Carter, Jodi M.

Perineuriomas are rare nerve sheath tumors, divided into intraneural and extraneural (soft tissue) types. Intraneural perineuriomas frequently contain TRAF7 mutations, and rarely, chr22q12 deletions. While chr22q losses can occur in soft tissue perineuriomas, comprehensive high-resolution molecular profiling has not been reported in these tumors and TRAF7 status is unknown. We used whole-exome sequencing and OncoScan single nucleotide polymorphism (SNP) array to evaluate 14 soft tissue perineuriomas. Thirteen cases showed 2 or more chromosomal abnormalities, composed primarily of large deletions. Recurrent chr22q deletions, containing the NF2 locus (n=6) and the previously unreported finding of chr17q deletions, with the NF1 locus (n=4) were frequent events and were mutually exclusive in all but1 case. In addition, 5 cases had varying chr2 deletions; and 4 cases had chr6 deletions. A chr10 deletion (previously reported in the sclerosing variant of soft tissue perineurioma) was observed in one case and another case had chr7 chromothripsis as the sole chromosomal abnormality. No TRAF7 mutations or alterations were identified in any case and no other evaluated gene (MAF<0.0001) had recurrent, deleterious mutations in >2 cases. The molecular genetic profiles showed no association with patient sex, age, tumoral histology or anatomic site. OncoScan SNP array analysis was performed on 10 cases and showed high concordance with the whole exome data, validating the large-scale deletions, duplications, and chr7 chromothripsis findings. In soft tissue perineuriomas, recurrent 22q12 deletions (with NF2) and 17q11 deletions (with NF1) appear to be mutually exclusive events, and alterations in NF1 or NF2 likely contribute to perineurioma pathogenesis, similar to other nerve sheath tumors. Moreover, the lack of TRAF7 mutations in soft tissue perineuriomas indicates divergent pathogenetic mechanisms from those of intraneural perineuriomas.

OBJECTIVEDesmoid-type fibromatosis (DTF) presents a therapeutic dilemma. While lacking metastatic potential, it is a locally aggressive tumor with a strong propensity for occurrence near nerve(s) and recurrence following resection. In this study, the authors introduce the association of an occult neuromuscular choristoma (NMC) identified in patients with DTF.METHODSAfter experiencing a case of DTF found to have an occult NMC, the authors performed a retrospective database review of all other cases of biopsy-proven DTF involving the extremities or limb girdles in patients with available MRI data. Two musculoskeletal radiologists with expertise in peripheral nerve imaging reviewed the MRI studies of the eligible cases for evidence of previously unrecognized NMC.RESULTSThe initial case of a patient with an occult sciatic NMC is described. The database review yielded 40 patients with DTF—18 (45%) in the upper limb and 22 (55%) in the lower limb. Two cases (5%) had MRI findings of NMC associated with the DTF, one in the proximal sciatic nerve and the other in the proximal tibial and sural nerves.CONCLUSIONSThe coexistence of NMC may be under-recognized in a subset of patients with extremity DTF. This finding poses implications for DTF treatment and the likelihood of recurrence after resection or biopsy. Further study may reveal crucial links between the pathogenesis of NMC and DTF and offer novel therapeutic strategies.

Abstract Neuromuscular choristoma (NMC) is a rare congenital nerve lesion that is classified by the presence of heterotopic muscle fibers intercalated within nerve fascicles. 1 The presence of NMC typically causes progressive neuropathy and bony/soft tissue undergrowth, often leading to a shortened atrophic limb. 2,3 The typical appearance of NMC on magnetic resonance imaging is an enlarged fusiform nerve that exhibits minimal gadolinium enhancement. 4 While there is increasing documentation of pathognomonic clinical and radiographic features for various diffuse fusiform peripheral nerve lesions, nerve biopsy is still occasionally required for some patients given the rarity of these diseases and progressive neuropathic features. The intraoperative appearance of NMC and its unique electrical stimulation properties are quite interesting. Intrafascicular replacement of nerve by skeletal muscle gives the nerve a red beefy color and causes the fascicles to contract with electrical stimulation. 5 In this video, we demonstrate the intraoperative appearance and contractile properties of NMC in a 60-yr-old woman with progressive sciatic neuropathy. Histologic and immunohistochemical studies identified a gradient of intralesional mature skeletal muscle within the NMC, with substantially fewer desmin-positive skeletal muscle fibers in the distal aspect. A gradient of contractility with intraoperative stimulation seemed to correlate with this pathology. These findings suggest that the lesional extent of NMC may not be clinically or grossly evident, reflecting a varying distribution of skeletal muscle within the affected nerve. The Mayo Clinic Institutional Review Board Office for Human Research Protection does not require approval for single participant case studies. The subject involved in this study was not identifiable and the general surgical consent form included permission for intraoperative photos and video.

