Second, Peculiar Recurrence of a Wilms Tumor – Pleural And Late

1. Introduction

Nephroblastoma (Wilms tumour) is the most common kidney malignancy in children and one of the most frequent abdominal tumours diagnosed in pediatric patients (1). It usually occurs in otherwise healthy individuals, but in about 10% of cases may occur in the context of genetic disorders such as WAGR (Wilms, Aniridia, Genitourinary anomalies, mental Retardation) syndrome/ 11p deletion or other Wilms Tumor 1 (WT1)- (1) related genetic syndromes (2). Nephroblastoma is usually diagnosed using imaging, both abdominal CT and MRI, and most of the time a biopsy is not required nor indicated (3, 4). In terms of treatment, the European recommenddations (SIOP protocol) include induction chemotherapy followed by surgery, then by risk-adapted adjuvant therapy, defined as chemotherapy with or without radiotherapy to the affected abdominal flank (5, 6). A more recent approach regarding radiotherapy is carefully aiming towards a more conformal irradiation, using advanced techniques such as IMRT/VMAT and smaller target volumes, in order to reduce toxicities while keeping good local control (7). On the other hand, the Children Oncology Group (COG) approach is up-front surgical resection followed by systemic therapy and radiation. This approach offers the advantage of having an initial pathologic assessment, without any chemotherapy-induced histological changes, but it also increases the risk of a tumour spill (8).

Survival of Wilms tumour patients can reach up to 90% (9) and recurrences usually occur in 3-20% of the patients, but can reach as high as 50%, depending on several prognostic factors such as age at diagnosis, disease stage, histology, response to induction chemotherapy, and molecular factors such as LOI 11p15 or LOH 11p15 (10, 11).

2. Case Report

A two-year-old boy presented in 2010 in a county hospital with a mass located in the left abdominal flank, which was diagnosed as nephroblastoma based on abdominal imaging. He received induction chemotherapy, following the SIOP WT 2001 protocol: 4 cycles of AV (Actinomycin D 45 microgram/kg week 1,3 + Vincristine 1.5mg/square meter/week 1,2,3,4), followed by surgical resection of residual tumour. The pathology report confirmed the diagnosis of nephroblastoma, describing more than two thirds of the tumour showing chemotherapy-induced changes, without viable tumoral cells being present, consistent with intermediate risk, stage III, regressive type Wilms tumour. The pathology report emphasised the presence of macroscopic extracapsular tumor extension and chemotherapy induced tumour necrosis that encompassed almost the entire tumor volume. There was no vascular or lymphatic invasion, with only one of the resected lymph nodes showing signs of necrosis. The patient continued systemic AV chemotherapy for 27 weeks. Flank irradiation recommended by the SIOP protocol was not delivered.

Eleven months after the last chemotherapy cycle, the patient returned with a left lung solitary nodule, which was diagnosed as a lung metastasis by imaging. This patient had several adverse prognostic factors including being older than 2 years of age, and an advanced stage (III, intermediate risk) and having an early recurrence (under 1 year since first diagnosis). However, the initial tumour had favourable histology, thus the patient was re-classified as high risk (Group C at recurrence) and received 7 cycles of Cyclophosphamide 440mg/square meter, Carboplatin 500mg/square meter and Etoposide 100mg/square meter, following the United Kingdom Children’s Cancer Study Group Wilms Tumour Group Protocol (UKWR 2001) protocol for relapsed Nephroblastoma.

After a nine-year disease-free interval, a routine follow-up chest CT scan (Figure 1) performed in February 2021 showed a left pleural-based lung nodule (10/5cm), compressing the left lung and invading into the left chest wall. It was considered a second, late recurrence of the Wilms tumor. The metastasis was completely resected, and pathology confirmed nephroblastoma. The pathology report described a tumour surrounded by a pseudo-capsule, with no anaplasia, vascular or lymphatic invasion, but presence of some blastemal tumour cells outside the pseudo-capsule. The resection margins were clear, but narrow (1 mm from the tumoral edge). Immunohistochemical stains for PAX8, CKAE1/AE3, CD56 and Vimentin (positive in stromal cells and diffusely positive in tumor cells) were positive. CD99, Desmin, Synaptophysin and WT1 stains were negative. Following surgery, the patient received 4 cycles of chemotherapy (Ifosfamide/ Cyclophosphamide, Carboplatin, Etoposide), as recommended by SIOP-UMBRELLA 2016 protocol for relapsed nephroblastoma, in this case in the left lung.

Figure 1. Chest CT Showing the Second Pleuro-Pulmonary Recurrence in the Left Lung

Table 1. Dosimetric Comparison for the PTV

HT= Helical Tomotherapy, VMAT= Volumetric Arc Therapy, 3DCRT= 3 D Conformal Radiotherapy, Gy= Gray, CI= Conformity Index (CI=PIV/TV, where PIV= Prescribed Isodose Volume, TV= Target Volume), PTV= Planning Target Volume

After the completion of the systemic therapy, the patient was referred to radiotherapy for local adjuvant treatment. The planning CT was performed with the patient laying in a supine position, with his arms raised above his head, without using any immobilisation devices or respiratory motion management (therefore no ITV (Internal Target Volume) was contoured and Clinical Target Volume ( CTV)-to-PTV margins were larger, in order to avoid geographical miss). He received a total dose of 25.5 Gy in 14 fractions on the tumour bed (CTV) plus a 1 cm margin, using a conformal helical intensity-modulated technique (Helical Tomotherapy).

