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Adenoid formation in medulloblastoma: A case report
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ELSEVIER
Adenoid Formation in Medulloblastoma: A Case Report Ho-Keung Ng, M.D., M.R.C.Path., F.R.C.P.A., F.C.A.P., and Wai-Sang Poon, M.B. Ch.B., F.R.C.S. Department of Anatomical and Cellular Pathology; Neurosurgical Unit, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong
Ng H-K, Poon W-S. Adenoid formation in medulloblastoma: a case report. Surg Neurol 1994;42:400-7.
A meduUoblastoma in a 3-year-old girl was described that showed epithelial features in the form of adenoid or acinar structure. UltrastructuraUy, these adenoid formations exhibited glandular features and immunohistochemically stained for cytokeratin. Such structures were interpreted to be a distinct and hitherto unreported form of epithelial differentiation in medulloblastoma, similar to other epithelial features described in rare cases of high grade astrocytomas. KEY WORDS. Medulloblastoma; Epithelial differentiation; Electron microscopy
Medulloblastomas are regarded as primitive neuroectodermal tumors with divergent differentiating potentials [6,30]. Although tumor cells are usually undifferentiated histologically, ultrastructurally, and immunohistochemically, neuroblastic differentiation is commonly seen [6,9,32]. Glial and other forms of mesenchymal differentiation are also well-known [6]. In this study, we described a medulloblastoma occurring in a 3-yearold child, which showed large numbers of adenoid or acinar structures. Such adenoid structures are interpreted as a distinctive form of epithelial differentiation in medulloblastoma, similar to epithelial differentiation in poorly differentiated astrocytomas [18,30].
Case R e p o r t A 3-year-old girl presented with an acute onset of repeated vomiting, unsteady gait and repeated falling. Computed tomography (CT) scan revealed a 4-cm contrast-enhancing tumor of the posterior fossa with hydro-
Address reprint requests to: Dr. H.K. Ng, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Shatin, Hong Kong. Received August 18, 1993; accepted February 1, 1994.
© 1994 by ElsevierScienceInc.
cephalus. No other tumor was detected clinically or radiologically. A ventriculoperitoneal shunt was performed to relieve the intracranial pressure. Subsequent posterior fossa craniectomy 2 weeks later revealed a fleshy tan tumor of the vermis of the cerebellum invading the fourth ventricle; a gross total resection was carried out. After overcoming two episodes of blocked shunts with infection and shunt revision, she finally made a good recovery and subsequently received a full course of craniospinal irradiation and chemotherapy with CCNU, vincristine, and procarbazine. She was last followed-up 27 months after operation, and was completely mobile and attending normal kindergarten. Follow-up CT scan showed only mild residual hydrocephalus with no recurrent tumor. Histologically, the tumor showed a predominant component consisting of densely cellular sheets of monotonous, undifferentiated round to carrot-shaped cells with no obvious differentiation (Figure 1). Homer-Wright's rosettes were not present but numerous neoplastic ganglion cells were seen focally (Figure 2). Patchy areas consisting of adenoid or acinar structures were encountered. They were lined by single-layered, round, palely eosinophilic cuboidal to low columnar cells with distinct membranebound luminal border and basal polarity (Figures 3 and 4). Blepharoblasts and perivascular rosettes, however, were not encountered. These acini gradually merged with the undifferentiated tumor cells mentioned previously. Necrosis, dystrophic calcifications, and desmoplastic changes were present focally. Melanotic areas were not seen. The following immunohistochemical preparations were carried out with monoclonal antibodies and the avidin-biotin peroxidase complex (ABC) method: neuron-specific enolase (Monosan, 1/50), synaptophysin (Dako, 1/20), neurofilament proteins (Dako, 1/80), glial fibrillary acidic protein (GFAP, 1/500), low molecular weight cytokeratin (CAM5.2) (Becton Dickenson, 1/50), smooth muscle actin (Dako, 1/200), desmin (Dako, 1/150), and epithelial membrane antigen (EMA) (Dako, 1/20). Some of the undifferentiated cells were strongly positive for neuronspecific enolase, and synaptophysin and the ganglion cells were intensely highlighted. Antineurofilament stained the 0090-3019/94/$7.00
Adenoid Formation in Medulloblastoma
Surg Neurol 1994;42:400-7
401
Figure 1. Most areas of the tumor consist of sheets of undifferentiated anaplastic tumor cells often encountered in medulloblastoma (x 150).
