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Meningeal Carcinomatosis in Two Cats
J. Comp. Path. 2004, Vol. 131, 246–251
SHORT PAPER
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Meningeal Carcinomatosis in Two Cats C. Salvadori, C. Cantile and M. Arispici Dipartimento di Patologia Animale Profilassi e Igiene degli Alimenti, Facolta` di Medicina Veterinaria, Universita` di Pisa, Pisa, Italy
Summary Multifocal to diffuse meningeal infiltration by neoplastic epithelial cells was observed in two aged cats with neurological signs and a history of surgical ablation of the auricular pinnae because of the presence of squamous cell carcinoma. In both cats, examination of the external ear canals revealed neoplastic lesions consistent with squamous cell carcinoma, but no changes of the tympanic bullae were noted. In one cat, post-mortem examination revealed marked thickening of the dura mater and infiltration of the arachnoid layer by cytokeratin-positive, neoplastic epithelial cells. In the other cat, no macroscopic brain lesions were noted, but multifocal dissemination of neoplastic epithelial cells to the leptomeninges was observed histologically. Several pathways by which neoplastic cells can reach the meninges have been suggested and haematogenous dissemination was considered most likely in these cats. Squamous cell carcinoma is the most common cutaneous malignant neoplasm in cats and meningeal carcinomatosis can be considered a rare complication. q 2004 Elsevier Ltd. All rights reserved. Keywords: cat; meningeal carcinomatosis; squamous cell carcinoma; tumour
Meningeal carcinomatosis (MC), well known in human oncology, consists of a focal, multifocal or diffuse infiltration of the leptomeninges of the brain or spinal cord, or both, by malignant cells originating from a solid tumour (Grossman and Krabak, 1999; Miyagui et al., 2003). In human beings, the primary tumours are most frequently located in mammary, pulmonary, melanomatous or genitourinary sites, and the most common histological type is adenocarcinoma (Grossman and Krabak, 1999; Bruna et al., 2003). The incidence of MC is estimated at 5% in breast cancer, 9 –25% in lung cancer and 23% in patients with melanoma (Grossman and Krabak, 1999). These rates seem to increase with improvements in neuro-imaging diagnostic techniques and in treatment, leading to prolonged survival (Grossman and Krabak, 1999; Miyagui et al., 2003). Multifocal central nervous system (CNS) involvement is recognized by Correspondence to: C. Cantile, Dipartimento di Patologia Animale, Facolta` di Medicina Veterinaria, Viale delle Piagge 2, I-56124 Pisa, Italy. 0021–9975/$ - see front matter doi: 10.1016/j.jcpa.2004.03.003
neurological signs such as headache, signs of meningeal irritation, radicular pain, altered mental status, cranial nerve deficits, or palsy and seizures (Bruna et al., 2003; Miyagui et al., 2003). In dogs, MC has been described as responsible for external hydrocephalus (Jubb and Huxtable, 1993), and as a complication of intestinal carcinoma (Stampley et al., 1987; Vandevelde et al., 1987) and anaplastic solid adenocarcinoma of the mammary gland (Pumarola and Balasch, 1996). Descriptions of this disease in cats are lacking in the literature. Squamous cell carcinoma is the most common cutaneous malignant neoplasm in cats, with nasal planum, pinnae and eyelids as the preferential sites (Walder and Gross, 1992). Generally, squamous cell carcinoma in dogs and cats is a well-differentiated subtype with a low incidence of metastasis (Walder and Gross, 1992). A retrospective study of ear canal tumours of dogs and cats indicated that squamous cell carcinoma was characterized by particularly aggressive biological behaviour, with a propensity for local invasion, regional lymph node q 2004 Elsevier Ltd. All rights reserved.
