Commentary
MALIGNANT MELANOMA HANS STORCK, M.D.
From the Department of Dermatology, University Clinic, Zurich, Switzerland
active and promising colleague with much initiative who accompanied his chief to several congresses (Fig. 2). His innovative spirit, his skill in experiments with animals, and his critical interpretations led soon to meteoric success for this young dermatologist. Later in New York, Sulzberger was one of the first to study the immunologic resistance of the organism against tumor cells and immunologic tolerance. He conducted some carefully planned animal experiments in this area. These subjects are presently important in the research effort centering on malignant melanoma. What can we assume to be established facts concerning melanoma and how are results obtained today? Until approximately 10 years ago, information from a variety of clinics and medical centers with relatively small and often different treatments were assembled and evaluated in the world literature. Intense controversy broke out concerning the success of conventional treatment such as surgery, radiotherapy or a combination of first surgery then radiotherapy, or radiotherapy then surgery. These battles, which reminded one of medieval wars, almost became a national problem (Anglo-Saxon and French for surgery, German and Scandinavian for radiotherapy). However, it was soon demonstrated that the prognosis depended less on the applied therapy than on early diagnosis and treatment, as well as on favorable or unfavorable factors at the beginning of treatment.
For a long time, the problem of the malignant melanomas has not been just the concern of dermatologists, but surgeons, radiotherapists, nuclear physicians, oncologists, epidemiologists and immunologists as well. They often have vehement differences of opinion on this problem. This may be attributed partially to the fact that morbidity and mortality of melanoma is increasing worldwide among Caucasians. Interestingly, Sulzberger addressed aspects of this problem half a century ago. In 1926 Sulzberger presented, with the recommendation of Professor Bloch, his Inaugural Dissertation: "Ein Fall von Leukoplakia et Craurosis vulvae mit Tumorbildung und histologischem Befund der Bowen'schen Krankheit" (Fig. 1). As a voluntary assistant (with scarce pocket money?) together with 4 other voluntary assistants from foreign countries. Professor Bloch, his head-physician Doctor Cuido Miescher and 4 Swiss assistants (among them Werner Jadassohn), he helped to treat in that year 1,160 patients with 29,728 consultations. He contributed to the 17 publications released in 1926. Until his departure in 1928, he was an Address for reprints: Prof. Dr. H. Storck, Kantonsspital Zurich, Dermatologische Universltatsklinik, Gloriastrasse 31, Zurich, Switzerland. 384
No. 5
MALIGNANT MELANOMA
Storck
385
Prognosis The most important facts for the prognosis is the stage, the patient's sex, size of lesion, depth of penetration, classification of melanoma, location and finally, the age when the disease began. According to our observations in 1971 of some 1,000 cases selected from the world literature, the 5-year survival rate in stage I (primary tumors without clinically confirmed enlarged regional lymph nodes) is 5 1 % , 'n stage II (primary tumor with enlarged regional lymph nodes) only 12.6%, and in stage III (primary tumor with and without regional lymph nodes but with clinically manifest lymphogenic and hematogenic dissemination) 0%. Considering sex, we found that females (all stages) had a significantly higher 5-year survival rate of 31% than that of males (18%). If the diameter of the melanoma was smaller than 2 cm, 62% of the patients survived 5 years. If it was over 2 cm, only 27% lived 5 years. With regard to the melanoma classification, melanoma arising from active nevus pigmentosus or de novo from a healthy skin, prognosis proved to be significantly worse than with melanoma arising from melanotic freckles. The most favorable locations were head, arms and legs with 5-year survival rates of 28%, 35%, and 32%, compared to the melanoma on the trunk with only 19% or anogenital with only 10%. The age when the disease begins is important because juvenile melanomas in general are benign, with the exception of some rare melanomas arising from expanded nevus pigmentosus et pilosus (Tierfell-Nevus). Morbidity and mortality increase gradually after puberty, as well as after the menopause, which leads to the probable conclusion that gonadal hormones do not play an important role in the disease, only perhaps those of the hypophysis.
