396

CASE REPORT
A rare case of invasive thymoma presented a dramatic response
to low-dose prednisolone as a single-drug therapy.
Masaki Hanibuchi1, Atsuro Saijo1, Atsushi Mitsuhashi2, Tatsuya Kajimoto1, and Tetsuya Kitagawa3
1
Department of Respiratory Medicine, 3Department of Cardiovascular Surgery, Shikoku Central Hospital of the Mutual aid Association ofPublic School teachers, Shikoku-Chuo, Japan, 2Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, JapanAbstract : A 76-year-old woman with a history of angina pectoris, hypertension and dyslipidemia was pointed out
an abnormal opacity in the right hilar region on routine chest X-ray. Chest computed tomography showed masses in the anterior mediastinum with the invasion of the adjacent ascending aorta, right brachiocephalic vein andright pleura. Histologic examination led to a diagnosis of Masaoka stage IVa thymoma. Three courses of chemotherapy were given, but further tumor progression was seen. Thereafter, the patient was followed without aggressive treatments. One year after the initial diagnosis, she presented with dyspnea and right chest pain. Chest
CT revealed right massive pleural effusion with pleural dissemination and much further progression of existingtumors. For the purpose of symptom palliation, a low dose (5 mg / day) of prednisolone was commenced, which
unexpectedly led to marked alleviation of patient’s symptoms and dramatic decrease of pleural effusion. To thebest of our knowledge, this is the first report of an invasive thymoma responded to low-dose corticosteroid. The
present case suggests that corticosteroids, even at low doses, might be potentially effective for invasive thymoma
after failure of surgery, chemotherapy and radiotherapy. J. Med. Invest. 68 : 396-399, August, 2021
Keywords : invasive thymoma, low-dose corticosteroid, single-drug therapy

INTRODUCTION

CASE REPORT

Thymoma is the most common tumor of the anterior mediastinum, and arises from thymic epithelial cells with non-neoplastic
T lymphocytes at varying degrees (1, 2). Surgical resection has
been advocated as the primary treatment of thymoma, since it isoften found well encapsulated (3, 4). In patients with advanceddiseases or a recurrence after primary therapy, systemic chemotherapy can be considered (5). It has been reported that moderate
to high doses of corticosteroids including steroid pulse therapy asa single-drug treatment also induced regression of thymoma (69). Kobayashi et al. demonstrated that the steroid pulse therapy
induced tumor regression in 8 of 17 (47.1%) patients with advanced thymoma and that the reduction in tumor size was mostprominent in World Health Organization (WHO) classification,
type B1 thymomas compared with type B3 (10). Although thepro-apoptotic effects are considered to play an important rolein the growth-inhibiting action (11), the significance and theoptimal dose of corticosteroid therapy in patients with thymoma
is poorly understood.
In this report, we demonstrated a patient who had Masaoka
clinical stage IVa invasive thymoma (WHO classification, typeB3) complicated with massive pleural effusion and pleural dissemination, which remarkably responded to low-dose prednisolone (PSL).

A 76-year-old woman with a history of angina pectoris, hypertension and dyslipidemia was pointed out an abnormal opacity
in the right hilar region on routine chest X-ray. Chest computed
tomography (CT) showed masses in the anterior mediastinum
adjacent to the ascending aorta, right brachiocephalic vein andright pleura. These findings contraindicated curative surgery.
A partial resection was performed and a diagnosis of Masaoka
clinical stage IVa thymoma with the invasion of surroundingorgans, such as right brachiocephalic vein, right internal thoracic vein, right mediastinum, right lung and pleura, was made.
A histologic examination revealed that tumors were composed
mainly of epithelial cells showing squamoid features and focal
mild atypia with scant lymphocytes (WHO classification, type
B3 thymoma). The positivity of Ki-67 was 20-30% in atypicalepithelial cells. After diagnosis, three courses of chemotherapy(carboplatin and paclitaxel) were given, but a mass adjacentto the ascending aorta further enlarged. Although alternative
chemotherapies were recommended, she refused the proposal.
Thereafter, the patient was referred to our hospital for supportive care and palliative treatments of invasive thymoma six
months after the initial diagnosis.
At the initial admission to our hospital, she did not complainof any respiratory symptoms and her general condition wasrelatively good. The physical examinations revealed body temperature of 36.3 ℃, blood pressure of 113 / 63 mmHg, pulse of 59
beats per minute and percutaneous oxygen saturation of 97% onroom air. The remainder of the physical examinations was also

Abbreviations
WHO, World Health Organization ; PSL, prednisolone ; CT, computed
tomography ; GR, glucocorticoid receptor

Received for publication May 14, 2021 ; accepted August 10, 2021.
Address correspondence and reprint requests to Masaki Hanibuchi,
Department of Respiratory Medicine, Shikoku Central Hospital of theMutual Aid Association of Public School teachers, 2233 Kawanoe-cho,
Shikoku-Chuo, 799-0193, Japan and Fax : +81-896-58-3464.

