Hematopath

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Homme de 65 ans, présentant une adenopathie cervicale. Bon état général. Asymptomatique par ailleurs. Bilan négatif.

Biopsie chirurgicale.

 

65 yo male, complaining of an enlarged cervical lymph node. Good general condition. No symptoms. Negative workup.

Surgical biopsy.

 
     
     
     
       
     
  p63   CK5/6  
     
  LCA   LCA  
     
  CD20   CD20  
       
  CD20      
 

Diagnostic proposé:

 

 

 

 

 

 

 

 

 

Lymphome malin diffus à grandes cellules B, variante anaplasique

 

Proposed diagnosis:

 

 

 

 

 

 

 

 

 

Diffuse Large B-Cell Lymphoma, Anaplastic variant.

 
  Arguments   Clues  
     
 
 
 
   
   
   
 

Diffuse large B-cell lymphoma

 
 

Diffuse large B-cell lymphoma (DLBCL) is the most complex and heterogeneous of all the non-Hodgkin lymphomas. The term replaces the old histiocytic lymphoma, which in turn replaced the older reticulum cell sarcoma. It is characterized morphologically by large size of the cells, vesicular nuclei with prominent nucleoli, and relatively abundant cytoplasm, and immunophenotypically by expression of B-lineage markers.

As a group, DLBCL occurs both in children and adults, but mostly in the latter. In comparison with most other types of lymphoma, it has a greater tendency for extranodal presentation and for being localized at the time of presentation. The progression is rapid and the prognosis is poor if untreated. Indeed, it constitutes a high percentage of so-called aggressive lymphomas. However, excellent responses have been obtained with multidrug chemotherapy, in particular in combination with rituximab (anti-CD20 therapy). In more than half of the cases, the tumor is limited to one side of the diaphragm (40%, as opposed to 90% for follicular lymphoma). Involvement of the bone marrow or liver is less common than in follicular or small lymphocytic lymphomas. Approximately 40% of the cases present in extranodal sites, such as the digestive system, skin, and skeletal system. When the liver or spleen is involved, it is usually in the form of scattered large tumor masses instead of the multiple smaller nodules or miliary type seen with the group of lymphomas composed of small lymphocytes. The involved nodes are usually markedly enlarged, homogeneous, individualized, and with little or no necrosis.

 
  Microscopically, the pattern of nodal involvement is by definition diffuse. However, it may be complete or partial, and on occasion it may be interfollicular or sinusal. There is commonly extranodal extension, sometimes with accompanying sclerosis. Mitoses are numerous and a starry sky pattern may be present. On cytologic grounds, a sharp separation used to be made between tumors composed of germinal center (large cleaved and noncleaved; centroblastic) cells and immunoblastic cells, but that distinction is not much stressed at present, one of the reasons being the poor intra- and interobserver reproducibility. Accordingly, some pathologists simply use the term DLBCL without qualifiers. Others prefer to keep subclassifying them whenever possible into the types listed below, the first one being by far the most common.  
 

Centroblastic. This is regarded as the diffuse counterpart of follicular lymphoma of large cell type (grade 3) and is thought to be more aggressive. It is composed of an admixture in varying proportions of cleaved and noncleaved large cells. When the latter predominate, the distinction with the immunoblastic variant described below becomes particularly difficult. The subtle differences are the lighter-staining and less pyroninophilic cytoplasm, the more peripheral location of the nucleoli, the absence of plasmacytoid differentiation, the presence of scattered small and large cleaved cells, and the presence of a coexisting component of follicular lymphoma.

Immunoblastic. In this form, the predominant tumor cell has the appearance of an immunoblast: large vesicular nucleus with prominent central nucleolus and thick nuclear membrane, and a deeply staining amphophilic and pyroninophilic cytoplasm with a distinct nuclear hof. Some of the cells are binucleated or multinucleated and simulate Reed–Sternberg cells, and others acquire plasmacytoid features (cartwheel chromatin, larger perinuclear hof). Immunoperoxidase staining often shows intracytoplasmic immunoglobulin. Immunoblastic lymphoma is the most common subtype of diffuse large B-cell lymphoma arising on the basis of natural immunodeficiency, immunosuppression, immunoproliferative states (such as angioimmunoblastic lymphadenopathy), and other immune-mediated diseases, such as Hashimoto thyroiditis, Sjögren disease, and lupus erythematosus.

