Jennifer Gao, Ephraim Paul Hochberg
Lymphomas are a malignancy arising from lymphoid cells, with more than 60 distinct variants identified by the World Health Organization (WHO). Lymphomas can originate in B cells, T cells, or natural killer cells, and are broadly categorized into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Within NHL, further differentiation is made based on clinical presentation and histology. About 85% of lymphomas in the United States and Western Europe are of B-cell origin. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL in North America and the focus of this chapter. The majority of the information in this chapter is applicable to DLBCL-NOS (not otherwise specified). Short discussions of other subtypes of diffuse large B-cell lymphoma and of other lymphomas of large B cells are included at the end of this chapter.
EPIDEMIOLOGY
DLBCL is a B-cell lymphoma characterized by malignant proliferations of lymphocytes at various stages during the normal B-cell maturation process and accounts for 30%-40% of all NHL cases. The annual incidence is approximately 16.5 per 100,000 people per year, with a slightly higher incidence in men compared to women (SEER). Comparing incidence based on race, Caucasians have the highest and American Indians/Alaskan Natives the lowest (SEER). The median age of diagnosis is 67 years old.
In a majority of patients, no clear risk factor can be identified; although the proportion of Epstein-Barr virus associated DLBCL is greater in the elderly, suggesting a possible viral connection. HIV strongly increases the risk of lymphoma, with DLBCL being the most common HIV-associated lymphoid malignancy. The underlying pathophysiology is likely due to chronic antigenic stimulation causing polyclonal B-cell expansion and then subsequent emergence of monoclonal B cells. Autoimmune rheumatologic diseases, such as Sjogren’s, lupus, and rheumatoid arthritis have also been associated with the development of DLBCL, especially in patients with detectable autoantibodies and substantial clinical involvement. In these diseases, chronic immune stimulation may promote lymphoma development although the role of immunosuppressive medication regimens is also being studied. Finally, a small number of patients present with histologic progression or transformation to DLBCL after a diagnosis of an indolent NHL, such as follicular lymphoma, or chronic lymphocytic leukemia. Transformation of chronic lymphocytic leukemia into diffuse large B-cell lymphoma is known as Richter’s transformation.
PATHOLOGY
Definitive diagnosis is made via excisional biopsy or core needle biopsy (fine needle aspiration is inadequate) with hematopathologic review of slides. Microscopic examination usually demonstrates a diffuse infiltrate of large lymphoid cells completely effacing the normal nodal architecture. The neoplastic cells are large lymphocytes with nuclei greater than twice the size of small lymphocyte nuclei, prominent nucleoli, and amphiphilic to basophilic cytoplasm. Histology can reveal centroblastic and immunoblastic cell types but these distinctions are not highly reproducible and do not have clinical implications. For most DLBCL subtypes, the cells express the pan-B cell markers CD19, CD20, and CD79a. CD5 is expressed in 5%–10% of cases and blastoid mantle cell lymphoma should be excluded in these cases by absence of the t(11;14). Overexpression of BCL6 is common.
CHARACTERISTICS
The WHO divides DLBCL into subtypes based on clinical, morphological, immunological, and genetic features (Table 31-1).
TABLE 31-1 DIFFUSE LARGE B-CELL LYMPHOMA SUBTYPES
Pathogenic mutations commonly seen in DLBCL-NOS involve BCL-6, BCL-2, c-Myc, as well as genes in the NF-κB pathway.
Gene-expression profiling has divided DLBCL into distinct molecular subtypes: activated B-cell subtype (ABC), germinal-center B-cell subtype (GCB), type 3, and primary mediastinal B-cell lymphoma (PMBL). These subtypes are characterized by distinct clinical presentations, differential gene expression, and likely arise from B cells at varying stages of differentiation. A number of immunohistochemical algorithms have been reported to replicate profiling based subtype classification. Further studies are underway to determine the impact of these subtypes on therapy choice and outcome, and gene expression profiling is not currently used routinely.
