Asian Cardiovascular and Thoracic Annals-2012-Vachlas-48-52 (01)

7/28/2019 Asian Cardiovascular and Thoracic Annals-2012-Vachlas-48-52 (01)

1/6

http://aan.sagepub.com/Asian Cardiovascular and Thoracic Annals

http://aan.sagepub.com/content/20/1/48The online version of this article can be found at:

DOI: 10.1177/0218492311433189

2012 20: 48Asian Cardiovascular and Thoracic Annalsonstantinos Vachlas, Charalambos Zisis, Dimitra Rontogianni, Antonios Tavernarakis, Argini Psevdi and Ion Bellen

Thymoma and myasthenia gravis: clinical aspects and prognosis

Published by:

http://www.sagepublications.com

On behalf of:

The Asian Society for Cardiovascular Surgery

can be found at:Asian Cardiovascular and Thoracic AnnalsAdditional services and information for

http://aan.sagepub.com/cgi/alertsEmail Alerts:

http://aan.sagepub.com/subscriptionsSubscriptions:

http://www.sagepub.com/journalsReprints.navReprints:

http://www.sagepub.com/journalsPermissions.navPermissions:

What is This?

- Feb 1, 2012Version of Record>>

by guest on June 19, 2013aan.sagepub.comDownloaded from
http://aan.sagepub.com/http://aan.sagepub.com/http://aan.sagepub.com/content/20/1/48http://aan.sagepub.com/content/20/1/48http://aan.sagepub.com/content/20/1/48http://www.sagepublications.com/http://www.sagepublications.com/http://www.ascvs.org/http://aan.sagepub.com/cgi/alertshttp://aan.sagepub.com/cgi/alertshttp://aan.sagepub.com/subscriptionshttp://aan.sagepub.com/subscriptionshttp://www.sagepub.com/journalsReprints.navhttp://www.sagepub.com/journalsReprints.navhttp://www.sagepub.com/journalsPermissions.navhttp://www.sagepub.com/journalsPermissions.navhttp://www.sagepub.com/journalsPermissions.navhttp://online.sagepub.com/site/sphelp/vorhelp.xhtmlhttp://online.sagepub.com/site/sphelp/vorhelp.xhtmlhttp://aan.sagepub.com/content/20/1/48.full.pdfhttp://aan.sagepub.com/http://aan.sagepub.com/http://aan.sagepub.com/http://online.sagepub.com/site/sphelp/vorhelp.xhtmlhttp://aan.sagepub.com/content/20/1/48.full.pdfhttp://www.sagepub.com/journalsPermissions.navhttp://www.sagepub.com/journalsReprints.navhttp://aan.sagepub.com/subscriptionshttp://aan.sagepub.com/cgi/alertshttp://www.ascvs.org/http://www.sagepublications.com/http://aan.sagepub.com/content/20/1/48http://aan.sagepub.com/


2/6

Original Article

Thymoma and myasthenia gravis:clinical aspects and prognosis

Konstantinos Vachlas1, Charalambos Zisis1,

Dimitra Rontogianni2, Antonios Tavernarakis3,

Argini Psevdi4 and Ion Bellenis1

Abstract

Myasthenia gravis is present in a significant proportion of patients with thymoma. We investigated particular features ofthe clinical behavior of thymoma and its relationship to myasthenia in a retrospective study of 79 patients who underwentthymectomy for thymoma during the last 20 years. The presence of myasthenia gravis, Masaoka stage, World Health

Organization histotype, myasthenia response, and survival were analyzed. The mean age of the patients was 56.1

12.4years, and 39 had myasthenia gravis. A significantly higher proportion of patients with myasthenia was found in B2 and B3histotypes compared to A, AB, and B1. Among myasthenic patients, 33.3% had no response, 50% had a partial response,and 16.7% achieved complete remission. During the follow-up period, 16 (21.1%) patients died. Mean survival was4.8 1.4 years for patients with no myasthenia response, whereas those with a partial or complete myasthenia responsehad significantly better survival.