ganglion cells moderately but not the undifferentiated cells. The epithelial areas were negative for the neuronal markers but stained strongly for cytokeratin and weakly for EMA (Figure 5). Focally, astrocytic differentiation was evident with positive GFAP staining (Figure 6). Actin and desmin staining was uniformly negative. Ultrastructural examination showed the adenoid structures to consist of round cells surrounded by basal lamina.
The borders of some cells showed small microvilli that sometimes formed complex aborizations (Figure 7). No cilia however where encountered. Long and occasionally intertwining cellular borders lined by desmosome-like intermediate junctions were present (Figures 7 and 8). Intracellular and extracellular dystrophic calcified bodies were also seen. In addition, the less well-differentiated portion of tumor showed cells with electron-lucent cyto-
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0 .
.
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-
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Figure 2. Neoplastic ganglion cells present in focal areas in the tumor (x 300).
4
402
Surg Neurol 1994;42:400-7
Ng and Poon
Figure 3. Small adenoid structures present in the tumor. They have discrete outlines and are lined by low cuboidal cells. These structures gradually merge with the undifferentiated tumor cells at the upper border of the field (x 300). plasm and complex cellular processes laden with microtubules and neurosecretory granules. Synapse-like junctions were also encountered focally.
Discussion Medulloblastoma now denotes a cerebellar tumor, usually of childhood, consisting of primitive undifferen-
tiated cells [6,19]. Although a highly malignant tumor if left untreated, recent studies have shown the success of adjuvant radiotherapy and chemotherapy in treating these tumors. The overall 5-year survival now approached 50% [3,12,13,29]. Although the histogenesis of this tumor remains in doubt, there is little doubt that it possesses diverse potentials for differentiation [6,30].
Figure 4. High power view of the adenoid structures showing discrete outline, and mostly single layer of cuboidal cells (x 450).
Adenoid Formation in Medulloblastoma
Surg Neurol 1994;42:400-7
403
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%
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Figure 5. Adenoid structures exhibiting positivity to cytokeratin ( x 300). Histologically, these tumors consist of undifferentiated cells, which often exhibit neuroblastic differentiation, ultrastructurally and immunohistochemically, and ganglion cells are not infrequently encountered [6,30]. They are often positive for the neural markers of neuron-specific enolase, synaptophysin, and neurofilament [14,17,31,34]. Ultrastructurally, a primitive, undifferentiated cell type predominates but neuroblastic features, with neuritic processes of microtubules and
neurosecretory granules, are commonly seen [6,9,30,33]. Mesenchymal metaplastic changes Cdesmoplastic" medulloblastomas), muscular differentiation, and melanotic features are also occasionally encountered [4,6,16]. Rare cases of lipomatous and cartilaginous differentiation were also described [1,7]. Astrocytic and oligodendroglial features commonly occur, and some 10% of medulloblastomas are GFAP positive [5,6]. In our literature review, we are unaware of any
Figure 6. Focal astrocytic differentiation highlighted by GFAP immunostaining (× 300).
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Figure 7. Ultrastructurally, clusters of cells joined by intermediate junctions (arrows) and surrounded by basal lamina (arrowheads) are seen. Many calcific bodies are also present (x 2600).
description of epithelial differentiation in medulloblastoma. In the medulloblastoma described in this report, aside from neuroblastic features, patchy areas showed numerous acinar structures with distinct luminal borders lined by cuboidal cells. Ultrastructurally, the adenoid areas showed epithelial features with desomosomes and some microvilli [10]. It is believed that the adenoid structures are akin to similar epithelial formations described in rare cases of high grade astrocytomas [11,18,23,24]. A metastatic undifferentiated carcinoma was extremely unlikely to be the diagnosis because of the young age of the patient. Also, the adenoid portion of the t u m o r clearly merged with the undifferentiated areas histologically. N o other primary t u m o r was detected clinically. It would also be unusual that an occult primary t u m o r had not yet manifested itself more than 2 years after the resection of a brain metastasis.