The Journal of Medical Investigation Vol. 68 2021

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The Journal of Medical Investigation Vol. 68 August 2021
normal including chest auscultation. Muscle weakness was notrecognized. The laboratory findings showed mild leukocytopenia
and anemia. The serum level of human chorionic gonadotropin
was within normal range and the acetylcholine receptor antibody was negative. The remainder of laboratory test results isshown in Table 1. We continued to follow the patient without

aggressive treatments.
One year after the initial diagnosis, she presented with dyspnea and right chest pain. Chest CT revealed right massive
pleural effusion and much further progression of existing tumors(Figure 1). Although the cytology of pleural effusion was negative(class II), we considered the etiology of pleural effusion as pleural

Table 1. Laboratory data at the first admission
Hematology

BiochemistryWBC

3,400 / μL

AST

25 IU / LBS

Neu

62.8 %

Lymph

29.5 %Mono

ALT

16 IU / L

HbA1c (NGSP)

5.8 %

ALP

192 U / L

BNP

26.3 pg / mL

5.9 %

LDH

159 IU / L

PT

11.8 secs

Eos

1.2 %

γ-GTP

27 U / L

PT activity

100 %

Baso

0.6 %

CK

87 U / L

APTT

27.8 secs

T-bil

0.5 mg / dL

CEA

1.3 ng / mL
3.4 ng / mL

RBC

324×104 / μL

Hb

11.1 g / dLTP

7.5 g / dLCYFRA 21-1

Ht

32.3 %

Alb

4.2 g / dL

hCG

Plt

17.6×104 / μL

T-cho

130 mg / dL

Anti-Ach-R AbAmy

115 IU / L

BUN

16.3 mg / dL

Cre

0.53 mg / dLNa

143 mEq / L

K

3.9 mEq / L

Cl

107 mEq / LCa

9.6 mg / dL

CRP

0.05 mg / dL

98 mg / dL

4.4 mIU / mL
< 0.2 nmol / L

BNP, brain natriuretic peptide ; CEA, carcinoembryonic antigen ; CYFRA 21-1, cytokeratin fraction 21-1 ; hCG, human chorionicgonadotropin ; Anti-Ach-R Ab, anti-acetylcholine receptor antibodyFigure 1. Chest X-ray and Chest CT findings before corticosteroid treatment.
Right massive pleural effusion and mass shadow in the right upper mediastinum was evident in chest X-ray (Figure 1A). Chest
CT revealed right massive pleural effusion and tumors in the right hilum, anterior mediastinum, and right pleura (Figure 1B).

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M. Hanibuchi, et al. A thymoma dramatically responded to PSL

dissemination of invasive thymoma. Thoracentesis, and palliative radiation therapy to the right hilum, apex and chest wall
temporarily alleviated her symptoms. Thoracic cavity drainage
by the chest drainage tube and pleurodesis were not performedfollowing the patient’s wishes. Even after that, thoracenteses
were performed as appropriate and supportive treatment forbilateral pretibial and foot-pad edema, such as anti-diuretics,
were commenced, however, pleural effusion gradually increased
and her symptoms, such as dyspnea and general fatigue gotworse. For symptom palliation, we started a low dose (5 mg / day)of PSL. As her body weight was 46.7 kg, the dose of PSL wasapproximately 0.1 mg / kg / day at the treatment initiation. Unexpectedly, her symptoms markedly improved and pleural effusion
dramatically decreased on chest X-ray at three-weeks after corticosteroid initiation. Chest CT also showed significant reductionof right pleural effusion and regression of tumors in the righthilum and pleura (Figure 2). The general condition and rightpleural effusion of the patient remain well-controlled even now
while continuing to receive 4 mg / day of PSL at six-months after
corticosteroid initiation. No adverse events have been reported
during treatment, with the exception of mild insomnia.

