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Anatomic Pathology / WHO Histologic Subtyping of Thymomas
Thymomas I
A Clinicopathologic Correlation of 250 Cases With Emphasis
on the World Health Organization Schema
Cesar A. Moran, MD,1 Annikka Weissferdt, MD,1 Neda Kalhor, MD,1 Luisa M. Solis, MD,1
Carmen Behrens, MD,1 Ivan I. Wistuba, MD,1 and Saul Suster, MD2
Key Words: Classification; Thymoma; Mediastinum; Tumor; Thymus
DOI: 10.1309/AJCP76KEGWQKWOKA
Abstract
We describe 250 cases of thymoma with emphasis
on World Health Organization (WHO) histologic
subtyping. The patients were 120 males and 130
females between the ages of 13 and 92 years. Surgical
resection was performed, and histologic material was
evaluated in every case. Macroscopically, the tumors
varied in size from 3 to 20 cm in greatest diameter;
about 12% were encapsulated, and about 88% were
invasive tumors. A minimum of 5 sections of tumor
was evaluated. Histologically, following the schema
proposed by the WHO, 21.6% of thymomas were type
A, 1.23% type B1, 3.2% type B2, and 9.2% type B3.
More than 50% of tumors after subtyping fell into the
mixed categories, which, in essence, diminishes the
clinical impact of histologic subtyping over staging.
The study herein described highlights that all thymomas
had the potential to become invasive tumors.
During the last 2 decades, the issue of the classification
of thymomas and the importance of their histologic subtype
has been discussed, and different viewpoints have emerged.
Some proponents consider that histologic subtyping has an
important role in their clinical behavior,1,2 while others consider that staging at the time of diagnosis is more important.3-5
In the 1990s, as a consequence of the different classification systems, the World Health Organization (WHO) convened a panel of pathologists with the idea of shedding some
light on this rather complicated subject. In 1999,6 a schema
was produced with the main idea being to use it as a sort of
translator/facilitator for 2 of the existing classifications.7,8
That system, as it still is today, was basically composed of letters and numbers with the corresponding meaning of 2 classification systems, the Bernatz classification7 and the so-called
histogenetic classification of Marino and Müller-Hermelink.8
In the 2004 publication by the WHO,2 this schema of letters
and numbers remained, and at this time, the authors added
clinical behavior to the different types of thymoma. However,
this particular issue of assigning specific clinical behavior to
particular histologic types has generated controversy, which
has been highlighted in different publications.9-11
Materials and Methods
We identified 250 thymomas from the files of the
Department of Pathology, M.D. Anderson Cancer Center,
Houston, TX, during a period from 1980 to 2009. The material was carefully selected among more than 400 cases of
thymic epithelial neoplasms. Specific requirements were
established for inclusion.
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DOI: 10.1309/AJCP76KEGWQKWOKA
© American Society for Clinical Pathology
Anatomic Pathology / Original Article
Results
Materials
Minimum requirements were established for inclusion
in the study: (1) histologic evaluation in every case; (2) at
least 5 histologic sections of tumor for proper subtyping,
as has been previously analyzed12; (3) surgical resection in
every case (biopsy material not included in the study).
The number of histologic sections in the evaluation of
these cases varied from 5 to 30 per case. The clinical records
of each case were reviewed and entered in a database for
further analysis.
Clinical Features
Methods
The tumors were divided into different subtypes following the WHO schema (type A, AB, B1, B2, and B3).
A minimum of 5% of a particular subtype was required
to further classify the tumor as having a mixed histologic
type. This procedure was performed by light microscopy
during the evaluation of all histologic sections available for
review. A case was deemed to have mixed histologic type
if the minimum of 5% would fulfill the requirement that by
itself would be coded under that particular subtype. Once
the subclassification was performed, further subtyping of
the different combinations of histologic types was also
documented.
