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I .'í I Ì- X £ Ï $ ï 5 (/> <. 1 <= Ï '■í®- 146 Y. Gecrts et al Neuropediatrics 27 (1996) of hemisyndromes (11%). Neurological examination revealed in about 3 3 % of the patients symptoms of hemisyndromes, cranial nerve palsy (25 %), ataxia and gait disturbances (17 %). Papilledema was the most common clinical finding (35%). Choroid plexus carcinomas have no specific radiological characteristics. On computed tomography, relation to ventricles is a radiological clue. Choroid plexus carcinomas usually have irregular margins surrounded by hypodensities due to edema because of infiltration in adjacent neural tissue. A marked contrast enhancement is noted (16, 37, 49). Hydro­ cephalus, usually of the obstructive type, is generally less severe than found in the case of benign choroid plexus papillomas, where hypersecretion of cerebrospinal fluid occurs (10, 16, 37, 42). Tumor calcification is uncommon (13, 14, 16, 22, 37, 47, 61). Magnetic resonance imaging does not provide more in­ formation about the nature of the tumor than computed tomography, but facilitates three-dimensional visualization be­ fore surgical treatment, postoperative evaluation of residual and recurrent tumor, am detection of leptomeningeal metastases (16, 37, 61). We found 46 cases in the literature with in­ vestigation for dissemination at the moment of diagnosis, recurrence of the tumor or autopsy (Cases 1 and 2 and ref. 1 , 4,10, 14,15,17,18, 22, 24,28-30,33, 34, 36, 38-39,41,43, 45,46,52, 54, 55,59-63). Investigation was done with analysis of the cerebrospinal fluid for malignant cells and/or lumbar myelography and, more recently, with magnetic resonance imaging. Twenty-two patients (48%) did not show cerebro­ spinal dissemination. Sub arachnoid seeding was found in 20 patients (43%). Occasionally metastases outside the central nervous system are described: pleura and lung (63), ascitic fluid (46), peritoneum (46) and bone (17, 33)* We report one case with several metastatic tumors in the omentum, bladder, uterus and rectum. We agree with Griffith that the real incidence of cerebrospinal dissemination is not known (30). Staging studies evaluating the entire neuraxis are particularly important after local tumor recurrence is proven, but a negative result does not exclude the development of subsequent metas­ tases (38). The diagnosis of choroid plexus carcinoma is based on histological examination; in typical cases, the tumor shows architectural disarray with poorly formed papillae, high cellularity, severe cytonuclear atypia and a high mitotic index (12). These carcinomas usually show immunohistochemical staining with epithelial markers (keratin, Cam 5.2, EMA), but compared to plexus papillomas staining with markers for glial differentiation (SI00, GFAP) is diminished or absent (2,19,21, 51, 58). Like in plexus papillomas, in plexus carcinomas ultrastructural features of normal choroid plexus epithelium (basal lamina, interdigitation of cell membranes, apical micro­ villi, desmosomes, scattered cilia) may be present (25, 47). The distinction between plexus carcinomas and plexus papillomas is sometimes difficult, atypical plexus papillomas may show sig­ nificant cytonuclear atypia and scattered mitotic figures (12). In our two cases the severe cytonuclear atypia and high mitotic index qualified these tumors as plexus carcinomas. Histopathologically, other malignant tumors like malignant ependymoma and metastatic carcinoma may resemble a choroid plexus carcinoma. In contrast to plexus carcinomas, malignant epen­ dymomas generally show clear-cut glial differentiation and GFAP-staining (12, 48). Table 3 up). Treatment and outcome: disease-free survival period H follow- Surge ty Adjuvant therapy Complete resection n t() None Radiotherapy