Purpose Women with atypical hyperplasia (AH) on breast biopsy have an aggregate increased risk of breast cancer (BC), but existing risk prediction models do not provide accurate individualized estimates of risk in this subset of high-risk women. Here, we used the Mayo benign breast disease cohort to develop and validate a model of BC risk prediction that is specifically for women with AH, which we have designated as AH-BC. Patients and Methods Retrospective cohorts of women age 18 to 85 years with pathologically confirmed benign AH from Rochester, MN, and Nashville, TN, were used for model development and external validation, respectively. Clinical risk factors and histologic features of the tissue biopsy were selected using L1-penalized Cox proportional hazards regression. Identified features were included in a Fine and Gray regression model to estimate BC risk, with death as a competing risk. Model discrimination and calibration were assessed in the model-building set and an external validation set. Results The model-building set consisted of 699 women with AH, 142 of whom developed BC (median follow-up, 8.1 years), and the external validation set consisted of 461 women with 114 later BC events (median follow-up, 11.4 years). The final AH-BC model included three covariates: age at biopsy, age at biopsy squared, and number of foci of AH. At 10 years, the AH-BC model demonstrated good discrimination (0.63 [95% CI, 0.57 to 0.70]) and calibration (0.87 [95% CI, 0.66 to 1.24]). In the external validation set, the model showed acceptable discrimination (0.59 [95% CI, 0.51 to 0.67]) and calibration (0.91 [95% CI, 0.65 to 1.42]). Conclusion We have created a new model with which to refine BC risk prediction for women with AH. The AH-BC model demonstrates good discrimination and calibration, and it validates in an external data set.

Abstract In breast adipose tissue, macrophages that encircle damaged adipocytes form “crown-like structures of breast” (CLS-B). Although CLS-B have been associated with breast cancer, their role in benign breast disease (BBD) and early carcinogenesis is not understood. We evaluated breast biopsies from three age-matched groups (n = 86 each, mean age 55 years), including normal tissue donors of the Susan G. Komen for the Cure Tissue Bank (KTB), and subjects in the Mayo Clinic Benign Breast Disease Cohort who developed cancer (BBD cases) or did not develop cancer (BBD controls, median follow-up 14 years). Biopsies were classified into histologic categories, and CD68-immunostained tissue sections were evaluated for the frequency and density of CLS-B. Our data demonstrate that CLS-B are associated with BBD: CLS-B–positive samples were significantly less frequent among KTB biopsies (3/86, 3.5%) than BBD controls (16/86 = 18.6%, P = 0.01) and BBD cases (21/86 = 24%, P = 0.002). CLS-B were strongly associated with body mass index (BMI); BMI &lt; 25: 7% CLS-B positive, BMI 25–29: 13%, and BMI ≥ 30: 29% (P = 0.0005). Among BBD biopsies, a high CLS-B count [&gt;5 CLS-B/sample: 10.5% (BBD cases) vs 4.7% (BBD controls), P = 0.007] conferred a breast cancer OR of 6.8 (95% CI, 1.4–32.4), P = 0.02, after adjusting for adipose tissue area (cm2), histologic impression, and BMI. As high CLS-B densities are independently associated with an increased breast cancer risk, they may be a promising histologic marker of breast cancer risk in BBD. Cancer Prev Res; 11(2); 113–9. ©2017 AACR.