Other differential diagnoses include a form of ependymomatous differentiation in medulloblastoma, ependymoblastoma, medulloepithelioma or a teratoma. Although ependymomas are also known to exhibit epithelial differentiation histologically and ultrastructurally [30,33], the Flexner's type of epithelial rosettes seen in ependymoma or retinoblastoma is devoid of the discrete outline seen in the adenoid structures of this case [2,15]. Similarly, the rosettes seen in ependymoblastoma are made up of pseudostratified cells and lack sharply delineated outlines, merging with the surrounding primitive cells [6,22,30]. Nor do these structures, in either ependymomas or ependymoblastomas, possess a well-formed basal lamina [2,6,25,30,33]. Perivascular pseudorosettes, a common feature observed in ependymomas, were absent. W e are unaware of any good description of ependymoma differentiation in medulloblastoma
Adenoid Formation in Medulloblastoma
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405
Figure 8. Higher power view showing tumor cells with desmosome-like junctions (arrowheads)and small microvillous processes (arrows) (x 6400). [5,6,9,32]. Medulloepithelioma is a very rare neuroectodermal tumor of the posterior fossa with prominent epithelial features resembling primitive medullary epithelium [30]. However, the small acini seen in this case lacked the complex papillary channels of medulloepithelioma [6,23]. Also, in the latter, the tumor cells are elongated and have a pseudostratified arrangement, in contrast to the low cuboidal, single-layered appearance of the acini seen in the present tumor. Although rare cases of intracranial teratomas occurring outside the preferred sites of the pineal gland and the suprasellar region are documented [28], the tumor studied here did not exhibit the broad differentiating potentials into tissues of different germ cell layers usually required for a diagnosis of teratoma [28]. The epithelial areas represented only small loci in a tumor otherwise dominated by sheets of undifferentiated cells.
Another primitive tumor of the posterior fossa that might enter into the differential diagnosis is a rhaboid tumor. However, this tumor lacked the usual glassy eosinophilic cytoplasm loaded with filaments, and immunopositivity for smooth muscle actin usually seen in rhabdoid tumor [6]. In balance, we believe the adenoid structures present in this tumor represent distinctive epithelial metaplastic changes seen in a medulloblastoma, a neuroectodermal tumor with divergent differentiating potentials. Epithelial-like features were described in high grade astrocytomas first by Kepes, Fulling, and Garcia [18] and subsequently by other authors [8,11,23,24,26]. In their original series of five cases, Kepes, Fulling, and Garcia described small adenoid or acinar formations in gliosarcomas [18]. M0rk, Rubinstein and Kepes further reported on medulloepithelioma-like areas in a glioblas-
406
Surg Neurol 1994;42:400-7
toma and a gliosarcoma [23]. In another article, the same group described squamous metaplastic changes in six gliosarcomas and glioblastomas [24]. The latter exhibited keratin pearls and were positive for cytokeratin immunohistochemically. The epithelial formations seen in this case are histologically reminiscent of the small adenoid formations described by Kepes, Fulling, and Garcia [18], and squamous changes were not present. This interpretation is supported by their staining for epithelial cytokeratin and their epithelial features ultrastructurally. To our knowledge, this is also the first ultrastructural study of epithelial differentiation in a neuroectodermal tumor. The factors leading to epithelial changes in neuroectodermal tumors remain unknown. Interestingly, 10 of the previously reported cases were described as gliosarcomas [18,23;24]. Experimentally, epithelial features have been noted in neoplastic glial elements in animal models of gliomas [20], and they have also been noted in glioblastoma after serial passage in nude mice [21]. Curiously, although epithelial properties are almost always associated with a particularly poor prognosis in the few cases described in astrocytomas, this does not appear to hold true in this case, as the patient has responded well to multimodality treatment. Whether this prognostic feature is unique to medulloblastomas remains to be confirmed by other cases. We conclude that epithelial features must be included as one of the diverse histological appearances of medulloblastoma. The findings in this case lend support to the previous observations that epithelial differentiation can be observed in poorly differentiated neuroectodermal tumors. They also add weight to the recommendation that cytokeratin positivity should not be taken as the sole criterion for diagnosing a metastatic carcinoma in neuropathology [24,27].
