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Thymoma

In medicine (oncology), thymoma is a neoplasm of the thymus. It is a rare disease, best known for its enigmatic association with the neuromuscular disorder myasthenia gravis. There are benign and malignant forms, which present similarly. more...

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Signs and symptoms

  • 33%-50% is detected accidentally on routine X-rays of the chest.
  • 33% presents with complaints due to compression of surrounding structures by the expanding tumor:
    • Vena cava superior syndrome (compression of the upper caval vein)
    • Dysphagia (trouble swallowing)
    • Cough, chest pain
  • A final 33% has autoimmune symptoms; thymomas in these are usually benign. The best known is myasthenia gravis, of which 25-50% is associated with a thymoma. Some others are: pure red cell aplasia and Good's syndrome (thymoma with combined immunodeficiency and hypoimmunoglobulinemia G).
    • Rare associations that have been reported are: acute pericarditis, Addison's disease, agranulocytosis, alopecia areata, ulcerative colitis, Cushing's disease, hemolytic anemia, limbic encephalopathy, myocarditis, nephrotic syndrome, panhypopituitarism, pernicious anemia, polymyositis, rheumatoid arthritis, sarcoidosis, scleroderma, sensorimotor radiculopathy, stiff person syndrome, systemic lupus erythematosus and thyroiditis.

Malignant thymomas can metastasize, generally to pleura, kidney, bone, liver or brain.

Diagnosis

When a thymic pass is identified, the diagnosis is achieved with histology (obtaining a tissue sample of the mass). When a thymoma is suspected, a CT/CAT scan is generally performed to estimate the size of the tumor, and can be biopsied with a CT-guided needle. Although there is a risk of pneumomediastinum, mediastinitis and the risk of damaging the heart or large blood vessels.

The tumor is generally located inside the thymus, and can be calcified. Increased vascular enhancement can be indicative of malignancy, as can be pleural deposits.

If the suspicion is real, some blood tests are often performed to gain an appreciation of associated problems or possible spread. These include: full blood count, protein electrophoresis, antibodies to the acetylcholine receptor (indicative of myasthenia), electrolytes, liver enzymes and renal function.

The final diagnosis is made by removing the thymus. Pathological investigation of the specimen will reveal if the tumor was benign or malignant.

Pathophysiology

Thymomas originate from the epithelial cell population in the thymus. Many subtypes are recognised, some of which have a better- or worse-than-general prognosis.

Epidemiology

Men and women are equally affected. The main age for thymomas is 30-40, although cases have been described in every age group.

Treatment

Surgery is the mainstay of treatment. If the tumor was benign and was removed in its entirety, no further therapy is necessary. Malignant tumors may need additional treatment with radiotherapy, or sometimes with chemotherapy (cyclophosphamide, doxorubicin and cisplatin).

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Multidisciplinary therapy including high-dose chemotherapy followed by peripheral blood stem cell transplantation for invasive thymoma - selected reports
From CHEST, 12/1/02 by Yoshinobu Iwasaki

We describe two patients with invasive thymomas who responded to high-dose chemotherapy followed by peripheral blood stem cell transplantation (PBSCT) combined with surgery and radiotherapy. The first patient was a 42-year-old man admitted to the hospital with chest pain, and the second patient was a 45-year-old man admitted with myasthenia gravis. Both patients had nonresectable thymomas (stage IVa) because of invasion of the aorta, pulmonary artery, or both, and dissemination to the pericardium. They initially received two cycles of chemotherapy consisting of adriamycin (40 mg/[m.sup.2], day 1), cisplatin (50 mg/[m.sup.2], day 1), vincristine (0.6 mg/[m.sup.2], day 3), and cyclophosphamide (700 mg/[m.sup.2], day 4) at 3-week intervals. Four weeks later, they were administered high-dose etoposide (300 mg/[m.sup.2], days 1 to 5) followed by granulocyte colony-stimulating factor (G-CSF) [50 [micro]g/[m.sup.2]/d] subcutaneously to mobilize stem cells into the blood. After two additional cycles of adriamycin, cisplatin, vincristine, and cyclophosphamide (ADOC), the patients received high-dose ifosfamide (1.5 g/[m.sup.2], days 1 to 4), earboplatin (400 mg/[m.sup.2], days 3 to 5), and etoposide (200 mg/[m.sup.2], days 1 to 5) followed by PBSCT. They were administered G-CSF (50 [micro]g/[m.sup.2]/d) after PBSCT, with subsequent rapid recovery of neutrophil and platelet level. The tumors shrank remarkably, and could be excised completely in both patients. Postoperatively, 50 Gy of irradiation was administered. Disease-free status has been maintained for 5 years in the first patient and 2 years in the second patient. Our findings suggest that high-dose ifosfamide, carboplatin, and etoposide followed by PBSCT in combination with an ADOC regimen, surgery, and radiotherapy is very effective and well tolerated in patients with advanced nouresectable thymoma.

