Long-term outcomes and patterns of relapse in patients with bilateral Wilms tumor or bilaterally predisposed unilateral Wilms tumor, a report from the COG AREN0534 study.

The objective of this study is to report the long-term timing and patterns of relapse for children enrolled in Children's Oncology Group AREN0534, a multicenter phase III clinical trial conducted from 2009 to 2015. Participants included children with bilateral Wilms tumor (BWT) or unilateral WT with genetic predisposition to develop BWT followed for up to 10 years. Smoothed hazard (risk) functions for event-free survival (EFS) were plotted so that the timing of events could be visualized, both overall and within pre-specified groups. Two hundred and twenty-two children (190 BWT and 32 unilateral WT with BWT predisposition) were followed for a median of 8.6 years. Fifty events were reported, of which 48 were relapse/progression. The overall 8-year EFS was 75% (95% confidence interval: 69%-83%). The highest risk for an EFS event was immediately after diagnosis with a declining rate over 2 years. A second peak of events was observed around 4 years after diagnosis, and a small number of events were reported until the end of the follow-up period. In subset analyses, later increases in risk were more commonly observed in patients with female sex, anaplastic histology, negative lymph nodes or margins, and favorable histology Wilms tumor patients with post-chemotherapy intermediate risk. Among relapses that occurred after 2 years, most were to the kidney. These patterns suggest that late events may be second primary tumors occurring more commonly in females, although more investigation is required. Clinicians may consider observation of patients with BWT beyond 4 years from diagnosis.

Bilateral Wilms tumor with anaplasia: A report from the Children's Oncology Group Study AREN0534.

INTRODUCTION: The purpose of this study is to examine the outcomes in children with anaplastic bilateral Wilms tumor (BWT) from study AREN0534 in order to define potential prognostic factors and areas to target in future clinical trials. METHODS: Demographic and clinical data from AREN0534 study patients with anaplasia (focal anaplasia [FA], or diffuse anaplasia [DA]) were compared. Event-free survival (EFS) and overall survival (OS) were reported using Kaplan-Meier estimation with 95% confidence bands, and differences in outcomes between FA and DA compared using log-rank tests. The impact of margin status was analyzed. RESULTS: Twenty-seven children who enrolled on AREN0534 had evidence of anaplasia (17 DA, 10 FA) in at least one kidney and were included in this analysis. Twenty-six (96%) had BWT. Nineteen percent had anaplastic histology in both kidneys (four of 17 DA, and one of 10 FA). Forty-six percent with BWT had bilateral nephron-sparing surgery (NSS); one child who went off protocol therapy, eventually required bilateral completion nephrectomies. Median follow-up for EFS and OS was 8.6 and 8.7 years from enrollment. Four- and 8-year EFS was 53% [95% confidence interval (CI): 34%-83%] for DA; 4-year EFS was 80% [95% CI: 59%-100%], and 8-year EFS 70% [95% CI: 47%-100%] for FA. Three out of 10 children with FA and eight out of 17 children with DA had events. EFS did not differ statistically by margin status (p = .79; HR = 0.88). Among the six children who died (five DA, one FA), all experienced prior relapse or progression within 18 months. CONCLUSION: Events in children with DA/FA in the setting of BWT occurred early. Caution should be taken about interpreting the impact of margin status outcomes in the context of contemporary multimodal therapy. Future targeted investigations in children with BWT and DA/FA are needed.

Putting It All Together: Postmortem Diagnosis of a Rare Ichthyosis Syndrome.

Neu-Laxova syndrome (NLS) is a rare lethal disorder with autosomal recessive inheritance and is characterized by multiple congenital anomalies. Our case of NLS presented with severe intrauterine growth restriction (IUGR), abnormal facial features, severe central nervous system malformations, skeletal muscle contractures, and the hallmark signs of NLS: ichthyotic skin and excessive subcutaneous tissue with edema. Additionally, testing amniotic fluid from a prior pregnancy with a fetus showing similar abnormalities revealed several regions of homozygosity; one of these regions involved chromosome 1p13.2-p11.2, where the PHGDH gene is located. Based on the pattern of findings on serial fetal ultrasounds, postmortem neonatal exams, gross and microscopic exams, radiographs, and genetic analysis in conjunction with the clinical history and the prior pregnancy with the above-described molecular alteration, a final diagnosis of NLS was made. This rare developmental disorder is characterized by heterogenous neuroectodermal defects. Fetal ultrasound in the second trimester can help diagnose it. It is postulated to be caused by loss-of-function mutations in the PHGDH (phosphoglycerate dehydrogenase), PSAT1 (phosphoserine aminotransferase 1), and PSPH (phosphoserine phosphatase) genes, which are responsible for de novo L-serine synthesis.

Pathology of Wilms' tumour in International Society of Paediatric Oncology (SIOP) and Children's oncology group (COG) renal tumour studies: Similarities and differences.

