CENTRAL NERVOUS SYSTEM MELANOMA
ATKl NSON
MELANOMA OF THE CENTRAL NERVOUS SYSTEM LEIGH ATKINSON Princess Alexandra Hospital, Brisbane The neurological manifestations o f melanoma are analysed i n this review of 1,500 patients in the Queensland Melanoma Project from 1963 t o 1969. Three hundred and f i f t y patients have died, and 113 w e r e recognized as having central nervous system metastases. The natural history of these metastases was examined, together w i t h the results of a limited number o f autopsies. The results of treatment are discussed.
THE increasing awareness of the natural history of melanoma has resulted in the very early presentation of disseminated melanoma t o the neurologist. The increasingly obvious benefits of early treatment (Shaw e l a/i, 1977) of the primary tumour, however, may be causing inflated optimism with respect t o the management of cerebral metastases. Papers referring t o the treatment of cerebral melanoma often speak of mean improvements t o life expectancy of three t o six months (Beresford, 1969; Pennington and Milton, 1975), and one might be excused for thinking that this was really a significant breakthrough for the patient. More often, the patient is hospitalized, becomes invalid, and the quality of life is poor. Admittedly melanoma is unpredictable. Many clinicians may be spurred on by the occasional patient w h o survives many years following treatment. We must ask ourselves the question: are w e entitled t o chase the occasional unpredictable success at the expense of extra suffering and distress for the unsuccessful majority? One thousand five hundred cases in the Queensland Melanoma Project were collected between 1963 and 1969 at the Princess Alexandra Hospital; these were examined, and the results were compared with the experience in other units.
RESULTS This series was reviewed in 1977, t o assess the effect of melanoma on the central nervous system. Three hundred and fifty patients had died. Records showed that 113 patients had clinical evidence of cerebral metastases. Of these, 69 Reprints: Dr L. Atkinson, "Alexandra", 201 Wickham Terrace, Brisbane, Old. 4000.
14
were males and 44 were females, with a mean age of 6 3 . 5 years. The mean time between diagnosis of the primary lesion and death was 35 months. The mean time between the development of neurological symptoms and death was four months. Twenty-nine patients with neurological symptoms came t o autopsy. Eighteen were males, 11 were females. Twenty-six had multiple metastases and three had single metastases. Twenty-four patients in this series had other systems of the body involved. I n this select group, symptoms existed for six months, while the primary melanoma had been diagnosed 28 months before. Associated neurological conditions were examined. Forty-four patients with a mean age of 7 2 . 5 years were reported t o have died from "strokes". Six patients had Parkinson's disease, t w o had motor neurone disease, one had peripheral neuropathy, while six had paraplegia due t o spinal metastases. T w o patients had associated, confirmed cerebral gliomas. Twenty-one patients in the series came t o craniotomy. Their mean age was 4 3 . 5 years. The mean life expectancy following surgery was 5 . 6 months, the longest period being 27 months. The mean time from the discovery of primary melanoma t o death in this series was 28.5 months.
DISCUSSION I n the natural history of melanoma, cerebral involvement is a terminal event. One hundred and thirteen of our 350 patients (32%) w h o died had cerebral symptoms before death. The most common symptoms were headaches, personality changes, epilepsy, nausea, vomiting, and visual deterioration. Common signs included weight loss, papilloedema, hemiparesis, and ataxia. A AUST. N.Z. J. SURG., VOL. 48-No.
1, FEBRUARY,1978
CENTRAL NERVOUS SYSTEM MELANOMA
further 44 patients died from "stroke", and sometimes the sudden haemorrhage into a cerebral secondary melanoma can mimic cerebrovascular disease. Some of these 44 patients may well have had cerebral metastases. The mean time from the diagnosis of the primary lesion to death was 35 months. In 113 cases the mean time from the onset of cerebral symptoms to death was four months. This figure compares with Beresford's mean of 2.6 months (1969), the figure of 3 . 5 months of Gottlieb et alii (1972), while Einhorn eta/;; (1974) found a mean survival of 2.75 months. These results are all very uniform, emphasizing the poor life expectancy, once cerebral symptoms are evident. Melanoma is one of the most common tumours that metastasize t o the brain and spinal cord. Clinically, in those patients who died in this series, 32% spread t o the brain. Daasguta recorded a similar spread of 39% and Pack 38% (Savitz and Anderson, 1974). Post-mortem examination of 29 brains revealed that 89% had multiple metastases, single metastases being uncommon. Single metastases that can be identified by an electroencephalogram and a CAT scan need t o be at least t w o centimetres in diameter (Rowan et a h , 1974). Both at postmortem examination and at surgery, it is quite striking to see the brain speckled with thousands of pin-point metastatic melanoma lesions. The oedema around melanoma deposits in the brain is quite remarkable. Six patients had paraplegia at the time of death. Spinal cord damage may result from a pathological crush fracture of the vertebrae compressing the spinal contents. Extradural metastases within the spinal canal are uncommon. Edelson et alii (1972) showed that intramedullary spinal metastases were more common. These tumours may spread from the lungs via the arterial supply or along Batson's venous epidural plexus. However, 20 of their 37 patients had cerebral metastases, and it is argued that the intramedullary spinal metastases had seeded downwards.
