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Natural History and Treatment of Malignant Thymoma

Natural History and Treatment of Malignant Thymoma

ABSTRACT: Thymomas are rare, slow-growing neoplasms that are considered to be malignant because of their potential invasiveness. The most widely used staging system is that of Masaoka and colleagues, which takes into account the extent of clinical and histopathologically determined disease involvement. However, recent data suggest that the staging system of the French Study Group on Thymic Tumors (GETT system), which is based on the surgical and pathologic features of the tumor, may be superior to the Masaoka system. Total resection followed by radiation therapy is the treatment of choice for all thymomas, except stage IA tumors, which can be treated with surgery alone. Chemotherapy can improve the outcome of invasive Masaoka stage III and IV thymomas or recurrent thymomas. Only platinum-containing regimens show consistent efficacy. [ONCOLOGY 12(7)1001-1005, 1998].

Introduction

Thymomas are rare neoplasms that arise from tissue elements of the
thymus and develop in the anterior mediastinum. Although usually
slow-growing tumors, thymomas are considered to be malignant because
of their potential invasiveness: Invasion beyond the capsule is a
major prognostic factor that correlates with a worse outcome.

Surgery is usually the first step in the management of thymomas, and
radiotherapy is used widely for invasive thymomas and by some authors
for noninvasive thymomas. Chemotherapy is no longer controversial and
should be used more in the future.

Normal Thymus Development

The thymus gland is a lymphatic organ involved in lymphoid cell
development and maturation. However, its embryologic origins come
from the endoderm as epithelial outgrowths of the lower portion of
the third pharyngeal pouches. Cells of these epithelial outgrowths
grow into the surrounding mesenchyma and subsequently constitute the
medullary areas of the lobules of the thymus.

In some areas, epithelial cells accumulate and undergo keratinization
and degeneration, leading to distinct structures called Hassall’s
corpuscles, which are localized in the medulla of the lobules.
Lymphocytes derived from hematopoietic stem cells of the bone marrow
are secondarily localized within the spaces between the epithelial
cells of the cortex of the lobules. The lymphoid cells are generally
concentrated in the periphery of the cortex, while medullary areas of
the lobules of the mature thymus contain mostly epithelial cells and
few lymphocytes.[1] These epithelial cells have a major role in the
production of humoral factors necessary for lymphoid differentiation,
which occurs in fetal and early postnatal life.

The thymus gland reaches its maximal size in the adolescent, weighing
30 to 40 g. Lymphoid components gradually disappear after puberty and
the gland involutes, leading to a fatty residue. Hassall’s
corpuscles remain, and the thymus never completely disappears.
Although the gland is usually situated beneath the upper part of the
sternum, thymic tissue can be found in ectopic areas, such as the
retrocarinal adipose tissue.

Pathology

Thymomas emerge from the epithelium of the thymus. The tumors always
arise from the epithelial elements, although lymphocytic cells may be
present, sometimes in a high percentage. Although epithelial
neoplastic cells usually grow slowly and do not show cytologic
characteristics of malignancy, all thymomas are considered to be
malignant neoplasms because of their potential for invasion.

Immunohistochemical studies of thymomas have shown that the thymic
epithelium expresses hormones, HLA antigens, acetylcholine receptor
epitopes, and cytokeratin. Such studies have also investigated the
tumors’ lymphocytic cells and have substantiated the
nonneoplastic nature of these cells.

Classification Systems

Several pathologic classifications of thymomas have been proposed.

Rosai and Levine System--The most widely used classification
system is that of Rosai and Levine,[1] which defines thymomas as
neoplasms of thymic epithelial cells, regardless of the presence of a
lymphoid component. In 1978, Rosai and Levine modified the definition
such that thymic tumors containing cells with the cytologic aspect of
malignancy were separately classified as thymic carcinomas,[2] which
have a very different clinical outcome.[3,4]

Walker et al recently[5] summarized the classification system of
Rosai and Levine. Thymomas are divided into three types depending on
the predominant cell-type. The tumor is called a lymphocytic thymoma
or epithelial thymoma if the predominant cells derive from the
lymphocytes or epithelial cells, respectively. If these two cellular
components are found in equal parts, the tumor is designated a
lymphoepithelial, or mixed, thymoma. In all cases, the number of
mitotic cells is low.[6,7] Some also suggest a spindle-shaped type[8]
and an oval-cell type, which are thought to be variants of the
principal types.