Excellent outcomes for patients with Wilms' tumour (WT), >90% for all stages together, have been achieved through researching WT in multicentre and multinational trials and studies in the last 50 years, led by two major groups-the International Society of Paediatric Oncology (SIOP) and the Children's Oncology Group (COG) (previously the National Wilms' Tumour Study Group). Despite the two groups having different approaches, the survival outcomes are remarkably similar. In general, in the SIOP approach, which is followed in Europe and most other countries around the world, patients are first treated with preoperative chemotherapy; this is followed by surgery and, if necessary, postoperative chemotherapy and radiotherapy. In the COG approach, which is mainly followed in North America, patients are treated with upfront surgery, followed, if necessary, by postoperative chemotherapy and radiotherapy. In both groups, postoperative treatment primarily depends on tumour histological classification and stage, although, in recent studies, other prognostic factors have also been included (tumour volume, response to preoperative chemotherapy, and molecular markers). Owing to separate initial treatments, there are differences in histological assessment and subtyping of WT, and, more importantly, in staging criteria. In this review, we discuss the similarities and differences between the two groups in order to help pathologists who are dealing with WT to understand and follow the pathological protocol that is appropriate for a particular case, because, in many centres, both approaches may be followed, depending on individual case/patient circumstances.

It Takes a Village: Providing International Pediatric Pathology Services in a Resource-Limited Setting

OBJECTIVES: Partnerships between low- to middle-income countries (LMICs) and high-income countries (HICs) is one strategy to mitigate observed health disparities. Cambodia's Angkor Hospital for Children (AHC), an LMIC institution, faces shortages in health care resources, including pathology services. A partnership was created with Children's Wisconsin (CW), an HIC hospital, including provision of pathology services. We describe our established pathology workflow, examine cases seen in AHC patients, and evaluate the impact of CW's interpretations. METHODS: AHC provides clinical history and impression and ships samples to CW, which processes the samples, and pathologists provide interpretations, sending reports electronically to AHC. For analysis, final diagnoses were considered "concordant," "refined," or "discordant" based on agreement with the clinical impression. Cases were also classified as "did not change management" or "changed management" based on how CW interpretation affected clinical management. RESULTS: We included 347 specimens (177 malignant, 146 benign, 24 insufficient for diagnosis). Of these cases, 31% were discordant and 44% of cases with clinical follow-up had a change in management with CW interpretation. CONCLUSIONS: Inclusion of pathology services in LMIC-HIC partnerships is crucial for resolving health disparities between the institutions involved. The described partnership and established pathology workflow can be adapted to the needs and resources of many institutions.

Correlation of anal cytology with follow-up histology and Human Papillomavirus genotyping: A 10-year experience from an academic medical center.

BACKGROUND: Anal cytology (AC) is accepted as a practical screening modality for anal cancer. However, studies suggest that AC and anal biopsy dysplasia correlation is less robust than in cervicovaginal specimens. The current study goals were to look at our institutional experience in a subset of ACs and correlate with surgical pathology (SP), as well as evaluate their Human Papillomavirus (HPV) status. METHODS: 377 ACs from 169 patients (151 males and 18 females) from 2008 to 2017 were included. HPV genotyping (n = 47) and SP within one year of AC (n = 58) were reviewed. RESULTS: AC/SP was discrepant in 22 cases (37.9%), with a tendency towards AC underestimating the degree of dysplasia. Specifically, any abnormality on AC was 93.8% sensitive for detecting high-grade dysplasia (HGD). However, when requiring a high-grade AC diagnosis, the sensitivity decreases to 12.5%. "Other high-risk HPV" was the most common genotype (57.4%). When considered with all AC with a high-grade diagnosis, co-testing with HPV improved the sensitivity for HGD to 56.3%. Sensitivity improved further to 87.5% when only considering cases with both AC and HPV testing, and were high-risk HPV positive. Furthermore, following review and consensus diagnosis, 8 cases changed from "Discrepant" to "Agreed", reducing the discrepancy rate to 24.1%. Remaining discrepancies were explained by sampling error. CONCLUSION: Given the enhanced sensitivity of AC and HPV testing together, and sampling error seen with AC leading to underestimating dysplasia, we recommend AC and HPV co-testing, as well as describing confounding factors in AC reports and obtaining consensus opinion in equivocal cases.

Wilms Tumor: Challenges and Newcomers in Prognosis.

Wilms tumor is the most common renal tumor of childhood. It is a biologically and morphologically diverse entity, with ongoing studies contributing to our understanding of the pathobiology of various subgroups of patients with Wilms tumor. The interplay of histologic examination and molecular interrogation is integral in prognostication and direction of therapy. This review provides an overview of some of the challenging aspects and pitfalls in pathologic assessment of Wilms tumor, along with discussion of current and up-and-coming markers of biological behavior with prognostic significance.