Chemotherapy Radio- i- chemotherapy 10 10 5 1 60 (5-1181 64 (4-240) 54 (8-156) 12 Total 26 58 Partial resection n t() — 4 6 — 10 — 32 (12-48) 34 (5-72) 33 n: number of patients; ( j; range of disease-free survival period (In months); t: median disease-free survival period Reviewing the literature it is not possible to establish the optimal therapy for choroid plexus carcinomas. Therapy was described for 121 of the 231 patients. Four children just underwent inspection of the brain; follow-up data were not available for 2 patients. A group of 25 (21 %) patients died preop era tively or within two months after surgery; they are considered as perioperative deaths and are excluded from Table 3. The treatment varied from surgical resection alone to more aggressive therapy with surgery followed by radiotherapy and/or chemotherapy. The follow-up period ranged from 3 months to 20 years. Most authors described gross total, subtotal or partial resection of the tumor. However, in many cases postsurgical evaluation of the tumor is not available. Information about the exact field and dosage of radiotherapy is often lacking and the chemotherapeutic scheme varies widely. A group of 28 patients who died within the period of follow-up, had a median survival of 13 months after diagnosis. Surgery without adjuvant therapy can be curative as shown in Table 3 (Case 1 and ref. 1 , 4-6, 10, 1 1 , 14, 17, 18, 20, 22-25, 28, 32, 39, 50-52, 56, 60, 64). Table 3 indicates that, whenever pos­ sible, complete resection of the choroid plexus carcinoma has to be pursued. We did not find a difference between surgery alone and surgery followed by radiotherapy when complete resection was performed. This was also noted by Packer et al and Pierga et al (52, 56). The shorter median relapse-free period for patients who underwent complete resection followed by che­ motherapy may be due to the more recent use of chemother­ apeutic treatment as adjuvant therapy Adjuvant therapy fol­ lowing surgery of choroid plexus carcinoma is useful when only partial resection of the tumor was obtained. There is no difference in disease-free interval between the groups receiving either chemotherapy or radiotherapy after partial resection: median period of 34 and 32 months respectively (Table 3). No difference could be found between children and adults concerning the outcome of adjuvant therapy as there were only a few adults amongst the 16 reported cases with a detailed follow-up history after diagnosis. Knowing the possible long­ term sequelae of irradiation with intellectual deterioration, leukoencephalopathy, endocrinopathy, especially in the very young children, delay of radiotherapy is sought until the age of at least four years is reached. This delay of radiotherapy is important because 44% of the patients with choroid plexus carcinoma are younger than 2 years. Several schemes of drugs have been used but the value of each of them can not be evaluated due to the small number of patients in each scheme. Because of her age, our youngest patient received chemother­ apy after gross total resection of the tumor. Interestingly, the metastasis which was present at the moment of diagnosis disappeared under chemotherapy whereas ten months after Choroid Plexus Carcinoma surgery several intracerebral, spinal and cranial leptomeningeal metastases had occurred. Reviewing the literature, leptomenin­ geal seeding of the tumor can disappear after craniospinal radiotherapy (54, 56, 59), whereas chemotherapy is less favor­ able (1, 10, 24, 52). Conclusion Reviewing the literature, initial staging studies evaluating the entire neuraxis should be performed at the moment of diagnosis of a choroid plexus carcinoma, as sub­ arachnoid seeding occurs in almost half of the patients. Even under chemotherapeutic treatment, peritoneal