DIAGNOSIS AND STAGING
DLBCL patients may present with symptoms of a rapidly enlarging lymph nodes, commonly in the neck or abdomen, sometimes accompanied by B symptoms of fevers, night sweats, and unintentional weight loss (Table 31-2). Up to 40% of patients will present with extranodal disease.
TABLE 31-2 B SYMPTOMS
Fever >38°C
Drenching sweats, especially at night
Unintentional weight loss >10% of body weight over a period of 6 mo or less
Staging is via the Ann Arbor staging system, which was originally developed for Hodgkin lymphoma (HL) (Table 31-3).
TABLE 31-3 ANN ARBOR STAGING SYSTEM (NCCN)
Stage I: single lymph node group
Stage II: two or more lymph node groups on the same side of the diaphragm
Stage III: lymph nodes on both sides of the diaphragm involved, subscript S = splenic involvement
Stage IV: disseminated disease involving extranodal organs (not including spleen, which is considered lymphoid tissue)
For stages I-III subscript E = extralymphatic organ/site involvement
• A = absence of systemic symptoms; B = presence of systemic symptoms
• X = bulky disease (>10-cm nodal mass or >1/3 intrathoracic diameter if mediastinal mass)
Approximately 27% will presents with stage I disease and 50% with advanced stage disease at diagnosis (SEER).
Initial evaluation of newly diagnosed DLBCL should include (NCCN) (1):
• Thorough history and physical examination with attention to nodal areas and to the liver and spleen
• B symptom inventory
• Performance status assessment
• International Prognostic Index score calculation (see Prognosis below)
• Laboratory studies: CBC with differential, comprehensive metabolic panel, LDH, uric acid, hepatitis B testing
• Imaging: CT of the chest/abdomen/pelvis with attenuation corrected PET or full diagnostic PET-CT
• Cardiac status: assessment of ejection fraction if anthracycline based chemotherapy regimen is planned
• Bone marrow biopsy with or without aspirate
• Pregnancy test
In selected cases, lumbar puncture (in patients with neurologic signs or symptoms or bone marrow involvement), HIV test, CNS imaging, and fertility discussions may also be useful (NCCN).
Functional imaging (FDG-PET) is used at diagnosis to accurately stage patients as well as early during the course of chemotherapy to risk stratify patients and guide treatment. It is nearly 100% sensitive for DLBCL when lymph nodes are above the size detection limit.
PROGNOSIS
Prognosis is determined based on the International Prognostic Index (IPI) (2), a scoring system prognostic in the setting of rituximab-based chemotherapy regimens for event-free survival, progression-free survival, and overall survival in 2010 (3). It is based on five clinical factors (Table 31-4):
TABLE 31-4 REVISED INTERNATIONAL PROGNOSTIC INDEX (IPI)
1. Age > 60
2. Serum LDH above upper value of normal
3. ECOG performance status 2 or greater
4. Ann Arbor stage III or IV
5. Two or more extranodal disease sites
The overall survival of patients at 4 years ranges from 94% for zero risk factors, down to 55% for patients with 3–5 risk factors.
Between 5% and 11% of patients with newly diagnosed diffuse large B-cell lymphoma will have concurrent translocations of myc and BCL-2. These cases are colloquially known as “double hit lymphomas” and have a poor prognosis with standard therapy.
Two recent studies have demonstrated that 20%–30% of newly diagnosed patients will have increased expression of myc and BCL-2 without a translocation. These patients have a response rate, progression-free survival, and overall survival intermediate between standard DLBCL and double hit lymphomas (4). The standard chemotherapy regimen of R-CHOP (Table 31-5) does not appear to provide satisfactory outcomes in this population and the therapeutic standard of care has not yet been established.
TABLE 31-5 R-CHOP CHEMOTHERAPY REGIMEN
Rituximab 375 mg/m2 IV on day 1
Cyclophosphamide 750 mg/m2 IV on day 1
Doxorubicin (hydroxydaunorubicin) 50 mg/m2 IV on day 1
Vincristine (Oncovin) 1.4 mg/m2 (max 2 mg) IV on day 1
Prednisone 100 mg po daily on days 1–5
Cycles are given every 21 days.
