9941308
The role of T-cells in the initiation of autoantibody responses in thymoma patients. SO - Pathol Res Pract 1999;195(8):535-401

Loehrer PJ, Eastern Cooperative Oncology Group: Phase II Study of VIP (VP-16/IFF/CDDP) for Invasive Thymoma (Summary Last Modified 12/97), E-1C93, clinical trial, closed, 02/27/1997.

OBJECTIVES: I. Evaluate the objective response rate to VIP (etoposide/ifosfamide/cisplatin) with granulocyte colony-stimulating factor in patients with extensive thymoma. II. Evaluate the duration of remission and survival of patients treated with this regimen. III. Evaluate the toxicity of this regimen. PROTOCOL ENTRY CRITERIA: --Disease Characteristics-- Histologically confirmed thymoma or thymic carcinoma Unresectable stage III/IVA/IVB disease (Masaoka classification) Extensive disease required, i.e.: Distant disease Pleural or pulmonary disease with or without mediastinal involvement Distant metastasis or documented progressive disease in previously irradiated fields required in the case of prior radiotherapy No de novo limited disease, i.e., disease confined to the mediastinum and ipsilateral supraclavicular lymph nodes (e.g., confined to a single radiotherapy port), that is eligible for surgical resection or definitive radiotherapy Bidimensionally measurable disease required --Prior/Concurrent Therapy-- Biologic therapy: Not specified Chemotherapy: No prior systemic chemotherapy Endocrine therapy: Corticosteroids for myasthenia gravis allowed provided dose remains stable following baseline measurements Radiotherapy: Prior radiotherapy allowed Surgery: No postsurgical complications --Patient Characteristics-- Age: 18 and over Performance status: ECOG 0-2 Hematopoietic: WBC at least 4,000 Platelets at least 125,000 Hepatic: Bilirubin no greater than 2.0 mg/dL (34.2 micromoles/L) Renal: Creatinine no greater than 1.5 times normal OR Creatinine clearance at least 50 mL/min Cardiovascular: No history of uncontrolled congestive heart failure that precludes hydration Other: No acute intercurrent complications (e.g., infection) No second malignancy within 5 years except: Previously treated basal cell carcinoma of the skin Carcinoma in situ of the cervix or breast No pregnant or nursing women Effective contraception required of fertile patients

A phase II study of the European Organization for Research 10(9)/L and Treatment of Cancer Lung Cancer Cooperative Group
Giaccone G, Ardizzoni A, Kirkpatrick A, et al.: Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma: a phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. Journal of Clinical Oncology 14(3): 814-820, 1996.

BACKGROUND: Thymomas are rare neoplasms of the mediastinum. The role of chemotherapy in advanced thymomas is not fully established. PATIENTS AND METHODS: In the European Organization for Research and Treatment of Cancer (EORTC) Lung Cancer Cooperative Group, 16 patients with recurrent or metastatic malignant thymoma were entered over 6 years onto a study of combination chemotherapy that consisted of cisplatin 60 mg/m2 on day 1 and etoposide 120 mg/m2 on days 1, 2, and 3, every 3 weeks. RESULTS: A median of six courses per patient was administered. Main side effects of treatment were leukopenia, nausea and vomiting, and alopecia. Five complete responses and four partial responses were obtained, with a median response duration of 3.4 years. The median progression-free survival and survival times were 2.2 years and 4.3 years, respectively, with a median follow-up duration of 7 years. CONCLUSION: The combination of cisplatin and etoposide is highly effective and well tolerated in advanced thymoma. The investigation of this combination in a neoadjuvant setting in unresectable invasive thymoma is warranted.

Mornex F, Resbeut M, Richaud P, et al.: Radiotherapy and chemotherapy for invasive thymomas: a multicentric retrospective review of 90 cases. International Journal of Radiation Oncology, Biology, Physics 32(3): 651-659, 1995.

