LIFE EXPECTANCY AND INCIDENCE OF MALIGNANT DISEASE V. MALIGNANT LYMPHOMA, FIBROSARCOMA, MALIGNANT MELANOMA, AND OSTEOGENIC SARCOMA

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1 LIFE EXPECTANCY AND INCIDENCE OF MALIGNANT DISEASE V. MALIGNANT LYMPHOMA, FIBROSARCOMA, MALIGNANT MELANOMA, AND OSTEOGENIC SARCOMA IRA T. NATHANSON,l M.D., AND CLAUDE E. WELCH,2 M.D. (From the Collis P. Huntington Memorial Hospital of Harvard University, and the Pondville State Hospital, Wrenthaw, Mars.) This is the fifth and last of a series of papers dealing with the life expectancy in the more common types of malignant disease. Carcinomas of the breast, buccal cavity, gastro-intestinal, and genito-urinary systems have been discussed in previous communications (1-4). Malignant lymphoma, including Hodgkin's disease, the leukemias, malignant melanoma, fibrosarcoma, and osteogenic sarcoma will now be considered. The selection of cases and the methods of calculation have been described fully in the earlier papers. MALIGNANT LYMPHOMA All malignant disease primary in the lymphatic systkm is considered under this heading. This includes the tumors diagnosed as giant follicular-cell lymphoma, of which there are very few examples, lymphocytoma, lymphosarcoma, and Hodgkin's disease. The number of cases included in the subgroups is too small for the preparation of individual curves, except for Hodgkin's disease and lymphosarcoma. While it is probable that a careful histological review of all specimens would lead to a change in the type classification of malignant lymphoma in several instances, such a regrouping should have no effect upon the combined curve, and very little upon the subgroups of Hodgkin's disease and lymphosarcoma. There is, in any event, much controversy over the classification of these subgroups, though any discussion of this phase of the subject is beyond the scope of the present paper. There were 310 cases of malignant lymphoma, exclusive of Hodgkin's disease. Of these patients, 25 per cent were dead in 14 months, 50 per cent in 24 months, and 75 per cent in 57 months. Five years after onset 94 per cent were dead. Five patients lived over 10 years from onset, while one is living after 26 years. Included in the age incidence series were 384 cases, 273 (71.0 per cent) in males. The median age at onset was 45---of the males 43, and of the females 49. The striking feature about the age incidence is the diffuse spread throughout the entire age group. The youngest patient was 1 year of age and the oldest 88. Of Pack and LeFevre7s series (5) 64 per cent were males. The greatest distribution of cases occurred between the ages of 35 and 39. Their average age at onset was 43. Thirty-two cases of malignant lymphoma were primary in the tonsil. Of the 32 patients, 25 per cent were dead in 1 year, 50 per cent in 16 months, and 1 Lucius N. Littauer Fellow in Cancer. "esident Surgeon, Massachusetts General Hospital. 593

2 LIFE EXPECTANCY AND INCIDENCE OF MALIGNANT DISEASE per cent in 24 months. Five years after onset, 90 per cent were dead. This curve is practically identical with that of carcinoma of the tonsil. Fifty-five of the cases of malignant lymphoma were designated as lymphosarcoma. Of this group, 25 per cent were dead in 12 months, 50 per cent in 20 months, and 75 per cent in 36 months. Five years after onset 82 per cent were dead. The life expectancy is somewhat less for the first 8 years after onset than for the other combined cases of malignant lymphoma. After that period the curves continue together. Hodgkin's Disease: The usual histological criteria by which Hodgkin's disease is differentiated are the presence of Dorothy Reed cells and of eosinophils, necrosis, and fibrosis. There were 184 cases classified under this heading. Twenty-five per cent of the patients were dead in 16 months, 50 per cent in 30 months, and 75 per cent in 57 months. Five years after onset 77 per cent were dead. There is, therefore, no significant statistical variation in the life expectancy of patients with Hodgkin's disease and those with malignant lymphoma. The age incidence series included 220 patients of whom 67.6 per cent were males. The median age was 34, being the same for males as for females. There is no definite peak of age incidence, but the distribution is proportionately larger in younger age groups than for malignant lymphoma. The aver-

