Thymoma

Synonyms: Spindle Cell Thymoma (Type A), Medullary Thymoma (Type A), Mixed Thymoma (Type AB), Lymphocyte-Rich Thymoma (Type B1), Organoid Thymoma (Type B1), Predominantly Cortical Thymoma (Type B1), Cortical Thymoma (Type B2), Mixed Lymphocytic and Epithelial Thymoma (Type B2), Well-Differentiated Thymic Carcinoma (Type B3)

View full-size image

Definition

Benign to intermediate malignant thymic tumors with a differentiation toward thymic epithelial cells, generally accompanied by a variable proportion of lymphocytes.

Clinical Features

Usually adult1–7
Exceptionally familial 8
If clinically evident usually large
Coronary bypass surgery has led to discovery of many small sometimes microscopic thymomas9

Other Diseases

Associated with many systemic disorders, usually immune mediated, including:
- hypogammaglobulinemia:
  - 12% of cases
- erythroid hypoplasia:
  - 5% of cases19
- more rarely:
  - white blood cell aplasia20
  - myositis
  - myocarditis
  - dermatomyositis
  - lupus erythematosus
  - rheumatoid arthritis
  - scleroderma
  - Sjögren's disease
  - multiple myeloma
  - Kaposi's sarcoma21
  - subacute motor neuronopathy22
  - inappropriate antidiuretic hormone secretion23
  - bullous dermatoses
  - hyperglobulinemic purpura
  - mucocutaneous candidiasis24,25
  - graft-versus-host-like colitis 26
  - autoimmune enteropathy27
  - peripheral T-cell lymphocytosis:28–30
    - some due to aberrant T-cell oligoclone in thymoma 31
  - T-cell chronic lymphocytic leukemia32
  - T-cell lymphoblastic lymphoma/leukemia33
- Claimed association with increased incidence of malignant tumors, including lymphoma34,35

Spread and Metastases

≈70–80% are encapsulated
Direct local invasion:
- later into adjacent structures such as lung (Fig. 1
  Fig. 1: Gross appearance of malignant thymoma invading lung.
  )
May implant into pleural or pericardial surfaces
Direct local invasion and implants more common than distant metastases
Extensive local invasion apparent at thoracotomy:
- fibrous adhesions from secondary inflammatory, necrotic, and multilocular cystic changes can give false impression that tumor is invasive
Minimal invasion refers to complete capsular breaks or tumor islands in mediastinal fat
Presence of large nerves surrounded by tumor represents indirect evidence of invasion (sometimes only such evidence)
Distant metastases:
- exceptional
- documented in:
  - mediastinal and cervical lymph nodes
  - lung
  - liver
  - bone (particularly spine)
  - ovary
  - other sites36,37
- usually develop months or years after detection and treatment
- exceptionally first clinical manifestation

Pathogenesis

Myasthenia gravis usually related to defect in nicotinic acetylcholine receptor (AChR) in subsynaptic membrane of neuromuscular junction (motor end plate) due to binding with circulating autoantibodies 38–40
AChR or related protein is detected in normal thymus41,42 and is mainly if not entirely localized to subset of intrathymic cells that:
- are generally designated as myoid cells 43,44
Theory has evolved that autosensitization leading to myasthenia is initiated in thymus through an aberrant confrontation of myoid cells with AChR-specific autoimmune T lymphocytes followed by emigration of these activated thymic T cells to the peripheral immune system and induction of complementary B lymphocytes to produce myasthenogenic autoantibodies 45,46
The role that thymoma when present plays in this pathogenetic scheme not clear:
- others postulate that thymoma is directly responsible for myasthenia through presence of one or more proteins in the tumor that share an antigenic determinant with nicotinic AChR or other structures of the neuromuscular junction and that trigger an autoimmune response 38,47,48
- ≈12% of patients with myasthenia have other autoimmune diseases such as Graves’ disease and rheumatoid arthritis 49
Lymphocytes do not show evidence of clonality:50,51
- corroborating evidence for non-neoplastic nature

Gross Pathology

Location:
- also:
  - in neck 52,53
  - within thyroid
  - within pericardial cavity 54
  - in pulmonary hilum within lung parenchyma55–57
  - in pleura itself, sometimes coating it in mesothelioma-like fashion 58–60
Largely or entirely solid
Yellowish gray
Separated in lobules by connective tissue septa 61–63 (Figs 2 and 3
Fig. 2: Gross appearance of a thymoma showing distinct multinodularity. There is focal cystic change in the larger nodule.
Fig. 3: Close-up of the cut surface of thymoma. Note the sharp lobulation induced by the fibrous bands. The pointed ends of some of the nodules are particularly typical of this entity.
)
≈80% well encapsulated and tumor can be removed with ease
≈20% infiltration of surrounding structures
Foci of necrosis and cystic degeneration common, particularly if larger tumor:
- sometimes entire tumor undergoes prominent cystic, necrotic and hemorrhagic changes (Fig. 4
  Fig. 4: Thymoma with extensive necrosis and cystic degeneration. Only one of many microscopic sections showed residual neoplasm. This lesion is likely to be misdiagnosed as a thymic cyst.
  )64

Histopathology

Usually mixture of neoplastic epithelial cells and non-neoplastic lymphocytes (Fig. 5
Fig. 5: Type B2 thymoma. There is an even proportion of neoplastic epithelial cells and non-neoplastic lymphocytes.
):
- proportions vary widely from:
  - case to case
  - in different lobules of same tumor63,65,66
Neoplastic epithelial cells:
- shape may be:
  - spindle oval (Fig. 6
    Fig. 6: Type A (spindle, medullary) thymoma. The pseudomesenchymal appearance of the tumor is striking.
    )
- nuclei:
  - vesicular
  - smooth contour
  - nucleolus may be conspicuous, particularly when nuclei round or polygonal
Non-neoplastic lymphocytes:
- may appear mature (inactive), or
- show varying degrees of ‘activation’ manifested by:
  - larger nuclear size
  - open chromatin pattern
  - visible nucleolus
  - identifiable cytoplasmic rim
  - mitotic activity
- should not appear convoluted or cleaved
- number greatly decreased if treated preoperatively with corticosteroids67
Often one or more features of organoid differentiation if sizable component of epithelial cells:
- correlate with various subtypes
- include:
  - perivascular spaces containing lymphocytes, proteinaceous fluid, red blood cells, foamy macrophages, or fibrous tissue (Fig. 7
    Fig. 7: Perivascular space in type B2 thymoma. The space is occupied by a proteinaceous fluid and lymphocytes.
    )
  - rosettes without central lumina (Fig. 8
    Fig. 8: Type A thymoma with prominent rosette formation. Notice the absence of a central lumen in the rosettes. This tumor should not be confused with thymic carcinoid.
    )
  - glandlike formations within tumor or more often in tumor capsule
  - true glandular structures (exceptional)
  - whorls suggestive of abortive Hassall's corpuscle formation62,66,68
Occasionally well-formed Hassall's corpuscles
Commonly round lighter foci of medullary differentiation in lymphocyte-rich (type B1) thymomas:
- important clue to diagnosis (Fig. 9
  Fig. 9: Type B1 thymoma with prominent foci of medullary differentiation.
  )
May be:
- prominent vascularization
- focally prominent microcystic and pseudopapillary formations
- extensive sclerosis, possibly as manifestation of tumor regression69
Exceptionally:
- massive plasma cell infiltrate70
- deposition of amyloid71
Often important population of S-100 protein-positive cells:
- presumably:
  - non-neoplastic
  - interdigitating reticulum cell nature72–74
- number and distribution correlate with microscopic type but not invasiveness 75
Also population of interdigitating cells (asteroid cells) in medullary portion of more organoid thymomas
Ultrastructurally:
- neoplastic epithelial cells exhibit:
  - branching tonofilaments
  - complex desmosomes
  - elongated cell processes
  - basal lamina76,77