Aus der dcrmatologisdicn UniversitatsUlinik Zurich DlHDKTORi PROP. DR. B. BI-OCH
Ein Fall von Leukoplakia et Kraurosis vulvae mit Tumorbildung und histo= logischem Befund der Bowen'sdien Krankheit. INAUGURAL - DISSERTATION Eriangung der Doktorwiirde der medizinisclien Fakulrat der Universitat Zurich vorj^clcgt van MARION
B. SULZBERGER
NEW-YORK (U, S. A.> Geiitfhmiai Auf Antreg non Ptof. Dr. B . B L O C H .
Z U R I C H 1926 Dfudk von H. Haidi, Ziiridi 6 Nacdarratse 203
Fig. 1.
Malignancy Index If one wants to draw conclusions from small groups treated differently, this is only possible when favorable as well as unfavorable factors are taken into consideration. A procedure which takes both types of factors into account is the "malignancy index," which we developed for a group of 144 melanoma patients in 1968 and recently repeated with 315 cases. This index can be calculated by subtracting in a group of cases with a special treatment method the sum of all unfavorable factors (male, larger than 2 cm, arising from nevus pigmentosus or de novo, localization on trunk or anogenital) the sum of all favorable factors (female, smaller than 2 cm, arising from melanotic precancerosis, localization on head or extremities) and divide it by the number of patients of this
386
INTERNATIONAL JOURNAL OF DERMATOLOGY
June 1977
Vol. 16
ment of the lymph nodes, and that even in stage II, surgical removal was just as good as additional x-ray therapy before or after excision if you took into account the initial situation (malignancy index). In this biased group from a single clinic, the major effect of the stages could be demonstrated — 5-year survival rate for phase I from 71.8 ± 3.4%, phase II from 12.7 ± 3.7% and phase III from 4.4 ± 4.3%. . ._
Cooperative Studies
Fig. 2. Prof. Bruno Bloch, Dr. Guido Mieschr, Dr. Marion Sulzberger, Zurich 1927, starting for a congress.
group in question. The more positive the index, the less favorable is the initial situation. It became evident later that either the methods of treatment (surgery, radiotherapy, or combined surgery and then radiotherapy or radiotherapy and then surgery) produced no variations in the results. If there appeared to be differences, as in phase II, it was that the elevation of the malignancy index, that is, the initial situation, was decisive and not the method of treatment. This is disappointing and seems to make intense controversy senseless. Early diagnosis and early treatment is most important and the simplest method is total excision of the tumor from the healthy tissue. It became evident as well that nothing was gained through prophylactic treat-
Today, it is a national and international custom to investigate large groups. This presumes a reliable cancer register with the best possible histological diagnosis to judge morbidity and mortality, even though there is a 25% possibility for false diagnoses. In some countries, several clinics have joined together for cooperative and prospectiye studies, as has the German melanoma research group, which consists of 9 clinics in Western Germany. This group has 1,500 cases evaluated and programmed by computer and can apply the information for evaluation of homogenous groups and for "symptom twins." More and more randomized studies are carried out but they presuppose careful planning and selection. The big research projects are very expensive and leave little room for individual initiative, but they have the advantage of producing positive results as well as new possibilities for therapy, such as immunotherapy (BGG, Corynebacterium parvum, Levamisol), or Cytostatica (Oncovin, GGNU or DTIG). Some of these large investigations seem to confirm the influence of the previously mentioned favorable and unfavorable factors and also the minor effect of variations in conventional therapy. The significance of additional immunotherapy and of cytostatic therapy, especially in late stages, has not been proved yet.
