Koster, Matthew J.

ObjectiveAlthough granulomatosis with polyangiitis (GPA; Wegener’s granulomatosis) is classically characterized by systemic disease involving the kidneys and airway, approximately 10% of patients who have it present with isolated central nervous system disease. When involving the skull base, GPA frequently mimics more common pathology, resulting in diagnostic challenges and delay. The primary objective of this study is to characterize the cranial base manifestations of GPA, highlighting aspects most relevant to the skull base surgeon.Study DesignRetrospective review.SettingTertiary academic referral center.Subjects and MethodsRetrospective analysis of all patients with skull base GPA treated at a tertiary referral center from January 1, 1996, to May 1, 2018.ResultsTwenty‐nine patients met inclusion criteria. Twenty‐one (72%) initially presented with skull base symptomatology as their cardinal manifestation of GPA. Twenty‐four (82%) presented with cranial neuropathy at some point in their disease course. The trigeminal nerve was most commonly involved (12 of 24, 50%), followed by the facial (11 of 24, 46%) and optic (8 of 24, 33%) nerves. Eighteen patients reported hearing loss attributed to the GPA disease process, presenting as conductive, sensorineural, or mixed. The most common locations for GPA‐derived inflammatory skull base disease on imaging included the cavernous sinus (12 of 29, 41%) and the orbit (7 of 29, 24%).ConclusionEstablishing the diagnosis of skull base GPA remains challenging. Cranial neuropathy is diverse in presentation and often mimics more common conditions. Imaging findings are also unpredictable and frequently nonspecific. Careful review of patient history, clinical presentation, serology and biopsy results, and imaging can reveal important clues toward the diagnosis.

Abstract Objective To characterize inpatient epidemiology and economic burden of granulomatosis with polyangiitis (GPA). Methods Patients with GPA were identified from the Nationwide Inpatient Sample (NIS), the largest inpatient database in the USA consisting of over 4000 non-federal acute care hospitals, using the ICD-9 CM code. A cohort of comparators without GPA was also constructed from the same database. Data on demographics, procedures, length of stay, mortality, morbidity and total hospitalization charges were extracted. All analysed data were extracted from the database for the years 2005–2014. Results The inpatient prevalence of GPA was 32.6 cases per 100 000 admissions. GPA itself (38.3%), pneumonia (13.7%) and sepsis (8.4%) were the most common reasons for admission. After adjusting for potential confounders, the all-cause mortality adjusted odds ratio (aOR) of patients with GPA was significantly higher than that of patients without GPA (aOR 1.20; 95% CI: 1.41, 1.61). This was also true for several morbidities, including acute kidney injury, multi-organ failure, shock and need for intensive care unit admission. Hospitalizations of patients with GPA were associated with higher cost as demonstrated by an adjusted additional mean of $5125 (95% CI: $4719, $5531) for total hospital cost and an adjusted additional mean of $16 841 (95% CI: $15 280, $18 403) for total hospitalization charges when compared with patients without GPA. Conclusion Inpatient prevalence of GPA was higher than what would be expected from prevalence in the general population. Hospitalizations of patients with GPA were associated with higher morbidity, mortality and cost.

Abstract Introduction Histiocytic neoplasms are rare hematological malignancies that have protean clinical manifestations and can pose significant management challenges. Recently, vemurafenib was approved by the US-FDA for treatment of BRAF-V600-mutant Erdheim-Chester disease (ECD). However, there is a lack of FDA-approved therapies for other histiocytic neoplasms such as Langerhans cell histiocytosis (LCH) and Rosai-Dorfman disease (RDD). Over the last 5 years, immune checkpoint inhibitors such as programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have shown significant improvement in outcomes among patients with several hematological and solid organ malignancies. In order to identify appropriate treatment candidates for these therapies, predictive biomarkers have been developed in various cancers. Evidence from solid tumors has suggested a favorable response to checkpoint inhibitor therapy with higher tumor mutational burden (TMB), defined as the number of mutations within a tumor genome. Next generation sequencing (NGS) of various tumors has shown an association between TMB of < 5 mutations/megabase (mut/Mb) to be associated with an absence of benefit from checkpoint inhibitors. In addition, high levels of PD-1/PD-L1 expression and microsatellite instability (MSI) are also correlated with response to therapy. The latter may be a result of somatic or germline alterations in DNA mismatch repair genes. In this study, we report the results for these biomarkers using NGS in patients with histiocytic neoplasms. Methods We utilized TempusTM NGS platform to analyze the tissue specimen of patients with histiocytic neoplasm. The Tempus xO Assay (Tempus Labs; Chicago, IL) combines a 1,711 gene targeted somatic and germline DNA sequencing panel with RNA-sequencing to detect both germline and somatic single nucleotide polymorphisms, indels, copy number variants, and gene rearrangements causing chimeric mRNA transcript expression in a wide array of solid tumor types. The assay utilizes formalin-fixed paraffin-embedded tumor samples and matched blood samples. TMB was calculated and reported as somatic mutations in tumor tissue per million base-pairs or mut/Mb. RNA sequencing was utilized to assess for PD-L1 and PD-1 gene expressions as compared to matched tumor and normal reference sets. Both PD-L1 and PD-1 gene expressions were reported as percentiles. DNA mismatch repair status was predicted by analysis of alterations in five common mismatch repair genes in somatic and germline DNA (MSH2, MSH6, MLH1, PMS2, and EPCAM). If there were no alterations identified in these genes, the mismatch repair status was predicted as microsatellite stable (MSS). Results A total of 13 patients with histiocytic neoplasms were included in the study. The distribution of individual histiocytic neoplasms was as follows: RDD (n=9), ECD (n=3), and LCH (n=1). The median TMB for RDD and ECD patients was 0.17 mut/Mb. For the one patient with LCH, the TMB level was 0.51 mut/Mb. Individual TMB levels are shown in figure 1. PD-L1 and PD-1 expression levels are depicted in table 1. Compared to normal reference sets, the PD-L1 expression was elevated in one patient each with RDD and ECD, and PD-1 expression was elevated in two patients each with RDD and ECD. For both ECD patients with higher PD-1 expression, NGS also showed presence of BRAF-V600E in the tumor tissue. The LCH patient had a low level of PD-L1 and PD-1 expression. For patients where evaluation of DNA mismatch repair was feasible on the tissue specimen (n=4), none showed related somatic or germline alterations. Conclusions In our series, the histiocytic neoplasms RDD, ECD, and LCH demonstrated low levels of TMB. None of the RDD and ECD patients were found to have alterations in DNA mismatch repair genes. Other markers of immunotherapy such as PD-L1/PD-1 expression appeared to be higher in ECD patients with BRAF-V600E, but in only a small subset of RDD patients. The low TMB seen in our study suggests that these histiocytic neoplasms may be less likely to respond to immune checkpoint inhibitors such as anti-PD-1 and anti-PD-L1 agents as compared to the tumors with high TMB. Disclosures No relevant conflicts of interest to declare.