References 1. Anwer VE, Smith TW, De Girolami U, Wilkinson HA. Medulloblastoma with cartilaginous differentiation. Arch Pathol Lab Med 1989;113:84-8. 2. Apple DJ, Rabb MF. Ocular pathology. 4th ed. St Louis: Mosby, 1991: p 378-82. 3. Belza M, Donaldson SS, Steinberg GK, Cox RS, Cogen PH. Medulloblasroma: freedom from relapse longer than 8 years--a therapeutic cure? J Neurosurg 1991;75:575-82. 4. Biggs PJ, Powers JM. Neuroblastic medulloblastoma with abundant cytoplasmic actin filaments. Arch Pathol Lab Med 1984;108:326-9. 5. Burger PC, Grahmann FC, Bliestle A, Kleihues P. Differentiation in medulloblastoma. A histological and immunohistochemical study. Acta Neuropathologica 1987;73:115-23. 6. Burger PC, Scheithauer BW, Vogel FS. Surgical pathology of the nervous system and its coverings. 3rd ed. New York: Churchill Livingstone, 1991:339-352, 357-9, 372-3.
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7. Chimelli L, Hahn MD, Budka H. Lipomatous differentiation in a medulloblastoma. Acta Neuropathologica 1991;81:471-3. 8. Cruz-Sanchez FF, Garcia-Bachs M, Rossi ML, Rodriguez-Prados S, Ferrer I, Coakham HB, Ferreres JC, Figos J, Palacin A. Epithelial differentiation in gliomas, meningiomas and choroid plexus papillomas. Virchow Arch B Cell Pathol 1992;62:25-34. 9. Cruz-Sanchez FF, Rossi ML, Hughes JT, Esiri MM, Cockham HB. Medulloblastoma. An immunohistological study of 50 cases. Acta Neuropathologica 1989;79:205-10. 10. Dickersin GR. Diagnostic electron microscopy. A Text/Atlas. New York: Igaku-Shoin, 1988:26-30. 11. Galloway PG, Roessmann U. Anaplastic astrocytoma mimicking metastatic carcinoma. Am J Surg Pathol 1986;10:728-32. 12. Garton GR, Schomberg PJ, Scheithauer BW, Shaw EG, Ilstrup DM, Blackwell CR, Laws ERJr, Earle JD. Medulloblastoma-prognostic factors and outcome of treatment: review of Mayo Clinic experience. Mayo Clin Proc 1990;65:1077-86. 13. Geyer R, Levy M, Berger MS, Milstein J, Griffin B, Bleyer WA. Infants with medulloblastoma. A single institution review of survival. Neurosurgery 1991;29:707-11. 14. Giangaspero F, Rigobello L, Badiali M, Loda M, Andreini L, Basso G, Zorzi F, Montaldi A. Large-cell medulloblastomas. A distinct variant with highly aggressive behavior. Am J Surg Pathol 1992;16:687-93. 15. Hardman JM, Yang H-Y. The central nervous system. In: Silverberg SG, ed. Principles and practice of surgical pathology. 2nd ed. New York: Churchill Livingstone, 1990:2106-8. 16. Holl T, Kleihues P, Yasargil MG, Wiestler OD. Cerebellar medullomyoblastoma with advanced neuronal differentiation and hamartomatous component. Acta Neuropathologica 1991;82:408-13. 17. Katsetos CD, Herman MM, Frankfurter A, Gass P, Collins VP, Walker CC, Rosemberg S, Barnard RO, Rubinstein LJ. Cerebelar desmoplastic medulloblastoma. A further immunohistochemical characterization of the reticulin-free pale isolands. Arch Pathol Lab Med 1989;113:1019-29. 