Region: 11. Clinic6patholo cal Studies

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1 Tumors of the Thvmus and ThVIIliC Region: 11. Clinic6patholo cal Studies on Hodgkin s Disease of Re Thymus N. P. Bergh, M.D., P. Gatzinsky, M.D., S. Larsson, M.D., P. Lundin, M.D., and B. Ridell, M.D. ABSTRACT Among 82 patients with a tumor in the thymic region, 17 had a lesion that fulfilled the criteria for Hodgkin s disease of the thymus; the histopathological differentiation of this entity from thymomas is discussed. All patients received surgical treatment and postoperative radiotherapy. After a mean observation time of 10 years there was no local recurrence and no death due to the disease, though 3 deaths were caused by the treatment. New clinical manifestations occurred in 3 of the 14 long-term survivors; they were treated successfully by operation or irradiation. A very aggressive surgical approach involving extirpation of all tumor tissue, extensive excision of the surrounding tissues and adjacent lymph nodes, and supplementary radiotherapy seems to be the treatment of choice. Lymphomas are the most common malignant tumors in the thymic region of the mediastinum. In large series, 50 to 60% of mediastinal lymphomas are Hodgkin s disease [l, 31; in about half of the cases the thymus is involved [5]. Much confusion has arisen concerning mediastinal masses because various histological tumor types have been lumped together. The consensus seems to be that the so-called granulomatous thymomas [6] in fact are Hodgkin s disease of the thymus gland [2, 4, 5, 91. Little is known about the biology of this localized form of Hodgkin s disease or about the results of combined surgical treatment and radiotherapy. The aim of the present work was to study clinicopathological features, and in particular the results of combined surgical treatment and From the Departments of Thoracic Surgery and Pathology I, Sahlgren s Hospital, University of Goteborg, Gothenburg, Sweden. Accepted for publication June 21, Address reprint requests to Dr. Larsson, Thoracic Surgical Clinic, Sahlgren s Hospital, Gothenburg, Sweden. radiotherapy, in patients with histological signs of Hodgkin s disease in the thymus. Material and Methods There were 17 patients with Hodgkin s disease in the thymic region among 82 patients with benign or malignant thymomas or other malignant tumors in the upper anterior mediastinurn. The patients average age was 36 years with a range of 23 to 58 years. There were 10 men and 7 women. Eleven patients had originally been given the diagnosis of Hodgkin s disease, while 3 had been diagnosed as having granulomatous thymoma and 3, a tumor of unspecified type. None of the patients had signs of Hodgkin s disease outside the mediastinum when first observed. The 17 patients were subjected to exploratory thoracotomy at the Department of Thoracic Surgery in Gothenburg between 1957 and All were followed until death or to March 31, All deaths occurred in the hospital. Case records and postmortem examination reports were reviewed in every case, and all available histological material was reexamined. The survival and the course of the disease were analyzed in order to evaluate the results of treatment. Survival rates were calculated at the end of 1, 3, 5, 10, and 15 years. Correction was made for intercurrent deaths and for deaths caused by the treatment. Fatal and nonfatal complications were investigated. Clinical Findings Table 1 shows the clinical findings. The tumor was fortuitously discovered in 10 patients, 7 of whom had no symptoms at all. Mediastinal widening on roentgenograms had been found in 2 patients 16 months and 6 years earlier, respectively. Pruritus occurred in only 1 patient. Local symptoms indicating advanced disease were by The Society of Thoracic Surgeons