Key words: high-dose chemotherapy; invasive thymoma; multidisciplinary therapy; peripheral blood stem cell transplantation

Abbreviations: ADOC = adriamycin, cisplatin, vincristine, and cyclophosphamide; ICE = ifosfamide, carboplatin, and etoposide; G-CSF = granulocyte colony-stimulating factor; PAC = cisplatin, doxorubicin, and cyclophosphamide; PBSCT = peripheral blood stem cell transplantation

**********

Thymomas are rare, slowly growing neoplasms with peak incidence at approximately 50 years of age. (1) Thymomas are histologically classified into predominantly epithelial, predominantly lymphocytic, and mixed lymphoepithelial types, (2) regardless of cytologic abnormalities of the neoplastic epithelial cells. Their malignant behavior is defined according to macroscopic and microscopic signs of invasiveness, not histologic criteria. The presence of tumor invasion is considered the most important predictor of future behavior (3) and forms the basis for the clinical staging system described by Masaoka et al. (4) After total resection, noninvasive thymomas carry a good prognosis, with 10-year survival rates ranging from 67 to 80%. (3,5) Because postoperative relapse of noninvasive thymomas is rare, (1,6) surgery alone is the treatment of choice. In contrast, invasive thymomas have a considerably worse outcome. Large invasive thymomas are difficult to resect completely. Radiation is sometimes administered preoperatively to facilitate resection of bulky tumors and can be useful for salvage therapy after unsuccessful surgical treatment. (7) Radiotherapy also plays an important role in the postoperative management of completely resected invasive thymomas, but is associated with a high frequency of pleural recurrence in stage III disease. More effective adjuvant strategies are thus needed. (8) Chemotherapy is also required in patients with stage III and IV invasive thymomas. Combination chemotherapy is usually effective and has been used preoperatively to facilitate resection of locally advanced disease. (9) Peripheral blood stem cell transplantation (PBSCT) has been widely used to manage the hematologic toxicity caused by high-dose chemotherapy in patients with chemosensitive solid tumors. (10) We describe two patients with invasive thymomas (stage IVA) who responded to high-dose chemotherapy followed by PBSCT, combined with conventional chemotherapy, radiotherapy, and surgery.

