Michael Andrew Arnold

All Publications

• Loss of H3K27me3 Is Not Specific to Malignant Triton Tumor: Immunohistochemical Analysis of 23 Cases of Embryonal Rhabdomyosarcoma. Archives of pathology & laboratory medicine Warmke, L. M., Davis, J. L., Al-Ibraheemi, A., Arnold, M., Tan, S., Shenoy, A., Surrey, L. F., Parham, D. M., Rudzinski, E. R. 2025

  Abstract

  Malignant peripheral nerve sheath tumor (MPNST) is a rare, often high-grade sarcoma. A small subset of MPNST shows evidence of heterologous rhabdomyoblastic differentiation, also known as malignant triton tumor (MTT). Immunohistochemical loss of histone 3 lysine 27 trimethylation (H3K27me3) has previously been described as a reliable marker for both MPNST and MTT.To assess the loss of H3K27me3 as a potential tool for discriminating MTT from embryonal rhabdomyosarcoma (ERMS).We studied the immunohistochemical expression of H3K27me3 in 23 pediatric cases of confirmed ERMS. Of the 23 patients, 21 were male and 2 were female, with an age range of 2 months to 18 years (median, 5 years). Most of the tumors arose in the paratesticular soft tissue (n = 14), with other locations including the pelvis (n = 3), thigh (n = 2), abdomen (n = 1), orbit (n = 1), prostate gland (n = 1), and parotid gland (n = 1). All cases had characteristic morphologic features of ERMS.By immunohistochemistry, all tested cases expressed desmin (18 of 18), myogenin (20 of 20), and MyoD1 (5 of 5). More than half of the cases (12 of 23; 52%) showed loss (nuclear absence) of H3K27me3, defined as staining in less than 5% of the tumor cells. The remaining cases demonstrated some degree of partial staining with H3K27me3, ranging from 5 to 40% of the tumor cells. No significant correlation between H3K27me3 expression and clinicopathologic features was identified.Loss of H3K27me3 frequently occurs in ERMS (52%) and is not reliable in distinguishing ERMS from MTT.

  View details for DOI 10.5858/arpa.2024-0199-OA

  View details for PubMedID 39957203

• Children and young adults with newly diagnosed rhabdomyosarcoma metastatic to bone treated on Children's Oncology Group studies. Pediatric blood & cancer Schloemer, N. J., Xue, W., Qumseya, A., Luo, L. Y., Hiniker, S. M., Lautz, T. B., Rhee, D. S., Arnold, M. A., Venkatramani, R. 2024: e31200

  Abstract

  Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Despite bone metastases being present in 5% of patients at diagnosis, there are limited studies examining these outcomes. We sought to define the prognostic factors, clinical courses, and outcomes of children treated on Children's Oncology Group (COG) clinical trials with RMS metastatic to bone at diagnosis.We performed a retrospective analysis of patients diagnosed with bone metastatic RMS enrolled on COG RMS clinical trials (D9802, D9803, ARST0431, or ARST08P1) between 1997 and 2013.RMS metastatic to bone was identified in 154 patients at a median age of 14.9 years at diagnosis. Fifty-eight percent of patients were male, 90% had metastases at additional sites, 74% had alveolar histology, and extremity was the most common primary site (31%). Eighty-six percent of patients (n = 133) received radiation therapy. The 3- and 5-year event-free survival (EFS) was 15.4% and 14.5%, respectively. The 3- and 5-year overall survival (OS) was 30.4% and 18.0%, respectively. We identified alveolar histology, FOXO1 fusion presence, unfavorable primary location, higher Oberlin score, and lack of radiation as poor prognostic characteristics for both EFS and OS in univariate analysis. Lack of radiation was not significant when excluding patients with events prior to 20 weeks.This study is the largest analysis of patients with bone metastatic RMS, and defines the poor overall outcomes and negative prognostic factors for these patients. They may be eligible for therapy deintensification for improved quality of life or pursuit of novel treatments/approaches, which are desperately needed.