Feline Meningeal Carcinomatosis
involvement and distant pulmonary metastasis in the late stage of the disease (London et al., 1996). In human beings, a few descriptions of squamous cell carcinoma spreading to the leptomeninges from skin cancer have been reported (Schwarze et al., 1999; Gil Contel et al., 2002; Begemann et al., 2003). In this report we describe the clinical and pathological findings in two cats with squamous cell carcinoma of the external ear, associated with severe neurological signs and meningeal carcinomatosis. Cat 1, a 14-year-old shorthaired white-coated, neutered male, had a 5-month history of progressive ataxia, left head tilt, circling to the left, and occasional episodes of hyperexcitability and aggressive behaviour. Approximately one year before the onset of neurological signs, the cat underwent bilateral total ablation of the auricular pinnae for the presence of raised ulcerated neoplastic masses in both ears, diagnosed as squamous cell carcinoma. In the early stage of the disease, neurological signs improved with corticosteroid treatment. With progression of the disease, the cat showed ataxia, falling, frequent recumbency, and anorexia. Physical examination revealed weight loss, mandibular trismus, enlargement of the right submandibular lymph node and a lobulated neoplastic mass (2 £ 3 mm) in the horizontal part of the right external ear canal. Cat 2, a 15-year-old shorthaired neutered female, showed sudden onset of disorientation, ataxia, and circling, with progression to stupor, recumbency and anorexia. A raised neoplastic mass (3 £ 4 mm) was detected in the horizontal part of the right external ear canal. Seven months previously, a bilateral total ablation of the auricular pinnae was performed for squamous cell carcinoma of the tips of the pinnae. Both cats were fed a dry commercial cat food and vaccination histories were normal. No history of toxin exposure was reported. No consistent abnormalities were found upon haematological, biochemical and urine analyses, and serological tests for feline leukaemia virus and feline immunodeficiency virus infections yielded negative results. Thoracic and skull radiography did not reveal abnormalities or metastases, and the tympanic bullae appeared normal. Both owners refused further ancillary diagnostic tests and requested euthanasia because of poor prognosis. A complete necropsy was performed on both cats. Post-mortem examination of cat 1 revealed a diffuse, moderate hepatic lipidosis with moderate loss of fat in the abdominal cavity. No neoplastic
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masses were detected in the thoracic and abdominal cavities. A round, irregular, non-pedunculated neoplastic mass (3 £ 3 mm) was detected in the right external ear canal, together with irregular enlargement and discoloration of the right submandibular lymph node, which measured 6 £ 4 mm. A diffuse thickening of the dura mater was observed in the anterior fossa and the calvarium. The meninges at the base of the skull were severely affected; they were soft and pinkish, with a fleshy appearance, but did not adhere to the periosteum (Fig. 1). Examination of the tympanic bullae and transverse sections of fixed brain disclosed no gross abnormalities, and no other gross lesions were present. Post-mortem examination of cat 2 revealed an oval, irregular and ulcerated neoplastic mass (5 £ 3 mm) in the right external ear canal. Examination of both tympanic bullae revealed no abnormalities. A diffuse yellowish discoloration of the liver, consistent with hepatic lipidosis, and bilateral multifocal fibrosis of the renal cortex were the only gross lesions detected. Samples of thickened meninges and submandibular lymph node of cat 1, samples of liver and kidneys of cat 2, and ear canal tumours and brains of both cats were fixed in phosphate-buffered 4% formalin solution and processed by routine methods for histological examination. Sections (4 mm) were stained with haematoxylin and eosin (HE), and Gomori’s trichrome and reticulin stains. The avidin-biotin peroxidase complex (ABC) immunohistochemical technique was carried out to establish the immunophenotype of the neoplastic cells, with monoclonal antibodies against cytokeratin (clone MNF116; DakoCytomation, Glostrup, Denmark) and vimentin (Novocastra Laboratories, Newcastle-upon-Tyne, UK), diluted 1 in 800 and 1 in 50, respectively. In both cases the morphological diagnosis of the ear masses was squamous cell carcinoma with different degrees of differentiation, according to the WHO classification (Goldschmidt et al., 1998). In cat 1, the ear canal tumour was well-differentiated, with numerous keratin pearls. Metastasis to the right submandibular lymph node was also observed. In cat 2, the tumour was poorly differentiated, with nests of epithelial cells and occasionally partly keratinized cells. Histological examination of liver and kidney samples of cat 2 revealed fatty accumulation in the hepatocytes, chronic interstitial nephritis and mild membranous glomerulonephritis. In cat 1 the dura mater showed multifocal infiltration by islands and nests of large, round
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Fig. 1. Meningeal carcinomatosis in cat 1. Base of the skull after removal of the brain: there is marked thickening and fleshy appearance of the dura mater, especially evident in the anterior fossa (arrowheads).
neoplastic cells with distinct cell borders and intercellular bridges, accompanied by fibrosis and diffuse hyperplasia of the meningothelial cells. Neoplastic cells had large, round nuclei with clumped chromatin and prominent nucleoli. Mitoses were present with moderate degrees of anisocytosis and anisokaryosis. Keratinization of
individual cells and small keratin pearls were occasionally observed. Neoplastic cells were strongly labelled by anti-cytokeratin antibody (Fig. 2) but were negative with anti-vimentin antibody. Microscopical examination of cerebral cortical areas revealed multifocal spreading of neoplastic squamous cells to the arachnoid
Fig. 2. Meningeal carcinomatosis in cat 1. The dura mater is infiltrated by islands of cytokeratin-positive malignant squamous cells surrounded by marked meningothelial cell hyperplasia. ABC, haematoxylin counterstain. £ 320.
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Fig. 3. Meningeal carcinomatosis in cat 1. Cerebral cortex of frontal lobe: groups of neoplastic epithelial cells arranged in pseudoglandular structures in the arachnoid and subarachnoid space (arrows). HE. £ 400.
