Rhabdomyosarcoma in a Patient with Mosaic Klinefelter Syndrome and Transformation of Immature Teratoma

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1 Rhabdomyosarcoma in a Patient with Mosaic Klinefelter Syndrome and Transformation of Immature Teratoma T YAMAMOTO, J TAMURA, S ORIMA, T SAITOH, M SAKURAYA, T MAEHARA, A SHIROTA, A MAEZAWA, Y NOJIMA AND T NARUSE Third Department of Internal Medicine, Gunma University School of Medicine, Showa Maebashi, Japan A 27-year-old man was found to have a mediastinal tumour and the histological diagnosis was immature teratoma. Remission was achieved by chemotherapy and total resection. However, he developed anaemia and leukoerythroblastosis after 2 years of remission, and was referred to our hospital. Rhabdomyosarcoma cells were detected in the bone marrow and pleural effusion. Moreover, karyotype analysis of peripheral blood and bone marrow cells revealed mosaic-type Klinefelter. We diagnosed the case as transformation of teratoma into rhabdomyosarcoma in Klinefelter. Although intensive chemotherapy was performed, the patient died with meningeal infiltration. KEY WORDS: TERATOMA; RHABDOMYOSARCOMA; KLINEFELTER SYNDROME; TRANSFORMATION; GERMINAL TUMOUR; TUMOUR MARKER INTRODUCTION Klinefelter has a karyotype abnormality of 47, XXY, and is occasionally complicated by certain malignancies. Although germinal cell tumour is one of the most common malignancies occurring in Klinefelter, the relationship between germinal cell tumour and mosaic type Klinefelter is still unclear. 1-4 We encountered a rare case of mosaic Klinefelter with immature teratoma of the mediastinum transformed into rhabdomyosarcoma. This case is discussed here in terms of the relationship between Klinefelter and germinal tumour, and the transformation of germinal tumour into other malignancies. 196

2 T Yamamoto, J Tamura, S Drima et al, 0/ cyclosphospharnide for two courses) were performed and complete remission was achieved with normalization of tumour marker levels. In June a 39 C fever. high levels of lactate dehydrogenase. anaemia. thrombocytopenia. and leukoerythroblastosis were noted. The tumour markers a-fetoprotein and human chorionic gonadotrophin were. however, within the normal range at that time. Bone marrow aspiration was dry tap. Secondary myelofibrosis due to chemotherapy was suspected. and the patient was referred to our hospital. On admission. his height was 179 cm and body weight was 78 kg. The signs of Klinefelter. eunuchism. gynecomastia and disturbance of sexual development. were not remarkable. Routine laboratory findings were as follows: haemoglobin 8.4 g/dl, platelet count CASE REPORT In April a 27-year-old man was found to have a mediastinal tumour on X-ray examination. and was admitted to another hospital. High levels of tumour markers such as a-fetoprotein 55().4 ng/ml (normal: < 10 ng/ml) and human chorionic gonadotrophin 2.0 ng/ml (normal: < 0.1 ng/ml) were noted. A large mass in the right mediastinum was noted on a computed tomography scan as shown in Fig. 1. Open biopsy was performed. and the histological diagnosis was immature teratoma (Fig. 2). Intensive chemotherapy with cisplatin/ etoposide/bleomycin for two courses. cisplatin/actinomycin O/vinblastine/ bleomycin/cyclophosphamide for two courses. and total resection followed by chemotherapy (cisplatin/etoposide for DlW course and vincristine/actinomycin FIGURE 1 Chest computed tomography scan with large mass to the right of the mediastinum. 197

3 T Yumomoto, I Tamura, S Orima et al. FIGURE 2. /.... ~. i: v:..~":" Various tissues including muscle, fat, gland and nerve, are seen in the specimen of mediastinal tumour (X fool. rhabdomyosarcoma was made. Furthermore, karyotype analysis of peripheral blood mononuclear cells, stimulated by phytohaemagglutanin, revealed the abnormal karyotype: 47, XY. + X (9/20). 46, XY (11120), which indicated mosaic Klinefelter. Bone marrow cells, not stimulated by phytohaemagglutanln, showed the abnormal karyotype: 47, XY, + X (18/20), 46, XY (2/20). Endocrinological studies including luteinzing hormone. follicle-stimulating hormone, testosterone, oestrogen, thyroidstimulating hormone and thyroid hormone were normal. The patient was treated with aggressive combination chemotherapy (cyclophosphamide 2400 mg/adriamycin 80 mgt carboplatin 750 mg/etoposide 200 mg every day for 5 days) for three courses, but he died 4.8 x 104/111, leukocyte count 6900/111 with immature granulocytes and nucleated red blood cells. Biochemical tests were normal without high levels of lactate dehydrogenase 1078 lull (normal: IU/I) and uric acid 10.0 mg/dl (normal: mg/dl). a-fetoprotein was 2.3 ng/ml and human chorionic gonadotrophin was < 0.1 ng/ml. Bone marrow biopsy revealed mild fibrosis with infiltration of atypical large cells which suggested sarcoma cells. An immunohistochemical study revealed that antidesmin and anti-myosin were positive (Fig. 3). Pleural effusion. multiple lung metastases, and right facial muscle and liver metastases were noted on X-ray examination and computed tomography scan. Atypical large cells were found in pleural effusion. Considering all of the findings, the diagnosis of transformation of immature teratoma into 198

