Publications by authors named "David M Parham"

99 Publications

Rhabdomyosarcoma: How Advanced Molecular Methods Are Shaping the Diagnostic and Therapeutic Paradigm.

Pediatr Dev Pathol 2021 Jun 9:10935266211013621. Epub 2021 Jun 9.

Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA (retired).

For the past 40 years, progress in rhabdomyosarcoma (RMS) has been focused on understanding its molecular basis and characterizing the mutations that drive its tumorigenesis and progression. Genetic predisposition to RMS has allowed discovery of key genetic pathways and driver mutations. Subclassification of RMS into embryonal (ERMS) and alveolar (ARMS) subtypes has shifted from histology to PAX-FOXO1 fusion status, and new driver mutations have been found in spindle cell RMS. Comprehensive molecular profiling leveraging genome-scale next-generation sequencing (NGS) indicates that the RAS/RAF/PI3K axis is mutated in the majority of ERMS and modulated by downstream effects of PAX-FOXO1 fusions in ARMS. Because of the continued poor outcome of high-risk RMS, a variety of molecular targets have been or are now being tested in current or recent therapy trials. New techniques such as single cell sequencing, spatial multi-omics, and CRISPR/Cas9 genome editing offer potential for further discovery, but a need for clinically annotated specimens persists.
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http://dx.doi.org/10.1177/10935266211013621DOI Listing
June 2021

Epithelioid Sarcoma Arising in a Long-Term Survivor of an Atypical Teratoid/Rhabdoid Tumor in a Patient With Rhabdoid Tumor Predisposition Syndrome.

Pediatr Dev Pathol 2021 Mar-Apr;24(2):164-168. Epub 2021 Jan 20.

Department of Pathology and Laboratory, Medical University of South Carolina, Charleston, South Carolina.

Rhabdoid tumor predisposition syndrome (RTPS) is defined as the presence of a or genetic aberration in a patient with malignant rhabdoid tumor. Patients with RTPS are more likely to present with synchronous or metachronous rhabdoid tumors. Based on the current state of rhabdoid tumor taxonomy, these diagnoses are based largely on patient demographics, anatomic location of disease, and immunohistochemistry, despite their nearly identical histologic and immunohistochemical profiles. Thus, the true distinction between such tumors remains a diagnostic challenge. Central nervous system atypical teratoid/rhabdoid tumor (AT/RT) is a rare, aggressive, primarily pediatric malignancy with variable histologic features and a well documented association with loss of SMARCB1 expression. Epithelioid sarcoma (ES) is a rare soft tissue tumor arising in patients of all ages and characteristically staining for both mesenchymal and epithelial immunohistochemical markers while usually demonstrating loss of SMARCB1 expression. To our knowledge we herein present the first documented case of a patient with RTPS who presented with metachronous AT/RT and ES.
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http://dx.doi.org/10.1177/1093526620986492DOI Listing
January 2021

Rhabdomyosarcoma: From Obscurity to Clarity in Diagnosis … But With Ongoing Challenges in Management: The Farber-Landing Lecture of 2020.

Pediatr Dev Pathol 2021 Mar-Apr;24(2):87-95. Epub 2021 Jan 13.

Innovative Genomics Institute, University of California, Berkeley, California.

Rhabdomyosarcoma, the most common soft tissue sarcoma in childhood, has challenged and intrigued soft tissue pathologists ever since the original descriptions. Once based on the identification of rhabdomyoblastic cells with elongate eosinophilic cytoplasm, the diagnosis has evolved to include tumors composed only of primitive mesenchymal cells but now relies heavily on immunohistochemical stains for desmin, myogenin, and MyoD. Rhabdomyosarcomas show a variety of histological patterns, giving rise to classifications that have included embryonal, alveolar, botryoid, pleomorphic, spindle cell, and sclerosing subtypes. These have been linked to prognosis and treatment assignment in the past, but that concept has been superseded by the identification of or fusions. Fusion testing results are more predictive of outcome and have become standard practice in clinical management. However, high risk tumors with alveolar histology or metastatic disease continue to resist oncologic treatment.
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http://dx.doi.org/10.1177/1093526620977720DOI Listing
January 2021

A History of Board Certification in Pediatric Pathology on Its 30th Anniversary.

Pediatr Dev Pathol 2021 Jan-Feb;24(1):3-9. Epub 2021 Jan 12.

Retired pathologist, Little Rock, Arkansas.

In 1983 under the leadership of Dr. Daria Haust, the Pediatric Pathology Club (PPC; forerunner of the Society for Pediatric Pathology [SPP]), promulgated bylaws that included recognition of the special expertise required in pediatric pathology. This standard followed formal discussion that began as early as 1970, suggesting that special certification should be pursued, and the idea was vetted by the PPC in 1980 following a special report by Dr. Benjamin Landing and a letter to PPC members. Under the leadership of Dr. William Donnelly in 1984, a relationship between the SPP and the American Board of Pathology (ABPath) began in order to receive recognition of pediatric pathology as a special discipline. As a result, a test committee chaired by Dr. Jerald Schenken began preparing question categories and examples for ABPath examination. These efforts culminated in the first pediatric pathology subspecialty examination, held in Atlanta, Georgia on November 20, 1990. With this article we wish to detail the history of ABPath pediatric pathology board certification from its beginnings to the current time.
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http://dx.doi.org/10.1177/1093526620971180DOI Listing
January 2021

The prognostic significance of anaplasia in childhood rhabdomyosarcoma: A report from the Children's Oncology Group.

Eur J Cancer 2021 01 7;143:127-133. Epub 2020 Dec 7.

Seattle Children's Hospital, Seattle, WA, United States.

Background: Established prognostic indicators in rhabdomyosarcoma (RMS), the most common childhood soft tissue sarcoma, include several clinicopathologic features. Among pathologic features, anaplasia has been suggested as a potential prognostic indicator, but the clinical significance of anaplasia remains unclear.

Methods: Patients enrolled on one of five recent Children's Oncology Group clinical trials for RMS (D9602, n = 357; D9802, n = 80; D9803, n = 462; ARST0331, n = 335; and ARST0531, n = 414) with prospective central pathology review were included in this study. Clinicopathologic variables including demographic information, risk group, histologic subtype, and anaplasia were recorded along with overall survival (OS) and failure-free survival (FFS) with failure defined by recurrence, progression, or death. The log-rank test was used to compare OS and FFS.