Keywords

myasthenia gravis, prognosis, survival rate, thymectomy, thymoma

Introduction

Thymoma is a tumor originating from the epithelial

cells of the thymus gland, and the term thymic epithe-

lial tumor (TET) is more accurate for the histogenetic

description of this entity. The overall incidence of thy-

moma is rare, with approximately 0.15 cases per

100,000 of the population per year.1,2 Almost one

third of cases are found incidentally on radiographic

examinations during workup for an associated autoim-

mune disorder, most usually myasthenia gravis (MG).3

The relationship between MG and thymoma has been

repeatedly suggested, but many questions and contro-

versies remain on this issue.4 The biological and clinical

behavior of thymomatous MG after thymoma removal

has not been adequately investigated, and evidence is

missing on both the clinical course of MG and the

prognosis of thymomas related to MG after surgical

management. This retrospective analysis was carried

out to elucidate some parameters of thymomatous

MG, and MG-related thymomas were compared to

thymomas without MG.

Patients and Methods

The records of patients who underwent thymectomy in

our department from January 1990 to December 2009,

were reviewed. Diagnosis of thymoma was suggested

preoperatively from the radiological appearance and

computed tomography (CT) findings, and was con-

firmed in all patients by histology on the resected speci-

men. There were 79 patients enrolled in this

retrospective study (Table 1). Their ages ranged

between 33 and 79 years (mean, 56.1 12.4 years).

All pathological specimens were examined by the

Asian Cardiovascular & Thoracic Annals

20(1) 4852

The Author(s) 2012

Reprints and permissions:

sagepub.co.uk/journalsPermissions.nav

DOI: 10.1177/0218492311433189

aan.sagepub.com

1Department of Thoracic and Vascular Surgery, Evangelismos Hospital,

Athens, Greece.2Department of Pathology, Evangelismos Hospital, Athens, Greece.3Department of Neurology, Evangelismos Hospital, Athens, Greece.4Department of Anesthesiology, Evangelismos Hospital, Athens, Greece.

Corresponding author:

Konstantinos Vachlas, MD, FETCS, Amorgou 28 Gerakas, Athens

15351, Greece

Email: [email protected]

http://aan.sagepub.com/http://aan.sagepub.com/http://aan.sagepub.com/http://aan.sagepub.com/


3/6

same pathologist, and classified histologically accord-

ing to the WHO thymoma classification (2004 revision),

whereas clinical and pathological staging was based on

the Masaoka system. In cases of co-existence of more

than one histological feature in the same sample (e.g.,

B2 and B3) the tumor was categorized as the most

aggressive histological type (less differentiated feature;

B3). Oncological follow-up of the patients was per-

formed in collaboration with the oncology department

of our hospital, and the last communication was in themonth prior to statistical analysis, to update the data.

Three patients were missing during the last follow-up.

Classification of MG was made by the neurology

department of our hospital, according to the clinical

classification proposed by the Medical Scientific

Advisory Board of the Myasthenia Gravis

Foundation of America. A consultant neurologist was

responsible for administering the medical therapy and

follow-up of the patients. MG response to thymectomy

was evaluated at 1 year postoperatively, given that the

beneficial effect of thymectomy appears several months

after surgery. MG course was assessed as: complete

stable remission, considered to be lack of all symptoms

or signs of MG without any kind of medical therapy;

partial remission, considered pharmacologic remission

or minimal manifestation of the disease, as defined by

the Myasthenia Gravis Foundation of America (patient

continues to take some form of therapy for MG, with

no symptoms or functional limitations from MG but

some weakness on examination and a substantial

decrease in preoperative clinical manifestations or

reduction in need for MG medications); no remission

was defined as no substantial change in

pre-interventional clinical manifestations, no reduction

in MG medications, or aggravation of the MG clinical

course and symptoms and upgrading in the Myasthenia

Gravis Foundation of America classification. The last

neurological evaluation was performed 1 month prior

to statistical analysis.

Extended thymectomy was performed in all cases asthe standard of care for Masaoka stage I and II

patients. The patient was placed in the supine position.

A median sternotomy was performed, followed by en-

bloc resection of anterior mediastinal fat tissue includ-

ing the thymus gland and the thymoma. Dissection was

carried out bluntly from the pericardium, and all medi-

astinal fat and thymic tissue was excised by wide open-

ing of both pleuras. The adipose tissue around the

upper poles of the thymus was removed. Borders of

resection were the diaphragm caudally, the thyroid

gland cephalad, and the phrenic nerves laterally.

Masaoka stage III and IV patients underwent more

extensive resections. The surgical approach and deci-

sion for each individual case was based on the specific

oncological characteristics. Thirteen patients had en-

bloc resection of the invaded pericardium; in 12 of

them, additional en-bloc wedge resection of invaded

pulmonary parenchyma was carried out. Two patients

underwent extrapleural pneumonectomy, one had

extended diaphragmatic resection for local recurrence,

and one had recurrent pleural implant resection. The 3

most recent cases in our group of 13 patients in stage

III received neoadjuvant treatment before thymectomy.