and subarachnoid space of frontal, parietal and temporal lobes. Frequently, neoplastic cells formed pseudoglandular structures of different size with partial individual cell keratinization (Fig. 3). Moderate and diffuse gliosis and occasional accumulation of lipofuscin in neurons, which were detected in cerebrocortical and brain stem areas, were interpreted as age-related changes. In cat 2, diffuse infiltration of neoplastic epithelial cells with phenotypic features similar to those in cat 1 extended mainly to the subarachnoid space and pial surface of the ventral aspect of the brain stem, piriform lobes, cerebellar peduncles, and oculomotor and trigeminal nerves. Keratinization was consistently absent in these areas. Occasionally, neoplastic infiltration extended to the subpial brain parenchyma without clear relationship to the penetrating vessels (Fig. 4). Oedema of the subpial white matter was also observed in these areas. Neurological signs such as ataxia, circling, and altered mental status, observed in both cats, resulted from diffuse meningeal infiltration by neoplastic epithelial cells, most likely originating from squamous cell carcinoma of the external ear. Infiltrating neoplastic cells had the same phenotypic features of primary carcinoma as those observed in the external ear canals, and were characterized by enlargement and immunolabelling for cytokeratin. Neoplastic infiltration involved both leptomeninges and dura mater,
with hyperplasia of meningothelial cells. The meningothelial reaction and fibrosis observed in cat 1 can be considered due to neoplastic dissemination, as described in human MC (Miyagui et al., 2003). The neoplastic masses in the external ear canals in both cases appeared to reflect recurrence of squamous cell carcinoma of the auricular pinnae. Indeed, squamous cell carcinoma is regarded as the most locally aggressive tumour of the ear in dogs and cats (London et al., 1996). The pathways by which neoplastic cells reach the meninges are unclear and several possibilities have been suggested (Grossman and Krabak, 1999; Miyagui et al., 2003). One hypothesis is based on possible direct extension to the leptomeninges from contiguous CNS primary tumours such as ependymomas, pineoblastomas and medulloblastomas, which, developing in areas adjacent to the ventricular system or the subarachnoid space, can frequently exfoliate into the cerebrospinal fluid. In veterinary neuro-oncology, the term MC has been used in cases of dissemination along the neuraxis by primary canine choroid plexus carcinoma (Patnaik et al., 1980; Lipsitz et al., 1999), but this designation in man is preferably restricted to extraneural solid tumour metastases. Metastatic intraparenchymal brain tumours can reach the meninges by direct extension (Grossman and Moynihan, 1991). A second hypothesis suggests that the infiltration of the meninges is related to arachnoid vessels or
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Fig. 4. Meningeal carcinomatosis in cat 2. Cerebellar peduncle and subarachnoid space: diffuse spreading of neoplastic epithelial cells and subpial intraparenchymal metastasis (arrow). HE. £ 125.
choroid plexus metastases following haematogenous dissemination of the tumour, and this has been consistently reported in lymphoproliferative disorders in human beings (Lantos et al., 1997; Grossman and Krabak, 1999). In feline lymphoma, occasional dissemination of neoplastic lymphocytes can be detected in the subarachnoid space of brain or spinal cord, or both (Summers et al., 1995). Seeding of the leptomeninges, followed by widespread dissemination in the subarachnoid space, has frequently been reported in human patients with melanoma, lung cancer and breast cancer (Grossman and Krabak, 1999), but intraparenchymal brain neoplastic masses are not usually observed. The cellular and molecular mechanisms by which neoplastic cells invade the meninges and proliferate are complex, and haematogenous dissemination may be enhanced by the expression of specific organ endothelial adhesion molecules and cytokines. It has also been suggested that subclinical bacterial infections that are prone to cause meningitis facilitate the extravasation of neoplastic cells into the subarachnoid space, as they are a main cause of endothelial cell activation (Mareel et al., 1998). According to a third hypothesis, neoplastic cells may reach the subarachnoid space by direct extension along peripheral nerves. Perineural invasion is suspected in cases of squamous cell and nasopharyngeal carcinoma in human beings,
and wrapping of tumour cells around the peripheral nerves with involvement of the perineurium has been demonstrated (Schwarze et al., 1999; Wang and Wang, 2000; Begemann et al., 2003). In one study of cats with carcinoma of the middle ear, the most frequent neurological signs were facial nerve paralysis, peripheral vestibular signs and Horner’s syndrome (London et al., 1996). Since in both our cats middle ear structures were not apparently involved, a direct extension of the tumour from the external ear to the meninges can probably be excluded. A fourth hypothesis implies that neoplastic cells are seeded during surgical treatment of intraparenchymal tumours (Grossman and Krabak, 1999; Begemann et al., 2003; Miyagui et al., 2003). Regardless of the different routes, once the neoplastic cells reach the subarachnoid space, they can be disseminated throughout the nervous system by cerebrospinal fluid flow. Nurtured by this fluid, the neoplastic cells proliferate rapidly (Mareel et al., 1998; Grossman and Krabak, 1999). Haematogenous dissemination seems most likely in our cats, thereby explaining the coexistence of both leptomeningeal and pachymeningeal involvement. The occasional neoplastic cell nests observed in the subpial neuroparenchyma can be regarded as focal extensions of the tumour from the meninges. Indeed, the consistent absence of metastatic foci in the neuroparenchyma
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indicated that the meninges were the primary site of metastasis. The increased severity of lesions on the ventral surface of the brain probably reflected the slow flow of cerebrospinal fluid and the effect of gravity in that area (Grossman and Krabak, 1999). In human patients with presumptive MC, examination of the cerebrospinal fluid usually yields no specific findings other than the presence of elevated pressure, low glucose and high protein concentrations. Often, the cytological detection of neoplastic cells confirms the diagnosis (Grossman and Krabak, 1999; Miyagui et al., 2003). In canine MC, cerebrospinal fluid cytology has proved a useful diagnostic tool in disclosing the presence of neoplastic epithelial-like cells (Vandevelde et al., 1987; Pumarola and Balasch, 1996). In conclusion, MC can be regarded as a rare complication in cats with histories of squamous cell carcinoma (not necessarily restricted to the structures of the external ear) and onset of neurological signs consistent with multifocal involvement of the CNS.