A subset of 41 cases of pure (single histologic type)
invasive spindle cell thymomas from this series of cases has
been reported.13
❚Table 1❚ depicts some of the most relevant features of
the 250 cases evaluated. The patients were 120 males and 130
females between the ages of 13 and 92 years, with the majority of tumors occurring in the fifth, sixth, and seventh decades
of life (median age, 57 years). The most common symptoms
were chest pain, cough, and dyspnea. Of the patients, 6 had a
history of another malignancy: breast carcinoma, 2; prostatic
carcinoma, 2; colonic adenocarcinoma, 2; and papillary carcinoma of the thyroid, 1. None of the patients in our study had
associated myasthenia gravis. All patients had surgical resection of the tumor. Statistical analysis of age and sex compared
with the histologic types of thymoma demonstrated that types
A and A + B1 tumors seemed to be more common in older
patients (older than the median of 57 years) compared with
the same tumor types in younger patients (younger than the
median age, 58/78 [74%] vs 20/78 [26%]). On the other hand,
B1 and any B2/B3 thymomas seemed to be more common in
younger people (younger than the median age) than in older
patients (105/172 [61.0%] vs 67/172 [39.0%]; P < .0001;
Fisher exact test). In addition, thymoma type B1 seemed to be
more common in females than in males (24/33 [73%] vs 9/33
[27%]; P = .0144; Fisher exact, 2-tailed). We did not observe
any differences among types A, A + B1, or any of the other
type B thymomas.
Statistical Analysis
Analysis was performed by using Statistica software,
version 6 (StatSoft, Tulsa, OK). Survival analysis was performed using the Kaplan-Meier method. Statistical significance was defined as a P value of less than .05.
Macroscopic Features
Grossly, the size of the tumors varied from 3 to 20 cm in
greatest diameter (median, 7 cm). The tumors were described
as round to ovoid tumor masses, which at the cut surface
were white to light brown, had a solid consistency, and had a
❚Table 1❚
Correlation Between Clinicopathologic Features and Thymoma Type*
Characteristic
Age (median, 57 y)
<Median
≥Median
Sex
Female
Male
Size (median, 7 cm)‡
<7
≥7
Invasive
No
Yes
Mean follow-up (y)
*
†
‡
Type A and A + B1
(n = 78)
Type B1 and any
B2/B3 (n = 172)
Total (n = 250)
20 (26)
58 (74)
105 (61.0)
67 (39.0)
125 (50.0)
125 (50.0)
38 (49)
40 (51)
92 (53.5)
80 (46.5)
130 (52.0)
120 (48.0)
33/57 (58)
24/57 (42)
44/104 (42.3)
60/104 (57.7)
77/161 (47.8)
84/161 (52.2)
12 (15)
66 (85)
3.19
19 (11.0)
153 (89.0)
3.63
31 (12.4)
219 (87.6)
3.49
P†
<.0001
.4954
.0702
.4074
—
Data are given as number (percentage) or, when different from the number in the column heading, as number/total (percentage).
Fisher exact test, 2-tailed.
Information not available for 89 patients.
© American Society for Clinical Pathology
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❚Table 2❚
Thymomas by Histologic Type (n = 250)
Histologic Type
No. of Cases
Percentage of Total
A
A+B
A + B1
A + B1 + B2
A + B1 + B2 + B3
A + B2
A + B3
B
B1
B2
B3
B1 + B2
B1 + B2 + B3
B2 + B3
B1 + B3
54
38
24
6
6
1
1
158
33
8
23
47
29
15
3
21.6
15.2
9.6
2.4
2.4
0.4
0.4
63.2
13.2
3.2
9.2
18.8
11.6
6.0
1.2
❚Image 1❚ Thymoma showing dual histologic features of
types A and B1 (H&E, ×10).
homogeneous surface. In 7 cases, focal areas of necrosis and
cystic changes were recorded. The size of the tumor did not
correlate with any particular histologic growth pattern.