PURPOSE: Thymoma is a rare disease. The treatment of patients with invasive thymoma remains controversial. The prognosis of such patients is poor, even with the use of postoperative radiation therapy and chemotherapy. We retrospectively reviewed the outcome and prognostic factors in a series of 90 patients presenting with an invasive thymoma treated by partial resection or biopsy and radiation therapy. METHODS AND MATERIALS: From 1979-1990, 163 patients with the diagnosis of lymphoepithelial thymoma were treated in 10 French cancer centers. Patients were staged using the postoperative "GETT" classification derived from that of Masaoka. Ninety patients who presented with an invasive thymoma, 58 Stage III (21 IIIA: partial resection and 37 IIIB: biopsy) and 32 Stage IVA (intrathoracic thymoma spread), are the subject of this report. Treatment combined surgery and radiation therapy (+/- chemotherapy), with curative intent. Surgery consisted of partial resection in 31 patients (21 Stage III), and biopsy in 55 patients (37 Stage III). The median radiation dose to the tumor was 50 Gy (30-70 Gy). Supraclavicular radiation was performed in 59 patients (median dose 40 Gy). Chemotherapy, combined with radiation in 59 patients, consisted of multidrug regimens, mainly platinum based. RESULTS: The median follow-up is 105 months (20-165 months). The 5- and 10-year overall survival rates are 51 and 39%, respectively. There is a great impact of the extent of surgery on survival: the 5- and 10-year survival rates were 64% and 43%, respectively, after partial resection, compared to 39% and 31% after biopsy (p < 0.02). Local control at 8.5 years was obtained in 59 of 90 patients (66%): 40 Stage III, 19 Stage IVA. There is a significant relationship between the extent of surgery and the local control (16% of relapse after partial resection vs. 45% after biopsy, p < 0.05). Seven patients developed significant (grades 3-4 WHO grading system) treatment-induced side effects. Stage, histologic type, and chemotherapy were not prognostic factors. CONCLUSION: In this large multicentric retrospective study of invasive thymomas (Stage III-IVA) treated by surgery and radiation, results show the importance of loco-regional treatments, such as surgery and radiation therapy. There is also a great impact of radiation on local control. However, the rate of local recurrence (34%) justifies recommending a higher dose of radiation (> 50 Gy) than doses used in this study, for incompletely resected patients. The role of chemotherapy needs to be further assessed.

Egea AM, Albasini JL, Paricio PP, et al.: Prognostic factors of thymomas. European Journal of Surgical Oncology 21(5): 482-485, 1995.

Thymomas are uncommon tumours. This study analyses the prognostic value of certain clinical variables and of two different histological classifications. Thirty cases were analysed; 24 were women and six men, with a mean age of 50 years (range 22-69). The pre-operative study included: clinical data (Masaoka's and Osserman's clinical classification); chest radiography; and computed axial tomography. Surgery was divided into three categories: total tumour resection, partial resection and biopsy alone. For the pathological study we followed Salyer-Eggleston and Marino-Muller classifications. Follow-up averaged 5.5 years (range: 2-11). As a statistical method we used Kaplan-Meier's survival curves and Cox's regression model. Eleven of the patients had associated myasthenia gravis, this being the most common clinical type. Age, sex, association with myasthenia gravis, surgical technique and Salyer-Eggleston's classification showed no prognostic value; conversely, clinical staging and Marino-Muller's classification had a high prognostic value. The first treatment that should be considered is surgery, with an attempt to perform total tumour resection. Myasthenia gravis did not modify the prognosis of the disease. The factors of greatest prognostic significance were clinical staging and Marino-Muller's histological classification.

Park HS, Shin DM, Lee JS, et al.: Thymoma: a retrospective study of 87 cases. Cancer 73(10): 2491-2498, 1994.