Association With Myasthenia Gravis

Relative proportion of epithelial cells and lymphocytes does not seem to correlate with presence of myasthenia
No consistent ultrastructural or immunohistochemical differences between myasthenic and nonmyasthenic thymomas 78

Special Stains and Immunohistochemistry

Epithelial reactivity for:
- keratin (Fig. 10
  Fig. 10: Type B1 (lymphocyte-rich) thymoma stained for keratin. The cytoplasm and cell processes of the neoplastic epithelial cells are strongly immunoreactive for this marker.
  ):
  - types vary according to thymoma subtype79
- epithelial membrane antigen (EMA):
  - usually restricted to glandlike formations of spindle thymomas or tumors predominantly composed of round or polygonal cells80
- carcinoembryonic antigen (CEA)81–84
Also express:
- peanut agglutinin receptor antigens 85
- MHC class II molecules86
- p63 (particularly in isoporm Δn-p63α)87
- epidermal and nerve growth factor receptors88
- growth hormone89
- metallothionein90
- viral protein p1982
React for two antibodies that recognize neuroendocrine cells:
- A2B5
- Leu782
Claimed reactivity for thymic hormones:91–93
- thymulin and thymosin α-1
- controversial finding
- needs investigation
Stains for basement membrane material such as laminin or type IV collagen:
- paucity in tumors of stellate or round or polygonal cells 94
Lymphocytes:
- T-cell derivation except for those in lymphoid follicles (whether associated myasthenia or not)95
- most have enzymatic and immunohistochemical phenotype of immature thymocytes and reactive for:96–98
  - CD1a 99,100
- many positive for Ki-67:
  - in keeping with ‘stimulated’ status 101
- close correlation between morphologic features of more organoid thymomas and phenotype:
  - in more lymphocyte-rich areas, lymphocytes have features of cortical (very immature) thymocytes
  - in areas of medullary differentiation lymphocytes acquire features of medullary (less immature) thymocytes
Asteroid cells:
- react for B-cell marker CD20:102
  - potentially misleading diagnostically because this marker sometimes reacts with neoplastic epithelial cells103

Diagnosis

Neoplasm of thymic epithelial cells, independently of presence or number of lymphocytes109,110
A dual population of epithelial cells and lymphocytes with appropriate cytologic features 111–113

Helpful Diagnostic Features Of Thymoma

Thick, often calcified fibrous capsule
Lobular arrangement induced by fibrous bands
Sharp interphase between tumor lobules and fibrous tracts
Angular shape of some lobules
Foci of medullary differentiation (see Fig. 9)

Likelihood of Myasthenia Gravis

Most accurate way to predict likelihood of myasthenia with thymoma is to find lymphoid follicles in:
- adjacent non-neoplastic thymic tissue
- exceptionally, in thymoma itself114

Classification

Controversial

Morphofunctional Scheme 119,120

Medullary thymoma
Mixed thymoma
Predominantly cortical (organoid) thymoma
Cortical thymoma
Well-differentiated thymic carcinoma:
- potentially misleading terminology 121

WHO Committee for Histologic Typing of Thymic Tumors Scheme122

Incorporates two classifications above and takes into account:
- uniqueness of thymus in that it can be viewed as two different organs:
  - active functional gland of fetus and infant
  - inactive ‘postmature’ structure of adult life
- presence, as an expression of differentiation, of a non-neoplastic lymphocytic component in tumors composed of functional thymic tissue
General rules of tumor pathology apply:
- better differentiated tumors (lymphocyte-rich or predominantly cortical types):
  - recapitulate normal organ structure in terms of cortical and medullary regions
  - progression in tumors composed of functional thymic tissue manifest by:
    - increase in number of neoplastic epithelial cells
    - increasing degree of atypia of these cells
    - corresponding decrease in non-neoplastic lymphocytic component
Consists of combination of letters and numbers:
- two major types according to whether neoplastic epithelial cells and their nuclei have:
  - a spindle/oval shape (type A)
  - dendritic or plump (epithelioid) appearance (type B)
  - type AB if these two morphologies combined
- type B subdivided into three subtypes B1, B2 and B3 on basis of:
  - proportional increase in relation to lymphocytes
  - emergence of atypia of neoplastic epithelial cells
- thymic carcinomas are an additional subtype (type C)123,124
Term combined thymoma used for combinations of thymomas other than AB followed by a listing of various components and relative amounts

Type A Thymoma (Spindle Cell; Medullary)

Composed of neoplastic thymic epithelial cells:
- few or no non-neoplastic lymphocytes (see Figs 6 and 8 )
Can simulate mesenchymal neoplasm
Immunohistochemical and ultrastructural features of epithelial tissue
May be:
- rosette-like formations (without central lumen)
- foci with storiform pattern of growth
- glandlike formations (often within or immediately beneath tumor capsule)
Many features reminiscent of cells in adult atrophic thymus, some of which are in subcapsular (rather than medullary) region
Exceptional thymomas are composed of spindle cells but exhibit nuclear hyperchromasia, pleomorphism, mitotic activity, and/or necrosis:
- not clear whether:
  - atypical or poorly differentiated forms of type A thymomas
  - ‘spindle cell variants’ of type B3 thymomas
  - sarcomatoid (spindle cell) thymic carcinomas
- clues to their recognition include:
  - prominent reticulin fiber network among individual tumor cells
  - lack or paucity of palisading cells around perivascular spaces
Micronodular thymoma:
- micronodular pattern of growth and florid lymphoid follicular hyperplasia of stroma 125
- B-cell type lymphocytes so does not qualify as a type AB thymoma despite dual cell composition126,127

Type AB Thymoma (Mixed)

Foci have features of type A thymoma admixed with foci rich in lymphocytes (Fig. 12
Fig. 12: Type AB (mixed) thymoma. The type A areas can be easily confused with hypercellular septa. This is one of the most common thymoma subtypes.
)
Segregation of two patterns can be sharp or indistinct
Wide range in relative amount of two components:
- in particular type A areas can be extremely scant

Type B1 Thymoma (Lymphocyte-Rich; Lymphocytic; Predominantly Cortical; Organoid)

Resembles normal functional thymus because combines:
- large expanses with appearance practically indistinguishable from normal thymic cortex:
  - distinction from normal active thymus may be impossible on high-power examination128
- areas resembling thymic medulla (see Fig. 9).

