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Malignant Melanoma of the Skin
1171
these curious findings by postulating that the infant received a dose of maternal lymphoid cells across the placenta during foetal life and was unable, because of immunological incompetence, to reject this unwanted homograft, which thus survived to mount a graft-versus-host reaction whose products masked the host’s own congenital deficiencies of y-globulin and lymphoid cells. This explanation, if true, raises some interesting possibilities concerning the role of lymphoid-cell chimaerism in the causation of disease, not only in the newborn but perhaps in later life also. Although it can easily be made immunologically tolerant to some antigens, the normal foetus is capable of immune reaction against microorganisms, and at birth the cord blood contains antibodies of foetal origin which react with y-globulin. 33 The findings of KADOWAKI et al. certainly suggest that for the foetus immunologically competent lymphoid cells provide a defence against invasion by unwanted similar cells of maternal origin; perhaps this is as necessary to normal development in utero as is immunological capability to postnatal life. to
explain
Malignant
Melanoma of the Skin
WHEN malignant melanoma of the skin is diagnosed early and treated adequately, the five-year survival-rate is better than that for most other forms of cancer 34 35 ; and, even if the initial treatment is delayed or inadequate, five-year and ten-year survival figures are not wholly discouraging.36 Yet, to many medical minds, diagnosis is a death certificate. So often, however the unpredictably delayed, recurrence and eventual death seem inexorable. Some patients may run a rapidly downhill course in spite of every therapeutic device, others may remain free of disease for ten or fifteen years before succumbing to widespread metastases. It is not uncommon to find visible subcutaneous metastases which show no sign of growth for long periods, or patients who can be kept " free from disease " by excision of successive recurrences. Spontaneous regression has occasionally been noted, sometimes temporary, sometimes apparently permanent. 31 37 In view of this unpredictable course and the rarity of malignant melanoma (about 2 new cases per 100,000 population per year 35 38), adequate statistical evidence on which to base therapy and prognosis has been slow to accumulate; but some relatively large series published during the past few years 34 35 39-42 have clarified the epidemiology of the disease and how best to treat it. Many malignant melanomas begin in pre-existing simple pigmented lesions, and the junctional naevus is 33. 34. 35.
Epstein, W. V. Science, N.Y. 1965, 148, 1591. Cade, S. Ann. R. Coll. Surg. 1961, 28, 331. Petersen, N. C., Bodenham, D. C., Lloyd, O. C. Br. J. plast. Surg. 1962, 15, 49. 36. Mundth, E. D., Guralnick, E. A., Raker, J. W. Ann. Surg. 1965, 162, 15. 37. Levison, V. B. Br. med. J. 1955, i, 458. 38. Clemmesen, J., Schultz, G. Dan. med. Bull. 1960, 7, 168. 39. Block, G. E., Hartwell, S. W., Jr. Ann. Surg. 1961, 154, 74. 40. Charalambidis, P. H., Patterson, W. B. Surg. Gynec. Obstet. 1962, 115, 333.
41. 42.
Daland, E. New Engl. J. Med. 1959, 260, 453. Gumport, S. L., Meyer, H. W. Ann. Surg. 1959, 150,
989.
