Omission of adjuvant chemotherapy in patients with completely necrotic Wilms tumor stage I and radiotherapy in stage III: The 30-year SIOP-RTSG experience.

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.

Outcomes of patients with Wilms' tumour stage III due to positive resection margins only: An analysis of patients treated on the SIOP-WT-2001 protocol in the UK-CCLG and GPOH studies.

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.

Stage I epithelial or stromal type Wilms tumors are low risk tumors: An analysis of patients treated on the SIOP-WT-2001 protocol in the UK-CCLG and GPOH studies (2001-2020).

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.

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.

Prognostic significance of histopathological response to preoperative chemotherapy in unilateral Wilms' tumor: An analysis of 899 patients treated on the SIOP WT 2001 protocol in the UK-CCLG and GPOH studies.

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.

Dataset for the reporting of nephrectomy specimens for Wilms' tumour treated with preoperative chemotherapy: recommendations from the International Society of Paediatric Oncology Renal Tumour Study Group.

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 yet been published by the ICCR. The assessment of Wilms' tumours differs according to the treatment approach. The Children's Oncology Group, whose approach is followed mainly in North America, advocates primary surgery, and the International Society of Paediatric Oncology Renal Tumour Study Group (SIOP-RTSG), whose approach is followed in most countries around the world, uses 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.

The effect of preoperative chemotherapy on histological subtyping and staging of Wilms tumors: The United Kingdom Children's Cancer Study Group (UKCCSG) Wilms tumor trial 3 (UKW3) experience.

BACKGROUND: Two principal approaches to Wilms tumor (WT) treatment are immediate surgery (IS) and preoperative chemotherapy (PCT), and both treatments use the risk-adapted approach that includes histological subclassification of the tumor, combined with additional prognostic factors. In the UKW3 trial, these two approaches were compared. The aim of the present study was to compare histological features between the two groups, to assess the impact of PCT on distribution of histological subtyping and staging and to evaluate whether PCT resulted in more staging discrepancies between local and central pathology review (CPR). MATERIALS AND METHODS: The cases were identified from the UKW3 trial database. The criteria for inclusion in the study were unilateral, nonmetastatic, nonanaplastic WTs, and submitted for CPR with an adequate number of slides. They were subclassified according to the NWTS and later the SIOP 9301 criteria. RESULTS: There were 244 WTs in the IS and 182 in the PCT group subclassified as follows: blastemal 86 (35%) vs 9 (5%), epithelial 34 (14%) vs 12 (7%), stromal 12 (5%) vs 25 (14%), mixed 112 (46%) vs 45 (25%), respectively, plus 40% regressive and 10% completely necrotic WTs in the PCT group. The differences between the two groups for blastemal and mixed types were statistically significant. In the PCT group, there was a significant decrease in stage III tumors. The discrepancies in staging between local and CPR were not significant. CONCLUSION: PCT significantly altered histological features and typing of WTs. It resulted in fewer stage III tumors, and staging discrepancies were equally represented in both groups.

Treatment of patients with stage I focal anaplastic and diffuse anaplastic Wilms tumour: A report from the SIOP-WT-2001 GPOH and UK-CCLG studies.