CASE REPORTS

Case 1

A 42-year-old man was admitted to the hospital because of chest pain. A large mass in the anterior mediastinum was seen on the chest radiograph and confirmed by CT (Fig 1). Surgery was performed, but the tumor was nonresectable because it had invaded the aorta and pulmonary artery and disseminated to the pericardium. Invasive thymoma (stage IVA, lymphocytic predominant histology) was diagnosed. The patient initially received two cycles of chemotherapy consisting of adriamycin (40 mg/[m.sup.2]) and cisplatin (50 mg/[m.sup.2]) administered on day 1, vincristine (0.6 mg/[m.sup.2]) on day 3, and cyclophosphamide (700 mg/[m.sup.2]) on day 4, at 3-week intervals. Four weeks after the first two cycles of adriamycin, cisplatin, vincristine, and cyclophosphamide (ADOC), he was administered 300 mg/[m.sup.2] of etoposide for 5 days, followed by granulocyte colony-stimulating factor (G-CSF) [50 [micro]g/[m.sup.2]] subcutaneously to mobilize stem cells into the blood. The number of WBCs exceeded 5,000/[micro]L on day 17, and peripheral blood stem cell collection was performed on days 17 and 18. A total of 8.54 x [10.sup.5] granulocyte-macrophage colony-forming units per kilogram was obtained. After two additional cycles of ADOC, he received high-dose ifosfamide, carboplatin, and etoposide (ICE) therapy. Ifosfamide was administered at 1.5 g/[m.sup.2]/d as a 3-h IV infusion on days 1 to 4. Carboplatin was administered at 400 mg/[m.sup.2]/d as a 6-h IV infusion on days 3 to 5. Etoposide was administered at 200 mg/[m.sup.2]/d as a continuous infusion on days i to 5. Mesna, 400 mg/[m.sup.2], was administered as a 1-h IV infusion i h before and 4 h and 8 h after ifosfamide administration. Forty-eight hours after the end of chemotherapy, 2.45 x [10.sup.5] granulocyte-macrophage colony-forming units per kilogram was reinfused and G-CSF was administered subcutaneously a dosage of 50 [micro]g/[m.sup.2]/d. Posttransplant neutropenia < 500/[micro]L and thrombocytopenia < 50,000/[micro]L lasted for 9 days and 14 days, respectively. The tumor was confirmed to have shrunk remarkably on a chest radiograph and CT scan (Fig 2). Three months later, total surgical resection was performed, and a complete response was confirmed pathologically. Postoperatively, 50 Gy of irradiation was administered. Disease-free status has continued for 5 years.

[FIGURES 1-2 OMITTED]

Case 2

A 45-year-old man was admitted to the hospital because of myasthenia gravis with a large mass in the anterior mediastinum (Fig 3). Surgery was performed, but the tumor was unresectable because it had invaded the aorta and disseminated to the pericardium. Invasive thymoma (stage IVA, mixed lymphoepithelial histology) was diagnosed. The patient initially received two cycles of ADOC at 3-week intervals. Four weeks later, he was administered 300 mg/[m.sup.2] of etoposide for 5 days followed by G-CSF (50 [micro]g/[m.sup.2]) subcutaneously to mobilize stem cells into the blood. The number of WBCs was > 5,000/[micro]L on day 21, and peripheral blood stem cell collection was performed on days 21 and 22. A total of 25.9 x [10.sup.6] CD34-positive cells per kilogram was obtained. After two additional cycles of ADOC, he received high-dose ICE therapy. Forty-eight hours after the end of chemotherapy, 2.4 x [10.sup.6] CD34-positive cells per kilogram was reinfused, and G-CSF was administered subcutaneously at a dose of 50 [micro]g/[m.sup.2]/d. Posttransplant neutropenia < 500/[micro]L and thrombocytopenia < 50,000/[micro]L lasted for 7 days and 11 days, respectively. The tumor was demonstrated to have shrunk markedly on a chest radiograph and CT scan (Fig 4). Three months later, total surgical resection was performed. Postoperatively, 50 Gy of irradiation was administered. Disease-free status has been maintained for 2 years.

[FIGURES 3-4 OMITTED]

DISCUSSION

Recurrence after surgery for noninvasive thymoma is rare (0 to 3.8%) (1,6); consequently, most patients do not receive postoperative adjuvant treatment. In contrast, invasive thymomas have a much worse prognosis. (11) Large invasive thymomas with invasion of major vessels or cardiac structures are difficult to resect completely. Despite improved surgical techniques, radical resection is feasible in only approximately one half of patients with stage III disease and is usually impractical in those with stage IV disease. (12) Although most thymomas are considered to follow an indolent course, with recurrence limited to the thorax, invasive thymomas have been associated with distant metastases, most commonly to the liver, bone, kidney, and extrathoracic lymph nodes. Arriagada et al (13) reported that distant metastasis was the primary cause of death (64%) in a retrospective review of patients with invasive thymomas. Systemic chemotherapy thus plays a very important role in the treatment of invasive thymomas.