4 T YCll1wmolo, / Tamura, S Orima et at. Rhabdomvosarcoma in Klinefelter. FIGURE 3 ~j', ;, jt,~...'~._-. Anti-desmin positive tumour cell is seen in bone marrow tissue with mild fibrosis (X 400). XY/47, XY, + X mosaicism occurs in 10% of patients. In some of those with the mosaicism. any signs of gonadal failure and phenotypic features of Klinefelter are absent, as in the present case. Because case reports of mosaic Klinefelter complicated by malignancies are very rare. the relationship between mosaic Klinefelter and the occurrence of malignancy is unclear. However, a case of mosaic Klinefelter with primary mediastinal germ cell tumour! is frequently associated with the common type of Klinefelter.s-' and a case of mosaic Klinefelter with rhabdomyosarcoma" have been reported. Furthermore. in the present case karyotype analysis of bone marrow cells showed that most of the analysed cells were of the Klinefelter type. strongly suggesting that the rhabdomyosarcoma cell originates from somatic cells with the 47, XY. + X abnormality like the common type of Klinefelter. with meningeal sarcomatosis 6 months after admission. Systemic autopsy was not permitted. However. the metastatic embryonal rhabdomyosarcoma. exhibiting variable histological patterns ranging from poorly differentiated to well differentiated. was present in autopsied specimens of bone marrow. lung and liver. DISCUSSION The case presented had two characteristic clinical features: the occurrence of immature teratoma associated with mosaic-type Klinefelter, and the transformation of teratoma into rhabdomyosarcoma. It is well known that the karyotype abnormality of Klinefelter is a risk factor for developing malignancies, such as breast cancer. extragonadal germ-cell tumour and leukaemia. Most patients with Klinefelter have a 47, XY. + X chromosome pattern. but the variant karyotype of

5 T Yamamoto, J Tamura, S Orima et al. The history of our case showed that an immature teratoma was transformed into a rhabdomyosarcoma, which is the most common soft-tissue sarcoma and can arise from any anatomical location. There is no specific marker for rhabdomyosarcoma, and pathological study with immunohistochemistry for anti-desmin and antimyosin is needed for definitive diagnosis. At the transformation stage, the tumour markers a-fetoprotein and human chorionic gonadotrophin were not increased in the present case, and this delayed the diagnosis of rhabdomyosarcoma. Although the possibility of secondary malignancy cannot be excluded in the present case, a recent report suggests that rhabdomyosarcoma is a common malignancy following malignant transformation of a teratoma. It is possible that rhabdomyosarcoma cells in the teratoma were resistant to chemotherapy and that clonal selection occurred." In such a case, tumour markers might become useless for long-term follow up. Indeed, the recurrence of malignancy cannot be detected early because follow-up is dependent on tumour markers, and some transformation to rhabdomyosarcoma has already occurred at the time of diagnosis. Megadose chemotherapy focused on haematopoietic stem-cell transfusion should be considered before clonal selection occurs. REFERENCES 1 Derenoncourt AN, Castro-Magana M, Jones KL: Mediastinal teratoma and precocious puberty in a boy with Klinefelter. Am J Med Genetics 1995; 55: Hasle H, Jacobsen BB, Asschenfeldt P, et ail Mediastinal germ cell tumor associated with Klinefelter. Eur JPediatr 1992; 151: Halse H, Mellemgaard A, Nielsen J, et al: Cancer incidence in men with Klinefelter. Br J Cancer 1995; 71: Ogur G, Sengun Z, Arel-Kilic G, et a1: Clinical and cytogenic studies of two cases of Klinefelter with hereditary retinoblastoma and rhabdomyosarcoma. Cancer Genet Cytogenet 1996; 89: Comiter CV, Kibel AS, Richie JP, et aj: Prognostic features of teratomas with malignant transformation: a clinicopathological study of 21 cases. J Urol 1998; 159: T Yamamoto, J Tamura, S Orima, T Saitoh, M Sakuraya, T Maehara, A Shirota, A Maezawa, Y Nojima and T Naruse Rhabdomyosarcoma in a Patient with Mosaic Klinefelter Syndrome and Transformation of Immature Teratoma The Journal ofinternational Medical Research 1999; 27: Received for publication 9 June 1999 Accepted 16 June 1999 Copyright 1999 Cambridge Medical Publications Address for correspondence DR/TAMURA Third Department of Internal Medicine, Gunma University School of Medicine, Showa-machi, Maebashi , Japan. 200