Results: Anaplasia was more common in embryonal RMS (27% of all embryonal RMS) than other subtypes of RMS (11% for alveolar RMS, 7% for botryoid RMS, 11% for spindle cell RMS). On multivariate analyses, anaplasia was not an independent prognostic factor in RMS (OS:hazard ratio (HR) = 1.12, p = 0.43; FFS:HR = 1.07, p = 0.56) across all subtypes or within embryonal RMS only (OS:HR = 1.41, p = 0.078; FFS:HR = 1.25, p = 0.16). Among tumors with TP53 mutations, 69% had anaplasia, while only 24% of tumors with anaplasia had a tumoral TP53 mutation.

Conclusions: Anaplasia is not an independent indicator of adverse outcomes in RMS. Emerging information on the prognostic significance of TP53 mutations raises the possibility that anaplasia may be a surrogate marker of TP53 mutations in some cases. Tumoral TP53 mutation status may be investigated as a prognostic indicator in future studies.
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http://dx.doi.org/10.1016/j.ejca.2020.10.018DOI Listing
January 2021

Alveolar rhabdomyosarcoma with regional nodal involvement: Results of a combined analysis from two cooperative groups.

Pediatr Blood Cancer 2021 03 27;68(3):e28832. Epub 2020 Nov 27.

University Hospital Vall d'Hebron, Barcelona, Spain.

Background: Treatment of children and adolescents with alveolar rhabdomyosarcoma (ARMS) and regional nodal involvement (N1) have been approached differently by North American and European cooperative groups. In order to define a better therapeutic strategy, we analyzed two studies conducted between 2005 and 2016 by the European paediatric Soft tissue sarcoma Study Group (EpSSG) and Children's Oncology Group (COG).

Methods: We retrospectively identified patients with ARMS N1 enrolled in either EpSSG RMS2005 or in COG ARST0531. Chemotherapy in RMS2005 comprised ifosfamide + vincristine + dactinomycin + doxorubicin (IVADo), IVA and maintenance (vinorelbine, cyclophosphamide); in ARST0531, it consisted of either vincristine + dactinomycin + cyclophosphamide (VAC) or VAC alternating with vincristine + irinotecan (VI). Local treatment was similar in both protocols.

Results: The analysis of the clinical characteristics of 239 patients showed some differences between study groups: in RMS2005, advanced Intergroup Rhabdomyosarcoma Study Group (IRS) and large tumors predominated. There were no differences in outcomes between the two groups: 5-year event-free survival (EFS), 49% (95% confidence interval [CI]: 39-59) and 44% (95% CI: 30-58), and overall survival (OS), 51% (95% CI: 41-61) and 53.6% (95% CI: 40-68) in RMS2005 and ARST0531, respectively. In RMS2005, EFS of patients with FOXO1-positive tumors was significantly inferior to those with FOXO1-negative (49.3% vs 73%, P = .034). In contrast, in ARST0531, EFS of patients with FOXO1-positive tumors was 45% compared with 43.8% for those with FOXO1-negative.

Conclusions: The outcome of patients with ARMS N1 was similar in both protocols. However, patients with FOXO1 fusion-negative tumors enrolled in RMS2005 showed a significantly better outcome, suggesting that different strategies of chemotherapy may have an impact in the outcome of this subgroup of patients.
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http://dx.doi.org/10.1002/pbc.28832DOI Listing
March 2021

Clinicopathologic Characteristics of Late Acute Antibody-Mediated Rejection in Pediatric Liver Transplantation.

Transplantation 2020 Oct 7. Epub 2020 Oct 7.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA.

Background: An early and accurate diagnosis of liver antibody-mediated rejection (AMR) followed by timely intervention is important for clinical management but remains challenging. The aim of this study was to assess the clinicopathologic characteristics and outcomes of late acute AMR in pediatric liver transplantation recipients.

Methods: We performed a retrospective review of 739 ABO-identical/compatible allograft liver biopsies from 199 pediatric transplantation recipients.

Results: Based on Banff 2016 AMR criteria, 3 recipients fulfilled the criteria for definite for late acute AMR, 2 met the criteria for suspicious for AMR, and 2 were indeterminate for AMR. We further assessed the clinicopathologic characteristics of these 7 patients. All 7 patients had at least 1 biopsy with a histopathologic pattern compatible with acute AMR. Additionally, we observed accompanied moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury in all 7 patients; periportal/perivenular hepatocyte necrosis was seen in 6/7 patients; and arteritis was seen in 3/7 patients. In each case, microvascular C4d deposition was present in at least 1 biopsy. Posttransplant donor specific anti-HLA antibodies were detected in 5 patients. Two of 7 patients were retransplanted, and 2 died after developing refractory AMR. The remaining 5 patients were alive with stable graft function at a median follow-up of 4.1 years.

Conclusions: Our data suggest that acute AMR in pediatric liver grafts is rare, can develop late, and may be associated with graft loss or patient death. The recurrent histopathologic findings of moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury are features that appear unique to pediatric acute AMR of liver grafts.
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http://dx.doi.org/10.1097/TP.0000000000003469DOI Listing
October 2020

Histopathologic features of alveolar capillary dysplasia with misalignment of pulmonary veins with atypical clinical presentation.

Cardiovasc Pathol 2021 Jan - Feb;50:107289. Epub 2020 Sep 16.

Department of Pathology and Laboratory medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA; Keck School of Medicine, University of Southern California, Los Angeles, California, USA. Electronic address:

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare neonatal lung disease with fatal outcome. Typically, respiratory symptoms present in the first 24 hours of life and patients die within the neonatal period. Atypical, delayed clinical presentations and/or longer survival have also been reported. Here, we studied the clinicopathologic relationship of ACD/MPV by examining 16 cases of ACD/MPV, focusing on atypical features. Based on the presence of diffuse vs. focal/patchy ACD/MPV histopathologic changes, we divided the cases into classic and nonclassic pathology groups. MPV was found in all ACD/MPV. Ten of 16 cases exhibited classic diffuse abnormalities, while 6 of 16 had a nonclassic focal/patchy distribution. However, among 7 patients with atypical clinical features, only 2 had nonclassic pathology, while 4 out of 9 clinically typical cases had nonclassic ACD/MPV pathology. Marked intrapulmonary aberrant arteriovenous vessels were present in all atypical cases. In conclusion, clinical presentation is not always correlated with histopathology in ACD/MPV. Atypical ACD/MPV should be suspected in any infants with fulminant pulmonary hypertension. Abnormal pulmonary veins and aberrant intraseptal vessels are the most important clues for diagnosis. Additional studies are needed for further elucidation of diagnostic histological criteria of atypical ACD/MPV and to explore its pathogenesis.
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http://dx.doi.org/10.1016/j.carpath.2020.107289DOI Listing
December 2020

A risk-based treatment strategy for non-rhabdomyosarcoma soft-tissue sarcomas in patients younger than 30 years (ARST0332): a Children's Oncology Group prospective study.