References Begemann, M., Rosenblum, M. K., Loh, J., Kraus, D. and Raizer, J. J. (2003). Leptomeningeal metastases from recurrent squamous cell cancer of the skin. Journal of Neuro-oncology, 63, 295–298. Bruna, J., Rojas-Marcos, I., Martı´nez-Yelamos, S., Catala`, I., Vidaller, A., Gala`n, C., Krupinski, J. and Rubio, F. (2003). Meningeal carcinomatosis as the first manifestation of a transitional cell carcinoma of the bladder. Journal of Neuro-oncology, 63, 63–67. Gil Contel, M. C., Girons Bonnell, J., Martinez Egido, I., Bruch Andreu, G., Jimenez Montoya, R. and Dicenta Sousa, M. (2002). Advanced squamous carcinoma of external ear canal. Anales Otorrinolaringologicos IberoAmericanos, 29, 605 –611. Goldschmidt, M. H., Dunstan, R. W., Stannard, A. A., Von Tscharner, C., Walder, E. J. and Yager, J. A. (1998). Histological Classification of Epithelial and Melanocytic Tumors of the Skin of Domestic Animals, Armed Forces Institute of Pathology; American Registry of Pathology; The World Health Organization Collaborating Center for Worldwide Reference on Comparative Oncology. Second series, Vol. III, Washington, D.C., pp. 20– 21. Grossman, S. A. and Krabak, M. J. (1999). Leptomeningeal carcinomatosis. Cancer Treatment Reviews, 25, 103 –119. Grossman, S. A. and Moynihan, T. J. (1991). Neoplastic meningitis. Neurologic Clinics, 9, 843 –856. Jubb, K. V. F. and Huxtable, C. R. (1993). The nervous system. In: Pathology of Domestic Animals, Vol. 1,
4th Edit., K. V. F. Jubb, P. C. Kennedy and N. Palmer, Eds, Academic Press, San Diego, p. 278. Lantos, P. L., Vanderberg, S. R. and Kleihues, P. (1997). Tumours of the nervous system. In: Greenfield’s Neuropathology, Vol. 1, 6th Edit., D. I. Graham and P. L. Lantos, Eds, Arnold, London, pp. 583– 879. Lipsitz, D., Levitski, R. E. and Chauvet, A. E. (1999). Magnetic resonance imaging of a choroid plexus carcinoma and meningeal carcinomatosis in a dog. Veterinary Radiology and Ultrasound, 40, 246– 250. London, C. A., Dubielzig, R. R., Vail, D. M., Ogilvie, G. K., Hahn, K. A., Brewer, W. B., Hammer, A. S., O’Keefe, D. A., Chun, R., McEntee, M. C., McCaw, D. L., Fox, L. E., Norris, A. M. and Klausner, J. S. (1996). Evaluation of dogs and cats with tumors of the ear canal: 145 cases (1978 –1992). Journal of the American Veterinary Medical Association, 208, 1413 –1418. Mareel, M., Leroy, A. and Bracke, M. (1998). Cellular and molecular mechanisms of metastasis as applied to carcinomatous meningitis. Journal of Neuro-oncology, 38, 97–102. Miyagui, T., Luchemback, L., Maia do Canto Teixeira, G. H. and Martins Lopes de Azevedo, K. (2003). Meningeal carcinomatosis as the initial manifestation of a gallbladder adenocarcinoma associated with a Krukenberg tumor. Revista do Hospital das Clı´nicas, 58, 169–172. Patnaik, A. K., Erlandson, R. A., Lieberman, P. H., Fenner, W. R. and Prata, R. G. (1980). Choroid plexus carcinoma with meningeal carcinomatosis in a dog. Veterinary Pathology, 17, 381–385. Pumarola, M. and Balasch, M. (1996). Meningeal carcinomatosis in a dog. Veterinary Record, 138, 523–524. Schwarze, H. P., Loche, F., Gorguet, M. C., Kuchta, J. and Bazex, J. (1999). Invasive cutaneous squamous cell carcinoma associated with actinic keratosis. Dermatologic Surgery, 25, 587– 589. Stampley, A., Swayne, D. and Prasse, K. (1987). Meningeal carcinomatosis secondary to a colonic signet-ring cell carcinoma in a dog. Journal of the American Animal Hospital Association, 23, 655–658. Summers, B. A., Cummings, J. F. and de Lahunta, A. (1995). Veterinary Neuropathology, Mosby-Year Book, St Louis, Missouri, p. 394. Vandevelde, M., Richard, A. and Fankhauser, R. (1987). Liquoruntersuchungen bei neurologisch kranken Hunden und Katzen. Schweizer Archiv fu¨r Tierheilkunde, 129, 443 –456. Walder, E. J. and Gross, T. L. (1992). Neoplastic disease of the skin. In: Veterinary Dermatopathology, T. L. Gross, P. J. Ihrke and E. J. Walder, Eds, Mosby-Year Book, St Louis, Missouri, pp. 336–338. Wang, C. J. and Wang, C. Y. (2000). Nasopharyngeal carcinoma with leptomeningeal dissemination: case report. Chang Gung Medical Journal, 23, 118 –122.