Type B2 Thymoma (Cortical)

Neoplastic epithelial component appears as scattered plump cells with vesicular nuclei and distinct nucleoli among heavy population of lymphocytes
Perivascular spaces common and sometimes very prominent
May be perivascular arrangement of tumor cells resulting in palisading effect (see Figs 5 and 7 )
Tumor cells:
- tend to have abundant cytoplasm
- round or polygonal shape:
  - alternative designation (large) polygonal cell thymoma
- Like B1 lymphocyte rich (but to lesser degree), sometimes resulting in mixed lymphocyte–epithelial pattern

Type B3 Thymoma (Epithelial; Atypical; Squamoid; Well-Differentiated Thymic Carcinoma)

Predominantly epithelial cells having round or polygonal shape and exhibiting no or mild atypia admixed with a minor component of lymphocytes, resulting in sheetlike growth of neoplastic epithelial cells (Fig. 13
Fig. 13: Type B3 thymoma. This tumor, which is predominantly composed of slightly atypical neoplastic thymic epithelial cells, is also known as squamoid thymoma, atypical thymoma, and well-differentiated (organotypic) thymic carcinoma.
):
Traditionally known as epithelial, but misleading because implies that other types of thymoma are not
Atypical designation also inaccurate because degree of atypia may not be greater than in type B2 thymoma, from which it is distinguished primarily on proportionally larger number of epithelial cells
Well-differentiated thymic carcinoma designation potentially confusing because included with thymomas rather than with thymic carcinomas
Squamoid thymoma designation due to presence of squamoid or squamous features in tumor cells is neither constant nor exclusive feature

Thymic Carcinoma (Type C Thymoma)

Clearcut cytologic atypia and a set of cytoarchitectural features no longer specific to thymus but analogous to those in carcinomas of other organs (Figs 14 and 15
Fig. 14: Chromogranin reactivity in some tumor cells of thymic carcinoma (type C thymoma). This is a common finding in this subtype, as opposed to types A, AB, and B thymomas.
Fig. 15: Thymic carcinoma of basaloid type. The tumor islands are connected with the epithelium lining a cystic cavity.
)

Other Investigations

Radiograph:
- usually a lobulated shadow that may be calcified (Fig. 11
  Fig. 11: Lobulated large benign thymoma located in anterior portion of mediastinum.
  )
CT scan and MRI:
- methods of choice for preoperative diagnosis and evaluation of extent104
Fine needle aspiration
Special techniques that have failed to separate consistently encapsulated from invasive and/or metastatic tumors include:
- morphometry
- nuclear proliferation markers
- nucleolar organizer regions
- ploidy analysis105–108

Differential Diagnosis

Select up to 2 differential diagnoses to compare with Thymoma

Predominantly cystic thymomas should be distinguished from multilocular thymic cysts (which can coexist) and other thymic neoplasms prone to undergo cystic changes129
Large numbers of Hassall's corpuscles usually indicate preexisting structures surrounded by a tumor and more common in other neoplasms (such as malignant lymphoma of thymus) than in thymoma
Rosette-like structures with well-defined lumina suggest thymic carcinoid rather than thymoma
Prominent vascularization may result in misdiagnosis of hemangiopericytoma
Thymoma vs lymphoblastic lymphoma:
- lymphocytes usually exhibit immature T phenotype, so cell marker studies cannot be used to differentiate these disorders
- can be differentiated because lymphocytes of thymoma do not show clonality50,51

Myasthenia Gravis

Lambert–Eaton syndrome:
- also immune related 130

Other Anterior Mediastinal Tumors

Such as:
- thymic carcinoid
- malignant lymphoma
- seminoma
- solitary fibrous tumor77,131

Staging/Grading

Traditional Staging

Any type (other than thymic carcinoma) that appears totally encapsulated regarded as benign
If evidence of aggressiveness in form of local invasion, pleural or pericardial implants, or distant metastases designated malignant 132,133 (Fig. 16 and
Fig. 16: Minimal invasion of the mediastinal fat beyond the thick fibrous capsule of a thymoma.
see Fig. 1)

‘Clinical’ Staging System 1981134

.

	I	Macroscopically completely encapsulated and microscopically no capsular invasion
	II1	Macroscopic invasion into surrounding fatty tissue or mediastinal pleura
	II2	Microscopic invasion into capsule
	III	Macroscopic invasion into neighboring organ, i.e., pericardium, great vessels, or lung
	Iva	Pleural or pericardial dissemination
	IVb	Lymphogenous or hematogenous metastasis

TNM Staging System135,136

.

	T factor
	N factor
	M factor

	T1	Macroscopically completely encapsulated and microscopically no capsular invasion
	T2	Macroscopically adhesion or invasion into surrounding fatty tissue or mediastinal pleura or microscopic invasion into capsule
	T3	Invasion into neighboring organs, such as pericardium, great vessels, and lung
	T4	Pleural or pericardial dissemination
	N0	No lymph node metastasis
	N1	Metastasis to anterior mediastinal lymph nodes
	N2	Metastasis to intrathoracic lymph nodes except anterior mediastinal lymph nodes
	N3	Metastasis to extrathoracic lymph nodes
	M0	No hematogenous metastasis
	M1	Hematogenous metastasis

Comparison of Staging Systems

When comparing TNM staging system with traditional evaluation of thymomas based on presence or absence of invasion:
- all other stages correspond to ‘malignant’ thymoma
  - although substantially correct, misleading because stage T2 (included with malignant thymomas) much closer prognostically to stage T1 (benign) than stage T3 137
- Might be preferable to diagnose thymomas according to type followed by a descriptive equivalent of the staging system (if can be determined from specimen) as follows:
- 1 Encapsulated (equivalent to stage T1)
- 2 Minimally invasive (equivalent to stage T2) (see Fig. 16)
- 3 Widely invasive and/or with pleural or pericardial implants (equivalent to stages T3 and T4) (see Fig. 1)
- 4 Metastatic (equivalent to stages N1, N2 and M1)
- A new staging system based on thymomas treated at National Cancer Institute at Milan, Italy seems to better predict survival138

Genetics

Most frequent aberrations on chromosome 6:
- 50% in region 6q25.2139,140
- type and frequency vary among thymoma subtypes 141
Coexpression of bcl-2 and p53:
- most cases
- seems stronger in clinically aggressive tumors142–144
Fas antigen:
- an apoptosis-related marker 145
- commonly expressed

Management

Surgical excision:146
- primary treatment
- if entirely encapsulated thymoma and removed in toto no additional therapy necessary regardless of microscopic type
Postoperative radiation therapy:
- if any possibility of residual tumor for tumors other than types A or AB (unless extensively invasive)
- tends to be recommended if only minimal invasion147–151
Excision plus radiation therapy:152
- if gross invasion or implants
Additional chemotherapy:
- for distant metastases
- combination regimens containing cis-platinum show best results153–157

Myasthenia Gravis

Thymectomy:
- regardless of presence or absence of thymoma 158
- usually transcervical unless large tumor
- symptomatic improvement more likely if follicular hyperplasia than if thymus is normal or thymoma159
- long-term results related to duration and severity of myasthenic symptoms but not age of patient14,159–161
- persistence of symptoms attributed to residual thymic tissue with lymphoid hyperplasia 162
Specific immunotherapy may eventually be developed163

Prognosis

Prognostic Factors

Stage

Most important prognostic determinant
Fully encapsulated thymoma after complete surgical excision has excellent prognosis:
- recurrence:
  - 2–10% of cases164–166
  - amenable to surgical removal 167
For invasive tumors prognosis:
- correlates with degree of invasion:
- if minimally invasive (stage T2) not significantly different from that of encapsulated tumors
- drops markedly if gross invasion or implants and even more if distant metastases168–170

Microscopic Type

Definite relationship 165,171
Contained in and largely superseded by staging system:
- if stage is taken into account, prognostic value of microscopic type drops almost to clinical insignificance 172
Microscopic type shows close correlation with likelihood of invasion and prognosis as follows:
- A<AB<B1<B2<B3<C168,173–175
- any thymoma type (Figs 17 and 18
  Fig. 17: This tumor had the morphologic features of a type A (spindle cell, medullary) thymoma, yet it was widely invasive.
  Fig. 18: This tumor had the morphologic features of a type A (spindle cell, medullary) thymoma, yet it was widely invasive.
  )

Completeness of Excision

Related to tumor stage168,169,170

References

1 Chatten J, Katz SM. Thymoma in a 12-year-old boy. Cancer. 1976;37:953–957.

2 Furman WL, Buckley PJ, Green AA, Stokes DC, Chien LT. Thymoma and myasthenia gravis in a 4-year-old child. Case report and review of the literature. Cancer. 1985;56:2703–2706.

