Hodgkin s Disease of the Mediastinum
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1 THE ANNALS OF THORACIC SURGERY Journal of The Society of Thoracic Surgeons and the Southern Thoracic Surgical Association VOLUME 3 NUMBER 4 APRIL 1967 Hodgkin s Disease of the Mediastinum William A. Burke, M.D., Thomas H. Burford, M.D., and Ronald F. Dorfman, M.B., B.Ch. A lthough Thomas Hodgkin first described the disease that bears his name 134 years ago, the etiology is still unknown. Until recently Hodgkin s disease was widely held to be progressively fatal and incurable [l] while varying greatly in its malignant potential. Our own clinical impression that Hodgkin s disease localized to the mediastinum has a favorable prognosis prompted this study. Recent reports correlating the clinical stage of the disease at onset with a revised histological classification and with survival times would seem to confirm this impression [6, 121. The method of staging (Table 1) suggested by a committee of the American Cancer Society [15] is a modification of the classification of Peters and Middlemiss [ 161. The new histological classification proposed by Lukes et d. [I31 is shown in Table 2 and is compared with that of Jackson and Parker [8], widely employed since The new histological classification includes an entity which Lukes called nodular sclerosing Hodgkin s disease [ 121. This is of particular significance in our study, since both he and Hanson [6] have shown initial involvement From the Division of Thoracic and Cardiovascular Surgery and the Division of Surgical Pathology, Barnes Hospital and Washington University School of Medicine, St. Louis, Mo. This study was supported in part by U.S. Public Health Service Grant No. CST 33765(66) and by an institutional grant to Washington University (IN-36H) by the American Cancer Society. Presented at the Third Annual Meeting of The Society of Thoracic Surgeons, Kansas City, Mo., Jan , VOL. 3, NO. 4, APRIL,
2 BURKE, BURFORD, AND DORFMAN Stageb I I1 I11 IV TABLE 1. REVISED CLASSIFICATION OF HODGKIN S DISEASEa Description Disease limited to 1 anatomical region. (1) Disease limited to 2 contiguous anatomical regions on same side of diaphragm. (2) Disease in more than 2 anatomical regions or in 2 noncontiguous regions on same side of diaphragm. Disease on both sides of diaphragm but limited to involvement of lymph nodes, spleen, and Waldeyer s ring. Involvement of bone marrow, lung parenchyma, pleura, liver, bone, skin, kidneys, gastrointestinal tract, or any tissue or organ other than lymph nodes, spleen, or Waldeyer s ring. Devised by Peters et nl. C151. DAll stages will be subclassified as A or B to indicate the absence or presence, respectively, of systemic symptoms. of the mediastinum by this type of Hodgkin s disease to be four times greater than mediastinal involvement in the Hodgkin s granuloma group (mixed type of Lukes et al.). Hanson has also reported a very favorable prognosis in association with nodular sclerosing Hodgkin s disease. In addition, the results of the study of Lukes et al. indicate that histological types manifested by lymphocyte proliferation in the stroma are associated with prolonged median survivals. Those with lymphocyte depletion have a poorer prognosis. Our study includes patients presenting with an asymptomatic mediastinal mass (Stage I disease) or a mediastinal mass associated with enlarged supraclavicular lymph nodes (Stage I1 disease). These are patients whom the thoracic surgeon is frequently called upon to investigate and to initiate therapy. Utilization of accurate clinical staging together with a precise histological classification should enable the surgeon to institute a logical therapeutic regime and give a reasonably accurate prognosis. TABLE 2. COMPARISON OF HISTOLOGICAL CLASSIFICATIONS OF HODGKIN S DISEASEa Jackson and Parker [81 Paragranuloma Granulomas& Lukes, Butler, and Hicks Lymphocytic andor histiocyticb a. Nodular b. Diffuse = Nodular sclerosis Mixed - Diffuse fibrosis Sarcoma Reticular From Lukes et nl. [HI. bl & H types may have predominance of either lymphocytes or histiocytes. 288 THE ANNALS OF THORACIC SURGERY
3 Hodgkin s Disease of Mediastinurn MATERIAL AND METHODS During a 14-year period ( ) 296 thoracotomies for mediastinal tumors were performed by the chest surgical service at Barnes Hospital. In 12 cases (4.1%) a diagnosis of Hodgkin s disease was made on microscopic examination of excised tissue from the mediastinum. These 12 patients were found to have a mediastinal mass on routine chest x-rays. They ranged in age from 14 to 52 years, with an average age of 33 years. There were 8 males and 4 females. These comprise the patients with Stage I disease. Complete excision of the tumor mass was possible in 7 of the 12 patients. Four had a biopsy only because of involvement of vital structures. In the remaining patient, an irremovable remnant of tumor surrounding the innominate vein was left in