Primary mediastinal lymphoma with large B cells
Histological Description
The operating room measures 7 x 6 x 6 cm and has a whitish appearance at the cut. At low magnification, the appearance is heterogeneous with some areas of necrosis and tumor areas more or less limited by thick irregular bands of fibrosis (Photo 1). The tumor zones are of varying density, either very massive cellular or less cellular because of the presence of a fibrous stroma compartmentalizing cells in isolation or in small groups (Photo 2). Lymphoid-looking cells are large in size with a nucleus with nucleoli often eccentric, centroblastic-like (Photo 4). The mitoses are numerous, the cytoplasm is abundant, sometimes somewhat clarified.
In immunohistochemistry, the cells remain negative with the anti-cytokeratin antibody that underlines the thymic cells in the vicinity. They react with anti-pan antibodies leukocyte CD45, pan B CD20 and CD79a, and for more than 80% with Ki67-MIB1. They remain negative with anti-Bcl2, anti-bcl6 and anti-CD30 antibodies.
In the vicinity of lymphoid proliferation, there are thymic remnants that frequently exhibit a cystic transformation (Photo 6).
Discussion
Mediastinum's primary lymphomas began to be described in the years 80, and it is in 1986 that "diffuse large-cell lymphoma of mediastinum with multiple sclerosis" is individualized (1). In the same year, another team (2) noted the clear appearance of the cells and proposed the term "Mediastinum's clear cell lymphoma". Also at the same time, Addis and Isaacs (3) Assume that these B-cell lymphomas have a thymic origin. It is the sclerosis of this lymphoma that has been most often retained in the literature. Prior to this period, i.e. before the immunohistochemistry was contributed, and because of the compartmentalization of the tumor by fibrosis, these lymphomas were taken for thymic carcinomas or Hodgkin's diseases, or seminomas (clear appearance of Cells).
Large B-cell mediastinal lymphoma is a lymphoma occurring in the anterior mediastinum, especially from B cells in the thymic medullary zone. It is apparently unrelated to the follicular centers or the mantle area. It is individualized in the last two classifications, REAL (4) and WHO (5), as a variant of diffuse large cell lymphoma B (DLBCL). It accounts for 2.4% of non-Hodgkin lymphomas.
In fact, compared to conventional DLBCL, Mediastinal lymphoma has clinical, evolutionary, histological, immunohistochemical and genetic characteristics.
1 – Clinical Features (1-4, 6)
Mediastinal lymphoma has clinical signs different from those seen in DLBCL:
The subjects are younger, with an average age of 37 years (versus 64 years for DLBCL).
There is a female predominance with an M: F ratio of 1:2 (versus a low male predominance: 1.2:1 for DLBCL).
Subjects often show up with superior cave syndrome or symptoms related to a mediastinal mass (cough, dyspnea).
The tumour is often voluminous, greater than 10 cm, compared to that of DLBCL (52% versus 30%).
66% of patients are at a stage I or II at the time of diagnosis (versus 50% for DLBCL).
Medullary biopsy is rarely invaded (3% versus 17% for DLBCL).
Microglobulin B2 was low in mediastinal lymphomas, whereas LDH was increased as in DLBCL.
2-Evolutionary peculiarities
During evolution, the disease tends to spread in unusual sites (ovaries, kidney, adrenals, intestines).
When mediastinal lymphoma is treated only with conventional chemotherapy, such as CHOP, survival is poor. The prognosis is better if a radiotherapy is associated with it or if the lymphoma is treated with more intense poly-chemotherapy. The figures are then comparable to those of DLBCL (80% complete remission, and 50 to 60% of disease-free survival at 5 years) (4, 6).
3 – Histological features
Like DLBCL, mediastinal lymphoma may have a broad morphological spectrum: medium to large cells, round or multilobed nuclei, amphophile or clear cytoplasm, presence of more irregular, voluminous cells, pleomorphic, Bizarre, "Sternbergoïdes. However, mediastinal lymphoma has some particular histological signs which, although not pathognomonic, are very suggestive of this lymphoma:
Clear appearance of cells (Photo 3) found in 40% of cases, whereas it is rare in DLBCL (2, 6);
Frequent presence of multiple sclerosis in the form of thick strips of hyaline fibrosis, or in the form of a fine collagen weft, surrounding the cells, "compartimentalisant" (Photos 2, 3, 4);
Persistence of thymic epithelial tissue that can be hyperplasic or present a cystic transformation (Photo 6) with the formation of multiple cysts disseminated in the lymphoma.