3 Groisman GM, Ben-Izhak O, Best LA. Thymoma with foci of medullary differentiation in an 11-year-old-boy. Arch Pathol Lab Med. 1994;118:653–655.

4 Kaplinsky C, Mor C, Cohen IJ, Goshen Y, Yaniv I, Tamary H, et al. Childhood malignant thymoma: Clinical, therapeutic, and immunohistochemical considerations. Pediatr Hematol Oncol. 1992;9:261–268.

5 Pescarmona E, Giardini R, Brisigotti M, Callea F, Pisacane A, Baroni CD. Thymoma in childhood. A clinicopathological study of five cases. Histopathology. 1992;21:65–68.

6 Dehner LP, Martin SA, Sumner HW. Thymus related tumors and tumor-like lesions in childhood with rapid clinical progression and death. Hum Pathol. 1977;8:53–66.

7 Ramon Y, Cajal S, Suster S. Primary thymic epithelial neoplasms in children. Am J Surg Pathol. 1991;15:466–474.

8 Wick MR, Scheithauer BW, Dines DE. Thymic neoplasia in two male siblings. Mayo Clin Proc. 1982;57:653–656.

9 Pescarmona E, Rosati S, Pisacane A, Rendina E, Venuta F, Baroni CD. Microscopic thymoma. Histological evidence of multifocal cortical and medullary origin. Histopathology. 1992;20:263–266.

10 Lewis JE, Wick MR, Scheithauer BW, Bernatz PE, Taylor WF. Thymoma. A clinicopathologic review. Cancer. 1987;60:2727–2743.

11 Wekerle H, Müller-Hermelink HK. The thymus in myasthenia gravis. Müller-Hermelink HK editors. In: Current topics in pathology. The human thymus. Histophysiology and pathology. vol. 75:New York: Springer-Verlag; 1986.

12 Azer MS, Zikria E, Ford WB. Myasthenia gravis appearing after removal of a thymoma. Report of a case and review of the literature. Am Surg. 1971;37:109–113.

13 Namba T, Brunner NG. Myasthenia gravis in patients with thymoma, with particular reference to onset after thymectomy. Medicine (Baltimore). 1978;57:411–433.

14 Monden Y, Nakahara K, Kagotani K, Fujii Y, Masaoka A, Kawashima Y. Myasthenia gravis with thymoma. Analysis of and postoperative prognosis for 65 patients with thymomatous myasthenia gravis. Ann Thorac Surg. 1984;38:46–52.

15 Butler WM, Diehl LF, Taylor HG, Weltz MD. Metastatic thymoma with myasthenia gravis. Complete remission with combination chemotherapy. Cancer. 1982;50:419–422.

16 Monden Y, Nakahara K, Nanjo S, Fujii Y, Matsumura A, Masaoka A, et al. Invasive thymoma with myasthenia gravis. Cancer. 1984;54:2513–2518.

17 Slater G, Papatestas AE, Genkins G, Kornfeld P, Horowitz SH, Bender A. Thymomas in patients with myasthenia gravis. Ann Surg. 1978;188:171–174.

18 Wilkins EW, Edmunds LH, Castleman B. Cases of thymoma at the Massachusetts General Hospital. J Thorac Cardiovasc Surg. 1966;52:322–330.

19 Hirst E, Robertson TT. The syndrome of thymoma and erythroblastopenic anemia. A review of 56 cases including 3 case reports. Medicine (Baltimore). 1967;46:225–264.

20 Ackland SP, Bur ME, Adler SS, Robertson M, Baron JM. White blood cell aplasia associated with thymoma. Am J Clin Pathol. 1988;89:260–263.

21 Moysset I, Lloreta J, Miguel A, Vadell C, Ribalta T, Estrach T, et al. Thymoma associated with CD4+ lymphopenia, cytomegalovirus infection, and Kaposi's sarcoma. Hum Pathol. 1997;28:1211–1213.

22 Stoll DB, Lublin F, Brodovsky H, Laucius F, Patchefsky A, Cooper H. Association of subacute motor neuronopathy with thymoma. Cancer. 1984;54:770–772.

23 Levin L, Sealy R, Barron J. Syndrome of inappropriate antidiuretic hormone secretion following cis-dichlorodiammineplatinum II in a patient with malignant thymoma. Cancer. 1982;50:2279–2282.

24 Kirkpatrick CH, Windhorst DB. Mucocutaneous candidiasis and thymoma. Am J Med. 1979;66:939–945.

25 Palestine RF, Su WPD, Liesegang TJ. Late-onset chronic mucocutaneous and ocular candidiasis and malignant thymoma. Arch Dermatol. 1983;119:580–586.

26 Kornacki S, Hansen FC, Lazenby A. Graft-versus-host-like colitis associated with malignant thymoma. Am J Surg Pathol. 1994;19:224–228.

27 Mais DD, Mulhall BP, Adolphson KR, Yamamoto K. Thymoma-associated autoimmune enteropathy. A report of two cases. Am J Clin Pathol. 1999;112:810–815.

28 Griffin JD, Aisenberg AC, Long JC. Lymphocytic thymoma associated with T-cell lymphocytosis. Am J Med. 1978;64:1075–1079.

29 Lishner M, Ravid M, Shapira J, Radnay J, Amiel A, Leytin V, et al. Delta-T-lymphocytosis in a patient with thymoma. Cancer. 1994;74:2924–2929.

30 Smith GP, Perkins SL, Segal GH, Kjeldsberg CR. T-cell lymphocytosis associated with invasive thymomas. Am J Clin Pathol. 1994;102:447–453.

31 De Jong D, Richel DJ, Schenkeveld C, Boerrigter L, Van't Veer LJ. Oligoclonal peripheral T-cell lymphocytosis as a result of aberrant T-cell development in cortical thymoma. Diagn Mol Pathol. 1997;6:244–248.

32 Thomas J, De Wolf-Peeters C, Tricot G, Bekaert J, Broeckaert-van Orshoven A. T-cell chronic lymphocytic leukemia in a patient with invasive thymoma in remission with chemotherapy. Cancer. 1983;52:313–317.

33 Friedman HD, Inman DA, Hutchison RE, Poiez BJ. Concurrent invasive thymoma and T-cell lymphoblastic leukemia and lymphoma. A case report with necropsy findings and literature review of thymoma and associated hematologic neoplasm. Am J Clin Pathol. 1994;101:432–437.

34 Skinnider LF, Alexander S, Horsman D. Concurrent thymoma and lymphoma. A report of two cases. Hum Pathol. 1982;13:163–166.

