Brain Pathology Case of the Month - September 2010

DIAGNOSIS

Embryonal tumor with abundant neuropil and true rosettes (ETANTR).

DISCUSSION

Embryonal neoplasms are a diverse and complex group of malignant neoplasms, predominantly affecting the pediatric population and generally associated with poor clinical outcomes. Histologically, all of embryonal neoplasms share the presence of undifferentiated primitive ("embryonal") tumor cells. Unique histologic characteristics permit additional sub-classification within this group of malignancies.

According to the World Health Organization (WHO) 2007 classification of central nervous system tumors, three categories of embryonal tumors are recognized: medulloblastoma, atypical teratoid/rhabdoid tumor (AT/RT), and CNS primitive neuroectodermal tumor (PNET).

While medulloblastoma and atypical teratoid/rhabdoid tumor are clearly defined entities, the CNS PNET category comprises a much more diverse collection, containing several entities defined by histopathologic features. These are the medulloepithelioma, ependymoblastoma, CNS neuroblastoma, and CNS ganglioneuroblastoma. The embryonal tumor with abundant neuropil and true rosettes (ETANTR), first described by Eberhart et al in 2000, combines features of both cerebral neuroblastoma and ependymoblastoma (1). A pubmed literature search revealed a total of 35 cases; 29 reported by Eberhart et al and Gessi et al (1,2), 1 by Spina et al (3), 2 by Fuller et al (4), 1 by Dunham et al (5), 1 by Al-Hussain et al (6), and 1 by Pfister et al (7). ETANTR occurs in both infants and young children with a mean age of 26 months, ranging from 9 to 48 months. In contrast to meduloblastoma, ETANTR predominantly occurs in females, with a female: male ratio of 2:1. It preferentially affects the supratentorial region, most commonly occurring in the frontal and parietal lobes, in isolation or with extension into the thalamus. Less frequently, this tumor has been encountered in the brainstem, cerebellum, pineal/tectal plate, and spinal cord. Three of the reported cases were dural based. Akin to the other CNS embryonal tumors, ETANTR can disseminate through the CSF. In one case, the tumor presented as multiple lesions in the spinal cord.

Clinical symptoms are a combination of focal neurologic effects of the tumor and increased intracranial pressure. Most commonly, patients present with nausea, vomiting, visual and movement disturbance. Radiologically, the tumor appears well demarcated, with variable mass effect and surrounding edema. MRI studies usually demonstrate hypodensity on T1-weighted images with hyperintensity on T2 weighted studies. Patchy post gadolinium contrast enhancement can be variable. The prognosis is extremely poor with the majority of children dying 1 to 30 months after presentation.

Histologically the lesion is unique in its biphasic composition of hypercellular regions alternating with paucicellular fibrillar neuropil with lumen containing rosettes. These rosettes characteristically contain small circular or slit-like lumens, some filled with granular debris. The neuropil exhibits synaptophysin positivity. Unlike rosettes encountered in ependymal tumors, the rosettes in ETANTRs do not react with antibodies to GFAP, although small foci of GFAP positive glial cells may be encountered elsewhere within the tumor. A single case of ETANTR with prominent neurocytic differentiation has been reported (5). The main histologic differential diagnosis includes medulloepithelioma, ependymoblastoma, neuroblastoma, and atypical teratoid/rhabdoid tumor (AT/RT).

Medulloepithelioma is an embryonal tumor composed of tall pseudostratified primitive epithelium arranged in glands, tubules, or canals with long surfaces resembling embryonic neural tube. This epithelium is delineated by well-defined, periodic acid-Schiff-positive basement membrane material on its outer surface. Its inner or luminal surfaces, demonstrate ill-defined amorphous pseudomembranes. Mitotic figures are often identified adjacent to the lumen. In contrast to ETANTR, medulloepitheliomas do not contain neuropil rich areas. The long surfaces and and PAS+ outer basement membranes characteristic of medulloepithelioma are absent in ETANTR. Ependymoblastomas also lack paucicellular neuropil, so characteristic of ETANTR. Ependymoblastic rosettes tend to be elongated structures, while ETANTR rosettes tend to be round (resembling Flexner-Wintersteiner rosettes). Neuroblastoma does not contain true rosettes, but instead may show Homer Wright rosettes. Occasionally, ETANTR may manifest mesenchymal differentiation and/or large pleomorphic cells, bringing AT/RT into the differential diagnosis. However, rhabdoid cells have not been described in ETANTR. Furthermore unlike AT/RT immunostaining for epithelial membrane antigen is negative, and INI-1 is positive in ETANTR.