BACKGROUND. The authors retrospectively analyzed 87 patients with malignant thymoma treated at M.D. Anderson Cancer Center between 1951 and 1990. The analysis examined the clinical stages, histologic types, and treatment modalities and attempted to determine if chemotherapy had an impact on survival. METHODS. The patients were divided into three groups by their year of treatment and treatment modality. Patients treated between 1951 and 1975 were in Group I; patients treated between 1976 and 1980 were in Group II; and patients treated between 1981 and 1990 were in Group III. Most of the patients (18 [72%] in Group I; 16 [62%] in Group II; and 18 [50%] in Group III) had surgical resection alone or with radiotherapy. Patients with advanced-stage disease in Group I received single-agent chemotherapy, whereas patients with advanced-stage disease in Group II received a different, combination chemotherapy regimen, and those in Group III were treated primarily with cisplatin- and doxorubicin-based combination chemotherapy, e.g., the cyclophosphamide doxorubicin, and cisplatin with or without prednisone. The 17 patients treated with cisplatin with or without prednisone were separately evaluated for survival according to their response. RESULTS. Twenty-eight patients (5 [20%] in Group I; 6 [23%] in Group II; and 17 [47%] in Group III) received chemotherapy alone or after surgery or radiotherapy. The cisplatin with or without prednisone regimen was used in 17 Group III patients for initial treatment or for relapse. The overall response rate among the patients receiving the cisplatin with or without prednisone regimen was 64%; 6 (35%) had a complete response, and 5 (29%) had a partial response. Thirty-one (36%) of the 87 total patients had 45 recurrent tumors; the lung (29%), pleura (22%), and mediastinum (18%) were the most common sites of recurrence, whereas bone was the most common distant metastatic site. The 5-year survival rate was 70% in patients with Stage I disease, 71% in patients with Stage II or III disease, and 46% in patients with Stage IV disease. The 10-year survival rate was 70% in patients with Stage I disease, 47% in patients with Stage II or III disease, and 21% in patients with Stage IV disease. Statistical analysis indicated a significant difference among the survival rates of patients with noninvasive Stage I, invasive Stage II plus III (P = 0.033), and Stage II plus III and IV tumors (P = 0.056), but not between patients with Stage II or III tumors. Patients with a major response to the cisplatin with or without prednisone regimen had a significant survival improvement compared to those with no response (P = 0.002, log-rank test). CONCLUSIONS. Because thymoma is a chemosensitive tumor and frequently recurs in patients with Stage II or greater disease, chemotherapy carries a potential survival benefit and should be incorporated into the multimodality approach to prolong disease-free survival.

Ciernik IF, Meier U, Lutolf UM: Prognostic factors and outcome of incompletely resected invasive thymoma following radiation therapy. Journal of Clinical Oncology 12(7): 1484-1490, 1994.

BACKGROUND: Stage III and stage IV thymomas with significant macroscopic infiltration to the neighboring structures are rarely completely resectable. It therefore remains unclear to what extent tumors must be surgically debulked to improve prognosis. PATIENTS AND METHODS: We reviewed the cases of 31 patients with incompletely resected invasive thymoma and residual macroscopic disease who were referred to postoperative irradiation. Survival and local tumor control were analyzed. All patients were treated between 1958 and 1990 with megavoltage irradiation at doses ranging from 42 to 66 Gy. The shortest follow-up time for living patients was more than 5 years. RESULTS: The overall median 5-year survival rate was 45%. Eighteen stage III patients had a 5-year survival rate of 61% and a 10-year survival rate of 57%. Thirteen patients had stage IV disease and 5- and 10-year survival rates of 23% and 8%, respectively. Univariate and multivariate analyses confirmed a worse prognosis for stage IV disease. Epithelial or spindle-cell thymoma was associated with stage IV disease. Twenty-two percent of patients with stage III disease had epithelial or spindle-cell thymoma, versus 69% of patients with stage IV disease (P = .02 for univariate and P = .05 for multivariate analysis). Initial tumor diameter greater than 10 cm correlated with poor prognosis in the univariate analysis (P = .05). However, more importantly, debulking of tumor did not significantly improve outcome when compared with patients who received biopsy only. The median survival rate of patients with stage IVa disease did not differ from that of those with stage IVb disease. Mediastinal control was achieved in 23 patients (74%). Stage IV disease did not correlate with an increase in local treatment failure after irradiation, although epithelial or spindle-cell thymoma predisposed for local treatment failure (46% v 11%; P = .04 in univariate and P = .055 in multivariate analysis). CONCLUSION: Tumor debulking leaving macroscopic residual thymoma, as opposed to biopsy alone, does not improve prognosis when followed by radiation. Radiation therapy for local tumor control is most effective in nonepithelial-predominant thymomas.

Loehrer PJ, Kim K, Aisner SC, et al.: Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. Journal of Clinical Oncology 12(6): 1164-1168, 1994.

No abstract presently available

Morgenthaler TI, Brown LR, Colby TV, et al.: Symposium on intrathoracic neoplasms - part IX: thymoma. Mayo Clinic Proceedings 68(11): 1110-1123, 1993.