FRONT-LINE CHEMOTHERAPY
The mainstay of DLBCL treatment is combination chemotherapy. The current standard chemotherapy regimen is R-CHOP every 21 days (Table 31-5).
Rituximab is a chimeric monoclonal anti-CD20 IgG1 antibody that has demonstrated an additive effect when combined with CHOP to improve both progression-free and overall survival. One of the earliest reports of this survival benefit was from the Groupe d’Etude des Lymphomas de l’Adulte (GELA), which showed that in DLBCL patients over 60 years of age, regardless of IPI score at diagnosis, the addition of rituximab to CHOP improved complete remission and overall survival rates at 2 years by 10%–15% (5). Since then, several subsequent studies have confirmed this benefit in other DLBCL patient cohorts, affirming R-CHOP as first line treatment in DLBCL. R-CHOP given every 14 days has been compared to R-CHOP at 3-week intervals and is not superior.
LIMITED-STAGE DIFFUSE LARGE B-CELL LYMPHOMA: STAGES I AND II
Patients with stage I or II bulky disease, defined as ≥10 cm in size, should receive 6 cycles of R-CHOP. Radiation therapy does not improve outcome over chemotherapy alone.
Patients with nonbulky disease, defined as <10 cm in size, can receive either 3 cycles of R-CHOP with radiation therapy or 6 cycles of R-CHOP without radiation therapy. The use of radiation therapy places the patient at a lifetime increased risk of second malignancy.
The decision to proceed with radiation therapy after chemotherapy completion depends on PET imaging results after completing R-CHOP. Biopsy should be considered in this setting with a positive PET scan:
• If there is a complete response (PET negative), then treatment is complete.
• Patients with a partial response (PET positive) should undergo biopsy. Those with persistent disease have the option of: (1) receiving radiation therapy to the PET positive site, (2) receiving high dose therapy with autologous stem-cell transplant, or (3) enrollment in a clinical trial. Repeat PET imaging is performed after completing the course of treatment with a repeat biopsy needed if scans return yet again positive.
• Patients with no response or progressive disease after the initial chemotherapy should receive treatment for refractory disease (see below).
Advanced-Stage Diffuse Large B-Cell Lymphoma: Stages III And IV
Patients with advanced stage disease should receive 6 cycles of R-CHOP. After the first 2–4 cycles of R-CHOP interim PET scans may sometimes be used to guide treatment; however, this approach has not been validated in prospective clinical trials.
• Those with a complete response (PET negative) should complete 6 cycles of R-CHOP and then have repeat PET scans. If the final scans continue to be negative; observation is indicated. If the final scans are positive, then treatment should be based on the algorithm for refractory disease below (after a biopsy has been obtained).
• Those with an interim partial response (PET positive) should complete 6 cycles of R-CHOP and have a final scan performed. Then the patient is managed as above for those with final scan negative or positive.
• For those without any response on interim restaging, patients should be treated for refractory disease. However, it is very rare that a PET scan is required to detect the failure of chemotherapy to produce a response. Refractory disease is nearly always a clinical diagnosis, often made by the patient.
In cases of poor left ventricular function, standard anthracyclines or anthracenediones cannot be used and alternative chemotherapy regimens and schedules are preferred (Table 31-6) (6).
TABLE 31-6 FIRST-LINE CHEMOTHERAPY IN PATIENTS WITH POOR LEFT VENTRICULAR FUNCTION
RCEPP: rituximab, cyclophosphamide, etoposide, prednisone, procarbazine
RCDOP: rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, prednison
RCNOP: rituximab, cyclophosphamide, mitoxantrone, vincristine, prednisone
DA-EPOCH: etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin + rituximab
RCEOP: rituximab, cyclophosphamide, etoposide, vincristine, prednisone
Rarely, patients will present with central nervous system involvement at initial diagnosis. In patients with CNS parenchymal disease, high-dose systemic methotrexate is incorporated into first-line chemotherapy regimens. In leptomeningeal disease, intrathecal methotrexate and cytarabine or high-dose systemic methotrexate are both options. Limited data suggest that autologous stem-cell transplantation in first remission for these patients may improve outcome.