Histologic Features
❚Table 2❚ and ❚Table 3❚ depict some of the most salient
histologic features of the 250 thymomas. The tumors were
divided following the schema of the WHO. A minimum of 5
histologic sections per tumor was evaluated, and a minimum
of 5% histologic subtype was used to classify the tumor as of
mixed histologic type. The highest concordance of thymomas with a single histologic subtype was observed in type
A (spindle cell–medullary thymoma) in 54 cases, equivalent
to 21.6%. Types B1, B2, and B3 represented 13.2%, 3.2%,
and 9.2%, respectively, of the total number of cases with a
single histologic type. Based on these results, the percentage of cases using strict criteria of 5 histologic sections and
at least 5% of a different histologic subtype accounted for
approximately 47.2% of the cases. Approximately 52.8% of
the tumors showed mixed histologic types ❚Image 1❚, ❚Image
2❚, and ❚Image 3❚. However, it is important to highlight that
the majority of cases (158 cases) were of the B-type thymoma,
54 cases showed single histologic type A thymoma, and 38
cases showed a combination of type A and any type B thymoma. Therefore, based on these results, the possibilities of
placing a particular tumor with a single subtype into any of
the categories established by WHO is not higher than 21%
for type A thymomas, while those of placing a tumor with a
single histologic type into the B subtypes is not higher than
25%. In addition, the minimum requirement of 5 sections of
tumors seems to hold true because the more sections available
for evaluation, the more likely the tumor will show mixed
histologic types. ❚Figure 1❚ and ❚Table 4❚ show the analysis of
❚Table 3❚
Clinicopathologic Analysis of 250 Thymomas With Histologic Type Detail
Characteristic A
Sex
Female
Male
Total
Age
<Median
≥Median
Total
Invasive
No
Yes
Total
Size (cm)
<7
≥7
Total
Not available
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B1 and
B2
B1
B1, B2,
and B3
AB1
B3
B2 and
B3
B2
A, B1, B2, B1 and A, B1 A and
and B3
B3
and B2 B2
A and
B3
Total
26 (48) 24 (51) 24 (73) 12 (41) 12 (50) 11 (48) 8 (53)
3 (37) 4 (67)
28 (52) 23 (49) 9 (27)
17 (59) 12 (50) 12 (52) 7 (47)
5 (63) 2 (33)
54 (100) 47 (100) 33 (100) 29 (100) 24 (100) 23 (100) 15 (100) 8 (100) 6 (100)
1 (33) 4 (67) 0 (0)
1 (100) 130 (52.0)
2 (67) 2 (33) 1 (100) 0 (0)
120 (48.0)
3 (100) 6 (100) 1 (100) 1 (100) 250 (100.0)
15 (28) 33 (70) 20 (61) 18 (62) 5 (21)
13 (57) 8 (53)
5 (63) 2 (33)
39 (72) 14 (30) 13 (39) 11 (38) 19 (79) 10 (43) 7 (47)
3 (37) 4 (67)
54 (100) 47 (100) 33 (100) 29 (100) 24 (100) 23 (100) 15 (100) 8 (100) 6 (100)
2 (67) 3 (50) 0 (0)
1 (100) 125 (50.0)
1 (33) 3 (50) 1 (100) 0 (0)
125 (50.0)
3 (100) 6 (100) 1 (100) 1 (100) 250 (100.0)
9 (17)
11 (23) 3 (9)
2 (7)
3 (13)
0 (0)
1 (7)
0 (0)
0 (0)
45 (83) 36 (77) 30 (91) 27 (93) 21 (88) 23 (100) 14 (93) 8 (100) 6 (100)
54 (100) 47 (100) 33 (100) 29 (100) 24 (100) 23 (100) 15 (100) 8 (100) 6 (100)
1 (33) 1 (17) 0 (0)
0 (0)
31 (12.4)
2 (67) 5 (83) 1 (100) 1 (100) 219 (87.6)
3 (100) 6 (100) 1 (100) 1 (100) 250 (100.0)
23 (61)
15 (39)
38 (100)
16
1 (100)
0 (0)
1 (100)
2
12 (44)
15 (56)
27 (100)
20
10 (45)
12 (55)
22 (100)
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13 (62)
8 (38)
21 (100)
8
10 (53)
9 (47)
19 (100)
5
1 (9)
10 (91)
11 (100)
12
2 (25)
6 (75)
8 (100)
7
3 (60)
2 (40)
5 (100)
3
0 (0)
4 (100)
4 (100)
2
1 (33)
2 (67)
3 (100)
3
1 (100)
0 (0)
1 (100)
0
0 (0)
1 (100)
1 (100)
0
77 (47.8)
84 (52.2)
161 (100.0)
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© American Society for Clinical Pathology
Anatomic Pathology / Original Article
❚Image 2❚ Thymoma showing dual histologic features of
types B1 and B3 (H&E, ×10).