Stage IV Masaoka patients were managed surgically for

recurrent tumors, and had previously undergone onco-logical treatment. All patients with invasive stage II,

III, and IV were referred to the oncologists for adjuvant

chemotherapy and radiotherapy.

All qualitative variables are expressed as absolute

and relative frequencies. Pearsons chi-squared and

Fishers exact tests were used for the comparisons.

Continuous variables are expressed as mean standard

deviation or as median values (interquartile range). For

the follow-up period, Kaplan-Meier survival estimates

for events were graphed. Log-rank tests were used for

comparison of survival curves. All reported p values are

2-tailed. Statistical significance was set at p< 0.05, and

analyses were conducted using SPSS software (SPSS,

Inc., Chicago, IL, USA). Thymoma patients who died

due to complications of MG, other thymus-related syn-

dromes, or unrelated diseases are considered as cen-

sored in the survival analysis.

Results

The mean follow-up period was 76.4 years (median,

4.8 years; interquartile range, 1.5 to 12 years). During

the follow-up period, 16 (21.1%) patients died; 7 of

Table 1. Characteristics of 79 patients with thymoma

Variable Stage/Type No of Patients

Myasthenia gravis No 40 (50.6%)

Yes 39 (49.4%)

Masaoka stage I 14 (18.4%)

II 45 (59.2%)

III 13 (17.1%)

IV 4 (5.2%)

WHO type A 10 (13.2%)

AB 6 (7.9%)

B1 14 (18.4%)

B2 25 (32.9%)

B3 17 (22.4%)

C 4 (5.3%)

Mortality 16 (21.1%)

Response None 12/36 (33.3%)

Partial 18/36 (50.0%)Complete 6/36 (16.7%)

Vachlas et al. 49



4/6

them suffered from MG (Table 2). The mean time inter-

val between surgery and death was 3.73.1 years.

Among the 9 non-MG patients who died, 5 deaths

occurred for oncological reasons due to thymoma inva-

sion, and 4 were not related to thymoma (cardiovascu-

lar or cerebrovascular events). Of the 7 deceased MG

patients, 3 died due to causes unrelated to thymoma

(small-cell lung cancer, colorectal cancer, and myocar-

dial infarction). The other 4 MG patients died from

causes related to MG (myasthenic crisis) and needed

prolonged mechanical ventilation. One of them died

in the immediate postoperative period (17th postopera-

tive day), which corresponds to a perioperative mortal-

ity of 1.3%. Cause of death was nosocomial infection

and systemic sepsis due to prolonged intubation related

to myasthenia exacerbation. The proportion of patients

with myasthenia was greater in B2, B3, and C

WHO types compared to A, AB, B1 types (p = 0.048;

Figure 1). No significant association was found

between Masaoka stage and myasthenia (p = 0.858;

Table 3). Mean survival time was 15.7 1.4 years

for patients without MG and 14.5 1.3 years for

those with MG (log-rank test: p = 0.681; Figure 2).

Mean survival time was 4.8 1.4 years for patients

with no MG response after thymectomy. Patients

with partial or complete MG response after thymec-

tomy had improved survival (log-rank test: p


5/6

classification offers the most accurate prognostic and

clinical assessment.7

Several paraneoplastic syndromes are associated

with thymomas. The most common is MG, an autoim-

mune neuromuscular disease caused by antibodies to

muscle acetylcholine receptors, resulting in muscle

weakness.4,8,9 The proportion of thymoma patients

who suffer from MG varies between 20% and 65%.1,2

The nature of the relationship between MG and thy-

moma is unclear. Although no definite pathological

basis for the association between thymomas and an

autoimmune mechanism has been identified, some evi-

dence suggests that myasthenic patients with thymoma

harbor different immunoregulatory abnormalities from

those without thymoma.10,11 The thymus gland pro-

vides an environment for development and maturation

of T lymphocytes from hematopoietic progenitor cells.

One of the most important roles of the thymus is the

induction of central tolerance to self-antigens.12 Recent

studies suggest that the failure of the thymoma micro-

environment to induce T-cell tolerance to self-antigens

may be responsible for its association with MG.13

A 2-fold increase in the risk of a second cancer hasalso been reported for thymomas.14 Two of 7 deaths in

MG thymomatous patients in our series were due to

second malignancies (small-cell lung cancer, colorectal

cancer) manifested less than 5 years after thymectomy.