Received; December 15th; 2003 Accepted; March 8th; 2004
SHORT PAPER
www.elsevier.com/locate/jcpa
Meningeal Carcinomatosis in Two Cats C. Salvadori, C. Cantile and M. Arispici Dipartimento di Patologia Animale Profilassi e Igiene degli Alimenti, Facolta` di Medicina Veterinaria, Universita` di Pisa, Pisa, Italy
Summary Multifocal to diffuse meningeal infiltration by neoplastic epithelial cells was observed in two aged cats with neurological signs and a history of surgical ablation of the auricular pinnae because of the presence of squamous cell carcinoma. In both cats, examination of the external ear canals revealed neoplastic lesions consistent with squamous cell carcinoma, but no changes of the tympanic bullae were noted. In one cat, post-mortem examination revealed marked thickening of the dura mater and infiltration of the arachnoid layer by cytokeratin-positive, neoplastic epithelial cells. In the other cat, no macroscopic brain lesions were noted, but multifocal dissemination of neoplastic epithelial cells to the leptomeninges was observed histologically. Several pathways by which neoplastic cells can reach the meninges have been suggested and haematogenous dissemination was considered most likely in these cats. Squamous cell carcinoma is the most common cutaneous malignant neoplasm in cats and meningeal carcinomatosis can be considered a rare complication. q 2004 Elsevier Ltd. All rights reserved. Keywords: cat; meningeal carcinomatosis; squamous cell carcinoma; tumour
Meningeal carcinomatosis (MC), well known in human oncology, consists of a focal, multifocal or diffuse infiltration of the leptomeninges of the brain or spinal cord, or both, by malignant cells originating from a solid tumour (Grossman and Krabak, 1999; Miyagui et al., 2003). In human beings, the primary tumours are most frequently located in mammary, pulmonary, melanomatous or genitourinary sites, and the most common histological type is adenocarcinoma (Grossman and Krabak, 1999; Bruna et al., 2003). The incidence of MC is estimated at 5% in breast cancer, 9 –25% in lung cancer and 23% in patients with melanoma (Grossman and Krabak, 1999). These rates seem to increase with improvements in neuro-imaging diagnostic techniques and in treatment, leading to prolonged survival (Grossman and Krabak, 1999; Miyagui et al., 2003). Multifocal central nervous system (CNS) involvement is recognized by Correspondence to: C. Cantile, Dipartimento di Patologia Animale, Facolta` di Medicina Veterinaria, Viale delle Piagge 2, I-56124 Pisa, Italy. 0021–9975/$ - see front matter doi: 10.1016/j.jcpa.2004.03.003
neurological signs such as headache, signs of meningeal irritation, radicular pain, altered mental status, cranial nerve deficits, or palsy and seizures (Bruna et al., 2003; Miyagui et al., 2003). In dogs, MC has been described as responsible for external hydrocephalus (Jubb and Huxtable, 1993), and as a complication of intestinal carcinoma (Stampley et al., 1987; Vandevelde et al., 1987) and anaplastic solid adenocarcinoma of the mammary gland (Pumarola and Balasch, 1996). Descriptions of this disease in cats are lacking in the literature. Squamous cell carcinoma is the most common cutaneous malignant neoplasm in cats, with nasal planum, pinnae and eyelids as the preferential sites (Walder and Gross, 1992). Generally, squamous cell carcinoma in dogs and cats is a well-differentiated subtype with a low incidence of metastasis (Walder and Gross, 1992). A retrospective study of ear canal tumours of dogs and cats indicated that squamous cell carcinoma was characterized by particularly aggressive biological behaviour, with a propensity for local invasion, regional lymph node q 2004 Elsevier Ltd. All rights reserved.
Feline Meningeal Carcinomatosis
involvement and distant pulmonary metastasis in the late stage of the disease (London et al., 1996). In human beings, a few descriptions of squamous cell carcinoma spreading to the leptomeninges from skin cancer have been reported (Schwarze et al., 1999; Gil Contel et al., 2002; Begemann et al., 2003). In this report we describe the clinical and pathological findings in two cats with squamous cell carcinoma of the external ear, associated with severe neurological signs and meningeal carcinomatosis. Cat 1, a 14-year-old shorthaired white-coated, neutered male, had a 5-month history of progressive ataxia, left head tilt, circling to the left, and occasional episodes of hyperexcitability and aggressive behaviour. Approximately one year before the onset of neurological signs, the cat underwent bilateral total ablation of the auricular pinnae for the presence of raised ulcerated neoplastic masses in both ears, diagnosed as squamous cell carcinoma. In the early stage of the disease, neurological signs improved with corticosteroid treatment. With progression of the disease, the cat showed ataxia, falling, frequent recumbency, and anorexia. Physical examination revealed weight loss, mandibular trismus, enlargement of the right submandibular lymph node and a lobulated neoplastic mass (2 £ 3 mm) in the horizontal part of the right external ear canal. Cat 