situ. Nine patients received postoperative radiation therapy in the range of 2,000 or 4,000 R. During the same period of time, 10 patients were encountered that had x-ray evidence of a mediastinal mass together with histologically proved Hodgkin s disease involving supraclavicular or scalene lymph nodes. Their ages ranged from 15 to 61 years, with an average age of 36 years. The sexes were evenly divided. These comprise the group with Stage I1 disease. Ten patients were excluded from this study when mediastinal involvement was found to be associated with widespread dissemination of the disease (Stages 111 and IV). RESULTS STAGE I DISEASE All 12 patients with Stage I disease are alive from 1 to 12 years following thoracotomy (Fig. 1). Eight of this group have survived from 5 to 12 years. Review of the histological sections showed nodular sclerosing Hodgkin s disease in 5 cases (Fig. 2). The mixed type was present in 5 patients and was associated in 3 with lymphocyte predominance in the stroma (Fig. 3A). Lymphocyte and histiocyte predominance (L & H type) was noted in 2 cases. The thymus was involved or composed the excised specimen in 4 patients (Fig. 4). In 2 of these the microscopic pattern was that of nodular sclerosis, while the other 2 showed a mixed pattern (granuloma type). Of the 8 patients with mediastinal lymph node involvement, 3 showed nodular sclerosis, 3 a mixed pattern with lymphocyte predominance, and 2 the L & H type. No. Patients -Each Histologic Group FIG. 1. Patients with Stage I of Hodgkin s disease, comparing survival with histological type. VOL. 3, NO. 4, APRIL,
4 BURKE, BURFORD, AND DORFMAN FIG. 2. Nodular sclerosing Hodgkin s disease of the thymus gland. Bands of collagen surround nodules of lymphoid tissue containing Reed-Sternberg cells (inset, right lower corner). (H&E, ~ 12.) A FIG. 3. Hodgkin s disease with typical Reed-Sternberg cells. (A) Lymphocyte predominance in the stroma. (HhE, X48O.J (B) Lymphocyte depletion. (H&E, ~800.) The disease has recurred in 3 of this group of patients. The first developed supraclavicular adenopathy and x-ray evidence of a mediastinal mass two years following his initial surgery and radiation therapy. He received a second course of radiation therapy, and his chest film four years later is normal. One patient with nodular sclerosis involving mediastinal lymph nodes developed an enlarged supraclavicular lymph node two years after his original operation. This was biopsied and showed a microscopic change to a mixed B 290 THE ANNALS OF THORACIC SURGERY
5 Hodgkin s Disease of Mediastinum FIG. 4. Thymus gland, the normal architecture of which is replaced by nodular sclerosing Hodgkin s disease, illustrated in Figure 2. FIG. 5. Right lung with many foci of Hodgkin s disease, nodular sclerosing type, in all three lobes. A large area of radiation fibrosis is seen in the posterior basilar segment of the lower lobe (arrow). pattern. Further radiation therapy was given, and he is now free of disease at five years. A patient with nodular sclerosing Hodgkin s disease received intensive radiation therapy following biopsy of a mediastinal lesion which showed involvement of the thymus gland. Because of a disabling cough with bronchoscopic and x-ray evidence of severe radiation fibrosis, a right pneumonectomy was performed five years after his initial surgery. In addition to radiation fibrosis, there was gross VOL. 3, NO. 4, APRIL,
6 BURKE, BURFORD, AND DORFMAN 12 Nodular Sclemaia 9 P 8, 8 i s e3 I 2 I No. Patients - Each Histologic Group FIG. 6. Patients zoith Stage IZ of Hodgkin s disease, comparing survival with histological type. and microscopic evidence of nodular sclerosing Hodgkin s disease in the lung (Fig. 5) and mediastinal lymph nodes. One year later he has presumptive clinical evidence of retroperitoneal lymph node involvement and represents the 1 failure in this group. Figure 6 shows the years of survival for each patient related to the histological type of disease. STAGE I1 Of the 10 patients in the Stage I1 group (Fig. G), the microscopic diagnosis on review of the supraclavicular lymph node biopsies was Hodgkin s disease, mixed type (granuloma) in 8 and nodular sclerosis in 2. All 10 patients received radiation therapy to the involved supraclavicular lymph nodes and mediastinum. Following the diagnosis of Hodgkin s disease Stage 11, no surgical extirpation of the involved anatomical regions was contemplated. There have been 5 deaths in this group. Four of these had a mixed pattern in the initial biopsy. In the other, a 15-year-old boy who died within 3 years, the microscopic pattern was that of nodular sclerosis. No autopsy was performed, but there was clinical evidence of disseminated disease. Autopsy examination of 3 patients showed widespread dissemination of the disease with lymphocyte depletion (see Fig. 3B) and fibrosis. Although our study includes a relatively small number of patients, there is a significant difference in survival in the Stage I group as compared with Stage 11. While all patients with Stage I disease are alive from 1 to 12 years after thoracotomy, 50% of Stage I1 patients have died (see Fig. 6). DISCUSSION Far from the dismal picture which a diagnosis of Hodgkin s disease suggests to many, review of several recent reports suggests that Stage I disease with the histological pattern of nodular sclerosis or lymphocyte predominance is associated with a high percentage of longterm survivals. According to Easson [4] survival for 10 years should be equated with cure. There is some controversy in the literature concerning the treatment of choice in localized Hodgkin s disease. Although radical lymph 292 THE ANNALS OF THORACIC SURGERY