❚Image 3❚ Thymoma showing dual histologic features of
types B2 and B3 (H&E, ×10).
histologic sections compared with the histologic subtyping of
thymoma and the mean number of sections examined.
recurrent or metastatic disease. Of the remaining patients, 46
died in the same period, 4 of them with documented recurrent
or metastatic disease. Clinical follow-up was not obtained for
19 patients. Kaplan-Meier curves were developed to correlate
the histologic type of the thymoma with the survival rate
in 231 cases, with follow-up information giving a P value
of .452, which is not statistically significant. Also not statistically significant was the P value of .226 obtained when
comparing types A and A + B1 with any B type ❚Figure 2❚
and ❚Figure 3❚. A possible significant trend with a P value of
.056 was obtained when comparing types A and A + B1 with
B1 and any B2-B3 thymomas for recurrence-free survival
❚Figure 4❚.
Staging
Of the 250 cases evaluated, 31 were encapsulated tumors
(Masaoka stage I), and 219 cases corresponded to invasive
thymomas, most of them in Masaoka stages II and III and only
a few cases in stage IV.
Follow-up
Clinical follow-up information was obtained for 231
patients, ranging from 1 to 16 years (mean follow-up, 3.49
years). Of the patients, 185 were alive, of whom 22 had
❚Table 4❚
Histologic Subtyping in 250 Thymomas Compared With the
Mean Number of Sections Examined*
140
120
No. of Slides
100
80
Slides per
tumor analyzed
>20
16-20
11-15
6-10
5
60
40
20
0
A
B1
B2
B3
Mixed
Histologic Subtype
❚Figure 1❚ The number of sections analyzed and the likely
outcome of thymoma subtyping.
Histologic Type
No. of
Cases
Percentage
of Total
Mean No. of
Slides per Tumor
A
A+B
A + B1
A + B1 + B2
A + B1 + B2 + B3
A + B2
A + B3
B
B1
B2
B3
B1 + B2
B1 + B2 + B3
B2 + B3
B1 + B3
54
38
24
6
6
1
1
158
33
8
23
47
29
15
3
21.6
15.2
9.6
2.4
2.4
0.4
0.4
63.2
13.2
3.2
9.2
18.8
11.6
6.0
1.2
10
11
9
14
14
14
14
12
12
16
12
13
13
13
10
*
We examined at least 5 H&E-stained slides per tumor (range, 5-30; mean, 12).
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1.0
0.9
Complete
Censored
A, AB1
0.8
Overall Survival
0.7
0.6
B1, any B2-B3
0.5
0.4
0.3
0.2
0.1
0.0
–0.1
0
2
4
6
8
10
12
14
16
18
20
Time (y)
❚Figure 2❚ Comparison of histologic subtyping for types A
and AB1 vs B1, B2, and B3 and overall survival (Kaplan-Meier
analysis; cumulative proportion surviving, n = 231). P = .226
(statistically not significant).
Discussion
The knowledge that thymomas represent a heterogeneous group of tumors and that their histologic classification is difficult has been previously emphasized in
the literature.14,15 As a matter of fact, Rosai and Levine15
stated: “…once the term thymoma is restricted to the tumor
of epithelial thymic cells, with or without a lymphocytic
component, all further subdivisions are artificial.” Also
of common knowledge are the different features that have
been evaluated in thymomas to predict clinical outcome. In
that regard, parameters such as histologic type, grading, and
1.0
Overall Survival
0.7
0.6
0.5
Any B2-B3
B1
0.3
0.2
0.1
0
2
4
6
8
10
12
14
16
18
20
Time (y)
❚Figure 3❚ Different overall survival curve separating types A
and AB1 from B1 and other B2-B3 thymomas (Kaplan-Meier
analysis; cumulative proportion surviving, n = 231). P = .452
(statistically not significant).
