2.5. WHO classification

prognosis compared to those with DLBCL without these mutations. FISH for MYC, BCL2 and BCL6 gene rearrangements should be tested for patients with expression of MYC and either BCL2 or BCL6 by IHC and a GCB like immunophenotype to identify these double- (or triplehit) lymphomas [10]. They have very poor outcomes with standard R-CHOP-based chemotherapy [11]. While the cases identified by FISH positive results are called double- (or triplehit) lymphomas, those patients with high expression of MYC and BCL2 protein by Immunohistochemistry (IHC) alone in the absence of gene rearrangements by FISH are labeled as

In a study on 193 patients who were double expressor the 3 year OS rate was 46 vs. 75% and

Under light microscopy, the normal architecture of lymph nodes is completely effaced by the sheets of atypical lymphoid cells. The tumor cells resemble normal centroblasts or immunoblasts with nuclei size at least twice the size of a small lymphocyte. While the centroblasts are large,

Figure 1. Lymph node sections showing GC type DLBCL (a) The H&E stained sections of lymph node showing diffuse infiltration of atypical lymphoid cells that are large in size with irregular nuclear contours, vesicular chromatin, and some with prominent nucleoli (X10 and X40 magnification). (b) On immunohistochemistry, CD20 highlights the infiltrating cells

(X20 magnification) (c) cells are negative for MUM1 (major subset) (X20 magnification).

double expressor and they seem to have an intermediate prognosis.

the 3 year PFS rate was 46 vs. 65% [11].

42 Hematology - Latest Research and Clinical Advances

2.4. Morphology

The revised WHO classification 2016 [8] classifies DLBCL NOS into GCB and ABC/non-GC subtypes based on cell of origin. The use of IHC algorithm is accepted [8]. We also now have a

Figure 2. Lymph node sections showing ABC type DLBCL (a) The H&E stained sections showing diffuse infiltration of large atypical lymphoid cells with irregular nuclear contours and vesicular chromatin (X40 magnification). On immunohistochemistry cells are (b) CD20 positive (X20 magnification) (c) MUM1 positive (X20 magnification) (d) CD 79A positive (X20 magnification).

example oropharyngeal plasmablastic lymphomas occur most frequently in HIV-patients and are positive for EBV. Another rare variant of plasmablastic lymphoma is characterized by

Recent Advances in Diffuse Large B Cell Lymphoma http://dx.doi.org/10.5772/intechopen.74263 45

Primary large B cell lymphoma of the mediastinum is a distinct clinicopathological entity that arises from the thymic (medullary) B cell. It has clinical and pathologic features that differ from

This is variously known as intravascular lymphomatosis, angiotropic large cell lymphoma, and malignant angioendotheliomatosis. It usually presents with disseminated intravascular proliferation of large lymphoid cells involving small blood vessels without an obvious extravascular tumor mass or leukemia. It commonly affects central nervous system, kidneys, lungs,

It manifests as red or bluish (violaceous) nodules or tumors on one or both legs, usually below the knee; 10–15% develop outside of the lower extremities. Contrary to other cutaneous B cell lymphomas, these tumors frequently disseminate to extracutaneous sites and pursue an

Also known as pyothorax-associated DLBCL, it usually develops in patients with a long standing history of pyothorax; however it may also arise at other sites with chronic inflammation [14]. It is seen worldwide but is more common in Japan and China. Clinically, it is an aggressive tumor. These tumors are almost always EBV-positive and are believed to arise from EBV-infected post germinal center B cells. The pattern of EBV gene expression present in this type of lymphoma (LMPI and EBNA2 positivity) suggests the role of local immunosuppres-

This is also an EBV-positive large B cell lymphoma with a T cell-rich background which is clinically and pathologically distinct from DLBCL [15]. The usual manifestations are cough and fever (60%), rash/nodules (40%), malaise and weight loss (35%), neurological abnormalities and dyspnea (30%), or chest pain (15%) [16]. Extranodal involvement is common. The lungs are commonly affected. Other commonly involved sites include kidney, liver, brain, and skin. Lymph nodes and splenic involvement is rare. Histologically, the infiltrates are either angiocentric or angioinvasive. Often extensive necrosis is present with only a few atypical large B cells in a pleomorphic background of lymphocytes, plasma cells, and histiocytes. The large atypical B cells represent the neoplastic component and show evidence of EBV infection

with in situ hybridization. Pulmonary nodules exhibit central necrosis and cavitation.

aggressive course. MYD88 L265P mutations are seen in ~50% of cases.

2.6.6. Diffuse large B cell lymphoma associated with chronic inflammation

rearrangements of the ALK tyrosine kinase gene [7].

2.6.3. Primary mediastinal large B cell lymphoma

2.6.4. Intravascular large B cell lymphoma

and skin, but virtually any site may be involved.

2.6.5. Diffuse large B cell lymphoma, leg type

sion within the sites of chronic inflammation.

2.6.7. Lymphomatoid granulomatosis

DLBCL.

Figure 3. Lymph node sections showing very aggressive DLBCL on immunohistochemistry. (a) bcl-2 positive (X20 magnification) (b) bcl-6 positive (X20 magnification) (c) ki 67 proliferation index is approximately 70-80% positive (X20 magnification).

better understanding of MYC alterations in DLBCL. These are included in a new category of "High grade B cell lymphoma with MYC and BCL2 and/or BCL6 translocations". Co-expression of MYC and BCL2 is considered a new prognostic marker (double-expressor lymphoma). High grade lymphoma, NOS replaces B cell lymphoma unclassifiable (BCLU) category. It includes blastoid appearing large B cell lymphomas and cases lacking MYC and BCL2 or BCL6 that would formerly have been called BCLU.

## 2.6. Other distinctive clinicopathological subtypes of DLBCL

#### 2.6.1. T cell histiocyte-rich large B cell lymphoma

As the name suggests this variant is characterized by the predominance of infiltrating reactive T cells and macrophages (histiocytes). Presence of <10% cellularity, has been suggested to label this diagnosis. This pathological subtype does not appear to affect the outcome when adjusted for IPI. In a study of 40 patients comprising of predominantly middle-aged males, splenomegaly, bone marrow involvement, and hepatomegaly were present in 60, 43, and 40%, respectively [12]. The International Prognostic Index (IPI) (Table 3) was ≥2 in 77% of the patients. Tumor cells were uniformly positive for CD20 and negative for CD5, CD10, CD15, and CD138. Although these patients were relatively young, the use of combination chemotherapy, led to complete remission in only 40%, with an overall survival of 50% at 3 years. On multivariate analysis, only the IPI and deletions or point mutations in p53 were predictive of survival. In another study, the 5-year overall or event-free survival between this variant and DLBCL was not different among the IPI matched patients [13].

#### 2.6.2. Plasmablastic lymphoma

The tumor cells in plasmablastic lymphoma have large eccentrically placed nuclei, usually with single placed nucleoli and abundant basophilic cytoplasm. However these cells are distinct immunophenotypically. Instead of pan B cell markers which are present in typical DLBCL (CD 20, CD 79a), these tumors comprise of late B cell and express plasma cell markers like CD 138. MYC rearrangement is present in up to 50% of cases and 70% of these patients are Epstein-Barr virus (EBV) positive. Some tumors in this subtype are distinct genetically and clinically. For example oropharyngeal plasmablastic lymphomas occur most frequently in HIV-patients and are positive for EBV. Another rare variant of plasmablastic lymphoma is characterized by rearrangements of the ALK tyrosine kinase gene [7].
