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Voi. 114, No. 3 BONE INVOLVEMENT IN HODGKIN'S DISEASE By MICHAEL C. BEACHLEY, E. RICHARD RICHMOND, M.D.,t B. PECK KING, M.D. VIRGINIA LAU, M.D., and H ODGKIN'S disease is a neoplastic dis- ease of unknown etiology, primarily involving lymphatic and hemopoietic tis- sue, but occasionally involving other tis- sues. Its effects on bone are by:3 I . Direct extension (a) Pressure irritation leading to pen- osteal reaction, sclerosis of the "ivory" vertebra type, or anterior marginal erosion of vertebral bodies. ( b) Direct invasion of bone from without, entering through the periosteum from contiguous eased lymph nodes. 2. Blood borne emboli or transference disof an agent capable of inciting foci (mul- tifocal origin) in the medullary por- tion of bone, in the same way as by metastases. Opinion in the literature concerning the prognostic significance of bone involve- ment in Hodgkin's disease is divided,2'3'5'6 and some investigators feel that survival time is prolonged in patients with bone lesions.'6 From 1949 through 1966, we re- viewed 6i cases in our Tumor Board Regis- try with the primary diagnosis of Hodg- kin's disease involving the soft tissue, to determine the incidence and prognosis of patients with bone involvement. These were not all the cases of Hodgkin's disease seen at our institution during this time, in that from 1959 to 1965 the Tumor Board Registry was most incomplete and the ma- jority of cancer cases seen in the hospital were not registered. This report presents our findings together with a brief review of the literature on the subject. Ten cases were excluded because ofinadequate patho- logic data, and 2 because they were seen merely for diagnostic procedures and were not treated or followed. We have, therefore, 49 cases ofsoft tissue Hodgkin's disease for analysis, 10 of which also had bone in- volvement. Detection of bone involvement roent- genographically depends on changes re- lated to cortical bone involvement. The re- ported over-all incidence of i per cent is probably low because of asymptomatic cortical bone lesions which are not dis- covered. Four of io patients were asympto- matic, and 2 of asymptomatic patients had bone lesions when the diagnosis of Hodgkin's disease was made initially. W.B. and J.C. were discovered because the initial work-up of the majority of patients includes a chest roentgenogram and an intravenous pyelogram, which show the bones most likely to be involved (Table i). In the literature, Hodgkin's disease is re- ported to occur twice as frequently in men as in women, and usually between the ages of 35 to 55 years.3 In our series, the mean age of occurrence of Hodgkin's disease is approximately 40 years, and is also the same mean age in our patients with bone involvement. Our sex ratio is equal. Dif- fering from other reports, we found no sig- nificant difference in prognosis between males and females (Table ii). Roentgenographic appearance of Hodg- kin's disease of bone simulates that of any metastatic malignancy and may be sclerot- ic, lytic, or a mixture. Approximately two- thirds of the reported cases showed mixed lytic and blastic lesions. Osteolytic lesions, with areas of sclerosis confined to margins * From the Department of Radiology, Division of Radiation Therapy, Medical Virginia Commonwealth University, Richmond, Virginia. t Present Present Professor Address: Chief, Radiology Service, U. S. Patterson Army Hospital, Address: 515, North Palm Avenue, Fresno, California 93704. and Chairman of the Division of Radiation Therapy and Oncology. College of Virginia, Fort Monmouth, and the Health Sciences New Jersey 07703. Division, 559 560 M. C. Beachley, B. P. Lau and E. R. King MARCH, 1972 DATA ON PATIENTS TABLE I IN PRESENT SERIES WITH BONE INVOLVEMENT Lymph Node Name Sex Age Pathology Site of Lesion Local Treatment Survival (yr.) After Diagnosis After Bone Involvement R.W. H.M.* M T.S. M.S. S.H. 35 Granuloma 46 Paragranuloma Granuloma 43 Granuloma 22 Granuloma 46 Granuloma P.G. i6 Granuloma J.C. 84 Granuloma M.K. M 33 Granuloma W.B. M 5' Sarcoma J.D.