Journal of Clinical Neuroscience 18 (2011) 811–813

Contents lists available at ScienceDirect

Journal of Clinical Neuroscience

journal homepage: www.elsevier .com/ locate/ jocn

Neuropathology Report

Pineal anlage tumour - a rare entity with divergent histology

Arvind Ahuja a, Mehar Chand Sharma a,⇑, Vaishali Suri a, Chitra Sarkar a, B S Sharma b,⇑, Ajay Garg c

a Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, Indiab Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, Indiac Department of Neuroradiology, All India institute of Medical Sciences, New Delhi, India

a r t i c l e i n f o a b s t r a c t

Article history:Received 1 July 2010Accepted 22 September 2010

Keywords:Brain tumourCentral nervous system tumourNeuroepithelial and ectomesenchymaldifferentiationPineal anlage tumourPineal gland

0967-5868/$ - see front matter � 2010 Elsevier Ltd. Adoi:10.1016/j.jocn.2010.09.016

⇑ Corresponding authors. Tel.: +91 11 26593371;Sharma).

E-mail address: sharmamehar@yahoo.co.in (M.C. S

Pineal anlage tumour is a rare tumour of the pineal gland that is not listed in the 2007 World HealthOrganization classification of tumours of the central nervous system. Pineal anlage has been defined asa primary pineal tumour with both neuroepithelial and ectomesenchymal differentiation but withoutendodermal differentiation. We report a pineal anlage tumour in a 4-month-old boy, the youngest patientreported with this rare tumour, with a brief review of the literature. Clinicians and neuropathologistsshould be aware of this entity as it is likely to be misdiagnosed as a teratoma or a melanocytic tumourof the central nervous system.

� 2010 Elsevier Ltd. All rights reserved.

1. Introduction

Pineal anlage tumour was first reported by Schmidbauer et al. in1989.1 They described it as a pineal tumour that exhibited neuro-nal, retinoblastic and ectomesenchymal differentiation. Since thenonly five patients have been reported.1–5 Pineal anlage tumour is arare tumor that is not listed in the 2007 World Health Organizationclassification of tumours of the central nervous system.6

2. Report

2.1. Clinical summary

A 4-month-old boy was brought by his parents to the Neurosur-gery Outpatient Department with an 8-day history of progressivedrowsiness, altered sensorium and an enlarging head. There wasno history of seizure or vomiting. His antenatal history was unre-markable. Ultrasonography of the fetus during the antenatal periodwas normal. On clinical examination, he had an enlarged head cir-cumference for his age, with a bulging and tense anterior fontanel.His pupils were sluggishly reactive to light but eye movementswere normal. Routine blood examination, serum chemistry andcerebrospinal fluid (CSF) examination revealed no abnormalities.Serum beta-human chorionic gonadotropin, alpha-fetoprotein(AFP) and placental alkaline phosphatase (PLAP) levels were within

ll rights reserved.

fax +91 11 26588663 (M.C.

harma).

the normal range. A head CT scan showed a large, cystic, partiallycalcified and contrast-enhancing tumour in the posterior third ven-tricular region. On MRI this lobulated mass was isointense tohyperintense on T1-weighted and hypointense on T2-weightedimaging, and showed enhancement on contrast injection (Fig. 1).A normal pineal gland was not visualized separately. The aqueductwas compressed and there was massive hydrocephalus and peri-ventricular edema.

A right ventriculoperitoneal shunt was inserted 2 days beforesurgery. Subtotal resection of the tumour was performed througha left occipital craniotomy (occipital–transtentorial, Poppen’s ap-proach). At surgery this tumour was blackish, firm and moderatelyvascular. Deep veins identified during surgery were saved and aprimary dural closure was done. The postoperative period wasuneventful and he was discharged on day 5 after surgery.

2.2. Pathologic examination

The tumour tissue was fixed in 10% neutral buffered formalin,routinely processed and paraffin embedded. Sections (5 lm) werecut for routine staining with hematoxylin and eosin and for immu-nohistochemistry (IHC). For IHC staining, the streptavidin biotinconjugate immunoperoxidase method was used after appropriateantigen retrieval wherever required. Monoclonal antibodies to syn-aptophysin (1:100), neuron-specific enolase (1:100), glial fibrillaryacidic protein (GFAP, 1:1000), microtubule associated protein(MAP, 1:200), smooth muscle antigen (SMA, 1:50), desmin (1:50),myogenin (1:100), S-100 (1:100), AFP (1:50), PLAP (1:50),cytokeratin (1:200), epithelial membrane antigen (EMA, 1:100),

Fig. 1. (A) Sagittal T2-weighted, (B) axial T1-weighted and (C) axial T2-weighted MRI showing a well-defined lobulated mass in the pineal region isointense to hyperintenseon T1-weighted MRI (B) and hypointense on T2-weighted MRI (A, C). The mass is compressing the aqueduct with resultant hydrocephalus.