RELAPSED/REFRACTORY DLBCL
Although R-CHOP has improved outcome in DLBCL patients, approximately a third of patients will either relapse or prove refractory to initial therapy. The majority of relapses occur within 2–3 years of treatment. Late relapses (after 5 years) constitute ∼7% of all progressions after R-CHOP.
Autologous stem-cell transplant has been the standard of care for patients with relapsed DLBCL.
In the European PARMA trial, Philip et al. (7) studied 215 patients with relapsed NHL who had received two courses of conventional chemotherapy. Of these, 109 responded to the initial chemotherapy and 54 of these were assigned to receive four more courses of chemotherapy with or without radiation therapy, and 55 were assigned to receive intensive chemotherapy and an autologous bone marrow transplant. They followed the patients for 63 months and found a response rate of 84% in the transplant group and 44% in the nontransplant group. At 5 years, the event-free survival rate was 46% in the transplant group and 12% in the nontransplant group (P = 0.001). The overall survival rate was 53% and 32% in the two groups (P = 0.038). The PARMA trial was performed before rituximab entered the standard of care for DLBCL.
The CORAL trial (8) included relapsed or refractory patients with CD20+ DLBCL. The majority of patients had been treated with R-CHOP as their initial therapy. These patients were randomized to receive R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) versus R-ICE (rituximab, ifosfamide, etoposide, carboplatin). Those who responded to this second treatment then received autologous stem-cell transplant followed by a second randomization to maintenance rituximab or observation. Approximately 200 patients were randomized to the R-ICE and R-DHAP arms, with no difference in overall response rates seen between the groups (63.5% vs 62.8%). Of the 206 patients that went on to receive ASCT, there was no difference noted between the R-ICE and R-DHAP groups when comparing event-free (26% vs 35%, P = 0.6) or overall survival (47% vs 51%, P = 0.5). Notably the response rate, event-free survival, and overall survival were significantly inferior for patients who had received rituximab in the front-line setting.
Second-line chemotherapy regimens are listed in Table 31-7. Fit patients with complete or partial responses should proceed to HD-SCT. Patients with chemotherapy-resistant relapse should be evaluated for clinical trials or palliative treatment.
TABLE 31-7 SECOND-LINE CHEMOTHERAPY BEFORE HD-SCT, ALL USUALLY WITH RITUXIMAB
ICE: ifosfamide, carboplatin, etoposide
DHAP: dexamethasone, high-dose cytarabine/anthracycline, procarbazine
ESHAP: etoposide, methylprednisolone, cytarabine/anthracycline, cisplatin
GDP: gemcitabine, dexamethasone, cisplatin/carboplatin
GemOx: gemcitabine, oxaliplatin
MINE: mesna, ifosfamide, mitoxantrone, etoposide
For patients not eligible for HD-SCT or with relapse after HD-SCT, several new agents are currently under investigation (Table 31-8).
TABLE 31-8 NOVEL TARGETED THERAPIES
Enzastaurin
BCR-signaling inhibitors
Bortezomib
Lenalidomide
Navitoclax
BCL-6 inhibitors
Bruton’s tyrosine kinase inhibitors
Novel unconjugated monoclonal antibodies
Antibody drug conjugates
CENTRAL NERVOUS SYSTEM PROPHYLAXIS
Central nervous system recurrence in DLBCL is rare, with risk estimates ranging from 3% to 9% in the rituximab era. While rituximab has been shown to have partial protective effects against CNS relapse, patients with advanced disease stage, elevated LDH, IPI 3–5, and involvement of extra-nodal sites (particularly orbit, sinus/posterior nasal space, breast, testicle, bone, and bone marrow) are still at high risk for CNS relapse (9). Options for prophylaxis of central nervous system relapse include intrathecal methotrexate as well as systemic intravenous methotrexate. Our standard approach is to provide intravenous methotrexate prophylaxis at a dose of 3.5 g/m2 with leukovorin rescue on day 15 of R-CHOP cycles 1, 3, and 5 to patients with either bone marrow involvement, testicular disease, or the combination of an elevated LDH and more than one extranodal site of disease.