2, a 15-year-old shorthaired neutered female, showed sudden onset of disorientation, ataxia, and circling, with progression to stupor, recumbency and anorexia. A raised neoplastic mass (3 £ 4 mm) was detected in the horizontal part of the right external ear canal. Seven months previously, a bilateral total ablation of the auricular pinnae was performed for squamous cell carcinoma of the tips of the pinnae. Both cats were fed a dry commercial cat food and vaccination histories were normal. No history of toxin exposure was reported. No consistent abnormalities were found upon haematological, biochemical and urine analyses, and serological tests for feline leukaemia virus and feline immunodeficiency virus infections yielded negative results. Thoracic and skull radiography did not reveal abnormalities or metastases, and the tympanic bullae appeared normal. Both owners refused further ancillary diagnostic tests and requested euthanasia because of poor prognosis. A complete necropsy was performed on both cats. Post-mortem examination of cat 1 revealed a diffuse, moderate hepatic lipidosis with moderate loss of fat in the abdominal cavity. No neoplastic
247
masses were detected in the thoracic and abdominal cavities. A round, irregular, non-pedunculated neoplastic mass (3 £ 3 mm) was detected in the right external ear canal, together with irregular enlargement and discoloration of the right submandibular lymph node, which measured 6 £ 4 mm. A diffuse thickening of the dura mater was observed in the anterior fossa and the calvarium. The meninges at the base of the skull were severely affected; they were soft and pinkish, with a fleshy appearance, but did not adhere to the periosteum (Fig. 1). Examination of the tympanic bullae and transverse sections of fixed brain disclosed no gross abnormalities, and no other gross lesions were present. Post-mortem examination of cat 2 revealed an oval, irregular and ulcerated neoplastic mass (5 £ 3 mm) in the right external ear canal. Examination of both tympanic bullae revealed no abnormalities. A diffuse yellowish discoloration of the liver, consistent with hepatic lipidosis, and bilateral multifocal fibrosis of the renal cortex were the only gross lesions detected. Samples of thickened meninges and submandibular lymph node of cat 1, samples of liver and kidneys of cat 2, and ear canal tumours and brains of both cats were fixed in phosphate-buffered 4% formalin solution and processed by routine methods for histological examination. Sections (4 mm) were stained with haematoxylin and eosin (HE), and Gomori’s trichrome and reticulin stains. The avidin-biotin peroxidase complex (ABC) immunohistochemical technique was carried out to establish the immunophenotype of the neoplastic cells, with monoclonal antibodies against cytokeratin (clone MNF116; DakoCytomation, Glostrup, Denmark) and vimentin (Novocastra Laboratories, Newcastle-upon-Tyne, UK), diluted 1 in 800 and 1 in 50, respectively. In both cases the morphological diagnosis of the ear masses was squamous cell carcinoma with different degrees of differentiation, according to the WHO classification (Goldschmidt et al., 1998). In cat 1, the ear canal tumour was well-differentiated, with numerous keratin pearls. Metastasis to the right submandibular lymph node was also observed. In cat 2, the tumour was poorly differentiated, with nests of epithelial cells and occasionally partly keratinized cells. Histological examination of liver and kidney samples of cat 2 revealed fatty accumulation in the hepatocytes, chronic interstitial nephritis and mild membranous glomerulonephritis. In cat 1 the dura mater showed multifocal infiltration by islands and nests of large, round
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Fig. 1. Meningeal carcinomatosis in cat 1. Base of the skull after removal of the brain: there is marked thickening and fleshy appearance of the dura mater, especially evident in the anterior fossa (arrowheads).
neoplastic cells with distinct cell borders and intercellular bridges, accompanied by fibrosis and diffuse hyperplasia of the meningothelial cells. Neoplastic cells had large, round nuclei with clumped chromatin and prominent nucleoli. Mitoses were present with moderate degrees of anisocytosis and anisokaryosis. Keratinization of
individual cells and small keratin pearls were occasionally observed. Neoplastic cells were strongly labelled by anti-cytokeratin antibody (Fig. 2) but were negative with anti-vimentin antibody. Microscopical examination of cerebral cortical areas revealed multifocal spreading of neoplastic squamous cells to the arachnoid
Fig. 2. Meningeal carcinomatosis in cat 1. The dura mater is infiltrated by islands of cytokeratin-positive malignant squamous cells surrounded by marked meningothelial cell hyperplasia. ABC, haematoxylin counterstain. £ 320.
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249
Fig. 3. Meningeal carcinomatosis in cat 1. Cerebral cortex of frontal lobe: groups of neoplastic epithelial cells arranged in pseudoglandular structures in the arachnoid and subarachnoid space (arrows). HE. £ 400.
