Japanese Journal of Clinical Oncology

DISCUSSION

MG and PRCA are occasionally associated with thymoma. MG appears in about 20-40% of patients with thymoma and PRCA develops in about 2-5% of those patients (5). On the other hand, thymoma is detected in 10-17% of patients with MG (6) and in 5-13% of patients with PRCA (7). However, the simultaneous occurrence of MG, PRCA and thymoma is extremely rare.

Since the first description of MG with thymoma and PRCA in 1939 (8), 28 patients with this clinical triad have been reported in the literature (6,8-29) (Table 1). In two of the 28 cases, MG developed after thymomectomy or thymothymectomy for PRCA (17,23) and in another case, both MG and PRCA developed after thymothymectomy (27). Therefore, in 25 cases MG, PRCA and thymoma existed simultaneously. Of these 25 patients, 14 were men and the ages of the patients ranged from 33 to 88 years. Twenty-three patients had developed PRCA 1-21 years (mean, 7.3 years) after the onset of MG, when the MG with thymoma was well controlled by medication in the majority of these patients. In the remaining two cases, PRCA preceded the onset of MG by 9 and 1 month (22,28).

Furthermore, to our knowledge, only one case has been reported of MG with PRCA but without thymoma. That patient developed MG and PRCA after chemotherapy for Hodgkin's disease (30). Therefore, even if no remarkable chest roentgenogram findings are noted for a patient with MG and PRCA, further examination of the chest is necessary. A roentgenogram of the chest has an 85-90% chance of detecting an anterior mediastinal mass (31). Rosenow and Hurley (32) reported that 16 (23%) of 69 thymomas were not detected in posteroanterior roentgenograms. On the other hand, a CT scan will always detect a mass and is, therefore, the preferred procedure (31). In the present case, although a chest roentgenogram of the posteroanterior view was interpreted as unremarkable, a chest roentgenogram of the lateral view and a CT scan of the thorax indicated the presence of an anterior mediastinal mass. When the patient was diagnosed as having MG 8 years earlier, a chest roentgenogram of the posteroanterior view showed no abnormality; however the thymoma might have been present at that time.

Table 1. Reported cases of the clinical triad of MG, PRCA and thymoma <

Patient No.	Source, year	Patient's sex/age	Period	Treatment of PRCA	Response
1	Opsahl (8), 1939	M/56	NR	NR	NR
2	Chalmers et al. (9), 1954	M/48	1.5 yr	Adenocorticotropic hormone, thymothymectomy, splenectomy	Remission
3	Bakker (10), 1954	F/62	NR	Thymothymectomy	Remission
4	Weinbaum and Thompson (11), 1955	F/76	4 yr	Dietary supplements	None
5	Therenard and Marques (12), 1955	F/NR	1 yr	Strychnine	None
6	Castaigne et al. (13), 1961	F/33	3 yr	None	NR
7	Radermecker et al. (14), 1964	F/59	17 yr	Thymothymectomy, triamcinolone, prednisolone	Rapid favorable response
8	Roland (15), 1964	F/68	4 yr	Thoracotomy, thymomectomy alone, iron supplements, prednisolone, testosterone, pyridoxine hydrochloride	None
9	Hinrichs and Stevenson (16), 1965	M/47	5 yr	Transfusions only	None
10	Miyata et al. (17), 1971	F/53	2 yr	Thoracotomy, thymomectomy alone, splenectomy, prednisolone	Died
11	DeSevilla et al. (18), 1975	M/55	10 yr	Corticosteroids, cyclophosphamide	None
12	Oosterhuis et al. (6), 1976	M/50s	NR	Prednisolone	Favorable
13	Oosterhuis et al. (6), 1976	F/50s	NR	Prednisolone	Favorable
14	Oosterhuis et al. (6), 1976	F/50s	NR	Prednisolone	Favorable
15	Oosterhuis et al. (6), 1976	F/50s	NR	Durabolin	Thrombopenia
16	Oosterhuis et al. (6), 1976	F/60s	NR	NR	Thrombopenia
17	Houghton et al. (19), 1978	M/51	5 yr	Hydrocortisone, prednisolone	Remission
18	Imamura et al. (20), 1978	M/68	4 yr	NR	None
19	Zeok et al. (21), 1979	M/58	14 yr	Thymothymectomy, irradiation	None
20	Socinski et al. (22), 1983	F/72	9 mon	Prednisolone, cyclophosphamide Pyridostignin bromide*, prednisolone*	Remission
21	Fujimura et al. (23), 1985	M/58	10 mon	Thymothymectomy, steroid	Remission
22	Harris and Weinberg (24), 1985	M/49	21 yr	Thymothymectomy, prednisolone, cyclophosphamide, antithymocyte globulin	Favorable
23	Bailey et al. (25), 1988	M/88	7 yr	Transfusion	None
24	Masaoka et al. (26), 1989	M/58	NR	Thymothymectomy, steroid	Remission
25	Masaoka et al. (26), 1989	M/67	NR	Thymothymectomy, steroid, azathioprine	Remission
26	Murase (27), 1993	M/47	2 yr	Tymothymectomy, predonisolone, cyclophosphamide	Remission
27	Handa et al. (28), 1994	M/73	1 mon	Thymothymectomy	Remission
28	Nishioka et al. (29), 1995	M/43	6 yr	Irradiation, cyclophosphamide, doxorubicin, vincristine, prednisolone	None