INVESTIGATIONS If major surgery is t o be carried out on any form of disseminated melanoma, it is probably wise to consider seriously the central nervous system investigations. Of cerebral metastases in one series (Einhorn et alii, 1974), 27% were picked up with brain scans and electroencephalograms before clinical symptoms developed. The electroencephalogram remains a useful screening test, AUST. N.Z.J. SURG., VOL. 48-No.
1, FEBRUARY,1978
ATKINSON
but it is t o be remembered (Rowan et alii, 1974) that secondary tumours need to be tw o centimetres in size before the diagnostic focal delta wave activity is seen. Lumbar air encephalography and cerebral angiography have been replaced by the much more reliable brain scanning. Cerebral isotope scans are only about 75% as reliable as CAT scans in defining cerebral metastases (Wigg, 1975). The computerized axial tomography is an accurate, non-invasive, and rapid way of defining metastases of a size of t w o centimetres and larger. Still, it is not uncommon t o find at autopsy undemonstrated metastatic lesions, comparable in size with those shown on the CAT scan (Wigg, 1976). The CAT scan is most helpful in defining the extensive oedema around cerebral metastases. Useful conclusions regarding the use of cytotoxic drugs could not be drawn from this series. Numbers of patients receiving drugs were small. Most were covered with corticosteroids. However, there has been n o cause for optimism with the use of cytotoxic drugs in the later Queensland cases. The use of Thiotepa, imidizo carboxamide, endoxan, BCNU, and CCNU has been reported by others (Pennington and Milton, 1975; Gottlieb et alii, 1972). In a series of 47 patients that Einhorn et alii (1974) treated with cytotoxic preparations, there was a mean survival of 2.75 months. The eight patients who responded had a median survival of five months. Cytotoxic drugs have not been of any convincing benefit in cerebral metastatic melanoma. No conclusions could be drawn from Queensland cases regarding the effectiveness of radiotherapy. However, Young reported (Wigg, 1976) that of all patients with cerebral metastatic tumours, two-thirds could expect t o benefit symptomatically. Mean survivals of up to six months from the onset of cerebral symptoms have been reported by Pennington and Milton (1975) and Beresford (1 969); these were small series of cases, and most patients were covered with corticosteroids. Savitz and Anderson (1974) conclude that "radiation therapy has been essentially ineffective in almost all cases". If a convincing case is to be made out for the routine use of radiotherapy, significant results need to be reported in patients not receiving corticosteroids. Corticosteroids are readily accepted as a means of treating cerebral secondary neoplasms. It is well recognized that they reduce the oedema around neoplastic lesions in the brain (Beresford, 1969). They may act by affecting the enzyme systems in the brain or by mediating water and 15
ATKINSON
CENTRAL NERVOUS SYSTEM MELANOMA
electrolyte transport in the brain. Corticosteroids may alter the permeability of cerebral metastases. There is even some evidence that they may slow down the growth of melanoma deposits. The CAT scan clearly identifies the wide ranging areas of cerebral oedema, which on occasions are up t o three times the size of the tumour. Within 48 hours of commencement of corticosteroids, the unpleasant symptoms and signs will be reversed in some degree. Still, cerebral metastases expand, and treatment will rapidly become ineffective. Steroids certainly give a useful remission, and it is difficult t o assess scientifically other forms of treatment when patients are being maintained with steroids. The indication for surgery is the presence of a single metastatic melanoma, causing severe headaches or a major neurological deficit. Multiple cerebral metastases are a contraindication t o surgery. Twenty-one patients underwent craniotomy while under steroid cover. There was a mean age of 43.5 years, and this was significantly lower than the average. It would point to the great clinical activity in the younger patient. CAT scans were not available for this group, and today investigations are more accurate because of the availability of the CAT scans. However, tumours smaller than t w o centimetres are missed. The mean life expectancy following surgery was 5 . 6 months (one day t o 27 months); usually the quality of life was not impressive. Expectations were seldom realized. If surgery is t o be advocated, one should remember that 90%