  View details for DOI 10.1002/pbc.31200

  View details for PubMedID 39016936

• Adolescents and young adults with rhabdomyosarcoma: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Pediatric blood & cancer Harrison, D. J., Qumseya, A., Xue, W., Arnold, M., Lautz, T. B., Hiniker, S. M., Thomas, S. M., Venkatramani, R., Weiss, A. R., Mascarenhas, L. 2024: e30847

  Abstract

  The impact of established prognostic factors on survival outcomes for childhood rhabdomyosarcoma (RMS) have not been well described in the adolescent and young adult (AYA) RMS patient population.This is a retrospective analysis of patients with newly diagnosed RMS enrolled between 1997 and 2016 on seven previously reported Children's Oncology Group (COG) clinical trials. Demographics, clinical features, treatment details, and outcome data were collected. Five-year event-free survival (EFS) and overall survival (OS) were estimated for patients diagnosed at age 15-39 years and those diagnosed under age 15 years using the Kaplan-Meier method. Log-rank test was used to compare prognostic factors for EFS and OS. Factors significant in the univariable analysis were included in a Cox proportional hazards regression model. Nonsignificant covariates were removed from the multiple regression model.Total 2151 patients including 402 AYAs were analyzed. AYAs were more likely to present with primary tumors ≥5 cm in size, metastatic disease, alveolar histology, and have FOXO1 fusions compared to children. Five-year EFS for the AYA cohort was 44.2% versus 67% for children (p < .001), and 5-year OS was 52% for the AYA cohort versus 78% for children (p < .001). Multivariable analysis revealed tumor site, size and invasiveness, clinical group, and histology were prognostic in AYAs.AYAs with RMS have a poorer prognosis compared to younger children due to multiple factors. Further research focused on AYAs to better understand RMS biology and improve treatments is critical to improve survival.

  View details for DOI 10.1002/pbc.30847

  View details for PubMedID 38282125

• Prognosis of children and young adults with newly diagnosed rhabdomyosarcoma metastatic to bone marrow treated on Children's Oncology Group studies. Pediatric blood & cancer Schloemer, N. J., Xue, W., Qumseya, A., Luo, L. Y., Hiniker, S. M., Lautz, T. B., Rhee, D. S., Arnold, M. A., Venkatramani, R. 2023: e30701

  Abstract

  Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Metastatic disease occurs in 16% of all RMS cases and has a poor prognosis. There are limited studies examining the outcomes specific to patients with RMS metastatic to bone marrow despite an incidence of 6% at diagnosis. Our study aims to document the outcomes, prognostic factors, and clinical courses of children presenting with RMS metastatic to bone marrow treated on Children's Oncology Group (COG) cooperative trials.We performed a retrospective analysis of the patients diagnosed with RMS metastatic to bone marrow between 1997 and 2013 enrolled on one of four COG RMS clinical trials of D9802, D9803, ARST0431, and ARST08P1.We identified 179 cases with RMS metastatic to bone marrow. Patients had a median age of 14.8 years, 58% were male, predominantly alveolar histology (76%), extremity was the most common primary site (32%), and 87% had metastatic disease to additional sites; 83% (n = 149) received radiation as a treatment modality. The 3- and 5-year event-free survival was 9.4% and 8.2%, respectively. The 3- and 5-year overall survival was 26.1% and 12.6%, respectively. Age ≥10 years, alveolar histology, FOXO1 fusion presence, unfavorable primary location, higher Oberlin score, and lack of radiation were identified as poor prognostic/predictive characteristics.This study represents the largest analysis of RMS metastatic to bone marrow, defining the poor prognostic outcome for these patients. These patients may be eligible for therapy deintensification or early pursuit of novel treatments/approaches that are desperately needed.