and subarachnoid space of frontal, parietal and temporal lobes. Frequently, neoplastic cells formed pseudoglandular structures of different size with partial individual cell keratinization (Fig. 3). Moderate and diffuse gliosis and occasional accumulation of lipofuscin in neurons, which were detected in cerebrocortical and brain stem areas, were interpreted as age-related changes. In cat 2, diffuse infiltration of neoplastic epithelial cells with phenotypic features similar to those in cat 1 extended mainly to the subarachnoid space and pial surface of the ventral aspect of the brain stem, piriform lobes, cerebellar peduncles, and oculomotor and trigeminal nerves. Keratinization was consistently absent in these areas. Occasionally, neoplastic infiltration extended to the subpial brain parenchyma without clear relationship to the penetrating vessels (Fig. 4). Oedema of the subpial white matter was also observed in these areas. Neurological signs such as ataxia, circling, and altered mental status, observed in both cats, resulted from diffuse meningeal infiltration by neoplastic epithelial cells, most likely originating from squamous cell carcinoma of the external ear. Infiltrating neoplastic cells had the same phenotypic features of primary carcinoma as those observed in the external ear canals, and were characterized by enlargement and immunolabelling for cytokeratin. Neoplastic infiltration involved both leptomeninges and dura mater,
with hyperplasia of meningothelial cells. The meningothelial reaction and fibrosis observed in cat 1 can be considered due to neoplastic dissemination, as described in human MC (Miyagui et al., 2003). The neoplastic masses in the external ear canals in both cases appeared to reflect recurrence of squamous cell carcinoma of the auricular pinnae. Indeed, squamous cell carcinoma is regarded as the most locally aggressive tumour of the ear in dogs and cats (London et al., 1996). The pathways by which neoplastic cells reach the meninges are unclear and several possibilities have been suggested (Grossman and Krabak, 1999; Miyagui et al., 2003). One hypothesis is based on possible direct extension to the leptomeninges from contiguous CNS primary tumours such as ependymomas, pineoblastomas and medulloblastomas, which, developing in areas adjacent to the ventricular system or the subarachnoid space, can frequently exfoliate into the cerebrospinal fluid. In veterinary neuro-oncology, the term MC has been used in cases of dissemination along the neuraxis by primary canine choroid plexus carcinoma (Patnaik et al., 1980; Lipsitz et al., 1999), but this designation in man is preferably restricted to extraneural solid tumour metastases. Metastatic intraparenchymal brain tumours can reach the meninges by direct extension (Grossman and Moynihan, 1991). A second hypothesis suggests that the infiltration of the meninges is related to arachnoid vessels or
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Fig. 4. Meningeal carcinomatosis in cat 2. Cerebellar peduncle and subarachnoid space: diffuse spreading of neoplastic epithelial cells and subpial intraparenchymal metastasis (arrow). HE. £ 125.
choroid plexus metastases following haematogenous dissemination of the tumour, and this has been consistently reported in lymphoproliferative disorders in human beings (Lantos et al., 1997; Grossman and Krabak, 1999). In feline lymphoma, occasional dissemination of neoplastic lymphocytes can be detected in the subarachnoid space of brain or spinal cord, or both (Summers et al., 1995). Seeding of the leptomeninges, followed by widespread dissemination in the subarachnoid space, has frequently been reported in human patients with melanoma, lung cancer and breast cancer (Grossman and Krabak, 1999), but intraparenchymal brain neoplastic masses are not usually observed. The cellular and molecular mechanisms by which neoplastic cells invade the meninges and proliferate are complex, and haematogenous dissemination may be enhanced by the expression of specific organ endothelial adhesion molecules and cytokines. It has also been suggested that subclinical bacterial infections that are prone to cause meningitis facilitate the extravasation of neoplastic cells into the subarachnoid space, as they are a main cause of endothelial cell activation (Mareel et al., 1998). According to a third hypothesis, neoplastic cells may reach the subarachnoid space by direct extension along peripheral nerves. Perineural invasion is suspected in cases of squamous cell and nasopharyngeal carcinoma in human beings,
and wrapping of tumour cells around the peripheral nerves with involvement of the perineurium has been demonstrated (Schwarze et al., 1999; Wang and Wang, 2000; Begemann et al., 2003). In one study of cats with carcinoma of the middle ear, the most frequent neurological signs were facial nerve paralysis, peripheral vestibular signs and Horner’s syndrome (London et al., 1996). Since in both our cats middle ear structures were not apparently involved, a direct extension of the tumour from the external ear to the meninges can probably be excluded. A fourth hypothesis implies that neoplastic cells are seeded during surgical treatment of intraparenchymal tumours (Grossman and Krabak, 1999; Begemann et al., 2003; Miyagui et al., 2003). Regardless of the different routes, once the neoplastic cells reach the subarachnoid space, they can be disseminated throughout the nervous system by cerebrospinal fluid flow. Nurtured by this fluid, the neoplastic cells proliferate rapidly (Mareel et al., 1998; Grossman and Krabak, 1999). Haematogenous dissemination seems most likely in our cats, thereby explaining the coexistence of both leptomeningeal and pachymeningeal involvement. The occasional neoplastic cell nests observed in the subpial neuroparenchyma can be regarded as focal extensions of the tumour from the meninges. Indeed, the consistent absence of metastatic foci in the neuroparenchyma
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indicated that the meninges were the primary site of metastasis. The increased severity of lesions on the ventral surface of the brain probably reflected the slow flow of cerebrospinal fluid and the effect of gravity in that area (Grossman and Krabak, 1999). In human patients with presumptive MC, examination of the cerebrospinal fluid usually yields no specific findings other than the presence of elevated pressure, low glucose and high protein concentrations. Often, the cytological detection of neoplastic cells confirms the diagnosis (Grossman and Krabak, 1999; Miyagui et al., 2003). In canine MC, cerebrospinal fluid cytology has proved a useful diagnostic tool in disclosing the presence of neoplastic epithelial-like cells (Vandevelde et al., 1987; Pumarola and Balasch, 1996). In conclusion, MC can be regarded as a rare complication in cats with histories of squamous cell carcinoma (not necessarily restricted to the structures of the external ear) and onset of neurological signs consistent with multifocal involvement of the CNS.