2 Background: Women with atypical hyperplasia (AH) on breast biopsy have an aggregate increased risk of breast cancer (BC), but accurate personalized risk prediction is desirable to facilitate individual clinical management decisions. Currently used models provide poor BC risk prediction for women with AH. Our goal was to develop and validate an improved risk prediction model for women with AH. Methods: From a cohort of 13,538 women with benign breast disease from 1967-2001, pathology review confirmed 699 with AH. Clinical risk factors and histologic features of the tissue biopsy were recorded, and BC events were ascertained from study questionnaires, tumor registry, and review of medical records. Using a lasso approach, 23 variables were assessed for model inclusion. Lasso-identified features were then fit in a Cox regression model to estimate BC risk. Model discrimination was assessed with C-statistics in the model-building set and in a separate external validation set. Calibration was assessed by comparing observed to predicted breast cancer counts. Results: The model-building set comprised 699 women with 142 BC events (median follow-up 8.1 years), and the external validation set comprised 461 women with 114 BC events (median follow-up 11.4 years). The final model included three covariates: age at biopsy, age squared, and number of foci of AH. Model performance was good, with a C-statistic of 0.622 (SE = 0.027) in the model-building set and 0.594 (SE = 0.029) in the external validation set. The model is well-calibrated, with observed to expected numbers of BCs nearly equal across all post-biopsy follow-up years. Conclusions: We propose a new model for predicting BC risk in women with AH based on age at biopsy and number of foci of atypia. This model provides absolute risk estimates for women with AH, has good discriminatory ability, is well-calibrated, and validates in an external cohort.

Abstract Purpose: Little is known about the role of the immune system in the earliest stages of breast carcinogenesis. We studied quantitative differences in immune cell types between breast tissues from normal donors and those from women with benign breast disease (BBD). Experimental Design: A breast tissue matched case–control study was created from donors to the Susan G. Komen for the Cure Tissue Bank (KTB) and from women diagnosed with BBD at Mayo Clinic (Rochester, MN) who either subsequently developed cancer (BBD cases) or remained cancer-free (BBD controls). Serial tissue sections underwent immunostaining and digital quantification of cell number per mm2 for CD4+ T cells, CD8+ T cells, CD20+ B cells, and CD68+ macrophages and quantification of positive pixel measure for CD11c (dendritic cells). Results: In 94 age-matched triplets, BBD lobules showed greater densities of CD8+ T cells, CD11c+ dendritic cells, CD20+ B cells, and CD68+ macrophages compared with KTB normals. Relative to BBD controls, BBD cases had lower CD20+ cell density (P = 0.04). Nearly 42% of BBD cases had no CD20+ B cells in evaluated lobules compared with 28% of BBD controls (P = 0.02). The absence of CD20+ cells versus the presence in all lobules showed an adjusted OR of 5.7 (95% confidence interval, 1.4–23.1) for subsequent breast cancer risk. Conclusions: Elevated infiltration of both innate and adaptive immune effectors in BBD tissues suggests an immunogenic microenvironment. The reduced B-cell infiltration in women with later breast cancer suggests a role for B cells in preventing disease progression and as a possible biomarker for breast cancer risk. Clin Cancer Res; 23(14); 3945–52. ©2017 AACR.

By the current WHO classification, benign notochordal cell tumor (BNCT) and chordoma comprise the entire spectrum of notochordal-derived tumors. They have defined radiologic and histologic criteria, and differ considerably in management and clinical outcome. Chordomas are malignant tumors; they show progressive, destructive growth and have the capacity for metastasis. In contrast, BNCT are benign and show limited intraosseous growth. Patients with BNCT can be managed with serial imaging or conservative excision, whereas patients with spinal/sacral chordomas typically undergo radical en bloc resection often with adjuvant therapy and significant morbidity. As such, the distinction between BNCT and chordoma is critically important. We have seen 4 unusual notochordal tumors with radiologic and/or histologic features that defy classification as either BNCT or chordoma. Cases occurred in 4 adults (53 to 83 y), and involved the lumbar spine (N=2) and sacrum (N=2). Three cases had subtle radiologic features of cortical permeation with minimal soft tissue extension. All 4 cases had the characteristic histologic features of BNCT; however, 2 cases also had focal myxoid change. Three patients were followed with serial imaging (follow-up range, 26 to 120 mo); 2 showed no disease progression and 1 had a 10-year cumulative interval growth of 3.7 mm. One patient underwent sacrectomy. The tumor was examined in toto and had the characteristic histologic features of BNCT, with the exception of minimal soft tissue extension. On the basis of these observations, we propose a provisional designation of atypical notochordal cell tumors (ANCT) be used for the subset of notochordal-derived tumors that fail to fulfill current diagnostic criteria for either BNCT or chordoma. We would argue that designating these atypical notochordal tumors as chordoma precipitates potentially overly aggressive surgical management. Patients with ANCT may be better managed by close observation and serial imaging. Additional studies with more cases and longer clinical follow-up should clarify the relationship of ANCT to BNCT and chordoma.