Lancet Oncol 2020 01 27;21(1):145-161. Epub 2019 Nov 27.

Seattle Children's Hospital, Seattle, WA, USA.

Background: Tumour grade, tumour size, resection potential, and extent of disease affect outcome in paediatric non-rhabdomyosarcoma soft-tissue sarcoma (NRSTS), but no risk stratification systems exist and the standard of care is poorly defined. We developed a risk stratification system from known prognostic factors and assessed it in the context of risk-adapted therapy for young patients with NRSTS.

Methods: In this prospective study, eligible patients enrolled in 159 hospitals in three countries were younger than 30 years, had a Lansky (patients ≤16 years) or Karnofsky (patients >16 years) performance status score of at least 50, and a new diagnosis of a WHO (2002 criteria) intermediate (rarely metastasising) or malignant soft-tissue tumour (apart from tumour types eligible for other Children's Oncology Group studies and tumours for which the therapy in this trial was deemed inappropriate), malignant peripheral nerve sheath tumour, non-metastatic and grossly resected dermatofibrosarcoma protuberans, undifferentiated embryonal sarcoma of the liver, or unclassified malignant soft-tissue sarcoma. Each patient was assigned to one of three risk groups and one of four treatment groups. Risk groups were: low (non-metastatic R0 or R1 low-grade, or ≤5 cm R1 high-grade tumour); intermediate (non-metastatic R0 or R1 >5 cm high-grade, or unresected tumour of any size or grade); or high (metastatic tumour). The treatment groups were surgery alone, radiotherapy (55·8 Gy), chemoradiotherapy (chemotherapy and 55·8 Gy radiotherapy), and neoadjuvant chemoradiotherapy (chemotherapy and 45 Gy radiotherapy, then surgery and radiotherapy boost based on margins with continued chemotherapy). Chemotherapy included six cycles of ifosfamide 3 g/m per dose intravenously on days 1-3 and five cycles of doxorubicin 37·5 mg/m per dose intravenously on days 1-2 every 3 weeks with sequence adjusted on the basis of timing of surgery or radiotherapy. The primary outcomes were event-free survival, overall survival, and the pattern of treatment failure. Analysis was done per protocol. This study has been completed and is registered with ClinicalTrials.gov, NCT00346164.

Findings: Between Feb 5, 2007, and Feb 10, 2012, 550 eligible patients were enrolled, of whom 21 were treated in the incorrect group and excluded from this analysis. 529 evaluable patients were included in the analysis: low-risk (n=222), intermediate-risk (n=227), high-risk (n=80); surgery alone (n=205), radiotherapy (n=17), chemoradiotherapy (n=111), and neoadjuvant chemoradiotherapy (n=196). At a median follow-up of 6·5 years (IQR 4·9-7·9), 5-year event-free survival and overall survival were: 88·9% (95% CI 84·0-93·8) and 96·2% (93·2-99·2) in the low-risk group; 65·0% (58·2-71·8) and 79·2% (73·4-85·0) in the intermediate-risk group; and 21·2% (11·4-31·1) and 35·5% (23·6-47·4) in the high-risk group, respectively. Risk group predicted event-free survival and overall survival (p<0·0001). No deaths from toxic events during treatment were reported. Nine patients had unexpected grade 4 adverse events (chemoradiotherapy group, n=2; neoadjuvant chemoradiotherapy group, n=7), including three wound complications that required surgery (all in the neoadjuvant chemoradiotherapy group).

Interpretation: Pre-treatment clinical features can be used to effectively define treatment failure risk and to stratify young patients with NRSTS for risk-adapted therapy. Most low-risk patients can be cured without adjuvant therapy, thereby avoiding known long-term treatment complications. Survival remains suboptimal for intermediate-risk and high-risk patients and novel therapies are needed.

Funding: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation, American Lebanese Syrian Associated Charities.
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http://dx.doi.org/10.1016/S1470-2045(19)30672-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946838PMC
January 2020

Expanding the spectrum of dicer1-associated sarcomas.

Mod Pathol 2020 01 19;33(1):164-174. Epub 2019 Sep 19.

Division of Hematology, Oncology and Blood and Marrow Transplantation, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

DICER1 syndrome is a hereditary cancer predisposition syndrome caused by deleterious germline DICER1 mutations. Characteristic "hotspot" somatic mutations of DICER1 have been identified in DICER1-associated tumors. With the exception of genitourinary embryonal rhabdomyosarcoma and anaplastic sarcoma of the kidney, sarcomas are rarely reported in DICER1 syndrome. Herein, we report the clinical, histopathologic, and molecular findings of a germline DICER1-associated ovarian sarcoma in a 5-year-old female, a somatic DICER1-associated metastatic peritoneal sarcoma in a 16-year-old female, and a somatic DICER1-associated primary intracranial sarcoma in a 4-year-old male. A comprehensive review of the literature, including 83 DICER1-associated sarcomas, illustrates an unequivocal histologic pattern mimicking pleuropulmonary blastoma, regardless of the site of origin. The features include undifferentiated small round blue cells, poorly differentiated spindle cells, and large bizarre pleomorphic cells (anaplasia), often with rhabdomyoblastic and/or chondroid differentiation, and rare bone/osteoid formation. This unique heterogeneous histologic pattern should raise suspicion for pathogenic DICER1 mutation(s) warranting a detailed review of the family history and DICER1 mutation analysis. In addition to expanding the phenotypic spectrum of DICER1-associated conditions, identification of pathogenic DICER1 variants facilitates optimized genetic counseling, caregiver education and judicious imaging-based surveillance.
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http://dx.doi.org/10.1038/s41379-019-0366-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528621PMC
January 2020

Risk-based treatment for patients with first relapse or progression of rhabdomyosarcoma: A report from the Children's Oncology Group.

Cancer 2019 08 8;125(15):2602-2609. Epub 2019 May 8.

Department of Pediatrics, Seattle Children's Hospital, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington.

Background: The purpose of this study was to evaluate risk and response-based multi-agent therapy for patients with rhabdomyosarcoma (RMS) at first relapse.