Chemotherapy is effective against most invasive thymomas and can be used preoperatively to improve resectability. (9) Chemotherapeutic regimens containing platinum are usually more effective than regimens without platinum. (14) In a review of platinum-containing regimens, Loehrer et al (15) reported the response to combination therapy with cisplatin, doxorubicin, and cyclophosphamide (PAC) in invasive thymoma. In their study, 20 patients with stage III or IV invasive thymomas received PAC therapy at 3-week intervals. Three complete and 11 partial responses were confirmed (overall response rate, 70%). The median duration of response was 13 months, and the median survival time was 59 months.

Combination therapy with etoposide, ifosfamide, and cisplatin was evaluated in patients with invasive thymomas or thymic carcinomas and was reported by Loehrer et al. (16) In their report, 28 patients with invasive thymoma or thymic carcinoma received etoposide, ifosfamide, and cisplatin at 3-week intervals for four cycles. There were no complete responses and nine partial responses.

Fornasiero et al (17) reported on the response to ADOC therapy. In their study, 37 patients with stage III or IV invasive thymomas received ADOC therapy at 3-week intervals. The overall response rate was 92%, with a complete response rate of 43%.

A few studies have used high-dose chemotherapy to treat invasive thymoma. Hanna et al (18) reported that high-dose carboplatin and etoposide followed by PBSCT was effective with acceptable toxicity in patients with recurrent thymoma. Our patients received four cycles of the ADOC regimen at 3-week intervals and thereafter high-dose ICE followed by PBSCT. We used ICE for high-dose chemotherapy because these drags have been demonstrated to be safe and effective in patents with invasive thymomas. (19-21) A complete response was obtained in the first case, and a partial response was obtained in the second.

Several studies have assessed the response to combination chemotherapy followed by radiotherapy in invasive thymoma. Loehrer et al (22) reported encouraging results in patients administered a PAC regimen combined with radiation therapy. In their study, 23 patients received two to four cycles of PAC therapy at 3-week intervals followed by a total dose of 54 Gy to the primary tumor and regional lymph nodes in patients who had a stable, partial, or complete response to chemotherapy. There were 5 complete and 11 partial responses to chemotherapy (overall response rate, 70%). The median time to treatment failure was 93 months, and the median survival time was 93 months. The 5-year survival rate was 53%.

The role of radiation after complete resection of invasive thymomas is controversial. Curran et al (23) reported that 53% of patients treated with surgery alone had recurrence within 5 years. The rate of local failure was 0% after complete resection with radiation and 21% after subtotal resection or biopsy with radiation. (23) In our patients, complete resection could be performed after high-dose ICE therapy, and irradiation was administered subsequently. The optimal dose of irradiation for invasive thymomas remains unclear. Cox (24) reported that better locoregional control was obtained at a dose [greater than or equal to] 60 Gy. Mornex et al (25) showed that a 50-Gy dose adequately controlled tumor recurrence after complete resection. Our patients also received 50 Gy after complete resection.

Our findings suggest that high-dose ICE followed by PBSCT in combination with ADOC therapy, surgery, and radiotherapy is highly effective and well tolerated in patients with advanced nonresectable thymoma. Invasive thymomas may be cured by such multidisciplinary therapy, including high-dose chemotherapy followed by PBSCT.

REFERENCES

(1) Maggi G, Giaccone G, Donadio M, et al. Thymomas: a review of 169 cases, with particular reference to results of surgical treatment. Cancer 1986; 58:765-776

(2) Bernatz PE, Harrison EG, Clagett OT. Thymoma: a clinico-pathologic study. Thorac Cardiovasc Surg 1961; 42:424-433

(3) Verley JM, Hollmann KH. Thymoma: a comparative study of clinical stages, histologic features, and survival in 200 cases. Cancer 1985; 55:1074-1086

(4) Masaoka A, Monden Y, Nakahara K, et al. Follow-up study of thymoma with reference to their clinical stages. Cancer 1981; 4:2485-2492

