Chapter 60: Diffuse Large B-Cell Lymphoma and Related Diseases

• 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 60–1 lists the variants and subtypes of DLBCL.

• This is the most common B-cell lymphoid neoplasm in the United States and Europe and accounts for approximately 28% 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.

• This molecularly heterogeneous disease with multiple complex chromosomal translocations and genetic abnormalities is 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% of cases in immunocompetent persons and approximately 20% of human immunodeficiency virus (HIV)-related cases display BCL6 rearrangements.

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

• Approximately 30% 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% of cases and targets multiple loci (eg, 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 (Table 60–2).

  — Activated B-cell–like (ABC) may arise from postgerminal center B cells that are arrested during plasmacytic differentiation (see Table 60–2).

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

• Lymph nodes are enlarged, nontender, and firm but rubbery, and they are typically found in the neck or as a mass in the abdomen.

• Systemic “B” symptoms of fever, night sweats, and weight loss occur in 30% of patients at presentation.

• Approximately 60% of patients have disseminated DLBCL (stage III or IV) on presentation.

• Other extranodal 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% of patients.

• CNS involvement may occur in concert with 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 cells in blood are found in approximately 5% of cases.

• Lymphoma involvement of the marrow is found in approximately 15% 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

• Three cytologic patterns of lymphocytes are recognized: centroblastic, immunoblastic, and anaplastic.

• 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) (Table 60–3).

• 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%, respectively (Table 60–4).

• Gene expression profiling has also been used to delineate groups of patients with DLBCL who may differ in their response to therapy and prognosis (Figure 60–1).

• 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% 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% 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; and 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 patient’s response to therapy.

• A negative PET scan at the end of therapy is the best definition for a complete remission and best predictor of survival free from relapse.

• DLBCL is potentially curable with combination chemotherapy.

• The best outcomes are seen when full doses are administered on schedule.

Early Stage DLBCL (Stages I and II)

• Localized disease occurs in approximately 25% of patients.

• Combining an abbreviated course of immunochemotherapy with radiation therapy or giving a complete course of immunochemotherapy and only using radiotherapy in patients with a residual abnormal PET scan is each a reasonable approach.

• Table 60–5 contains treatment approaches for limited-stage aggressive DLBCL.

• Radiotherapy might particularly benefit patients older than age 60 and those with large masses (ie, > 7.5 cm).

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

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

• Table 60–6 lists different chemotherapy regimens for intermediate- and high-grade lymphoma.

• Rituximab-cyclophosphamide, hydroxydaunorubicin (doxorubicin), vincristine (Oncovin) and prednisone (R-CHOP) now is the standard of care for younger patients with DLBCL.

  — Comparing R-CHOP and R-EPOCH (addition of etoposide to R-CHOP) could modify current treatment recommendations.

  — It may be that certain genetic subgroups will benefit from specific regimens.

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 in Initial Therapy

• High-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT) is not recommended for most patients with DLBCL.

• A subgroup of patients with poor prognostic features such as having two or three factors in the age adjusted IPI may benefit from such aggressive therapy and should be considered for auto-HSCT.

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 can occur later.

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

Autologous Stem Cell Transplantation (Auto-HSCT)

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

• Disease sensitivity at the time of auto-HSCT is 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% probability of post-transplant 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% compared with 38% in the auto-HSCT patients.

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

Principles of Therapy for Relapsed or Refractory Patients

• Radioimmunotherapy as monotherapy is 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.

Treatment of Specific Subtypes and Clinical Presentations

Primary Testicular Lymphoma

• This type of lymphoma represents 1% to 2% of all lymphomas, with an estimated incidence of 0.26 per 100,000 males per year.

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

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

• Most patients present with stage I–II disease 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 (eg, R-CHOP) is recommended after orchiectomy.

• Patients should have radiotherapy to the remaining testicle and CNS prophylaxis should be strongly considered.

Lymphoma during Pregnancy

• This lymphoma is the 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 in the second and third trimesters should be treated with immunochemotherapy.

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

• Variant type of DLBCL accounts for approximately 3% 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% 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 with no radiotherapy resulted in a 91% event-free survival.

  — R-CHOP, often followed by radiotherapy, is also an effective regimen.

• This rare lymphoproliferative disorder is 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

• The most common site of involvement is the lungs (90%). Other common sites of involvement include the skin (~40%), kidney (~35%), liver (~30%), and the CNS (~25%).

• 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 (eg, ulcerations, plaques, maculopapules) but is 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 grade of lymphomatoid granulomatosis is determined by 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.

• Grade 3 lesions contain frequent large atypical cells.

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 interferon in grade 1 and 2 lesions and immunochemotherapy as is used in diffuse large B-cell lymphoma for grade 3 lesions.

• This rare type of extranodal large B-cell lymphoma is characterized by selective growth of lymphoma cells within the lumen 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:

  — In European countries, patients develop brain and skin involvement.

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

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

• A cutaneous variant is seen in females in Western countries.

  — The lesions 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.

• Rituximab/anthracycline-based chemotherapy has been used for treatment.

  — Progression-free survival and overall survival rates at 2 years after diagnosis were 56% and 66%.

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

• Post-transplant lymphoproliferative disorder (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% 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 allo-HSCT ranges from 0.5% to 1%.

• The onset of post-transplant 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% 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 is 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.

• This lymphoma is characterized by effacement of the architecture of the lymph node by a lymphohistiocytic infiltrate with a diffuse or vaguely nodular growth pattern.

• It accounts for less than 5% 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% 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% 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.

• This uncommon neoplasm of large immunoblast-like B cells stains 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 includes 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 frequently negative for CD20, making the utility of rituximab uncertain.