Cytogenetic studies have been presented in three studies (4, 5, 7). Fuller et al. performed FISH on two cases of ETANTR (4). One case showed isochromosome i (17) q, an uncommon molecular anomaly encountered in approximately 40% of medulloblastomas, suggesting that despite arising at locations outside the cerebellum ETANTR may be related more closely to medulloblastoma than to supratentorial PNET. The other case showed polysomies of chromosomes 2,8,17 and 22. Subsequently, Duham et al studied one case using FISH, which showed normal dosages of chromosomes 2,8 and 17 (5). Finally, Pfister et al perfomed array-based comparative genomic hybridization (array GCH) on one case and discovered high level genomic amplification of 0.89 Mb at chromosome band 19q13.42 (7). This region contains several protein coding genes, but more importantly encodes a group of miRNAs, including miRNA-372 and miRNA-373. These two miRNAs are potent oncogenes in the development of germ cell tumors, and act by interfering with the p53 pathway. This unique chromosomal abnormality has not been described in any other brain tumor to date.

In summary, ETANTR is a rare, recently described entity within the CNS-PNET tumor family. It should be differentiated from medulloepithelioma, ependymoblastoma, neuroblastoma, and AT/RT by its unique histologic and immunohistochemical features.

REFERENCES

1. Eberhart CG, Brat DJ, Cohen KJ, Burger PC. (2000) Pediatric neuroblastic brain tumors containing abundant neuropil and true rosettes. Pediatr Dev Pathol 3(4): 346-52.
2. Gessi M, Giangaspero F, Lauriola L, Gardiman M, Scheithauer BW, Halliday W, Hawkins C, Rosenblum MK, Burger PC, Eberhart CG (2009) Embryonal tumors with abundant neuropil and true rosettes: a distinctive CNS primitive neuroectodermal tumor. Am J Surg Pathol 33(2):211-7.
3. La Spina M, Pizzolitto S, Skrap M, Nocerino A, Russo G, Di Cataldo A, Perilongo G. Embryonal tumor with abundant neuropil and true rosettes. (2006) A new entity or only variations of a parent neoplasms (PNETs)? This is the dilemma. J Neurooncol 78(3):317-20.
4. Fuller C, Fouladi M, Gajjar A, Dalton J, Sanford RA, Helton KJ (2006) Chromosome 17 abnormalities in pediatric neuroblastic tumor with abundant neuropil and true rosettes. Am J Clin Patho 126(2):277-83.
5. Dunham C, Sugo E, Tobias V, Wills E, Perry A (2007) Embryonal tumor with abundant neuropil and true rosettes (ETANTR): report of a case with prominent neurocytic differentiation. J Neurooncol. 84(1):91-8. Epub 2007 Feb 28.
6. Al-Hussain TO, Dababo MA (2009) Posterior fossa tumor in a 2 year-old girl. Brain Pathol. 19(2):343-6.
7. Pfister S, Remke M, Castoldi M, Bai AH, Muckenthaler MU, Kulozik A, von Deimling A, Pscherer A, Lichter P, Korshunov A (2009) Novel genomic amplification targeting the microRNA cluster at 19q13.42 in a pediatric embryonal tumor with abundant neuropil and true rosettes. Acta Neuropathol 117(4):457-64.

Contributed by Ilya Lim, MD, Irina Mikolaenko, MD, Mark Cohen, MD

International Society of Neuropathology