Methods: Patients with RMS and measurable disease at first relapse with unfavorable-risk (UR) features were randomized to a 6-week phase 2 window with 1 of 2 treatment schedules of irinotecan with vincristine (VI) (previously reported). Those with at least a partial response to VI continued to receive 44 weeks of multi-agent chemotherapy including the assigned VI regimen. UR patients who did not have measurable disease at study entry, did not have a radiographic response after the VI window, or declined VI window therapy received 31 weeks of multi-agent chemotherapy including tirapazamine (TPZ) at weeks 1, 4, 10, 19, and 28. Favorable-risk (FR) patients received 31 weeks of the same multi-agent chemotherapy without VI and TPZ.

Results: One hundred thirty-six eligible patients were enrolled. For 61 patients not responding to VI, the 3-year failure-free survival (FFS) and overall survival (OS) rates were 17% (95% confidence interval [CI], 8%-29%) and 24% (13%-37%), respectively. For 30 UR patients not treated with VI, the 3-year FFS and OS rates were 21% (8%-37%) and 39% (20%-57%), respectively. FR patients had 3-year FFS and OS rates of 79% (47%-93%) and 84% (50%-96%), respectively. There were no unexpected toxicities.

Conclusions: Patients with UR RMS at first relapse or disease progression have a poor prognosis when they are treated with this multi-agent therapy, whereas FR patients have a higher chance of being cured with second-line therapy.
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http://dx.doi.org/10.1002/cncr.32122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069123PMC
August 2019

Clinical features and outcomes of young patients with epithelioid sarcoma: an analysis from the Children's Oncology Group and the European paediatric soft tissue Sarcoma Study Group prospective clinical trials.

Eur J Cancer 2019 05 5;112:98-106. Epub 2019 Apr 5.

Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.

Background: Data on the clinical features, optimal treatment and outcomes of paediatric patients with epithelioid sarcoma (ES) are limited and mostly retrospective.

Methods: A subset analysis of ES patients < 30 years of age enrolled on two international prospective clinical trials conducted between 7/2005 and 11/2015 was performed. Risk-adapted therapy was based on tumour diameter, histologic grade, extent of surgery and presence/absence of metastases and included surgery ± radiotherapy for all patients with the addition of ifosfamide/doxorubicin chemotherapy for intermediate-/high-risk patients. Response to therapy, event-free and overall survival and pattern and predictors of treatment failure were evaluated.

Results: Sixty-three ES patients (median age 13.1 years, 52% male) were eligible. Clinical features included the following: 68% extremity, median tumour diameter 3.5 cm, 56% high histologic grade, 14% nodal metastases, 14% distant metastases. Thirty-four low-risk patients underwent surgery (n = 30) or surgery/radiotherapy (n = 4); 16 intermediate-risk and 13 high-risk patients received chemotherapy ± surgery ± radiotherapy. Partial response was observed in 11/22 (50%) patients receiving neoadjuvant therapy. Events were local recurrence (n = 10) and distant recurrence (n = 15); estimated 5-year survival was 86.4%, 63.5% and 0%, respectively, for low-, intermediate- and high-risk patients. Locoregional nodal involvement, invasive tumour, high grade and lesser extent of resection predicted event-free survival in patients without metastases.

Conclusions: Most low-risk ES patients who have undergone an adequate resection fare well without adjuvant therapy. Large tumour size, high histologic grade, tumour invasiveness, inadequate tumour resection and metastatic disease predict poorer outcomes in higher risk ES patients, for whom more effective therapies are needed.

Clinical Trial Registration: COG ARST0332: ClinicalTrials.gov Identifier NCT00346164, EpSSG NRSTS 2005: European Union Drug Regulating Authorities Clinical Trials No. 2005-001139-31.
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http://dx.doi.org/10.1016/j.ejca.2019.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944741PMC
May 2019

Magnetic resonance and computed tomography imaging features of epithelioid sarcoma in children and young adults with pathological and clinical correlation: a report from Children's Oncology Group study ARST0332.

Pediatr Radiol 2019 06 30;49(7):922-932. Epub 2019 Mar 30.

Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA.

Objective: To correlate imaging features of epithelioid sarcoma in children and young adults enrolled in Children's Oncology Group study ARST0332 with clinical and pathological findings.

Materials And Methods: Fifteen patients (6 males; median age 16.1 years, range 6.5-24.8 years) with epithelioid sarcoma enrolled in ARST0332 had preoperative imaging (MRI, n=10; CT, n=5) that was reviewed by two radiologists who recorded numerous features including presence and percentage of tumor necrosis, presence of surrounding edema, and lymph node involvement. Discrepancies between reviewers were adjudicated by concurrent re-review. We correlated imaging findings with histological assessment of percentage tumor necrosis, proximal- vs. classic-type histology, lymph node involvement and recurrence.

Results: Eleven patients (11/15, 73%) had proximal-type histology tumors. Ten of 14 tumors (71%) had imaging evidence of necrosis. Among the nine tumors with imaging and histological estimates of percentage necrosis, agreement was within 30% (in six tumors there was ≤10% difference between pathology and imaging). All 10 tumors imaged with MRI had surrounding edema. Four patients had biopsy-proven nodal involvement; all had necrotic nodes on imaging. There were four false-positives for nodal involvment by imaging. Twelve patients (12/15, 80%) had recurrences (local only, n=1; local and distant, n=1; distant only, n=10).

Conclusion: Proximal-type histology was prevalent in this young cohort with preoperative imaging. Necrosis is common in primary tumors and involved nodes. There is good agreement between histological and imaging estimates of primary tumor necrosis. Surrounding tumor edema is common in this tumor, which is known to spread along fascial planes.
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http://dx.doi.org/10.1007/s00247-019-04389-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6576270PMC
June 2019

Fibroblastic and myofibroblastic tumors of children: new genetic entities and new ancillary testing.

Authors:
David M Parham

F1000Res 2018 20;7. Epub 2018 Dec 20.

Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.