believed to be the usual source; most nsevi are small and it is not surprising that estimates of the proportion of malignant melanomas arising from simple lesions has varied from 18 43 to 83%.- They are very rare before puberty, although malignant change has now been reported 44 in a total of 26 children with congenital giant hairy naevi. Women seem more susceptible than men, and the highest sex-ratio so far was reported by PETERSEN et al. (women 68-8%, men 31-4%). Most series show that the prognosis is better in women, perhaps because they seek treatment earlier for skin blemishes. The head and neck is the commonest site, followed by the lower limb, trunk, upper limb, and genitalia in that order. The patient often mentions trauma as the cause of the melanoma, but the evidence has been equivocal. LEA 45 has compared 193 cases of malignant melanoma with 530 cases of basal-cell skin carcinoma so far as the history of trauma was concerned, and the result was highly significant statistically. 38% of the malignant melanomas had a history of trauma compared with only 12% of the basal-cell carcinomas. Another suggestion is that trauma may increase the early dissemination of established tumour in sites such as the sole; but estimates of prognosis based on site vary so much in different series that no firm conclusion can be drawn. The rarity of the disease before puberty, its greater incidence and better prognosis in women, and the evidence for the existence of a melanocytestimulating hormone in the anterior pituitary 46 suggest some hormonal dependence, but it is very unlikely that this is clinically important. Even the influence of pregnancy is doubtful, and CADE 34 emphasises that women with malignant melanomas need neither avoid conception nor have their pregnancy terminated. In theory malignant melanoma is partly a preventable disease. Excise all simple pigmented lesions and the incidence would be drastically reduced; but most white people have many such lesions and the task is virtually impossible. For the established tumour early diagnosis and definitive treatment are the most important controllable factors which improve prognosis. Early diagnosis is not always easy; itching, enlargement, or ulceration in an existing nsevus may arouse suspicion, but histological examination is the only reliable guide. Herein lies the surgeon’s dilemma; since a biopsy is necessary for final diagnosis, and since " inadequate " excision is universally and justifiably condemned, should he excise widely every suspicious lesion ? In situations where the scar is of little moment, this is probably the wisest course, though it may occasionally mean the radical ablation of a simple tumour. Otherwise radical excision must be two-staged, the interval between stages being governed solely by the speed with which the histologist can confirm the diagnosis. All authorities agree that the longer definitive excision is delayed, the worse the prognosis. What margin of healthy skin must be excised in the recommended " wide ", adequate ", "
43. 44.
Allen, A. C., Spitz, S. Cancer, 1953, 6, 1. Greeley, P. W., Middleton, A. G., Curtin, J. W. Plast. Reconstr. Surg. 1965, 36, 26. 45. Lea, A. J. Ann. R. Coll. Surg. 1965, 37, 169. 46. Fitzpatrick, T. B., Lerner, A. B. Archs Derm. Syph. 1954, 69, 133.
1172 "
radical " excision ? CADE 34 described as inadequate any excision which could be closed directly without skin grafting. PETERSEN et all analysing their results in 220 cases, recommended an optimum eccentric excision of 6 cm. distally (i.e., furthest from the regional nodes), 8 cm. on each side, and 15 cm. proximally. MUNDTH et all believe that more modest excisions are " adequate " : for lesions less than 1 cm., a clear margin of not less than 1 cm.; for larger lesions and those with satellites, a margin one to two times the diameter of the entire lesion. Such figures are obviously empirical; when circumstances permit (for example, on the lower limb) it seems advisable to excise as widely as PETERSEN et al. recommend; elsewhere, until there are better criteria on which to base the limits of excision, this advice should be tempered with functional and oesthetic mercy. It was long judged essential to excise the deep fascia underlying the lesion because of its close relation to the lymphatics draining the skin. Several recent studies, however,36 41 47 have shown that inclusion of or
regional perfusion with cytotoxic drugs can produce dramatic if brief regression of recurrences confined to the limbs 51 ’2; but other forms of chemotherapy have been disappointing. The surgeon who first operates on a malignant melanoma has a great responsibility; prompt and competent action will give the patient a chance of survival better than in most other forms of cancer. The only additional operative skill required is the ability to cut and apply split skin-grafts. If he lacks confidence therein, let the surgeon refer the case at once and certainly before he has ruined, by niggling interference, the patient’s chance of survival. Annotations NO CHARGE
