Ellen D'HOoghe

Background/Objectives: Wilms tumors, the most common pediatric renal tumors, are heterogeneous and consist of varying amounts of three components: blastema, epithelium, and stroma. Postoperative chemotherapy is tailored based on risk group classification and stage. Due to this heterogeneity, pathologists perform extensive tumor sampling to ensure accurate classification. Higher-harmonic-generation microscopy (HHGM) is an innovative imaging technique that enables rapid visualization of fresh tissue without preparation or staining. This makes it particularly valuable for sample selection, as the tissue can be reused for further analysis. This study aims to evaluate the accuracy of pathologists in distinguishing normal renal tissue, abnormal renal tissue, and three types of pediatric renal tumors, Wilms tumor, renal cell carcinoma, and congenital mesoblastic nephroma, in HHGM images. Methods: Twenty-nine samples from eighteen patients with a pediatric renal tumor were imaged using an HHG microscope and subsequently processed for histological analysis. Overview images of the samples were acquired at a rate of 10 s per mm², while high-quality images took 1 min per mm². A multi-observer study involving ten international expert pathologists of the SIOP-RTSG was conducted. Results: Pathologists were able to differentiate between normal and abnormal tissue with 100% (29/29) accuracy and correctly identified tumor versus non-tumor tissue with 97% (28/29) accuracy. Conclusions: These results show that HHGM is a highly promising technique for the rapid assessment of pediatric renal tumor samples, particularly for evaluating sample representativeness.

Background: Completely necrotic Wilms tumor (CN‐WT) following preoperative chemotherapy has been regarded as low‐risk WT since the International Society of Paediatric Oncology (SIOP) 93‐01 study, and patients have been treated with reduced postoperative therapy. The aim of the study was to evaluate whether the omission of adjuvant chemotherapy in patients with localized CN‐WT stage I and radiotherapy in stage III was safe.Patients and methods: The retrospective observational study of outcomes of patients diagnosed with localized CN‐WT on central pathology review and treated according to the SIOP 93‐01 and SIOP‐WT‐2001 protocols (1993–2022).Results: There were 125 patients with localized CN‐WT: 90 with stage I, 10 with stage II, and 25 with stage III. Sixty‐two of 125 (49.6%) patients had a discrepant diagnosis and/or staging between the institutional pathologist and central pathology review. In the group of 90 patients with stage I, postoperative chemotherapy was not given to 41 (46%) patients, whereas 49 patients received postoperative chemotherapy—in the latter group, two patients relapsed, and one of them died. One stage I and one stage II patient developed chemotherapy‐induced toxicity and died. Nineteen of 25 patients with stage III received no flank radiotherapy. No stage III patient relapsed or died. The overall 5‐year event‐free survival (EFS) estimate for the entire cohort (stages I–III) was 96.8% [95% confidence interval, CI: 93.6%–99.6%] and the overall survival (OS) was 97.6% [95% CI: 95.0–100%]. The EFS and OS were 97% and 98%, respectively, for stage I, and 100% for stage III.Conclusion: Omission of postoperative chemotherapy for patients with CN‐WT stage I, and radiotherapy for stage III is safe. Rapid central pathology review is required to assign appropriate treatment and avoid treatment‐related side effects.

