1.Victor Babes University of Medicine, Pharmacy, Department of Morphologic Microscopy, Angiogenesis Research Center Timisoara, Timisoara, Romania (MR); University of Bari, Department of Basic Medical Sciences, Neurosciences, Sensory Organs, Bari, Italy (DR)
Myasthenia gravis and thymomaIn patients with myasthenia gravis the thymus shows a marked lymphoid follicle hyperplasia, as unique morphologic abnormality in 65% of cases. In 10% of patients myasthenia gravis is associated with thymoma (with or without follicular hyperplasia) and there are not found abnormalities in the other 25% of cases. This relation is also supported by the fact that 30 to 45% of patients with thymoma develop clinically evident myasthenia gravis (Raica et al., 1999). Until now, there were not demonstrated ultrastructural or immunohistochemical differences between thymomas with and without myasthenia gravis. Recent studies on large series were not able to demonstrate that myasthenia is a prognostic element for the behavior of thymoma. In all cases, myasthenia gravis is associated with a defect of the nicotinic receptor for acetylcholine (AchR). A similar (or even identical) protein was identified in the normal human thymus. This protein is located in a subset of thymic cells that have similar immunophenotype as striated muscle cells (myoglobin and desmin positive), called myoid cells. In the non-neoplastic thymus of patients with myasthenia gravis were identified aggregates of myoid cells, infiltrating the stroma. T cells activate AchR reactive B lymphocytes. Therefore, the process begins in the thymus and than continues in the entire immune system by autoantibodies production. Surgical treatment is more efficient if the thymus has follicular hyperplasia, and persistence of clinical signs is attributed to resting thymic parenchyma.
- Thymoma type AB (mix) is characterized by type A areas and lymphocyte-rich areas. Between the two different patterns of the tumor may be a clear-cut edge or the transition between them is gradual. Frequently, type A area is reduced, but it has the same aspects as described above. The term "mix" is used to draw attention on the dual cell population: neoplastic epithelial and non-neoplastic lymphocytes.
- Thymoma type B1 (lymphocyte-rich, lymphocytic, cortical) is similar to the normal functional thymus and consists of areas that are close in structure with the cortex (that predominate) and medulla. Differentiation from the normal thymus may be impossible at low power magnification. Medullary differentiated areas are usually round and may be erroneously interpreted as germ center; on occasion, they may contain aggregates of epithelial cells or Hassall bodies. Perivascular spaces are rarely found and are less prominent than in other forms of thymoma.
- Thymoma type B2 (cortical) consists of isolated or in small groups arranged epithelial cells and many lymphocytes. Usually, perivascular spaces are numerous and large. Occasionally, epithelial cells are arranged in palisade around perivascular spaces. Foci of medullary differentiation are less evident (with or without Hassall corpuscles) or they are absent. Epithelial cells are polygonal in shape (thymoma with large polygonal cells), more numerous than in thymoma type B1, they have nuclei with fine granular chromatin, prominent nucleoli, and rich cytoplasm. Lymphocytes may be immature, with large nuclei, visible cytoplasm and high mitotic activity (Ki67 index over 80%). Opposite to thymoma B1, this tumor does not recapitulate the differentiation of the normal thymus.
- Thymoma type B3 (epithelial, atypical, well differentiated thymic carcinoma) consists of epithelial cells that are round or polygonal in shape. Atypical elements are mild or absent, but the epithelial component proliferates in large sheets and lymphocytes are reduced in number. Epithelial cells have small nucleoli and mitotic figures are rare. The tumor preserves some characters of thymic differentiation: lobulation, dual cell population, and perivascular spaces. The perivascular arrangement of epithelial cells and squamous differentiated areas are frequently found. This tumor is more frequently invasive than "conventional" thymoma, but it may co-exist with thymoma B1, B2 or C.
There were described some unusual variants of thymoma with polygonal and round cells: microcystic, cystic, cribriform, with clear cells, rich in plasma cells, with myoid cells and starry sky. The classification of these forms is often based on the expression of monoclonal cytokeratin to differentiate them from thymic carcinoma with similar features.
- Pathology of thymoma after the preoperative treatment with corticosteroids. Corticosteroids are well-known inducers of thymic involution. It was noticed that preoperative administration of corticosteroids significantly reduces the diameter of the tumor. There are few studies on this subject, but data are extremely useful for pathologist. There are significant microscopic differences between the biopsies before and after the treatment with corticosteroids. Tateyama et al. (2001) noticed reduction of the tumor mass between 5 to 70%, depending the dose and length of the treatment. The predominance of proliferating epithelial cells may change. In some cases the dominant cell population becomes spindle in shape, and in others were noticed glandular-like or haemangiopericytoma-like structures. Atypical cells were rare or absent and many epithelial cells had acidophilic cytoplasm and condensed nuclei. The number of lymphocytes dramatically decreased, some of them showing fragmented nuclei. In tumors with massive regression extensive fibrosis, foamy macrophages, and necrosis are frequently noticed. Perivascular palisade of epithelial cells, cystic structures, and bizarre multinucleated giant cells, or giant cells with lobulated nucleus may be noticed in some cases. In all cases published until now it was observed the transformation in thymoma with epithelial predominance. The presence of degenerative lesions does not necessary means regression of the tumor. It is thought that epithelial cells degeneration is a consequence of depletion in immature T lymphocytes. In these conditions, the knowledge of preoperative medication is essential to avoid a possible confusion with well-differentiated carcinoma (as defined in Marino-Muller-Hermelink classification).
