THYMOMA AND THYMIC CARCINOMA- CELLULAR CLASSIFICATION

Cellular Classification of Thymoma and Thymic Carcinomas

The following cellular classification of thymoma and thymic carcinoma is largely based on the classification scheme presented in a World Health Organization (WHO) monograph published in 1999.[1] Malignant thymoma is invasive disease (as defined either macroscopically or microscopically) that continues to retain typically "bland" cytologic characteristics. Thymomas are a mixture of epithelial cells and lymphocytes, often T-cells, and the malignant component is represented by the epithelial cells. Malignant cytologic characteristics are considered thymic carcinomas.

Both histologic classification of thymomas and stage may have independent prognostic significance.[2,3] A few series have reported the prognostic value of the WHO classifications. In large, retrospective analyses of 100 and of 178 thymoma cases, disease-free survivals at 10 years were 95% to 100% for type A, 90% to 100% for type AB, 83% to 85% for type B1, 71% to 83% for type B2, 36% to 40% for type B3, and 28% for type C.[4,5] In both series, stage and complete resection were significant independent prognostic factors. An analysis of 273 patients treated over a 44-year period found 20-year survival rates of 100%, 87%, 91%, 59%, and 36% for patients with type A, AB, B1, B2, and B3 tumors, respectively.[2]

Recurrent karyotype abnormalities have been documented in thymomas.[6] Type A thymomas have chromosome 6q deletions including the HLA locus and p21. Type B2 and B3 thymomas have additional chromosome 5q (adenomatous polyposis coli locus), 13q (retinoblastoma locus), and 17p (p53) deletions.[7] Amplifications in regions of chromosome 16 (cadherin-encoding gene) and chromosome 18 (bcl-2) have also been seen.[8] Gene expression profiling study has shown a correlation of expression of a number of genes including adhesion molecule cten, ets-1 oncogene and glycosylphosphatidyl inositol-anchored protein with thymoma stage.[9-11]

Thymoma

Thymoma is a thymic epithelial tumor in which the epithelial component exhibits no overt atypia and retains histologic features specific to the normal thymus.[1] Immature non-neoplastic lymphocytes are present in variable numbers depending on the histologic type of thymoma. The histologic types of thymoma are as follows:

·         Type A thymoma

Type A thymoma (also known as spindle cell thymoma and medullary thymoma) accounts for approximately 4% to 7% of all thymomas.[2,3] Approximately 17% of this type may be associated with myasthenia gravis.[2] Morphologically, the tumor is composed of neoplastic thymic epithelial cells that have a spindle/oval shape, lack nuclear atypia, and are accompanied by few, if any, nonneoplastic lymphocytes.[1] The appearance of this tumor can be confused with that of a mesenchymal neoplasm, but the immunohistochemical and ultrastructural features are clearly those of an epithelial neoplasm. Most type A thymomas are encapsulated. (Refer to the Stage Information for Thymoma and Thymic Carcinomas of this summary for more information). Some, however, may invade the capsule and, on rare occasion, may extend into the lung. Chromosome abnormalities, when present, may correlate with an aggressive clinical course.[12] The prognosis for this tumor type is excellent and have long-term survival rates (15 years or more) that are reported to be close to 100% in retrospective studies.[2,3]

·         Type AB thymoma

Type AB thymoma (also known as mixed thymoma) accounts for approximately 28% to 34% of all thymomas.[2,3] Approximately 16% of this type may be associated with myasthenia gravis.[2] Morphologically, type AB thymoma is a thymic tumor in which foci having the features of type A thymoma are admixed with foci rich in nonneoplastic lymphocytes.[1] The segregation of the different foci can be sharp or indistinct, and a wide range exists in the relative amount of the two components. The prognosis for this tumor type is good and have long-term survival rates (≥15 years ) that are recently reported to be approximately 90%.[2,3]

·         Type B1 thymoma

Type B1 thymoma (also known as lymphocyte-rich thymoma, lymphocytic thymoma, predominantly cortical thymoma, and organoid thymoma) accounts for approximately 9% to 20% of all thymomas and depends on the study cited.[2,3] Approximately 57% of cases may be associated with myasthenia gravis.[2] Morphologically, this tumor resembles the normal functional thymus because it contains large numbers of cells that have an appearance almost indistinguishable from normal thymic cortex with areas resembling thymic medulla.[1] The similarities between this tumor type and the normal active thymus are such that distinction between the two may be impossible on microscopic examination. The prognosis for this tumor type is good and has a long-term survival rate (20 years or more) of approximately 90%.[2,3]

