b cell lymphoma survival rate | Evolution of the lymphomas not hodgkiniens histopathological classifications

Evolution of the lymphomas not hodgkiniens histopathological classifications



Old classifications that distinguished the lymphosarcoma, lympho-reticulosarcomes, fiance or Lymphocytic sarcomas have not withstood the progress in the physiopathogenie of the lymphoid system. The international formulation in clinical use or Working formulation (WF) [1], born in 1982 of a compromise between several classifications, rested solely on morphological criteria. If it proved relatively practical recognizing certain common categories of lymphomas (lymphomas diffuse small lymphocytes type LLC; follicular lymphomas diffuse large cell lymphomas; Burkitt lymphomas), she is now exceeded, ignoring many described entities more recently. Kiel classification, updated in 1988 [2], is the first to integrate the data of Immunology, separating lymphomas B and T, and the data of the physiology of normal lymphoid tissue. Many entities of the Kiel classification are found in the classification published recently, better known under the term REAL classification [3] and in the who classification currently under publication [4]. By integrating all of the morphological, phenotypic, genetic and clinical data acquired in recent decades, they have the advantage of providing the up-to-date list of entities anatomocliniques of lymphomas, common or rare, currently recognized. The absence of consolidation in histological grade of malignancy may surprise, but can be explained by the need to also take into account the clinical prognostic factors and therapeutic progress that partly erased tumor evolution spontaneous. Schematically, the criteria that rely on these classifications are:

architecture (follicular or diffuse) and cytology (cells of small or large, outlines nuclear; cytoplasm);

the phenotype B or T, and often more accurate phenotypic analysis;

cytogenetics and molecular biology, data sometimes necessary for diagnosis.

to these data, should be added the tumour location. Lymphomas of similar morphological appearance, but occurring in different sites, may have clinical and prognostic behavior separate. This might be explained by differences in the expression of oncogenes or membership molecules, cytokines profile likely to induce changes in tumor growth in tumors of morphological appearance identical. This is well known for the lymphoma anaplastic T (CD30 +) skin primitives, deemed better prognosis than no skin equivalents.

Description of the main anatomocliniques according to the who classification

In the following text, we will cover the main features of the anatomocliniques, the most common entities. Some few entities, but which are lymphomagenese models, will be mentioned. Table 1 reproduces the list of entities according to the who classification [4].

Lymphoma B
They represent, in Western countries, about 85% of all lymphomas no hodgkiniens. The most frequent entities are diffuse large B-cell lymphomas, follicular Lymphoma lymphomas of the coat, the edge zone of type MALT lymphomas and diffuse Lymphocytic lymphomas of type chronic lymphoid leukemia (LLC ) [5]. In immunological terms, recent analysis studies of the somatic mutations of the genes of immunoglobulin (Ig) allow to distinguish between these different entities according to their origin centrofolliculaire or pre/postcentre germinative [6]. These studies have shown that most NHL B (follicular lymphomas, but also lymphomas diffuse large cell B of the marginal zone of the MALT type, and lymphoplasmocytaires) show somatic mutations and are derived from cells in the Center germ or B memories (postcentre germ) cells. The only exceptions are lymphomas of the coat and some NHL type LLC, devoid of mutations of Ig genes, appear derived from pregerminatives naïve cells [6].

Follicular lymphomas (figure 1): recent biological data have confirmed the validity of this entity individualized in 1966 in the Rappaport classification on the basis of a characteristic morphology (architecture reproducing one of) normal follicles), and to a particular clinical picture (often spread in contrast with a slow evolution stage). In addition to his follicular architecture, this NHL is defined by a cell composition comparable to that of normal germinal centers (centrocytes centroblasts), where the name of centroblastique-centrocytique according to the classification of Kiel [2] . The clinical value of the individualization of cytologic grades (small cells traditional, mixed, large cells according to the WF, or grades 1, 2 and 3 according to the REAL and the who classification) is very discussed, and deserves to be evaluated on large series prospective multicenter. The field of IMMUNOHISTOCHEMISTRY, tumor cells B express rule CD10 (Calla) Antigen, but not the antigens, CD5 and CD23. They are enclosed in a network of follicular dendritic cells, which can be detected by Immunohistochemistry (R4/23 +, + CD35). Classical cytogenetics showed, in the vast majority of cases, the existence of a translocation t (14; 18). This translocation leads the oncogene bcl - 2, normally located on chromosome 18, near the genes of the heavy chains of immunoglobulins. It is the basis of residual disease, PCR detection, in the follow-up of patients treated by autologous transplant. The deregulation of bcl-2 resulting led to a hyperexpression of protein, with its consequences on cell survival, due to the role of bcl - 2 in apoptosis protection. This phrase, detected by IMMUNOHISTOCHEMISTRY, is a vital interest in the differential diagnosis with some follicular hyperplasias. Despite its usual spread, with especially very common spinal cord localization, the NHL is characterized by a slow evolution, before the transformation into Lymphoma of great malignancy. This cytological transformation comes an enrichment in genetic abnormalities [7], in particular mutations of p53, often associated with nuclear accumulation of the protein detectable by Immunohistochemistry.