Outcome analysis of stage I epithelial-predominant favorable-histology Wilms tumors: A report from Children's Oncology Group study AREN03B2.

BACKGROUND: Stage I epithelial-predominant favorable-histology Wilms tumors (EFHWTs) have long been suspected to have an excellent outcome. This study investigates the clinical and pathologic features of patients with stage I EFHWTs to better evaluate the potential for a reduction of chemotherapy and its associated toxicity. METHODS: All patients registered in the Children's Oncology Group (COG) AREN03B2 study between 2006 and 2017 with stage I EFHWTs were identified. EFHWTs were defined as tumors with at least 66% epithelial differentiation, regardless of the degree of differentiation. Clinical information was abstracted from COG records. Event-free survival (EFS) and overall survival (OS) were calculated and compared between groups based on age and therapy. RESULTS: The 4-year EFS rate was 96.2% (95% confidence interval, 92%-100%), and the OS rate was 100%; EFS and OS did not statistically significantly differ with the age at diagnosis (<48 vs ≥48 months; P = .37) or treatment (EE4A vs observation only; P = .55). Six events were reported. Three patients developed contralateral tumors and did not otherwise relapse; none of these had nephrogenic rests or a recognized predisposition syndrome. Three patients developed metastatic recurrence; all 3 had received EE4A as their primary therapy after nephrectomy. CONCLUSIONS: These findings demonstrate an excellent outcome for stage I EFHWTs with >95% EFS and OS. These data support the utility of investigating the treatment of stage I EFHWTs with observation alone after nephrectomy.

Adequacy and Accuracy of Core Biopsy in Children: A Radiologic/Pathologic Correlation Study.

Core biopsy (CB) is increasingly popular for assessing solid lesions in children. To date, pediatric literature is limited regarding factors contributing to diagnostically inadequate or inaccurate CB. Therefore, we retrospectively examined radiologic/pathologic factors associated with adequacy/accuracy of CB in pediatric patients. A search of the surgical pathology database for CB between January 2007 and December 2014 yielded 134 CB from 99 patients. Age, sex, anatomic site of lesion, CB diagnosis, and final diagnosis were acquired from the electronic medical record. Image guidance modality, lesion size, and CB sampling device were obtained from radiology records. CB hematoxylin and eosin slides were reviewed for fragmentation, percentage of fibrosis, and percentage of necrosis. Overall, CB length was measured using cellSens software and a DP71 camera. Groups were compared using 2-sided homoscedastic Student's t tests; 87.3% (117/134) CB were diagnostic; final diagnosis was available for 105 cases, with a concordance rate of 80.0% (84/105). Image guidance modality, lesion site (extremity vs nonextremity), and CB needle gauge did not significantly differ between diagnostic versus nondiagnostic CB or concordant versus discordant CB. Diagnostic CB had less necrosis and fibrosis than did nondiagnostic CBs (6.8% vs 29.7%, P = .0002 and 10.3% vs 29.1%, P = .0006). Nondiagnostic and discordant CB were more likely to be from bony lesions than soft tissue ( P = .01 and P = .0248). CB is valuable for diagnosing solid lesions in children, with good overall diagnostic rates regardless of lesion size, location, or imaging modality used for biopsy. Nondiagnostic and discordant CB were more often obtained from bony lesions; sampling via open biopsy may be more useful in that setting. Nondiagnostic and discordant CB have more necrosis and fibrosis, suggesting that on-site evaluation of CB tissue viability-for example, by touch imprint or fine needle aspiration-may be useful in further enhancing CB utility.

Fine needle aspiration of alveolar soft part sarcoma in a child: Cytomorphological clues for the surgical pathologist.

Alveolar soft part sarcoma (ASPS) is a rare soft tissue neoplasm generally affecting adolescents and young adults. Its unique histologic and ultrastructural features have been well-described; however, the cytopathological features of ASPS are less well-characterized, and recognition of this entity's features on cytologic preparations can ensure that the specimen adequacy and appropriate/rapid tissue allocation for additional testing. Herein we report a FNA case of ASPS with emphasis on cytomorphologic characteristics.

Clinicopathologic analysis of malignant effusions in pediatric patients.