Thymomas and thymic carcinomas are thymic epithelial tumors that constitute approximately 15% of all mediastinal masses. From 28 to 66% of thymomas cause chest symptoms as the initial manifestation; the rest are discovered on routine chest roentgenograms or during investigations prompted by the presence of a paraneoplastic syndrome. Forty percent of patients with thymoma have one or more paraneoplastic syndromes, including myasthenia gravis, pure red cell aplasia, and hypogammaglobulinemia. Extrathymic malignant lesions develop in up to 20% of patients. Traditional histologic classifications have not accurately predicted tumor behavior; a recently developed classification based on cellular differentiation toward thymic medullary or cortical epithelium may correlate better with prognosis. Nevertheless, the prognosis is best predicted by stage of the tumor determined intraoperatively and is poorer in patients with incomplete resection than in those with complete resection of the thymoma. In addition to surgical intervention, irradiation and chemotherapy have important roles in the management of thymomas, particularly in advanced stages. In this article, the clinical manifestations, diagnosis, pathologic features, staging, and treatment of thymomas are reviewed, and the prognosis of affected patients is discussed. (78 Refs)

Rea F, Sartori F, Loy M, et al.: Chemotherapy and operation for invasive thymoma. Journal of Thoracic and Cardiovascular Surgery 106(3): 543-549, 1993.

Sixteen patients with invasive thymoma (stage III and stage IVA) were treated with chemotherapy and then operation. All tumors were considered nonresectable after first staging, and patients were treated with the following chemotherapy in 4-day courses, administered intravenously: cisplatin (50 mg/m2) and doxorubicin (40 mg/m2) on day 1, vincristine (0.6 mg/m2) on day 3, and cyclophosphamide (700 mg/m2) on day 4. The courses were repeated every 3 weeks, and toxic effects were well tolerated. Seven patients (43%) had a complete remission, and nine patients (57%) had a partial remission, with an overall complete remission plus partial remission rate of 100%. After chemotherapy all patients underwent operation. We performed 12 sternotomies and four posterolateral thoracotomies. At operation 11 patients had radical resection and five had partial resection. We administered radiotherapy in 11 patients who had histologically demonstrated tumor after operation. In five patients, the specimen showed only fibrosis; these patients received three cycles of chemotherapy but not radiotherapy. Median survival was 66 months with a 3-year survival of 70%. We believe that neoadjuvant chemotherapy with surgical intervention is justified for advanced invasive thymoma; a longer follow-up and a larger number of patients will determine the impact of this treatment on long-term survival.

Bonomi PD, Finkelstein D, Aisner S, et al.: EST 2582 phase II trial of cisplatin in metastatic or recurrent thymoma. American Journal of Clinical Oncology 16(4): 342-345, 1993.

In 1982 there were four reports of cisplatin-induced remissions of invasive thymoma. These observations led the Eastern Cooperative Oncology Group (ECOG) to conduct a Phase II trial of cisplatin (50 mg/m2 intravenously every 3 weeks). During a 4-year period 24 patients were entered on this trial; 3 were excluded because review of histologic material failed to confirm the presence of thymoma. The characteristics of the remaining 21 patients were as follows: median age, 51; males/females, 11/10; ECOG performance status, 0-1/2-3, 16/5; previous treatment with chemotherapy, 3; previous surgery, 20; previous radiation, 15; weight loss, < 5%/ > or = 5%: 17/4. One patient was eliminated from response analysis because of failure to return for follow-up tumor measurements. The following responses were observed in the remaining 20 patients. Partial remission, 2 (10%); stable disease, 8 (40%); and progression, 10 (50%). The median survival was 76 weeks, and the 2-year survival rate was 39%. Four patients experienced severe nausea and vomiting, but life-threatening and lethal toxicities were not observed. Cisplatin given at this dose was relatively ineffective in producing tumor regression in recurrent or metastatic thymoma.

Urgesi A, Monetti U, Rossi G, et al.: Aggressive treatment of intrathoracic recurrences of thymoma. Radiotherapy and Oncology 24(4): 221-225, 1992.