References Begemann, M., Rosenblum, M. K., Loh, J., Kraus, D. and Raizer, J. J. (2003). Leptomeningeal metastases from recurrent squamous cell cancer of the skin. Journal of Neuro-oncology, 63, 295–298. Bruna, J., Rojas-Marcos, I., Martı´nez-Yelamos, S., Catala`, I., Vidaller, A., Gala`n, C., Krupinski, J. and Rubio, F. (2003). Meningeal carcinomatosis as the first manifestation of a transitional cell carcinoma of the bladder. Journal of Neuro-oncology, 63, 63–67. Gil Contel, M. C., Girons Bonnell, J., Martinez Egido, I., Bruch Andreu, G., Jimenez Montoya, R. and Dicenta Sousa, M. (2002). Advanced squamous carcinoma of external ear canal. Anales Otorrinolaringologicos IberoAmericanos, 29, 605 –611. Goldschmidt, M. H., Dunstan, R. W., Stannard, A. A., Von Tscharner, C., Walder, E. J. and Yager, J. A. (1998). Histological Classification of Epithelial and Melanocytic Tumors of the Skin of Domestic Animals, Armed Forces Institute of Pathology; American Registry of Pathology; The World Health Organization Collaborating Center for Worldwide Reference on Comparative Oncology. Second series, Vol. III, Washington, D.C., pp. 20– 21. Grossman, S. A. and Krabak, M. J. (1999). Leptomeningeal carcinomatosis. Cancer Treatment Reviews, 25, 103 –119. Grossman, S. A. and Moynihan, T. J. (1991). Neoplastic meningitis. Neurologic Clinics, 9, 843 –856. Jubb, K. V. F. and Huxtable, C. R. (1993). The nervous system. In: Pathology of Domestic Animals, Vol. 1,
4th Edit., K. V. F. Jubb, P. C. Kennedy and N. Palmer, Eds, Academic Press, San Diego, p. 278. Lantos, P. L., Vanderberg, S. R. and Kleihues, P. (1997). Tumours of the nervous system. In: Greenfield’s Neuropathology, Vol. 1, 6th Edit., D. I. Graham and P. L. Lantos, Eds, Arnold, London, pp. 583– 879. Lipsitz, D., Levitski, R. E. and Chauvet, A. E. (1999). Magnetic resonance imaging of a choroid plexus carcinoma and meningeal carcinomatosis in a dog. Veterinary Radiology and Ultrasound, 40, 246– 250. London, C. A., Dubielzig, R. R., Vail, D. M., Ogilvie, G. K., Hahn, K. A., Brewer, W. B., Hammer, A. S., O’Keefe, D. A., Chun, R., McEntee, M. C., McCaw, D. L., Fox, L. E., Norris, A. M. and Klausner, J. S. (1996). Evaluation of dogs and cats with tumors of the ear canal: 145 cases (1978 –1992). Journal of the American Veterinary Medical Association, 208, 1413 –1418. Mareel, M., Leroy, A. and Bracke, M. (1998). Cellular and molecular mechanisms of metastasis as applied to carcinomatous meningitis. Journal of Neuro-oncology, 38, 97–102. Miyagui, T., Luchemback, L., Maia do Canto Teixeira, G. H. and Martins Lopes de Azevedo, K. (2003). Meningeal carcinomatosis as the initial manifestation of a gallbladder adenocarcinoma associated with a Krukenberg tumor. Revista do Hospital das Clı´nicas, 58, 169–172. Patnaik, A. K., Erlandson, R. A., Lieberman, P. H., Fenner, W. R. and Prata, R. G. (1980). Choroid plexus carcinoma with meningeal carcinomatosis in a dog. Veterinary Pathology, 17, 381–385. Pumarola, M. and Balasch, M. (1996). Meningeal carcinomatosis in a dog. Veterinary Record, 138, 523–524. Schwarze, H. P., Loche, F., Gorguet, M. C., Kuchta, J. and Bazex, J. (1999). Invasive cutaneous squamous cell carcinoma associated with actinic keratosis. Dermatologic Surgery, 25, 587– 589. Stampley, A., Swayne, D. and Prasse, K. (1987). Meningeal carcinomatosis secondary to a colonic signet-ring cell carcinoma in a dog. Journal of the American Animal Hospital Association, 23, 655–658. Summers, B. A., Cummings, J. F. and de Lahunta, A. (1995). Veterinary Neuropathology, Mosby-Year Book, St Louis, Missouri, p. 394. Vandevelde, M., Richard, A. and Fankhauser, R. (1987). Liquoruntersuchungen bei neurologisch kranken Hunden und Katzen. Schweizer Archiv fu¨r Tierheilkunde, 129, 443 –456. Walder, E. J. and Gross, T. L. (1992). Neoplastic disease of the skin. In: Veterinary Dermatopathology, T. L. Gross, P. J. Ihrke and E. J. Walder, Eds, Mosby-Year Book, St Louis, Missouri, pp. 336–338. Wang, C. J. and Wang, C. Y. (2000). Nasopharyngeal carcinoma with leptomeningeal dissemination: case report. Chang Gung Medical Journal, 23, 118 –122.
Received; December 15th; 2003 Accepted; March 8th; 2004