DISCUSSION
Corticosteroids are known to induce regression of thymoma,
whereas these are often administered to patients with thymoma
to treat associated symptoms of myasthenia gravis (6) and pure
red-cell aplasia (12) rather than the tumor itself. There has beena small number of single case reports of response to corticosteroids alone in patients with thymoma, mostly after failure of
combined chemoradiotherapy and surgery (6-8). In these reports,
moderate to high doses of corticosteroids including steroid pulse
therapy (more than 30 mg / day of PSL) were administered, however, there is no report describing therapeutic efficacy of low-dose
corticosteroid in patients with invasive thymoma. To the best of

our knowledge, this is the first report of an invasive thymoma
presented a dramatic response to low-dose corticosteroid as asingle-drug therapy.
Since the first description of regression of thymoma by thetreatment of adrenocorticotropic hormone (13), several reports
have indicated that corticosteroids might be potentially effective
for invasive thymoma (7, 14), primarily in cases of lymphocytic
thymoma, and have been attributed to the apoptotic effects ofcorticosteroids, mainly on the lymphocytic component of thetumor (8, 12). On the other hand, glucocorticoid receptor (GR)is shown to be expressed on neoplastic thymic epithelial cells aswell as on non-neoplastic thymocytes and lymphocytes in thymoma. Glucocorticoids induced apoptosis via G1 cell cycle arrestof thymic epithelial cells, indicating that glucocorticoids directly
suppressed in vitro proliferation of GR-positive neoplastic thymic
epithelial cells (15). In addition, studies to evaluate histopathologic changes of thymoma preoperatively treated with high dosesof corticosteroids, such as steroid pulse therapy, demonstrated
apoptosis induction in neoplastic thymic epithelial cells, as wellas lymphocytes in the specimens resected after corticosteroid
treatment (9, 10). These findings suggested that corticosteroids
cause degenerative changes in neoplastic thymic epithelial cells,
as well as lymphocytes in thymoma.
The association of therapeutic efficacies of corticosteroid
with histological subtypes of thymoma remains controversial.
Kobayashi et al. demonstrated that the steroid pulse therapy
induced tumor regression in patients with advanced thymoma
and that the tumor reduction was most prominent in type B1thymoma (also known as lymphocytic thymoma) compared with
type B3 thymoma (also known as epithelial thymoma) (10).
Moreover, glucocorticoids directly suppressed the proliferationof GR-positive neoplastic thymic epithelial cells via the inductionof apoptosis (15), and the numbers of GR sites were reported
to be much greater in lymphoepithelial thymoma as comparedto those in pure epithelial thymoma (16). These observations
support a hypothesis that lymphocytic component of thymoma

Figure 2. Chest X-ray and Chest CT at six-months after corticosteroid initiation.
Right pleural effusion dramatically decreased and the shrinkage of tumor in the right upper mediastinum also observed inchest X-ray (Figure 2A). Chest CT showed significant reduction of right pleural effusion and regression of tumors in the righthilum and pleura (Figure 2B).

The Journal of Medical Investigation Vol. 68 August 2021
is more responsive to corticosteroid treatment. At the otherextreme, Hu et al. reported that glucocorticoid therapy induced
thymoma regression in 11 of 13 cases, regardless of different
histologic findings (17). In addition, it is shown that high doses ofcorticosteroids, such as steroid pulse therapy, induced apoptosisof neoplastic thymic epithelial cells, as well as lymphocytes inthymoma (9). In the present case, although we could not evaluate
the pathological change after treatment, corticosteroid therapy,
even at low doses, might affect not only lymphocytic components
but also neoplastic thymic epithelial cells in WHO classification,
type B3 thymoma.
In terms of the prognostic markers for thymoma, the histological subtype is considered to be a promising candidate.
However, previous study to examine the histopathologic featuresof pretreatment biopsies and posttreatment surgical specimensof thymoma demonstrated the significant changes of the histological subtypes after treatment including corticosteroids (9).
As the conversion of histological subtype might affect the therapeutic response and the clinical course, it is possible that thepretreatment histopathologic features do not necessarily reflect
the prognosis of thymoma. Recently, Mimae et al. reported thatGR revealed a high rate of expression (82.9%) in thymomas andthymic carcinomas. Multivariate analysis demonstrated thatGR expression was associated with better prognosis in patientswith surgically resected thymomas and thymic carcinomas (18).
Moreover, Kobayashi et al. showed that the reduction in tumor
size after steroid pulse therapy was accompanied with a marked
reduction in the CD4+8+ double-positive immature lymphocytes(10), and indicated that tumor size reduction of thymomas waspartly explained by the reduction in the bulk of these lymphocytes. Thus, GR expression and CD4+8+ double-positive
immature lymphocytes might be new promising candidates as
prognostic markers for thymoma. However, abovementioned observations need to be interpreted cautiously, because the sample
size in each study was quite limited. Further large-scale studies
would be required to show the more clinically significant data in
the future.
In conclusion, we herein reported a rare case of invasive thymoma presented a dramatic response to low-dose corticosteroid
as a single-drug therapy. Five mg / day of PSL that used for thepurpose of symptom palliation markedly alleviated patient’ssymptoms and pleural effusion dramatically decreased. To thebest of our knowledge, this is the first report of an invasive
thymoma responded to low-dose corticosteroid. The present casesuggests that corticosteroids even at low doses, as well as thoseat high doses, might be potentially effective for invasive thymoma after failure of surgery, chemotherapy and radiotherapy.

