Our study aimed to evaluate the quality of registration and treatment outcome of pediatric VRTs in Lithuania – a small Eastern European country of 2.92 million inhabitants and 524.5 thousand of children below 18 years of age (as reported in 2015, www.stat.gov). Overall, 37 VRT cases of 18 different histological types were identified over 16 years with the median of 1.5 new cases per year. This means that each Lithuanian pediatric oncology center encountered one-two new VRT cases per year. The small numbers rendered impossible accumulation of sufficient expertise to deal with extremely rare pediatric malignancies. Therefore, close internal and international collaboration e.g. with tumor-specific expert groups and / or the European Reference Network for Paediatric Oncology (ERN PaedCan) is crucial to ensure the best care and cure.
A substantial percentage of unregistered tumors in our study (16.2%) 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 LCR. However, the legal status of the registry was not appropriately formalized. This resulted in different interpretation of the reporting obligation and restriction in data flow. All unregistered cases came from one of two pediatric oncology centers and reflected institutional policy with regard to data sharing. Most of the missing data identified during this study were recovered retrospectively. Different interpretation of regulatory requirements for data reporting contributed to the data incompleteness also in the Estonian Cancer Registry (10).
As listed in Table 1, all unregistered tumors were localized at diagnosis. One could speculate that a potential contributing factor to the under-reporting of local malignancies 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. 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 (12, 13). 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 (14, 15). Improvement in multidisciplinary collaboration between pediatric oncologist, surgeons, and cancer registry could ensure completeness of registration and data reliability.
As expected, the 5-year survival rate of the unregistered patients was significantly higher than the one of the registered cohort – 100% vs 51.6%. The 5-year survival rate calculated for the registered patients at the age of 0-14 years – a common parameter used across studies to compare treatment outcome and cancer incidence (1, 7-10) – increased up to 10% when missing cases were included: 42.1% vs 52.2%. 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 reported for 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 (8). 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 population-based quality study carried out in Estonia figured out a significant number of under-reported childhood cancer cases that increased 5-year survival from 70 to 76% for children treated in 2010-2014 (10). Thus, completeness of the registration should be improved across Europe.
The main limitation of our population-based study was its retrospective design that did not allow us to verify relevant parameters (e.g. details on adverse events, treatment etc.) due to limited data availability. The overall survival rate in our VRT cohort was inferior (the total OS5y was 59.5%) as compared to the average 80% cure rate of more common childhood cancers. Similar outcomes were reported for adults in a population-based Surveillance of Rare Cancers in Europe (EUROCARE) project (17) – rare cancers displayed lower survival rate (47%) than the common cancers (65%). A scarce expertise due to the rarity of cases and absence of clinical trials were main contributors to the inferior survival. Pediatric tumor-specific studies likewise reported lower survival rate, e.g. 55% for adrenocortical carcinoma (18), 60% for rhabdoid tumor (19), although some local pediatric VRTs (e.g. thyroid and salivary gland carcinoma) can achieve a decent survival over 90% (20, 21).
The lack of improvement in cure rate over time (the OS5y was 61.1% in 2000-2007 vs 57.9% in 2008-2015) was rather unexpected. National population-based studies on leukemia (22, 23) and single-center reports on solid tumors (24-26) demonstrated significant improvement in overall survival over the last two decades. Disease recurrence or development of a second malignancy was responsible for 95% of deaths (in 19 out of 20 cases) in our VRT cohort. Drug-resistant cancer remains the main challenge for pediatric oncology community: a recent review of the Surveillance, Epidemiology, and End Results (SEER) database demonstrated little improvement in treatment outcome for specific cancer types, mostly considered as VRT, diagnosed in adolescents or young adults during 1975-2011 (27). Of note, in our study a cancer predisposition syndrome was documented in five patients (Table 1). Impaired somatic host genome could be implicated in development of drug-resistance or secondary malignancy (28, 29). We could suggest that the diagnosis of a VRT in a child should prompt a search for possible hereditary genetic susceptibility syndrome.
Disease recurrence compromised the cure beyond 5 years – a conventional cut-off for long-term remission. The survival estimates at 10 years were lower as those at 5 years calculated with regard to various aspects: for different age groups, completeness of the registration, comparing registered and unregistered cohorts as well as two treatment periods. Late events were related exclusively to disease progression or second malignancy. The above mentioned analysis of SEER database reported a substantial number of the disease-related adverse events occurring between 5 and 10 year in patients diagnosed with rare cancers at the age of 15-39 years (27). Given the fact that 75% of VRTs develop between the ages of 15 to 19 years old (3-5) a longer follow-up for potential disease recurrence beyond 5 years from diagnosis is warranted.
Our results clearly demonstrated that timely 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 will certainly strengthen registration at the national level.