BACKGROUND: Anaplasia is an unfavourable prognostic histological feature in Wilms tumour (WT). Patients with stage I anaplastic WT (AWT) typically achieve good outcomes, albeit with more treatment than for stage I non-AWT. Since the SIOP-WT-2001 study, patients with focal AWT (FAWT) have been classified as intermediate risk and received less intense treatment than patients with diffuse AWT (DAWT). The aim of the study was to analyse outcomes in these patients. PATIENTS AND METHODS: This was a retrospective analysis of clinicopathological features and outcomes of 59 patients with stage I AWT (19 FAWT, 40 DAWT) from the SIOP-WT-2001 GPOH and UK-CCLG groups. The patients with FAWT were treated as intermediate-risk WT, with 8 weeks of vincristine and actinomycin D (4 weeks pre-operatively, and 4 weeks post-operatively). For comparison, we also assessed outcomes in 818 patients with stage I intermediate-risk non-AWT (IR-non-AWT). The patients with DAWT were treated with vincristine, actinomycin D and doxorubicin for 31 weeks. No group received radiotherapy. RESULTS: Median follow-up was 67.6 months; 4-year event-free survival and overall survival were 87% (95% confidence interval [CI] = 72-100) and 100%, respectively, in the FAWT group, 85% (95% CI = 74-98) and 93% (95% CI 85-100), respectively, in the DAWT group and 91% (95% CI = 89-93) and 98% (95% CI = 97-99), respectively, in the IR-non-AWT group. CONCLUSIONS: Outcomes for patients with stage I FAWT were comparable with those of other, identically treated, patients with stage I IR-non-AWT. Patients with stage I DAWT also showed good outcomes, albeit with more intensive chemotherapy than IR-non-AWT, but without radiotherapy.

Renal Tumors of Childhood-A Histopathologic Pattern-Based Diagnostic Approach.

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.

Allergic contact dermatitis from fragrance components in specific topical pharmaceutical products in Belgium.

OBJECTIVES: To determine which topical pharmaceutical products marketed in Belgium contain fragrances and to examine the nature of the fragrance allergens in specific pharmaceutical products having caused iatrogenic contact dermatitis. METHODS: All topical pharmaceutical products marketed in Belgium, that is 3820 products, were examined as to their fragrance content as labelled. Data of 18, 960 patients investigated for contact allergy between 1978 and 2008 were retrieved from our database, including information on the nature of the topical pharmaceutical products used, the results of patch tests, and the sensitization sources. RESULTS: Three hundred and seventy (10%) of 3280 of the topical pharmaceutical products were found to contain a total of 66 fragrance substances. Among 3378 patients suffering from iatrogenic allergic contact dermatitis, 127 were found to react to 48 specific products, for which 38 different fragrance substances gave relevant positive reactions. Women were more affected than men, and legs, hands, and face were the most commonly affected body sites. CONCLUSIONS: Fragrances, the presence of which is in most cases unnecessary, do contribute to iatrogenic allergic contact dermatitis. Moreover, sensitized patients have difficulties in avoiding their specific allergens because standardized labelling of the ingredients in pharmaceutical products is lacking.

"Teratoid" Wilms Tumor: The Extreme End of Heterologous Element Differentiation, Not a Separate Entity.

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%, P<0.00001), and intralobar nephrogenic rests (35.7% vs. 11.9%, P=0.0001), when compared with non-"teratoid" WT. We also found that stromal-type WT, regardless of HE differentiation, was itself associated with younger age, bilateral disease, and intralobar nephrogenic rest. Furthermore, >80% 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.

Publisher Correction: The UMBRELLA SIOP-RTSG 2016 Wilms tumour pathology and molecular biology protocol.

In the version of this article initially published online it was not open access, this has now been corrected.

The UMBRELLA SIOP-RTSG 2016 Wilms tumour pathology and molecular biology protocol.

On the basis of the results of previous national and international trials and studies, the Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP-RTSG) has developed a new study protocol for paediatric renal tumours: the UMBRELLA SIOP-RTSG 2016 protocol (the UMBRELLA protocol). Currently, the overall outcomes of patients with Wilms tumour are excellent, but subgroups with poor prognosis and increased relapse rates still exist. The identification of these subgroups is of utmost importance to improve treatment stratification, which might lead to reduction of the direct and late effects of chemotherapy. The UMBRELLA protocol aims to validate new prognostic factors, such as blastemal tumour volume and molecular markers, to further improve outcome. To achieve this aim, large, international, high-quality databases are needed, which dictate optimization and international harmonization of specimen handling and comprehensive sampling of biological material, refine definitions and improve logistics for expert review. To promote broad implementation of the UMBRELLA protocol, the updated SIOP-RTSG pathology and molecular biology protocol for Wilms tumours has been outlined, which is a consensus from the SIOP-RTSG pathology panel.