Anaplastic. This rare variant is characterized by the presence of large bizarre tumor cells, some resembling Reed–Sternberg cells, often growing in a cohesive pattern and/or sinusal pattern mimicking carcinoma. Despite the obvious morphologic similarities, this tumor is biologically unrelated to the anaplastic large cell lymphoma (a T-cell neoplasm).

 

 
 

Morphologic variants. Numerous morphologic variations on the theme of DLBCL have been described, some of a cytologic and others of an architectural/topographic nature. Some of them relate to the lymphoma types described above and others do not. Most of these variations do not have an impact on therapy or prognosis, but they are important because they may result in a mistaken diagnosis. They include the following:

1 Sclerosis. Diffuse large cell lymphomas can undergo marked sclerosing changes, similar to those seen in follicular lymphomas. This material is mainly composed of types I, III, and V collagen and fibronectin. Sclerosis is a particularly common feature in mediastinal (thymic) large B-cell lymphomas.

2 Spindling of tumor cells. This phenomenon, which is probably related to the aforementioned fibrosis, seems to be more common in large cell lymphomas of mediastinum and bone, but it can be seen in any location, including lymph nodes. It is thought to be related to the presence of markers characteristic of a germinal center B-cell origin.

3 Presence of a myxoid stroma that can simulate the appearance of myxoid malignant fibrous histiocytoma or myxoid chondrosarcoma.

4 Rosette formation. This peculiar change, originally described in follicular lymphoma, has also been seen in large cell lymphoma. Ultrastructural studies have shown that the material in the center of the rosettes is made up of complex cell prolongations.

5 Filiform cell prolongations. This phenomenon, which is probably related to that described in the previous paragraph, is appreciable in ultrastructural preparations and is similar to that sometimes seen in carcinomas, mesotheliomas, and other neoplasms. Large cell lymphomas exhibiting this spectacular feature have been designated anemone cell, microvillous, filiform cell, villiform cell, and porcupine lymphomas.

6 Signet ring features. This alteration, which is more common in follicular lymphoma, is rarely seen in large cell lymphoma and may simulate metastatic adenocarcinoma.

7 Sinusal pattern of spread, in which the tumor cells are predominantly or entirely confined to the lymph node sinuses (and therefore should be referred to as sinusal rather than sinusoidal) resulting in an appearance closely simulating that of metastatic carcinoma, malignant melanoma, or anaplastic large cell lymphoma.

8 Interfollicular pattern of growth. This is more common in T-cell tumors but has also been described in B-cell neoplasms.

9 Nuclear multilobation. Although originally thought to be a feature of T-cell tumors, this alteration is now known to be more common in B-cell neoplasms.

 
 

Immunophenotypically, DLBCL is by definition positive for B-lineage markers (most importantly CD20) and variably immunoglobulin (surface or cytoplasmic). The follicle center cell markers CD10 and BCL6 are expressed in 40% and 60% of cases, respectively. A proportion of cases express postgerminal center cell or plasma cell-associated markers such as CD38, VS38, and MUM1. About 50% of cases express BCL2 protein. A minority of DLBCLs express CD30, usually in a heterogeneous pattern. CD5 is expressed in 10% of cases. Ki-67 staining usually shows a high proliferation index, with some cases showing an index approaching 100%. An exceptionally rare occurrence is immunoreactivity for cytokeratin, which may lead the unwary to a misdiagnosis of carcinoma.