  View details for DOI 10.1002/pbc.30701

  View details for PubMedID 37783659

• The Pathologic Diagnosis of Pediatric Soft Tissue Tumors in the Era of Molecular Medicine: The Sarcoma Pediatric Pathology Research Interest Group Perspective. Archives of pathology & laboratory medicine Black, J. O., Al-Ibraheemi, A., Arnold, M. A., Coffin, C. M., Davis, J. L., Parham, D. M., Rudzinski, E. R., Shenoy, A., Surrey, L. F., Tan, S. Y., Spunt, S. L. 2023

  Abstract

  Pediatric soft tissue tumors are one of the areas of pediatric pathology that frequently generate consult requests. Evolving classification systems, ancillary testing methods, new treatment options, research enrollment opportunities, and tissue archival processes create additional complexity in handling these unique specimens. Pathologists are at the heart of this critical decision-making, balancing responsibilities to consider expediency, accessibility, and cost-effectiveness of ancillary testing during pathologic examination and reporting.To provide a practical approach to handling pediatric soft tissue tumor specimens, including volume considerations, immunohistochemical staining panel recommendations, genetic and molecular testing approaches, and other processes that impact the quality and efficiency of tumor tissue triage.The World Health Organization Classification of Soft Tissue and Bone Tumors, 5th edition, other recent literature investigating tissue handling, and the collective clinical experience of the group are used in this manuscript.Pediatric soft tissue tumors can be difficult to diagnose, and evaluation can be improved by adopting a thoughtful, algorithmic approach to maximize available tissue and minimize time to diagnosis.

  View details for DOI 10.5858/arpa.2022-0364-RA

  View details for PubMedID 37196343

• Survival outcomes of patients with localized FOXO1 fusion-positive rhabdomyosarcoma treated on recent clinical trials: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Cancer Heske, C. M., Chi, Y. Y., Venkatramani, R. n., Li, M. n., Arnold, M. A., Dasgupta, R. n., Hiniker, S. M., Hawkins, D. S., Mascarenhas, L. n. 2020

  Abstract

  The objective of this analysis was to evaluate the clinical factors influencing survival outcomes in patients with localized (clinical group I-III), FOXO1 fusion-positive rhabdomyosarcoma (RMS).Patients with confirmed FOXO1 fusion-positive RMS who were enrolled on 3 completed clinical trials for localized RMS were included in the analytic cohort. Outcomes were analyzed using the Kaplan-Meier method to estimate event-free survival (EFS) and overall survival (OS), and the curves were compared using the log-rank test. A Cox proportional hazards regression model was used to perform multivariate analysis of prognostic factors that were significant in the univariate analysis.The estimated 4-year EFS and OS of 269 patients with localized, FOXO1 fusion-positive RMS was 53% (95% CI, 47%-59%) and 69% (95% CI, 63%-74%), respectively. Univariate analysis revealed that several known favorable clinical characteristics, including age at diagnosis between 1 and 9 years, complete surgical resection, tumor size ≤5 cm, favorable tumor site, absence of lymph node involvement, confinement to the anatomic site of origin, and PAX7-FOXO1 fusion, were associated with improved outcomes. Multivariate analysis identified older age (≥10 years) and large tumor size (>5 cm) as independent, adverse prognostic factors for EFS within this population, and patients who had both adverse features experienced substantially inferior outcomes.Patients with localized, FOXO1 fusion-positive RMS can be further risk stratified based on clinical features at diagnosis, and older patients with large primary tumors have the poorest prognosis.

