Posterior fossa immature teratoma in an infant with trisomy 21: A case report and review of the literature.

BACKGROUND: Intracranial teratoma associated with Down syndrome is rare. With only three previously reported cases, our case is the first one presenting an immature component. CASE DESCRIPTION: A 2-month-old boy with trisomy 21 presented with lethargy and head enlargement. A magnetic resonance imaging (MRI) study showed an obstructive hydrocephalus with 0.5 cm posterior fossa tumor compressing the cerebellum. The tumor revealed a mixed intensity on T1- and T2-weighted MRI images and was surrounded by peritumoral cysts. It was heterogeneously enhancing and showed multinodular mass. The tumor was gross totally removed via suboccipital craniotomy and histologically diagnosed as immature teratoma. Four cycles of chemotherapy consisting of cisplatin and etoposide followed the surgery. The radiotherapy was withheld due to infancy. Recurrent lesions in the tumor bed were noted 10 months later. They were removed in the second surgery and histologically identified as mature teratoma.
CONCLUSION: Maturation of immature teratoma may be a result of natural conversion of multipotent embryonal cells into mature tissues and following chemotherapy.

INTRODUCTION

Teratomas, neoplasms which are composed of tissues derived from three germ cell layers, constitute approximately 0.2% of all intracranial tumors.[17] They mostly occur in children during the first decade and grow frequently in the midline region including the pineal gland.[317] Here, we report a rare case of posterior fossa immature teratoma in an infant with Down syndrome.

CASE REPORT

A 2-month-old boy with known Down syndrome (trisomy 21) was referred to our department with presentation of rapid head enlargement. He was born as a full-term baby to a 30-year-old mother by normal delivery without perinatal complications.

On examination, the boy was lethargic and found to have variable waveforms of nystagmus (congenital nystagmus). The head circumference was 39 cm with bulging of the anterior fontanel. Computed tomography (CT) [Figure 1a] of the brain showed a large heterogeneously dense midline posterior fossa tumor, 5 cm in diameter, involving the cerebellum. Small speckles of calcification were also seen. Severe hydrocephalus with periventricular lucency was present. The tumor was of mixed intensity on T1- and T2-weighted magnetic resonance images (MRI) and consisted of various sized cysts [Figure 1b and c]. The tumor strongly enhanced with gadolinium and was multiloculated [Figure 1d–f]. Serum α-fetoprotein (AFP) was elevated to 2.91 × 106 UI/L. Serum levels of human chorionic gonadotropin (HCG) and β-HCG were normal, 1.1 and 0.2 mlU/ml, respectively.

Figure 1

Preoperative computed tomography (CT) (a) showed a large tumor with inhomogeneous density compressing cerebellum. Hydrocephalus was present with periventricular lucency. It is also inhomogeneous and multiloculated on T1-weighted (b) and T2-weighted (c) magnetic resonance images (MRIs). Gadolinium enhanced MRI (d-f) showed heterogeneous enhancement effect

Midline suboccipital craniotomy exposed a highly vascularized tumor with variable consistency; cystic, solid, and elastic hard. Gross total removal was achieved in a piecemeal fashion. The tumor capsule was easily detached from the cerebellar hemisphere, but not from the cerebellar vermis. An intact pineal gland was seen in the supracerebellar cistern after tumor removal. Postoperative MRI showed the total removal of the tumor [Figure 2a–c].

Figure 2

Postoperative axial (a), sagital (b), and coronal (c) MRIs revealed the total resection of tumor with improvement of the hydrocephalus state. Note pineal gland remained intact (arrow)

Histopathologically, the tumor was composed of incompletely differentiated components resembling fetal tissues. The most immature elements were primitive embryonal mesenchymal tissue or neuroectodermal tissue with canalicular structure resembling a developing neural tube or neuroepithelial rosettes [Figure 3a]. This tumor showed a positive reaction to AFP immunostaining [Figure 3b]. Neuroepithelial rosettes reacted positively to β-tubulin 3 and MAP2 [Figure 3c and d]. Glial fibrillary acidic protein (GFAP) immunostaining was negative [Figure 3e]. The MIB-1 index was approximately 10% [Figure 3f].