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448
0.8
B1
0.7
Any B2-B3
0.6
0.5
0.4
0.3
0.2
0.0
–0.1
Complete
Censored
0.9
0.8
0.4
A, AB1
1.0
Complete
Censored
A, AB1
Recurrence-Free Survival
0.9
staging have been previously analyzed. More recently, the
issue of histologic subtyping has gained popularity in the
evaluation of thymomas with certain histologic types being
associated with more or less aggressive clinical behavior.2
Needless to say, owing to the rarity of these tumors, it
is difficult to obtain a sizable number of cases to be able to
produce important and meaningful conclusions. Thus, one
is left to attempt to obtain information from various studies,
which might not have addressed the same issues, and then
to draw conclusions from those studies. Based on some of
those studies, one can determine that, for the most part, sex,
age, clinical manifestations, size of the tumor, and even the
association of myasthenia gravis have not produced enough
statistically significant information to properly correlate
any of those features with tumor behavior.16-26 Nevertheless, the 2 most important parameters that have been mentioned in the literature for clinical outcome of thymomas are
staging and histologic type. Of those two, let us concentrate
on the histologic features and subtyping of thymomas.
Type A thymoma (spindle cell–medullary thymoma)
is considered by the WHO to be a benign tumor. However,
21% of the cases herein presented belong to that histologic
type (invasive tumors previously reported), and the tumors
were observed to be in different stages of invasion,13 thereby casting serious doubt as to the validity of such a clinical
designation. Important to note is the fact that the definition
of thymoma AB by the WHO is that of a spindle cell thymoma (type A) with lymphocytes. In practice, those tumors
most likely are grouped under type A as the association of
type A and B1 thymoma can occur, as documented in the
cases herein presented.
Am J Clin Pathol 2012;137:444-450
DOI: 10.1309/AJCP76KEGWQKWOKA
0.1
0
2
4
6
8
10
12
14
16
18
20
Time (y)
❚Figure 4❚ There is a possible trend in the recurrence-free
survival for types A, AB1 vs the other types of thymoma.
However, the value is not statistically significant (P = .056).
Kaplan-Meier analysis; cumulative proportion surviving, n = 231.
© American Society for Clinical Pathology
Anatomic Pathology / Original Article
On the other hand, when proper sampling is done, the
type B1 and B2 thymomas in the WHO classification, in
their pure form, become uncommon tumors, as one is most
likely to find a mixture of histologic types in these particular
tumors. In our experience, such histologic categorization can
be accomplished in no more than 14% of these tumors.
Furthermore, one of the most important parameters that
has not been taken into account when dealing with the WHO
schema or any other classification system is the issue of sampling. Based on our experience, when these tumors are amply
sampled, the most likely outcome is that the majority will show
mixed histologic types, which in turn raises the question of the
validity of any subtyping. However, that is not surprising, as
previous studies have analyzed such features. The sampling
issue can actually be viewed in 2 ways: 1, for proper histologic
subtyping, and 2, probably even more important, to rule out
the possibility of tumors showing thymoma and thymic carcinoma.27 The fact that fewer than 50% of thymomas will show
a single histologic type speaks in favor of the artificial and
arbitrary nature of any schema or classification system. On the
other hand, the WHO schema was not intended as an official
classification system but rather as a “translator” of 2 already
existing classification systems. The designation of letters and
numbers themselves has no meaning other than the specific
designation of a particular tumor for a particular classification.
Therefore, the use of this schema, without proper designations
as to what it means, is meaningless.
One additional feature that we have been able to introduce in this study is the amount of tumor that one needs to
have present to be able to diagnose a thymoma as of mixed
histologic type. In our experience, there has to be at least
5% of a tumor that unequivocally will, by itself, be diagnosed using any other classification system. However, more
important is the fact that regardless of the histologic subtype
of thymoma, histologic type alone cannot be correlated with
clinical outcome, as statistically demonstrated in this study.
We have presented a study of 250 thymomas in which
we have documented, regardless of the histologic subtype,
that all are capable of invasion and aggressive behavior. We
consider that sampling is an important issue in the subtyping
of these tumors and recommend that a minimum of 5 sections of tumor (when feasible) is needed to assign a specific
subtype. Also important is to properly assess at least 5% of a
different histologic growth pattern to determine that a tumor
is of mixed histologic type. We believe that the subclassification of thymomas should not be done on biopsy material.
Furthermore, we judge that a decision on treatment should
not be based on the histologic subtype of these tumors, as
we have clearly demonstrated that not only are all histologic
types capable of invasion, but also that the majority of these
tumors show mixed histologic types.
From the Departments of Pathology, 1M.D. Anderson Cancer
Center, Houston, TX, and 2Medical College of Wisconsin,
Milwaukee.
Address reprint requests to Dr Moran: Dept of Pathology,
M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX
77030.
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