Between 1974 and 1988, 21 patients with intrathoracic recurrences of thymoma received radiotherapy with radical intent; surgery was always attempted when considered feasible: 11 patients were partially (6 cases) or totally (5 cases) resected before irradiation, while in the other 10 radiotherapy was the only treatment. In 7 cases the recurrence was confined to the anterior mediastinum, 9 had pleural nodules without mediastinal lesions and 5 had both mediastinal and pleural lesions. Mediastinal recurrences were treated by opposed parallel mediastinal fields with 2/3 of the dose delivered through the anterior port: doses ranged between 38 and 44 Gy; a boost of 10-16 Gy was given in patients not radically resected. Pleural nodules were treated with a variety of techniques according to the extent of the lesions. The 7-year survival of the whole group was 70%; 5 patients died: 4 with intrathoracic progression and one with distant metastases. The survival was 74% in the 11 patients having received surgery, either radical or subtotal, and 65% in the 10 patients treated with radiotherapy alone: the difference is not significant. Patients with Karnofsky index greater than 70 had a significantly better survival (100%, versus 28%, p = 0.0015). This is a selected series of patients presenting recurrences still amenable to a radical treatment either by surgery and radiotherapy or by radiotherapy alone: the results confirm that an aggressive approach is warranted in patients in good general conditions with recurrences confined to the mediastinum and/or 1 hemithorax.

Maggi G, Casadio C, Cavallo A, et al.: Thymoma: results of 241 operated cases. Annals of Thoracic Surgery 51(1): 152-156, 1991.

Clinical and histopathological aspects of 241 thymomas were reviewed. One hundred sixty of the patients with thymoma had myasthenia gravis and 15 had other autoimmune diseases; 55% of the thymomas were encapsulated and 45% invasive. Operation was radical resection in 87.5% of the patients, subtotal resection with residual tumor in 8.7%, and simple biopsy in 3.7%. A tumor relapse was observed in 24 patients (10%): 2 (1.5%) of 133 with encapsulated thymomas and 22 (20.4%) of 108 with invasive thymomas; among these patients, a relapse was found in 20.6% of the patients who received radiotherapy postoperatively and in 24.6% who did not. Adverse prognostic factors were clinical stage IVa (multiple pleural nodes), not feasible resection (for technical reasons), inoperable tumor relapse, and association with one of the following autoimmune diseases: pure red cell aplasia, hypogammaglobulinemia, and lupus erythematosus. Conversely, myasthenia gravis is now a curable disease; it contributes to early discovery of associated thymoma, thus allowing a better survival for patients with thymoma who have myasthenia gravis compared with patients with thymoma but without myasthenia gravis (p less than 0.05). Postoperative radiotherapy does not seem necessary after removal of encapsulated thymomas, but it is advisable in case of invasive thymomas, regardless of the extent of the resection.

Harper PG, Highly M, Rankin E, et al.: Ifosfamide monotherapy demonstrates high activity in malignant thymoma. Proceedings of the American Society of Clinical Oncology 10: A-1049, 300, 1991.

Thymic tumors may be difficult to treat with local infiltration into adjacent structures making adequate surgical excision impossible, and their size giving rise to a significant risk of pulmonary fibrosis after radiotherapy. Fourteen patients (pts; age 26-70 yr) with biopsy-proven malignant thymoma have been treated with Ifosfamide in a total dose of 7.5 g/m2/cycle q 3 wk. This was given as a 30-min infusion of 1.5 g/m2 daily x 5 in 11 pts and as a continuous infusion over 5 days in 13 pts with large anterior mediastinal masses, had superior vena caval obstruction (SVCO). One pt had bone marrow infiltration. One pt had a preceding history of myasthenia gravis. Three pts had failed prior treatment, two with radiotherapy and one with a combination of cis-platinum and VP16-213. Thirteen pts are evaluable for response (one too early). Seven of 13 pts (54%) achieved a complete remission (CR). All CR have proved durable at follow-up of 6-66 mo (median 38 mo). In the first two pts, CR was proven at second thoracotomy with multiple biopsies. One pt (8%) achieved partial remission (PR) at the second cycle but then progressed. Five pts (38%) had stable disease after 2-6 cycles of ifosfamide. One subsequently progressed and died 4 mo after stopping treatment, three achieved PR after radiotherapy, one of which is durable at 28 mo and one achieved PR after cis-platinum etoposide (durable at 12 mo). Complete resolution of SVCO by the 4th wk was seen in 4 of 5 pts. Toxicity has been limited to alopecia and WHO grade 2 nausea and vomiting. Treatment was delayed by leukopenia for 1 wk in 3 of 73 treatment cycles. Conclusion: Ifosfamide as a single agent has proved to have activity in this disease and should be considered as first line therapy. Toxicity has been low. The results are comparable with recently published data using combination chemotherapy.

