Non-Hodgkin's Lymphoma¶

Chapter 113 | Part 4: Oncology and Hematology · Part 4 – Oncology: Hematologic Malignancies

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points¶

NHL incidence has nearly doubled over the past 20–40 years and continues to rise by 1.5–2% each year.
Approximately 90% of all lymphomas are of B-cell origin; about 80–85% of HL patients are cured, whereas NHL prognosis is more variable.
The International Prognostic Index (IPI) uses 5 risk factors: Age ≥60, elevated LDH, Performance status ≥2, Stage III/IV, and >1 extranodal site.
Burkitt's lymphoma has a doubling time of <24 hours and requires immediate intensive chemotherapy with CNS prophylaxis.
DLBCL is the most common NHL subtype, representing about one-third of all cases, with a median age at diagnosis of 64.
Gene expression profiling identifies GCB and ABC subtypes of DLBCL, with GCB-like having a better prognosis.
Infectious agents like EBV, HTLV-1, HIV, HCV, and H. pylori are associated with specific NHL subtypes.
FDG-PET is useful for aggressive lymphomas (DLBCL, BL) but PET during therapy is recommended only as part of clinical trials.
Relapsed DLBCL may be treated with CD79b ADC polatuzumab, tafasitamab, loncastuximab, or bispecific antibodies.
Approximately 30% of NHLs in immunosuppressed patients arise as polyclonal B-cell proliferation evolving into clonal malignancy.

📑 Table of Contents¶

1. DEFINITION & OVERVIEW
1.1 WHO Classification
2. EPIDEMIOLOGY
2.1 Risk Factors
3. ETIOLOGY & PATHOPHYSIOLOGY
3.1 Genetic Features
4. CLINICAL FEATURES
4.1 Specific Subtypes
5. DIFFERENTIAL DIAGNOSIS
6. INVESTIGATIONS & DIAGNOSIS
6.1 Staging Systems
7. MANAGEMENT & TREATMENT
7.1 Treatment of DLBCL
8. PROGNOSIS & COMPLICATIONS
9. SPECIAL CONSIDERATIONS
9.1 Immunodeficiency
10. KEY PEARLS & CLINICAL TRAPS
Flowcharts & Algorithms
Figures & Illustrations

📋 Figures in This Chapter¶

#	Type	Description
1	🔀 Flowchart	Pathway of normal B-cell differentiation and relationship to B-cell used to distinguish...
2	🔀 Flowchart	Pathway of normal T-cell differentiation and relationship to T-cell lymphomas
1	🖼 Figure	Relative frequency of lymphoid malignancies
2	🖼 Figure	Burkitt’s lymphoma
3	🖼 Figure	Follicular lymphoma
4	🖼 Figure	Diffuse large B-cell lymphoma

1. DEFINITION & OVERVIEW¶

Non-Hodgkin's lymphomas (NHLs) are cancers of mature B, T, and natural killer (NK) cells.
They were distinguished from Hodgkin's lymphoma (HL) upon recognition of the Reed-Sternberg (RS) cell and difference from HL with respect to their biologic and clinical characteristics.
NHL can be classified as either a mature B-NHL or a mature T/NK-NHL depending on whether the cancerous lymphocyte is a B, T, or NK cell, respectively.
Within each category are lymphomas that grow quickly and behave aggressively, as well as lymphomas that are more indolent, or slow growing, in nature.
Whereas ~80–85% of patients with HL will be cured of their lymphoma by chemotherapy with or without radiotherapy, the prognosis and natural history of NHL tend to be more variable.
NHLs are cancers of mature B, T, and natural killer (NK) cells.
They were distinguished from Hodgkin's lymphoma (HL) upon recognition of the Reed-Sternberg (RS) cell and difference from HL with respect to their biologic and clinical characteristics.
NHL can be classified as either a mature B-NHL or a mature T/NK-NHL depending on whether the cancerous lymphocyte is a B, T, or NK cell, respectively.
Within each category are lymphomas that grow quickly and behave aggressively, as well as lymphomas that are more indolent, or slow growing, in nature.