Lymphomas of the coat (small traditional cells, WF, centrocytiques, Kiel lymphomas diffuse lymphomas) (figure 2) are a particular entity within the B blooms to small cells: proliferation very monomorphic of architecture broadcasts or Nodular, consisting of small irregular, sometimes arranged cells around reaction germinal centers of phenotype B IgM + / IgD +, CD5 +, CD10, CD23. Recently, the cytogenetic showed the existence of a translocation t(11;14) which brings the oncogene bcl - 1, normally located on chromosome 11, near the heavy chains of immunoglobulin genes. It has been shown that the oncogene bcl - 1, hyperexprimé in this situation, coded for a cyclin (cyclin D1 or Prad-1) plays a role in cell proliferation. The demonstration of the translocation by conventional cytogenetics, hybridization techniques in situ on chromosomes (FISH), or molecular (PCR) and its consequence, the hyperexpression of bcl - 1 by Northern blot techniques, RT - PCR or of Immunohistochemistry is a valuable diagnostic help in difficult cases. Clinically, these lymphomas are often clinical stage scattered with polyadenopathie, splenomegaly, with spinal cord or even blood and frequent amygdala impairment. Gastrointestinal damage can achieve the clinical picture of the polyposis polyposis. Despite a cytology in small cells, various studies show that lymphomas of the coat have a severe prognosis [5] with a poor response to chemotherapy treatments, including those involving anthracyclines. The 5-year survival rate is 25%. The forms of nodular architecture have a longer survival and could match at an early stage. (Blast) transformed cytologic variants have been described; they may occur on immediately or over the course of a Lymphoma of the known coat, and are even more pejorative prognosis. They are associated with the accumulation of additional genetic anomalies, including mutations of p53 [8].

Lymphomas B of the marginal zone of the lymphoid tissue associated with mucous (of type MALT) (figure 3). Described by Isaacson, these NHL consist of cells of small size which the cytological appearance may vary (centrocyte-like, Lymphocytic, lymphoplasmocytaire, monocytoide). They infiltrate the epithelial structures realizing lymphoepitheliales lesions which recognition can help Immunohistochemistry (antibodies against the cytokeratine). Tumor proliferation is often accompanied by reaction follicles, having long interpret these lesions as the pseudo-lymphomes. It is accepted that tumor B cells, in particular phenotype IgM + / IgD, CD5 and CD10, CD23, derive from the edge zone of mucosal lymphoid follicles. These lymphomas develop after acquiring a lymphoid tissue of type Malt that could be secondary to antigenic stimulation. In the stomach, the most frequent locations, Helicobacter pylori plays this role: history of gastritises to Helicobacter are very common in these patients, and experiments in vitro have shown that this bacterium was necessary to the tumor growth [9]. In addition, the eradication of Helicobacter pylori with antibiotics, is often followed by regression, or even of remission [10]. In other locations, the responsible Antigen is not identified, but it should be noted that thyroid and salivary lymphomas occur in a context of autoimmune pathology, thyroiditis and Hashimoto syndrome, respectively of Gougerot Sjögren. Beside Trisomy 3, the most frequent in these lymphomas cytogenetic abnormality is the translocation t (11; 18), that appears characteristic, if not specific of the MALT lymphomas, and would have ended up in about 30-50% of cases, whatever their location gastric, lung, thyroid. This translocation was recently cloned: she brings the API2 gene (inhibitor of apoptosis gene 2) located in q 11, 21 close the TRMS (Malt lymphoma associated translocation) gene in q 18, 21 [11]. The knowledge of chromosome break points will allow the development of sensitive detection of this translocation techniques, that will be useful in the diagnosis and especially the follow-up of patients with Lymphoma of the Malt. In rare cases of NHL gastric type Malt are associated with a translocation t (1; 14) that led to identify a new oncogene, bcl-10, located in 1p22 [12] whose apoptotic functions and/or proliferative are still hurting established. In the Malt lymphomas, mutations in bcl - 10 could be more frequent than the bcl-10/IgH rearrangements that seem very rare. Malt lymphomas are very long limited to the Mucosa (stomach, lung, salivary glands, thyroid). The simultaneous achievement of several mucous is not uncommon and translated special homing of tumour cells in different lymphoid tissue associated with mucous membranes. Their clinical course is very slow. In Helicobacter pylori associated gastric localizations, antibacterial treatment would lead to a clinical and histological remission in nearly two out of three cases, whose duration is not established. The transformation in large cell lymphoma, seems to be a late and rare event.