18. Kepes JJ, Fulling KH, Garcia JH. The clinical significance of "adenoid" formations of neoplastic astrocytes, imitating metastatic carcinoma, in gliosarcomas. A review of five cases. Clin Neuropathol 1982;1:139-50. 19. Kleihues P, Burger PC, Scheithauer BW. W H O lecture on CNS tumors. Berlin: Springer-Verlag, 1993. 20. Mandybur TI, Sawaya R, Ormsby I. The morphology and biologic behavior of human glioblastoma growing in nude mice. Cancer 1986;58:1061-9. 21. Manuelidis EE. Heterologous transplantation of two tissue culture lines of glioblastoma multiforme (TC178 and TC224). Proc Soc Exp Biol Med 1961;107:636-9. 22. M0rk SJ, Rubinstein LJ. Ependymoblastoma. A reappraisal of a rare embryonal tumor. Cancer 1985 ;55 : 1536-42. 23. Mcrk SJ, Rubinstein LJ, Kepes JJ. Patterns of epithelial metaplasia in malignant gliomas. I. Papillary formations mimicking medulloepithelioma. J Neuropathol Exp Neurol 1988;47: 93-100. 24. Mcrk SJ, Rubinstein LJ, Kepes J J, Perentes E, Uphoff DF. Patterns of epithelial metaplasia in malignant gliomas. II. Squamous differentiation of epithelial-like formations in gliosarcomas and glioblastomas. J Neuropathol Exp Neurol 1988;47:101-18. 25. Murphy MN, Dhalla SS, Diocee M, Halliday W, Wiseman NE, deSa DJ. Congenital ependymoblastoma presenting as a sacrococcygeal mass in a newborn: an immunohistochemical, light and electron microscopic study. Clin Neuropathol 1987;6: 169-73.
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26. Ng HK. Epithelial-like formations in astrocytomas. (Abs) XVIIIth International Congress of the International Academy of Pathology, Buenos Aires, 1990. 27. Ng HK, Lo STH. Cytokeratin immunoreactivity in gliomas. Histopathology 1989;14:359-68. 28. Ng HK, Pooh WS, Chan YL. Basal ganglia teratomas: report of three cases. Aust N Z Surg 1992;60:436-40. 29. Roberts RO, Lynch CF, Jones MP, Hart MN. Medulloblastoma: a population-based study of 532 cases. J Neuropathol Exp Neurol 1991 ;50:134-44. 30. Russell DS, Rubinstein LJ. Pathology of Tumours of the Nervous System. London: Edward Arnold, 1989:216-9, 251-79.
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31. Schwechheimer K. Wiedenmann B, Franke WW. Synaptophysin: a reliable marker for medulloblastomas. Virchows Arch A 1987;411:53-9. 32. Sime PJ, Gordon A, Hooper ML, Bell JE. Differentiation in medulloblastomas and other primitive neuroectodermal tumours. Br J Neurosurg 1989;3:89-100. 33. Tabuchi K, Nishimoto A. Atlas of brain tumors. Light- and electron-microscopic features. Tokyo: Springer-Verlag, 1988: 41-49, 75-86. 34. Velasco ME, Ghobrial MW,Ross ER. Neuron-specific enolase and neurofilament protein as markers of differentiation in medulloblastoma. Surg Neurol 1985;23:177-82.
ELSEVIER
Adenoid Formation in Medulloblastoma: A Case Report Ho-Keung Ng, M.D., M.R.C.Path., F.R.C.P.A., F.C.A.P., and Wai-Sang Poon, M.B. Ch.B., F.R.C.S. Department of Anatomical and Cellular Pathology; Neurosurgical Unit, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong
Ng H-K, Poon W-S. Adenoid formation in medulloblastoma: a case report. Surg Neurol 1994;42:400-7.