(5) Wilkins EW, Edmunds LH Jr, Castleman B. Cases of thymoma at the Massachusetts General Hospital. Thorac Cardiovasc Surg 1966; 52:322-330

(6) Curran WJ Jr, Kornstein MJ, Brooks JJ, et al. Invasive thymoma: the role of mediastinal irradiation following complete or incomplete surgical resection. J Clin Oncol 1988; 6:1722-1727

(7) Ohara K, Okumura T, Sugahara S, et al. The role of preoperative radiotherapy for invasive thymoma. Acta Oncol 1990; 29:425-429

(8) Haniuda M, Morimoto M, Nishimura H, et al. Adjuvant radiotherapy after complete resection of thymoma. Ann Thorac Surg 1992; 54:311-315

(9) Tomiak EM, Evans WK. The role of chemotherapy in invasive thymoma: a review of the literature and considerations for future clinical trials. Crit Rev Oncol Hematol 1993; 15:113-124

(10) Elias A, Ibrahim J, Skarin AT, et al. Dose-intensive therapy for limited-stage small-cell lung cancer: long-term outcome. J Clin Oncol 1999; 17:1175-1184

(11) Kirkove C, Berghmans J, Noel H, et al. Dramatic response of recurrent invasive thymoma to high doses of corticosteroids. Clin Oncol 1992; 4:64-66

(12) Maggi G, Casadio C, Cavallo A, et al. Thymoma results of 241 operated cases. Ann Thorac Surg 1991; 51:152-156

(13) Arriagada R, Bretel JJ, Caillaud JM, et al. Invasive carcinoma of the thymus: a multicenter retrospective review of 56 cases. Eur J Cancer 1984; 20:69-74

(14) Hu E, Levine J. Chemotherapy of malignant thymoma: case report and review of the literature. Cancer 1986; 57:1101-1104

(15) Loehrer PJ, Perez CA, Roth LM, et al. Chemotherapy for advanced thymoma: preliminary results of an intergroup study. Ann Intern Med 1990; 113:520-524

(16) Loehrer PJ, Jiroutek M, Aisner S, et al. Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial. Cancer 2001; 91:2010-2015

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

(18) Hanna N, Gharpure VS, Abonour R, et al. High-dose carboplatin with etoposide in patients with recurrent thymoma: the Indiana university experience. Bone Marrow Transplant 2001; 28:435-438

(19) Highley MS, Underhill CR, Parnis FX, et al. Treatment of invasive thymoma with single-agent ifosfamide. J Clin Oncol 1999; 17:2737-2744

(20) 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. J Clin Oncol 1996; 14:814-820

(21) Iwasaki Y, Kubota Y, Yokomura I, et al. Invasive thymoma successfully treated with high-dose chemotherapy followed by peripheral blood stem cell transplantation (PBSCT). Nihon Kokyuki Gakkai Zasshi 1998; 36:288-293

(22) Loehrer PJ, Chen M, Kim K, et al. Cisplatin, doxorubicin, and cyclophosphamide plus thoracic radiation therapy for limited-stage unresectable thymoma: an intergroup trial. J Clin Oncol 1997; 15:3093-3099

(23) Curran WJ Jr, Kornstein MJ, Brooks JJ, et al. Invasive thymoma: the role of mediastinal irradiation following complete or incomplete surgical resection. J Clin Oncol 1988; 6:1722-1727

(24) Cox JD. The lung and thymus. In: Moss WT, Cox JD, eds. Radiation oncology rationale, technique, and results. St. Louis, MO: CV Mosby Company, 1989; 305-308

(25) Mornex F, Resbeut M, Richaud P, et al. Radiotherapy and chemotherapy for invasive thymomas: a multicentric retrospective review of 90 cases. Int J Radiat Oncol Biol Phys 1995; 32:651-659

* From the Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Manuscript received March 1, 2002; revision accepted June 16, 2002.

Correspondence to: Yoshinobu Iwasaki, MD, Second Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602, Japan; e-mail: yiwasaki@koto.kpu-m.ac.jp

COPYRIGHT 2002 American College of Chest Physicians
COPYRIGHT 2003 Gale Group

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