·         Type B2 thymoma

Type B2 thymoma (also known as cortical thymoma and polygonal cell thymoma) accounts for approximately 20% to 36% of all thymomas and depends on the study cited.[2,3] Approximately 71% of cases may be associated with myasthenia gravis.[2] Morphologically, the neoplastic epithelial component of this tumor type appears as scattered plump cells with vesicular nuclei and distinct nucleoli among a heavy population of nonneoplastic lymphocytes.[1] Perivascular spaces are common and on occasion very prominent. A perivascular arrangement of tumor cells that results in a palisading effect may be seen. This type of thymoma resembles type B1 thymoma in its predominance of lymphocytes, but foci of medullary differentiation are less conspicuous or absent. Long-term survival is decidedly worse than for thymoma types A, AB, and B1. The 20-year survival rate (as defined by freedom-from-tumor death) for this thymoma type is approximately 60%.[2]

·         Type B3 thymoma

Type B3 thymoma (also known as epithelial thymoma, atypical thymoma, squamoid thymoma, and well-differentiated thymic carcinoma) accounts for approximately 10% to 14% of all thymomas. Approximately 46% of this type of tumor may be associated with myasthenia gravis.[2] Morphologically, this tumor type is predominantly composed of epithelial cells that have a round or polygonal shape and that exhibit no atypia or mild atypia.[1] The epithelial cells are admixed with a minor component of nonneoplastic lymphocytes, which results in a sheet-like growth of neoplastic epithelial cells. The 20-year survival rate (as defined by freedom-from-tumor death) for this thymoma type is approximately 40%.[2]

Thymic Carcinoma

Thymic carcinoma (also known as type C thymoma) is a thymic epithelial tumor that exhibits a definite cytologic atypia and a set of histologic features no longer specific to the thymus but rather similar to those histologic features observed in carcinomas of other organs.[1] In contrast to type A and B thymomas, thymic carcinomas lack immature lymphocytes. Any lymphocytes that are present are mature and usually admixed with plasma cells. Hypothetically, thymic carcinoma may arise from malignant transformation of a pre-existing thymoma.[13] This hypothetical evolution could account for the existence of thymic epithelial lesions that exhibit combined features of thymoma and thymic carcinoma within the same tumor.[14]

Thymic carcinomas are usually advanced when diagnosed and have a higher recurrence rate and worse survival compared with thymoma.[15,16] In a retrospective study of 40 patients with thymic carcinoma, the 5-year and 10-year actuarial overall survival rates were 38% and 28%, respectively.[15] In contrast to the thymomas, the association of thymic carcinoma and autoimmune disease is rare.[17]

Histologic subtypes of thymic carcinoma include the following:

·         Squamous cell (epidermoid) thymic carcinoma

This type of thymic carcinoma exhibits clear-cut cytologic atypia. In routinely stained sections, the keratinizing form exhibits equally clear-cut evidence of squamous differentiation in the form of intercellular bridges and/or squamous pearls, while the nonkeratinizing form lacks obvious signs of keratinization. Another subtype, basaloid carcinoma, is composed of compact lobules of tumor cells that exhibit peripheral palisading and an overall basophilic staining pattern caused by the high nucleocytoplasmic ratio and the absence of keratinization.

·         Lymphoepithelioma-like thymic carcinoma

This type of thymic carcinoma has morphologic features indistinguishable from those of lymphoepithelial carcinoma of the respiratory tract. The differential diagnosis with germ cell tumors, particularly seminomas, can be difficult but important for treatment.

·         Sarcomatoid thymic carcinoma (carcinosarcoma)

This is a type of thymic carcinoma in which part or all of the tumor resembles one of the types of soft tissue sarcoma.

·         Clear cell thymic carcinoma

This is a type of thymic carcinoma composed predominantly or exclusively of cells with optically clear cytoplasm.

·         Mucoepidermoid thymic carcinoma

This type of thymic carcinoma has an appearance similar to that of mucoepidermoid carcinoma of the major and minor salivary glands.

