Chapter 61: Diffuse Large B-Cell Lymphoma

• Diffuse large B-cell lymphomas (DLBCLs) are a heterogeneous group of aggressive lymphomas of large, transformed B cells.

• DLBCLs can arise de novo or may transform from a low-grade lymphoma, such as small lymphocytic lymphoma or follicular lymphoma.

• Table 61–1 lists the variants and subtypes of DLBCL.

• Most common B-cell lymphoid neoplasm in the United States and Europe and accounts for approximately 28 percent of all mature B-cell lymphomas.

• The most common presentation is in late middle-aged and older persons.

• Median age at diagnosis is approximately 65 years.

• Molecularly heterogeneous disease with multiple complex chromosomal translocations and genetic abnormalities as identified by cytogenetics and gene expression profiling.

• Disease is derived from B cells that have undergone somatic mutation in the immunoglobulin (Ig) genes.

• BCL6 gene rearrangements may be specific for DLBCL.

  — Approximately 40 percent of cases in immunocompetent persons and approximately 20 percent of HIV-related cases display BCL6 rearrangements.

  — BCL6 protein mediates the specific binding of several transcription factors to DNA.

• Approximately 30 percent of patients have the t(14;18) translocation involving BCL2 and the Ig-heavy-chain gene.

  — The presence of p53 mutation in combination with BCL2 denotes that the tumor is derived from a transformation of a prior follicular lymphoma.

• Aberrant somatic mutation occurs in more than 50 percent of cases and targets multiple loci (e.g., IGH, PIM1, MYC, RhoH/TTF (ARHH), PAX5, c-MYC).

• Three molecular subtypes have been identified determined by gene expression profiling:

  — Germinal center B-like (GCB): arise from normal germinal center B cells.

  — Activated B-cell-like (ABC): may arise from postgerminal center B cells that are arrested during plasmacytic differentiation.

  — Primary mediastinal B-cell lymphoma: might arise from thymic B cells.

• Lymph nodes are enlarged, nontender, firm but rubbery and are typically found in the neck or abdominal mass.

• Systemic "B" symptoms of fatigue, fever, night sweats, and weight loss occur in 30 percent of patients at presentation.

• Approximately 50 to 60 percent of patients have disseminated DLBCL (stage III or IV) upon presentation.

• Other sites that may be affected include testis, bone, thyroid, salivary glands, skin, liver, breast, nasal cavity, paranasal sinuses, pleural cavity, and central nervous system (CNS).

• Marrow involvement occurs in 15 percent of patients.

• CNS involvement may occur after testicular or paranasal sinuses involvement.

• Some patients might have discordant disease in which the lymph nodes are involved with DLBCL but the marrow histopathology may be that of a low-grade lymphoma.

• Patients with lymphoma in the Waldeyer ring have an increased risk of gastrointestinal lymphoma.

Blood and Marrow

• Lymphoma involvement of the marrow occurs in approximately 15 percent of cases.

Cell Immunophenotype

• The malignant cells have surface monoclonal Ig of either κ or λ light-chain type.

  — The most commonly expressed surface Ig is IgM.

• Lymphoma cells generally express the pan-B cell antigens: CD19, CD20, CD22, PAX5, and CD79a.

  — The cells also express CD45 and less commonly CD10 or CD5.

• CD5+ DLBCL may be more aggressive with worse prognosis.

Histopathology

• Lymph nodes are usually effaced by a diffuse infiltrate of large lymphocytes.

• Other rare morphologic variants occur, for example, with a myxoid or fibrillary appearance.

• In 1993, a model was proposed to assign a prognosis to patients with aggressive lymphoma undergoing treatment with doxorubicin-containing chemotherapeutic regimens termed the international prognostic index (IPI) (see Table 61–2).

  — The 5-year survival rates for patients age 60 years or younger with IPI scores of 0, 1, 2, and 3 were 83, 69, 46, and 32 percent, respectively (see Table 61–3).