TUMOR LYSIS SYNDROME
Tumor lysis syndrome is fully discussed in Chapter 20. DLBCL is generally considered to be intermediate risk for tumor lysis syndrome and recommended prophylaxis includes hydration and allopurinol.
HEPATITIS B REACTIVATION
Reactivation of the hepatitis B virus has been reported in patients treated with rituximab monotherapy, chemotherapy, or with the combination. This reactivation may result in severe hepatitis including hepatic failure or death. Patients who are HBsAg positive are at a high risk of reactivation but HBsAg-negative HBcAb-positive patients can also reactivate. Antiviral prophylaxis reduces the risk of reactivation substantially, but the optimal duration of prophylaxis after the completion of therapy is unknown. Viral load should be monitored monthly.
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
PML is a fatal central nervous system infection caused by JC virus. It has been reported in patients treated with rituximab for a variety of indications. Diagnosis is usually made by PCR of the virus from the CSF or a brain biopsy.
CHEMOTHERAPY SIDE EFFECTS
Common and important serious adverse events seen with R-CHOP include infection in 7%–10%, thrombocytopenia and anemia in less than 1%, nausea and vomiting in 4% (with proper antiemetic prophylaxis), and alopecia in 40% of patients.
While empiric granulocyte colony-stimulating factor (G-CSF) use is not routinely recommended, R-CHOP falls into an intermediate febrile neutropenia risk category. G-CSF should be considered in patients with the following characteristics:
• >65 years old
• Poor performance status
• Bone marrow involvement
• Impaired renal or hepatic function
• Chemotherapy-induced neutropenia severe enough to cause delays in treatment
It is recommended that 24 hours elapse between chemotherapy and G-CSF. Antibiotic prophylaxis, especially against Pneumocystis jiroveci pneumonia should be considered in regimens containing glucocorticoids, purine analogs, or high-dose chemotherapy.
Other common chemotherapy side effects include a low risk of cardiotoxicity, therapy-induced myelodysplasia, sensory neuropathy, and infertility.
DLBCL SUBTYPES
In this section, we will highlight some key aspects of a few DLBCL subtypes.
Primary Mediastinal Large B-Cell Lymphoma (PMBCL)
PMBCL is a rare subtype accounting for 5% of all DLBCL and is thought to arise from thymic medullary B cells. It is commonly seen in adolescents and young adults, with a median age of diagnosis in the fourth decade of life and a male-female ratio of 1:2. It is sometimes histologically confused with nodular sclerosis classical Hodgkin lymphoma; however, PMBCL has upregulation of the NFkB pathway and usually expresses the pan B-cell markers CD20 and CD 79a. PMBCL typically presents as a rapidly progressive and locally invasive anterior mediastinal mass, frequently causing symptoms of cough, dyspnea, dysphagia, and superior vena-cava syndrome (seen in up to 30%–50% of patients) due to local compressive effects. Regional spread can also cause lung, chest wall, pleural, and pericardial infiltration. PMBCL is diagnosed at stage I or II in 80% of patients. Because of the rarity of this subtype, prospective trials have not fully defined the standard of care. Chemotherapy commonly consists of DA-EPOCH chemotherapy regimen and is associated with a 5-year survival of ~95%. Radiation therapy is not needed when DA-EPOCH chemotherapy is used.