4 – Peculiarities Immunohistochemical
Mediastinal lymphoma cells exhibited the same immuno-phenotype as those of DLBCL. These are B cells expressing CD19, CD20, CD22, CD79a (Photo 5). However, some peculiarities exist:
Cells often do not express surface immunoglobulin, while expressing the CD79a molecule that is associated with immunoglobulin;
Bcl6 is usually negative, whereas it is positive in more than 50% of DLBCL (7).
Recent work (8) reported that 69% of mediastinal Lymphomas expressed CD30 in the form of membrane tagging.
14% (8) to 35% (6) of mediastinal lymphomas do not express the pan leukocyte-CD45 antigen.
5-Genetic peculiarities
As in the DLBCL, the genes of the heavy and light chains of immunoglobulins are rearranged. No specific chromosomal translocation was found in mediastinal lymphoma. However, some genetic anomalies distinguish it from the DLBCL:
Rearrangement of Bcl6 is rarely found (4-6%, versus 35% in DLBCL); The mutation of BCL6 is rare (10%, versus 50% in DLBCL) (7);
There is no rearrangement of Bcl2, contrasting with 20 to 30% in DLBCL.
Recently (9), an over-expression of the evil gene was identified in 7 out of 9 mediastinal lymphomas, whereas it was absent in the 8 DLBCL tested comparatively. The expression of the wrong gene was reported in T lymphocytes during their differentiation and in T lymphoid leukemias but never in lymphoid proliferations B. Although mutations or translocations or mechanisms of over-expression of the gene MAL are unknown, this over-expression could serve as a marker for mediastinal lymphoma.
6 – Mediastinal Lymphoma Diagnosis problems
1)-Large B-cell lymphomas of the anterior mediastinum Group Two entities:
1. Real thymic B large cell lymphomas;
2. The DLBCL occurred in the mediastinal ganglia.
Only the first group corresponds to mediastinal lymphoma with its peculiarities (young women, absence of expression of surface immunoglobulin), the second group being a classical DLBCL occurring more often in the older man and with presence of a surface immunoglobulin.
However, on biopsies of anterior mediastinal lymphoma, it is generally impossible to distinguish between these two groups. Perhaps the search for over-expression of the evil gene will make a difference.
2)-mediastinal lymphomas are often confused with thymic carcinoma. In favor of lymphoma, we will look for:
An infiltration of the fibrous SEPTA
An invasion of the vascular walls
multilobed nuclei.
If there is a doubt, the immunohistochemistry, with markers epithelial and leucocyte, will solve the problem.
3)-If the biopsy is concerned with dense areas of clear cells associated with lymphoid infiltration, the diagnosis of seminoma may be evoked. In favor of lymphomas, the nuclear membrane is more irregular and the cytoplasm is not negative. In case of doubt, immunohistochemistry with PLAP for Seminoma and lymphoid markers for lymphoma will easily solve the problem.
4)-The most difficult differential diagnosis is that of lichen-nodular Hodgkin's disease in its Syncitiales cell variant, especially on small biopsies. The presence of many eosinophilic polynuclears will be in favor of Hodgkin's disease. The immunohistochemistry will make the difference: large B cells of mediastinal lymphoma are strongly positive with B markers, while large cells of Hodgkin's disease are either CD20 negative, or show a positivity Heterogeneous CD20 (some are positive, others weakly or negatively). The cells of Hodgkin's disease are more positive with CD15-LeuM1, CD30-BerH2 (but mediastinal lymphoma cells can also be), and often with EBV-LMP.
The intake of immunohistochemistry is generally essential to interpret biopsy of a mediastinal tumor especially if these biopsies are of poor quality: small, crushed, with cells with hyperchromatic stretched nuclei in a Fibrous stroma. Before responding to the surgeon "Uninterpretable biopsies, it is necessary to do a immunohistochemical examination with, to begin with, 3 AC: a PanB (CD20), the Ki67-Mib1 and an AC Anti-cytokeratin (KL1). The pathologist will be surprised, when it is a large B cell lymphoma of mediastinum, to find that the tumor cells react strongly with the CD20 and for more than 80% with the MIB1, thus avoiding a new mediastinoscopy.
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