These 3 histological varieties of NHL belong to all of B lymphomas in small cells, which also includes other varieties that we will quote quickly:

Lymphocytic lymphomas (to small lymphocytes), occurring in the framework or not chronic lymphoid leukemia. They are characterized by a diffuse proliferation of small lymphocytes B phenotype CD5, CD23 +, CD10, and usually IgM + / IgD +. The slow evolution is characterized by the frequency of a transformation in the NHL large cell B, formerly called Richter syndrome.

Lymphomas lymphoplasmocytaires that can make the painting of Waldenstrom's disease are rare. Some of them may be associated with a translocation t(9;14) involving the Pax gene on chromosome 9 [13].

Ganglion lymphomas of the marginal zone, morphological appearance often 'monocytoide' are rare; splenic marginal zone lymphomas are characterized clinically by a splenic presentation without significant ganglionic syndrome, an often moderate hyperlymphocytose of cytological appearance varied (villeuses cells, in) pododermatitis differentiation), a tumor rate prevailing at the level of the marginal zone of the splenic white pulp, a constant spinal cord impairment of sometimes sinus topography, and an indolent evolution despite the possibility of progress cytological. These last 2 varieties share with type MALT lymphomas a phenotype B CD5, CD23, CD10, usually IgM + / IgD. Instead of the NHL of the MALT, there is currently no recognized characteristic translocation. It is worth noting that the impact of some of these lymphomas, including lymphoplasmocytaires or splenic marginal zone, seems to increase in carrying patients of hepatitis C.

Lymphomas diffuse large cell B (DLBCL) (figure 4) 30 to 40% of non-hodgkiniens lymphoma. They are a heterogeneous group in cytological, clinical and biological terms. It's diffuse large B cell proliferations, occurring in a context of low histological grade of malignancy lymphomas or novo. The distinction between the centroblastique subtypes (and its variants), immunoblastique and anaplastic clinical and biological significance is discussed. The diagnosis is generally easy on routine draw, using specific antibody to B (CD20, CD79a) cells. Extranodal presentation forms (by digestive example, amygdala, brain, skin) are frequent. Overall, the prognosis essentially seems to depend on simple clinical factors (age, general condition and stage of extension) and biological (rate of the LDH) which are the parameters of the international prognostic index (IPI) [14]. The establishment of the IPI score will guide the intensity of treatment which is based on a combination chemotherapy using anthracyclines. The cytogenetic map, a translocation t (14; 18) is found in 20% of cases, these introductions correspond to a transformation of outset of unknown pre-existing follicular lymphoma. Abnormalities of the Laz-3/bcl-6 gene, located in q 3, 27, are particularly frequent: it is a rearrangement in approximately 30% of cases and/or mutations in 70% of cases [15]. A rearrangement or amplification of c - myc is more rarely observed. The existence of a hyperexpression of bcl-2 protein, mutations of p53 seems to be pejorative prognostic factors, which are about to be used in clinical practice [16, 17]. It is increasingly accepted that entities could exist, according to the site of origin of the tumor. Thus, the NHL large cell B of the mediastinum are a particular variety, probably derived from thymic B cells: large clear cell proliferation, associated with fibrosis, B without GI, occurring detectable phenotype preferentially in young women. They are associated with specific molecular anomalies as the gain of the long arm of chromosome 9 and expression of the gene bad [18]. According to a recent study, their prognosis would be similar to that of the other NHL B large cell B [19]. Anatomocliniques other varieties exist: we will quote the intravascular DLBCL and especially Lymphoma of PEL (figure 4 c). The latter, recent description, arises in immunocompromised patients (most HIV +, sometimes transplanted organs) or the elderly, in the form of a pleural, pericardial or peritoneal effusion containing tumor cells lymphoid large size, morphology immunoblastique or anaplastic, usually devoid of lymphoid markers (CD20, CD79a) apart from immunoglobulins and CD30 [20]. The clonal rearrangement of genes for Ig sign their origin B. essential characteristic, the HHV-8 virus, known for its oncogeniques properties, whose genome is found consistently in the cells, appears to play an important role in the pathogenesis of This lymphoma. Tumor cells are often infected by the Epstein - Barr (EBV) virus.