National Health Service prescription charges were abolished on Feb. 1 this year. We wish they had never been put on and we do not want to see them back. Many people claim to know with certainty how prescription charges (or their removal) are reflected in the drug bill and in the general practitioner’s work-load; but those who favour these charges are much less convincing when they declare that the poorer patients and the chronically sick suffer no hardship when charges are
deep fascia does not improve cure or recurrence rates. Doubt can no longer exist that local excision of a malignant melanoma should be followed by prophylactic dissection of the regional nodes. MUNDTH et al.36 found that the five-year and ten-year survival-rates for patients who had had prophylactic removal of regional nodes were 77% and 64% respectively when the nodes were imposed. What are the commentators making of the prescription when were and nodes uninvolved and 59% 38% positive found. In patients in whom node dissection had been figures announced by Mr. Kenneth Robinson in the last week ? In the seven months from abolition delayed until clinically positive, the five-year and ten- Commons to Aug. 31, chemists in England and Wales dispensed year survival-rates were only 22% and 3% respectively. 23 million more than in the corresponding The operation (first described by PRINGLE 48 in 1908) of months of 1964 prescriptions of (an increase 19%) and the cost was excising a strip of lymphatic-bearing skin between the E13 million (22%) higher. " An unnecessary wastage of lesion and the regional nodes was long popular-but it is the nation’s resources, a considerable additional burden illogical, since lymphatic dissemination is not confined to on our general practitioners," cried the Opposition. The distinct anatomical channels. To excise all the skin and subcutaneous tissue between the lesion and the nodes would be logical but practicable only when they are immediately adjacent. Otherwise, excision of regional nodes is a separate interval procedure. PETERSEN et al. recommend a gap of two to three weeks so that the lymphatics draining the excised area may clear themselves of malignant cells. A possible alternative to block dissection is endolymphatic chemotherapy, and radioactive gold 49 and radioactive iodine 50 have been used for this purpose. A big clinical trial will be needed, however, before we can judge the relative merits of surgery and chemotherapy in the treatment of lymphatic metastases. There are two accessory methods of treatment which, when recurrences are inoperable, may cause the tumour to regress at least temporarily, and so prolong survival. Firstly, irradiation is occasionally effective; MUNDTH et al.36 found that of 67 patients who had radiotherapy, a third had a beneficial response. CADE 34 emphasised that there is no question of radiotherapy being an alternative to surgery, but it is definitely indicated when operation is impossible. Secondly, 47. 48. 49. 50.
Kragh, L. V., Erich, J. B. Ann. Surg. 1960, 151, 91. Pringle, J. H. Edinb. med. J. 1908, 23, 496. Jantet, G. H., Edwards, J. M., Gough, M. H., Kinmonth, J. J. 1964, ii, 904. Fischer, H. W. Cancer, N.Y. 1965, 18, 1059.
increase in the number of prescriptions since abolition was certainly a good deal higher than expected, Mr. Robinson admitted, but the average cost per prescription was lower than expected, mainly because small quantities were being prescribed. When he was reminded of earlier Government estimates suggesting that the effect of abolition would be much less, the Minister remarked that " the degree of deterrence, and perhaps the hardship which the existence of charges brought about, was underestimated " (which was one way of putting it); and though this interpretation drew some wry smiles, few were heard to disagree with Mr. Robinson’s final point: " there is no doubt that these figures are not solely the result of the abolition of charges." That is about the only thing in fact which is in no doubt. In the analysis of variables which affect National Health Service prescribing, a new symbol should perhaps now be added to the long equation-to represent the morale of general practitioners. The drug bill is controllable by careful prescribing; but demoralised doctors are not careful prescribers, and signs of demoralisation have become increasingly evident. On the reasonable text of a widespread discontent among general practitioners, the British Medical Association unreasonably preached resignation, alternative services, and non-cooperation. 51. Creech, O.
