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Clinically important variants of diffuse large B-cell lymphoma
Transfusion and Apheresis Science, 1, 49, pages 27 - 30
It has become clear that diffuse large B-cell lymphoma is not a uniform antibody. Several recognizable variants have clinically distinct features and, frequently, require specific treatment approaches. Recognition of these variants and utilization of the appropriate treatments will improve the outcome for the patients.
The initial recognition of lymphomas as specific clinical entities is often ascribed to Thomas Hodgkin’s observations in the 1830s  . At the turn of the twentieth century, Reed and Sternberg independently described the cell that bears their name and is characteristic of the entity we currently call Hodgkin lymphoma  and . This allowed separation of lymphomas into Hodgkin lymphoma (i.e. then Hodgkin disease) and the other types of lymphoma referred to as non-Hodgkin lymphoma. In the 1940s Gall and Mallory provided the first histological classification of the non-Hodgkin lymphomas that was widely used for the next two decades  . In the 1950s Rappaport first purposed a division of the non-Hodgkin lymphomas into groups based on cell size, shape, and growth pattern  . The recognition that all lymphomas originated in lymphocytes led to several new classifications that subdivided lymphomas based on T or B cell origin  and . A compromise classification system was proposed in the early 1980s that was known as the Working Formulation  . It did not make any distinction between T and B cell lymphoma. In the 1990s the REAL (Revised European American Lymphoma) classification  was proposed incorporating histological, clinical, immunological, and genetic observations to identify clinical pathological entities. A study applying this system in the clinic showed it to be highly relevant and predictive  . This was adopted as the World Health Organization classification non-Hodgkin lymphomas  . This has been revised in 2008  .
Diffuse large B-cell lymphoma represents the largest subgroup of lymphomas, accounting for approximately 30% of all patients with lymphoma  . It has been clear since this entity was first described that it is not a uniform disease process. For many years the distinction between immunoblastic and centroblastic morphologic subtypes has been debated in the literature. More recently, gene profiling studies have demonstrated that those lymphomas with a germinal center genotype vary clinically from those whose gene expression pattern resembles activated, post germinal center B-cells , , and . In addition, gene expression studies have documented the diffuse large B-cell lymphomas of thymic origin, frequently occurring in young women, represents a specific subtype  and .
It has also become clear that diffuse large B-cell lymphoma presenting at different anatomic sights might have different clinical characteristics. For example, primary central nervous system tumors have different therapeutic implications than those presenting outside the central nervous system. Lymphomas that are diagnosed as diffuse large B-cell lymphoma of the skin vary from highly aggressive subtypes to those requiring only local therapy.
New subtypes identified by genetic and biological characteristics of the tumor (e.g. proliferative rate or activation or deletion of specific genes) are also being diagnosed and sometimes require specific treatments. For example, certain highly proliferative lymphomas such as those with abnormalities involving MYC or MYC + BCL-2, are poorly treated with standard regimens. It is also clear that lymphomas occurring at the interface between mediastinal large B-cell lymphoma and Hodgkin lymphoma, and at the interface between diffuse large B-cell lymphoma and Burkitt lymphoma, pose special clinical problems.
It is increasingly apparent that diffuse large B-cell lymphoma has a number of variants that are sufficiently unique as to require specific treatment approaches ( Table 1 ). The clinical characteristics and management of several of these subtypes will be discussed in the following sections.
|Special treatment approaches|
|Plasmablastic||Usually CD20-negative, so rituximab is not useful|
|DLBCL arising from lymphomatoid granulomatosis||Sometimes relapses as low-grade lymphomatoid granulomatosis and can be treated with interferon or rituximab|
|Specific sites of involvement|
|Testes||Frequent CNS metastasis and recurrence in the opposite testicle necessitate CS prophylaxis and scrotal irradiation|
|CNS||Does not benefit from CHOP-R and requires high-dose intravenous methotrexate-based regimen|
|Skin||Must distinguish between cutaneous DLBCL, leg type, which requires systemic treatment such as CHOP-R, and other tumors (termed cutaneous follicle center cell lymphoma) that need only local treatment|
|Highly proliferative variants|
|Lymphoma with features intermediate between DLBCL and Burkitt lymphoma||Have a high failure rate with CHOP-R and are best treated with Burkitt regimens (e.g., EOPCH-R, CODOX-M/IVAC)|
|Double-hit lymphoma (MYC and BCL-2)|
2. Plasmablastic lymphoma
Plasmablastic lymphoma was originally thought to occur predominantly in patients infected by the human immunodeficiency virus (HIV) and to primarily present as a jaw tumor  . Patients had a very poor prognosis. Because plasmablasts are typically CD20 negative, rituximab has not been useful in the management of the great majority of these patients. A recent report of plasmablastic lymphoma in HIV negative patients noted that the disease can present anywhere in the body  . In that report 89% of the patients presented with extra nodal rather than nodal involvement, but a minority presented with jaw tumors. Unfortunately, chemotherapy regimens such as CHOP yielded a poor outcome with most series showing a median survival of less than one year.