• Gene-expression profiling has also been used to delineate groups of patients with DLBCL who may differ in their response to therapy and prognosis.

• The relative expression of six genes can identify three prognostic groups:

  — High-level expression of LMO2, BCL6, and FNI correlated with prolonged survival.

  — High-level expression of BCL2, CCND2, and SCYA3 correlated with short survival.

• Patients with an elevated β₂-microglobulin level and high serum lactic acid dehydrogenase (LDH) have a poor prognosis.

• Approximately 70 percent of DLBCL cases are of germinal center origin, as demonstrated by BCL6 protein and have a more favorable prognosis.

• Survivin, a member of the inhibitor of apoptosis family of proteins, is expressed in 60 percent of patients with DLBCL and is associated with a poor prognosis.

• High number of infiltrating CD4+ T cells in lymph nodes involved with DLBCL is associated with a better prognosis.

• High-level expression of cyclin D3, serum vascular endothelial growth factor, plasma cytokines such as interleukin (IL)-2, IL-10, and IL-6, or p53 gene mutation are associated with a poor prognosis.

• Fluorine-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) is used for staging and monitoring patients.

• DLBCL is potentially curable with combination chemotherapy.

• The dose intensity administered during the first 12 weeks of therapy determines survival.

Early Stage DLBCL (Stages I and II)

• Localized disease occurs in approximately 25 percent of patients.

• Combining chemotherapy with radiation therapy improved outcome (see Table 61–4).

  — Patients in a study received eight cycles of cyclophosphamide, hydroxydaunorubicin, Oncovin (vincristine), and prednisone (CHOP) chemotherapy or three cycles of CHOP plus involved-field radiotherapy and had a 5-year overall response rate of 82 percent and a progression-free survival rate of 72 percent compared with patients who received chemotherapy alone.

  — Patients with poor risk factors had a worse overall survival.

  — The treatment advantage of CHOP plus involved-field radiation for the first 7 years diminished as a result of lymphoma recurrence between 5 and 10 years.

• Systemic chemotherapy has improved the outcome of patients with localized aggressive lymphoma.

• Rituximab has changed the therapeutic paradigm in advanced DLBCL and is incorporated in most treatment regimens.

Advances Stages of DLBCL (Bulky Stages I and II or III and IV)

• Table 61–5 lists different chemotherapy regimens for intermediate- and high-grade lymphoma.

• The results of the Monoclonal Antibody Therapeutic International Trial (MInT) suggest that six cycles of rituximab with a CHOP-like regimen is the best therapy for young patients with good-prognosis DLBCL.

  — R-CHOP now is the standard of care for younger patients with DLBCL.

  — Adding etoposide to R-CHOP or intensifying the doses of drugs in CHOP therapy is under study.

Chemotherapy in Patients Older than Age 60 Years

• Patients older than age 60 years with a low or low-intermediate IPI have a lower relapse-free and overall survival rate than younger patients.

• The best therapy based on recent studies for patients over the age of 60 years is six cycles of R-CHOP.

Role of High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation (Auto-HSCT) in Initial Therapy

• High-dose chemotherapy and auto-HSCT is not recommended for most patients with diagnosed DLBCL.

• A subgroup of patients with poor prognostic features may benefit from such aggressive therapy and should be considered for auto-HSCT in the context of a clinical trial.

• Abbreviated courses of chemotherapy prior to transplantation are not beneficial, and patients should receive a full course of standard chemotherapy and achieve a maximum response prior to transplantation.

Recurrent and Refractory DLCBL

Chemotherapy

• A substantial proportion of patients are either refractory or will relapse after chemotherapy.

• Relapse usually occurs within the first 2 to 3 years after diagnosis but is uncommon after 4 years of diagnosis.

• Cure of relapsed or refractory patients may first require response to a differently configured regimen followed by auto-HSCT.

• Responses to monotherapy are generally not long-lasting.

• The addition of rituximab to the ifosfamide-carboplatin-etoposide (ICE) chemotherapy regimen (R-ICE) increased the complete response rate of patients with relapsed or primary refractory DLBCL under consideration for auto-HSCT.