A meduUoblastoma in a 3-year-old girl was described that showed epithelial features in the form of adenoid or acinar structure. UltrastructuraUy, these adenoid formations exhibited glandular features and immunohistochemically stained for cytokeratin. Such structures were interpreted to be a distinct and hitherto unreported form of epithelial differentiation in medulloblastoma, similar to other epithelial features described in rare cases of high grade astrocytomas. KEY WORDS. Medulloblastoma; Epithelial differentiation; Electron microscopy
Medulloblastomas are regarded as primitive neuroectodermal tumors with divergent differentiating potentials [6,30]. Although tumor cells are usually undifferentiated histologically, ultrastructurally, and immunohistochemically, neuroblastic differentiation is commonly seen [6,9,32]. Glial and other forms of mesenchymal differentiation are also well-known [6]. In this study, we described a medulloblastoma occurring in a 3-yearold child, which showed large numbers of adenoid or acinar structures. Such adenoid structures are interpreted as a distinctive form of epithelial differentiation in medulloblastoma, similar to epithelial differentiation in poorly differentiated astrocytomas [18,30].
Case R e p o r t A 3-year-old girl presented with an acute onset of repeated vomiting, unsteady gait and repeated falling. Computed tomography (CT) scan revealed a 4-cm contrast-enhancing tumor of the posterior fossa with hydro-
Address reprint requests to: Dr. H.K. Ng, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Shatin, Hong Kong. Received August 18, 1993; accepted February 1, 1994.
© 1994 by ElsevierScienceInc.
cephalus. No other tumor was detected clinically or radiologically. A ventriculoperitoneal shunt was performed to relieve the intracranial pressure. Subsequent posterior fossa craniectomy 2 weeks later revealed a fleshy tan tumor of the vermis of the cerebellum invading the fourth ventricle; a gross total resection was carried out. After overcoming two episodes of blocked shunts with infection and shunt revision, she finally made a good recovery and subsequently received a full course of craniospinal irradiation and chemotherapy with CCNU, vincristine, and procarbazine. She was last followed-up 27 months after operation, and was completely mobile and attending normal kindergarten. Follow-up CT scan showed only mild residual hydrocephalus with no recurrent tumor. Histologically, the tumor showed a predominant component consisting of densely cellular sheets of monotonous, undifferentiated round to carrot-shaped cells with no obvious differentiation (Figure 1). Homer-Wright's rosettes were not present but numerous neoplastic ganglion cells were seen focally (Figure 2). Patchy areas consisting of adenoid or acinar structures were encountered. They were lined by single-layered, round, palely eosinophilic cuboidal to low columnar cells with distinct membranebound luminal border and basal polarity (Figures 3 and 4). Blepharoblasts and perivascular rosettes, however, were not encountered. These acini gradually merged with the undifferentiated tumor cells mentioned previously. Necrosis, dystrophic calcifications, and desmoplastic changes were present focally. Melanotic areas were not seen. The following immunohistochemical preparations were carried out with monoclonal antibodies and the avidin-biotin peroxidase complex (ABC) method: neuron-specific enolase (Monosan, 1/50), synaptophysin (Dako, 1/20), neurofilament proteins (Dako, 1/80), glial fibrillary acidic protein (GFAP, 1/500), low molecular weight cytokeratin (CAM5.2) (Becton Dickenson, 1/50), smooth muscle actin (Dako, 1/200), desmin (Dako, 1/150), and epithelial membrane antigen (EMA) (Dako, 1/20). Some of the undifferentiated cells were strongly positive for neuronspecific enolase, and synaptophysin and the ganglion cells were intensely highlighted. Antineurofilament stained the 0090-3019/94/$7.00
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Figure 1. Most areas of the tumor consist of sheets of undifferentiated anaplastic tumor cells often encountered in medulloblastoma (x 150).
ganglion cells moderately but not the undifferentiated cells. The epithelial areas were negative for the neuronal markers but stained strongly for cytokeratin and weakly for EMA (Figure 5). Focally, astrocytic differentiation was evident with positive GFAP staining (Figure 6). Actin and desmin staining was uniformly negative. Ultrastructural examination showed the adenoid structures to consist of round cells surrounded by basal lamina.