35 Souadjian JV, Silverstein MN, Titus JL. Thymoma and cancer. Cancer. 1968;22:1221–1225.

36 Guillan RA, Zelman S, Smalley RL, Iglesias PA. Malignant thymoma associated with myasthenia gravis, and evidence of extrathoracic metastases. An analysis of published cases and report of a case. Cancer. 1971;27:823–830.

37 Wick MR, Nichols WC, Ingle JN, Bruckman JE, Okazaki H. Malignant, predominantly lymphocytic thymoma with central and peripheral nervous system metastases. Cancer. 1981;47:2036–2043.

38 Marx A, Wilisch A, Schultz A, Gattenlohner S, Nenninger R, Müller-Hermelink HK. Pathogenesis of myasthenia gravis. Virchows Arch. 1997;430:355–364.

39 Vincent A. Immunology of acetylcholine receptors in relation to myasthenia gravis. Physiol Rev. 1980;60:756–824.

40 Vincent A. Timeline: Unravelling the pathogenesis of myasthenia gravis. Nat Rev Immunol. 2002;2:797–804.

41 Kirchner T, Tzartos S, Hoppe F, Schalke B, Wekerle H, Müller-Hermelink HK. Pathogenesis of myasthenia gravis. Acetylcholine receptor-related antigenic determinants in tumor-free thymuses and thymic epithelial tumors. Am J Pathol. 1988;130:268–280.

42 Schluep M, Willcox N, Vincent A, Dhoot GK, Newsom-Davis J. Acetylcholine receptors in human thymic myoid cells in situ. An immunohistological study. Ann Neurol. 1987;22:212–222.

43 Dardenne M, Savino W, Bach J-F. Thymomatous epithelial cells and skeletal muscle share a common epitope defined by a monoclonal antibody. Am J Pathol. 1987;126:194–198.

44 Koeda T. Immunopathological study related to myoglobin in myasthenic and non-myasthenic thymuses. Acta Pathol Jpn. 1986;36:209–223.

45 Meinl E, Klinkert WEF, Wekerle H. The thymus in myasthenia gravis. Changes typical for the human disease are absent in experimental autoimmune myasthenia gravis of the Lewis rat. Am J Pathol. 1991;139:995–1008.

46 Wekerle H, Ketelsen U-P. Intrathymic pathogenesis and dual genetic control of myasthenia gravis. Lancet. 1977;1:678–680.

47 Geuder KI, Marx A, Witzemann V, Schalke B, Kirchner T, Müller-Hermelink HK. Genomic organization and lack of transcription of the nicotinic acetylcholine receptor subunit genes in myasthenia gravis-associated thymoma. Lab Invest. 1992;66:452–458.

48 Marx A, O'Connor R, Geuder KI, Hoppe F, Schalke B, Tzartos S, et al. Characterization of a protein with an acetylcholine receptor epitope from myasthenia gravis-associated thymomas. Lab Invest. 1990;62:279–286.

49 Monden Y, Uyama T, Nakahara K, Fujii Y, Hashimoto J, Ohno K, et al. Clinical characteristics and prognosis of myasthenia gravis with other autoimmune diseases. Ann Thorac Surg. 1984;41:189–192.

50 Katzin WE, Fishleder AJ, Linden MD, Tubbs RR. Immunoglobulin and T-cell receptor genes in thymomas. Genotypic evidence supporting the nonneoplastic nature of the lymphocytic component. Hum Pathol. 1988;19:323–328.

51 Pizer ES, McGrath SD, Hruban RH, Drachman DB, Bulkley GB, Zehnbauer BA. Partial T-cell receptor gene rearrangement. A source of pseudo-clonal populations in thymomas and other thymic tissues. Am J Clin Pathol. 1996;105:262–267.

52 Martin JME, Randhawa G, Temple WJ. Cervical thymoma. Arch Pathol Lab Med. 1986;110:354–357.

53 Yamashita H, Murakami N, Noguchi S, Noguchi A, Yokoyama S, Moriuchi A, et al. Cervical thymoma and incidence of cervical thymus. Acta Pathol Jpn. 1983;33:189–194.

54 Mirra M, Zanella M, Bussani R, Falconieri G. Intrapericardial thymoma: report of two incidental autopsy cases and review of the literature. Arch Pathol Lab Med. 1997;121:59–63.

55 Green WR, Pressoir R, Gumbs RV, Warner O, Naab T, Qayumi M. Intrapulmonary thymoma. Arch Pathol Lab Med. 1987;111:1074–1076.

56 Kung I, Loke SL, So SY, Lam WK, Mok CK, Khin MA. Intrapulmonary thymoma. Report of two cases. Thorax. 1985;40:471–474.

57 Srivastava A, Padilla O, Alroy J, Ucci A, Pilichowska M, Daley B, Wolfe HT. Primary intrapulmonary spindle cell thymoma with marked granulomatous reaction: report of a case with review of literature. Int J Surg Pathol (in press, 2004).

58 Attanoos RL, Galateau-Salle F, Gibbs AR, Muller S, Ghandour F, Dojcinov SD. Primary thymic epithelial tumours of the pleura mimicking malignant mesothelioma. Histopathology. 2002;41:42–49.

59 Fushimi H, Tanio Y, Kotoh K. Ectopic thymoma mimicking diffuse pleural mesothelioma: a case report. Hum Pathol. 1998;29:409–410.

60 Moran CA, Travis WD, Rosado-de-Christenson M, Koss MN, Rosai J. Thymomas presenting as pleural tumors. Report of eight cases. Am J Surg Pathol. 1992;16:138–144.

61 LeGolvan DP, Abell MR. Thymomas. Cancer. 1977;39:2142–2157.

62 Otto HF. Pathologie des thymus. New York: Springer-Verlag; 1984;.

63 Salyer WR, Eggleston JC. Thymoma. A clinical and pathological study of 65 cases. Cancer. 1976;37:229–249.

64 Moran CA, Suster S. Thymoma with prominent cystic and hemorrhagic changes and areas of necrosis and infarction: a clinicopathologic study of 25 cases. Am J Surg Pathol. 2001;25:1086–1090.

65 Rosai J. The pathology of thymic neoplasia. International Academy of Pathology Monograph No. 29. Baltimore: Williams & Wilkins; 1987;.

66 Rosai J, Levine GD. Tumors of the thymus. In Atlas of tumor pathology, series 2, fascicle 13. Washington D.C.: Armed Forces Institute of Pathology; 1975;.

67 Tateyama H, Takahashi E, Saito Y, Fukai I, Fujii Y, Niwa H, et al. Histopathologic changes of thymoma preoperatively treated with corticosteroids. Virchows Arch. 2001;438:238–247.

68 Osborne B, Mackay B, Battifora H. Thymoma. A clinicopathologic study of 23 cases. Pathol Annu. 1985;20(Pt 2):289–315.

69 Kuo T. Sclerosing thymoma. A possible phenomenon of regression. Histopathology. 1994;25:319–322.

70 Moran CA, Suster S, Koss MN. Plasma cell-rich thymoma. Am J Clin Pathol. 1994;102:199–201.

71 Kuo T-T, Lee M-C. Amyloid production in a thymoma. Surg Pathol. 1991;4:69–74.

72 Kornstein MJ, Hoxie JA, Levinson AI, Brooks JJ. Immunohistology of human thymomas. Arch Pathol Lab Med. 1985;109:460–463.

73 Lauriola L, Michetti F, Stolfi VM, Tallini G, Cocchia D. Detection by S-100 immunolabelling of interdigitating reticulum cells in human thymomas. Virchows Arch (Cell Pathol). 1984;45:187–195.