7 Hodgkin s Disease of Mediastinurn node dissection with or without radiation therapy is favored by some [5, 7, 141 the consensus of opinion is swinging toward radiation therapy as the treatment of choice [9, 15, 161. The present study would suggest, however, that Hodgkin s disease of the mediastinum is best treated by a combination of surgery and radiation therapy. Nine of our Stage I patients were treated in this manner. The incidence of mediastinal Hodgkin s disease in our study (4.1% of all mediastinal tumors) is similar to that reported by Blades [21 and Curreri and Gale [3]. Almost half of the patients with Stage I disease had a histological pattern of nodular sclerosis. This compares favorably with the findings of Lukes et al. [13] in their much larger series. The incidence of this type of disease was lower in Stage I1 (only 2 of 10 in our series) which may account for the relatively high mortality in our Stage I1 group. In Hanson s study [6], Stage I1 patients with nodular sclerosing Hodgkin s disease had prolonged survivals as compared with those with Hodgkin s granuloma (mixed type). The L & H type (corresponding to Hodgkin s paragranuloma) was seen in 2 long-term survivors with Stage I disease in our study. A mixed pattern (corresponding to the granuloma type of Jackson and Parker [S]) associated with lymphocyte predominance in the stroma was also associated with a better prognosis than those cases with lymphocytic depletion. Hanson found no cases of nodular sclerosing Hodgkin s disease with extension below the diaphragm at onset. Progression of the disease below the thorax did occur subsequently. Two patients with nodular sclerosis were excluded from our study when lymphangiography demonstrated abdominal lymph node involvement (Stage I11 disease). Progression of the disease to involve the right lung occurred in one patient with nodular sclerosis of the thymus gland five years after biopsy and radiation therapy. Change in the histological pattern from nodular sclerosis to the mixed type was noted in a Stage I patient with mediastinal lymph node involvement who developed a recurrence in a supraclavicular lymph node. A 15-year-old boy with Stage I1 nodular sclerosing Hodgkin s disease died within 3 years with clinical evidence of disseminated disease. These findings would prompt us to be cautious before giving a favorable prognosis based solely on the histological pattern. The latter must be correlated with accurate staging of the disease in this regard. We believe the entity described by Lowenhaupt and Brown [ll] and by Lattes [ 101 as granulomatous thymoma represents nodular sclerosing Hodgkin s disease. Concomitant or subsequent involvement of lymph nodes and other tissues provided evidence of the true nature of the disease in several of our patients with thymic involvement. Hodgkin s disease of the mediastinum may mimic other mediastinal tumors. Symptoms such as dyspnea due to pressure of mediastinal VOL. 3, NO. 4, APRIL,
8 BURKE, BURFORD, AND DORFMAN FIG. 7. X-ray of the chest demonstrating a mediastinal mass. Thoracotomy and biopsy showed Hodgkin s disease involuing lymph nodes. lymph nodes, brassy cough, and dysphagia may all occur with Stage I disease. Investigation of such patients should include plain chest films (Fig. 7). Bronchoscopy and biopsy may show evidence of pulmonary involvement. Developing expertise in lymphangiography makes this procedure a valuable part of the clinical evaluation of the patient with Hodgkin s disease. Hematological studies are also essential in assessing the stage of the disease. On the basis of accurate clinical staging and pathological interpretation the thoracic surgeon can do much to overcome the erroneous impression of many physicians and most patients that a diagnosis of Hodgkin s disease is tantamount to a death sentence. For Stage I Hodgkin s disease of the mediastinurn, excision if possible, followed by radiation therapy, would appear to be the best treatment for this small but fortunate group of patients. It offers them a good chance for a long survival period or cure. SUMMARY 1. Twenty-two cases of Hodgkin s disease involving the mediastinum have been studied, 12 with Stage I disease and 10 with Stage I1 disease. All patients in Stage I are alive from 1 to 12 years after thoracotomy. Of patients with Stage I1 disease, 50% are alive from 2 to 11 years after the onset. 2. The importance of accurate clinical staging is emphasized. 3. A revised histological classification of Hodgkin s disease recently proposed by Lukes et al. [13] has been utilized in this study. The frequency with which the nodular sclerosing type occurs as Stage I 294 THE ANNALS OF THORACIC SURGERY