Intravascular Large-B Cell Lymphoma
Intravascular DLBCL is a rare subtype of DLBCL, occurring in less than 1 person per 1 million. Initially described in 1959, it was characterized as an angiotropic large-cell lymphoma. By 2008, the WHO defined this as an extranodal DLBCL, with growth restricted to the lumina of small vessels, particularly capillaries. It primarily affects the elderly population and 91% of patients present at advanced stage. The most common presenting symptoms are caused by occlusion of terminal vascular beds and include cutaneous findings, CNS symptoms (including sensorimotor deficits, paresthesias, aphasias, seizures, visual changes, vertigo, and altered mental status) as well as renal involvement. Fever and B symptoms are relatively common. It frequently also involves the kidneys, lungs, and endocrine glands, although lymph nodes are usually spared. R-CHOP chemotherapy is the mainstay of care although some centers include CNS-directed therapies given the proclivity of this lymphoma for involvement of vascular structures within the brain parenchyma. There may be two distinct subtypes of this disease, a Western form with predominant end-organ manifestations and an Asian form that presents with prominent systemic symptoms, pancytopenia and hemophagocytosis.
EBV-Positive DLBCL of the Elderly
EBV-positive DLBCL was originally described in elderly Japanese patients (Oyama). It is a clonal EBV+ B cell neoplasm seen in patients over the age of 50 without known prior lymphomas or immunodeficiencies. It is an aggressive subtype and frequently has extranodal involvement on presentation, which carries a poor prognosis. There is speculation that this particular DLBCL subset is related to immunosenescence. Many elderly patients who are diagnosed with EBV-positive DLBCL have other medical comorbidities that limit the chemotherapy regimens and number of cycles that can be given.
T-cell/Histiocyte-Rich Large B-cell Lymphoma
T-cell/histiocyte-rich large B-cell lymphoma (THRBCL) is characterized by scattered single neoplastic malignant B cells in a background of reactive T cells and histiocytes. The B cells are never seen in sheets or substantial aggregates. Cases of THRBCL are seen in patients with nodular lymphocyte predominant Hodgkin lymphoma and the interrelationship between these diseases has not been fully defined. Care must be taken to distinguish these two entities as the therapies and outcomes are distinct. Epidemiologically, it is most frequent in middle-aged men. Compared with DLBCL-NOS, THRBCL has a propensity toward involvement of the bone marrow, liver, and spleen. Treatment involves R-CHOP-based chemotherapy regimens, with a response rate similar to that of traditional DLBCL.
Primary DLBCLs of the CNS
Discussed in Central Nervous System Malignancies (see Chapter 62).
Double hit lymphomas Double hit lymphomas are a group of B-cell lymphomas with recurrent chromosomal breakpoints that results in activation of oncogenes. Of these, BCL2 and myc rearrangements are most common; however, rearrangements involving bcl6 are also seen. These lymphomas are typically highly aggressive and may have clinical features that overlap with Burkitt lymphoma and DLBCL. At presentation, extra-nodal disease, bone marrow, and CNS involvement are frequently seen. The overall prognosis is poor and as of 2013, no standard therapy has yet been defined.
B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (BclU) Burkitt lymphoma (BL) is an aggressive B-cell non-Hodgkin lymphoma which is characterized by c-myc translocations and a high proliferation index. Morphologically, BL has a “starry sky” appearance, with numerous macrophages that have ingested apoptotic debris amidst a background of neoplastic lymphoid cells. Epstein-Barr virus (EBV) is strongly associated with endemic BL, but also occurs in sporadic and HIV-associated cases. BclU are diseases with biological, clinical, and genetic features of both BL and DLBCL. Clinically most patients present with advanced stage disease and extranodal involvement is common. There is substantial overlap between this clinically and morphologically defined entity and DHL which is defined genetically. The optimal therapy of this disease is unknown although many centers use R-EPOCH with high response rates and excellent long-term survival.
B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma This disease is defined as a B-cell lymphoma with clinical, morphologic, and immunophentypic features of classical HL and DLBCL, most commonly the primary mediastinal subtype. These lymphomas typically present in younger men in the second and third decade of life with a mediastinal mass. Histologically sheets of tumor cells are seen within fibrous stroma although often the architecture varies in different areas of the same tumor from the appearance of classical HL to that of PMBL. Rare true composite lymphomas of PMBL and cHL have also been reported. These lymphomas are typically CD20 and CD79a while also expressing CD30 and CD15. There is no consensus on the optimal therapy of this rare disease.
REFERENCES
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