B. Br. med. 52.
J., Jr., Ryan, R. F., Krementz, E. T. J. Am. med. Ass. 1959, 169, 339. Golomb, F. M., Postel, A. H., Hall, A. B., Gumport, S. L., Cox, K. R., Wright, J. C. Cancer, N.Y. 1962, 15, 828.
these curious findings by postulating that the infant received a dose of maternal lymphoid cells across the placenta during foetal life and was unable, because of immunological incompetence, to reject this unwanted homograft, which thus survived to mount a graft-versus-host reaction whose products masked the host’s own congenital deficiencies of y-globulin and lymphoid cells. This explanation, if true, raises some interesting possibilities concerning the role of lymphoid-cell chimaerism in the causation of disease, not only in the newborn but perhaps in later life also. Although it can easily be made immunologically tolerant to some antigens, the normal foetus is capable of immune reaction against microorganisms, and at birth the cord blood contains antibodies of foetal origin which react with y-globulin. 33 The findings of KADOWAKI et al. certainly suggest that for the foetus immunologically competent lymphoid cells provide a defence against invasion by unwanted similar cells of maternal origin; perhaps this is as necessary to normal development in utero as is immunological capability to postnatal life. to
explain
Malignant
Melanoma of the Skin
WHEN malignant melanoma of the skin is diagnosed early and treated adequately, the five-year survival-rate is better than that for most other forms of cancer 34 35 ; and, even if the initial treatment is delayed or inadequate, five-year and ten-year survival figures are not wholly discouraging.36 Yet, to many medical minds, diagnosis is a death certificate. So often, however the unpredictably delayed, recurrence and eventual death seem inexorable. Some patients may run a rapidly downhill course in spite of every therapeutic device, others may remain free of disease for ten or fifteen years before succumbing to widespread metastases. It is not uncommon to find visible subcutaneous metastases which show no sign of growth for long periods, or patients who can be kept " free from disease " by excision of successive recurrences. Spontaneous regression has occasionally been noted, sometimes temporary, sometimes apparently permanent. 31 37 In view of this unpredictable course and the rarity of malignant melanoma (about 2 new cases per 100,000 population per year 35 38), adequate statistical evidence on which to base therapy and prognosis has been slow to accumulate; but some relatively large series published during the past few years 34 35 39-42 have clarified the epidemiology of the disease and how best to treat it. Many malignant melanomas begin in pre-existing simple pigmented lesions, and the junctional naevus is 33. 34. 35.
Epstein, W. V. Science, N.Y. 1965, 148, 1591. Cade, S. Ann. R. Coll. Surg. 1961, 28, 331. Petersen, N. C., Bodenham, D. C., Lloyd, O. C. Br. J. plast. Surg. 1962, 15, 49. 36. Mundth, E. D., Guralnick, E. A., Raker, J. W. Ann. Surg. 1965, 162, 15. 37. Levison, V. B. Br. med. J. 1955, i, 458. 38. Clemmesen, J., Schultz, G. Dan. med. Bull. 1960, 7, 168. 39. Block, G. E., Hartwell, S. W., Jr. Ann. Surg. 1961, 154, 74. 40. Charalambidis, P. H., Patterson, W. B. Surg. Gynec. Obstet. 1962, 115, 333.
41. 42.
Daland, E. New Engl. J. Med. 1959, 260, 453. Gumport, S. L., Meyer, H. W. Ann. Surg. 1959, 150,
989.