812 A. Ahuja et al. / Journal of Clinical Neuroscience 18 (2011) 811–813

melanoma monoclonal antibody HMB-45 (1:100) and proliferativemarker MIB-1(1:200) were used. All antibodies were obtainedfrom M/S Dakopatts (Glostrup, Denmark). At least 500 cells werecounted using a 1 mm2 eyepiece pinhole to calculate the MIB-1labeling index.

2.3. Microscopic examination

A detailed histopathological examination was performed and apanel of immunostains was used to establish the range of differen-tiation of the tumour. The tumour had a variegated appearance.The predominant component of the tumour was comprised ofsmall undifferentiated cells arranged in nests, tubules, or cord-likestructures and a few displayed fleurettes with abundant melaninpigment (Fig. 2a, b). This pigment became more prominent withFontana Masson stain but was bleached with potassium

Fig. 2. Photomicrographs of tumour sections showing: (a, b) sheets of small round undcytoplasm, hyperchromatic nuclei with frequent mitoses, and tubule formation by pigmecytoplasm and frequent mitotic activity; and (d) lobules of cellular cartilage ([www.sciencedirect.com.)

permanganate, thereby confirming the melanin pigment. In the so-lid areas, the tumour cells showed hyperchromatic nuclei, frequentmitoses and a scant amount of cytoplasm. There was high mitoticactivity and apoptosis in the solid areas.

The second component was made up of plump- to spindle-shaped cells with a moderate amount of eosinophilic cytoplasmand frequent mitotic activity (Fig. 2c). Lobules of cellular cartilagewere the third component present in the tumour (Fig. 2d). The car-tilage looked immature but no features of malignancy were seen.The neuroepithelial differentiation seen in our patient includedneuronal and retinal elements. Ectomesenchymal differentiationcomprised fibroblastic spindle cells and cartilage formation. Onextensive searching no endodermal component was found. Thepigment was reactive to HMB-45 antibody. The cytokeratin, EMA,desmin, GFAP, AFP and PLAP immunostains were negative butthe primitive cellular component was immunoreactive to

ifferentiated cells in nests, tubules or cord-like structures with a scant amount ofnted cells; (c) plump- to spindle-shaped cells with moderate amount of eosinophilica–d] haematoxylin and eosin, � 200). (This figure is available in colour at

A. Ahuja et al. / Journal of Clinical Neuroscience 18 (2011) 811–813 813

synaptophysin and MAP (Supplementary Fig. 1a, b). The spindlecell component was immunopositive for vimentin but was nega-tive for SMA (Supplementary Fig. 1c), desmin and myogenin. TheMIB-1 labeling index of the primitive cell area was 35%, whereasthe remaining tissue had a MIB-1 index of less than 1% (Supple-mentary Fig. 1d).

Based on the clinical features, pathology, and microscopic stud-ies, the possibility of a pineal anlage tumour with divergent histol-ogy was entertained. The child was given four courses ofchemotherapy but the parents refused for the fifth course as childwas doing well at the 6-month follow-up.

3. Discussion

Pineal anlage tumour is an entity described relatively recently,which behaves very aggressively. The fourth edition of the WorldHealth Organization (2007) classification of tumours included anew entity, ‘‘papillary tumour of the pineal region’’, in additionto pineocytoma, pineal parenchymal tumor of intermediate differ-entiation and pineoblastoma in the pineal region.6 Pineal anlagetumour is another new entity or variant in this line. Although thename was first used by Schmidbauer et al. more than 20 yearsago, to our knowledge there have been only five patients reported(Supplementary Table 1). Schmidbauer et al. described this new tu-mour in an autopsy of a nine-year-old girl, which on histopatholo-gical examination showed neuroectodermal and ectomesenchymaldifferentiation.1 All other reported patients have been male andhad been diagnosed in the first year of life.1The current patient isa 4-month-old boy and is the youngest reported.