* M 25 Paragranuloma Sarcoma Average 40.1 L4-Lg spine C7-TI Spine (Biopsy confirmed) Lumbar spine T9-T,o spine Left os pubis Skull (Biopsy confirmed) Left femur Left S-I joint Thoracic skeleton Right ilium Right S-I joint L-S spine 3,000 r 3,500 r None None None None 3 .6oo r 6,ooo rt None Yes- ? amount 6oo r Yes- ? amount * H.M. sarcoma, t Total and J.D. were histologically respectively. dose given in more than classified as paragranuloma i course of radiation therapy. on initial biopsy, but subsequently, 7.0 5.0 9.0 4.0 1.7 o.8 5.7 5.0 7.0 2.5 3.5 (live) 1.5 6.8 0.3 2.0 3.5 1.5 6.8 0.3 2.0 4.5 3.' biopsy showed granuloma and of lesions, or with are most common. are seen almost (ivory vertebra).2 prominent trabeculation, Pure osteoblastic lesions exclusively in the spine Peniosteal new bone for- SURVIVAL - TABLE 11 BY VARIOUS --- CATEGORIES OF DISEASE Category No. of Patients Average Survival After Diagnosis (yr.) Paragranuloma Granuloma Sarcoma Stage J* Stage 11* Stage JJJ* Patients with bone involvement Survival after develop- ment ofbone lesion(s) Patients without bone involvement Malest Femalest 8 33 8 6 12 3' o 39 27 22 * Classification t Representing classification, according comparable to M. V. Peters.' stages of disease 4.0 4. I o.86 5 .I 2.0 3.8 4.5 3 .I 3.3 3.7 3.4 and pathologic mation, as a result of cortical irritation from adjacent gland masses or intramedul- lary disease, occurs along the lumbar spine, ribs, and long bones.3 Our patients showed mostly osteolytic (Fig. I) and mixed type lesions (Fig. 2) and the majority were located in the lumbo- dorsal spine. Only 2 of 10 patients with bone involvement, however, had multiple lesions. Two of the 10 patients had histo- logic confirmation of the bone lesions, whereas in the remainder, the diagnosis was made roentgenographically. A com- parison of the bone histology with the lymph node pathology was not made in either instance. Table i shows the per- tinent data of those with bone involve- ment. Radiation therapy of bone lesions in Hodgkin's disease is generally considered palliative. Radiation therapy was delivered with eith.er a 300 kv. Maxitron orthovol- tage unit or a 2 mev. G. E. Maxitron. Doses to bone lesions ranged from 6oo-6,ooo r, calcul.ated at the depth of the lesion. All patients had a single course of irradiation VOL. 114, No. Bone Involvement in Hodgkin's Disease delivered to the bone lesions except for H.M. and P.G., who had 2 courses of ra- diation therapy. In neither of these cases did the bone lesions heal completely, al- though the progress of the bone destruc- tion, and pain, were arrested. Several of the patients who had spine and pelvis in- volvement also received an unknown addi- tional amount of irradiation to the bone lesions during courses of mediastinal and abdominal lymph node irradiation. Most of our patients were also receiving chemo- therapy and we can, therefore, not corre- late our local therapy for bone lesions with survival, nor state an optimum dose re- quired for bone lesions, based on our stud alone. tic.. 2. Same Patient as in Figure i, showing mixed osteolvtic and osteoblastic lesions of the skull. SURVIVAL In several reports, survival with Hodg- kin's disease and bone involvement is better than without demonstrable bone lesions. Vieta et al.,6 in a study of 38 cases with a brief review of the literature up to 1942, concluded that in the year follow-up period, survival was significantly better in the group with bone involvement, but the survival curves approximate each other at years and beyond (Fig. 3). Stuhlbarg and .1 - FIG. I. Purely osteolytic lesion of the right ilium in a 33 year old male (M. K.) with Hodgkin's granuloma. Ellis5 surveyed the literature more recently and added 30 cases of Hodgkin's disease with bone involvement. They noted in- creased survival in the group with bone in- volvement at the end of years compared to the non-involved group (Fig. 4). The foregoing authors were of the opinion that one could not infer that if patients with Hodgkin's disease lived long enough, bone lesions necessarily would become manifest. In our analysis we have considered all patients lost to follow-up, even though clinically free of disease at the last ex- amination, as deceased. Table ii shows the average survival by pathologic class, clinical stage, and with and without bone involvement. The most important determinant of prognosis is the stage of the disease on pre- sen tation. Although Hodgkin's sarcom a has a notoriously poor prognosis, there was no difference in survival between patients with paragranuloma and granuloma. In Stage i disease, however, there was a 5.1 year average survival compared with 2.0 years for Stage II and 3.8 years for Stage III. Those patients with bone involvement had an average survival after diagnosis of 4.5 years, and survival after development of the bone lesion(s) of 3.! years. Over-all survival of all patients without bone in- volvement is 3.3 years. The difference in 562 NI. C. Beachlev, B. P. Lao and E. R. King MARCH, 1972 SURVIVAL RATE OF PATIENTS HODGKIN'S DISEASE WITH 00 Comparison Of Groups With And Without Osseous Involvement 0x 80 0--- WITH BONE LESIONS - 55 CASES `.4 `.4 #{149}- WITHOUT BONE LESIONS -198 CASES 60 `.4 `.4 4"a' 40 `.4 `.4 `.4 `.4 20 0 2 24 36 48 60 72 84 MONTHS AFTER DIAGNOSIS ( Vieto, Friedell and Caver. 