- Atypical thymoma: a distinct entity? Based on the difficulties in the classification of thymoma, Suster and Moran (1999) proposed the term "atypical thymoma". In this category were included all the cases that preserve some organo-typical characters of thymic differentiation, but associated with a given grade of cell atypia. The cell population is predominant epithelial, with the tendency to squamous transformation at the level of both architecture and individual tumor cells. Frequently, tumor cells are arranged around perivascular spaces, mimicking glandular differentiation. This lesion is equivalent to the "well differentiated thymic carcinoma" from Marino-Muller-Hermelink classification. Atypical thymoma is more frequently invasive than the conventional thymoma and can be found in association with typical areas of thymoma or/and thymic carcinoma. Although the existence of this subtype is supported by some data, until now atypical thymoma was not included in WHOs classification.
- Thymic carcinoma (former thymoma type C) is a rare tumor with poor prognosis in comparison with thymoma (Tomita et al., 2002), and is defined as an epithelial proliferation whose individual cells show clear characters of malignancy. Opposite to conventional thymoma, it is not associated with myasthenia gravis. The diagnosis is usually by exclusion, because there are not clear criteria to differentiate this tumor from carcinoma developed in other organs. The thymic carcinoma shows no character of thymoma (perivascular spaces, abortive Hassall bodies, a/o). The only major difference is the positive immunoreaction for CD5 in epithelial cells (this immunoreaction is negative in typical thymoma and non-thymic carcinoma). Lymphocytes may be present, even in large number, but always they are mature T (or rarely B) in type. The most common form is the squamous cell carcinoma (90% of cases), but there were reported many other variants: lymphoepithelioma-like, sarcomatoid, clear cell, basaloid, papillary, and anaplastic (Snover et al., 1982; Iezzoni and Nass, 1996; Shimosato and Mukai, 1997; Matsuno et al., 1998). The prognosis of thymic carcinoma largely depends of the pathologic variant (better in cornified squamous cell carcinoma).
CD70, a member of the TNF family, is expressed by many cases with thymic carcinoma and usually is negative in thymoma type B3, and therefore, the method is useful for the differential diagnosis (Rosai, 2004). Tumor cells also express Ki67 and p53, but the prognostic relevance of these markers is not yet clarified.
Differential diagnosis of thymoma and related tumors may represent itself the topic of a review: it includes malignant lymphomas, carcinoid, neuroendocrine carcinoma, germ cell tumors, stromal tumor, and cervical tumors with thymic derivates. Involution of the thymus should be also considered, particularly in the case of small specimens taken by endoscopic procedures. In this condition, aggregates of epithelial cells can be over-interpreted as thymoma (Raica et al., 2007). Actually, an extensive immunophenotyping is frequently needed. It is important to mention here especially cervical tumors with thymic derivate that include cervical ectopic thymoma, hamartomatous thymoma, spindle epithelial tumor with thymus like elements (SETTLE) and carcinoma with thymus like elements (CASTLE).The ectopic cervical thymoma has a clear preference for female, a benign behavior and the same features as the mediastinal counterpart.Ectopic hamartomatous thymoma occurs mainly in males, supraclavicular or suprasternal, and consists of spindle shaped cells with mesenchymal aspect. The tumor lacks atypical aspects, necrosis and mitotic activity. One component of the tumor that may be noticed only focal consists of solid squamous nests, anastomosed cords and cysts lined by epithelium. Small aggregates of adipose cells are found between neoplastic cells. Lymphocytes are scant, but present in all cases. Some authors reported a concentration of myoid cells, but their significance is unknown. Despite such a tumor can rich large diameter, it has not a corresponding tumor in the mediastinum and is benign (Zhao et al., 2000).Spindle epithelial tumor with thymus like elements (SETTLE) is rare, occurs in younger and develops around the thyroid. It is a biphasic tumor, one component is spindle and shows mitotic activity, and the other is cystic glandular. The natural evolution is slow, and metastasis was reported after years or even decades.Carcinoma with thymus like elements (CASTLE) also has the tendency to be present around or even within the thyroid. On the basis of conventional pathologic diagnosis, it cannot be differentiated from thymic carcinoma. Despite local recurrences are frequent, the long-term prognosis is good.
Marius Raica ; Domenico Ribatti
Head and Neck: Thymus: Thymoma: an overview
Atlas Genet Cytogenet Oncol Haematol. 2012-10-01
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