74 Ruco LP, Pisacane A, Pomponi D, Stopacciaro A, Pescarmona E, Rendina EA, et al. Macrophages and interdigitating reticulum cells in normal human thymus and thymomas: Immunoreactivity of interleukin-1 alpha, interleukin-1 beta and tumour necrosis factor alpha. Histopathology. 1990;17:291–299.

75 Kondo K, Mukai K, Sato Y, Matsuno Y, Shimosato Y, Monden Y. An immunohistochemical study of thymic epithelial tumors. III. The distribution of interdigitating reticulum cells and S-100 beta-positive small lymphocytes. Am J Surg Pathol. 1990;14:1139–1147.

76 Levine GD, Bensch KG. Epithelial nature of spindle-cell thymoma. An ultrastructural study. Cancer. 1972;30:500–511.

77 Levine GD, Rosai J, Bearman RM, Polliack A. The fine structure of thymoma, with emphasis on its differential diagnosis. A study of ten cases. Am J Pathol. 1975;81:49–66.

78 Willcox N, Schluep M, Ritter MA, Schuurman HJ, Newsom-Davis J, Christensson B. Myasthenic and nonmyasthenic thymoma. An expansion of a minor cortical epithelial cell subset? Am J Pathol. 1987;127:447–460.

79 Kuo T-t. Cytokeratin profiles of the thymus and thymomas: histogenetic correlations and proposal for a histological classification of thymomas. Histopathology. 2000;36:403–414.

80 Fukai I, Masaoka A, Hashimoto T, Yamakawa Y, Mizuno T, Tanamura O. The distribution of epithelial membrane antigen in thymic epithelial neoplasms. Cancer. 1992;70:2077–2081.

81 Chan WC, Zaatari GS, Tabei S, Bibb M, Brynes RK. Thymoma. An immunohistochemical study. Am J Clin Pathol. 1984;82:160–166.

82 Mokhtar N, Hsu S-M, Lad RP, Haynes BF, Jaffe ES. Thymoma. Lymphoid and epithelial components mirror the phenotype of normal thymus. Hum Pathol. 1984;15:378–384.

83 Sato Y, Watanabe S, Mukai K, Kodama T, Upton MP, Goto M, et al. An immunohistochemical study of thymic epithelial tumors. Am J Surg Pathol. 1986;10:862–870.

84 Savino W, Durand D, Dardenne M. Immunohistochemical evidence for the expression of the carcinoembryonic antigen by human thymic epithelial cells in vitro and in neoplastic conditions. Am J Pathol. 1985;121:418–425.

85 Wiley EL, Nosal JM, Freeman RG. Immunohistochemical demonstration of H antigen, peanut agglutinin receptor, and saphora japonica receptor expression in infant thymuses and thymic neoplasias. Am J Clin Pathol. 1990;93:44–48.

86 Datta MW, Shahsafei A, Nadler LM, Freeman GJ, Dorfman DM. Expression of MHC class II-associated invariant chain (li; CD74) in thymic epithelial neoplasms. Appl Immunohistochem Mol Morphol. 2000;8:210–215.

87 Chilosi M, Zamò A, Brighenti A, Malpeli G, Montagna L, Piccoli P, et al. Constitutive expression of ΔN-p63α isoform in human thymus and thymic epithelial tumours. Virchows Arch. 2003;443:175–183.

88 Pescarmona E, Pisacane A, Pignatelli E, Baroni CD. Expression of epidermal and nerve growth factor receptors in human thymus and thymomas. Histopathology. 1993;23:39–44.

89 Lauriola L, Maggiano N, Serra FG, Nori S, Tardio ML, Capelli A, et al. Immunohistochemical and in situ hybridization detection of growth-hormone-producing cells in human thymoma. Am J Pathol. 1997;151:55–61.

90 Kuo T-t, Lo SK. Immunohistochemical metallothionein expression in thymoma: correlation with histologic types and cellular origin. Histopathology. 1997;30:243–248.

91 Giraud F, Fabien N, Auger C, Girod C, Loire R, Monier JC. Human epithelial thymic tumours. Heterogeneity in immunostaining of epithelial cell markers and thymic hormones. Thymus. 1990;15:15–29.

92 Savino W, Manganella G, Verley J-M, Wolff A, Berrih S, Levasseur P, et al. Thymoma epithelial cells secrete thymic hormone but do not express class II antigens of the major histocompatibility complex. J Clin Invest. 1985;76:1140–1146.

93 Hirokawa K, Utsuyama M, Moriizumi E, Hashimoto T, Masaoka A, Goldstein AL. Immunohistochemical studies in human thymomas. Localization of thymosin and various cell markers. Virchows Arch B (Cell Pathol). 1988;55:371–380.

94 Mizuno T, Hashimoto T, Masaoka A. Distribution of fibronectin and laminin in human thymoma. Cancer. 1990;65:1367–1374.

95 Kornstein MJ, Kay S. B cells in thymomas. Mod Pathol. 1990;3:61–63.

96 Lauriola L, Maggiano N, Marino M, Carbone A, Piantelli M, Musiani P. Human thymoma. Immunologic characteristics of the lymphocytic component. Cancer. 1981;48:1992–1995.

97 Palestro G, Valente G, Botto Micca F, Novero D, Arisio R. Detection and distribution of alfa-naphthyl acetate esterase activity in thymocytes of normal, myasthenic thymus and thymoma. Histochemical and cytochemical study in relation to E-Rosetting. Virchows Arch (Cell Pathol). 1980;35:33–43.

98 Woda BA, Bain K, Salm TV. The phenotype of lymphocytes in a thymoma as studied with monoclonal antibodies. Clin Immunol Immunopathol. 1984;30:197–201.

99 Dorfman DM, Pinkus GS. CD99 (p30/32MIC2) immunoreactivity in the diagnosis of thymic neoplasms and mediastinal lymphoproliferative disorders: A study of paraffin sections using monoclonal antibody 013. Appl Immunohistochem. 1996;4:34–42.

100 Pomplun S, Wotherspoon AC, Shah G, Goldstraw P, Ladas G, Nicholson AG. Immunohistochemical markers in the differentiation of thymic and pulmonary neoplasms. Histopathology. 2002;40:152–158.

101 Chilosi M, Iannucci A, Menestrina F, Lestani M, Scarpa A, Bonetti F, et al. Immunohistochemical evidence of active thymocyte proliferation in thymoma. Am J Pathol. 1987;128:464–470.

102 Taubenberger JK, Jaffe ES, Medeiros LJ. Thymoma with abundant L26-positive “asteroid” cells. A case report with an analysis of normal thymus and thymoma specimens. Arch Pathol Lab Med. 1991;115:1254–1257.

103 Chilosi M, Castelli P, Martignoni G, Pizzolo G, Montresor E, Facchetti F, et al. Neoplastic epithelial cells in a subset of human thymomas express the B-cell associated CD20 antigen. Am J Surg Pathol. 1992;16:988–997.

104 Keen SJ, Libshitz HI. Thymic lesions. Experience with computed tomography in 24 patients. Cancer. 1987;59:1520–1523.

105 Kuo T-T, Lo S-K. DNA flow cytometric study of thymic epithelial tumors with evaluation of its usefulness in the pathologic classification. Hum Pathol. 1993;24:746–749.

106 Pich A, Chiarle R, Chiusa L, Palestro G. Argyrophilic nucleolar organizer region counts predict survival in thymoma. Cancer. 1994;74:1568–1574.