Fornasiero A, Daniele O, Ghiotto C, et al.: Chemotherapy for invasive thymoma: a 13-year experience. Cancer 68(1): 30-33, 1991.

From 1977 to 1990, 37 patients with Stage III or IV invasive thymoma (20 men and 17 women; median age, 40 years) were referred for chemotherapy to the Padova Medical Oncology Department. All patients initially received the same regimen (50 mg/m2 of cisplatin and 40 mg/m2 of doxorubicin intravenously (IV) on day 1, 0.6 mg/m2 of vincristine IV on day 3, and 700 mg/m2 of cyclophosphamide IV on day 4 [ADOC]), recycling at monthly intervals. No life-threatening side effects were noted. The overall clinical response rate (complete response plus partial response) was 91.8%, with 43% complete remissions. Median duration of response and survival were 12 months (range, 2 to 96+ months) and 15 months (range, 5 to 96+ months), respectively. Seven of the 16 complete remissions were pathologically confirmed at subsequent thoracotomy. Other chemotherapy combinations and radiation therapy have been applied as second-line treatment, achieving only minimal responses. In the opinion of the authors, such chemotherapy deserves evaluation for adjuvant and neo-adjuvant treatment of invasive (and/or inoperable) thymoma due to the high complete response rate and overall response rate.

Jackson MA, Ball DL: Post-operative radiotherapy in invasive thymoma. Radiotherapy and Oncology 21(2): 77-82, 1991.

The experience of a large Cancer Institute in treating invasive thymoma has been reviewed. Twenty-eight patients received radiotherapy following biopsy or incomplete resection of a thymoma. The overall survival was 53% at 5 years and 44% at 10 years. Treatment was generally well tolerated but three patients (11%) developed significant side effects from the radiotherapy and two of these died. Radiotherapy appeared to be more effective in patients who had a small volume of residual disease after surgery. An attempt was made to identify prognostic factors, but none reached statistical significance. The radiation dose, field size and the use of systemic treatment are discussed. (26 Refs)

Macchiarini P, Chella A, Ducci F, et al.: Neoadjuvant chemotherapy, surgery, and postoperative radiation therapy for invasive thymoma. Cancer 68(4): 706-713, 1991.

Between January 1988 and June 1990, seven previously untreated patients with histologically confirmed and clinically staged IIIa invasive thymoma (IT) were enrolled in a prospective, single treatment arm study of neoadjuvant chemotherapy (NC) followed by surgery and postoperative radiation therapy (4600 to 6000 cGy). The NC included three cycles of cisplatin (75 mg/m2 on day 1), epirubicin (100 mg/m2 on day 1), and etoposide (120 mg/m2 on days 1, 3, and 5), every 3 weeks. All patients showed a partial response (greater than 50%) and underwent complete (n = 4) or incomplete (gross [n = 1] or microscopic [n = 2] residual tumor) surgical resection. Histologic examination was negative for two completely resected patients. Projected 2-year survival was 80%; all patients but one currently are alive and disease-free. This approach appeared to be feasible and may be a new therapeutic choice in the management of IT, but its use on a regular basis should be reserved until a larger number of patients and longer follow-up are available.

Pescarmona E, Rendina EA, Venuta F, et al.: The prognostic implication of thymoma histologic subtyping: a study of 80 consecutive cases. American Journal of Clinical Pathology 93(2): 190-195, 1990.

In this study the authors have investigated the clinicopathologic correlations in 80 consecutive cases of thymoma in order to establish the clinical usefulness of histologic subtyping of these tumours. All cases were histologically examined and classified according to Salyer and Eggleston and to Marino and Muller-Hermelink classifications. Therefore, thymomas were subtyped as predominantly lymphocytic, mixed and predominantly epithelial and cortical, mixed and medullary, respectively. The frequency of the different histologic subtypes was determined, and histologic findings were related to patients' age, surgical stage, and survival. Through the application of Salyer and Eggleston classification, the three histologic subtypes did not correlate with patients' ages at time of diagnosis, surgical stage as determined by local infiltration, and prognosis as determined by survival curves. On the contrary, when Marino and Muller-Hermelink classification was applied, statistically significant relationships between histologic results and age, surgical stage, and prognosis were demonstrated. These results and their implications are discussed, with special reference to the important problem of histogenesis of thymomas and of their clinicopathologic staging.