16
of metastases are multiple, and only in rare cases is a useful result obtained. In conclusion, disseminated melanoma commonly metastasizes t o the central nervous system. The vast majority of these patients have multiple secondary growths. Central nervous system involvement is a terminal event in disseminated melanoma. The clinical history is a reliable indication of cerebral involvement. The electroencephalogram, and in particular computerized axial tomography, are the most useful complementary investigations. There is little evidence t o support the use of radiotherapy, chemotherapy, or surgery in the routine treatment of cerebral metastases. Corticosteroids convincingly reverse distressing clinical symptoms for a short time. REFERENCES
H. R. ( 1 969). Neurology (Minneap.). 19: 59. BERESFORD. EDELSON,R., DECK,D. F. and POSNER,J. B. (1972). Neurology (Minneap.), 22: 122. EINHORN, L. H.. BURGESS.M. A,, VALLEJOS.C., BODEY.G. P.. GUTTERMAN,J., MAVIGIT, G., HERSH, E. M., LUCE. J. K.. FREI, E., FREIREICH.E. J. and GOTTLIEB,J. (1974). Cancer Res., 34: 1995. GOTTLIEB,J., FREI, E. and LUCE, J. K. (1972). Cancer (Philad.). 29: 701. PENNINGTON, D. G. and MILTON,G. W. (1975), AUST. N.Z. J. SURG.,45: 405. ROWAN,A. J., RUDOLF,N. DE M . and SCOTT, D. F. (1974). J . Neurol. Neurosurg. Psychiat., 37: 888. SnAw, H. M.. MCCARTHY,W . H. and MILTON,G. W. (1977). Med. J . Aust.. 2: 77. SAVITZ, M. H. and ANDERSON,P. J. (1974). J . Mt Sinai Hosp., 41: 774. WIGG, D. W. (1976). Anti-Cancer Council of Victoria, Report 29.
AUST.
N.Z. J. SURG., VOL. 48-No.
1, FEBRUARY,1978
ATKl NSON
MELANOMA OF THE CENTRAL NERVOUS SYSTEM LEIGH ATKINSON Princess Alexandra Hospital, Brisbane The neurological manifestations o f melanoma are analysed i n this review of 1,500 patients in the Queensland Melanoma Project from 1963 t o 1969. Three hundred and f i f t y patients have died, and 113 w e r e recognized as having central nervous system metastases. The natural history of these metastases was examined, together w i t h the results of a limited number o f autopsies. The results of treatment are discussed.
THE increasing awareness of the natural history of melanoma has resulted in the very early presentation of disseminated melanoma t o the neurologist. The increasingly obvious benefits of early treatment (Shaw e l a/i, 1977) of the primary tumour, however, may be causing inflated optimism with respect t o the management of cerebral metastases. Papers referring t o the treatment of cerebral melanoma often speak of mean improvements t o life expectancy of three t o six months (Beresford, 1969; Pennington and Milton, 1975), and one might be excused for thinking that this was really a significant breakthrough for the patient. More often, the patient is hospitalized, becomes invalid, and the quality of life is poor. Admittedly melanoma is unpredictable. Many clinicians may be spurred on by the occasional patient w h o survives many years following treatment. We must ask ourselves the question: are w e entitled t o chase the occasional unpredictable success at the expense of extra suffering and distress for the unsuccessful majority? One thousand five hundred cases in the Queensland Melanoma Project were collected between 1963 and 1969 at the Princess Alexandra Hospital; these were examined, and the results were compared with the experience in other units.
RESULTS This series was reviewed in 1977, t o assess the effect of melanoma on the central nervous system. Three hundred and fifty patients had died. Records showed that 113 patients had clinical evidence of cerebral metastases. Of these, 69 Reprints: Dr L. Atkinson, "Alexandra", 201 Wickham Terrace, Brisbane, Old. 4000.
