Pathology and Molecular Biology of Teratomas in Childhood and Adolescence

Abstract

The biologic behaviour of teratomas depends on various interdependent clinical and epidemiologic variables such as the age at diagnosis, sex, tumor site, histology which all correlate to different cytogenetic and molecular biologic aberrations. Thus, testicular teratomas of infancy are generally benign. Accordingly, prepubertal teratomas show no cytogenetic or molecular genetic aberrations. In contrast, postpubertal testicular teratomas can present as clinically malignant tumors and may show complex cytogenetic aberrations such as the isochromosome 12p, which is pathognomonic of malignant germ cell tumors. Notably, teratomas of both age groups show an at least partial erasure of the genomic imprinting, correlating with their origin from primordial germ cells. The Kiel Pediatric Tumor Registry includes 541 teratoma specimens, and among these, the most frequent tumor sites (in descending order) are: the sacrococcygeal region (33.8 %), the ovaries (31.2 %) and the testes (10.5 %). Rare localizations include the mediastinum, the retroperitoneum, the head and neck region as well as the central nervous system. The WHO classification of germ cell tumors distinguishes mature and immature teratomas as well as teratomas with malignant transformation. In immature teratomas, primitive neuroectodermal structures predominate. According to the grading system (Gonzalez-Crussi, 1982), mature teratomas (G0) are more frequent (54.5 %) than immature teratomas (G1-G3, 45.5 %). Only 7.8 % of all teratomas show the highest grade of immaturity (G3). The frequency of additional microscopic foci of malignant yolk sac tumor correlates with the grade of immaturity. In sacrococcygeal teratomas, the yolk sac tumor microfoci may give rise to a malignant relapse after incomplete resection. The rare teratomas with malignant transformation contain components with “conventional” somatic type malignancy such as leukaemia, carcinoma or sarcoma. Here, molecular genetic analysis has demonstrated the origin of the somatic malignancy from a malignant transformation within the germ cell tumor with retention of the cytogenetic changes characteristic of malignant germ cell tumors.

Zusammenfassung

Das biologische Verhalten der Teratome (wie auch das der übrigen Keimzelltumoren) wird durch die Faktoren Lebensalter zum Zeitpunkt der Diagnose, Geschlecht, Tumorlokalisation, Histologie sowie Zytogenetik und Molekularbiologie richtunggebend beeinflusst. So sind etwa die Hodenteratome des jungen Kindes prinzipiell gutartig, während diese Tumoren von der Pubertät an in aller Regel bösartig sind. Entsprechend zeigen präpubertäre Teratome keine konsistenten zyto- oder molekulargenetischen Aberrationen. Bei testikulären Teratomen im Erwachsenenalter finden sich hingegen komplexe genetische Aberrationen, einschließlich des pathogomonischen Markers für maligne Keimzelltumoren, des Isochromosoms 12p. Teratome aller Altersgruppen zeigen einen zumindest teilweisen Verlust des genomischen Imprinting, der auf ihre histogenetische Abstammung von primordialen Keimzellen hinweist. Hauptlokalisationen der Teratome sind in abnehmender Häufigkeit die Steißbeinregion (183/541 = 33,8 % aller Teratompräparate), Ovarien (31,2 %) und Hoden (10,5 %). Seltenere Lokalisationen sind das Mediastinum, das Retroperitoneum, die Kopf- und Halsregion sowie das ZNS. Nach den WHO-Klassifikationen werden reife und unreife Teratome sowie Teratome mit maligner Transformation unterschieden. Innerhalb der unreifen Tumorareale dominieren primitive neuroektodermale Strukturen quantitativ. Nach dem Gradingverfahren von Gonzalez-Crussi (1982) sind reife Teratome (G0) mit 54,5 % der Präparate etwas häufiger als die unreifen Teratome (G1-G3) zusammengenommen (45,5 %). Nur 7,8 % aller Teratome zeigen den höchsten Unreifegrad G3. Je unreifer Teratome sind, desto größer ist die Wahrscheinlichkeit zusätzlicher, oft nur mikroskopisch kleiner Dottersacktumorherde, welche die Prognose nach inkompletter Resektion ungünstig beeinflussen, jedoch offensichtlich chemosensibel sind. Die sehr seltenen Teratome mit maligner Transformation enthalten „konventionelle” (somatische) Malignomkomponenten, wie Leukämien, Karzinome und Sarkome verschiedenen Typs. Molekulargenetische Untersuchungen haben gezeigt, dass es sich hier um eine durch sekundäre Kanzerisierung mit Retention der für maligne Keimzelltumoren charakteristischen zytogenetischen Veränderungen handelt.

teratoma, mature, immature - yolk sac tumor - gliomatosis peritonei - comparative genomic hybridization

Teratom, reif, unreif - Dottersacktumor - Gliomatosis peritonei - komparative genomische Hybridisierung

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1 Presented in part at the International Scientific Symposium on the occasion of the 10^th anniversary of the regional Pediatric Hematologic and Oncologic Center in Perm, Russia, 13^th of June 2006.