3 600 IRA T. NATHANSON AND CLAUDE E. WELCH age age in Pack and LeFevre's series was 35, while 60 per cent of their patients were males and the peak of age incidence was between 30 and 34 years. Sex and Life Expectancy: Since the life expectancies of patients with Hodgkin's disease and malignant lymphoma are nearly the same, they have been considered together and curves drawn for the two sexes. Females seem to have a somewhat better life expectancy in the earlier years. The Leukemias. It is obviously difficult to determine the exact date of onset of either type of chronic leukemia; therefore we have taken the date Per cent of onset as that time at which the patient noticed the first symptom referable to the disease. There were 96 cases of lyliiphatic leukemia, including both acute and chronic cases. Twenty-five per cent of the patients were dead in 9 months, 50 per cent in 21 months, and 75 per cent in 48 months. Five years after onset 82 per cent were dead. With myelogenous leukemia the prognosis is better, provided both acute and chronic cases are included. There were 141 cases, with 25 per cent of the patients dead in 19 months, 50 per cent in 36 months, and 75 per cent in 55 months. Five years after onset 78 per cent were dead. There are relatively more acute lymphatic than acute myelogenous leukemias. If the acute forms are eliminated, the life expectancies for the two

4 types are essentially the same. About 75 per cent of the patients with acute leukemia are dead in 6 months, and the remainder within a year. There were 117 patients with lymphatic and 156 with myelogenous leukemia included in the age incidence series; 78.6 per cent of those with lymphatic leukemia were males as compared with 59.6 per cent of those having myelogenous leukemia. The median age of the patients with lymphatic leukemia was 50--of the females 43, a,nd of the males 52. The median age in myelogenous leukemia was 40, being the same in males and females. It is of interest that the median age of patients with lymphatic leukemia is 5 years greater than that of those with malignant lymphoma. Many patients developed lymphatic leukemia several years after the onset of malignant lymphoma. Of the cases of lymphatic leukemia 42.5 per cent occurred between the ages of 49 and 60. There are many cases of lymphatic leukemia in early childhood, usually of the acute type. In 11.2 per cent of the series the onset was before 10 years of age, while only 1.8 per cent of the cases of myelogenous leukemia occurred during the same period. Myelogenous leukemia is uncommon below the age of 25; 49.6 per cent of the patients were between the ages of 31 and 45. We do not have enough cases to confirm the interesting conclusion of Warren (6) and Minot (7) that the greatest incidence of lymphatic leukemia in the fifth decade of lifei.e., the menopausal period-is in females. Discussion: For a detailed discussion of the life expectancy of patients

5 602 IRA T. NATHANSON AND CLAUDE E. WELCH with malignant lymphoma, Hodgkin's disease, and the leukemias, the excellent papers of Minot and Isaacs (7, 8), and of Minot, Buckman, and Isaacs (9) should be consulted. They found the average duration of life in 401 fatal cases of malignant lymphoma to be 2.76 years. The duration was practically as long in the untreated cases as in the treated, although early irradiation or thorough surgery apparently increased the duration of life. The age and sex incidence were almost identical with our series. A curve constructed from Minot's 83 untreated cases of malignant lymphoma and Hodgkin's disease is included in Fig. 1. It indicates that there is a significant difference between treated and untreated patients. In the median patient the life expectancy is prolonged 7 months by treatment. Jackson (10) has recently studied the age incidence and prognosis of the individual types of malignant lymphoma. For a summary of the differential features of these subgroups the reader is referred to his paper. He found that in lymphosarcoma the average duration was 2.2 years while in reticulumcell sarcoma the length of life was 1.8 years after onset. No patient with lymphosarcoma, however, survived the ten-year period, whereas 2 per cent of those with reticulum-cell sarcoma lived beyond that limit. Jackson divides Hodgkin's disease into three types-early Hodgkin's, classical Hodgkin's, and Hodgkin's sarcoma. Of his first group, 20 per cent had the disease 15 years