metastases can occur by ventriculo-peritoneal shunting. No difference could be found between radiotherapy and chemotherapy following par­ tial resection of the tumor, but radiotherapy should be delayed as much as possible for the youngest patients because of possible long-term sequelae. In the past, several chemothera­ peutic schemes have been used and therefore more cases or protocols are needed to decide for the best therapy. Neuropediatrics 27 (1996) 10 Coates, T. L., D . B . Hinshazo, N. Peckman, ƒ. R. Thompson, A . N. Hasso, B, A. Hoshauser et al: Pediatric choroid plexus neoplasms: MR, CT, and pathologic correlation. Radiology 173 (1989) 81-88 17 Coffin, C. A i, M. R. Wick, }. F. Braun, L P. Dehner: Choroid plexus neoplasms: clinicopathologic and immunohistochemical studies. Am. J. Surg. Pathol. 10 (1986) 394-404 IK Coons, S., P C. Johnson, C. A. Dickman, H. Rekate: Choroid plexus carcinoma in siblings: a study by light and electron microscopy with Ki67 immunocytochemistry. J. Neuropathol. Exp. Neurol. 48 (1989) 483493 10 Cruz-Sanchez, E F., M . L. Rossi, /. T. Hughes, H. B, Coakham, ƒ, Figols, P. M. Eynaud: Choroid plexus papillomas: an immunohistochemical study of 16 cases. Histopathology 15 (1989) 61-69 20 Cucciniello, B., S, De Marco: Choroid plexus carcinoma: a case report. J. Neurosurg. Sci. 23 (1979) 153-157 21 Doglioni, C., P. Dell'Orto, G. Coggi, P. luzzolino, L. Bontempini, G. Viale: Choroid plexus tumours: an immunocytoehemical study with particular reference to the coexpression of intermediate filament proteins. Am. J. Pathol. 127 (1987) 519-529 22 Dohrmann, G. ],, ƒ, C. Collias: Choroid plexus carcinoma: case report, J. Neurosurg. 43 (1979) 225-232 2;j Duffner, P K M. E. Co/?en, M. Horowitz, L Kim, P, C Burger, R. Kadata et al: The treatment of choroid plexus carcinoma in infancy with chemotherapy. Abstract 18th Annual Meeting Child Neurology Society, October 12-14, 1989, San Antonio, Texas. Aim, Neurol. 26 (1989) 460 Ellenbogen, R . G., K. R, Winston, W. /. Kupsky: TUmours of the choroid plexus in children. Neurosurgery 25 (1989) 327-335 25 Felix, L, S. Phudhichareonrat, W. C. Halliday, L. E, Becker: Choroid plexus tumours in children: immunohistochemical and scanning-electronmicrosopic features. Pediat Neurosci, 13 (1987) 263-269 2(5 Filipek, P. A., D. ƒ. Kennedy, V. S, Caviness: Morphometrie analysis of central nervous system neoplasms. Abstract 18th Annual Meeting Child Neurology Society, October 12-14, 1989, San Antonio, Texas. Ann. Neurol, 26 (1989) 461 27 Fujhoara, S,, N. Kodama, S. Endoh, A. Takaku, A. Suzuki: A case of a giant choroid plexus carcinoma in a child. Neurol. Surg. 7 (1979) 889-892 Gianella-Borradori, A., P. M. Zeltzer, B, Bodey, M . Nelson , H . Britton, A. Marlin: Choroid plexus tumours in childhood: response to chemother­ apy, and immunophenotypic profile using a panel of monoclonal anti­ bodies. Cancer 69 (1992) 809-810 20 Graves, G. W., M. M. Flicss: Neoplasm of the choroid plexus: report of a case with review of the literature. Am. X Dis. Child. 47 (1934) 97-103 IÎO Griffin, B. R., G. R. Stewart, M. S. Berger, ƒ. R, Geyer, M. O'Dell, S. Rostad: Choroid plexus carcinoma of the fourth ventricle: report of a case in an infant. Pediatr. Neurosci. 14 (1988) 134-139 ;u Gullotta, F., A S. De Melo: Das Karzinom des Plexus choroideus: Klinische, lichtmikroskopische und elektronenoptische Untersuchungen. Neurochirurgia 22 (1979) 1-9 Hawkins, /. C.: IVeaLment of choroid plexus papillomas in children: a brief analysis of twenty years’ experience. Neurosurgery 6 (1980) 380384 Hayakawa, I., K. Fujhoara, T. Tsuchida, M. Aoki: Choroid plexus carcinoma with metastasis to hone. Neurol. Surg. 7 (1979) 815-818 34 Hoytema van, G. ƒ., W, E. Winckel: Zur Frage des primären Plexuskar­ zinoms. Zentralbl. Neurochir. 