2 100 The Annals of Thoracic Surgery Vol 25 No 2 February 1978 Table 1. Clinical Presentation of the Disease Table 2. Histopathological Findings Symptoms and Signs Microscopical Findings None 7 Cough 4 Dyspnea Chest pain Fever Fatigue Anorexia Weight loss Pruritus 1 Anemia 2 High erythrocyte sedimentation 5 rate Hoarseness 1 Superior vena cava syndrome 2 observed in 3 patients. Mediastinoscopy was performed in 11 patients. Biopsies from the mediastinal lymph nodes were positive in 2 of them. Extent of the Lesion The resected tumors weighed 280 gm on the average, ranging from 62 to 1,835 gm. Involvement of surrounding organs was found in 12 patients. The lungs were involved macroscopically in 6 patients. In 10 cases remnants of the thymic horns were seen as projections from the tumors. In 7 patients the tumor was situated in the thymic region but nothing was mentioned about the thymus in the surgeon s report. Lymph node enlargement was observed in 10 patients. Morphological Findings The thymic tumor was grossly nodular and usually traversed by broad sclerotic bands. Small areas of necrosis were occasionally seen, and in 2 cases obvious cyst formation was observed. The microscopical findings are summarized in Table 2. Microscopically, sclerotic bands surrounded cellular tumor nodules containing varying numbers of lymphocytes, histiocytes, eosinophilic and neutrophilic leukocytes, and multinucleated giant cells (Figs 1-3). The cellular composition varied among the different tumors and also within individual lesions. Not only did the Thymic epithelium in tumor 17 tissue Normal thymus present 13 Tumor growth adjacent to 10 thymus Hodgkin s disease in lymph 10 nodes No disease in lymph nodes 5 No lymph nodes examined 2 sclerosis surround the tumor nodules, but often finely dispersed sclerotic bands traversed the cellular areas of the tumors (Fig 4). This dispersed sclerosis was present to varying degrees in 15 patients. Giant cell formation was observed in all patients and was pronounced in 5 (Fig 5). The giant cells often had abundant cytoplasm with large, vesicular nuclei containing one or several nucleoli. Some of the giant cells fulfilled the criteria for a Reed-Sternberg cell (Fig 6). Mitotic figures were found in all cases and were often numerous. In 11 patients atypical mitotic figures were observed. The thymus was identified macroscopically in 10 patients. In all cases thymic tissue (epithelial cells and Hassall bodies) was found at the periphery of the lesion or within the tumor tissue. In 10 patients the mediastinal lymph nodes contained tumor tissue; in 8 cases there was only partial involvement of the lymph nodes. In these 8 cases small foci of large, atypical cells with vesicular nuclei containing nucleoli and sparse giant cells of Reed-Sternberg type were found (Fig 7). Occasionally there was a small area of necrosis in the center of these foci. Scattered eosinophilic leukocytes were observed in the involved lymph nodes. Thus, the microscopical appearance of the lymph nodes was consistent with Hodgkin s disease of mixed cellularity type. Treatment The treatment given to the patients is summarized in Table 3. Fourteen patients had

3 101 Bergh et al: Hodgkin s Disease of the Thymus Fig I. Lou1-pori)rr viezi1 of fhyniic Hodgkin s disease. Nodular cellular. parts (N) art separated by sclerotic bands (SB). Reninants of the thymusgland (TH) are also seen. (H&.) radical resection of the tumor, 2 had nonradical resection, and 1 had exploration only. The 15 operative survivors received full courses of radiotherapy varying from 4,000 to 6,000 rads. Two patients later had chemotherapy and additional radiotherapy, 1 because of enlarged cervical lymph nodes and 1 because of suspected pulmonary lesions. The surgical approaches that were used are shown in Table 4. In 6 patients the tumor had to be removed through a combined lateral thoracotomy and median sternotomy. The operative procedures performed are shown in Table 5. Pulmonary tissue was resected in 6 patients, l of whom had a pneumonectomy. The left innominate vein was sacrificed in 4 patients, the superior vena cava in 1 patient, and one of the phrenic nerves in 7 patients. Direct nerve suture and reconstruction with an intercostal nerve graft was done in 3 patients each, with success judged from observations of the diaphragmatic movements. Complications that could be attributed to the combined treatment are shown in Table 6. There were 3 deaths. One patient had had only a nonradical resection despite removal of 1,835 gm of tumor tissue with resection of the superior vena cava and insertion of an artificial graft. He had superior vena cava syndrome postoperatively from thrombosis in the graft and died 14 days after the operation. One patient with superior vena cava syndrome and a very large tumor underwent exploration only. He died 2 days after the operation. The third patient died 4 months after operation from infection and cardiac complications caused by the surgical and radiological treatment. There were 2 serious nonfatal complications. One patient had a severe esophageal stricture and pulmonary fibrosis caused by irradiation. This patient died of cor pulmonale and respiratory failure 10 years after the operation. Another patient had superior vena cava syndrome after postoperative radiotherapy and additional irradiation of enlarged cervical lymph nodes thought to be Hodgkin s lymphomas. This patient is alive and clinically free from disease 15 years after the operation.