Background: Patients treated with preoperative chemotherapy with stage I intermediate‐risk Wilms tumor (IR‐WT) represent the largest group of patients with Wilms tumor (WT), and they have excellent outcomes.Methods: The authors performed a retrospective analysis of patients with stage I epithelial (ET‐WT) or stromal type WT (ST‐WT) treated pre‐ and postoperatively according to the International Society of Paediatric Oncology‐WT‐2001 protocol in the UK Children's Cancer and Leukaemia Group and Gesellschaft für Pädiatrische Onkologie und Hämatologie groups' participation in the relevant WT trials and studies (2001–2020).Results: There were 880 patients with stage I IR‐WT, including 124 with ET‐WT, 156 with ST‐WT, and 600 with other IR‐WT (oIR‐WT). Patients with stage I ET‐WT or ST‐WT were significantly younger than patients with oIR‐WT, represented a large proportion of stage I WTs in their groups, and tumors showed poor histologic response to preoperative chemotherapy. The 5‐year event‐free survival (EFS) estimates for patients with stage I ET‐WT (96.8% ± 1.8 SE) or ST‐WT (96.8% ± 1.6 SE) were significantly better than for patients with oIR‐WT (90.3% ± 1.3 SE) (p = .014 and p = .009, respectively). A multivariate analysis showed that histologic type (ET‐WT or ST‐WT) remained a significant factor for EFS when adjusted for age and gender (p = .032 and p = .022, respectively). In both groups, relapses occurred in 3.2% of patients, and the overall survival was 99.2%.Conclusions: The results suggest that stage I ET‐WT or ST‐WT could be regarded as low‐risk WT, for which omission of postoperative chemotherapy should be considered.Plain Language Summary: Patients with pretreated intermediate‐risk Wilms tumor (WT) represent the largest group of patients with WT. This study reports the outcomes of patients with stage I epithelial type (ET‐WT) or stromal type WT (ST‐WT). These patients were significantly younger and had a larger proportion of stage I cases than patients with other intermediate‐risk WT (oIR‐WT). The event‐free survival for patients with stage I ET‐WT and ST‐WT was significantly better than for patients with oIR‐WT. Rare relapses were curable resulting in 99.2% overall survival.

Stage III Wilms' tumour (WT) represents a heterogeneous group which includes different criteria, but all stage III patients are treated according to the same study regiment. The aim of the study was to retrospectively analyse outcomes in patients with stage III due to positive resection margins (RM) only, sub-grouped in RM with viable (RM-v) and nonviable (RM-nv) tumour. Patients were treated pre- and postoperatively according to the SIOP-WT-2001 protocol in the UK-CCLG and GPOH WT trials and studies (2001-2020). There were 197 patients, including 134 with localised, abdominal stage III and 63 with overall stage IV, but abdominal stage III. Stage III due to RM-v had 126 patients, and due to RM-nv 71 patients. The overall 5-year local-relapse-free survival (RFS), event-free (EFS) and overall survival (OS) estimates for all patients with abdominal stage III RM were 95.7% (±SE1.5%), 85.1 (±SE2.6%) and 90.3% (±SE2.2%), respectively. Patients with stage III RM-nv had significantly better RFS and EFS than patients with RM-v (P = .027 and P = .003, respectively). A multivariate analysis showed that RM-v remained a significant factor for EFS when adjusted for age, presence of metastasis at diagnosis, histological risk group and overall stage in Cox regression analysis (P = .006). Patients with stage III due to RM-nv only exhibited no local recurrence and have a significantly better RFS and EFS than patients with RM-v. The results suggest that exclusion of RM-nv as a stage III criterion in the UMBRELLA staging system and consequent treatment reduction is warranted.

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.

In the SIOP Wilms' tumor (WT) studies, preoperative chemotherapy is used as primary treatment, and tumors are classified thereafter by pathologists. Completely necrotic WTs (CN‐WTs) are classified as low‐risk tumors. The aim of the study was to evaluate whether a subset of regressive type WTs (RT‐WTs) (67%‐99% chemotherapy‐induced changes [CIC]) showing an exceptionally good response to preoperative chemotherapy had comparably excellent survivals as CN‐WTs, and to establish a cut‐off point of CIC that could define this subset. The study included 2117 patients with unilateral, nonanaplastic WTs from the UK‐CCLG and GPOH‐WT studies (2001‐2020) treated according to the SIOP‐WT‐2001 protocol. There were 126 patients with CN‐WTs and 773 with RT‐WTs, stages I‐IV. RT‐WTs were subdivided into subtotally necrotic WTs (>95% CIC) (STN‐WT96‐99) (124 patients) and the remaining of RT‐WT (RR‐WT67‐95) (649 patients). The 5‐year event‐free survival (EFS) and overall survival (OS) for CN‐WTs were 95.3% (±2.1% SE) and 97.3% (±1.5% SE), and for RT‐WTs 85.7% (±1.14% SE, P < .01) and 95.2% (±0.01% SE, P = .59), respectively. CN‐WT and STN‐WT96‐99 groups showed significantly better EFS than RR‐WT67‐95 (P = .003 and P = .02, respectively), which remained significantly superior when adjusted for age, local stage and metastasis at diagnosis, in multivariate analysis, whereas OS were superimposable (97.3 ± 1.5% SE for CN‐WT; 97.8 ± 1.5% SE for STN‐WT96‐99; 94.7 ± 1.0% SE for RR‐WT67‐95). Patients with STN‐WT96‐99 share the same excellent EFS and OS as patients with CN‐WTs, and although this was achieved by more treatment for patients with STN‐WT96‐99 than for patients with CN‐WT, reduction in postoperative treatment of these patients may be justified.