107 Pollack A, El-Naggar AK, Cox JD, Ro JY, Sahin A, Komaki R. Thymoma. The prognostic significance of flow cytometric DNA analysis. Cancer. 1992;69:1702–1709.

108 Tateyama H, Mizuno T, Tada T, Eimoto T, Hashimoto T, Masaoka A. Thymic epithelial tumours. Evaluation of malignant grade by quantification of proliferating cell nuclear antigen and nucleolar organizer regions. Virchows Arch [A]. 1993;422:265–269.

109 Levine GD, Rosai J. Thymic hyperplasia and neoplasia. A review of current concepts. Hum Pathol. 1978;9:495–515.

110 Müller-Hermelink HK, Marino M, Palestro G. Pathology of thymic epithelial tumors. Müller-Hermelink HK editors. In: Current topics in pathology. The human thymus. Histophysiology and pathology. vol. 75:New York: Springer-Verlag; 1986.

111 Chhieng DC, Rose D, Ludwig ME, Zakowski MF. Cytology of thymomas: Emphasis on morphology and correlation with histologic subtypes. Cancer Cytopathol. 2000;90:24–32.

112 Dahlgren S, Sandstedt B, Sundström C. Fine needle aspiration cytology of thymic tumors. Acta Cytol [Baltimore]. 1983;27:1–6.

113 Tao L-C, Pearson FG, Cooper JD, Sanders DE, Weisbrod G, Donat EE. Cytopathology of thymoma. Acta Cytol (Baltimore). 1984;28:165–170.

114 Alpert LI, Papatestas A, Kark A, Osserman RS, Osserman K. A histologic reappraisal of the thymus in myasthenia gravis. A correlative study of thymic pathology and response to thymectomy. Arch Pathol. 1971;91:55–61.

115 Lattes R. Thymoma and other tumors of the thymus. An analysis of 107 cases. Cancer. 1962;15:1224–1260.

116 Lattes R, Jonas S. The pathological and clinical features in eighty cases of thymoma. Bull N Y Acad Med. 1957;33:145–147.

117 Lewis JE, Wick MR, Scheithauer BW, Bernatz PE, Taylor WF. Thymoma. A clinicopathologic review. Cancer. 1987;60:2727–2743.

118 Bernatz PE, Harrison EG, Glagett OT. Thymoma. A clinicopathologic study. J Thorac Cardiovasc Surg. 1961;42:424–444.

119 Quintanilla-Martinez L, Wilkins E, Ferry J, Harris N. Thymoma—morphologic subclassification correlates with invasiveness and immunohistologic features. A study of 122 cases. Hum Pathol. 1993;24:958–969.

120 Quintanilla-Martinez L, Wilkins EW, Choi N, Efird J, Hug E, Harris NL. Thymoma. Histologic subclassification is an independent prognostic factor. Cancer. 1994;74:606–617.

121 Kirchner T, Schalke B, Buchwald J, Ritter M, Marx A, Müller-Hermelink HK. Well-differentiated thymic carcinoma. An organotypical low-grade carcinoma with relationship to cortical thymoma. Am J Surg Pathol. 1992;16:1153–1169.

122 Rosai J. Histological typing of tumours of the thymus. Berlin: Springer; 1999;.

123 Suarez Vilela D, Salas Valien JS, Gonzalez Moran MA, Izquierdo Garcia F, Riera Velasco JR. Thymic carcinoma associated with a spindle cell thymoma. An immunohistochemical study. Histopathology. 1992;21:263–268.

124 Suster S, Moran CA. Primary thymic epithelial neoplasms showing combined features of thymoma and thymic carcinoma: A clinicopathologic study of 22 cases. Am J Surg Pathol. 1996;20:1469–1480.

125 Suster S, Moran CA. Micronodular thymoma with lymphoid B-cell hyperplasia: clinicopathologic and immunohistochemical study of eighteen cases of a distinctive morphologic variant of thymic epithelial neoplasm. Am J Surg Pathol. 1999;23:955–962.

126 Pan C-C, Chen WY, Chiang H. Spindle cell and mixed spindle/lymphocytic thymomas: an integrated clinicopathologic and immunohistochemical study of 81 cases. Am J Surg Pathol. 2001;25:111–120.

127 Tateyama H, Saito Y, Fujii Y, Okumura M, Nakamura K, Tada H, et al. The spectrum of micronodular thymic epithelial tumours with lymphoid B-cell hyperplasia. Histopathology. 2001;38:519–527.

128 Pescarmona E, Pisacane A, Rendina EA, Ricci C, Ruco LP, Baroni CD. Organoid thymoma. A well-differentiated variant with distinctive clinicopathologic features. Histopathology. 1991;18:161–164.

129 Suster S, Rosai J. Cystic thymomas. A clinicopathologic study of ten cases. Cancer. 1992;69:92–97.

130 Kim YI, Neher E. IgG from patients with Lambert-Eaton syndrome blocks voltage-dependent calcium channels. Science. 1988;239:405–408.

131 Hammond EH, Flinner RL. The diagnosis of thymoma. A review. Ultrastruct Pathol. 1991;15:419–438.

132 Levine GD, Rosai J. Thymic hyperplasia and neoplasia. A review of current concepts. Hum Pathol. 1978;9:495–515.

133 Walker AN, Mills SE, Fechner RE. Thymomas and thymic carcinomas. Semin Diagn Pathol. 1990;7:250–265.

134 Masaoka A, Monden Y, Nakahara K, Tanoika T. Follow-up study of thymomas with special reference to their clinical stage. Cancer. 1981;48:2485–2492.

135 Tsuchiya R, Koga K, Matsuno Y, Mukai K, Shimosato Y. Thymic carcinoma. Proposal for pathological TNM and staging. Pathol Int. 1994;44:505–512.

136 Yamakawa Y, Masaoka A, Hashimoto T, Niwa H, Mizuno T, Fujii Y, et al. A tentative tumor-node-metastasis classification of thymoma. Cancer. 1991;68:1984–1987.

137 Koga K, Matsuno Y, Noguchi M, Mukai K, Asamura H, Goya T, et al. A review of 79 thymomas. Modification of staging system and reappraisal of conventional division into invasive and non-invasive thymoma. Pathol Int. 1994;44:359–367.

138 Bedini AV, Andreani SM, Tavecchio L, Fabbri A, Giardini R, Camerini T, Bufalino R, Rosai J. Proposal of a novel TNM-based system to stage thymic epithelial tumors according to the World Health Organization pathologic classification (submitted for publication).

139 Inoue M, Marx A, Zettl A, Strobel P, Muller-Hermelink HK, Starostik P. Chromosome 6 suffers frequent and multiple aberrations in thymoma. Am J Pathol. 2002;161:1507–1513.

140 Zettl A, Strobel P, Wagner K, Katzenberger T, Ott G, Rosenwald A, et al. Recurrent genetic aberrations in thymoma and thymic carcinoma. Am J Pathol. 2000;157:257–266.

141 Zhou R, Zettl A, Strobel P, Wagner K, Muller-Hermelink HK, Zhang S, et al. Thymic epithelial tumors can develop along two different pathogenetic pathways. Am J Pathol. 2001;159:1853–1860.

142 Chen F-F, Yan J-J, Jin Y-T, Su I-J. Detection of bcl-2 and p53 in thymoma: Expression of bcl-2 as a reliable marker of tumor aggressiveness. Hum Pathol. 1996;27:1089–1092.