14
were males and 44 were females, with a mean age of 6 3 . 5 years. The mean time between diagnosis of the primary lesion and death was 35 months. The mean time between the development of neurological symptoms and death was four months. Twenty-nine patients with neurological symptoms came t o autopsy. Eighteen were males, 11 were females. Twenty-six had multiple metastases and three had single metastases. Twenty-four patients in this series had other systems of the body involved. I n this select group, symptoms existed for six months, while the primary melanoma had been diagnosed 28 months before. Associated neurological conditions were examined. Forty-four patients with a mean age of 7 2 . 5 years were reported t o have died from "strokes". Six patients had Parkinson's disease, t w o had motor neurone disease, one had peripheral neuropathy, while six had paraplegia due t o spinal metastases. T w o patients had associated, confirmed cerebral gliomas. Twenty-one patients in the series came t o craniotomy. Their mean age was 4 3 . 5 years. The mean life expectancy following surgery was 5 . 6 months, the longest period being 27 months. The mean time from the discovery of primary melanoma t o death in this series was 28.5 months.
DISCUSSION I n the natural history of melanoma, cerebral involvement is a terminal event. One hundred and thirteen of our 350 patients (32%) w h o died had cerebral symptoms before death. The most common symptoms were headaches, personality changes, epilepsy, nausea, vomiting, and visual deterioration. Common signs included weight loss, papilloedema, hemiparesis, and ataxia. A AUST. N.Z. J. SURG., VOL. 48-No.
1, FEBRUARY,1978
CENTRAL NERVOUS SYSTEM MELANOMA
further 44 patients died from "stroke", and sometimes the sudden haemorrhage into a cerebral secondary melanoma can mimic cerebrovascular disease. Some of these 44 patients may well have had cerebral metastases. The mean time from the diagnosis of the primary lesion to death was 35 months. In 113 cases the mean time from the onset of cerebral symptoms to death was four months. This figure compares with Beresford's mean of 2.6 months (1969), the figure of 3 . 5 months of Gottlieb et alii (1972), while Einhorn eta/;; (1974) found a mean survival of 2.75 months. These results are all very uniform, emphasizing the poor life expectancy, once cerebral symptoms are evident. Melanoma is one of the most common tumours that metastasize t o the brain and spinal cord. Clinically, in those patients who died in this series, 32% spread t o the brain. Daasguta recorded a similar spread of 39% and Pack 38% (Savitz and Anderson, 1974). Post-mortem examination of 29 brains revealed that 89% had multiple metastases, single metastases being uncommon. Single metastases that can be identified by an electroencephalogram and a CAT scan need t o be at least t w o centimetres in diameter (Rowan et a h , 1974). Both at postmortem examination and at surgery, it is quite striking to see the brain speckled with thousands of pin-point metastatic melanoma lesions. The oedema around melanoma deposits in the brain is quite remarkable. Six patients had paraplegia at the time of death. Spinal cord damage may result from a pathological crush fracture of the vertebrae compressing the spinal contents. Extradural metastases within the spinal canal are uncommon. Edelson et alii (1972) showed that intramedullary spinal metastases were more common. These tumours may spread from the lungs via the arterial supply or along Batson's venous epidural plexus. However, 20 of their 37 patients had cerebral metastases, and it is argued that the intramedullary spinal metastases had seeded downwards.
INVESTIGATIONS If major surgery is t o be carried out on any form of disseminated melanoma, it is probably wise to consider seriously the central nervous system investigations. Of cerebral metastases in one series (Einhorn et alii, 1974), 27% were picked up with brain scans and electroencephalograms before clinical symptoms developed. The electroencephalogram remains a useful screening test, AUST. N.Z.J. SURG., VOL. 48-No.