In the vast majority of cases, the DLBCL occur in patients without known immune deficiency; they can also be observed in a context of immunosuppression (patients HIV +, immunosuppressive treatments).

Burkitt lymphomas are a rare entity initially described in Africa, combining a characteristic morphology (cells monomorphic at the core of size average CrossMatch vacuole of many mitoses, dotted with cytoplasm of) macrophages to responsible tingibles body of a starry sky appearance), a B phenotype with an IgM surface and CD10 antigen expression, t(8;14) or variant t(2;8) or t (8; 22) translocation interesting the oncogene c - myc, whose expression is deregulated. The clinical picture is also characteristic. In the form African endemic, associated with the virus Epstein - Barr (EBV), the jaw is the preferential attack while in the sporadic forms observed in the West, very inconstamment associated with EBV, abdominal achieving (ileocaecale, mesenteric) is the most common. Outside these 2 forms occurring preferentially in childhood, the NHL of Burkitt is relatively common in HIV-infected subjects. This lymphoma is clinically very aggressive, but his prognosis, especially in children, has been substantially transformed by modern chemotherapy.

Morphological interpretation difficult tumors, especially on samples of inadequate fixation between Lymphoma Burkitt (significant mitotic activity, macrophages in body tingibles) or diffuse large B-cell Lymphoma (cells of) large, Pleomorphic) are often called Lymphoma Burkitt or Burkitt-like type. To date, no clinical or biological arguments to support the reality of this subgroup or its attachment to a particular variety or DLBCL Burkitt lymphomas.

Lymphomas T

These include fiance lymphomas, derived from immature cells thymic and peripheral T lymphomas that reattach rare lymphomas NK (natural killer) [4, 21, 22]. All lymphomas are characterized by a diffuse proliferation of small blast cells in the kernel to powdered, fine chromatin, involved in numerous mitoses, phenotype tdt (terminal deoxynucleotidyl transferase) +, + CD1 /, CD4/CD8 or CD4 + / CD8 +, a Mediastinal presentation in young subjects with frequent top cellar syndrome, and the possibility of an attack spinal cord and blood that can achieve the T lymphoblastic leukemia table. Among the peripheral T or NK lymphomas, we don't quote the entities to essentially Leukemic presentation: T prolymphocytaire leukemia, leukemia T lymphocytes to grains (LGL), Leukemia/Lymphoma T + HTLV1, leukemia cells NK, syndrome of Sézary. Peripheral T lymphomas are defined by a non lymphoblastic morphology and a post-thymique T (CD1, tdt) phenotype. They are rare in the West, not representing only about 10 to 15% of the NHL. They are sometimes difficult diagnosis because accompanied gladly cell polymorphism (polymorphonuclear, histiocytes, plasma cells) linked to the secretion by the tumour cells many cytokines, and a pleomorphism cytological [21]. They grow readily in extraganglionnaires sites, including the skin, and their prognosis, to equivalent cytology, is more pejorative than that of NHL - B [23]. Outside of the mycosis fungoides and the Sézary syndrome, well characterized in both clinical and histopathologic, some entities are currently individualized. He is including Lymphadenopathy angio-immunoblastique (LAI) type T Lymphoma, lymphoma anaplastic T phenotype or no, and some entities extraganglionnaires, rarer.

Lymphomas T angio-immunoblastiques (lymphomas T type LAI) (figure 5). This condition, initially described as a non tumoral affection dysimmunitaire, is now considered a T Lymphoma, cytogenetic and phenotypic, genotypic data showing that it is a clonal of proliferation cell T CD4, with frequent Trisomy 3 or 5. She realizes a polymorphic proliferation constituted of small lymphocytes, eosinophils, histiocytes, plasma cells of a tumor cell population T size small to medium clear cytoplasm and a few B immunoblastes. Clinical associates typically polyadenopathie, splenomegaly, General signs, and frequent spinal cord damage. Biological anomalies, have a hypergammaglobulinemie, and autoimmune hemolytic anemia is frequent. Despite a little disturbing cytological appearance, the NHL type LAI have a worse prognosis with a survival rate at 5 years of the order of 30%, even in patients receiving polychimiotherapiques treatment [23]. The involvement of cytokines in the pathogenesis of this condition (IL6, lymphotoxine, TNF) showed that the EBV virus, whose genome is mainly found in the B immunoblastes, is probably not directly involved.