17 (1957) 353-363 35 Jänisch, W., W. Staneczek: Primärgeschwülste des Plexus choroideus: Häufigkeit, Lokalisation und Lebensalter. Zentralbl. Allg. Pathol. Anat, 135 (1989) 235-240 30 Kemshead, j. T,, H. B. Coakham: The use. of monoclonal antibodies for the diagnosis of intracranial malignancies and the small round cell tumours of childhood, X Pathol. 141 (1983) 249-257 37 Kendall, B., 1. Reider-Grosswasser, A, Valentine: Diagnosis of masses presenting within the ventricles on computed tomography. Neuroradio­ logy 25 (1983) 11-22 Kidn, H., M . Kojiro, A, Yonekura, M. Yamamoto, Y. Sasguri: Malignant choroid plexus papilloma: an autopsy case report. Brain Nerve 30 (1978) 99-105 39 Kirn, 1C, S. H Greenblatt, M. G. Robinson: Choroid plexus carcinoma: report of a case with cytopathologic. differential diagnosis. Acta Cytol, 29 (1985) 846-849 40 Krol, G., P. Farmer, S. Stein: Carcinoma of choroid plexus in a premature infant. Case report, X Comput. Assist. Tomogr. 3 (1979) 530-532 2-1 But this review suggests that whenever possible complete resection of the tumor has to he pursued, and no further therapy is necessary. References J Allen, F. C.# }, Wisoff, ƒ. Pierce, L. Helson: Choroid plexus carcinoma: responses to chemotherapy alone in newly diagnosed young children, Abstract 18th Annual Meeting Child Neurology Society, October 12-14, 1989, San Antonio, Texas. Ann. Neurol. 20 (1989) 401 2 Aug, L, C., A. R, Taylor: An immunohistochemical study of papillary tumours in the central nervous system. Cancer 05 (1990) 2712-2719 :i Anguilar, D u J. M. M artin, ƒ. Aneiros, V. Arjona, ƒ. L Lara, E Nogales: The fine structure of choroid plexus carcinoma. Histopathology 7 (1983) 939-940 1 Arico, M., E. Raileri, G. Bossi, M . T, Giordana, F. Corbella, D, Locatelli, S. Pezzottn; Choroid plexus carcinoma: report of one case with favourable response to treatment. Med. Pediatr. Oncol. 22 (1994) 274-278 r> Ausman, J. L, C. Shrontz, /. Cltason, R. S. Knighton, H. Pak, S. Patel: Aggressive choroid plexus papilloma. Surg. Neurol. 22 (1984) 472-476 b Baskaya, M. K., S, Erekul, N. Egemen, H , Z. Gokalp, A. Sertgelik: Choroid plexus carcinoma of the lateral ventricle: report of a case in an adult. Clin. Neurol. Neurosurg. 90 (1994) 47-51 7 Blcyer, W. A„ j, Milstein, F. Bn/is: Eight drugs in one day chemotherapy for brain tumours: a new approach and rational for pre-irradiation chemotherapy. Med, Pediatr. Oncol. 11 (1983) 213-217 8 Boesel, C. P., /. P Suhan: A pigmented choroid plexus carcinoma: histochemical and ultras true Lural studies. J. Neuropathol. Exp. Neurol. 38 (1979) 177-180 9 Bohm, E., R. Strang: Choroid plexus papillomas. J. Neurosurg. 18 (1971) 493-500 10 Boyd, M. C., P Steinbok: Choroid plexus tumours: problems in diagnosis and management. J. Neurosurg. 00 (1987) 800-805 11 Broad, R. W., P B. Allen: Third ventricle choroid plexus carcinoma. Can, J. Neurol. Sci. 11 (1984) 461-465 12 Burger, P. C,f B . W. Schcithauser: Thmors of the Central Nervous System. Atlas of Tumor Pathology, 3rd series, fascicle 10. Washington, D. C.„ Armed Forces Institute of Pathology (1994) 136-142 13 Cardauns, H>: Uber ein malignes Plexuspapillom. Zentralbl. Neurochir. 17 (1957) 349-353 1,1 Carpenter, D. B„ W, /. Michelsen, A. P. Hays: Carcinoma of the choroid plexus: case report. J. Neurosurg. 50 (1982) 722-727 1H Casentini, L , L Rigobello, M . Gerosa, H. Pardatscher, G. C. Andrioli: Choroid plexus carcinoma: case report. Zentralbl. Neurochir. 40 (1979) 239-244 Y. Geerts et al Neuropediatrics 27 (1996) • il Lana-Peixoto, M. A., ƒ. Lflgos, S. IV. Silbert: Primary pigmented carcinoma of the choroid plexus: a light and electron microscopic study. J. Neurosurg. 47 (1977) 442-450 12 Laurence, K. M.: The biology of choroid plexus papilloma in infancy and childhood. Acta Neurochir. 