The borders of some cells showed small microvilli that sometimes formed complex aborizations (Figure 7). No cilia however where encountered. Long and occasionally intertwining cellular borders lined by desmosome-like intermediate junctions were present (Figures 7 and 8). Intracellular and extracellular dystrophic calcified bodies were also seen. In addition, the less well-differentiated portion of tumor showed cells with electron-lucent cyto-
O *~ ,h .
0 .
.
0,11
-
¢J
Figure 2. Neoplastic ganglion cells present in focal areas in the tumor (x 300).
4
402
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Ng and Poon
Figure 3. Small adenoid structures present in the tumor. They have discrete outlines and are lined by low cuboidal cells. These structures gradually merge with the undifferentiated tumor cells at the upper border of the field (x 300). plasm and complex cellular processes laden with microtubules and neurosecretory granules. Synapse-like junctions were also encountered focally.
Discussion Medulloblastoma now denotes a cerebellar tumor, usually of childhood, consisting of primitive undifferen-
tiated cells [6,19]. Although a highly malignant tumor if left untreated, recent studies have shown the success of adjuvant radiotherapy and chemotherapy in treating these tumors. The overall 5-year survival now approached 50% [3,12,13,29]. Although the histogenesis of this tumor remains in doubt, there is little doubt that it possesses diverse potentials for differentiation [6,30].
Figure 4. High power view of the adenoid structures showing discrete outline, and mostly single layer of cuboidal cells (x 450).
Adenoid Formation in Medulloblastoma
Surg Neurol 1994;42:400-7
403
D
e Qq
B
%
F
Figure 5. Adenoid structures exhibiting positivity to cytokeratin ( x 300). Histologically, these tumors consist of undifferentiated cells, which often exhibit neuroblastic differentiation, ultrastructurally and immunohistochemically, and ganglion cells are not infrequently encountered [6,30]. They are often positive for the neural markers of neuron-specific enolase, synaptophysin, and neurofilament [14,17,31,34]. Ultrastructurally, a primitive, undifferentiated cell type predominates but neuroblastic features, with neuritic processes of microtubules and
neurosecretory granules, are commonly seen [6,9,30,33]. Mesenchymal metaplastic changes Cdesmoplastic" medulloblastomas), muscular differentiation, and melanotic features are also occasionally encountered [4,6,16]. Rare cases of lipomatous and cartilaginous differentiation were also described [1,7]. Astrocytic and oligodendroglial features commonly occur, and some 10% of medulloblastomas are GFAP positive [5,6]. In our literature review, we are unaware of any
Figure 6. Focal astrocytic differentiation highlighted by GFAP immunostaining (× 300).
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Ng and Poon
Figure 7. Ultrastructurally, clusters of cells joined by intermediate junctions (arrows) and surrounded by basal lamina (arrowheads) are seen. Many calcific bodies are also present (x 2600).
description of epithelial differentiation in medulloblastoma. In the medulloblastoma described in this report, aside from neuroblastic features, patchy areas showed numerous acinar structures with distinct luminal borders lined by cuboidal cells. Ultrastructurally, the adenoid areas showed epithelial features with desomosomes and some microvilli [10]. It is believed that the adenoid structures are akin to similar epithelial formations described in rare cases of high grade astrocytomas [11,18,23,24]. A metastatic undifferentiated carcinoma was extremely unlikely to be the diagnosis because of the young age of the patient. Also, the adenoid portion of the t u m o r clearly merged with the undifferentiated areas histologically. N o other primary t u m o r was detected clinically. It would also be unusual that an occult primary t u m o r had not yet manifested itself more than 2 years after the resection of a brain metastasis.