Fibroblastic and myofibroblastic tumors comprise a morphologically diverse and biologically variable group of neoplasms that affect a wide age range. Specific entities tend to occur most frequently in infants and young children. Recent years have witnessed a proliferation of information concerning the unique biology of these tumors. In this report, I will review recent findings that serve to further characterize this group of neoplasms. Included will be newer information on fibrous hamartoma of infancy, infantile myofibromatosis, lipofibromatosis, and infantile fibrosarcoma and tumors resembling it, including primitive myxoid mesenchymal tumor of infancy and new genetic entities. I will also discuss the differential diagnosis, which includes spindle cell rhabdomyosarcoma, dermatofibrosarcoma protuberans, and calcifying aponeurotic fibroma.
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http://dx.doi.org/10.12688/f1000research.16236.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305242PMC
March 2019

Expanding the Spectrum of Pediatric NTRK-rearranged Mesenchymal Tumors.

Am J Surg Pathol 2019 04;43(4):435-445

Department of Laboratories, Seattle Children's Hospital, Seattle, WA.

Pediatric mesenchymal tumors harboring variant NTRK fusions (ETV6-negative) are being increasingly described; however, the histologic and clinical features of these variant NTRK tumors and their relationship to classic infantile fibrosarcoma are not well characterized. A better understanding of the clinicopathologic features of these tumors is necessary, and would aid in both early diagnosis and treatment. Therefore, the aim of this study was to characterize a series of pediatric NTRK-rearranged mesenchymal tumors, including classic ETV6-NTRK3 fused tumors and tumors with variant (non-ETV6) NTRK fusions. The clinical features, morphology, immunophenotype, and genetics of 12 classic ETV6-NTRK3 fused infantile fibrosarcoma and 18 variant NTRK-rearranged mesenchymal tumors were evaluated. For both classic and variant groups, the age at diagnosis ranged from birth to 15 years (median, 4 mo) with no sex predilection; the most common sites involved were the extremities and trunk. The rate of local recurrence and metastasis were not significantly different (recurrence rate: 11% classic, 40% variant; metastatic rate: 18% classic, 25% variant). Classic and variant NTRK tumors had an overlapping spectrum of histologic features, containing haphazardly arranged primitive cells in a myxoid background and/or spindle cells in long fascicles. Both groups showed diffuse pan-TRK expression by immunohistochemistry. Otherwise, the immunoprofile was nonspecific, but similar between both groups. No statistical difference was seen in any clinicopathologic feature between the classic ETV6-NTRK3 and variant fusion cohorts. Pediatric NTRK-rearranged mesenchymal tumors with both classic and variant fusions likely represent a spectrum of disease with shared, recognizable cliniopathologic features.
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http://dx.doi.org/10.1097/PAS.0000000000001203DOI Listing
April 2019

Profiling targetable immune checkpoints in osteosarcoma.

Oncoimmunology 2018;7(12):e1475873. Epub 2018 Sep 11.

Department of Translational Genomics.

Osteosarcomas are aggressive bone tumors for which therapeutic advances have not improved over several decades. Unlike most pediatric tumors, the osteosarcoma genome is remarkably unstable, characterized by numerous copy number alterations and chromosomal structural aberrations. In this study, we asked if the targetable immune checkpoints and are impacted by copy number alterations in osteosarcoma. Of the 215 osteosarcoma samples investigated, and were independently gained at frequencies of approximately 8-9%, with a cumulative frequency of approximately 24%. RNA sequencing data from two independent cohorts revealed that is the most highly expressed immune checkpoint gene among the four investigated. We also show that is preferentially expressed in pediatric solid tumors and that increased protein expression of B7-H3 and IDO1 are significantly associated with inferior survival in patient samples. Using human osteosarcoma cell lines, we demonstrate that is gained in MG63 and G292 cells and that the IDO1 inhibitor, epacadostat, inhibits the enzymatic activity of IDO1 in a dose-dependent manner in these cells. Together, these data reveal the genomic and transcriptomic profiles of and in osteosarcoma and identifies a potential context for targeted immunotherapeutic intervention in a subset of patients.
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http://dx.doi.org/10.1080/2162402X.2018.1475873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279416PMC
September 2018

The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy is feasible but does not improve outcome for patients with metastatic rhabdomyosarcoma: A report from the Children's Oncology Group.

Cancer 2019 01 23;125(2):290-297. Epub 2018 Oct 23.

Pediatric Hematology/Oncology, Seattle Children's Hospital, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: The outcome for patients with metastatic rhabdomyosarcoma (RMS) remains poor. A previous Children's Oncology Group (COG) study (ARST0431) for patients with metastatic RMS produced no improvement in outcome using multiple cytotoxic agents in a dose-intensive manner. The authors report results from the subsequent COG study (ARST08P1), which evaluated the feasibility and efficacy of adding cixutumumab (insulin-like growth factor-1 monoclonal antibody) or temozolomide to the ARST0431 intensive chemotherapy backbone.

Methods: Two nonrandomized pilot studies were conducted in patients with metastatic RMS, initially to determine feasibility, and both pilots were expanded to assess efficacy. All patients received 54 weeks of chemotherapy, including vincristine/irinotecan, interval-compressed vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, and vincristine/dactinomycin/cyclophosphamide. In pilot 1, patients received intravenous cixutumumab (3, 6, or 9 mg/kg) once weekly throughout therapy. In pilot 2, patients received oral temozolomide (100 mg/m ) daily for 5 days with irinotecan. All patients received radiation to the primary tumor and to metastatic sites.

Results: One hundred sixty-eight eligible patients were enrolled (97 on pilot 1 and 71 on pilot 2). Most patients were aged ≥10 years (73%), with alveolar histology (70%), and had bone and/or bone marrow metastases (59%). Toxicities observed in each pilot were similar to those reported on ARST0431. With a median follow-up of 2.9 years, the 3-year event-free survival rate was 16% (95% confidence interval, 7%-25%) with cixutumumab and 18% (95% confidence interval, 2%-35%) with temozolomide.

Conclusions: The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy for metastatic RMS was safe and feasible. Neither agent improved outcome compared with the same chemotherapy that was used on ARST0431.
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http://dx.doi.org/10.1002/cncr.31770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329653PMC
January 2019

OncoKids: A Comprehensive Next-Generation Sequencing Panel for Pediatric Malignancies.

J Mol Diagn 2018 11 20;20(6):765-776. Epub 2018 Aug 20.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California; Department of Pathology, Keck School of Medicine of USC, Los Angeles, California.