Figure 3

Histological patterns showed canalicullar structure resembling a developing neural tube or neuroephitelial rosettes (a). These patterns showed positive reaction with α-fetoprotein (AFP) immunostaining (B). Neuroepithelial rosettes react positively with β-tubulin 3 (c), and MAP2 (d). GFAP immunostaining was negative (e). The MIB 1 index was approximately 10% (f). (a) H and E, ×100; (b–f) ×100 (original magnification). Barr showed 100 μm

Four cycles of chemotherapy with regimens comprised of cisplatin and etoposide followed the surgery. The AFP serum level decreased to 2.74 × 104 UI/L after chemotherapy. In addition, it had dropped to 1.25 × 104 UI/L when two recurrent lesions were detected in the cerebellar vermis and tentorium on MRI [Figure 4a–c], performed 10 months after the first surgery. The second operation was done via the same approach, and histological diagnosis of the recurrent tumor was mature teratoma. No additional treatment has been given since then. The AFP serum level has remained normal in the range 2.06 × 103 to 2.31 × 103 UI/L since the second operation. The latest MRI studied 3 years after the second surgery [Figure 4d–f] showed no recurrences. The patient is now 4-year-old and has been living in the nursing house with minimum assistance.

Figure 4

Two recurrent tumors (arrows) were found on axial (a), sagital (b), and coronal (c) MRIs obtained 10 months after the first surgery. The latest axial (d), sagital (e), and coronal (f) MRIs studied 3 years after the second operation showed no recurrence

DISCUSSION

Teratomas represents 0.2% of all intracranial tumors[17] and 1.2–5% of intracranial tumors in children.[1117] In cases of Down syndrome, the proportion of germ cell tumors is quite high reaching to 61% of all intracranial tumors associated with this disease.[13] However, association of teratoma with Down syndrome is quite rare. We only found four cases of this type including ours, three of them being Japanese [Table 1].[71218] There was no gender preponderance. Symptoms at the diagnosis included weight loss, lethargy, strabismus, and head enlargement. The age at diagnosis ranged from newborn to 7 years, with three infants. Subtle neurologic manifestation by intracranial-occupying lesion in already retarded development of Down syndrome may result in delayed diagnosis.[1] In this case, signs of hydrocephalus expedited early diagnosis.

Table 1

Reported cases of teratoma in Down's syndrome

The midline part of brain is a location frequently harboring misplacements of embryonal tissues.[3] For intracranial teratomas, the pineal gland is the most frequent site.[28] Interestingly, the predilection of intracranial germ cell tumors in Down syndrome seems to be exceptional; it usually arises in places other than the pineal gland.[316] Of the four cases reported, only one case arose from the pineal region [Table 1]. Pathogenesis of intracranial germ cell tumors in Down syndrome is still unclear. Some authors suggest an excess of luteinizing hormone and follicle-stimulating gonadotropin caused by cryptorchidism[14] or inherent genetic changes associated with this disease relate to the tumorigenesis.[113]

In infancy and early childhood, 45% of brain tumors arise in infratentorial space,[1117] the common pathologies being astrocytoma in 36%, medulloblastoma in 30%, ependymoma in 23%, followed by mixed neural-glial tumor and atypical teratoid/rhabdoid tumor. In our case, known Down syndrome, elevated AFP, and MRI findings such as heterogeneity of the tumor intensity, multiple cysts, and cauliflower-like multinodular appearance fortunately led to correct preoperative diagnosis.

We generally treat immature teratoma with carboplatin–etoposide combination chemotherapy followed by radiation according to the protocol for intracranial germ cell tumors proposed by The Japanese Pediatric Brain Tumor Study Group.[5] In this case, however, radiation therapy was precluded due to the fear of damaging developing brain at this young age, so we adopted the more potent cisplatin–etoposide chemotherapeutic regimen. We encountered two recurrent lesions after four cycles of chemotherapy. The resected recurrent tumors were histologically mature, and further recurrence has not been detected for the last 3 years.

Maturation of immature teratoma may be a result of natural conversion of multipotent embryonal cells into mature tissues as seen in fetal development. In the case of extracranial immature teratomas, most of recurrent lesions after the chemotherapy showed features of maturation, whereas the majority that did not receive chemotherapy had recurrent lesions with initial immature features.[4] Clinical and experimental observation suggest that this apparent maturation results from destruction of the less-differentiated elements of the tumor by chemotherapy.[6910] However, the role of chemotherapy in intracranial immature teratoma maturation is still not explicitly clear, because of the rarity of such cases, with only two cases previously reported by Shaffrey et al.[15]

CONCLUSIONS

We reported a rare immature teratoma in an infant with Down syndrome which has been controlled with two surgeries and cisplatin-based chemotherapy at a 4-year follow-up. The biomechanism of the maturation process of intracranial immature teratoma cases have yet to be elucidated. Although a persistently normal AFP serum level and proof of histologic maturation on the second look surgery may serve as predictors of good outcome, regular MRI follow-up including the spinal column would be mandatory for the early detection of the development of any recurrent disease.