1.1 WHO Classification¶

For a list of the World Health Organization (WHO) classification of lymphoid neoplasms, see Table 113-1.
The WHO-HAEM5 Classification of Lymphoid Malignancies categorizes neoplasms into B-cell and T-cell mature (peripheral) neoplasms.
B-cell neoplasms include: Lymphoplasmacytic lymphoma (Waldenström's macroglobulinemia), Hairy cell leukemia, Splenic marginal zone B-cell lymphoma, Extranodal marginal zone B-cell lymphoma of MALT type, Nodal marginal zone B-cell lymphoma, Follicular lymphoma, Mantle cell lymphoma, Diffuse large B-cell lymphoma (including subtypes), High-grade B-cell lymphoma with MYC and BCL2 rearrangements, High-grade B-cell lymphoma NOS, High-grade B-cell lymphoma with 11q aberrations, Burkitt's lymphoma/Burkitt's cell leukemia, Primary mediastinal large B-cell lymphoma, Mediastinal grey zone lymphoma, Primary large B-cell lymphoma of immune-privileged sites, Plasmablastic lymphoma, Primary effusion lymphoma, Intravascular large B-cell lymphoma, ALK+ large B-cell lymphoma.
T-cell neoplasms include: T-cell granular lymphocytic leukemia, Adult T-cell leukemia/lymphoma (HTLV-1+), Extranodal NK/T-cell lymphoma, nasal type, Enteropathy-associated T-cell lymphoma, Hepatosplenic T-cell lymphoma, Subcutaneous panniculitis-like T-cell lymphoma, Mycosis fungoides, Sezary syndrome, Peripheral T-cell lymphoma NOS, Angioimmunoblastic T-cell lymphoma, Anaplastic large-cell lymphoma, ALK+, Anaplastic large-cell lymphoma, ALK–.

Table 1 — TABLE 113-1 WHO-HAEM5 Classification of Lymphoid Malignancies¶

B CELL	T CELL
Mature (peripheral) B-cell neoplasms	Mature (peripheral) T-cell neoplasms
Lymphoplasmacytic lymphoma (Waldenström's macroglobulinemia)	T-cell granular lymphocytic leukemia
Hairy cell leukemia	Adult T-cell leukemia/lymphoma (HTLV-1+)
Splenic marginal zone B-cell lymphoma	Extranodal NK/T-cell lymphoma, nasal type
Extranodal marginal zone B-cell lymphoma of MALT type	Enteropathy-associated T-cell lymphoma
Nodal marginal zone B-cell lymphoma	Hepatosplenic T-cell lymphoma
Follicular lymphoma	Subcutaneous panniculitis-like T-cell lymphoma
Mantle cell lymphoma	Mycosis fungoides
Diffuse large B-cell lymphoma (including subtypes)	Sezary syndrome
High-grade B-cell lymphoma with MYC and BCL2 rearrangements	Peripheral T-cell lymphoma NOS
High-grade B-cell lymphoma NOS	Angioimmunoblastic T-cell lymphoma
High-grade B-cell lymphoma with 11q aberrations	Anaplastic large-cell lymphoma, ALK+
Burkitt's lymphoma/Burkitt's cell leukemia	Anaplastic large-cell lymphoma, ALK–
Primary mediastinal large B-cell lymphoma
Mediastinal grey zone lymphoma
Primary large B-cell lymphoma of immune-privileged sites
Plasmablastic lymphoma
Primary effusion lymphoma
Intravascular large B-cell lymphoma
ALK+ large B-cell lymphoma

2. EPIDEMIOLOGY¶

In 2023, it is estimated that there will be 80,550 new cases of NHL in the United States, ~4% of all new cancers in both males and females.
It makes it the seventh most common cause of cancer-related death in both women and men.
The incidence is nearly 10 times the incidence of Hodgkin's lymphoma, plasma cell disorders, and lymphoid leukemias.
The incidence of NHL has nearly doubled over the past 20–40 years and continues to rise by 1.5–2% each year.
There is a slight male-to-female predominance and a higher incidence for Caucasians than for African Americans.
The incidence rises steadily with age, especially after age 40, but lymphomas are also among the most common malignancies in adolescent and young adult patients.
Patients with both primary and secondary immunodeficiency states are predisposed to developing NHL.
These include patients with HIV infection, patients who have undergone organ transplantation, and patients with inherited immune deficiencies and autoimmune conditions.
The 5-year survival rate for NHL is 74% and is higher for Caucasians than it is for African Americans.
The incidence of NHL and the patterns of expression of the various subtypes differ geographically and across age groups.
T-cell lymphomas are more common in Asia than in Western countries, whereas certain subtypes of B-cell lymphomas such as follicular lymphoma (FL) are more common in Western countries.
A specific subtype of NHL known as the angiocentric nasal T/NK-cell lymphoma has a striking geographic occurrence, being most frequent in southern Asia and parts of Latin America.
Another subtype of NHL associated with infection by human T-cell lymphotropic virus (HTLV) 1 is seen particularly in southern Japan and the Caribbean.
Likewise, there are differences in the age-dependent incidence of NHL by histologic subtype, with aggressive lymphomas like diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma (BL) being the most common entities in children, and DLBCL and indolent lymphomas including FL being the most common forms in adults.
The relative frequencies of the various types of lymphoid malignancies, including HL, plasma cell disorders, and lymphoid leukemias, are shown in Fig. 113-1.

