE, Jaffe R. Analysis of loss of heterozygosity in single-system and multisystem Langerhans’ cell histiocytosis. Pediatr Dev Pathol. 2007;10(1):18-24. [CrossRef] [PubMed]
 
Cotter FE, Pritchard J. Clonality in Langerhans’ cell histiocytosis. BMJ. 1995;310(6972):74-75. [CrossRef] [PubMed]
 
da Costa CET, Szuhai K, van Eijk R, et al. No genomic aberrations in Langerhans cell histiocytosis as assessed by diverse molecular technologies. Genes Chromosomes Cancer. 2009;48(3):239-249. [CrossRef] [PubMed]
 
Dacic S, Trusky C, Bakker A, Finkelstein SD, Yousem SA. Genotypic analysis of pulmonary Langerhans cell histiocytosis. Hum Pathol. 2003;34(12):1345-1349. [CrossRef] [PubMed]
 
De Filippi P, Badulli C, Cuccia M, et al. Specific polymorphisms of cytokine genes are associated with different risks to develop single-system or multi-system childhood Langerhans cell histiocytosis. Br J Haematol. 2006;132(6):784-787. [CrossRef] [PubMed]
 
Egeler RM, Annels NE, Hogendoorn PC. Langerhans cell histiocytosis: a pathologic combination of oncogenesis and immune dysregulation. Pediatr Blood Cancer. 2004;42(5):401-403. [CrossRef] [PubMed]
 
Murakami I, Gogusev J, Fournet JC, Glorion C, Jaubert F. Detection of molecular cytogenetic aberrations in Langerhans cell histiocytosis of bone. Hum Pathol. 2002;33(5):555-560. [CrossRef] [PubMed]
 
Rodig SJ, Payne EG, Degar BA, et al. Aggressive Langerhans cell histiocytosis following T-ALL: clonally related neoplasms with persistent expression of constitutively active NOTCH1. Am J Hematol. 2008;83(2):116-121. [CrossRef] [PubMed]
 
Weintraub M, Bhatia KG, Chandra RS, Magrath IT, Ladisch S. p53 expression in Langerhans cell histiocytosis. J Pediatr Hematol Oncol. 1998;20(1):12-17. [CrossRef] [PubMed]
 
Wu WS, McClain KL. DNA polymorphisms and mutations of the tumor necrosis factor-alpha (TNF-alpha) promoter in Langerhans cell histiocytosis (LCH). J Interferon Cytokine Res. 1997;17(10):631-635. [CrossRef] [PubMed]
 
Yousem SA, Colby TV, Chen YY, Chen WG, Weiss LM. Pulmonary Langerhans’ cell histiocytosis: molecular analysis of clonality. Am J Surg Pathol. 2001;25(5):630-636. [CrossRef] [PubMed]
 
Badalian-Very G, Vergilio JA, Degar BA, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010;116(11):1919-1923. [CrossRef] [PubMed]
 
Kamionek M, Welch M, Tomaszewicz K, et al. BRAF mutation analysis in pulmonary Langerhans cell histiocytosis [abstract]. Mod Pathol. 2012;25(suppl 2):479A.
 
Satoh T, Smith A, Sarde A, et al. B-RAF mutant alleles associated with Langerhans cell histiocytosis, a granulomatous pediatric disease [published correction in.PLoS One. 2012;7(6)]. PLoS ONE. 2012;7(4):e33891. [CrossRef] [PubMed]
 
Nikiforov YE, Ohori NP, Hodak SP, et al. Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules: a prospective analysis of 1056 FNA samples. J Clin Endocrinol Metab. 2011;96(11):3390-3397. [CrossRef] [PubMed]
 
De Oliveira Duarte Achcar R, Nikiforova MN, Yousem SA. Micropapillary lung adenocarcinoma: EGFR, K-ras, and BRAF mutational profile. Am J Clin Pathol. 2009;131(5):694-700. [CrossRef] [PubMed]
 
Amaria RN, Lewis KD, Jimeno A. Vemurafenib: the road to personalized medicine in melanoma. Drugs Today (Barc). 2012;48(2):109-118. [PubMed]
 
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