6 or more, although the average duration of life was 2.6 years. Patients in the second group (classical Hodgkin's) lived 2.5 years on the average, but none longer than 10 years. None of the patients in the third group lived over 3 years. Because of this division into subgroups, we cannot correlate the age incidence of our series with Jackson's. Leucutia (11) has collected and reviewed the statistics of malignant lymphoma. He found the five-year survival to be 30 per cent and the ten-year between 10 and 15 per cent. He believes that thorough irradiation will in- crease the length of life about a year in malignant lymphoma, while the corresponding increase in Hodgkin's disease is 1.5 years. Craver (12) had 12.7 per cent 5-year survivals in Hodgkin's disease, dated from the time of treatment, and 7 per cent in lymphosarcoma. Jackson, Parker, and Brues (13) reported 37 cases of malignant lymphoma of the tonsil (including Hodgkin's disease). The average duration of life from onset to death was 2.6 years, and the median 1.4 years. Four patients survived 5 years. Figures for age and sex incidence of the leukemias determined by Minot and Isaacs agree closely with those in this series. They state that the average survival of patients with chronic lymphatic leukemia is 3.45 years, while 50 per cent of those with the acute form die within 2 months of the onset of symptoms. Minot, Buckman, and Isaacs found that the average duration of life after the first symptom in 52 non-irradiated patients with chronic

7 604 IRA T. NATHANSON AND CLAUDE E. WELCH myelogenous leukemia was 3.04 years and in 68 irradiated patients 3.5 years. They agree with Hoffman and Craver (14) and Leucutia in emphasizing the increased period of efficient life resulting from irradiation, estimating it to be about 30 per cent of the total life expectancy. Hoffman and Craver's data on sex and age incidence agree closely with ours. Of Pack and LeFevre's patients with lymphatic leukemia, 72 per cent were males; the average age of the females in their series was 4 years greater than that of the males. Of 77 patients with myelogenous leukemia, 65 per cent were males; the average age was 41. Per cent Fi brosarcoma Age :Above 40 (88 cases) - - Normal life expectan YPS There were 161 cases of fibrosarcoma. Twenty-five per cent of the patients were dead 19 months after onset, 50 per cent in 43 months, and 75 per cent in 10 years. Five years after onset 58 per cent were dead. No attempt has been made to divide these cases into separate histological groups. Such a division would show marked variation in expectancy for, as Warren (15) has shown, while the average duration of life for fibrosarcoma proper is 7.0 years and for neurogenic sarcoma 7.8 years, if tumor giant cells are present, the average is reduced to 2.2 and 5.5 years respectively. Histological groupings, based upon different criteria, have been employed by Stewart and Copeland (16), and by Quick and Cutler (17). They also found variation with the type of tumor.

8 It must be recognized, therefore, that this group is heterogeneous, and the variations in life expectancy are great, depending upon the type of tumor. The prognosis of the combined group, as shown by the curve in Fig. 5, is better than that for any type of carcinoma studied, except those of the lip, penis, and fundus of the uterus. Age and Life Expectancy: The patients have been divided into two groups -those above 40 and those younger. A third small subgroup comprises the patients who developed the disease at the age of 60 or over. The number of cases in each group is not large, but the indication is that older patients with Per cent fibrosarcoma die more rapidly. When compared with normal life expectancy the disease is more malignant in the young (Fig. 6). Age Incidence: There were 176 patients available for age incidence studies; 120 were males (68.2 per cent). The median age of the entire group was 41, being the same for males and females. There is no sharp peak of age incidence, but a rather uniform spread between the ages of 20 and 60. The youngest patient was 2 years old, and the eldest 85 years of age at onset. In Stewart and Copeland's series of 83 neurogenic sarcomas, the greatest incidence was between 20 and 50 years. Warren found the average age at onset of all fibrosarcomas to be 49.1 years for males, and 50.1 years for females. Warren states that the age distribution of fibrosarcoma is not far different from that for carcinoma, although sarcoma is more frequent in the younger age groups.