2.1 Risk Factors¶

A number of environmental factors have been implicated in the occurrence of NHL, including infectious agents, chemical exposures, and medical treatments.
Several studies have demonstrated an association between exposure to agricultural chemicals and an increased incidence of NHL.
Patients treated for HL can develop NHL; it is unclear whether this is a consequence of the HL or its treatment, especially radiation.
Diseases of inherited and acquired immunodeficiency as well as autoimmune diseases are associated with an increased incidence of lymphoma.
The association between immunosuppression and induction of NHLs is compelling because if the immunosuppression can be reversed, a percentage of these lymphomas regress spontaneously.
The incidence of NHL is nearly a hundredfold increased for patients undergoing organ transplantation necessitating chronic immunosuppression and is greatest in the first year posttransplant.
About 30% of these arise as a polyclonal B-cell proliferation that evolves into a clonal B-cell malignancy.
The NHLs that occur in the context of immunosuppression or immunodeficiency, including HIV infection, are frequently associated with EBV.
Histologically, DLBCLs are most frequently associated with immunosuppression and autoimmune diseases, although almost all histologies can be seen, especially MALT lymphomas in the context of autoimmune diseases such as Sjögren's syndrome and Hashimoto's thyroiditis.
The rare inherited immunodeficiency diseases X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, Chédiak-Higashi syndrome, ataxia-telangiectasia, and common variable immunodeficiency syndrome are complicated by highly aggressive lymphomas.
An increased risk of NHL has been observed in first-degree relatives with NHL, HL, or chronic lymphocytic leukemia (CLL).
In large database studies, ~9% of patients with lymphoma or CLL have a first-degree relative with a lymphoproliferative disorder.

Table 2 — TABLE 113-2 Infectious Agents Associated with the Development of Lymphoid Malignancies¶

INFECTIOUS AGENT	LYMPHOID MALIGNANCY
Epstein-Barr virus	Burkitt's lymphoma
	Post–organ transplant lymphoma
	Primary CNS diffuse large B-cell lymphoma
	Hodgkin's lymphoma
	Extranodal NK/T-cell lymphoma, nasal type
HIV	Diffuse large B-cell lymphoma
	Burkitt's lymphoma
Human herpesvirus 8	Primary effusion lymphoma
Hepatitis C virus	Lymphoplasmacytic lymphoma
Helicobacter pylori	Gastric MALT lymphoma
HTLV-1	Adult T-cell leukemia/lymphoma

Table 3 — TABLE 113-3 Diseases or Exposures Associated with Increased Risk of Development of Malignant Lymphoma¶

Inherited immunodeficiency disease	Autoimmune disease
Klinefelter's syndrome	Sjögren's syndrome
Chédiak-Higashi syndrome	Celiac sprue
Ataxia-telangiectasia syndrome	Rheumatoid arthritis and systemic lupus erythematosus
Wiskott-Aldrich syndrome
Common variable immunodeficiency disease
Acquired immunodeficiency diseases
Iatrogenic immunosuppression
HIV-1 infection
Acquired hypogammaglobulinemia
Chemical or drug exposures
Phenytoin
Dioxin, phenoxy herbicides
Radiation
Prior chemotherapy and radiation therapy
Anti-TNF drugs