9 Hodgkin s Disease of Mediustinum disease in the mediastinum is stressed. Long-term survival is also associated with lymphocyte predominance in the stroma. 4. Long survival and cure of Hodgkin s disease of the mediastinum is frequent when accurate clinical staging, precise histological criteria, and appropriate surgery and radiation therapy are utilized. REFERENCES 1. Ackerman, L. V., and del Regato, J. A. Cancer: Diagnosis, Treatment and Prognosis (3d ed.). St. Louis: Mosby, Blades, B. Mediastinal tumors. Ann. Surg. 123:749, Curreri, A. R., and Gale, J. W. Mediastinal tumors. Arch. Surg. (Chicago) 58:797, Easson, E. C. Possibilities for the cure of Hodgkin s disease. Cancer 19:345, Gall, E. A. The surgical treatment of malignant lymphoma. Ann. Surg. 118:1064, Hanson, T. A. S. Histological classification and survival in Hodgkin s disease. Cancer 17: 1595, Hellwig, C. A. Malignant lymphoma: The value of radical surgery in selected cases. Surg. Gynec. Obstet. 84:950, Jackson, H., and Parker, F., Jr. Hodgkin s Disease and Allied Disorders. New York: Oxford, Kaplan, H. S. Role of intensive radiotherapy in the management of Hodgkin s disease. Cancer 19: 356, Lattes, R. Thymoma and other tumors of the thymus. Cancer 15:1224, Lowenhaupt, E., and Brown, R. Carcinoma of the thymus of granulomatous type: A clinical and pathological study. Cancer 4:1193, Lukes, R. J. Relationship of histologic features to clinical stages in Hodgkin s disease. Amer. J. Roentgen. 90:944, Lukes, R. J., Butler, J. J., and Hicks, E. B. Natural history of Hodgkin s disease as related to its pathologic picture. Cancer 19:317, Molander, D. W., and Pack, G. T. Management and survival of 833 patients with malignant lymphoma. Amer. J. Roentgen. 93: 154, Peters, M. V., Alison, R. E., and Bush, R. S. Natural history of Hodgkin s disease as related to staging. Cancer 19:308, Peters, M. V., and Middlemiss, K. C. H. Study of Hodgkin s disease treated by irradiation. Amer. J. Roentgen. 79: 114, DISCUSSION DR. BRUCE F. BAISCH (San Diego, Calif.): The results just reported by Dr. Burke leave little to be desired. I can only hope that in another 5 or 10 years our long-term results will be equally good. We have followed the same basic approach of excision followed by irradiation. During the 5 years from January, 1962, through December, 1966, we have treated 9 patients with anterior mediastinal Hodgkin s disease, 8 of whom would qualify as Stage I and 1 as Stage 11. The average period of follow-up has been 39 months. All patients are living and apparently free of their disease at this time. I would agree that the disease probably arises within the thymus, or at least the thymus always seems to be involved both grossly and microscopically. We feel that the disease should be excised as widely as our technical capabilities will safely permit, preferably including the lymph nodes from both pulmonary hili, from the lower cervical areas, and from the supraclavicular fossae. This type of excision of necessity requires a median sternotomy. VOL. 3, NO. 4, APRIL,
10 BURKE, BURFORD, AND DORFMAN We would suggest that regardless of the apparent margin of the excision, irradiation be given in relatively high dosage. This has averaged 4,700 rads at the tumor level in our series. With 1 exception, we have uniformly irradiated the supraclavicular and lower cervical areas in continuity with the mediastinum. The 1 patient who was the exception received a rather homeopathic level of irradiation to the supraclavicular areas, and 48 months later there was biopsy evidence of Hodgkin s disease in the right supraclavicular nodes and palpable evidence of Hodgkin s disease in the left supraclavicular region. We raised the irradiation level to 6,000 rads, and he now appears free of disease. DR. BURKE: I would like to thank Dr. Baisch for his comments. Perhaps our Stage I1 patients would have shown a better survival rate had extended procedures been performed. There are several reports in the literature suggesting improved results with lymph node dissections for Hodgkin s disease. Since the etiology is still unknown, the clinical staging of the patient combined with the particular cell type would seem to be the only objective criteria to use in evaluating therapy. Larger and well-controlled studies are certainly needed to draw any firm conclusions on the best treatment of early Hodgkin s disease. 296 THE ANNALS OF THORACIC SURGERY
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