Pathology of Histiocytic Disorders and Neoplasms and Related Disorders

Picarsic, Jennifer; Jaffe, Ronald

doi:10.1007/978-3-319-59632-7_1

Cited by 19 publications

(16 citation statements)

References 159 publications

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“…Following institutional review board approval (University of Pittsburgh IRB number PRO12110055), we retrieved cases from our pathology consult files for CNS-based JXG family lesions, which includes previously published pediatric cases [14, 55, 57]. In our initial inclusion criteria, we included all cases that were diagnosed as a JXG family neoplasm by morphology and immunophenotype, as previously described [8, 50, 59]. In brief, JXG family neoplasms range from 1) small to intermediate-sized mononuclear histiocytes, to 2) abundant foamy, xanthomatous (i.e.…”

Section: Methodsmentioning

confidence: 99%

BRAF V600E mutation in Juvenile Xanthogranuloma family neoplasms of the central nervous system (CNS-JXG): a revised diagnostic algorithm to include pediatric Erdheim-Chester disease

Picarsic

Pysher

Zhou

et al. 2019

acta neuropathol commun

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The family of juvenile xanthogranuloma family neoplasms (JXG) with ERK-pathway mutations are now classified within the “L” (Langerhans) group, which includes Langerhans cell histiocytosis (LCH) and Erdheim Chester disease (ECD). Although the BRAF V600E mutation constitutes the majority of molecular alterations in ECD and LCH, only three reported JXG neoplasms, all in male pediatric patients with localized central nervous system (CNS) involvement, are known to harbor the BRAF mutation. This retrospective case series seeks to redefine the clinicopathologic spectrum of pediatric CNS-JXG family neoplasms in the post-BRAF era, with a revised diagnostic algorithm to include pediatric ECD. Twenty-two CNS-JXG family lesions were retrieved from consult files with 64% (n = 14) having informative BRAF V600E mutational testing (molecular and/or VE1 immunohistochemistry). Of these, 71% (n = 10) were pediatric cases (≤18 years) and half (n = 5) harbored the BRAF V600E mutation. As compared to the BRAF wild-type cohort (WT), the BRAF V600E cohort had a similar mean age at diagnosis [BRAF V600E: 7 years (3–12 y), vs. WT: 7.6 years (1–18 y)] but demonstrated a stronger male/female ratio (BRAF V600E: 4 vs WT: 0.67), and had both more multifocal CNS disease ( BRAFV600E: 80% vs WT: 20%) and systemic disease (BRAF V600E: 40% vs WT: none). Radiographic features of CNS-JXG varied but typically included enhancing CNS mass lesion(s) with associated white matter changes in a subset of BRAF V600E neoplasms. After clinical-radiographic correlation, pediatric ECD was diagnosed in the BRAF V600E cohort. Treatment options varied, including surgical resection, chemotherapy, and targeted therapy with BRAF-inhibitor dabrafenib in one mutated case. BRAF V600E CNS-JXG neoplasms appear associated with male gender and aggressive disease presentation including pediatric ECD. We propose a revised diagnostic algorithm for CNS-JXG that includes an initial morphologic diagnosis with a final integrated diagnosis after clinical-radiographic and molecular correlation, in order to identify cases of pediatric ECD. Future studies with long-term follow-up are required to determine if pediatric BRAF V600E positive CNS-JXG neoplasms are a distinct entity in the L-group histiocytosis category or represent an expanded pediatric spectrum of ECD.

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Section: Methodsmentioning

confidence: 99%

BRAF V600E mutation in Juvenile Xanthogranuloma family neoplasms of the central nervous system (CNS-JXG): a revised diagnostic algorithm to include pediatric Erdheim-Chester disease

Picarsic

Pysher

Zhou

et al. 2019

acta neuropathol commun

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“…Thus, the focally high proliferation rate (40%) in the MS4A6A-BRAF JXG family lesion was the first correlate to its aggressive clinical behavior. On the contrary, the MTAP-BRAF malignant histiocytic neoplasm had only modestly elevated proliferation rate (up to 20%), which is lower than most malignant histiocytic neoplasms (often >30%) 20 . This may correlate with its more indolent behavior, despite its high-grade cytologic features.…”

mentioning

confidence: 73%

Novel BRAF fusions in pediatric histiocytic neoplasms define distinct therapeutic responsiveness to RAF paradox breakers