1, FEBRUARY,1978
ATKINSON
but it is t o be remembered (Rowan et alii, 1974) that secondary tumours need to be tw o centimetres in size before the diagnostic focal delta wave activity is seen. Lumbar air encephalography and cerebral angiography have been replaced by the much more reliable brain scanning. Cerebral isotope scans are only about 75% as reliable as CAT scans in defining cerebral metastases (Wigg, 1975). The computerized axial tomography is an accurate, non-invasive, and rapid way of defining metastases of a size of t w o centimetres and larger. Still, it is not uncommon t o find at autopsy undemonstrated metastatic lesions, comparable in size with those shown on the CAT scan (Wigg, 1976). The CAT scan is most helpful in defining the extensive oedema around cerebral metastases. Useful conclusions regarding the use of cytotoxic drugs could not be drawn from this series. Numbers of patients receiving drugs were small. Most were covered with corticosteroids. However, there has been n o cause for optimism with the use of cytotoxic drugs in the later Queensland cases. The use of Thiotepa, imidizo carboxamide, endoxan, BCNU, and CCNU has been reported by others (Pennington and Milton, 1975; Gottlieb et alii, 1972). In a series of 47 patients that Einhorn et alii (1974) treated with cytotoxic preparations, there was a mean survival of 2.75 months. The eight patients who responded had a median survival of five months. Cytotoxic drugs have not been of any convincing benefit in cerebral metastatic melanoma. No conclusions could be drawn from Queensland cases regarding the effectiveness of radiotherapy. However, Young reported (Wigg, 1976) that of all patients with cerebral metastatic tumours, two-thirds could expect t o benefit symptomatically. Mean survivals of up to six months from the onset of cerebral symptoms have been reported by Pennington and Milton (1975) and Beresford (1 969); these were small series of cases, and most patients were covered with corticosteroids. Savitz and Anderson (1974) conclude that "radiation therapy has been essentially ineffective in almost all cases". If a convincing case is to be made out for the routine use of radiotherapy, significant results need to be reported in patients not receiving corticosteroids. Corticosteroids are readily accepted as a means of treating cerebral secondary neoplasms. It is well recognized that they reduce the oedema around neoplastic lesions in the brain (Beresford, 1969). They may act by affecting the enzyme systems in the brain or by mediating water and 15
ATKINSON
CENTRAL NERVOUS SYSTEM MELANOMA
electrolyte transport in the brain. Corticosteroids may alter the permeability of cerebral metastases. There is even some evidence that they may slow down the growth of melanoma deposits. The CAT scan clearly identifies the wide ranging areas of cerebral oedema, which on occasions are up t o three times the size of the tumour. Within 48 hours of commencement of corticosteroids, the unpleasant symptoms and signs will be reversed in some degree. Still, cerebral metastases expand, and treatment will rapidly become ineffective. Steroids certainly give a useful remission, and it is difficult t o assess scientifically other forms of treatment when patients are being maintained with steroids. The indication for surgery is the presence of a single metastatic melanoma, causing severe headaches or a major neurological deficit. Multiple cerebral metastases are a contraindication t o surgery. Twenty-one patients underwent craniotomy while under steroid cover. There was a mean age of 43.5 years, and this was significantly lower than the average. It would point to the great clinical activity in the younger patient. CAT scans were not available for this group, and today investigations are more accurate because of the availability of the CAT scans. However, tumours smaller than t w o centimetres are missed. The mean life expectancy following surgery was 5 . 6 months (one day t o 27 months); usually the quality of life was not impressive. Expectations were seldom realized. If surgery is t o be advocated, one should remember that 90%
16
of metastases are multiple, and only in rare cases is a useful result obtained. In conclusion, disseminated melanoma commonly metastasizes t o the central nervous system. The vast majority of these patients have multiple secondary growths. Central nervous system involvement is a terminal event in disseminated melanoma. The clinical history is a reliable indication of cerebral involvement. The electroencephalogram, and in particular computerized axial tomography, are the most useful complementary investigations. There is little evidence t o support the use of radiotherapy, chemotherapy, or surgery in the routine treatment of cerebral metastases. Corticosteroids convincingly reverse distressing clinical symptoms for a short time. REFERENCES
H. R. ( 1 969). Neurology (Minneap.). 19: 59. BERESFORD. EDELSON,R., DECK,D. F. and POSNER,J. B. (1972). Neurology (Minneap.), 22: 122. EINHORN, L. H.. BURGESS.M. A,, VALLEJOS.C., BODEY.G. P.. GUTTERMAN,J., MAVIGIT, G., HERSH, E. M., LUCE. J. K.. FREI, E., FREIREICH.E. J. and GOTTLIEB,J. (1974). Cancer Res., 34: 1995. GOTTLIEB,J., FREI, E. and LUCE, J. K. (1972). Cancer (Philad.). 29: 701. PENNINGTON, D. G. and MILTON,G. W. (1975), AUST. N.Z. J. SURG.,45: 405. ROWAN,A. J., RUDOLF,N. DE M . and SCOTT, D. F. (1974). J . Neurol. Neurosurg. Psychiat., 37: 888. SnAw, H. M.. MCCARTHY,W . H. and MILTON,G. W. (1977). Med. J . Aust.. 2: 77. SAVITZ, M. H. and ANDERSON,P. J. (1974). J . Mt Sinai Hosp., 41: 774. WIGG, D. W. (1976). Anti-Cancer Council of Victoria, Report 29.
AUST.
N.Z. J. SURG., VOL. 48-No.
1, FEBRUARY,1978