The OncoKids panel is an amplification-based next-generation sequencing assay designed to detect diagnostic, prognostic, and therapeutic markers across the spectrum of pediatric malignancies, including leukemias, sarcomas, brain tumors, and embryonal tumors. This panel uses low input amounts of DNA (20 ng) and RNA (20 ng) and is compatible with formalin-fixed, paraffin-embedded and frozen tissue, bone marrow, and peripheral blood. The DNA content of this panel covers the full coding regions of 44 cancer predisposition loci, tumor suppressor genes, and oncogenes; hotspots for mutations in 82 genes; and amplification events in 24 genes. The RNA content includes 1421 targeted gene fusions. We describe the validation of this panel by using a large cohort of 192 unique clinical samples that included a wide range of tumor types and alterations. Robust performance was observed for analytical sensitivity, reproducibility, and limit of detection studies. The results from this study support the use of OncoKids for routine clinical testing of a wide variety of pediatric malignancies.
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http://dx.doi.org/10.1016/j.jmoldx.2018.06.009DOI Listing
November 2018

Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group.

J Clin Oncol 2018 09 9;36(27):2770-2777. Epub 2018 Aug 9.

Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK.

Purpose Intermediate-risk rhabdomyosarcoma (RMS) includes patients with either nonmetastatic, unresected embryonal RMS (ERMS) with an unfavorable primary site or nonmetastatic alveolar RMS (ARMS). The primary aim of this study was to improve the outcome of patients with intermediate-risk RMS by substituting vincristine and irinotecan (VI) for half of vincristine, dactinomycin, and cyclophosphamide (VAC) courses. All patients received a lower dose of cyclophosphamide and earlier radiation therapy than in previous trials. Patients and Methods Patients were randomly assigned at study entry to either VAC (cumulative cyclophosphamide dose, 16.8 g/m) or VAC/VI (cumulative cyclophosphamide dose, 8.4 g/m) for 42 weeks of therapy. Radiation therapy started at week 4, with individualized local control plans permitted for patients younger than 24 months. The primary study end point was event-free survival (EFS). The study design had an 80% power (5% one-sided α-level) to detect an improved long-term EFS from 65% (with VAC) to 76% (with VAC/VI). Results A total of 448 eligible patients were enrolled in the study. At a median follow-up of 4.8 years, the 4-year EFS was 63% with VAC and 59% with VAC/VI ( P = .51), and 4-year overall survival was 73% for VAC and 72% for VAC/VI ( P = .80). Within the ARMS and ERMS subgroups, no difference in outcome by treatment arm was found. Severe hematologic toxicity was less common with VAC/VI therapy. Conclusion The addition of VI to VAC did not improve EFS or OS for patients with intermediate-risk RMS. VAC/VI had less hematologic toxicity and a lower cumulative cyclophosphamide dose, making VAC/VI an alternative standard therapy for intermediate-risk RMS.
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http://dx.doi.org/10.1200/JCO.2018.77.9694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145831PMC
September 2018

Transmission of a germline mutation from unaffected male carrier associated with pediatric glioblastoma in his child and gestational choriocarcinoma in his female partner.

Cold Spring Harb Mol Case Stud 2018 04 2;4(2). Epub 2018 Apr 2.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, California 90027, USA.

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by germline alterations in the tumor suppressor gene LFS is associated with numerous malignancies including astrocytoma. Sanger sequencing and chromosomal microarray studies of blood and tumor tissue from a 4-yr-old boy with glioblastoma demonstrated a germline mutation with loss of heterozygosity for the short arm of Chromosome 17 as the second inactivating event in the tumor. There was no family history of LFS, but the child's mother had recently died from metastatic choriocarcinoma after antecedent normal term delivery of a then 6-mo-old daughter. The choriocarcinoma contained the same mutation detected in the proband and the 6-mo-old daughter was confirmed to be a carrier. Unexpectedly, the germline mutation was found to be inherited from the unaffected father. We report here the second genetically confirmed case of -mutated choriocarcinoma in the partner of an LFS patient. Based on this case and recent literature, female partners of LFS patients may have increased risk of choriocarcinoma due to transmission of germline mutation from male carriers. Although the Toronto protocol has established an effective approach to detect tumors and improve survival in children and adults with LFS, there is a need to expand the current criteria to include surveillance of female partners of LFS patients for choriocarcinoma and other gestational trophoblastic disease. Recognition of this unique mode of transmission of mutations should be considered in genetic counseling for cancer risk assessment and family planning.
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http://dx.doi.org/10.1101/mcs.a002576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880265PMC
April 2018

On the First Usage of the Term "Rhabdomyosarcoma".

Pediatr Dev Pathol 2019 Jan-Feb;22(1):87. Epub 2018 Mar 8.

3 Department of Pediatric Pathology, Children's Hospital of Los Angeles, California.

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http://dx.doi.org/10.1177/1093526618754637DOI Listing
January 2019

45 Gy is not sufficient radiotherapy dose for Group III orbital embryonal rhabdomyosarcoma after less than complete response to 12 weeks of ARST0331 chemotherapy: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

Pediatr Blood Cancer 2017 Sep 26;64(9). Epub 2017 May 26.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York.

Background: Recent Children's Oncology Group (COG) trials tested the efficacy of reduced therapy in an effort to lessen late effects compared to the Intergroup Rhabdomyosarcoma Study (IRS) IV regimen with associated hematologic and hepatic toxicity, and infertility. Here, we analyze the efficacy of 45 Gray (Gy) local radiotherapy (RT) in patients with Group III orbital embryonal rhabdomyosarcoma (ERMS) enrolled on the COG low-risk study ARST0331.

Procedure: Sixty-two patients with Group III orbital ERMS were treated on ARST0331 with four cycles of vincristine (VCR), dactinomycin (DACT), and cyclophosphamide (CPM; VAC, total cumulative CPM dose 4.8 g/m ) followed by four cycles of VCR and DACT over 22 weeks. Forty-five Gray of radiation was administered in 25 fractions beginning at week 13 of therapy.

Results: Fifty-three patients were evaluable for this response analysis; seven had missing week 12 response evaluation data and two had progressive disease prior to starting RT. Median follow-up was 7.8 years. None of the 15 patients with radiographic complete response (CR) compared to 6 of the 38 patients with
Conclusions: For patients with Group III orbital ERMS achieving a CR following VAC chemotherapy that includes modest dose CPM, 45 Gy may be sufficient for durable failure-free survival. However, for those with
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http://dx.doi.org/10.1002/pbc.26540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568701PMC
September 2017

Histology, fusion status, and outcome in metastatic rhabdomyosarcoma: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2017 Dec 18;64(12). Epub 2017 May 18.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California.