Jain

Surrey²,

Straka

et al. 2020

Preprint

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Running Title: Novel BRAF fusions in pediatric histiocytic tumors Histiocytic neoplasms are a diverse group of clonal hematopoietic disorders that are driven by mutations activating the mitogen-activated protein kinase (MAPK) and phosphoinositide 3kinases (PI3K) pathways 1-3 . While BRAF-V600E is the most common alteration in histiocytic neoplasms, multiple alternate pathway activating mechanisms have been described, including MAP2K1, ARAF, PIK3CA, NRAS, and KRAS mutations as well as BRAF, ALK, and NTRK1 fusions 1-3 . BRAF-fusions previously reported in cases of histiocytic neoplasms 1,4-7 were found to contain the N-terminal region of another gene (often of unclear significance) joined to the BRAF kinase domain (including exons 9-18 or 11-18), resulting in the loss of the BRAF N-terminal regulatory RAS-binding regions (exons 1-8). Despite the prevalence of BRAF-alterations in histiocytic tumors, to date there have been no detailed molecular investigations comparing BRAF-fusions found in distinct sub-types of histiocytic neoplasms and only one study explored responsiveness of such BRAF-fusions to single-agent RAF-therapies 4 . To address this, we present two pediatric histiocytosis cases with divergent pathologic and clinical features, each harboring a novel BRAFfusion as identified by a clinically validated next-generation sequencing panel (Supplemental Methods and Table 1) and study their in vitro responsiveness to RAF-targeted inhibitors.2 Case 1, a 16 year-old female with a 2.5 cm rapidly growing subcutaneous thigh mass was diagnosed with a malignant histiocytic neoplasm ("M group") 8 , with a phenotype spanning histiocytic sarcoma (CD163/CD14/CD68+) and Langerhans cell sarcoma (CD1a/Langerin/S100) with a modestly elevated Ki-67 proliferation index (up to 20%) ( Figure 1A-F). Targeted RNAsequencing identified a fusion of MTAP (NM_002451.3) exons 1-7 to BRAF (NM_004333.4) exons 9-18. Resection margins were negative. The patient is disease-free three years post-resection. Case 2, a 12-year-old female with a 5.3 cm rapidly enlarging heel mass encasing and invading the calcaneus was diagnosed with a juvenile xanthogranuloma (JXG) family lesion (CD163/CD68/CD14/fascin/Factor XIIIa+) ( Figure 1G-M). Despite the lack of cytologic atypia or increased mitotic rate by H&E stain, a Ki-67 proliferation index stain revealed increased staining in lesional cells up to 40%. Targeted RNA-seq identified a fusion of MS4A6A (NM_022349.3) exons 1-6 and BRAF (NM_004333.4) exons 11-18. During staging, the patient was found to have PET-avid dissemination to lymph nodes and lung ( Figure 1N-P). While the morphologic features were consistent with a low-grade histiocytic lesion of JXG phenotype, the integration of the 1) high Ki-67 proliferation index, 2) aggressive clinical behavior with lymphatic/metastatic-like spread, and 3) novel molecular BRAF-fusion suggested an atypical JXG family neoplasm with uncertain biological behavior. The patient was treated with 12 cycles of clofarabine with clinical remission of metastatic sites and ne...

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“…The biopsy specimens obtained from the second surgical debulking were most notable for having numerous “RDD cells”: large, S-100-positive histiocytes with “watery-clear” or “foamy” cytoplasm and a hypochromatic nucleus with a conspicuous nucleolus (Fig. 3 k) [ 25 ]. Emperipolesis, another canonical feature of RDD, was also observed (Fig.…”

Section: Discussionmentioning

confidence: 99%

Orbital Rosai-Dorfman disease initially diagnosed as IgG4-related disease: a case report

Iyengar¹,

Golub

McQuinn³

et al. 2020

acta neuropathol commun

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Inflammatory orbital lesions include a broad list of diagnoses, many of them with overlapping clinical and radiographic features. They often present a diagnostic conundrum, even to the most experienced orbital specialist, thus placing considerable weight on surgical biopsy and histopathological analysis. However, histopathological diagnosis is also inherently challenging due to the rarity of these lesions and the overlaps in histologic appearance among distinct disease entities. We herein present the case of an adolescent male with a subacutely progressive orbital mass that generated a significant diagnostic dilemma. Early orbital biopsy was consistent with a benign fibro-inflammatory lesion, but corticosteroid therapy was ineffective in halting disease progression. After an initial substantial surgical debulking, histopathological analysis revealed several key features consistent with IgG4-related disease (IgG4-RD), a systemic fibro-inflammatory process typically accompanied by multifocal tumor-like lesions. Surprisingly, within months, there was clear evidence of clinical and radiographic disease progression despite second-line rituximab treatment, prompting a second surgical debulking. This final specimen displayed distinctive features of Rosai-Dorfman disease (RDD), a systemic inflammatory disease characterized by uncontrolled histiocytic proliferation. Interestingly, certain features of this re-excision specimen were still reminiscent of IgG4-RD, which not only reflects the difficulty in differentiating RDD from IgG4-RD in select cases, but also illustrates that these diagnoses may exist along a spectrum that likely reflects a common underlying pathogenetic mechanism. This case emphasizes the importance of surgical biopsy or resection and histopathological analysis in diagnosing—and, ultimately, treating—rare, systemic inflammatory diseases involving the orbit, and, furthermore, highlights the shared histopathological features between RDD and IgG4-RD.

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Pathology of Histiocytic Disorders and Neoplasms and Related Disorders

Cited by 19 publications

References 159 publications

BRAF V600E mutation in Juvenile Xanthogranuloma family neoplasms of the central nervous system (CNS-JXG): a revised diagnostic algorithm to include pediatric Erdheim-Chester disease

BRAF V600E mutation in Juvenile Xanthogranuloma family neoplasms of the central nervous system (CNS-JXG): a revised diagnostic algorithm to include pediatric Erdheim-Chester disease

Novel BRAF fusions in pediatric histiocytic neoplasms define distinct therapeutic responsiveness to RAF paradox breakers

Orbital Rosai-Dorfman disease initially diagnosed as IgG4-related disease: a case report

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