  View details for DOI 10.1002/cncr.33334

  View details for PubMedID 33216382

• Gastrointestinal Tract-derived Pulse Granulomata Clues to an Underrecognized Pseudotumor AMERICAN JOURNAL OF SURGICAL PATHOLOGY Nowacki, N. B., Arnold, M. A., Frankel, W. L., Harzman, A., Limketkai, B. N., Yearsley, M. M., Arnold, C. A. 2015; 39 (1): 84-92

  Abstract

  Pulse granulomata (PG) in the lung and oral pathology literature are presumed due to food (pulse) introduced by mucosal injury. Herein, we report the largest series of PG in the gastrointestinal tract (GIT): 22 resections were prospectively collected from 17 patients (8 men, range=28 to 85 y). All patients had a history of intestinal injury/disease: diverticulitis, fistula, adenocarcinoma, perforation, ulcerative colitis, appendicitis, anastomotic site leak, and/or stent leak. Nine of 22 specimens were designated "masses"; most of these were clinically concerning for neoplasia. Sites of involvement included the small and large intestine, appendix, liver, gallbladder, mesentery, omentum, peritoneum, cervix, ovary, and skin. PG were typically nodular (21/22) and multifocal (15/22); most involved the external surface of the bowel (20/22), and they ranged in size from 1.5 to 100 mm. Histologically, they contained variable amounts of hyaline ribbons and rings, inflammation, foreign body giant cells, calcifications, and food; larger lesions displayed circumferential stellate fibrosis (12/22). We describe 3 morphologic variants: hyaline predominant (mimicking amyloid), cellular predominant (mimicking spindle cell neoplasms), and sclerosing mesenteritis-like. All patients are alive and well at the time of follow-up. Histologically processed legumes showed similar structures as those identified in PG, providing support for an entrapped food origin. In summary, we detail important clinicopathologic clues, describe the PG morphologic spectrum, and demonstrate how to distinguish PG from their mimics. Although PG can present as clinically concerning masses, we conclude that they are pseudotumors arising secondary to entrapped food introduced through mucosal trauma, similar to their lung and oral counterparts.

  View details for Web of Science ID 000346768600009

  View details for PubMedID 25118813

• Gastrointestinal Tract-derived Pulse Granulomata <i>Clues to an Underrecognized Pseudotumor</i> AMERICAN JOURNAL OF SURGICAL PATHOLOGY Nowacki, N. B., Arnold, M. A., Frankel, W. L., Harzman, A., Limketkai, B. N., Yearsley, M. M., Arnold, C. A. 2015; 39 (1): 84-92

  Abstract

  Pulse granulomata (PG) in the lung and oral pathology literature are presumed due to food (pulse) introduced by mucosal injury. Herein, we report the largest series of PG in the gastrointestinal tract (GIT): 22 resections were prospectively collected from 17 patients (8 men, range=28 to 85 y). All patients had a history of intestinal injury/disease: diverticulitis, fistula, adenocarcinoma, perforation, ulcerative colitis, appendicitis, anastomotic site leak, and/or stent leak. Nine of 22 specimens were designated "masses"; most of these were clinically concerning for neoplasia. Sites of involvement included the small and large intestine, appendix, liver, gallbladder, mesentery, omentum, peritoneum, cervix, ovary, and skin. PG were typically nodular (21/22) and multifocal (15/22); most involved the external surface of the bowel (20/22), and they ranged in size from 1.5 to 100 mm. Histologically, they contained variable amounts of hyaline ribbons and rings, inflammation, foreign body giant cells, calcifications, and food; larger lesions displayed circumferential stellate fibrosis (12/22). We describe 3 morphologic variants: hyaline predominant (mimicking amyloid), cellular predominant (mimicking spindle cell neoplasms), and sclerosing mesenteritis-like. All patients are alive and well at the time of follow-up. Histologically processed legumes showed similar structures as those identified in PG, providing support for an entrapped food origin. In summary, we detail important clinicopathologic clues, describe the PG morphologic spectrum, and demonstrate how to distinguish PG from their mimics. Although PG can present as clinically concerning masses, we conclude that they are pseudotumors arising secondary to entrapped food introduced through mucosal trauma, similar to their lung and oral counterparts.

  View details for Web of Science ID 000346768600009

  View details for PubMedID 25118813