Faculty Bibliography

Schwannomatosis has been linked to germline mutations in the SMARCB1 and LZTR1 genes, and is frequently associated with pain.In a cohort study, we assessed the mutation status of 37 patients with clinically diagnosed schwannomatosis and compared to clinical data, whole body MRI (WBMRI), visual analog pain scale, and Short Form 36 (SF-36) bodily pain subscale.We identified a germline mutation in LZTR1 in 5 patients (13.5%) and SMARCB1 in 15 patients (40.5%), but found no germline mutation in 17 patients (45.9%). Peripheral schwannomas were detected in 3 LZTR1-mutant (60%) and 10 SMARCB1-mutant subjects (66.7%). Among those with peripheral tumors, the median tumor number was 4 in the LZTR1 group (median total body tumor volume 30 cc) and 10 in the SMARCB1 group (median volume 85cc), (P=.2915 for tumor number and P = .2289 for volume). mutation was associated with an increased prevalence of spinal schwannomas (100% vs 41%, P = .0197). The median pain score was 3.9/10 in the LZTR1 group and 0.5/10 in the SMARCB1 group (P = .0414), and SF-36 pain-associated quality of life was significantly worse in the LZTR1 group (P = .0106). Pain scores correlated with total body tumor volume (rho = 0.32471, P = .0499), but not with number of tumors (rho = 0.23065, P = .1696).We found no significant difference in quantitative tumor burden between mutational groups, but spinal schwannomas were more common in LZTR1-mutant patients. Pain was significantly higher in LZTR1-mutant than in SMARCB1-mutant patients, though spinal tumor location did not significantly correlate with pain. This suggests a possible genetic association with schwannomatosis-associated pain.

This paper summarizes the highlights of the Special Scientific Sessions of the 44th Annual Scientific Meeting of the International Skeletal Society (ISS), which was hosted in New York, NY, in August 2017.

OBJECTIVES:Plexiform neurofibromas (PNs) are complex, histologically benign peripheral nerve sheath tumors that are challenging to measure by simple line measurements. Computer-aided volumetric segmentation of PN has become the recommended method to assess response in clinical trials directed at PN. Different methods for volumetric analysis of PN have been developed. The goal of this study is to test the level of agreement in volume measurements and in interval changes using two separate methods of volumetric magnetic resonance imaging analysis. METHODS:Three independent volume measurements were performed on 15 PN imaged at three time-points using 3DQI software at Massachusetts General Hospital (MGH) and National Cancer Institute (NCI) and MEDx software at NCI. RESULTS:Median volume differences at each time-point comparing MGH-3DQI and NCI-3DQI were -0.5, -4.2, and -19.9 mL; comparing NCI-3DQI and NCI-MEDx were -21.0, -47.0, and -21.0 mL; comparing MGH-3DQI and NCI-MEDx were -10.0, -70.3, and -29.9 mL. Median differences in percentage change over time comparing MGH-3DQI and NCI-3DQI were -1.7, 1.1, and -1.0%; comparing NCI-3DQI and NCI-MEDx were -2.3, 3.3, and -1.1%; comparing MGH-3DQI and NCI-MEDx were -0.4, 2.0, and -1.5%. Volume differences were <20% of the mean of the two measurements in 117 of 135 comparisons (86.7%). Difference in interval change was <20% in 120 of the 135 comparisons (88.9%), while disease status classification was concordant in 115 of 135 comparisons (85.2%). CONCLUSIONS:The volumes, interval changes, and progression status classifications were in good agreement. The comparison of two volumetric analysis methods suggests no systematic differences in tumor assessment. A prospective comparison of the two methods is planned.