9 606 IRA T. NATHANSON AND CLAUDE E. WELCH There were 128 cases of malignant melanoma in our series. Twenty-five per cent of the patients were dead in 18 months, 50 per cent in 39 months, and 75 per cent in 72 months. Five years after onset 67.5 per cent were dead. The life expectancy for malignant melanoma is distinctly lower than that for fibrosarcoma. This is due, however, to the fact that the median age of patients with malignant melanoma is 53. compared with only 41 for fibrosarcoma. If calculation is made of the percentage of patients that died of malignant disease at various intervals after onset, it will be found to be the same in both fibrosarcoma and malignant melanoma. Thus 10 years after onset 73 per cent of patients with fibrosarcoma are dead. Normally, at the median age of 41, 10 per cent would be dead 10 years later. In other words, 63 per cent may be considered to have died of fibrosarcoma. Similar calculations may be made for different time intervals and a table constructed as follows : Percentage of Patients Dead of Malignant Disease 1 Years after onset Fibrosarcoma Malignant melanoma It has been suggested by Masson (18) and later by Ewing that malignant melanomas are closely related to and may be tumors of neurogenic origin. This close correspondence of the life expectancies of patients with malignant melanoma and fibrosarcoma (Fig. 7) leads to further speculation concerning their relationship. Scharnagel (19) in an analysis of 81 malignant melanomas of the skin and vulva observed in the Radiumhemmet in found the average age at admission to be 54 years. Thirty-six per cent of the patients were males. Only 70 were treated; 45.7 per cent were " cured " 3 years later, 38.7 per cent in 5 years, and 35 per cent 10 years later. Adair (20) reported on 400 cases admitted to the Memorial Hospital from 1917 to In 70 the disease was classified as primary and operable; 33 per cent of this group survived the 5-year period. Fifty-five cases were recurrent but operable; 27 per cent of this number survived 5 years. The fiveyear survival rate of the 267 cases, primary and recurrent, admitted before 1931, was 14.5 per cent. Age Incidence: Of 156 patients admitted before 1936, 63.5 per cent were. males. The median age was 53---of the males 49, and of the females 55. The youngest patient was 2 years, and the oldest 93 years of age. The peak of incidence occurred between the ages of 49 and 66; 49.2 per cent of the cases were found in this age period. In Pack and LeFevre's series of 208 cases, the average age was 48.

10 There were 81 cases of osteogenic sarcoma. Twenty-five per cent of the patients were dead in 11 months, 50 per cent in 21 months, and 75 per cent 42 months after onset. Five years after onset 85 per cent were dead. The Registry of Bone Sarcoma at the last report contained 466 cases of osteogenic sarcoma treated 5 years or more ago. There were 67 five-year cures (14.4 per cent). Crowell (2 I), however, states that "a percentage of the curability of the disease is not given, as this series does not represent a consecutive series of cases treated, and there is a tendency for doctors to pay more attention to the registration of their unusually successful cases than to a registration of all their cases.'' Geschickter and Copeland (22), in a series of 69 patients with osteolytic sarcoma who were followed over 5 years, found 10 per cent living 5 years after treatment. Of 65 patients with sclerosing osteogenic sarcomas 26.2 per cent were alive 5 years after treatment. Our data indicate that patients less than 30 years of age tend to die more rapidly than those over that age until the fourth year after onset, beyond which time the rate is similar in both the young and the old. In other words, osteogenic sarcoma is more malignant in the young. This may be due to the different type of osteogenic sarcoma in the old; a number of these sarcomas arise from preexisting osseous lesions, such as Paget's disease or old fractures. Age Incidence: Ninety-six cases were available for age incidence studies. The youngest patient was 2 years of age and the oldest 76 years at onset; 64.6 per cent were males. Twenty-five per cent of the patients were between 16 and 2 1 years of age; the peak of incidence was between 16 and 18. Nearly half the cases occurred between the ages of 13 and 27. The median age at onset was 25 years. Geschickter and Copeland found the peak of incidence in both the sclerosing and osteolytic sarcomas to be between 16 and 20, although the osteolytic type of disease was definitely more common in the older group than in the younger. The average age at onset of 400 cases observed by Pack and LeFevre was 30; per cent of the patients were under 25 years of age. Twenty-nine per cent of all malignant tumors in patients under 25 in the Memorial Hospital were osteogenic sarcomas. The number of cases of Ewing's sarcoma was insufficient for statistical analysis. It is of interest to note that Crowell has reported that 105 cases have been accepted by the Bone Registry and 9 patients (8.6 per cent) lived 5 to 21 years following treatment. 1. There appears to be no significant variation in the life expectancy' of patients with Hodgkin's disease and those with other types of malignant lymphoma.,the median life expectancy for Hodgkin's disease is 30 months, of the other types, 24 months.