Autologous Stem Cell Transplantation (Auto-HSCT)

• Patients with relapsed or primary refractory DLBCL who achieve complete response before auto-HSCT generally have better outcomes than those who achieve only partial response.

• Disease sensitivity at the time of auto-HSCT has remained the most significant prognostic variable for predicting treatment outcome.

• Patients who undergo auto-HSCT when the disease is resistant to the initial induction therapy have less than a 20 percent probability of disease-free survival.

Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT)

• The overall relapse and progression rate for the allo-HSCT patients at 5 years was 23 percent compared with 38 percent in the auto-HSCT patients.

• Allo-HSCT cannot be recommended before auto-HSCT except in the context of a clinical trial.

• Radioimmunotherapy as monotherapy: not recommended for DLBCL.

• Patients with relapsed disease should receive multidrug chemotherapy.

• Auto-HSCT should be performed if chemosensitivity is demonstrated and no contraindications are present.

• If patients are elderly or have comorbid conditions, the goal should be palliation.

• Radiotherapy can be used to alleviate symptoms at a particular site of involvement.

Therapy for Specific Subtypes and Clinical Presentations

Primary Testicular Lymphoma

• Represents 1 to 2 percent of all lymphomas, with an estimated incidence of 0.26 per 100,000 males per year.

• Represents the most common testicular tumor in men older than 50 years of age.

• Eighty to 90 percent of primary testicular lymphomas are DLBCL, with a mean age at diagnosis of 68 years.

• Most patients present with stage I-II with isolated involvement of the right or left testis equal in frequency.

• Six percent of testicular lymphoma cases have bilateral involvement.

• Primary testicular lymphoma tends to disseminate to several extranodal sites, including the contralateral testis, CNS, skin, Waldeyer ring, lung, pleura, and soft tissues.

• Treatment using radiation therapy alone provides suboptimal disease control, even for patients with stage I disease.

• Chemotherapy with anthracycline-containing regimens (e.g., R-CHOP) is recommended after orchiectomy.

Lymphoma during Pregnancy

• Fourth most frequent malignancy diagnosed during pregnancy, occurring in approximately 1 in 6000 deliveries.

• The risks to the fetus of treatment are greatest during the first trimester.

• Patients with supradiaphragmatic stage I disease may be considered for localized radiotherapy as a temporary measure until the second trimester, when chemotherapy holds less risk for the fetus.

• Patients close to delivery should be treated with full-dose chemotherapy as soon after pregnancy as possible.

• Arises in the mediastinal lymphatic structures, probably from a thymic B-cell precursor.

• Variant type of DLBCL accounts for approximately 3 percent of lymphomas, and is most commonly seen in young and middle-aged adults, with about two-thirds of cases in females.

Clinical Features

• The clinical presentation is typically an anterior mediastinal mass that is locally invasive of neighboring tissues that may lead to airway obstruction and superior vena cava syndrome in approximately 40 percent of patients.

• Distant nodal involvement at presentation is more suggestive of typical DLBCL with mediastinal involvement.

• Relapses tend to be extranodal, including the liver, gastrointestinal tract, kidneys, ovaries, and CNS.

• Marrow involvement is very unusual.

Histopathologic Findings

• Primary mediastinal B-cell lymphoma and Hodgkin lymphoma share gene-expression profiles, raising questions about biologic relationships.

• Rarely, multinucleated cells may sometimes mimic Reed-Sternberg cells along with other morphologic similarities to Hodgkin lymphoma.

• Fibrotic bands may intersperse with the tumor cells, sometimes referred to as primary B-cell mediastinal lymphoma with sclerosis.

• Primary mediastinal lymphoma lacks the CD30 and CD15 antigens characteristic of Hodgkin lymphoma, and it expresses the B-cell–associated antigens CD19, CD20, CD22, and CD79a.