INTRODUCTION: The utility of cytologic evaluation of effusion fluids in adults is well established but has been less well documented in the pediatric population. We examined the clinicopathologic characteristics of children with malignant effusions to establish the value of cytologic examination of these specimens. MATERIALS AND METHODS: Pleural, pericardial, peritoneal, and intraoperative washing specimens obtained between January 2000 and October 2015 were identified via surgical pathology database search. Relevant clinical and pathologic data was recorded. Statistical analysis of patient groups was performed via two-sided heteroscedastic Student t tests, and Kaplan-Meier analysis was used to compare overall survival between patient groups. RESULTS: 474 effusion/washing specimens obtained from 342 patients were identified: 179 pleural effusions, 220 peritoneal fluids, 28 pericardial effusions, and 47 intraoperative washing specimens. Of these, 13.7% (56 of 474) effusion specimens were positive for malignancy. Among cancer patients with effusions, malignant effusions were seen in 54.5% of patients with rhabdomyosarcoma and 28.8% of patients with hematolymphoid malignancies. Regarding patient outcomes, malignant effusions were associated with statistically significantly shorter overall survival (P = 0.019). When compared with stage IV patients with benign effusions, those with malignant effusions had a shorter 5-year overall survival (P = 0.042); multiple malignant effusions were associated with a dramatically shorter survival than a single malignant effusion. CONCLUSIONS: The overall rate of malignant effusions in our patient population was 13.7%. Malignant effusions in children, particularly multiple, portend a poor prognosis. Our observations emphasize the importance of accurate cytologic diagnosis of effusion fluids, and reinforce the value of their cytologic evaluation.

Improving Detection of Metastatic Neuroblastoma in Bone Marrow Core Biopsies: A Proposed Immunohistochemical Approach.

Bone marrow (BM) nvolvement is common in stage 4/M neuroblastoma patients and profoundly impacts clinical decision-making and predicts outcomes, but to our knowledge no standard exists for immunohistochemical evaluation of staging BMs. We examined the use of three immuno-stains-synaptophysin, tyrosine hydroxylase (TH), and PGP9.5-in detecting metastatic neuroblastoma in BM. We retrospectively selected 174 BM core biopsies from 41 neuroblastoma patients. Immunohistochemistry for synaptophysin, TH, and PGP9.5 was performed. These slides and the hematoxylin and eosin (H&E)-stained slide from each BM were randomized and independently scored by three pathologists as positive, negative, or indeterminate. Cohen's κ coefficients (interobserver agreement), McNemar's test (for frequencies of positive/indeterminate interpretations), and sensitivities for each stain/combination were calculated. Interobserver agreement was higher for all immunostains (synaptophysin, 78%-90%, κ  =  0.548-0.787; TH, 77%-92%, κ  =  0.481-0.788; and PGP9.5, 83%-90%, κ  =  0.601-0.740) than for H&Es (77%-84%, κ  =  0.434-0.572). Indeterminate interpretations were more frequent with H&Es (8.9%) and synaptophysin (6.0%) than with PGP9.5 (3.5%) or TH (3.3%). TH (76%) and PGP9.5 (70%) were the immunostains most likely to correctly resolve indeterminate H&E interpretation. Mean sensitivity among all three pathologists for detection of metastasis compared to the consensus diagnosis was 42.5% for H&E alone, 70.7% to 78.8% for H&E plus one immunostain, and 81.6% to 85% for H&E plus two immunostains. Immunohistochemistry enhanced sensitivity for tumor detection particularly dramatically in cases of prior chemotherapy. PGP9.5 and TH showed good interobserver agreement, fewer indeterminate interpretations, and resolved indeterminate H&E diagnoses at the highest frequencies. Therefore, we recommend H&E and two immunostains, specifically PGP9.5 and TH, for optimal detection of metastatic neuroblastoma in BM.

Effects of solid-medium type on routine identification of bacterial isolates by use of matrix-assisted laser desorption ionization-time of flight mass spectrometry.

Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) is a rapid method for the identification of bacteria. Factors that may alter protein profiles, including growth conditions and presence of exogenous substances, could hinder identification. Bacterial isolates identified by conventional methods were grown on various media and identified using the MALDI Biotyper (Bruker Daltonics, Billerica, MA) using a direct smear method and an acid extraction method. Specimens included 23 Pseudomonas isolates grown on blood agar, Pseudocel (CET), and MacConkey agar (MAC); 20 Staphylococcus isolates grown on blood agar, colistin-nalidixic acid agar (CNA), and mannitol salt agar (MSA); and 25 enteric isolates grown on blood agar, xylose lysine deoxycholate agar (XLD), Hektoen enteric agar (HE), salmonella-shigella agar (SS), and MAC. For Pseudomonas spp., the identification rate to genus using the direct method was 83% from blood, 78% from MAC, and 94% from CET. For Staphylococcus isolates, the identification rate to genus using the direct method was 95% from blood, 75% from CNA, and 95% from MSA. For enteric isolates, the identification rate to genus using the direct method was 100% from blood, 100% from MAC, 100% from XLD, 92% from HE, and 87% from SS. Extraction enhanced identification rates. The direct method of MALDI-TOF analysis of bacteria from selective and differential media yields identifications of varied confidence. Notably, Staphylococci spp. from CNA exhibit low identification rates. Extraction enhances identification rates and is recommended for colonies from this medium.