Such a relationship between thymomas and a second

cancer has to be further investigated, and whether it is

attributable to the immunobiological particularities of

thymomas or the effect of adjuvant treatment remains

to be determined. Late thymoma mortality due to sec-

ondary cancers and associated immunological disorders

was more frequent than mortality from the thymoma

itself in a recent series.6 Different biological behavior

with prognostic implications and a significant survival

difference have been reported for thymomas of types B2

and B3 compared to A, AB, and B1.15 Thus a revision

of the WHO classification system for thymomas has

been proposed. Meta-analysis data suggest that further

simplification of the WHO system is needed, with fewer

classes of significant prognostic value, the 3 main cate-

gories suggested should be A/AB/B1, B2, and B3.16

According to the data of this retrospective study, the

presence of MG could be related to the histological

type of thymoma. It seems that MG occurs more fre-

quently in aggressive histotypes such as B2 and B3 thy-

moma than in A, AB, B1 types. Thymic carcinoma israrely associated with MG, and many reports suggest

that such cases should not be classified as thymoma. In

this study, there were 4 cases of thymic carcinoma; they

were included in the B2/B3/C subgroup for reasons of

homogeneity. Our analysis reveals that MG was signif-

icantly less frequent in the A/AB/B1 subgroup, even if

thymic carcinomas are removed from the B2/B3/C sub-

group. Earlier studies suggested that MG was a nega-

tive prognostic factor for survival, probably due to

previously inadequate medical treatment. However,

more recent studies show no MG impact on thymoma

prognosis. Furthermore, the most recent reports even

propose that MG prolongs both long-term thymoma

survival and disease-free survival, probably due to

early stage thymoma diagnosis.17 It is expected that

earlier thymectomy is likely to result in a better prog-

nosis by shortening the MG disease period.18 In accor-

dance with the observations of recent studies, in our

results reveal that MG does not significantly affect thy-

moma prognosis and survival.

Concerning the effect of thymectomy for MG in

patients with thymoma, the neurological outcome is

not as beneficial as that in patients without thymoma.

Figure 3. Kaplan-Meier estimates for survival according to

myasthenia gravis (MG) response after thymectomy for thymicepithelial tumor (TMT).

Table 4. Association of MG response after TET resection with

WHO type and Masaoka stage

MG Response After Thymectomy

Variable None Partial/Complete p Value

WHO type 0.709

A,AB, B1 3 (27.3%) 8 (72.7%)

B2, B3,C 9 (37.5%) 15 (62.5%)

Masaoka stage 0.515

I 2 (28.6%) 5 (71.4%)

II 5 (25%) 15 (75%)

III 4 (57.1%) 3 (42.9%)

IV 0 1 (100%)

MG = myasthenia gravis, TET = thymic epithelial tumor.

Vachlas et al. 51



6/6

MG patients have a less favorable rate of survival, and

thymoma has been considered a poor prognostic factor

in most studies because of more severe symptoms and

less responsiveness to treatment.19 In the past, well-dif-

ferentiated thymic carcinoma, age> 55 years, and less

than 1 year from the onset of symptoms to thymec-

tomy, were found to be independent predictors of noMG remission after thymectomy.20 Complete or partial

remission was observed in two thirds of myasthenic

patients in our series with thymoma after thymectomy.

On follow-up, all of these patients are alive without

recurrence.

Patients who achieve complete remission have been

considered to have a significantly better oncological

prognosis. A good neurological outcome is thought to

reflect a favorable oncological outcome, and such

patients might need a less strict radiological follow-

up.19 However, no MG response after thymectomy

has not been adequately estimated as an adverse prog-

nostic factor. Our findings suggest that no MG

response after thymectomy might be a negative prog-

nostic factor and also an independent predictor for a

more dismal thymoma prognosis. It is, to the best of

our knowledge, the first time that such a predictor has

been elicited, and it therefore needs further evaluation

because of the small number in our series. Another

important finding is that the rate of no MG response

was substantially higher (nearly 33%) in our series than

in other recent series of thymomatous MG. Lack of

homogeneity and comparability due to the retrospec-

tive character of most series remains a serious issue that

must be addressed.

Funding

This research received no specific grant from any funding

agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

None declared.

References

1. Wright CD. Management of thymomas. Crit Rev Oncol

Hematol 2008; 65: 109120.

2. Venuta F, Anile M, Diso D, Vitolo D, Rendina EA, De

Giacomo T, et al. Thymoma and thymic carcinoma. Eur J

Cardiothorac Surg 2010; 37: 1325.