Background: Distinguishing alveolar rhabdomyosarcoma (ARMS) from embryonal rhabdomyosarcoma (ERMS) has historically been of prognostic and therapeutic importance. However, classification has been complicated by shifting histologic criteria required for an ARMS diagnosis. Children's Oncology Group (COG) studies after IRS-IV, which included the height of this diagnostic shift, showed both an increased number of ARMS and an increase in the proportion of fusion-negative ARMS. Following diagnostic standardization and histologic re-review of ARMS cases enrolled during this era, analysis of low-risk (D9602) and intermediate-risk (D9803) rhabdomyosarcoma (RMS) studies showed that fusion status rather than histology best predicts prognosis for patients with RMS. This analysis remains to be completed for patients with high-risk RMS.

Procedure: We re-reviewed cases on high-risk COG studies D9802 and ARST0431 with an enrollment diagnosis of ARMS. We compared the event-free survival (EFS) and overall survival by histology, PAX-FOXO1 fusion, and clinical risk factors (Oberlin score) for patients with metastatic RMS using the log-rank test.

Results: Histology re-review resulted in reclassification as ERMS for 12% of D9802 cases and 5% of ARST0431 cases. Fusion-negative RMS had a superior EFS to fusion-positive RMS; however, poorer outcome for metastatic RMS was most related to clinical risk factors including age, primary site, and number of metastatic sites.

Conclusions: In contrast to low- or intermediate-risk RMS, in metastatic RMS, clinical risk factors have the most impact on patient outcome. PAX-FOXO1 fusion is more common in patients with a high Oberlin score, but fusion status is not an independent biomarker of prognosis.
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http://dx.doi.org/10.1002/pbc.26645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647228PMC
December 2017

Reduction of cyclophosphamide dose for patients with subset 2 low-risk rhabdomyosarcoma is associated with an increased risk of recurrence: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

Cancer 2017 Jun 17;123(12):2368-2375. Epub 2017 Feb 17.

Division of Hematology/Oncology, Seattle Children's Hospital, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington.

Background: Failure-free survival (FFS) and overall survival (OS) rates were found to improve on Intergroup Rhabdomyosarcoma Study (IRS) IV (IRS-IV) compared with IRS-III for patients with subset 2 (IRS stage 1, group III nonorbit or stage 3, group I/II) low-risk embryonal rhabdomyosarcoma with the addition of cyclophosphamide (total cumulative cyclophosphamide dose of 26.4 g/m ) to the combination of vincristine and dactinomycin (VAC). The goal of Children's Oncology Group ARST0331 for subset 2 low-risk patients was to reduce the total cumulative cyclophosphamide dose without compromising FFS.

Methods: Therapy included 4 cycles of VAC (total cumulative cyclophosphamide dose of 4.8 g/m ) followed by 12 cycles of vincristine and dactinomycin over 46 weeks. Patients with group II or III tumors received radiotherapy, except for girls with group III vaginal tumors who enrolled before September 2009 and achieved a complete response with chemotherapy with or without delayed surgical resection.

Results: Among 66 eligible patients who were followed for a median of 3.5 years, there were 20 failures versus 10.53 expected failures. The estimated 3-year FFS and OS rates were 70% (95% confidence interval [95% CI], 57%-80%) and 92% (95% CI, 83%-97%), respectively. The estimated 3-year FFS rate was 57% (95% CI, 33%-75%) for girls with subset 2 genital tract embryonal rhabdomyosarcoma (21 patients) and 77% (95% CI, 61%-87%) for all other subset 2 patients (45 patients) (P = .02).

Conclusions: The authors observed suboptimal FFS among patients with subset 2 low-risk rhabdomyosarcoma using reduced total cyclophosphamide. Eliminating radiotherapy for girls with group III vaginal tumors in combination with reduced total cyclophosphamide appeared to contribute to the suboptimal outcome. Cancer 2017;123:2368-2375. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662934PMC
June 2017

Fibrous hamartoma of infancy: a clinicopathologic study of 145 cases, including 2 with sarcomatous features.

Mod Pathol 2017 04 6;30(4):474-485. Epub 2017 Jan 6.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Fibrous hamartoma of infancy is a rare soft tissue lesion of infants and young children with characteristic triphasic morphology, which typically occurs in the axilla and less commonly in other locations. We reviewed 145 cases of fibrous hamartoma of infancy from our consultation archives. Cases occurred in 106 males and 39 females (mean age-15 months; range-birth to 14 years), and involved both typical sites (eg, axilla/back/upper arm) (n=69) and unusual locations (n=76). Six were congenital. The tumors presented as subcutaneous masses and ranged from 0.4 to 17 cm (mean 3 cm). All displayed triphasic morphology, but varied widely in the relative percentages of fat, fibroblastic fascicles, and primitive mesenchyme. Hyalinized zones with cracking artifact, mimicking giant cell fibroblastoma, were present in a 44 (30%) of cases; however FISH for PDGFB gene rearrangement was negative in five tested cases. In addition to classical fibrous hamartoma of infancy, two lesions contained large sarcomatous-appearing foci with high cellularity, high nuclear grade, and brisk mitotic activity. One occurred in a 10-month-old female as a new mass in a congenital fibrous hamartoma of infancy; the other occurred as a leg mass in a 6-year-old male. ETV6 gene rearrangement was negative in the tumor from the 10-month-old female. Genomic microarray (OncoScan) showed normal molecular karyotype in eight tested cases, whereas the two tumors with sarcomatous features showed a hyperdiploid/near tetraploid molecular karyotype with copy neutral loss of heterozygosity of chromosomes 1p and 11p, and loss of 10p, chromosome 14, and a large portion of chromosome 22q (22q11.23q13.33), respectively. Follow-up (52 patients; range: 1-208 months, median: 8 months) showed only two local recurrences and no metastases. Extensive local disease in the 10-month-old female with sarcomatous-appearing fibrous hamartoma of infancy necessitated forequarter amputation. In summary, our study confirms the classic clinicopathologic features, including the triphasic morphologic appearance of most cases. In contrast to earlier studies, our series illustrates a broader histologic spectrum than previously appreciated, including its close resemblance to giant cell fibroblastoma in one quarter of cases and the rare presence of 'sarcomatous' areas, the latter providing evidence that these are complex neoplasms rather than hamartomas.
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http://dx.doi.org/10.1038/modpathol.2016.215DOI Listing
April 2017

The impact of human epidermal growth factor receptor 2 neoadjuvant monoclonal antibody (trastuzumab) therapy in ductal carcinoma in situ of the breast.