·         Papillary thymic adenocarcinoma

This type of thymic carcinoma grows in a papillary fashion. This histology may be accompanied by psammoma body formation, which may result in a marked similarity with papillary carcinoma of the thyroid gland.

·         Undifferentiated thymic carcinoma

This is a rare type of thymic carcinoma that grows in a solid undifferentiated fashion but without exhibiting sarcomatoid (spindle cell or pleomorphic) features.

Combined Thymoma

Combinations of the above histologic types can occur within the same tumor. For these cases, the term, combined thymoma, can be used, followed by a listing of the components and the relative amount of each component.[1]

References

1.     Rosai J: Histological Typing of Tumours of the Thymus. New York, NY: Springer-Verlag, 2nd ed., 1999.

2.     Okumura M, Ohta M, Tateyama H, et al.: The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: a clinical study of 273 patients. Cancer 94 (3): 624-32, 2002. [PUBMED Abstract]

3.     Chen G, Marx A, Wen-Hu C, et al.: New WHO histologic classification predicts prognosis of thymic epithelial tumors: a clinicopathologic study of 200 thymoma cases from China. Cancer 95 (2): 420-9, 2002. [PUBMED Abstract]

4.     Kondo K, Yoshizawa K, Tsuyuguchi M, et al.: WHO histologic classification is a prognostic indicator in thymoma. Ann Thorac Surg 77 (4): 1183-8, 2004. [PUBMED Abstract]

5.     Rena O, Papalia E, Maggi G, et al.: World Health Organization histologic classification: an independent prognostic factor in resected thymomas. Lung Cancer 50 (1): 59-66, 2005. [PUBMED Abstract]

6.     Zettl A, Ströbel P, Wagner K, et al.: Recurrent genetic aberrations in thymoma and thymic carcinoma. Am J Pathol 157 (1): 257-66, 2000. [PUBMED Abstract]

7.     Inoue M, Starostik P, Zettl A, et al.: Correlating genetic aberrations with World Health Organization-defined histology and stage across the spectrum of thymomas. Cancer Res 63 (13): 3708-15, 2003. [PUBMED Abstract]

8.     Hirabayashi H, Fujii Y, Sakaguchi M, et al.: p16INK4, pRB, p53 and cyclin D1 expression and hypermethylation of CDKN2 gene in thymoma and thymic carcinoma. Int J Cancer 73 (5): 639-44, 1997. [PUBMED Abstract]

9.     Sasaki H, Kobayashi Y, Tanahashi M, et al.: Ets-1 gene expression in patients with thymoma. Jpn J Thorac Cardiovasc Surg 50 (12): 503-7, 2002. [PUBMED Abstract]

10.                       Sasaki H, Yukiue H, Kobayashi Y, et al.: Cten mRNA expression is correlated with tumor progression in thymoma. Tumour Biol 24 (5): 271-4, 2003 Sep-Oct. [PUBMED Abstract]

11.                       Sasaki H, Ide N, Sendo F, et al.: Glycosylphosphatidyl inositol-anchored protein (GPI-80) gene expression is correlated with human thymoma stage. Cancer Sci 94 (9): 809-13, 2003. [PUBMED Abstract]

12.                       Penzel R, Hoegel J, Schmitz W, et al.: Clusters of chromosomal imbalances in thymic epithelial tumours are associated with the WHO classification and the staging system according to Masaoka. Int J Cancer 105 (4): 494-8, 2003. [PUBMED Abstract]

13.                       Suster S, Moran CA: Thymic carcinoma: spectrum of differentiation and histologic types. Pathology 30 (2): 111-22, 1998. [PUBMED Abstract]

14.                       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 20 (12): 1469-80, 1996. [PUBMED Abstract]

15.                       Ogawa K, Toita T, Uno T, et al.: Treatment and prognosis of thymic carcinoma: a retrospective analysis of 40 cases. Cancer 94 (12): 3115-9, 2002. [PUBMED Abstract]

16.                       Blumberg D, Burt ME, Bains MS, et al.: Thymic carcinoma: current staging does not predict prognosis. J Thorac Cardiovasc Surg 115 (2): 303-8; discussion 308-9, 1998. [PUBMED Abstract]

17.                       Levy Y, Afek A, Sherer Y, et al.: Malignant thymoma associated with autoimmune diseases: a retrospective study and review of the literature. Semin Arthritis Rheum 28 (2): 73-9, 1998. [PUBMED Abstract]