The neuroectodermal differentiation comprises neuroblastic,ependymal and retinoblastomatous differentiation with or withoutFlexner–Winstersteiner and Homer–Wright rosettes. In addition,melanotic epithelium akin to retinal anlage tumour is consistentlypresent in all patients. The melanin pigment can be seen in thesmall undifferentiated cells or in the cells forming tubules. Theectomesenchymal differentiation includes striated muscles,rhabdomyoblasts and cartilaginous tissue. The cartilaginous tissueappears immature but not malignant. All pineal anlage tumourshave contained malignant neuronal or primitive components, ex-cept for one,4 in which the malignant component comprised ma-ture neuronal tissue, striated muscle and pigment-containingtubules.4

The differential histological diagnosis includes teratoma, ecto-mesenchymoma and medullomyoblastoma. The typical pineal an-lage tumour contains pigmented epithelium, ganglion cells,neuroblasts, glia, cartilage, and striated muscle, but no endo-derm-derived elements. A teratoma includes all these elementsas well as Schwann cells and endodermal derivatives.5 An ectomes-enchymoma is considered to be a rhabdomyosarcoma with neuraldifferentiation. It has rhabdomyoblasts, Schwann cells, ganglioncells, neuroblasts, and pigmented epithelium, mostly seen in softtissue but rarely in the brain. A medullomyoblastoma is a variant

of medulloblastoma that exhibits muscle differentiation and oc-curs in the cerebellum only.

The presence of melanin in the pineal tumour is consistent withits pineal origin6 and is reminiscent of the phylogeny of the humanpineal gland as melanin pigment occurs transiently in pineal celldevelopment.7 These tumours are similar to the melanotic neuro-ectodermal tumours of infancy that occur predominantly in thejaw bone; but have different behaviour, as pineal anlage tumoursare invariably fatal. Pineal parenchymal tumours may show diver-gent differentiation reminiscent of embryonal pineal cells, whichshow striated muscle differentiation, pigmented epithelium and aneuronal component.8,9

A pineal anlage tumour behaves aggressively, similar to a pine-aloblastoma. Patients with pineal tumours that showed neuronaldifferentiation have a better prognosis. Jouvet et al. showed thatnecrosis and more than six mitoses per 10 high-power fields wereassociated with a poorer outcome, whereas positive immunostain-ing for neurofilaments was associated with a better survival.10 Inanother study, MIB-1 (Ki-67) was used to assess the proliferativepotential of pineal tumours and its correlation with histologicalfeatures.11The MIB-1 labeling index (LI) correlated well with histo-logical grade of malignancy. In our patient, the MIB-1 LI was high(35%) in the areas with greatest proliferation.

Our patient is the youngest reported with a pineal anlage tu-mour and was doing well after 6 months of surgery with chemo-therapy, but long-term follow-up is required.

Appendix A. Supplementary material

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.jocn.2010.09.016.

References

1. Schmidbauer M, Budka H, Pilz P. Neuroepithelial and ectomesenchymaldifferentiation in a primitive pineal tumor (‘‘pineal anlage tumor’’). ClinNeuropathol 1989;8:7–10.

2. Raisanen J, Vogel H, Horoupian DS. Primitive pineal tumor withretinoblastomatous and retinal/ciliary epithelial differentiation: animmunohistochemical study. J Neurooncol 1990;9:165–70.

3. McGrogan G, Rivel J, Vital CL, et al. A pineal tumour with features of pinealanlage tumour. Acta Neurochir (Wien) 1992;117:73–7.

4. Gudinaviciene I, Pranys D, Zheng P, et al. A 10-month-old boy with a largepineal tumor. Brain Pathol 2005;15:263–4.

5. Stephen B, Pearl G. Review of pineal anlage tumor with divergent histology.Arch Pathol Lab Med 2006;130:1233–5.

6. Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumoursof the central nervous system. Acta Neuropathol (Berl) 2007;114:97–109.

7. Min KW. Ontogeny of human pineal gland. J Child Neurol 1988;3:275.8. Araki M, Kodama R, Eguchi G, et al. Retinal differentiation from multipotential

pineal cells of the embryonic quail. Neurosci Res 1993;18:63–72.9. Watanabe K, Aoyama H, Tamamaki N, et al. An embryonic pineal body as a

multipotent system in cell differentiation. Development 1988;103:17–26.10. Jouvet A, Saint-Pierre G, Fauchon F, et al. Pineal parenchymal tumors: a

correlation of histological features with prognosis in 66 cases. Brain Pathol2000;10:49–60.

11. Numoto RT. Pineal parenchymal tumors: cell differentiation and prognosis. JCancer Res Clin Oncol 1994;120:683–90.