Datasets for histopathological reporting of many cancer types are developed by the International Collaboration on Cancer Reporting (ICCR) and are used in order to ensure standardised and uniformly accepted reporting as one of the essential requirements for comparison across patient populations in evaluating and validating pathological prognostic and predictive factors. Wilms’ tumours are rare and international reporting guidelines have not been published by the ICCR yet. The assessment of Wilms’ tumours is different, depending on the treatment approach. The Children’s Oncology Group, followed mainly in North America, advocate primary surgery, and the International Society of Paediatric Oncology Renal Tumour Study Group (SIOP‐RTSG), followed in most countries around the world, use preoperative chemotherapy as a first step, resulting in different subclassifications, staging criteria and histopathological prognostic factors. This dataset is developed for the countries and institutions following the SIOP‐RTSG approach, and it contains core (required) and non‐core (recommended) elements, based on the results of the previous SIOP‐RTSG studies which are incorporated in the latest SIOP‐RTSG UMBRELLA 2016 Study protocol. The core elements include clinical information, additional specimen submitted, macroscopic tumour site and appearance, tumour focality, tumour dimensions, macroscopic extent of invasion, block identification key, histological tumour type, histological tumour grade and risk group assessment, microscopic extent of invasion, lymphovascular invasion, resection margin status, regional lymph node status, histologically confirmed distant metastases, and pathological staging (SIOP staging system). The dataset should improve communication for patient care and prognostic determination of the old and new histopathological features.

Renal tumors comprise approximately 7% of all malignant pediatric tumors. This is a highly heterogeneous group of tumors, each with its own therapeutic management, outcome, and association with germline predispositions. Histopathology is the key in establishing the correct diagnosis, and therefore pathologists with expertise in pediatric oncology are needed for dealing with these rare tumors. While each tumor shows different histologic features, they do have considerable overlap in cell type and histologic pattern, making the diagnosis difficult to establish, if based on routine histology alone. To this end, ancillary techniques, such as immunohistochemistry and molecular analysis, can be of great importance for the correct diagnosis, resulting in appropriate treatment. To use ancillary techniques cost-effectively, we propose a pattern-based approach and provide recommendations to aid in deciding which panel of antibodies, supplemented by molecular characterization of a subset of genes, are required.

Wilms tumor (WT) may show a diverse range of heterologous elements (HEs). Cases with predominant/prominent HEs have been reported as “teratoid” WT, albeit on the basis of poorly defined criteria. It has been suggested that “teratoid” WTs are rare, and associated with a poor response to chemotherapy, but a good outcome. However, these claims have not been tested previously in any large cohort of cases. Here, we performed a systematic study to determine the incidence, diversity, and clinicopathologic association of HEs in 691 WTs, all of which were treated according to the same protocol, which included preoperative chemotherapy, and all with central pathology review. We found that 4% (28/691) of WTs showed ≥3 HEs (“teratoid” WT in our study), which was comparable to the numbers of completely necrotic, epithelial, focal anaplastic, and blastemal WTs. “Teratoid” WTs were strongly associated with younger age at presentation (21 vs. 39 mo, P=0.0001), bilateral disease (28.6% vs. 7.2%, P=0.001), stromal-type WT (57.1% vs. 11.0%, P80% of cases with ≥3 HEs, and also of cases with 2 HEs and 1 HE, showed ≥50% stroma in their viable components. We conclude that a tendency toward stromal differentiation is a strong and unifying factor in HE formation. “Teratoid” WT represents the more extreme end of HE differentiation, rather than a separate entity, and therefore the term should not be used in the final diagnosis. The prognosis of WTs depends only on their overall histologic type and stage, and it is not additionally influenced by the presence of “teratoid” features.