DLBCLs show rearrangements of the immunoglobulin genes as expected for a B-lineage neoplasm. The variable region of the immunoglobulin heavy chain gene (IGH) is usually hypermutated, with some cases also showing ongoing somatic mutations, indicating a germinal center or postgerminal center stage of B-cell differentiation. There are at least two different molecular pathways in the genesis of DLBCL: a transformation pathway and a de novo pathway:

1 Approximately 20% of cases of DLBCLs show BCL2 rearrangement due to t(14;18)(q32;q21), a hallmark of follicular lymphoma. Such cases may have transformed from a known or occult follicular lymphoma, or may have even directly evolved to DLBCL without a precursor phase of follicular lymphoma. However, additional genetic alterations are required for the development of DLBCL, such as TP53 mutation.

2 The BCL6 gene encodes a transcription factor essential for formation of secondary lymphoid follicles and T-cell-dependent antibody responses, and its aberrant expression plays an important role in the de novo pathway of DLBCL formation. In about 35% of cases of DLBCLs, translocation of BCL6 (3q27) with a variety of partner genes (with IGH gene located on 14q32 being the commonest) results in constitutive overexpression of BCL6 protein, causing a sustained proliferative setting in which additional mutations can occur. This translocation is not specific for DLBCL, but is also found in a subset of follicular lymphomas. In addition, about 75% of cases of DLBCLs show somatic mutations in the 5′ noncoding regions of the BCL6 gene, a phenomenon also commonly observed in other germinal center and postgerminal center B-cell lymphomas. At least some of the mutations result in deregulation of BCL6 expression. These mutations, occurring independent of BCL6 translocation, are generated by the same somatic hypermutation mechanism that targets the variable regions of immunoglobulin genes.

 
  Gene expression profiling studies can identify two major groups of DLBCLs: (1) germinal center B-cell-like (GCB) DLBCL that expresses genes characteristic of germinal center B cells, and is correlated with presence of t(14;18) translocation andC-REL amplification; and (2) activated B-cell-like (ABC) DLBCL that expresses genes normally induced during in vitro activation of peripheral blood B cells, and is correlated with presence of BCL6 translocation, PRDM1/BLIMP1 inactivation, and constitutive activation of NFκB due to somatic mutations in genes encoding the NFκB pathway components, such as A20/TNFAIP3 and CARD11. The GCB group is associated with a better prognosis than the ABC group, with 5-year overall survival of 60% versus 35% with CHOP or CHOP-like therapy. However, currently it is not a requirement to distinguish between these two groups of DLBCLs, because reproducible techniques applicable in the diagnostic laboratories are not yet available. A promising marker for the GCB group is LMO2, which can be studied by measuring the mRNA level or immunostaining for protein. MYC (8q24) translocation is found in up to 10% of DLBCLs. In contrast to Burkitt lymphoma, the MYC gene is usually fused with a nonimmunoglobulin gene, and the karyotype is complex. MYC translocation is associated with a highly aggressive behavior.  
 

There are several types of DLBCL with distinctive clinicopathologic features, listed below.

Primary mediastinal (thymic) large B-cell lymphoma. (click to view observation)

Intravascular large B-cell lymphoma (angiotropic lymphoma). This systemic malignant disease, originally regarded as a multicentric malignant transformation of endothelial cells and designated as malignant angioendotheliomatosis, is now known to be a type of malignant lymphoma with a remarkable tropism for blood vessels.

T-cell/histiocyte-rich large B-cell lymphoma. In this type, the neoplastic B-cell population is overshadowed by a reactive population of T cells. There may also be a population of histiocytes, this being the reason why, in the WHO classification, this variant is referred to as T cell/histiocyte rich. The tumor cells may represent less than 10% of the entire cell population. The pattern of growth is predominantly diffuse and there may be a fine interstitial fibrosis. The main differential diagnosis is with NLPHL, with which it shares many phenotypic features, and which could be legitimately viewed as a special type of T-cell-rich B-cell lymphoma. As a matter of fact, some authors have questioned the validity of separating the two entities. It would seem, though, that there are enough clinical, morphologic, and molecular genetic differences to keep them apart for the time being. To wit, T-cell/histiocyte-rich large B-cell lymphoma is clinically more aggressive, has a different pattern of follicular dendritic cell staining, and is said to have a different genetic pattern on comparative genomic hybridization.