3. ETIOLOGY & PATHOPHYSIOLOGY¶

All lymphoid cells are derived from a common hematopoietic progenitor that gives rise to lymphoid, myeloid, erythroid, monocyte, and megakaryocyte lineages.
Through the ordered and sequential activation of a series of transcription factors, the cell first becomes committed to the lymphoid lineage and then gives rise to B and T cells.
About 90% of all lymphomas are of B-cell origin.
A cell becomes committed to B-cell development when it expresses the master B lineage transcription factor PAX5, which ultimately results in a transcriptional program that leads to the rearrangement of its immunoglobulin genes, which involves chromosomal recombination as well as somatic hypermutation to create an immunoglobulin gene that is unique to that cell-surface phenotype that characterizes normal B-cell development.
Most B-cell lymphomas arise following the process of immunoglobulin gene recombination and somatic hypermutation, which leads to class switching and affinity maturation of the mature immunoglobulin, respectively, suggesting that it is the error-prone nature of these genetic events that contributes to oncogenesis.
Certainly the frequency of chromosomal translocations that result in the activation of an oncogene or the inactivation of a tumor-suppressor gene in B-cell NHL may be the result of these normal cellular processes gone awry.
In addition, the key roles of the transcription factors MYC and BCL6 and the antiapoptotic protein BCL2 in the process of B-cell development explain why the genes encoding these proteins are commonly mutated in B-cell lymphomas.
A cell becomes committed to T-cell differentiation upon migration to the thymus and rearrangement of T-cell receptor (TCR) genes.
This requires the expression of the T-cell master regulatory transcription factor, NOTCH-1.
As in B cells, the development of the mature TCR involves the rearrangement and recombination of the TCR loci, which is error-prone and potentially oncogenic.
The sequence of the events that characterize T-cell development is depicted in Fig. 113-3.
Although lymphoid malignancies often retain the cell-surface antigen phenotype of lymphoid cells at particular stages of differentiation, this information is of little clinical or prognostic consequence.
The so-called stage of differentiation of a malignant lymphoma does not predict its natural history.
The antigen footprint, or immunophenotype, of the cell, however, is valuable diagnostically as it allows for the distinguishing of specific NHL subtypes.
It can be detected by flow cytometry of single-cell suspension from blood, bone marrow, body fluid, or disaggregated tissue using fluorescently labeled antibodies against these antigens or by immunohistochemical staining of paraffin-embedded tissue sections with enzyme-linked antibodies against these antigens followed by a colorimetric reaction.
Malignancies of lymphoid cells are associated with recurring genetic abnormalities including chromosomal translocations and genetic mutations that may in part be the result of aberrant immunoglobulin or TCR development.
While specific genetic abnormalities have not been identified for all subtypes of lymphoid malignancies, it is presumed that they exist.
As previously discussed, B cells are even more susceptible to acquiring mutations during their maturation in germinal centers; the generation of antibody of higher affinity requires the introduction of mutations into the variable region genes in the germinal centers.
Given this, other nonimmunoglobulin genes, e.g., bcl-6, may acquire mutations as well.
Likewise, many lymphomas contain balanced chromosomal translocations involving the antigen receptor genes; immunoglobulin genes on chromosomes 2, 14, and 22 in B cells; and T-cell antigen receptor genes on chromosomes 7 and 14 in T cells.
The rearrangement of chromosome segments to generate mature antigen receptors must create a site of vulnerability to aberrant recombination.
Examples of this type of event include the (8;14)(q24;q32) translocation in BL, involving the MYC proto-oncogene and the IgH gene; the (14;18)(q32;q32) translocation in FL, involving the BCL2 proto-oncogene and the IgH gene; and the (11;14) (q13;q32) translocation in mantle cell lymphoma (MCL), involving the gene encoding cyclin D1 (CCDN1) and the IgH gene.
Less commonly, chromosomal translocations produce fusion genes that encode chimeric oncogenic proteins.
Examples of this include the (2;5)(p23;q35) translocation involving the ALK and NPM1 genes in anaplastic large-cell lymphoma (ALCL) and the t(11;18)(q21;q21) translocation involving the API2 and MLT genes in MALT lymphoma.
Gene profiling using array technology allows the simultaneous assessment of the expression of thousands of genes.
This technology provides the possibility to identify new genes with pathologic importance in lymphomas, the identification of patterns of gene expression with diagnostic and/or prognostic significance, and the identification of new therapeutic targets.
Recognition of patterns of gene expression is complicated and requires sophisticated mathematical techniques.
Early successes using this technology in lymphoma include the identification of previously unrecognized subtypes of DLBCL whose gene expression patterns resemble either those of follicular or germinal center B (GCB) cells or activated peripheral blood B cells (ABC).
Patients whose lymphomas have a GCB-like pattern of gene expression have a considerably better prognosis than those whose lymphomas have a pattern resembling ABCs.
This improved prognosis is independent of other known prognostic factors.
These subcategories have been more specifically refined into five subcategories, using more advanced genetic sequencing techniques, that differ with respect to biology and driver genes, as well as prognosis, and may have important treatment implications in the future.
Similar information is being generated in FL and MCL.
The challenge remains to provide information from such techniques in a clinically useful time frame.