believed to be the usual source; most nsevi are small and it is not surprising that estimates of the proportion of malignant melanomas arising from simple lesions has varied from 18 43 to 83%.- They are very rare before puberty, although malignant change has now been reported 44 in a total of 26 children with congenital giant hairy naevi. Women seem more susceptible than men, and the highest sex-ratio so far was reported by PETERSEN et al. (women 68-8%, men 31-4%). Most series show that the prognosis is better in women, perhaps because they seek treatment earlier for skin blemishes. The head and neck is the commonest site, followed by the lower limb, trunk, upper limb, and genitalia in that order. The patient often mentions trauma as the cause of the melanoma, but the evidence has been equivocal. LEA 45 has compared 193 cases of malignant melanoma with 530 cases of basal-cell skin carcinoma so far as the history of trauma was concerned, and the result was highly significant statistically. 38% of the malignant melanomas had a history of trauma compared with only 12% of the basal-cell carcinomas. Another suggestion is that trauma may increase the early dissemination of established tumour in sites such as the sole; but estimates of prognosis based on site vary so much in different series that no firm conclusion can be drawn. The rarity of the disease before puberty, its greater incidence and better prognosis in women, and the evidence for the existence of a melanocytestimulating hormone in the anterior pituitary 46 suggest some hormonal dependence, but it is very unlikely that this is clinically important. Even the influence of pregnancy is doubtful, and CADE 34 emphasises that women with malignant melanomas need neither avoid conception nor have their pregnancy terminated. In theory malignant melanoma is partly a preventable disease. Excise all simple pigmented lesions and the incidence would be drastically reduced; but most white people have many such lesions and the task is virtually impossible. For the established tumour early diagnosis and definitive treatment are the most important controllable factors which improve prognosis. Early diagnosis is not always easy; itching, enlargement, or ulceration in an existing nsevus may arouse suspicion, but histological examination is the only reliable guide. Herein lies the surgeon’s dilemma; since a biopsy is necessary for final diagnosis, and since " inadequate " excision is universally and justifiably condemned, should he excise widely every suspicious lesion ? In situations where the scar is of little moment, this is probably the wisest course, though it may occasionally mean the radical ablation of a simple tumour. Otherwise radical excision must be two-staged, the interval between stages being governed solely by the speed with which the histologist can confirm the diagnosis. All authorities agree that the longer definitive excision is delayed, the worse the prognosis. What margin of healthy skin must be excised in the recommended " wide ", adequate ", "
43. 44.
Allen, A. C., Spitz, S. Cancer, 1953, 6, 1. Greeley, P. W., Middleton, A. G., Curtin, J. W. Plast. Reconstr. Surg. 1965, 36, 26. 45. Lea, A. J. Ann. R. Coll. Surg. 1965, 37, 169. 46. Fitzpatrick, T. B., Lerner, A. B. Archs Derm. Syph. 1954, 69, 133.
1172 "
radical " excision ? CADE 34 described as inadequate any excision which could be closed directly without skin grafting. PETERSEN et all analysing their results in 220 cases, recommended an optimum eccentric excision of 6 cm. distally (i.e., furthest from the regional nodes), 8 cm. on each side, and 15 cm. proximally. MUNDTH et all believe that more modest excisions are " adequate " : for lesions less than 1 cm., a clear margin of not less than 1 cm.; for larger lesions and those with satellites, a margin one to two times the diameter of the entire lesion. Such figures are obviously empirical; when circumstances permit (for example, on the lower limb) it seems advisable to excise as widely as PETERSEN et al. recommend; elsewhere, until there are better criteria on which to base the limits of excision, this advice should be tempered with functional and oesthetic mercy. It was long judged essential to excise the deep fascia underlying the lesion because of its close relation to the lymphatics draining the skin. Several recent studies, however,36 41 47 have shown that inclusion of or
regional perfusion with cytotoxic drugs can produce dramatic if brief regression of recurrences confined to the limbs 51 ’2; but other forms of chemotherapy have been disappointing. The surgeon who first operates on a malignant melanoma has a great responsibility; prompt and competent action will give the patient a chance of survival better than in most other forms of cancer. The only additional operative skill required is the ability to cut and apply split skin-grafts. If he lacks confidence therein, let the surgeon refer the case at once and certainly before he has ruined, by niggling interference, the patient’s chance of survival. Annotations NO CHARGE