BACKGROUND:Altered bone microarchitecture and higher marrow adipose tissue (MAT) may reduce bone strength. High resolution pQCT (HRpQCT) allows assessment of volumetric BMD (vBMD), and size and microarchitecture parameters of bone, while 1H-magnetic resonance spectroscopy (1H-MRS) allows MAT evaluation. We have reported impaired microarchitecture at the non-weight bearing radius in adolescents with anorexia nervosa (AN) and that these changes may precede aBMD deficits. Data are lacking regarding effects of AN on microarchitecture and strength at the weight-bearing tibia in adolescents and young adults, and the impact of changes in microarchitecture and MAT on strength estimates. OBJECTIVE:To compare strength estimates at the distal tibia in adolescents/young adults with AN and controls in relation to vBMD, bone size and microarchitecture, and spine MAT. DESIGN AND METHODS/METHODS:This was a cross-sectional study of 47 adolescents/young adults with AN and 55 controls 14-24years old that assessed aBMD and body composition using DXA, and distal tibia vBMD, size, microarchitecture and strength estimates using HRpQCT, extended cortical analysis, individual trabecular segmentation, and finite element analysis. Lumbar spine MAT (1H-MRS) was assessed in a subset of 19 AN and 22 controls. RESULTS:Areal BMD Z-scores were lower in AN than controls. At the tibia, AN had greater cortical porosity, lower total and cortical vBMD, cortical area and thickness, trabecular number, and strength estimates than controls. Within AN, strength estimates were positively associated with lean mass, aBMD, vBMD, bone size and microarchitectural parameters. MAT was higher in AN, and associated inversely with strength estimates. CONCLUSIONS:Adolescents/young adults with AN have impaired microarchitecture at the weight-bearing tibia and higher spine MAT, associated with reduced bone strength.

Bone marrow-derived myeloid cells can accumulate within tumors and foster cancer outgrowth. Local immune-neoplastic interactions have been intensively investigated, but the contribution of the systemic host environment to tumor growth remains poorly understood. Here, we show in mice and cancer patients (n = 70) that lung adenocarcinomas increase bone stromal activity in the absence of bone metastasis. Animal studies reveal that the cancer-induced bone phenotype involves bone-resident osteocalcin-expressing (Ocn⁺) osteoblastic cells. These cells promote cancer by remotely supplying a distinct subset of tumor-infiltrating SiglecF^high neutrophils, which exhibit cancer-promoting properties. Experimentally reducing Ocn⁺ cell numbers suppresses the neutrophil response and lung tumor outgrowth. These observations posit osteoblasts as remote regulators of lung cancer and identify SiglecF^high neutrophils as myeloid cell effectors of the osteoblast-driven protumoral response.

CONTEXT:Acromegaly is characterized by growth hormone (GH) and insulinlike growth factor-1 (IGF-1) hypersecretion, and GH and IGF-1 play important roles in regulating body composition and glucose homeostasis. OBJECTIVE:The purpose of our study was to investigate body composition including ectopic lipids, measures of glucose homeostasis, and gonadal steroids in patients with active acromegaly compared with age-, body mass index (BMI)-, and sex-matched controls and to determine changes in these parameters after biochemical control of acromegaly. DESIGN:Cross-sectional study of 20 patients with active acromegaly and 20 healthy matched controls. Prospective study of 16 patients before and after biochemical control of acromegaly. MAIN OUTCOME MEASURES:Body composition including ectopic lipids by magnetic resonance imaging/proton magnetic resonance spectroscopy; measures of glucose homeostasis by an oral glucose tolerance test; gonadal steroids. RESULTS:Patients with active acromegaly had lower mean intrahepatic lipid (IHL) and higher mean fasting insulin and insulin area under the curve (AUC) values than controls. Men with acromegaly had lower mean total testosterone, sex hormone-binding globulin, and estradiol values than male controls. After therapy, homeostasis model assessment of insulin resistance, fasting insulin level, and insulin AUC decreased despite an increase in IHL and abdominal and thigh adipose tissues and a decrease in muscle mass. CONCLUSIONS:Patients with acromegaly were characterized by insulin resistance and hyperinsulinemia but lower IHL compared with age-, BMI-, and sex-matched healthy controls. Biochemical control of acromegaly improved insulin resistance but led to a less favorable anthropometric phenotype with increased IHL and abdominal adiposity and decreased muscle mass.

