ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

Murine Double Minute Clone 2, located at 12q15, is an oncogene that codes for an oncoprotein of which the association with p53 was discovered 30 years ago. The most important function of MDM2 is to control p53 activity; it is in fact the best documented negative regulator of p53. Mutations of the tumor suppressor gene p53 represent the most frequent genetic change in human cancers. By overexpressing MDM2, cancer cells have another means to block p53. The sarcomas in which MDM2 amplification is a hallmark are well-differentiated liposarcoma/atypical lipomatous tumor, dedifferentiated liposarcoma, intimal sarcoma, and low-grade osteosarcoma. The purpose of this review is to summarize the typical clinical, histopathological, immunohistochemical, and genetic features of these tumors.

Purpose: Gastrointestinal stromal tumors (GIST) are commonly treated with tyrosine kinase inhibitors (TKI). The majority of patients with advanced GIST ultimately become resistant to TKI due to acquisition of secondary KIT mutations, while primary resistance is mainly caused by PDGFRA p.D842V mutation. We tested the activity of avapritinib, potent and highly selective inhibitor of mutated KIT and PDGFRA, in three patient-derived xenograft (PDX) GIST models carrying different KIT mutations, with differential sensitivity to standard TKI. Experimental Design: NMRI nu/nu mice (n=93) were transplanted with human GIST xenografts with KIT exon 11+17 (UZLX-GIST9^KIT11+17), exon 11 (UZLX-GIST3^KIT11) or exon 9 (UZLX-GIST2B^KIT9) mutations, respectively. We compared avapritinib (10 and 30 mg/kg/qd) vs. vehicle, imatinib (50 mg/kg/bid) or regorafenib (30 mg/kg/qd) [UZLX-GIST9^KIT11+17]; avapritinib (10, 30, 100 mg/kg/qd) vs. vehicle or imatinib [UZLX-GIST3^KIT11]; and avapritinib (10, 30, 60 mg/kg/qd) vs. vehicle, imatinib (50, 100 mg/kg/bid) or sunitinib (40 mg/kg/qd) [UZLX-GIST2B^KIT9].Results: In all models avapritinib resulted in reduction of tumor volume, significant inhibition of proliferation and reduced KIT signaling. In two models, avapritinib led to remarkable histologic responses, increase in apoptosis and inhibition of MAPK-phosphorylation. Avapritinib showed superior (UZLX-GIST9^{KIT 11+17} and -GIST2B^KIT9) or equal (UZLX-GIST3^KIT11) anti-tumor activity to standard dose of imatinib. In UZLX-GIST9^KIT11+17, the anti-tumor effects of avapritinib were significantly better than with imatinib or regorafenib. Conclusions: Avapritinib has significant anti-tumor activity in GIST PDX models characterized by different KIT mutations and sensitivity to established TKI. These data provide strong support for ongoing clinical trials with avapritinib in patients with GIST (NCT02508532, NCT03465722).

Background: Hemangioblastomas are associated with Von Hippel-Lindau disease (VHLD) in 10-40% of cases. Based upon a literature review we state the core features the neurosurgeon should be aware of. Methods: We performed a selective literature (Cochrane and Medline) search for hemangioblastoma, both sporadic and VHL associated. We reviewed general characteristics (epidemiology, symptomatology, diagnosis, and management) and focused on follow-up as well as screening modalities for sporadic and VHL associated lesions. Results: Based upon our literature search, we established guidelines for screening and follow-up in both sporadic and VHL associated hemangioblastoma patients. Conclusions: Screening for retinal angiomas, abdominal masses, and pheochromocytomas as well as genetic analysis is recommended for every patient with a newly diagnosed hemangioblastoma. Follow-up is by magnetic resonance imaging (MRI) of the clinical neuronal region at 6 and at 12-24 months postoperatively.For VHL-associated hemangioblastomas yearly investigation for craniospinal hemangioblastoma by MRI and yearly screening and follow-up for retinal angiomas is recommended. Annual abdominal ultrasound with triennial computed tomography (CT) imaging for abdominal masses is postulated. Annual audiometry is to be performed for possible endolymphatic sac tumor, detailed radiographic imaging of the skull base should be performed upon abnormality in auditory testing. Investigations for cystadenomas of the epidydimis and broad ligament only are mandatory on indication. Annual investigation for pheochromocytoma is recommended.