11 608 IRA T. NATHANSON AND CLAUDE E. WELCH 2. The median life expectancy of patients with chronic leukemia, either lymphatic or myelogenous, is about 40 months. 3. Acute lymphatic leukemia was more common than acute myelogenous in this series. 4. Treatment prolongs the life of patients with malignant lymphoma about 6 months. 5. The median life expectancy of patients with fibrosarcoma is 43 months, with malignant melanoma 39 months, and with osteogenic sarcoma 2 1 months. 6. Females with malignant lymphoma appear to have a slightly bett.er prognosis than males in early years. 7. A discussion of the sex and age incidence is included. NOTE: The authors desire to express their gratitude to Dr. Channing C. Simmons, Dr. Joseph C. Aub, and Prof. E. B. Wilson, members of the Cancer Commission of Harvard University, Dr. Herbert L. Lombard, Statistician of the Massachusetts Department of Health, and Dr. E. M. Daland, Surgeon-in-Chief of the Pondville Hospital, for helpful suggestions and advice in the preparation of this and the earlier papers in this series; but this statement should not be taken as transferring to them any responsibility for the correctness of the material or results. 1. NATHANSON, I. T., AND WELCH, C. E.: Am. J. Cancer 28: 40, WELCH, C. E., AND NATHANSON, I. T.: Am. J. Cancer 31: 238, NATHANSON, I. T., AND WELCH, C. E.: Am. J. Cancer 31: 457, NATHANSON, I. T., AND WELCH, C. E.: Am. J. Cancer 31: 586, PACK, G. T., AND LEFEVRE, R. G.: J. Cancer Res. 14: 167, WARREN, S. L.: Am. J. M. Sc. 178: 490, MINOT, G. R., AND ISAACS, R.: Boston M. & S. J. 191: 1, MINOT, G. R., AND ISAACS, R.: J. A. M. A. 86: 1185, 1265, MINOT, G. R., BUCKMAN, T. E., AND ISAACS, R.: J. A. M. A. 82: 1489, JACKSON, H., JR.: Surg. Gynec. & Obst. 64: 465, LEUCUTIA, T.: Am. J. M. Sc. 188: 612, CRAVER, L. F.: Surg. Gynec. & Obst. 60: 485, JACKSON, H., JR., PARKER, F., JR., AND BRUES, A. M.: Am. J. M. Sc. 191: 1, HOFFMAN, W. J., AND CRAVER, L. F.: J. A. M. A. 97: 836, WARREN, S., AND SOMMER, G. N. J., JR.: Arch. Surg. 33: 425, STEWART, F. W., AND COPELAND, M. M.: Am. J. Cancer 15: 1235, QUICK, D., AND CUTLER, M.: Ann. Surg. 86: MASSON, P.: Ann. d'anat. path. 3: 417, 657, SCHARNAGEL, I. M.: Acta Radiol. 14: 473, ADAIR, F.: Surg. Gynec. & Obst. 62: 406, CROWELL, B. C. : Am. J. Surg. 27 : 48, GESCHICKTER, C. F., AND COPELAND, M. M.: Tumors of Bone, pub. by Am. J. Cancer, 1936.