Our study aimed to address epidemiological data of pediatric VRTs in Lithuania – a small country of 2.92 million inhabitants, 524.5 thousand of which comprise the population of interest, namely children below 18 years of age (as reported in 2015, www.stat.gov). Overall, 44 VRT cases of 23 different histological subtypes were identified within 16 years with the median of two new cases per year. This means that each Lithuanian pediatric oncology center encountered one new VRT case per year. The main drawback of our population-based study was its retrospective nature that did not allow us to verify relevant parameters (e.g. details on adverse events, treatment etc.) due to limited data source availability. Nevertheless, we were able to demonstrate that the survival of VRTs in children was inferior (55.8% in total) as compared to the average 80% cure rate of pediatric malignancies. Similar results were reported in adults by population-based analysis of the Surveillance of Rare Cancers in Europe (EUROCARE) project (10) – with rare cancers displaying lower survival rate (47%) than the common cancers (65%). The scarce expertise due to rarity of cases and absence of clinical trials were main contributors to the inferior survival.
The lack of improvement in cure rate over time (54.2% in 2000–2007 vs 49.4% in 2008–2015) was rather unexpected. National population-based studies in leukemia (11, 12) and single-center reports in solid tumors (13–15) demonstrated significant improvement in overall survival over the last two decades. The main reason of treatment failure in VRTs was progressive malignancy: 95% of deaths (in 21 out of 22 cases) occurred due to tumor relapse or progression. Drug-resistant cancers remain the main challenge for pediatric oncology community in Europe as demonstrated by the population-based EUROCARE-5 study that reported no significant change in mortality for lymphoma and most common pediatric non-VRT childhood cancers in 1999–2007 (6). Thus, expanding national, regional and international collaboration with a special focus on VRTs is crucial to overcome incurable cancers.
As expected, the survival rate of unregistered patients was higher than the one of the registered patients (100% vs 45.1% at 5 years). The difference remained significant for at least 10 years after diagnosis. Given the extreme rarity of VRTs, accurate reporting to cancer registries is crucial for reliable calculation of treatment outcome. Insufficient registration of pediatric cancers was confirmed in more common childhood cancers, e. g. for CNS tumors – the study that analyzed survival of European children based on the national population-based cancer registry data highlighted incomplete registration of non-malignant entities in many countries and, as a consequence, a lower overall survival (7). The recent survey focused on the rate of pleuropulmonary blastoma in Europe also demonstrated lower than estimated number of reported cases in Eastern / Central European countries (16).
A high rate of unregistered tumors in our study (20.5%) could be partially underpinned by an inconsistency in the national regulatory requirements: there was a formal obligation for health care providers to report every new cancer case to the cancer registry, however the legal status registry was not accordingly formalized. This resulted in different interpretation of the reporting obligation and restriction data flow. The majority of the unregistered cases (88.9%) came from one of two pediatric oncology centers and reflected institutional policy with regard to the obligation to report new cancer cases to the LCR. All the missing data identified during this study were entered retrospectively and included death certificate only.
An additional contributing factor to the high proportion of unreported cases could be insufficient awareness of surgeons, who used to be the first to encounter a VRT in children and adolescents, about the importance of meticulous registration of every pediatric cancer case. In our study most of the tumors (88.6%) were localized at the time of diagnosis and did not required adjuvant chemotherapy subject complete tumor resection. Therefore, presumably pediatric oncologists were not involved in the patient care of at the initial stage. Several studies have shown that multidisciplinary teamwork affects the diagnosis, management and quality of care in cancer patients (17, 18), thus regular tumor boards, including virtual tumor boards as well as international collaborations, should be regarded as a standard of care in the management of childhood cancers (19, 20). Improvement in multidisciplinary collaboration between pediatric oncologist, surgeons, and other specialists could increase the registration rate.
Our results clearly demonstrated that timely (not retrospective) and complete registration must be ensured for accurate statistical analysis and data evaluation. In addition to mandatory national reporting regulations, an ongoing European PARTNER (Pediatric Rare Tumor Network – European Registry) project supported by the European Reference Network for Paediatric Cancer aims to create a pan-European system that should enhance international communications between members of the European Union by combining national registries focused on VRTs and creating registries for countries that do not have one, as well as linking these registries with virtual consultation systems (https://webgate.ec.europa.eu). The undertaken action could strengthen registration at the national level. It could be further improved by seeking an agreement on the entities to be registered, especially those of low-grade histology, as an absence of uniform guidelines defining registration of benign CNS tumors resulted in inequalities of survival rate across European countries (7). In our study we identified two cases of non-malignant inflammatory myofibroblastic tumor that is currently not defined as a VRT and not reported to the cancer registries (21). However, both affected patients underwent multiple surgical interventions resulting in almost mutilating late sequelae. Therefore, a revision of the registration criteria for some tumor entities should be considered.