3. Diffuse large B-cell lymphoma presenting in the setting of lymphomatoid granulomatosis
Lymphomatoid granulomatosis usually presents in the lung, central nervous system, kidneys, and skin. The lesions histologically show an angioinvasive pattern and represent an Epstein Barr virus driven lymphoproliferative disease  . While most lesions do not qualify for the diagnosis of malignant lymphoma, at least 10–20% evolve into diffuse large B-cell lymphoma  .
Patients with lymphomatoid granulomatosis without evidence of developing diffuse large B-cell lymphoma can be successfully treated with interferon or rituximab  and . However, patients with overt lymphoma need to be treated with regimens utilized in the management of diffuse large B-cell lymphoma. This would typically include a chemotherapy regimen such as CHOP plus rituximab.
4. Testicular diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma represents the most common testicular neoplasm in men over 60 years of age  . The frequency of diffuse large B-cell lymphoma presenting in the testicle appears to be increasing. Despite the fact that most patients present with local or regional disease (i.e. Ann Arbor stage I or II) treatment outcome has been disappointing and late relapse and metastasis to the brain and meninges have been more frequent than for other types of diffuse large B-cell lymphoma  and . Patients who do not receive radiation to the opposite testis have a high frequency of relapse in the scrotum  .
The International Extranodal Lymphoma Study Group carried out a trial in 53 men with stage I or II primary testicular lymphoma who received CHOP-R with intrathecal methotrexate, and radiation to the opposite testicle. With a five-year median follow-up, progression-free and overall survival rates were 74% and 85%  . No patients relapsed in the opposite testis. However, three (6%), had central nervous system relapse. Two patients progressed more than five years after therapy.
At the present time, a combination of an effective chemotherapy regimen that includes rituximab, central nervous system prophylactic therapy, and radiation to the contralateral testis can be considered the standard treatment for patients with testicular diffuse large B-cell lymphoma that presents in stage I or II. Unfortunately, this approach does not completely eliminate the risk of central nervous system relapse.
5. Primary central nervous system lymphoma
Diffuse large B-cell lymphoma presenting as a brain tumor is a major problem in patients with advanced HIV infection and a very low CD4 count  . Treatment with highly active antiretroviral therapy is reducing the incidence of this disease in patients with HIV infection  . Unfortunately, the incidence of this disease is increasing in recent years in patients who are HIV negative.
Although treatment with steroids or single agent radiotherapy is associated with a poor prognosis and a survival of less than one year, regimens that include high dose methotrexate with or without cytarabine can yield with a long-term, disease-free survival in 30–50% of patients  . In young patients a combination of high dose methotrexate containing regimens and radiotherapy might be the preferable treatment, but in patients over 60 years of age radiation is associated with a high frequency of late neurological toxicity  . Even if the initial treatment is a methotrexate based high dose chemotherapy regimen, progressive disease can still be regularly palliated with radiotherapy, and in this setting late neurological toxicity is less of a concern  .
6. Primary cutaneous diffuse large B-cell lymphoma
The diagnosis of tumors that might be called diffuse large B-cell lymphoma by a pathologist that present in the skin can be a confusing topic. One group of these tumors that are termed cutaneous diffuse large B-cell lymphoma, leg type in the WHO classification typically present on the lower legs of elderly women and is associated with a poor prognosis  . Another group of lymphomas that can have the histologic appearance of diffuse large B-cell lymphoma are termed primary cutaneous follicle center lymphoma in the current iteration of the WHO classification  . These lymphomas rarely metastasize and can be managed with excision or involved field radiotherapy. This widely varying clinical course makes it imperative to try as hard as possible to distinguish between these two entities.
7. Highly proliferative diffuse large B-cell lymphoma
Patients with diffuse large B-cell lymphoma whose tumor has a Ki-67 of greater than 90% are usually those that over express MYC and sometimes have a “double hit” with MYC rearrangement and a BCL 2 rearrangement. There is no question that patients with double hit lymphomas have an extremely poor outlook with traditional therapy for diffuse large B-cell lymphoma  and . Patients with double hit lymphomas are sometimes diagnosed as having a lymphoma at the interface between diffuse large B-cell lymphoma and Burkitt lymphoma  . Unlike those with double hit lymphoma, patients with diffuse large B-cell lymphoma and a high proliferative fraction whose tumors only over express MYC might not have a poor prognosis  and . However, in some studies patients reported as being MYC positive probably also included patients with double hit lymphoma. At least one report suggest that treatment with the EPOCH-R infusional chemotherapy regimen in patients whose lymphomas are MYC positive without a double hit can usually be treated successfully  .
At the present time patients with double hit lymphoma, and perhaps those with an isolated MYC expressing diffuse large B-cell lymphoma, are probably best treated with more intensive chemotherapy regimens such as EPOCH-R. In the case of patients with double hit lymphoma, most clinicians would do an autotransplant in first remission, but it is unclear that this will overcome the poor prognosis associated with this subtype.
It is increasingly clear that our previous histological subdivisions of lymphomas and other malignancies includes many different biological subtypes related to the particular genetic abnormalities and metabolic pathways that are activated or deleted. The treatment for patients with diffuse large B-cell lymphoma will have to be modified in many situations based on the specific variant for patients to get optimal treatment. It is likely that this will become more complex as we learn more about the biology of these diseases.
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University of Nebraska Medical Center, Omaha, NE 68198 USA
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