143 Engel P, Francis D, Graem N. Expression of bcl-2 in fetal thymus, thymomas and thymic carcinomas. Association with p53 expression and review of the literature. APMIS. 1998;106:449–455.

144 Weirich G, Schneider P, Fellbaum C, Brauch H, Nathrath W, Scholz M, et al. p53 alterations in thymic epithelial tumours. Virchows Arch. 1997;431:17–23.

145 Tateyama H, Eimoto T, Tada T, Inagaki H, Hattori H, Takino H. Apoptosis, bcl-2 protein, and Fas antigen in thymic epithelial tumors. Mod Pathol. 1997;10:983–991.

146 Thomas CR, Wright CD, Loehrer PJ. Thymoma: state of the art. J Clin Oncol. 1999;17:2280–2289.

147 Hejna M, Haberi I, Raderer M. Nonsurgical management of malignant thymoma. Cancer. 1999;85:1871–1884.

148 Cooper JD. Current therapy for thymoma. Chest. 1993;103(4 Suppl):334S–336S.

149 Curran WJ, Kornstein MJ, Brooks JJ, Turrisi AT. Invasive thymoma. The role of mediastinal irradiation following complete or incomplete surgical resection. J Clin Oncol. 1988;6:1722–1727.

150 Gripp S, Hilgers K, Wurm R, Schmitt G. Thymoma: prognostic factors and treatment outcomes. Cancer. 1998;83:1495–1503.

151 Haniuda M, Morimoto M, Nishimura H, Kobayashi OM, Yamanda T, Lida F. Adjuvant radiotherapy after complete resection of thymoma. Ann Thorac Surg. 1992;54:311–315.

152 Uematsu M, Kondo M. A proposal for treatment of invasive thymoma. Cancer. 1986;58:1979–1985.

153 Carlson RW, Dorfman RF, Sikic BI. Successful treatment of metastatic thymic carcinoma with cisplatin, vinblastine, bleomycin, and etoposide chemotherapy. Cancer. 1990;66:2092–2094.

154 Loehrer PJ, Chen M, Kim KM, Aisner SC, Einhorn LH, Livingston R, et al. Cisplatin, doxorubicin, and cyclophosphamide plus thoracic radiation therapy for limited-stage unresectable thymoma: an intergroup trial. J Clin Oncol. 1997;15:3093–3099.

155 Ogawa K, Uno T, Toita T, Onishi H, Yoshida H, Kakinohana Y, et al. Postoperative radiotherapy for patients with completely resected thymoma: a multi-institutional, retrospective review of 103 patients. Cancer. 2002;94:1405–1413.

156 Park HS, Shin DM, Lee JS, Komaki R, Pollack A, Putnam JB, et al. Thymoma. A retrospective study of 87 cases. Cancer. 1994;73:2491–2498.

157 Weide LG, Ulbright TM, Loehrer PJ, Williams SD. Thymic carcinoma. A distinct clinical entity responsive to chemotherapy. Cancer. 1993;71:1219–1223.

158 Drachman DB, McIntosh KR, Reim J, Balar L. Strategies for treatment of myasthenia gravis. Ann NY Acad Sci. 1993;681:515–528.

159 Scadding GK, Havard CWH, Lange MJ, Domb I. The long-term experience of thymectomy for myasthenia gravis. J Neurol Neurosurg Psychiatry. 1985;48:401–406.

160 Genkins G, Papatestas AE, Horowitz SH, Kornfeld P. Studies in myasthenia gravis. Early thymectomy. Electrophysiologic and pathologic correlations. Am J Med. 1975;58:517–524.

161 Monden Y, Nakahara K, Fujii Y, Hashimoto J, Ohno K, Masaoka A, et al. Myasthenia gravis in elderly patients. Ann Thorac Surg. 1985;39:433–440.

162 Rosenberg M, Jauregui WO, De Vega ME, Herrera MR, Roncoroni AJ. Recurrence of thymic hyperplasia after thymectomy in myasthenia gravis. Its importance as a cause of failure of surgical treatment. Am J Med. 1983;74:78–82.

163 Steinman L, Mantegazza R. Prospects for specific immunotherapy in myasthenia gravis. FASEB J. 1990;4:2726–2731.

164 Fechner RE. Recurrence of noninvasive thymomas. Report of four cases and review of the literature. Cancer. 1969;23:1423–1427.

165 Lewis JE, Wick MR, Scheithauer BW, Bernatz PE, Taylor WF. Thymoma. A clinicopathologic review. Cancer. 1987;60:2727–2743.

166 Maggi G, Giaccone G, Donadio M, Ciuffreda L, Dalesio O, Leria G, et al. Thymomas. A review of 169 cases, with particular reference to results of surgical treatment. Cancer. 1986;58:765–776.

167 Urgesi A, Monetti U, Rossi G, Ricardi U, Maggi G, Sannazzari GL. Aggressive treatment of intrathoracic recurrences of thymoma. Radiother Oncol. 1992;24:221–225.

168 Blumberg D, Weksler B, Delgado R, Rosai J, Bains MS, Ginsberg RJ, et al. Thymoma. A multivariate analysis of factors predicting survival. Ann Thorac Surg. 1995;60:908–913.

169 Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer. 1981;48:2485–2492.

170 Verley JM, Hollmann KH. Thymoma. A comparative study of clinical stages, histologic features, and survival in 200 cases. Cancer. 1985;55:1074–1086.

171 Lattes R. Thymoma and other tumors of the thymus. An analysis of 107 cases. Cancer. 1962;15:1224–1260.

172 Chalabreysse L, Roy P, Cordier JF, Loire R, Gamondes JP, Thivolet-Bejui F. Correlation of the WHO scheme for the classification of thymic epithelial neoplasms with prognosis:a retrospective study of 90 tumors. Am J Surg Pathol. 2002;26:1605–1611.

173 Okumura M, Miyoshi S, Fujii Y, Takeuchi Y, Shiono H, Inoue M, et al. Clinical and functional significance of WHO classification on human thymic epithelial neoplasms: a study of 146 consecutive tumors. Am J Surg Pathol. 2001;25:103–110.

174 Bedini AV, Andreani SM, Tavecchio L, Fabbri A, Giardini R, Camerini T, Bufalino R, Rosai J. Proposal of a novel TNM-based system to stage thymic epithelial tumors according to the World Health Organization pathologic classification (submitted for publication).

175 Begg CB, Cramer LD, Venkatraman ES, Rosai J. Comparing tumour staging and grading systems: a case study and a review of the issues, using thymoma as a model. Statist Med. 2000;19:1997–2014.

176 Pan C-C, Ho M-T, Chen WY-K, Huang C-W, Chiang H. Ki67 labelling index correlates with stage and histology but not significantly with prognosis in thymoma. Histopathology. 1998;33:453–458.

177 Yang W-I, Efird JG, Quintanilla-Martinez L, Choi N, Harris NL. Cell kinetic study of thymic epithelial tumors using PCNA (PC-10) and Ki-67 (MIB-1) antibodies. Hum Pathol. 1996;27:70–76.

178 Gripp S, Hilgers K, Ploem-Zaaijer JJ, Hartmann A, Schmitt G. Prognostic significance of DNA cytometry in thymoma. J Cancer Res Clin Oncol. 2000;126:280–284.

Last updated: 7 Mar 2006