No, 5
MALIGNANT MELANOMA
Retrospect In comparison to the years 1926-28, the time of Sulzberger's voluntary work, research has become exacting, expensive and for a single clinic with the "Stellenplafonierung," very difficult. In the clinic of Zurich, for instance, 50 years after Sulzberger, 1 chief with an assistant professor, 4 head physicians, 1 scientific head assistant and 16 assistant doctors, but unfortunately only too rarely with volunteers, treated 875 inpatients, 15,840 outpatients in 77,029 consultations, and published 22 papers. But the increasing incidence of malignant melanoma keeps pertinent the basic questions which possibly could be solved even today with a creative spirit a la Sulzberger— in a small clinic laboratory in cooperation with other disciplines of the medical faculty. That specific and nonspecific defense mechanisms of humoral and cellular immunity are important is no longer questioned. There may well be many other, mostly yet unknown, conditioning or causing factors. But as cultured human melanoma cells from primary tumor or metastasis change continuously in morphology, as Jurg Meyer in our clinic showed, this could correspond to changes in antigenicity. But how to outwit the malignant melanoma cells which cling
Storck
387
loosely together in the tissue or melastasize early, remain dormant "only to threaten" the life of a patient after years or decades? Would it be possible to incite the organism to kill those cells and cell complexes through a combination of specific and unspecific measures similar, for example, to the Shwartzman-Sanarelli phenomenon? Or, as found by Lipkin and Knecht, who worked for 1 year with us, could the newly identified, melanocytederived growth regulatory macromolecule (MCIF), which restores contact inhibition to malignant melanocytes, have important clinical bearing in the future? References 1, Sulzberger, M, B,: Ein Fall von Leukoplakia et Kraurosis vulvae mit Tumorbildung und histologischem Befund der Bowen'schen Krankheit, Inaugural-Dissertation, ZOrich, 1926, 2, Storck, H,, Ott, E,, and Schwarz, K,: Das maligne Melanom, In Handbuch der medizinischen Radiologie, Berlin, Springer, 1972, 19/1, pp, 161-257, 3, Storck, H,, and Ott, E,: Zu Verlauf und Therapie der malignen Melanome, Schweiz, Med, Wochenschr. 106:1871, 1976, 4, Lipkin, G,, and Knecht, M, E,: Wiederherstellung der Wachstumskontaktinhibition bei malignen Melanocyten von Mensch, Maus und Hamster, Schweiz, Med, Wochenschr, 105: 1360, 1975, 5, Meyer, J,: Unterschiedliches Verhalten von Melanomzellen aus Primartumor und Metastasen in vitro, Dermatologica, In press.
MALIGNANT MELANOMA HANS STORCK, M.D.
From the Department of Dermatology, University Clinic, Zurich, Switzerland
active and promising colleague with much initiative who accompanied his chief to several congresses (Fig. 2). His innovative spirit, his skill in experiments with animals, and his critical interpretations led soon to meteoric success for this young dermatologist. Later in New York, Sulzberger was one of the first to study the immunologic resistance of the organism against tumor cells and immunologic tolerance. He conducted some carefully planned animal experiments in this area. These subjects are presently important in the research effort centering on malignant melanoma. What can we assume to be established facts concerning melanoma and how are results obtained today? Until approximately 10 years ago, information from a variety of clinics and medical centers with relatively small and often different treatments were assembled and evaluated in the world literature. Intense controversy broke out concerning the success of conventional treatment such as surgery, radiotherapy or a combination of first surgery then radiotherapy, or radiotherapy then surgery. These battles, which reminded one of medieval wars, almost became a national problem (Anglo-Saxon and French for surgery, German and Scandinavian for radiotherapy). However, it was soon demonstrated that the prognosis depended less on the applied therapy than on early diagnosis and treatment, as well as on favorable or unfavorable factors at the beginning of treatment.