3. Detterbeck FC and Parsons AM. Thymic tumors

[Review]. Ann Thorac Surg 2004; 77: 18601869.

4. Drachman DB. Myasthenia gravis [Review]. N Engl J Med

1994; 330: 17971810.

5. Masaoka A. Staging system of thymoma [Review].

J Thorac Oncol 2010; 5(Suppl): S304S312.

6. Okereke IC, Kesler KA, Morad MH, Mi D, Rieger KM,

Birdas TJ, et al. Prognostic indicators after surgery for

thymoma. Ann Thorac Surg 2010; 89: 10711079.

7. Kim HK, Choi YS, Kim J, Shim YM, Han J and Kim K.

Type B thymoma: is prognosis predicted only by World

Health Organization classification? J Thorac Cardiovasc

Surg 2010; 139: 14311435.

8. Grob D, Brunner N, Namba T and Pagala M. Lifetime

course of myasthenia gravis. Muscle Nerve 2008; 37:

141149.

9. Vincent A, Willcox N, Hill M, Curnow J, MacLennan Cand Beeson D. Determinant spreading and immune

responses to acetylcholine receptors in myasthenia

gravis. Immunol Rev 1998; 164: 157168.

10. Marx A, Willcox N, Leite MI, Chuang WY, Schalke B,

Nix W and Stro bel P. Thymoma and paraneoplastic

myasthenia gravis [Review]. Autoimmunity 2010; 43:

413427.

11. Mitsui T, Kunishige M, Ichimiya M, Shichijo K, Endo I

and Matsumoto T. Beneficial effect of tacrolimus on

myasthenia gravis with thymoma. Neurologist 2007; 13:

8386.

12. Kosmrlj A, Jha AK, Huseby ES, Kardar M and

Chakraborty AK. How the thymus designs antigen-spe-cific and self-tolerant T cell receptor sequences. Proc Natl

Acad Sci U S A 2008; 105: 1667116676.

13. Suzuki E, Kobayashi Y, Yano M and Fujii Y. Infrequent

and low AIRE expression in thymoma: difference in

AIRE expression among WHO subtypes does not corre-

late with association of MG. Autoimmunity 2008; 41:

377382.

14. Owe JF, Cvancarova M, Romi F and Gilhus NE.

Extrathymic malignancies in thymoma patients with

and without myasthenia gravis. J Neurol Sci 2010; 290:

6669.

15. Zisis C, Rontogianni D, Tzavara C, Stefanaki K,

Chatzimichalis A, Loutsidis A, et al. Prognostic factors

in thymic epithelial tumors undergoing complete resec-tion. Ann Thorac Surg 2005; 80: 10561062.

16. Marchevsky AM, Gupta R, McKenna RJ, Wick M,

Moran C, Zakowski MF, et al. Evidence-based pathology

and the pathologic evaluation of thymomas: the World

Health Organization classification can be simplified into

only 3 categories other than thymic carcinoma [Review].

Cancer 2008; 15;112: 27802788.

17. Margaritora S, Cesario A, Cusumano G, Evoli A and

Granone P. Thirty-five-year follow-up analysis of clinical

and pathologic outcomes of thymoma surgery. Ann

Thorac Surg 2010; 89: 245252.

18. Kim HK, Park MS, Choi YS, Kim K, Shim YM, Han J,

et al. Neurologic outcomes of thymectomy in myasthenia

gravis: comparative analysis of the effect of thymoma.

Thorac Cardiovasc Surg 2007; 134: 601607.

19. Lucchi M, Ricciardi R, Melfi F, Duranti L, Basolo F,

Palmiero G, et al. Association of thymoma and myasthe-

nia gravis: oncological and neurological results of the

surgical treatment. Eur J Cardiothorac Surg 2009; 35:

812816.

20. Lo pez-Cano M, Ponseti-Bosch JM, Espin-Basany E,

Sa nchez-Garca JL and Armengol-Carrasco M. Clinical

and pathologic predictors of outcome in thymoma-asso-

ciated myasthenia gravis. Ann Thorac Surg 2003; 76:

16431649.

52 Asian Cardiovascular & Thoracic Annals 20(1)

by guest on June 19 2013aan sagepub comDownloaded from

Asian Cardiovascular and Thoracic Annals-2012-Vachlas-48-52 (01)

Documents

Transcript of Asian Cardiovascular and Thoracic Annals-2012-Vachlas-48-52 (01)