3.1 Genetic Features¶

Table 113-4 presents the most common translocations and associated oncogenes for various subtypes of lymphoid malignancies.
The sequence of cellular changes, including changes in cell-surface phenotype that characterizes normal B-cell development, is shown in Fig. 113-2.
The sequence of the events that characterize T-cell development is depicted in Fig. 113-3.

Table 4 — TABLE 113-4 Genetic Features of B- and T-Cell Lymphomas¶

DIFFERENTIATION	GENETIC FEATURE	GENES	LYMPHOMA
Thymus	t(8;14)	MYC/IgH	Burkitt's lymphoma
Prothymocyte	t(2;8)	MYC/Igκ	T-cell ALL
	t(8;22)	MYC/Ig λ
Stage I	t(11;14)	BCL1 (CCND1)/IgH	Mantle cell lymphoma; multiple myeloma
Thymocyte	t(14;18)	BCL2/IgH	Follicular lymphoma, diffuse large B-cell lymphoma (DLBCL)
	t(3;14)	BCL6/IgH
Stage II	t(11;18)	API2/MALT1	MALT lymphoma
	t(1;14)	BCL10/IgH
	t(14;18)	MALT1/IgH
Stage III	t(3;14)	FOXP1/IgH
Thymocyte	Trisomy 3	Unknown	Splenic marginal zone lymphoma
	7q21 deletion	CDK6
PERIPHERAL BLOOD AND NODES	t(9;14)	PAX5/IgH	Lymphoplasmacytic lymphoma
Majority of Mature T Helper Cell	inv(14)	TCRα/TCL1	Peripheral T-cell lymphoma, NOS; T-PLL
	t(14;14)	TCRα/TCL1
	t(2;5)	NPM1/ALK	Anaplastic large-cell lymphoma (ALCL)
	t(1;2)	TPM3/ALK	(ALCL)
Minority of Mature T Cytotoxic/Suppressor Cell	t(2;3)	TFG/ALK	T-CLL, NHL
	t(2;17)	CTLC/ALK
	inv(2)	ATIC/ALK
Minority of Trisomy 3	Trisomy 3	Unknown	Angioimmunoblastic T-cell lymphoma
	Trisomy 5	Unknown	Hepatosplenic T-cell lymphoma
	Isochromosome 7q	Unknown
	Trisomy 3	Unknown	Angioimmunoblastic T-cell lymphoma
	Trisomy 5	Unknown	Hepatosplenic T-cell lymphoma

4. CLINICAL FEATURES¶

The duration of symptoms and pace of symptomatic progression are important in distinguishing aggressive from more indolent lymphomas.
As are the presence or absence of "B" symptoms, such as fevers, night sweats, or unexplained weight loss.
Patients should be asked about localizing symptoms that may point toward lymphomatous involvement of specific sites, such as the chest, abdomen, or CNS.
Comorbid diagnoses that may impact therapy or monitoring on therapy should be reviewed and acknowledged, including a history of diabetes or congestive heart failure.
A physical examination should pay close attention to all the peripherally accessible sites of lymph nodes; the liver and spleen size; Waldeyer's ring; whether there is a pleural or pericardial effusion or abdominal ascites; whether there is an abdominal, testicular, or breast mass; and whether there is cutaneous involvement because all of these findings may influence further evaluation and disease management.
Laboratory studies should include a complete blood count, routine chemistries, liver function tests, and serum protein electrophoresis to document the presence of circulating monoclonal paraproteins.
The serum β-microglobulin level and serum lactate dehydrogenase (LDH) are important independent prognostic factors in NHL.
Staging of certain diseases may involve a bone marrow biopsy; results of other laboratory and staging studies may also warrant a marrow evaluation.
A lumbar puncture for evaluation of lymphomatous involvement may be indicated in the setting of concerning neurologic signs or symptoms or diseases that are high risk for CNS involvement.
The latter may include disease involving the paranasal sinuses, testes, breast, kidneys, adrenal glands, and epidural space, as well as highly aggressive histologies like BL.
Since HIV and hepatitis B and C infection can be risk factors for developing NHL, and since treatment for some NHLs can result in the potentially life-threatening reactivation of hepatitis B, patients with a new diagnosis of NHL should be screened for these viruses as well.
Lymphoma histology and clinical presentation dictate which imaging studies should be ordered.
Chest, abdominal, and pelvic computed tomography (CT) scans are essential for accurate staging to assess lymphadenopathy for indolent lymphomas.
Whereas positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG-PET) is useful for aggressive lymphomas, including BL, DLBCL, plasmablastic lymphoma, and the aggressive T-cell NHLs.
FDG-PET is highly sensitive for detecting both nodal and extranodal sites involved by NHL.
The intensity of FDG avidity, or standardized uptake value (SUV), correlates with histologic aggressiveness, and may be useful in cases when disease transformation from early-stage disease limited to a radiation field where local therapy with radiation is an option, all other disease is treated the same regardless of stage.
PET scanning can also differentiate between treated disease and active disease at the end of therapy in patients with residual masses on CT scans.
Consensus recommendations regarding PET scanning were published as a result of an International Harmonization Project and state that PET should only be used for DLBCL and HL, that scanning during therapy should only be done as part of clinical trials, and that the end-of-treatment scan should not be done before 3 weeks but preferably 6–8 weeks after chemotherapy and 8–12 weeks after radiation or chemoradiotherapy.
There is no evidence that long-term follow-up should include PET scanning.
More recently, though, PET scan results at the end of therapy for FL have been associated with prognosis, with patients with residual PET-avid disease at the end of treatment having a poorer prognosis than those who are PET negative, and so it may be used for this prognostic purpose.
Finally, magnetic resonance imaging (MRI) is useful in detecting bone, bone marrow, and CNS disease in the brain and spinal cord.
The staging evaluation is outlined in Table 113-5.