For a long time, the problem of the malignant melanomas has not been just the concern of dermatologists, but surgeons, radiotherapists, nuclear physicians, oncologists, epidemiologists and immunologists as well. They often have vehement differences of opinion on this problem. This may be attributed partially to the fact that morbidity and mortality of melanoma is increasing worldwide among Caucasians. Interestingly, Sulzberger addressed aspects of this problem half a century ago. In 1926 Sulzberger presented, with the recommendation of Professor Bloch, his Inaugural Dissertation: "Ein Fall von Leukoplakia et Craurosis vulvae mit Tumorbildung und histologischem Befund der Bowen'schen Krankheit" (Fig. 1). As a voluntary assistant (with scarce pocket money?) together with 4 other voluntary assistants from foreign countries. Professor Bloch, his head-physician Doctor Cuido Miescher and 4 Swiss assistants (among them Werner Jadassohn), he helped to treat in that year 1,160 patients with 29,728 consultations. He contributed to the 17 publications released in 1926. Until his departure in 1928, he was an Address for reprints: Prof. Dr. H. Storck, Kantonsspital Zurich, Dermatologische Universltatsklinik, Gloriastrasse 31, Zurich, Switzerland. 384
No. 5
MALIGNANT MELANOMA
Storck
385
Prognosis The most important facts for the prognosis is the stage, the patient's sex, size of lesion, depth of penetration, classification of melanoma, location and finally, the age when the disease began. According to our observations in 1971 of some 1,000 cases selected from the world literature, the 5-year survival rate in stage I (primary tumors without clinically confirmed enlarged regional lymph nodes) is 5 1 % , 'n stage II (primary tumor with enlarged regional lymph nodes) only 12.6%, and in stage III (primary tumor with and without regional lymph nodes but with clinically manifest lymphogenic and hematogenic dissemination) 0%. Considering sex, we found that females (all stages) had a significantly higher 5-year survival rate of 31% than that of males (18%). If the diameter of the melanoma was smaller than 2 cm, 62% of the patients survived 5 years. If it was over 2 cm, only 27% lived 5 years. With regard to the melanoma classification, melanoma arising from active nevus pigmentosus or de novo from a healthy skin, prognosis proved to be significantly worse than with melanoma arising from melanotic freckles. The most favorable locations were head, arms and legs with 5-year survival rates of 28%, 35%, and 32%, compared to the melanoma on the trunk with only 19% or anogenital with only 10%. The age when the disease begins is important because juvenile melanomas in general are benign, with the exception of some rare melanomas arising from expanded nevus pigmentosus et pilosus (Tierfell-Nevus). Morbidity and mortality increase gradually after puberty, as well as after the menopause, which leads to the probable conclusion that gonadal hormones do not play an important role in the disease, only perhaps those of the hypophysis.
Aus der dcrmatologisdicn UniversitatsUlinik Zurich DlHDKTORi PROP. DR. B. BI-OCH
Ein Fall von Leukoplakia et Kraurosis vulvae mit Tumorbildung und histo= logischem Befund der Bowen'sdien Krankheit. INAUGURAL - DISSERTATION Eriangung der Doktorwiirde der medizinisclien Fakulrat der Universitat Zurich vorj^clcgt van MARION
B. SULZBERGER
NEW-YORK (U, S. A.> Geiitfhmiai Auf Antreg non Ptof. Dr. B . B L O C H .
Z U R I C H 1926 Dfudk von H. Haidi, Ziiridi 6 Nacdarratse 203
Fig. 1.
Malignancy Index If one wants to draw conclusions from small groups treated differently, this is only possible when favorable as well as unfavorable factors are taken into consideration. A procedure which takes both types of factors into account is the "malignancy index," which we developed for a group of 144 melanoma patients in 1968 and recently repeated with 315 cases. This index can be calculated by subtracting in a group of cases with a special treatment method the sum of all unfavorable factors (male, larger than 2 cm, arising from nevus pigmentosus or de novo, localization on trunk or anogenital) the sum of all favorable factors (female, smaller than 2 cm, arising from melanotic precancerosis, localization on head or extremities) and divide it by the number of patients of this
386
INTERNATIONAL JOURNAL OF DERMATOLOGY
June 1977
Vol. 16
ment of the lymph nodes, and that even in stage II, surgical removal was just as good as additional x-ray therapy before or after excision if you took into account the initial situation (malignancy index). In this biased group from a single clinic, the major effect of the stages could be demonstrated — 5-year survival rate for phase I from 71.8 ± 3.4%, phase II from 12.7 ± 3.7% and phase III from 4.4 ± 4.3%. . ._
Cooperative Studies
Fig. 2. Prof. Bruno Bloch, Dr. Guido Mieschr, Dr. Marion Sulzberger, Zurich 1927, starting for a congress.