Period, period between the onset of MG and PRCA; NR, not reported; entries in italics, MG and/or PRCA occurred after thymectomy. *Treatment for recurrence of MG.

The involvement of both humoral and cell-mediated immunity components in the blood and thymus has been observed in patients with MG. In the thymus of patients with MG, B lymphocyte numbers increase and in vitro thymic lymphocytes produce immunoglobulin and an antibody to AChR (33). The indication for thymothymectomy in MG with thymoma is widely accepted (34). Moreover, in nonthymomatous MG, thymectomy clearly results in clinical improvement (35), although a prospective randomized study has not been performed.

Four different immune pathogenetic mechanisms of development of PRCA have been demonstrated. These include antibodies to erythroblasts, to erythropoietin-responsive cells and to erythropoietin, in addition to T cell suppression of erythropoiesis. The surgical treatment of PRCA has not been widely accepted as the first choice in therapy. When thymoma is present, thymothymectomy results in remission in 30% of cases (21,36). Although thymic excision in the absence of a thymic mass has been advocated by some (36), it remains of unproven value. Masaoka et al. (26) suggested that a thymoma or the thymus might have an antigen in common with the erythroblastic cells. On the other hand, Masuda et al. (37) described a case of PRCA with thymoma in which a monoclonal rearrangement of the T-cell receptor (TCR) [beta]-chain gene was found, using Southern blot analysis, in mononuclear cells from the peripheral blood and from the thymoma. This case was unresponsive to prednisolone and cyclophosphamide after thymothymectomy and was treated with cyclosporin A. The patient developed reticulocytosis. They proposed that the surgically refractory cases of PRCA with thymoma might be considered to have systemic invasion resulting from T-cell clonal expansion.

Of the 25 patients with MG, PRCA and thymoma, eight underwent thymothymectomy and one underwent thymomectomy alone by right thoracotomy. Seven of these eight patients (87.5%) entered transient remission or showed temporary improvement after surgery. On the other hand, of the 13 patients who were not treated surgically and whose progress was reported in the literature, only four (31%) showed improvement. Many patients who underwent thymothymectomy, however, continue to require immunosuppressive treatment to maintain the PRCA remission. One patient, whose condition was unresponsive to prednisolone and cyclophosphamide after thymothymectomy, was treated with antithymocyte globulin (ATG) and showed complete remission (24). ATG may induce remission by altering the cell-mediated processes. Another patient underwent splenectomy after thymothymectomy and a complete hematological remission followed (9). Therefore, the cases that are refractory after surgery might have been caused by a T-cell clonal disorder in the peripheral blood. Interestingly, Handa et al. (28) presented a case with clonal proliferation of T cells within the thymoma and demonstrated a TCR chain gene rearrangement. However, monoclonality of the peripheral T cells was not observed and the patient entered remission without receiving immunosuppressive treatment, after undergoing thymectomy. In the present case, the excellent long-term improvement of the PRCA and MG without treatment after the surgery may indicate that there was no T-cell clonal disorder in the peripheral blood, although the TCR gene rearrangement of the peripheral blood T cells was not investigated.

On the basis of the literature surveyed, we conclude that thymothymectomy was effective in transiently producing remission in patients with MG, PRCA and thymoma. Furthermore, it is likely that the detection of disorders of the peripheral blood T cells will aid the choice of treatment for PRCA after thymothymectomy. If peripheral blood T cell clonal expansion is not demonstrated, the patient may not require immunosuppressive treatment after thymectomy, as in the present case.