Pescarmona E, Rendina EA, Venuta F, et al.: Analysis of prognostic factors and clinicopathological staging of thymoma. Annals of Thoracic Surgery 50(4): 534-538, 1990.

The prognostic value of four clinical variables (age and sex of patients, association with myasthenia gravis, and clinical stage) and histological type was analyzed in 83 consecutive patients with thymoma, histologically classified as cortical, medullary, and mixed. Age, sex, and association with myasthenia gravis did not prove to represent significant prognostic factors; clinical stage and histological type, on the contrary, had a highly significant prognostic value (p less than 0.001). A model of clinicopathological staging, based on both clinical stage and histological type, in which three major prognostic groups are considered is proposed. The degree of significance of this model is higher (p less than 0.0001) than that of clinical stage and histological type considered individually; its validity is further supported by the results of multivariate analysis according to the Cox regression model (p = 0.0001). We think it represents a prognostically valuable approach to the problem of management of thymoma.

Curran WJ, Kornstein MJ, Brooks JJ, et al.: Invasive thymoma: the role of mediastinal irradiation following complete or incomplete surgical resection. Journal of Clinical Oncology 6(11):1722-1727, 1988.

To evaluate the role of mediastinal irradiation (RT) following surgery for invasive thymomas, a clinical and pathologic review of 117 patients with the diagnosis of thymoma was completed. Fourteen cases were excluded because of the lack of histologic criteria for a thymic tumor, and the remaining 103 were classified according to a staging system as follows: stage I, completely encapsulated (43); stage II, extension through the capsule or pericapsular fat invasion (21); stage III, invasion of adjacent structures (36); and stage IV, thoracic dissemination or metastases (3). The 5-year actuarial survival and relapse-free survival rates were 67% and 100% for stage I, 86% and 58% for stage II, and 69% and 53% for stage III. No recurrences occurred among stage I patients after total resection without RT. However, eight of 21 patients with invasive (stage II or III) thymomas had mediastinal recurrence as the first site of failure following total resection without RT. The 5-year actuarial mediastinal relapse rate of 53% in this group compares unfavorably with the mediastinal relapse rate seen among stage II or III cases following total resection with RT (0%) or following subtotal resection/biopsy with RT (21%). Despite attempted salvage therapy, five of eight patients with mediastinal relapse following total resection alone died of progressive disease. No significant difference was observed in the local relapse rate, overall relapse rate, or survival between those patients undergoing biopsy and RT v subtotal resection and RT for invasive thymomas (stages II and III). Total resection alone appears to be inadequate therapy resulting in an unacceptably high local failure rate with poor salvage therapy results.

Marino M, Muller-Hermelink HK: Thymoma and thymic carcinoma: relation of thymoma epithelial cells to the cortical and medullary differentiation of thymus. Virchows Archiv. A, Pathological Anatomy and Histology 407(2): 119-149, 1985.

Based on the light microscopical features of normal thymic epithelial cells, human thymoma was divided in different types, namely cortical, medullary, and mixed ones, according to the epithelial cell (EC) type. Lymphoid cell populations with morphological features of either cortical or medullary thymocytes were found according to different types of EC in thymoma. The histological variation of the different types of thymoma are demonstrated. In a retrospective study of 58 thymomas and 13 thymic carcinomas, malignant invasive character as well as the occurrence of myasthenia gravis were both found to be related to the neoplastic proliferation of the cortical epithelial cells, whereas in the usual mixed type of thymoma and the medullary type no gross invasion or metastases were noticed. These results are discussed in view of recent concepts and immunological findings of thymus microarchitecture.

Ariaratnam LS, Kalnicki S, Mincer F, et al.: The management of malignant thymoma with radiation therapy. International Journal of Radiation Oncology, Biology, Physics 5(1): 77-80, 1979.