4.1 Specific Subtypes¶

Burkitt's lymphoma/leukemia (BL) is a rare disease in adults in the United States, making up 95% of the cases.
The most common partners are chromosomes 14, 2, or 22, rearrangements that produce fusions of MYC with either the IgH (80%), kappa (15%), or lambda (5%) light chain genes, respectively.
While exquisitely chemosensitive, it is imperative that treatment for BL be initiated quickly given the rapid doubling time and high morbidity of this disease.
There are several effective intensive combination chemotherapy regimens, all of which incorporate high doses of cyclophosphamide.
Prophylactic therapy to the CNS is mandatory.
Cure can be expected in 80–90% of patients when treated promptly and correctly.
Modified Magrath and dose-adjusted EPOCH-R (rituximab, infusional etoposide/vincristine/doxorubicin, cyclophosphamide, prednisone) are highly effective regimens.
Salvage therapy has been generally ineffective in patients whose disease progresses after upfront therapy, emphasizing the importance of the initial treatment approach and referral to a tertiary cancer center with experience treating this disease.
Diffuse Large B-Cell Lymphoma (DLBCL) is the most common histologic subtype of NHL diagnosed, representing about one-third of all cases.
It is slightly more common in Caucasians and men, and the median age at diagnosis is 64.
The relative risk (RR) of DLBCL is higher among people with affected first-degree relatives (RR 3.5-fold), and patients with congenital or acquired immunodeficiency, patients on immunosuppression, and patients with autoimmune disorders also have a higher risk of developing DLBCL, often EBV-related.
The majority of patients present with advanced-stage disease, with only 30–40% of patients having stage I or II disease.
~40% of patients will have "B" symptoms, and 50% of patients will have an elevated LDH.
Up to 40% of patients will have involvement of non–lymph node sites including bone marrow, CNS, gastrointestinal tract, thyroid, liver, and skin.
Patients with extensive bone marrow involvement or involvement of the testes, breast, kidney, adrenal gland, paranasal sinus, or epidural space are at increased risk of CNS dissemination.
The tumor consists of a diffuse proliferation of large, atypical lymphocytes with a high proliferative index.
These cells typically express the B-cell antigens CD19, CD20, and CD79a.
Expression of CD10 and BCL6 is consistent with the tumor cell being of germinal center origin (GCB), while the expression of MUM1 corresponds with the non–germinal center or ABC subtype.
BCL2 is overexpressed in anywhere from 25 to 80% of DLBCLs, whereas BCL6 is positive in more than two-thirds of cases, as the result of translocations, gain of copy number, or promoter mutations.
MYC is rearranged in 10% of DLBCLs, and ~20% of MYC-rearranged cases have a concurrent BCL2 rearrangement, a combination referred to as "double-hit lymphoma."
These double-hit lymphomas constitute one subtype of high-grade B-cell lymphoma (HGBL) and are associated with an extremely poor performance status or certain comorbid conditions who are not candidates for such approaches are often managed with palliative intentions.
Radiation to symptomatic areas of disease can be transiently helpful.
Less intensive chemotherapy with drugs such as gemcitabine, cytarabine, or bendamustine can help control disease and symptoms for a limited period of time.
Newer drugs including the CD79b ADC polatuzumab in combination with bendamustine and rituximab (BR), the high-affinity CD19 monoclonal antibody (mAb) tafasitamab in combination with lenalidomide, the CD19 ADC loncastuximab, and the CD20-CD3 bispecific antibodies epcoritamab and glofitamab have been approved for use in these palliative settings as well as for patients who relapse after CAR-T therapy or autologous stem cell transplantation.
Some of these agents can be used as a bridge to a definitive allogeneic stem cell transplantation.
For patients in whom more aggressive therapy is an option, treatment for late relapsing patients is with combination chemotherapy using various combinations of drugs primarily in order to identify patients with chemosensitive disease.
Patients with chemosensitive disease have the greatest likelihood of benefiting from high-dose chemotherapy and autologous stem cell transplant, which improves response duration and survival.