50 (1979) 79-89 la Lewis, P.: Carcinoma of the choroid plexus. Brain 90 (1967) 177-180 ii Mannoji, H., L E. Becker: Ependymal and choroid plexus tumours: cytokcratin and GFAP expression. Cancer 61 (1988) 1377-1385 Maria, B, L , M. L. Graham, L. C. Strauss, M. D. Wliaram: Response of a recurrent choroid plexus tumour to combination chemotherapy. J. Neuro-oncoL 3 (1985) 259-262 ‘10 McCallum, S., K, Cooper, D. N, Franks: Choroid plexus carcinoma: cytologic identification of malignant cells in ascitic fluid. Acta Cytol. 32 (1988) 263-266 17 McComb, R . D., P. C. Burger: Choroid plexus carcinoma: report of a case with immunohistochemical and ultrastructural observations. Cancer 51 (1983) 470-475 48 Miettinen, M., R. Clark, I. Virianen: Intermediate filament proteins in choroid plexus and ependyma and their tumours. Am. J. Pathol 123 (1986) 231-240 41) Morrison, G., D. F. Sobel, W. M, Kelley, D. Norman: Intraventricular mass lesions. Radiology 153 (1984) 435-442 50 Namer, 7. J., M. N. Pamir, K. Benli, A Erbengi, S. Ruacan: Carcinome primitif du plexus choroïde: présentation de deux cas et revue de la littérature, Neurochirurgie 31 (1985) 429-434 SI Newbould, M. J., A M, Kelsey, J. C. Arango, ƒ, W. Ironside, J, Bird: The choroid plex is carcinomas of childhood: histopathology. Histopathology 26 (1995) 137-143 52 Packer, R. ]., G. Perilongo, D. Johnson, L. N. Sutton, G, Vezina, JR. A Zimmerman i-t al: Choroid plexus carcinoma of childhood. Cancer 69 (1992) 580-5É5 53 Pascuiü-Castroviejo, L, F. Villarejo, A. Perez-Higiteras, C. Morales, S. L Pascual-Pascuak Childhood choroid plexus neoplasms: a study of 14 cases less than 2 years. Eur. J. Pediatr. 140 (1983) 51-56 54 Pearson, A D., A W. Craft, R. H. Pearson, R> M, Kalbag, R, G. B. Evans: Four primary tumours in one child. Cancer 52 (1983) 2363-2368 Peschgens, T., C. Stollbrink-Peschgens, R. Mortens, A. Volker, A Thron, G, Heimann: Zur Therapie des Plexus-choroideus-Karzinoins im Kindosalter. Fallbeispiel und Literaturübersicht. Ivlin, Pàdiatr. 207 (1995) 52-58 tJ k ; Pierga, J.-Y, C. Kalifa, M.-J. Tevrier-Lacombe, J.~L. Habraud, J. Lemerle: Carcinoma of the choroid plexus: a pediatric experience. Med. Pediatr. Oncol. 21 (1993) 480-487 57 Rubinstein, L. J., J.-M. Brticker: Focal ependymal differentiation in choroid plexus papillomas: an immunoperoxidase study. Acta Neuro­ pathol. 53 (1981) 29-33 5H Taratuto, A. L., H. Molina, ƒ. Mtwges: Choroid plexus tumours in infancy and childhood: focal ependymal differentiation: an immunoper­ oxidase study. Acta Neuropathol. 59 (1983) 304-308 50 Valladares, I . B., R, H, Perry; R. M. Kalbag: Malignant choroid plexus papilloma with extraneural metastasis: case report. J, Neurosurg. 52 (1980)251-255 00 Vaquero, J,f J. Cabezudo, G. Leunda, R. Carrillo, ƒ. Gflrcifl Una: Primary carcinoma of the choroid plexus with metastatic dissemination within the central nervous system. Acta Neurochir 51 (1979) 105-111 01 Vazquez, E., W. S. Ball, E, C. Prenger, A Castellote, K. R. Crone: A'lagnetic resonance imaging of fourth ventricular choroid plexus neo­ plasms in childhood: a report of two cases. Pediatr. Neurosurg, 17 (1991) 48-52 Vinken, P. J,, A. C. Slooff: A case of carcinoma of the choroid plexus in a child. Zentralbl. Neurochir. 26 (1965) 313-317 03 Vraa-jenscn, G,; Papilloma of the choroid plexus with pulmonary metastases. Acta Psychiatr. Neurol. 25 (1950) 299-306 04 Wiukelmiiller , W„ P, Mehraein, E. Markakis: Zum hiologischen Verhalten des seltenen malignen Plexuspapilloms im Kindesalter: Langzeitbeobachtungen in zwei operierten Fallen. Neurochirurgia 25 (1982) 188-191 05 Yates, A. J., L. E. Becker, L. A Sachs: Brain tumours in childhood. Cliilds Brain 5 (1979) 31-39 R , Lippens, M. D. Centre of Child Oncology 921 KOC/B 80 University Hospital Nijmegen PB 9101 6500 HB Nijmegen The Netherlands