National Health Service prescription charges were abolished on Feb. 1 this year. We wish they had never been put on and we do not want to see them back. Many people claim to know with certainty how prescription charges (or their removal) are reflected in the drug bill and in the general practitioner’s work-load; but those who favour these charges are much less convincing when they declare that the poorer patients and the chronically sick suffer no hardship when charges are
deep fascia does not improve cure or recurrence rates. Doubt can no longer exist that local excision of a malignant melanoma should be followed by prophylactic dissection of the regional nodes. MUNDTH et al.36 found that the five-year and ten-year survival-rates for patients who had had prophylactic removal of regional nodes were 77% and 64% respectively when the nodes were imposed. What are the commentators making of the prescription when were and nodes uninvolved and 59% 38% positive found. In patients in whom node dissection had been figures announced by Mr. Kenneth Robinson in the last week ? In the seven months from abolition delayed until clinically positive, the five-year and ten- Commons to Aug. 31, chemists in England and Wales dispensed year survival-rates were only 22% and 3% respectively. 23 million more than in the corresponding The operation (first described by PRINGLE 48 in 1908) of months of 1964 prescriptions of (an increase 19%) and the cost was excising a strip of lymphatic-bearing skin between the E13 million (22%) higher. " An unnecessary wastage of lesion and the regional nodes was long popular-but it is the nation’s resources, a considerable additional burden illogical, since lymphatic dissemination is not confined to on our general practitioners," cried the Opposition. The distinct anatomical channels. To excise all the skin and subcutaneous tissue between the lesion and the nodes would be logical but practicable only when they are immediately adjacent. Otherwise, excision of regional nodes is a separate interval procedure. PETERSEN et al. recommend a gap of two to three weeks so that the lymphatics draining the excised area may clear themselves of malignant cells. A possible alternative to block dissection is endolymphatic chemotherapy, and radioactive gold 49 and radioactive iodine 50 have been used for this purpose. A big clinical trial will be needed, however, before we can judge the relative merits of surgery and chemotherapy in the treatment of lymphatic metastases. There are two accessory methods of treatment which, when recurrences are inoperable, may cause the tumour to regress at least temporarily, and so prolong survival. Firstly, irradiation is occasionally effective; MUNDTH et al.36 found that of 67 patients who had radiotherapy, a third had a beneficial response. CADE 34 emphasised that there is no question of radiotherapy being an alternative to surgery, but it is definitely indicated when operation is impossible. Secondly, 47. 48. 49. 50.
Kragh, L. V., Erich, J. B. Ann. Surg. 1960, 151, 91. Pringle, J. H. Edinb. med. J. 1908, 23, 496. Jantet, G. H., Edwards, J. M., Gough, M. H., Kinmonth, J. J. 1964, ii, 904. Fischer, H. W. Cancer, N.Y. 1965, 18, 1059.
increase in the number of prescriptions since abolition was certainly a good deal higher than expected, Mr. Robinson admitted, but the average cost per prescription was lower than expected, mainly because small quantities were being prescribed. When he was reminded of earlier Government estimates suggesting that the effect of abolition would be much less, the Minister remarked that " the degree of deterrence, and perhaps the hardship which the existence of charges brought about, was underestimated " (which was one way of putting it); and though this interpretation drew some wry smiles, few were heard to disagree with Mr. Robinson’s final point: " there is no doubt that these figures are not solely the result of the abolition of charges." That is about the only thing in fact which is in no doubt. In the analysis of variables which affect National Health Service prescribing, a new symbol should perhaps now be added to the long equation-to represent the morale of general practitioners. The drug bill is controllable by careful prescribing; but demoralised doctors are not careful prescribers, and signs of demoralisation have become increasingly evident. On the reasonable text of a widespread discontent among general practitioners, the British Medical Association unreasonably preached resignation, alternative services, and non-cooperation. 51. Creech, O.
B. Br. med. 52.
J., Jr., Ryan, R. F., Krementz, E. T. J. Am. med. Ass. 1959, 169, 339. Golomb, F. M., Postel, A. H., Hall, A. B., Gumport, S. L., Cox, K. R., Wright, J. C. Cancer, N.Y. 1962, 15, 828.