Treatment

• Incorporation of rituximab in dose-adjusted EPOCH resulted in 100 percent overall survival and 91 percent event-free survival, compared with 78 percent overall survival and 67 percent event-free survival observed with dose-adjusted EPOCH without rituximab.

  — Although outcomes appear to be superior for more intensive therapies over CHOP-type regimens in retrospective studies, they have not been compared in prospective randomized trials with R-CHOP.

• Rare lymphoproliferative disorder characterized by angiocentric and angiodestructive Epstein-Barr virus (EBV)-positive B-cell proliferation associated with extensive reactive T-cell infiltration.

  — Approximately two-thirds of cases occur in males.

  — The median age of presentation is in the fifth decade of life, although pediatric cases occur.

Clinical Findings

• Most common sites of involvement are the lungs (90%). Other common sites of involvement include the skin (25–50%), kidney (30–40%), liver (29%), and the CNS (26%).

• The spleen and lymph nodes are often less involved.

• The distribution of disease leads to cough, dyspnea, and sometimes chest pain.

• Fever, weight loss, and joint pain are very frequent.

• Abdominal pain and diarrhea as a result of gastrointestinal involvement and various neurologic signs, including diplopia, ataxia, mental status changes, and others may be evident.

• Skin involvement can be morphologically diverse (e.g., ulcerations, plaques, maculopapules) but are usually accompanied by subcutaneous nodules.

• The pulmonary lesions are usually bilateral, nodules in the lower half of the lung. They may cavitate. Nodules may also be found in the brain and kidney and sometimes other locales.

Histopathologic Findings

• The grading of lymphomatoid granulomatosis relates to the proportion of EBV-positive B cells relative to the reactive lymphocytes in the background.

• Grade 1 lesions contain a polymorphous lymphoid infiltrate without cytologic atypia.

• Grade 2 lesions contain occasional large lymphoid cells or immunoblasts in a polymorphous background.

Treatment and Prognosis

• The clinical prognosis is variable in lymphomatoid granulomatosis with a median survival of 2 years.

• Poor prognostic findings include neurologic involvement and higher pathologic grade.

• Treatment consists of combination chemotherapy containing a glucocorticoid.

• A rare type of extranodal large B-cell lymphoma characterized by selective growth of lymphoma cells within the lumina of vessels, sparing the large arteries and veins.

• This tumor usually occurs in adults in the sixth and seventh decade.

• It occurs equally in men and women.

• The clinical manifestations of this lymphoma are extremely variable.

• Symptoms are related to the organs affected.

• Two types of clinical patterns have been recognized:

  — European countries: patients develop brain and skin involvement.

  — Asian countries: patients present with multiorgan failure, hepatosplenomegaly, pancytopenia, and hemophagocytic syndrome.

  — B symptoms (fever, drenching sweats, and weight loss) are common in both types.

• Skin lesions range from single to striking clusters of nodules and tumors.

  — They may be painful and appear as violaceous plaques, erythematous nodules, or tumors that may ulcerate.

  — These lesions commonly appear on the arms and legs, abdomen and breasts but may occur anywhere.

• Increased LDH levels and β₂-microglobulin levels are observed in the serum of most patients.

• Elevated erythrocyte sedimentation rate and abnormalities in hepatic, renal, and thyroid function are common.

• Tumor cells express B-cell–associated antigens and occasionally express CD5.

• Anthracycline-based chemotherapy has been used for treatment. The addition of rituximab to chemotherapy regimens has improved clinical outcomes.

  — Progression-free survival (PFS) and overall survival (OS) rates at 2 years after diagnosis were 56 and 66 percent, respectively, in the rituximab-chemotherapy group, compared with 27 and 46 percent for patients in the chemotherapy group (p = 0.001 for PFS and p = 0.01 for OS).

• For patients with CNS involvement, more intensive chemotherapy with drugs such as methotrexate and cytarabine that reach the CNS is required.

• PTLD results from lymphoid or plasmacytic proliferations that develop in the setting of immunosuppressive therapy for solid organ or marrow transplantation.