Peripheral T lymphomas, without giving further details. This term is a set of heterogeneous, but frequent NHL t ganglion from which no separate entity is now formally recognized. Histologically, it is, according to the classification of Kiel, Pleomorphic T lymphomas and 2 rare varieties: the NHL T Lennert lymphoepithelioide and Lymphoma of T areas. There is no for the moment of clinical characteristics and genetic attached to these T lymphomas, without giving further details. It is however often NHL to immediately scattered, with frequency of General signs. Overall, they have a prognosis negative, worse than that of NHL B large cells [23].

Lymphoma large cell anaplastic (of T phenotype or no) (figure 6). In this entity that includes the old malignant histiocytoses, tumor cells are mostly of very large size, sometimes Polygone kernel and infiltrate the sinuses often preferentially. They express the CD30 and CD25 activation antigens and frequently the epithelial membrane antigen (EMA) and often have a cytotoxic phenotype, with expression of the proteins perforine and granzyme. Two clinical entities meet their definition: (i) primitive skin forms, very indolent, or even spontaneously regressive evolution, constitute a continuous spectrum with some papuloses lymphomatoides; (ii) the systemic forms are characterized by a more aggressive clinical picture with polyadenopathie and reached extranodal, including skin often attends a translocation t (2; 5). The translocation t (2; 5) has been cloned. It creates a gene from a merger between the nucleophosmine (NPM) on chromosome 5 and the anaplastic lymphoma kinase (ALK) on chromosome 2 gene. It is now accessible to the techniques of molecular biology by PCR [24], and the Immunohistochemistry of the ALK protein detection is a true reflection, although indirect to a rearrangement of the gene KLA [25, 26]. The hyperexpression of the ALK protein is indeed found in the majority of the anaplastic NHL, including forms with a so-called translocation variant, involving KLA and another gene that NPM. The NHL, which is frequent in children and young adults, have a favorable prognosis compared to other peripheral T lymphomas, with great sensitivity to chemotherapy treatment [26, 27].

Among lymphomas presentation extranodal NK/T, T/NK lymphomas to nasal location (figure 7) more common in Asia as in the West, constitute an entity apart from [28], characterized by: medio-facial damage sometimes realizing the table of centro-facial Granuloma; a Pleomorphic proliferation, of variable cell composition, often achieving figures of angiocentrisme; a very unusual CD5, CD3 + phenotype /, CD56 +, TCR silent, with expression of cytolytiques proteins TIA-1, granzyme B and perforine which, in the absence of rearrangement of the gamma of the receptor T genes strongly towards an NK cell origin [22]; an almost constant association with the Epstein-Barr virus. The expression of latency ppl of this virus, activity oncogenic protein, protein suggests the role of EBV in the development of these lymphomas. Another well defined entity is intestinal T Lymphoma associated with an enteropathy, occurring in a context of sprue disease or novo. There is a proliferation of Pleomorphic sometimes associated with an epitheliotropisme, consisting of lymphocytes T cytotoxic expressing, as series lymphocytes which they are derived, Integrin alphaEbeta7 (HML - 1, CD103). Delta hepatospleniques Tgamma lymphomas: are also a rare, special entity by the presentation clinic hepatosplenique in the young subject, topography sinus tumor cell infiltration in the spleen, the liver, spinal bone, the cellular origin Tgamma delta [29], an isochromosome 7 very common q and a severe prognosis.

CONCLUSION

The recognition of these entities anatomocliniques integrating morphological appearance, immunological profile, molecular abnormalities and clinical behavior, is essential to the treatment. It opens up prospects about the possibility of generating treatments adapted, if not specific of each entity. Helicobacter pylori associated gastric type MALT lymphomas are an example. The highlighting of specific genetic abnormalities that can be detected by sensitive PCR techniques has its application in the diagnosis of residual disease and therefore monitoring of patients. In addition, recognition, within these entities, histopathological markers and biological of prognostic interest, provides additional opportunities for appropriate treatment.