OBJECTIVE:To assess the radiographic and clinicopathologic features of synovial sarcoma of the nerve that were clinically or radiologically interpreted as benign peripheral nerve sheath tumor. MATERIALS AND METHODS/METHODS:Five patients with synovial sarcoma arising from the peripheral nerve and interpreted clinically and radiologically as peripheral nerve sheath tumors were identified. Clinicopathologic and imaging features were evaluated. RESULTS:There were three females and two males, ranging in age from 28 to 50 (mean 35.8) years. Most patients (4/5) complained of a mass, discomfort or pain. MR images demonstrated a heterogeneous, enhancing, soft tissue mass contiguous with the neurovascular bundle. On histologic examination, most tumors were monophasic synovial sarcoma (4/5). At the time of surgery, all tumors were noted to arise along or within a peripheral nerve. All patients were alive with no evidence of disease with median follow-up of 44 (range 32-237) months. For comparison, approximately 775 benign peripheral nerve sheath tumors of the extremities were identified during the same time period. CONCLUSIONS:Primary synovial sarcoma of the nerve can mimic peripheral nerve sheath tumors clinically and on imaging and should be included in the differential diagnosis for tumors arising from peripheral nerves.

OBJECTIVE:Hemispherical spondylosclerosis (HS) is a rare degenerative entity characterized by dome-shaped sclerosis of a single vertebral body that may pose a diagnostic dilemma. The goal of this study was to describe the MR imaging features of HS. MATERIALS AND METHODS/METHODS:We identified spine radiographs and CT examinations of subjects with HS who also had MR imaging for correlation. Two musculoskeletal radiologists independently assessed sclerosis characteristics, presence of endplate erosions, marrow signal intensity, and disk degeneration (Pfirrmann scale). RESULTS:We identified 11 subjects (six males, five females, mean 48 ± 10 years) with radiographic/CT findings of HS. The most commonly affected vertebral body was L4 (6/11; 55%). On MR imaging, variable signal intensity was noted, being most commonly low on T1 (8/11, 73%) and high on fat-suppressed T2-weighted (8/11, 73%) images. In two subjects, diffuse post-contrast enhancement was seen in the lesion. Moderate disk degeneration and endplate bone erosions adjacent to sclerosis were present in all subjects. Erosions of the opposite endplate were present in two subjects (2/11, 18%). CT data from nine subjects showed the mean attenuation value of HS was 472 ± 96 HU. CONCLUSIONS:HS appearance on MR imaging is variable and may not correlate with the degree of sclerosis seen on radiographs or CT. Disk degenerative changes and asymmetric endplate erosions are consistent markers of HS.

PURPOSE/OBJECTIVE:Osseous metastases often undergo an osteoblastic healing response following chemotherapy. The purpose of our study was to demonstrate the quantitative CT changes in attenuation of osseous metastases before and after chemotherapy. MATERIALS AND METHODS/METHODS:Our study was IRB approved and HIPAA compliant. Our cohort consisted of 86 consecutive cancer patients with contrast-enhanced CTs before and 14 ± 2 (12-25) months after initiation of chemotherapy (60 ± 11 years, 36 males, 50 females). The average and maximum metastasis attenuations were measured in Hounsfield units (HU) by two readers. Treatment effects were assessed using paired t-tests and Fisher exact tests. Intraclass correlation coefficients (ICCs) were calculated. Patient records were reviewed to determine the patient's clinical status (worse, unchanged, or improved) at the time of follow-up CT. RESULTS:The distribution of lesion types was as follows: lytic (30/86, 35%), blastic (43/86, 50%), and mixed lytic-blastic (13/86, 15%). There was a significant increase in average and maximum CT attenuation of metastases following chemotherapy for all patients, which remained statistically significant when stratified by lesion type, clinical status (worsening or improving/stable), cancer type (breast, lung), and radiation therapy (P < 0.05). In a subgroup of patients whose osseous metastases decreased in average attenuation (14/86, 16%), more patients had a worse clinical status (11/14, 79%) (P = 0.02). ICC was almost perfect for average attenuation and substantial for maximum attenuation. CONCLUSION/CONCLUSIONS:Quantitative assessment of osseous metastatic disease using CT attenuation measurements demonstrated a statistically significant increase in attenuation more than 12 months after initiation of chemotherapy.