group in question. The more positive the index, the less favorable is the initial situation. It became evident later that either the methods of treatment (surgery, radiotherapy, or combined surgery and then radiotherapy or radiotherapy and then surgery) produced no variations in the results. If there appeared to be differences, as in phase II, it was that the elevation of the malignancy index, that is, the initial situation, was decisive and not the method of treatment. This is disappointing and seems to make intense controversy senseless. Early diagnosis and early treatment is most important and the simplest method is total excision of the tumor from the healthy tissue. It became evident as well that nothing was gained through prophylactic treat-
Today, it is a national and international custom to investigate large groups. This presumes a reliable cancer register with the best possible histological diagnosis to judge morbidity and mortality, even though there is a 25% possibility for false diagnoses. In some countries, several clinics have joined together for cooperative and prospectiye studies, as has the German melanoma research group, which consists of 9 clinics in Western Germany. This group has 1,500 cases evaluated and programmed by computer and can apply the information for evaluation of homogenous groups and for "symptom twins." More and more randomized studies are carried out but they presuppose careful planning and selection. The big research projects are very expensive and leave little room for individual initiative, but they have the advantage of producing positive results as well as new possibilities for therapy, such as immunotherapy (BGG, Corynebacterium parvum, Levamisol), or Cytostatica (Oncovin, GGNU or DTIG). Some of these large investigations seem to confirm the influence of the previously mentioned favorable and unfavorable factors and also the minor effect of variations in conventional therapy. The significance of additional immunotherapy and of cytostatic therapy, especially in late stages, has not been proved yet.
No, 5
MALIGNANT MELANOMA
Retrospect In comparison to the years 1926-28, the time of Sulzberger's voluntary work, research has become exacting, expensive and for a single clinic with the "Stellenplafonierung," very difficult. In the clinic of Zurich, for instance, 50 years after Sulzberger, 1 chief with an assistant professor, 4 head physicians, 1 scientific head assistant and 16 assistant doctors, but unfortunately only too rarely with volunteers, treated 875 inpatients, 15,840 outpatients in 77,029 consultations, and published 22 papers. But the increasing incidence of malignant melanoma keeps pertinent the basic questions which possibly could be solved even today with a creative spirit a la Sulzberger— in a small clinic laboratory in cooperation with other disciplines of the medical faculty. That specific and nonspecific defense mechanisms of humoral and cellular immunity are important is no longer questioned. There may well be many other, mostly yet unknown, conditioning or causing factors. But as cultured human melanoma cells from primary tumor or metastasis change continuously in morphology, as Jurg Meyer in our clinic showed, this could correspond to changes in antigenicity. But how to outwit the malignant melanoma cells which cling
Storck
387
loosely together in the tissue or melastasize early, remain dormant "only to threaten" the life of a patient after years or decades? Would it be possible to incite the organism to kill those cells and cell complexes through a combination of specific and unspecific measures similar, for example, to the Shwartzman-Sanarelli phenomenon? Or, as found by Lipkin and Knecht, who worked for 1 year with us, could the newly identified, melanocytederived growth regulatory macromolecule (MCIF), which restores contact inhibition to malignant melanocytes, have important clinical bearing in the future? References 1, Sulzberger, M, B,: Ein Fall von Leukoplakia et Kraurosis vulvae mit Tumorbildung und histologischem Befund der Bowen'schen Krankheit, Inaugural-Dissertation, ZOrich, 1926, 2, Storck, H,, Ott, E,, and Schwarz, K,: Das maligne Melanom, In Handbuch der medizinischen Radiologie, Berlin, Springer, 1972, 19/1, pp, 161-257, 3, Storck, H,, and Ott, E,: Zu Verlauf und Therapie der malignen Melanome, Schweiz, Med, Wochenschr. 106:1871, 1976, 4, Lipkin, G,, and Knecht, M, E,: Wiederherstellung der Wachstumskontaktinhibition bei malignen Melanocyten von Mensch, Maus und Hamster, Schweiz, Med, Wochenschr, 105: 1360, 1975, 5, Meyer, J,: Unterschiedliches Verhalten von Melanomzellen aus Primartumor und Metastasen in vitro, Dermatologica, In press.