Other differential diagnoses include a form of ependymomatous differentiation in medulloblastoma, ependymoblastoma, medulloepithelioma or a teratoma. Although ependymomas are also known to exhibit epithelial differentiation histologically and ultrastructurally [30,33], the Flexner's type of epithelial rosettes seen in ependymoma or retinoblastoma is devoid of the discrete outline seen in the adenoid structures of this case [2,15]. Similarly, the rosettes seen in ependymoblastoma are made up of pseudostratified cells and lack sharply delineated outlines, merging with the surrounding primitive cells [6,22,30]. Nor do these structures, in either ependymomas or ependymoblastomas, possess a well-formed basal lamina [2,6,25,30,33]. Perivascular pseudorosettes, a common feature observed in ependymomas, were absent. W e are unaware of any good description of ependymoma differentiation in medulloblastoma
Adenoid Formation in Medulloblastoma
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Figure 8. Higher power view showing tumor cells with desmosome-like junctions (arrowheads)and small microvillous processes (arrows) (x 6400). [5,6,9,32]. Medulloepithelioma is a very rare neuroectodermal tumor of the posterior fossa with prominent epithelial features resembling primitive medullary epithelium [30]. However, the small acini seen in this case lacked the complex papillary channels of medulloepithelioma [6,23]. Also, in the latter, the tumor cells are elongated and have a pseudostratified arrangement, in contrast to the low cuboidal, single-layered appearance of the acini seen in the present tumor. Although rare cases of intracranial teratomas occurring outside the preferred sites of the pineal gland and the suprasellar region are documented [28], the tumor studied here did not exhibit the broad differentiating potentials into tissues of different germ cell layers usually required for a diagnosis of teratoma [28]. The epithelial areas represented only small loci in a tumor otherwise dominated by sheets of undifferentiated cells.
Another primitive tumor of the posterior fossa that might enter into the differential diagnosis is a rhaboid tumor. However, this tumor lacked the usual glassy eosinophilic cytoplasm loaded with filaments, and immunopositivity for smooth muscle actin usually seen in rhabdoid tumor [6]. In balance, we believe the adenoid structures present in this tumor represent distinctive epithelial metaplastic changes seen in a medulloblastoma, a neuroectodermal tumor with divergent differentiating potentials. Epithelial-like features were described in high grade astrocytomas first by Kepes, Fulling, and Garcia [18] and subsequently by other authors [8,11,23,24,26]. In their original series of five cases, Kepes, Fulling, and Garcia described small adenoid or acinar formations in gliosarcomas [18]. M0rk, Rubinstein and Kepes further reported on medulloepithelioma-like areas in a glioblas-
406
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toma and a gliosarcoma [23]. In another article, the same group described squamous metaplastic changes in six gliosarcomas and glioblastomas [24]. The latter exhibited keratin pearls and were positive for cytokeratin immunohistochemically. The epithelial formations seen in this case are histologically reminiscent of the small adenoid formations described by Kepes, Fulling, and Garcia [18], and squamous changes were not present. This interpretation is supported by their staining for epithelial cytokeratin and their epithelial features ultrastructurally. To our knowledge, this is also the first ultrastructural study of epithelial differentiation in a neuroectodermal tumor. The factors leading to epithelial changes in neuroectodermal tumors remain unknown. Interestingly, 10 of the previously reported cases were described as gliosarcomas [18,23;24]. Experimentally, epithelial features have been noted in neoplastic glial elements in animal models of gliomas [20], and they have also been noted in glioblastoma after serial passage in nude mice [21]. Curiously, although epithelial properties are almost always associated with a particularly poor prognosis in the few cases described in astrocytomas, this does not appear to hold true in this case, as the patient has responded well to multimodality treatment. Whether this prognostic feature is unique to medulloblastomas remains to be confirmed by other cases. We conclude that epithelial features must be included as one of the diverse histological appearances of medulloblastoma. The findings in this case lend support to the previous observations that epithelial differentiation can be observed in poorly differentiated neuroectodermal tumors. They also add weight to the recommendation that cytokeratin positivity should not be taken as the sole criterion for diagnosing a metastatic carcinoma in neuropathology [24,27].
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