Table 5 — TABLE 113-5 Staging Evaluation for Non-Hodgkin's Lymphoma¶

Physical examination	Documentation of B symptoms	Laboratory evaluation	Complete blood counts	Liver function tests	Uric acid	Calcium	Serum protein electrophoresis	Serum β-microglobulin	Chest radiograph	CT scan of abdomen, pelvis, and usually chest	Bone marrow biopsy	Lumbar puncture in lymphoblastic, Burkitt's, and diffuse large B-cell lymphoma with positive marrow biopsy	Gallium scan (SPECT) or PET scan in large-cell lymphoma

5. DIFFERENTIAL DIAGNOSIS¶

NHL must be distinguished from HL upon recognition of the Reed-Sternberg (RS) cell and difference from HL with respect to their biologic and clinical characteristics.
Whereas ~80–85% of patients with HL will be cured of their lymphoma by chemotherapy with or without radiotherapy, the prognosis and natural history of NHL tend to be more variable.
NHL can be classified as either a mature B-NHL or a mature T/NK-NHL depending on whether the cancerous lymphocyte is a B, T, or NK cell, respectively.
Within each category are lymphomas that grow quickly and behave aggressively, as well as lymphomas that are more indolent, or slow growing, in nature.
The WHO-HAEM5 Classification of Lymphoid Malignancies categorizes neoplasms into B-cell and T-cell mature (peripheral) neoplasms.
The relative frequencies of the various types of lymphoid malignancies, including HL, plasma cell disorders, and lymphoid leukemias, are shown in Fig. 113-1.