CONFLICT OF INTEREST DISCLOSURE
All authors state that they do not have any financial or otherrelationships for the present study that might lead to a conflictof interest.

ACKNOWLEDGEMENTS
We thank our colleagues at Shikoku Central Hospital of theMutual aid Association of Public School teachers, especially
Takumi Uda and Hitomi Komoda for technical assistance.

399

REFERENCES
1.

Levine GD, Rosai J : Thymic hyperplasia and neoplasia. A
review of current concepts. Hum Pathol 9 : 495-515, 1978
2. Verley J, Hollmann KH : Thymoma. A comparative studyof clinical stages, histologic features, and survival in 200
cases. Cancer 55 : 1074-1086, 1985
3. Gripp S, Hilgers K, Wurm R, Schmitt G : Thymoma : prognostic factors and treatment outcomes. Cancer 83 : 14951503, 1998
4. Okumura M, Miyoshi S, Takeuchi Y, Yoon HE, Minami M,Takeda SI, Fujii Y, Nakahara K, Matsuda H : Results ofsurgical treatment of thymomas with special reference tothe involved organs. J Thorac Cardiovasc Surg 117 : 605613, 1999
5. Chahinian AP, Bhardwaj S, Meyer RJ, Jaffrey IS, Kirschner
PA, Holland JF : Treatment of invasive or metastatic thymoma : report of eleven cases. Cancer 47 : 1752-1761, 1981
6. Kodama K, Doi O, MD, Higashiyama M, Yokouchi H,Yasuda T, Funai H : Dramatic response of postthymomectomy myasthenia gravis with multiple lung nodules to corticosteroids. Ann Thorac Surg 64 : 555-557, 1997
7. Termeer A, Visser FJ, Mravunac M : Regression of invasivethymoma following corticosteroid therapy. Neth J Med
58 : 181-184, 2001
8. Tiseo M, Monetti F, Ferrarini M, Serrano J, Chiaramondia
M, Aradizzoni A : Complete remission to corticosteroids inan octreotide-refractory thymoma. J Clin Oncol 23 : 15781579, 2005
9. Tateyama H, Takahashi E, Saito Y, Fukai I, Fujii Y, Niwa
H, Eimoto T : Histopathologic changes of thymoma preoperatively treated with corticosteroids. Virchows Arch438 : 238-247, 2001
10. Kobayashi Y, Fujii Y, Yano M, Sasaki H, Yukiue H, Haneda
H, Suzuki E, Endo K, Kawano O : Preoperative steroid
pulse therapy for invasive thymoma : clinical experienceand mechanism of action. Cancer 106 : 1901-1907, 2006
11. Kruman II, Matylevich NP, Beletsky IP, Afanasyev VN,
Umansky SR : Apoptosis of murine BW 5147 thymoma cells
induced by dexamethasone and gamma irradiation. J CellPhysiol 148 : 267-273, 1991
12. Palmieri G, Lastoria S, Colao A, Vergara E, Varrella P, Biondi
E, Selleri C, Catalano L, Lombardi G, Bianco AR, Salvatore
M : Successful treatment of a patient with thymoma andpure red-cell aplasia with octreotide and prednisone. New
Engl J Med 336 : 263-265, 1997
13. Soffer LJ, Gabrilove JL, Wolf BS : Effect of ACTH on thymicmasses. J Clin Endocrinol Metab 12 : 690-696, 1952
14. Kirkove C, Berghmans J, Noel H, van de Merckt J : Dramatic response of recurrent invasive thymoma to high dosesof corticosteroids. Clin Oncol 4 : 64-66, 1992
15. Funakoshi Y, Shiono H, Inoue M, Kadota Y, Ohta M, Matsuda
H, Okumura M, Eimoto T : Glucocorticoids induce G1 cell
cycle arrest in human neoplastic thymic epithelial cells. JCancer Res Clin Oncol 131 : 314-322, 2005
16. Ranelletti FO, Iacobelli S, Carmignani M, Sica G, Natoli C,Tonali P : Glucocorticoid receptors and in vitro corticosensitivity in human thymoma. Cancer Res 40 : 2020-2025, 1980
17. Hu E, Levine J : Chemotherapy of malignant thymoma.
Case report and review of the literature. Cancer 57 : 11011104, 1986
18. Mimae T, Tsuta K, Takahashi F, Yoshida A, Kondo T,
Murakami Y, Okada M, Takeuchi M, Asamura H, Tsuda
H : Steroid receptor expression in thymomas and thymic
carcinomas. Cancer 117 : 4396-4405, 2011