4 102 The Annals of Thoracic Surgery Vol 25 No 2 February 1978 Fix 2. High-power view of same tumor as in Figure I. Hassall bodies (HB), atypical giant cells (GC),and eosinophils (eo)are seen. (Hematoxylin-van Gieson.) Fig 3. Cellular area of tumor with mixed cell population. There is a Reed-Sternberg cell in the center (arrow).(ht?.)

5 103 Bergh et al: Hodgkin s Disease of the Thymus Fig4. T w o different tumors with fine sclerotic bands (sb)traversing the cellular part. ( H 6 E. J Fig 5. Prominerit giant cell formation in a thymic tumor. ( H b E. )

6 104 The Annals of Thoracic Surgery Vol 25 No 2 February 1978 Table 3. Treatment of the 17 Patients with Hodgkin's Disease Treatment Resection Radical Nonradical Nonexcisional procedure Postoperative radiotherapy Fig 6. Reed-Sternberg cell (RSC). ( H 6 E. ) Fig 7. Focal involvement of a lymph node. Several atypical cells (arrows) are seen. ( H 6 E. j Table 4. Surgical Approach in the 17 Patients with Hodgkin's Disease Approach Sternotomy Thoracotomy Combined approach" "Bilateral thoracotomy and stemotomy were used in 1 patient.

7 105 Bergh et al: Hodgkin's Disease of the Thymus Table 5. Operative Procedures in the 17 Patients with Hodgkin's Disease Extent of Resection Exploratory thoracotomy only Simple extirpation Wedge of a lung Lobe(s) Lung Pericardium Left innominate vein Superior vena cava Phrenic nerve Vagus nerve Table 6. Complications of Combined Treatment in 17 Patients with Hodgkin's Disease Severity of Complication Tracheostomy and respirator 6 required Serious nonfatal 2 Fatal 3 Results In the present series there was no local recurrence, and no deaths occurred due to the disease except for the 3 caused by treatment. The results are summarized in Table 7. One intercurrent death occurred 11 years after the operation. Thirteen patients remained alive and well, free from Table 7. Results of Combined Therapy in 17 Patients with Hodgkin's Disease Result Death due to treatment 3 Intercurrent death 1 it New clinical manifestations 3" Survival 1 Y' Y' 5 Y' 10 yr 15 yr aradiation damage contributory. "Treated successfully I clinical disease; 6 have been followed for 10 years or more. Three patients developed a pleural metastasis or lesions outside the thorax suspected to be Hodgkin's disease. One patient subjected tononradical excision of the tumor and postoperative radiotherapy developed enlarged cervical lymph nodes, first on the left and later on the right side. This patient had additional radiotherapy and also received chemotherapy. She was alive 15 years after the operation. Another patient had a metastatic pleural lesion removed at a second operation 4 months after the first one. He was alive and well almost 8 years after the last operation. The third patient had a cytologically proved Hodgkin's lesion of the thyroid gland 21/2 months after the operation. Radiotherapy was instituted postoperatively in this area also. Direct invasion of pulmonary tissue had been present initially in 6 patients; all but 1 remained alive. The 3 patients with recurrent disease belong to this group. Comment On the basis of morphological studies, it has been suggested that the thymus may be the site of origin of Hodgkin's disease [lo]. Most patients with Hodgkin's disease do not develop thymic tumors, however. In a postmortem study [8] of cases of advanced Hodgkin's disease, only 26% of the patients had involvement of the thymus; most of them also had widespread disease in the mediastinum. Hodgkin's disease in the upper anterior mediastinurn may be primary in the thymus or in the mediastinal lymph nodes. The best way to establish that the primary site is in the thymus seems to be the observation at operation that the tumor is situated in the thymic region and that the thymic horns project from the mass, supported by the microscopical finding of thymic epithelium in the tumor. In the present investigation, thymic tissue adjacent to the tumor was observed by the surgeon in 10 cases. Microscopically, thymic tissue was found near or in the mass in all cases, supporting the view that the processes were initially localized to the thymus. The histopathological differentiation of Hodgkin's disease of the thymus from thymomas has been debated by several authors [2,