The prognostic significance of pathologic classification is
controversial. Histologic aspects of noninvasive and invasive tumors
can be identical,[9-12] and the division into lymphocytic,
epithelial, or lymphoepithelial types may remain subjective. The
supposed influence of histologic subtypes disappears when linked with
strong prognostic factors, such as stage or extent of surgical
resection.[4,13] Whereas some reports demonstrate that
epithelial[7,14] or lymphoepithelial subtypes have a poor outcome,[3]
others associate lymphocytic or spindle-cell subtype with a favorable outcome.[15-17]

Classification by Malignant Cell Ontogeny--Another system
classifies thymomas according to malignant cell ontogeny. When
neoplastic cells look like those found in the cortex of the normal
thymus, the thymoma is designated a cortical thymoma. Otherwise, the
term "medullary lymphoma" is used to describe a
proliferation of cells thought to represent the neoplastic
equivalents of normal thymic medullary cells. When both cortical and
medullary cells are present in the malignant proliferation, the tumor
is called a mixed corticomedullary thymoma.[18]

Staging

Masaoka Staging System

Staging of thymomas is usually based on invasiveness, as considered
in the classifications of Bergh et al,[19] Wilkins et al,[20] Curran
et al,[21] and Verley and Hollmann.[7] However, the most widely used
system is that devised by Masaoka and colleagues,[22] which takes
into account the anatomic extent of involvement, as defined
clinically and histopathologically (Table
1
).

The invasiveness of the tumor is one of the most important prognostic
factors in thymomas. Tumor invasion beyond the capsule is associated
with an unfavorable outcome.[3,7,13,15,21-27] Noninvasive thymomas
have a very low[26] or zero[21,23-25] relapse rate, and an extensive
review[28] reported an average 80% survival rate for noninvasive
thymomas, as compared with < 50% for invasive tumors.

Pleural or pericardial effusion of the tumor is the most common form
of metastatic involvement. Involvement of regional nodes is rare.
Metastasis to distant organs is very unusual (< 10% at
presentation), and the most common extrathoracic sites of disease
involvement are the liver, kidney, brain, and spleen.

GETT Staging System

Among invasive tumors, disease-free survival is usually worse with
higher stages although the differencesare not always statistically
significant.[3,7,21,22] However, because the extent of surgery is a
prognostic factor of major importance, a staging system based on the
surgical and pathologic features of the tumor was described by the
French Study Group on Thymic Tumors (GETT) (Table
2
).[29,30]

In the GETT staging system, the predominant feature is the extent of
sur-gical resection: completely resected, noninvasive tumors are
stage I and completely resected invasive tumors are stage II tumors,
whereas incompletely resected tumors are stage III tumors. In the
Masaoka staging system, contiguous spread to the pericardium is a
stage III tumor, whereas in the GETT system, in case of total
resection, it becomes a stage II tumor. Conversely, an encapsulated
totally resected GETT stage I tumor is designated a stage II-2 tumor
in the Masaoka system if there is microscopic invasion of the capsule.

In a series of 163 patients,[23] our group studied the correspondence
of the two staging systems and showed that they were concordant in
88% of cases. However the Masaoka system tended to upgrade GETT stage
I and II tumors; 61% and 20% of GETT stage I and II tumors,
respectively, were Masaoka stage II and III thymomas. Analysis of
disease-free survival showed that the Masaoka II-GETT I patients
experienced a better outcome than the Masaoka II-GETT II patients and
should be managed differently. Similarly, the Masaoka III-GETT II
patients had a better prognosis than the Masaoka III-GETT III
patients. The disease-free survival of GETT I thymomas differs
significantly from the disease-free survival of GETT II thymomas, and
the disease-free survival of GETT II differs significantly from the
disease-free survival of GETT III. These findings indicate that the
GETT classification seems to be the best staging system.

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