Table 2. Dosimetric comparison for organs-at-risk

HT= Helical Tomotherapy, VMAT= Volumetric Arc Therapy, 3DCRT= 3 D Conformal Radiotherapy, Gy= Gray, PRV=planning risk volume, OAR= organ-at-risk

To ensure best target coverage, conformity, and homogeneity, as well as optimal healthy tissue sparing, two other comparative plans were calculated- one using VMAT (intensitymodulated/volumetric arc therapy) and another using a forward-planned, 3D conformal technique (Figure 2). Helical Tomotherapy showed better OAR sparing compared to 3DCRT and similar organ-at-risk dosimetry to VMAT, but better target dose homogeneity and conformity compared to both VMAT and 3DCRT. Overall, the helical tomotherapy plan proved to be of

higher quality and thus was chosen for patient treatment. Table 1 shows a dosimetric comparison of the target and several organs-atrisk (Table 2) using the three different techniques. Radiotherapy was well tolerated, without acute toxicities. Following irradiation, the patient received a high-dose chemotherapy regimen and underwent autologous stem-cell transplantation. At his last follow-up visit (June 2022) the patient had a good overall status, with no signs of recurrence or severe adverse effects.

Figure 2. Dose distribution for the 3 comparative radiotherapy plans – A. 3D Conformal Radiotherapy, B. Helical Tomotherapy, C. IMAT/VMAT/RapidArc

3. Discussions

The presented case is particular for several reasons. The patient was first treated in a county hospital and local radiotherapy was omitted at first diagnosis, despite the SIOP protocol’s recommendation for flank irradiation in stage III intermediate-risk patients. The patient’s subsequent disease presentation was not local but occurred as a pulmonary metastasis relatively early after completion of the initial treatment. Relapses usually occur within 2 years from diagnosis and are mainly solitary lung nodules. A distinct aspect of the first recurrence is the treatment, which was only systemic (chemotherapy), omitting local therapy such as surgery and/or radiotherapy which might also have been suitable treatment options at the time. The most peculiar feature of this case is the long 9-year disease-free period prior to the second relapse and the particular aspect of pleural involvement , with only a few similar cases reported in the literature (12–14). Thus, local control was good with no relapse in the flank, despite omitting local radiotherapy at first diagnosis. Being confronted with such a rare evolution of a nephroblastoma, the treatment was challenging, especially the local radiotherapy, with no guidelines for this particular clinical scenario. The dose prescription was chosen taking into consideration both the whole lung irradiation doses that are usually delivered in metastatic Wilms disease, but also a boost dose to ensure local control. The systemic therapy was prescribed following several protocols, with different approaches (SIOP, COG, UKWR). Given the relatively good outcome of this patient, we can only assume that the tumour might have had some genetic/molecular favourable features. However, no molecular profile was performed for this patient, which, together with some gaps in the case documentation, we consider as limitations in this reporting. Future cases might benefit from genetic testing and molecular profiling, for a better risk stratification and personalized treatment. This case highlights the importance of multidisciplinary tumour board discussion of these patients, at presentation, which is an essential component of cancer management. Having all the stakeholders (pediatric surgeon, pediatric oncologist, radiation oncologist and others) discussing treatment strategy is known to increase treatment quality and improve outcome. Moreover, pediatric patients should be treated in specialized treatment centres, in a centralized manner, as recommended by several international bodies (15–17).

4. Conclusion

In conclusion, nephroblastoma (Wilms tumor) is a malignant tumor occurring in the kidney especially in pediatric patients. It requires a complex, multidisciplinary approach to ensure best treatment, with good outcomes and without excess toxicities. Several clinical prognostic factors influence outcome, together with the genetic landscape and treatment management. Relapse usually occurs early, mainly as pulmonary metastases, with late pleural metastasis being rare. Particular cases such as this one can present with late relapses, which raise several challenges regarding therapy, having no guidelines to cover such situations. For future cases, molecular testing could improve patient management and facilitate a personalized treatment, with possible better outcomes. Furthermore, multidisciplinary decision-making, and case centralization in specialized centres is essential in such peculiar cases.

Abbreviations:

AV – Actinomycin + Vincristine

COG – Children Oncology Group

CT – Computed Tomography

CTV – Clinical Target Volume

LOH – loss of heterozygosity

LOI – loss of imprinting

MRI – Magnetic Resonance Imaging

HT – Helical Tomotherapy

IMRT – Intensity-Modulated RadioTherapy

ITV – Internal Target Volume

PTV – Planning Target Volume

PRV – Planning Risk Volume

SIOP – International Society for Paediatric Oncology

UKWR – United Kingdom Wilms Relapse

VMAT – Volumetric Arc Therapy

WAGR – Wilms tumor, aniridia, genitourinary anomalies, and intellectual disability (mental retardation)

WT – Wilms Tumour

Statements:

Authors’ contributions:

AT – conceptualization, data collection, manuscript writing

CD, GV, CG, CB – manuscript revision, part of the patient treatment management team

Consent for publication: As the corresponding author, I confirm that the manuscript has been read and approved for submission by all co-authors.

Conflict of interest: All authors declare having no competing interests associated with this publication.

Funding Sources: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.

Informed Consent: The informed consent was obtained from the patient for publication and any accompanying images.

Ethics Approval: The (radiotherapy) treatment strategy was approved by the institutional tumor board (Oncology Institute “Prof. Dr. Ion Chiricuta” Cluj-Napoca).

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