The results of radiotherapy (RT) in 11 patients (6 men, 5 women; 18-69 yr old, av 54 yr) with malignant true thymomas are reported. Histologically, two were epithelial, two lymphocytic, one spindle cell, and six mixed. All patients underwent thoracotomy: incomplete excision was done in 5/11 and biopsy only in 3/11. RT was performed soon after surgery in these eight patients and when recurrent disease appeared 1-6 yr after apparently complete tumor resection in the other three. RT was directed to the mediastinum in all patients and to part or all of the lung if there was parenchymal involvement. If pleural metastases were present, the entire hemithorax and lung were given 60Co RT by the moving strip technique. The dose to the mediastinum and roentgenographically visible masses ranged from 3,000 to 4,400 rads in 3-7 wk; one patient received a dose of 5,400 rads in 23 fractions over 51 days. Moving strip doses to the entire lung ranged from 1,400-2,100 rads in 12-14 days. Additional treatment to the mediastinum was given to all patients at a dose rate of 750-1,000 rads/wk. All patients were followed for a minimum of 2 yr. Eight patients were alive and well 2-16 yr after RT; 7/8 had received a dose of at least 3,500 rads in 3-7 wk. The mediastinal shadow did not disappear completely in two patients who were both alive at the time of report. Two patients who died presented with very extensive disease and received only 3,000 rads; the third received 4,000 rads and died with intra- and extrathoracic disease and acute leukemia. The above results confirm that RT at doses of 3,500-4,500 rads in 3-6 wk is effective in controlling malignant thymoma regardless of the residual volume of tumor after surgery. (16 Refs)

Bergh NP, Gatzinsky P, Larsson S, et al.: Tumors of the thymus and thymic region: I. clinicopathological studies on thymomas. Annals of Thoracic Surgery 25(2): 91-98, 1978.

The clinical presentation and treatment of 43 patients (23 men, 20 women; 17-73 yr, av 51) with thymoma were reviewed. The presenting symptoms, extent of tumor, and histological type contributed to the staging system. Stage I tumors were intact capsules or had growth within a capsule. Stage II tumors showed pericapsular growth into mediastinal fat. Stage III tumors exhibited invasive growth. There were 17 patients in stage I (3 lymphocytic, 8 lymphoepithelial, 6 epithelial), 8 in stage II (3, 1, 4), and 18 were in stage III (4, 6, 8). Complete surgical removal was done on all the stage I and II patients, 15 of whom received radiation therapy. The tumor could not be removed radically in four stage III patients. Thirteen patients with stage III tumors were given radiotherapy, and five were given adjuvant chemotherapy. Among stage I patients, there was one death, attributable to radiation damage, three intercurrent deaths, and no recurrences. There were two intercurrent deaths in stage II patients and one recurrence. In stage III patients there were three operative deaths and two further deaths caused by surgery and radiotherapy among the 14 patients who had the tumor completely removed. One of the stage III patients with a nonresectable tumor lived almost 5 yr after receiving radiotherapy; the other three died within 1 yr of treatment. Pleural metastases were found in eight patients at surgery. Eight patients in this group remained alive and well for at least one yr. Presence of myasthenia gravis was not a contraindiction for surgery. (18 Refs)

The place of radiotherapy in the management of malignant thymoma is still a matter of some dispute, and differences in opinions of various investigators in this regard are reviewed. Most investigators advocate postoperative radiotherapy. Surgery is nearly always attempted in the first instance, since, even if the lesion is inoperable, this may be the only way to establish a histological diagnosis. If complete removal is impossible or if local recurrence is feared following apparently complete removal, irradiation is usually given. The use of radiotherapy alone meets with little support in the literature; however, many cases of malignant thymoma are inoperable, and it has been the policy of the present authors to irradiate these patients unless they are hopelessly ill. In this article, the outcome of 18 cases of malignant invasive thymoma receiving radiotherapy at the London Hospital from 1948 to 1968 inclusive is reported. Fifteen of the 18 patients were submitted to thoracotomy. In 8 of the 15 thoracotomy patients, macroscopically complete removal was achieved; 7/8 were referred for postoperative radiotherapy, and 1/8 was eventually irradiated for local recurrence. In 2/7 remaining cases, removal was known to be incomplete; 5/7 remaining cases were regarded as part of the primary management; of these, 4 received a radical tumor dose (4,000 rad megavoltage or greater in 20 treatments over a period of 28 days), while 3 received conventional deep x-rays to an equivalent dose. The remaining eight patients were treated palliatively on the grounds of widespread disease or poor general condition. Of the seven patients treated with a full radical dose, all were alive at 3 yr; all of four such patients followed for 10 yr were alive at that time. Also, of these seven patients, only three had had macroscopically complete excision of the tumor at thoracotomy. These findings suggested that postoperative radiotherapy should be of benefit in all cases of invasive thymoma whether operable or otherwise. (21 Refs)