1942) .FIG. Survival is better in 5 years and of patients with Hodgkin's disease. In a c `ear follow-up period, it is noted the group with hone involvement, but that the survival curves approximate beyond. (Reprinted through the courtesy of Radiology.6) that survival each other at survival is riot satisticallv significant, but at least it shows that the survival rates are comparable. Figure c illustrates the sur- vival curves for patients with and without bone involvement. It may be thought that any patient with Hodgkin's disease, if he lives long enough, will develop bone involvement and, therefore, his average survival after diagnosis will appear to be longer. How- ever, in our series, most of the patients (7:10) had the appearance of a bone lesion during the first half of the disease. S U M MARY Approximately 15 per cent of all patients with Hodgkin's disease will have roentgen- ()graphic evidence of cortical bone involve- ment. Our series shows a 20 per cent in- cidence, with no predilection regarding sex, age, or pathologic classification. Representative roentgenograms are dem- onstrated. The most frequent areas in- volved are the spine and pelvis, and the lesions are usually mixed lvtic and blastic. Lesions sim ulate metastati c malignancies of any kind. Survival curves of 2 previous reports demonstrate an increased survival rate in patients with bone involvement. In our -J 00 0: K SURVIVAL RATE OF PATIENTS HODGKIN'S DISEASE WITH o WITH BONE LESIONS - 30 CASES #{149}WITHOUT BONE LESIONS- 128 CASES 0.., rno.. ".`O 44 0 0 24 48 72 96 20 MONTHS AFTER BIOPSY Stuhlborg and Ellis, 965) 11G. 4. Survival rates for patients with Hodgkin's disease.5 SOL. 114, No. 3 Bone Involvement in Hodgkin's Disease SURVIVAL RATES FOR PATIENTS WITH AND WITHOUT BONE INVOLVEMENT 563 WITHOUT BONE (39 PATIENTS) INVOLVEMENT 00 90 80 70 60 (1) 50 a WITH BONE INVOLVEMENT SURVIVAL HODGKIN'S AFTER DIAGNOSIS OF DISEASE (10 PATIENTS) WITH BONE INVOLVEMENT SURVIVAL AFTER DIAGNOSIS OF BONE INVOLVEMENT (10 PATIENTS) 40 30 20 10 0 0 I2 3 4 5 6 7 8 9 YEAR S FIG. 5. Survival rates for 49 patients with and without bone involvement seen at the Tumor Board Registry of the Medical College of Virginia from 1949 to 1966. series, the average survival after diagnosis of patients with bone involvement was 4.5 years, and 3.! years after the onset of bone involvement. The average survival after diagnosis without bone involvement was 3.3 years. We cannot statistically prove with the number of cases in this study that survival is improved in patients with bone involvement, but we can show that at least there is no significant difference in the sur- vival of the 2 groups. E. Richard King, M.D. l)ivision of Radiation Therapy Medical College of Virginia- Virginia Commonwealth University 1200 E. Broad Street. Richmond, Virginia. 23219 We are grateful to Dr. Seymour Levitt, Director of the Department Therapeutic Radiology, School of H. of Med- icine, University ohs, Minnesota, writing of this of Minnesota, for his assistance manuscript. Minneapin the REFERENCES I. 1)REssER, R., and SPENCER, J. Hodgkin's disease and allied conditions of bone. AM. J. ROENT- GENOL. & RAD. THERAPY, 1936, 36, 809-8 15. 2. 1L'CILLA, I. S., and HAMANN, A. Hodgkin's disease in bone. Radiology, 1961, 77, 53-60. 3. GRANGER, W., and WHITAKER, R. Hodgkin's dis- ease in bone: with special reference to periosteal reaction. Brit. 7. Radiol., 1967, 40, 939-948 4. PETERS, M. V. Study of survivals in Hodgkin's disease treated radiologically. AM. J. ROENT- GENOL. . STUHLBARG, & RAD. THERAPY, 1950, 63, 299-311. J., and ELLIS, F. W. Hodgkin's dis- ease of bone: favorable prognostic significance? AM. J. ROENTGENOL., RAD. THERAPY & NU- CLEAR MED., 1965, 93, 568-572. 6. V1ETA, J. 0., FRIEDELL, H. L., and CRAVER, L. F. Survey of Hodgkin's disease and lymphosar- coma in bone. Radiology, 1942, 39, 1-15.