8 106 The Annals of Thoracic Surgery Vol 25 No 2 February , 5, 91. Recently it has been pointed out that so-called granulomatous thymomas in fact are Hodgkin s disease of the thymus [4, 51. However, the cytological appearance of the thymic lesion has been found to differ from that generally seen in Hodgkin s disease. Thus, apart from Reed-Sternberg cells, other types of giant cells, considered to be derived from the thymic epithelium, have been observed. In our material 5 patients exhibited marked formation of giant cells in some areas of the tumor, with atypical mitotic figures. In 3 of these cases there were diagnostic signs of Hodgkin s disease in the lymph nodes. The thymic tumors are considerably larger than Hodgkin s lesions primarily involving lymph nodes at other sites. A large part of the weight is not due to tumor tissue, however, but to a desmoplastic reaction in and around the tumor. The fibrous reaction is found not only around the cellular tumor nodules but also within these structures. Thus, microscopical features are present which are usually not seen in Hodgkin s disease; but with the present morphological approach to diagnosing that entity, it seems appropriate to call these nodular sclerosing tumors Hodgkin s disease of the thymus. In our opinion, classification of the thymic lesion according to the system of Lukes, Butler, and Hicks [7] is not possible, but the focal involvement of lymph nodes must be classified as Hodgkin s disease of mixed cellularity. The results of the combined surgical and radiological treatment were remarkably good in the present series. Excluding intercurrent death and death due to treatment, there was 100% survival after a mean observation time of 10 years. Recurrent disease was observed in only 21% of the long-term survivors, including 1 patient with a pleural metastatic lesion that was successfully resected. Keller and Castleman [51 reported a 5-year survival of 79%, and more than half of their patients who were followed experienced recurrences. Katz and Lattes [4] reported mediastinal recurrences in 8 of 17 patients, and only 10 were apparently free from disease. Four of them had been followed for longer than 5 years. The good results in the present series may be due to our very aggressive surgical approach, with extirpation of all tumor tissue, extensive excision of surrounding tissues and adjacent lymph nodes, and adequate postoperative radiotherapy. Direct invasion of the lungs seems to be a poor prognostic sign [5]. All 3 patients with recurrent disease in the present series had pulmonary involvement, which obviously should be taken into consideration when postoperative irradiation is being planned. Another poor prognostic sign seems to be the superior vena cava syndrome. There is a high risk with nonexcisional operation as well as a high operative risk. In such cases preoperative irradiation may be useful in reducing the mass, thus facilitating the operation; otherwise these patients should be treated by radiation therapy alone or in combination with chemotherapy. Staging laparotomy has been considered useful in Hodgkin s disease. From our results, however, the value of such a procedure may be questioned in patients with Hodgkin s disease of the thymus and adjacent mediastinal lymph nodes who are treated by radical operation and adequate postoperative radiotherapy. References 1. Benjamin SP, McCormack LJ, Effler DB, et al: Primary lymphatic tumours of the mediastinum. Cancer 30:708, Fechner RE: Hodgkin s disease of the thymus. Cancer 23:16, van Heerden JA, Harrison EG, Berriatz PE, et al: Mediastinal malignant lymphoma. Chest 57:518, Katz A, Lattes R: Granulomatous thymoma or Hodgkin s disease of thymus?: a clinical and histologic study and a reevaluation. Cancer 23:1, Keller AR, Castleman B: Hodgkin s disease of the thymus gland. Cancer 33:1615, Lowenhaupt E, Brown R: Carcinoma of the thymus of granulomatous type: a clinical and pathological study. Cancer 4: 1193, Lukes R, Butler JJ, Hicks EB: Natural history of Hodgkin s disease as related to its pathologic picture. Cancer 19:317, Marshall AHE, Wood C: The involvement of the thymus in Hodgkin s disease. J Pathol Bacteriol 73:163, Nickels J, Franssila K, Hjelt L: Thymoma and Hodgkin s disease of the thymus. Acta Pathol Microbiol Scand [A]81:1, Thomson AD: The thymic origin of Hodgkin s disease. Br J Cancer 9:37, 1955