Pediatric teratomas: Still fascinating

T he incidence of malignant germ cell tumors is much higher in adults: International therapeutic guidelines are widely disseminated. Most of this knowledge is successfully transferred to pediatric malignant germ cell tumors taking in account specific localization and potential long term toxicities. When teratoma is a component of a mixed germinal tumor, the strategy is dictated by that of the most malignant component. Pure teratomas tell a different story: The strategy in adults may not apply because pediatric teratomas do not have similar biological significance and outcome. The second pediatric Italian study on mature and immature teratomas reported in this issue is a major contribution to this field. [1] Based on guidelines the Italian registry reports for the second time an exhaustive collection of data, This suggests an active ongoing collaboration between pathologists and clinicians that should be acknowledged. There are two types of teratomas: Mature teratoma contains well differentiated tissue derived from one or several germ layers (endodermal, mesodermal, ectodermal). Immature teratomas contain poorly differentiated tissue from these germ layers. They are graded I to III based on the amount of immature neural tissue. Preexisting undetected or overlooked malignant microfoci of yolk salk tumor (YST) in the initial tumor occur more likely in Grade III, and explain that half of the tumors in infants relapsing after exclusive surgery for pure teratoma, contain biologically and/or histologically YST. The Italian study reports a 95% concordance between local and central pathology, but type of inconsistency is not specified. Cytogenetic and molecular studies demonstrate the unique characteristics of pediatric teratoma: Most pediatric teratomas have a normal karyotype whereas adolescent and adult GCTs, including teratomas, harbor abnormalities of chromosome 12p. Immature teratomas have pathway and epigenetic signatures that differ from those of mature teratomas. WNT/b-catenin (an early embryonic development and carcinogenetic pathway) and SOX2 (a pluripotency-maintaining factor) show high levels expression in immature teratomas only. Mature teratomas have distinct epigenetic DNA methylation characteristics, but may sometimes segregate with immature teratomas or dysgerminomas. [2] Methylation patterns are dependent on tissue of origin. In ovarian teratomas, DNA loci that are typically methylated on the paternal allele have reducedmethylation in almost all samples, while loci that are typically methylated on the maternal allele have increased methylation. This adds to the hypothesis that ovarian teratoma have a parthenogenetic origin. The majority of extragonadal teratomas in both males and females have methylation levels more characteristic of normal tissues for an imprinted locus. [3] Teratomas occur most frequently in the ovary, the testis or extragonadal sites, with the sacrococcygeal region being the most common site of involvement. Location varies with age. Sacrococcygeal teratomas occur mostly in neonates and infants, testicular in the first 5 years of life and ovarian between 5 and 15 years of age Pure mature teratomas occurring in the testis of pre-pubertal males or in the ovary are usually benign tumors, whereas in adolescents and adults, testicular teratomas most commonly behave as malignant neoplasms. This justifies the 10% and 37% rate of enucleation in ovarian and testicularmature teratomas respectively in the Italian cohort. Immature teratomas are considered malignant most commonly in children and adults, but therapeutic strategiesmay differ. Complete surgical excision followed by a watch and wait attitude is the cornerstoneof treatment of pediatric teratomaswhether mature or immature. [4]. Since 1983 the MAKEI protocols have demonstrated that there is no role for chemotherapy in immature teratomas. [5] Similarly, the UK group reported no efficacy of JEB (carboplatin etoposide bleomycin) in some children treated differently than the wait and see approach recommended. [6] After exclusive surgery the POG/CCSG intergroup reported a nearly 100% EFS in pure immature teratomas of testis or ovary,[4] regardless of histologic grade or the presence ofmicroscopic foci of YST; Neither capsular rupture, gliomatosis peritonei, nor ascites had a negative impact.The Italian study reports very similar results for testicular and ovarian teratomas. The compliance to guidelines was good as only four cases of 69 immature teratomas received initial chemotherapy at the discretion of the physician in charge. Contralateralmetachronous teratomas developed with a delay of 11 to 84months in 5/95 patients with ovarian teratomas. [1] This is in line with a 66% 26% risk of metachronous teratomas published within 10 years. [7] This highlights the need for a yearly ultrasound follow-up during reproductive period, and ovary preserving surgery in the case of metachronous tumor. In case of malignant relapsewith YST component, a cure can usually be achieved by use of a platinum containing regimen followed by surgery if required. In contrast, grade II or III immature ovarian teratomas in adults are treated with cytotoxic chemotherapy, even in case of complete removal.