Histopathology 2017 05 7;70(6):1009-1011. Epub 2017 Feb 7.

Division of Cancer Studies, Kings College London, London, UK.

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http://dx.doi.org/10.1111/his.13145DOI Listing
May 2017

Opportunities for Improvement in Pathology Reporting of Childhood Nonrhabdomyosarcoma Soft Tissue Sarcomas:  A Report From Children's Oncology Group (COG) Study ARST0332.

Am J Clin Pathol 2016 Sep 10;146(3):328-38. Epub 2016 Aug 10.

Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA.

Objectives: Treatment of soft tissue tumors in young patients relies on the diagnostic information conveyed in the pathology report. We examined pathology reports from Children's Oncology Group ARST0332 for inclusion of data elements required in published guidelines.

Methods: Pathology reports for 551 eligible patients were examined for required data elements defined by the College of American Pathologists, including tissue type, procedure, tumor site, tumor maximum diameter, macroscopic extent of tumor, histologic type, mitotic rate, extent of necrosis, tumor grade, margin status, use of ancillary studies, and pathologic stage.

Results: Only 65 (12%) of 551 reports included all required data elements. Of reports containing synoptic templates, 57% were complete.

Conclusions: This study reveals significant opportunity to improve the quality of pathology reports in young patients with soft tissue tumors. Use of templates or checklists improves completeness of reports.
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http://dx.doi.org/10.1093/ajcp/aqw114DOI Listing
September 2016

An audit of residual cancer burden reproducibility in a UK context.

Histopathology 2017 Jan 27;70(2):217-222. Epub 2016 Sep 27.

Department of Histopathology, St Thomas' Hospital, London, UK.

Aims: The residual cancer burden score (RCB) is currently the preferred quantification tool for assessing residual disease following neoadjuvant chemotherapy (NACT) in breast cancer clinical trials. This has been shown to be highly reproducible at the MD Anderson Cancer Centre, where it was developed originally. We wanted to evaluate RCB in a UK context, where macroscopic handling of tissue may differ between sites.

Methods And Results: The pathology slides from 90 post-NACT patients from Guy's and St Thomas' NHS Foundation Trust and the Royal Bournemouth Hospital were reviewed independently by two specialist breast histopathologists who recalculated the RCB for each case. Data were collated and analysed statistically for interobserver reproducibility, for both numerical and categorical RCB. Overall, agreement between pathologists was 'good' [kappa = 0.775; 95% confidence interval (CI) = 0.668-0.882]. The overall concordance for continuous RCB score and for categorical RCB group was statistically significant (Spearman's correlation coefficient = 0.9497; 95% CI = 0.9235-0.9671; P < 0.0001 and Spearman's correlation coefficient = 0.9145; 95% CI = 0.8712-0.9437; P < 0.0001, respectively). Discordance could not be attributed to any one component of the RCB calculation.

Conclusions: These data suggest that the RCB score is reproducible in a UK context. Further data comparing it to other quantification systems is required, however, before any superiority can be established.
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http://dx.doi.org/10.1111/his.13054DOI Listing
January 2017

Histology, Fusion Status, and Outcome in Alveolar Rhabdomyosarcoma With Low-Risk Clinical Features: A Report From the Children's Oncology Group.

Pediatr Blood Cancer 2016 Apr 12;63(4):634-9. Epub 2016 Jan 12.

Division of Hematology, Oncology, and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background: Distinguishing alveolar rhabdomyosarcoma (ARMS) from embryonal rhabdomyosarcoma (ERMS) is of prognostic and therapeutic importance. Criteria for classifying these entities evolved significantly from 1995 to 2013. ARMS is associated with inferior outcome; therefore, patients with alveolar histology have generally been excluded from low-risk therapy. However, patients with ARMS and low-risk stage and group (Stage 1, Group I/II/orbit III; or Stage 2/3, Group I/II) were eligible for the Children's Oncology Group (COG) low-risk rhabdomyosarcoma (RMS) study D9602 from 1997 to 1999. The characteristics and outcomes of these patients have not been previously reported, and the histology of these cases has not been reviewed using current criteria.

Procedure: We re-reviewed cases that were classified as ARMS on D9602 using current histologic criteria, determined PAX3/PAX7-FOXO1 fusion status, and compared these data with outcome for this unique group of patients.

Results: Thirty-eight patients with ARMS were enrolled onto D9602. Only one-third of cases with slides available for re-review (11/33) remained classified as ARMS by current histologic criteria. Most cases were reclassified as ERMS (17/33, 51.5%). Cases that remained classified as ARMS were typically fusion-positive (8/11, 73%), therefore current classification results in a similar rate of fusion-positive ARMS for all clinical risk groups. In conjunction with data from COG intermediate-risk treatment protocol D9803, our data demonstrate excellent outcomes for fusion-negative ARMS with otherwise low-risk clinical features.

Conclusions: Patients with fusion-positive RMS with low-risk clinical features should be classified and treated as intermediate risk, while patients with fusion-negative ARMS could be appropriately treated with reduced intensity therapy.
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http://dx.doi.org/10.1002/pbc.25862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755849PMC
April 2016

Immunohistochemical Markers of Soft Tissue Tumors: Pathologic Diagnosis, Genetic Contributions, and Therapeutic Options.

Authors:
David M Parham

Anal Chem Insights 2015 29;10(Suppl 1):1-10. Epub 2015 Oct 29.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA. ; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

After ~30 years of widespread usage, immunohistochemistry (IHC) has become a standard method of diagnosis for surgical pathology. Because of the plethora of diagnoses and often subtle nature of diagnostic criteria, IHC finds particular utility in soft tissue tumors. The use of progressively small amounts of tissue for diagnosis highlights the importance of this method. The sensitivity and crispness of IHC stains have progressively improved with the advent of new techniques. Traditionally, IHC detects cell-typic markers that characterize cell phenotypes, such as chromogranin for neuroectodermal tissue, myogenin for skeletal muscle, and cytokeratin for epithelium. However, the advent of genetic discoveries have led to IHC testing for detection of fusion gene products or overexpressed oncogenes associated with deletions and mutations. Proliferation-based markers such as Ki-67 can also be used for prognosis and grading, but more standardization is needed. Development of monoclonal antibody-based pharmaceuticals, such as imatinib or crizotinib, holds the promise of tailored anticancer therapy. IHC thus has assumed importance not only for diagnosis but also for guidance of personalized medicine.
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http://dx.doi.org/10.4137/ACI.S32730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627416PMC
November 2015
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