• Occurs in approximately 1 to 2 percent of solid-organ transplant recipients.

  — There is a clear association between PTLD and the type of organ transplanted.

• Cardiac-lung and intestinal transplantation have the highest incidence of PTLD.

• The highest incidence occurs in the first years of transplantation.

• The incidence of PTLD after HSCT ranges from 0.5 to 1 percent.

• The onset of posttransplant lymphoma in most patients is related to B-cell proliferation induced by infection with EBV in the setting of chronic immunosuppression.

• Involvement of the grafted organ occurs in approximately 30 percent of patients and may lead to organ damage and fatal complications.

• Management of PTLD is not uniform.

• Reduction of immunosuppression is the first step in the treatment of these patients.

• Many cases of polyclonal PTLD may resolve completely with a reduction in immunosuppressive therapy.

• Patients with late PTLD and more aggressive monoclonal PTLD are less likely to respond.

• Rituximab has shown promising results when incorporated into treatment regimens.

• The only baseline factor predicting response was a normal level of serum LDH at day 80 of treatment.

• The following sequence is generally recommended:

  — If possible, the first step is reduction in immunosuppression, followed by four weekly cycles of rituximab if reduction of the immunosuppression is ineffective.

  — If both steps are ineffective, then six cycles of R-CHOP are recommended.

• Characterized by effacement of the architecture of the lymph node by a lymphohistiocytic infiltrate with a diffuse or vaguely nodular growth pattern.

• Accounts for less than 5 percent of all cases of DLBCL and occurs at a younger age on average.

• The median age of onset is in the fourth decade.

• A male predominance is noted.

• This subtype more often presents with advanced stage disease, and often in multiple extranodal sites, and with an elevated serum LDH.

• The lymphoma infiltrates the spleen, liver, and marrow with greater frequency than does DLBCL.

• Marrow involvement occurs in approximately one-third of the cases, a frequency considerably higher than in DLBCL and patients are more likely to develop "B" symptoms than patients with DLBCL.

• When treated with CHOP-like regimens, most series suggest that the outcome for these patients is similar to patients with typical DLBCL.

• Six cycles of R-CHOP for advanced disease would be a reasonable initial approach to therapy.

• Composed solely of large transformed B cells with a predilection for the skin of the leg.

• Primary cutaneous DLBCL, leg type constitutes approximately 4 percent of all primary cutaneous B-cell lymphomas.

• The median age at the time of presentation is 60 to 70 years.

• Lymphomatous tumors affect the skin of the legs in most cases, but approximately 10 percent arise at other sites.

• The B cells are usually positive for CD20 and usually express BCL2 and FOX-P1.

• Lymphoma cells often find translocations involving MYC, BCL6, or IGH genes.

• The gene-expression profile of these lymphoma cells is often the same as activated B-cell like DLBCL.

• Anthracycline-containing chemotherapy with rituximab should be considered as initial therapy. The incorporation of rituximab improves the response rates and overall survival.

• An uncommon neoplasm of large immunoblast-like B cells that stain for nuclear and or cytoplasmic anaplastic lymphoma kinase (ALK) protein.

• The lymphoma cells may undergo plasmablastic differentiation.

• The average age of presentation is in the fourth decade with a male predilection.

• Most patients present with advanced stage disease.

• The most common affected nodal areas are in the neck and mediastinum.

• Common extranodal involvement include the liver, spleen, bone, and gastrointestinal tract.

• The lymphoma cells are large immunoblasts with a large central nucleolus.

• The lymphoma cells stain for the ALK protein, usually with a granular cytoplasmic appearance but nuclear staining may also occur. These cells are usually CD3, CD20, CD30, CD79a negative.

• Occasional cases may have a t(2;17)(p23;q23) that results in a clathrin-ALK fusion protein.

• The clinical course of ALK-positive large B-cell lymphoma is aggressive with a median survival time of 24 months.

• Tumors are usually all negative for CD20, making the utility of rituximab uncertain.