6. INVESTIGATIONS & DIAGNOSIS¶

Regardless of the type of lymphoid malignancy, the initial evaluation of the patient should include performance of a careful history and physical examination.
These will help confirm the diagnosis, clarify the stage, and allow the physician to establish rapport with the patient that will make it possible to develop and carry out a therapeutic plan.
The duration of symptoms and pace of symptomatic progression are important in distinguishing aggressive from more indolent lymphomas.
As are the presence or absence of "B" symptoms, such as fevers, night sweats, or unexplained weight loss.
Patients should be asked about localizing symptoms that may point toward lymphomatous involvement of specific sites, such as the chest, abdomen, or CNS.
Comorbid diagnoses that may impact therapy or monitoring on therapy should be reviewed and acknowledged, including a history of diabetes or congestive heart failure.
A physical examination should pay close attention to all the peripherally accessible sites of lymph nodes; the liver and spleen size; Waldeyer's ring; whether there is a pleural or pericardial effusion or abdominal ascites; whether there is an abdominal, testicular, or breast mass; and whether there is cutaneous involvement because all of these findings may influence further evaluation and disease management.
Laboratory studies should include a complete blood count, routine chemistries, liver function tests, and serum protein electrophoresis to document the presence of circulating monoclonal paraproteins.
The serum β-microglobulin level and serum lactate dehydrogenase (LDH) are important independent prognostic factors in NHL.
Staging of certain diseases may involve a bone marrow biopsy; results of other laboratory and staging studies may also warrant a marrow evaluation.
A lumbar puncture for evaluation of lymphomatous involvement may be indicated in the setting of concerning neurologic signs or symptoms or diseases that are high risk for CNS involvement.
The latter may include disease involving the paranasal sinuses, testes, breast, kidneys, adrenal glands, and epidural space, as well as highly aggressive histologies like BL.
Since HIV and hepatitis B and C infection can be risk factors for developing NHL, and since treatment for some NHLs can result in the potentially life-threatening reactivation of hepatitis B, patients with a new diagnosis of NHL should be screened for these viruses as well.
Lymphoma histology and clinical presentation dictate which imaging studies should be ordered.
Chest, abdominal, and pelvic computed tomography (CT) scans are essential for accurate staging to assess lymphadenopathy for indolent lymphomas.
Whereas positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG-PET) is useful for aggressive lymphomas, including BL, DLBCL, plasmablastic lymphoma, and the aggressive T-cell NHLs.
FDG-PET is highly sensitive for detecting both nodal and extranodal sites involved by NHL.
The intensity of FDG avidity, or standardized uptake value (SUV), correlates with histologic aggressiveness, and may be useful in cases when disease transformation from early-stage disease limited to a radiation field where local therapy with radiation is an option, all other disease is treated the same regardless of stage.
PET scanning can also differentiate between treated disease and active disease at the end of therapy in patients with residual masses on CT scans.
Consensus recommendations regarding PET scanning were published as a result of an International Harmonization Project and state that PET should only be used for DLBCL and HL, that scanning during therapy should only be done as part of clinical trials, and that the end-of-treatment scan should not be done before 3 weeks but preferably 6–8 weeks after chemotherapy and 8–12 weeks after radiation or chemoradiotherapy.
There is no evidence that long-term follow-up should include PET scanning.
More recently, though, PET scan results at the end of therapy for FL have been associated with prognosis, with patients with residual PET-avid disease at the end of treatment having a poorer prognosis than those who are PET negative, and so it may be used for this prognostic purpose.
Finally, magnetic resonance imaging (MRI) is useful in detecting bone, bone marrow, and CNS disease in the brain and spinal cord.
The staging evaluation is outlined in Table 113-5.

6.1 Staging Systems¶

The Ann Arbor staging system developed in 1971 for HL was adapted for staging NHLs (Table 113-6).
This staging system focuses on the number of tumor sites (nodal and extranodal), location, and the presence or absence of systemic, or B, symptoms.
This anatomic based system is less useful in NHL, which disseminates widely, not in an ordered stepwise fashion.
A majority of patients with NHL have advanced-stage disease at diagnosis.
Apart from the presence of >4 nodal sites, an elevated serum LDH concentration, and a hemoglobin <12 were identified as independent prognostic variables, and summation of each variable identified three risk groups.
The median 10-year survival rates for patients with zero to one (low risk), two (intermediate risk), or three or more (high risk) of these adverse factors were 71, 51, and 36%, respectively.
Similar disease-specific IPIs have been developed for MCL and peripheral T-cell lymphoma (PTCL) as well.
These prognostic indices take into account the proliferative index and cell-surface markers, respectively.
Finally, as mentioned previously, gene expression profiling has identified DLBCLs with differential prognoses: GCB and ABC, where GCB-like DLBCL is associated with a significantly better OS.
A more readily accessible immunohistochemical algorithm has been developed, based on the presence or absence of CD10, BCL6, and MUM1, that correlates closely with gene expression profiles and can differentiate the majority of GCB from non–GCB-like DLBCL.
These profiles have prognostic importance but, to date, do not alter treatment recommendations for the primary treatment of DLBCL.
Current clinical trials do stratify by DLBCL subtype, and it appears that agents like the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and lenalidomide are most active in non-GCB DLBCL in the relapsed setting.
Treatment may then be differentiated by these subtypes in the future.

Table 6 — TABLE 113-6 Ann Arbor Staging for Lymphoma¶

STAGE	DESCRIPTION
I	Involvement of a single lymph node region (I) or single extranodal site (IE)
II	Involvement of two or more lymph node regions or lymphatic structures on the same side of the diaphragm alone (II) or with involvement of limited, contiguous, extralymphatic organ or tissue (IIE)
III	Involvement of lymph node regions on both sides of the diaphragm (III), which may include the spleen (IIIS), or limited, contiguous, extralymphatic organ or tissue (IIIE), or both (IIIES)
IV	Diffuse or disseminated foci of involvement of one or more extralymphatic organs or tissues, with or without associated lymphatic involvement

Table 7 — TABLE 113-7 International Prognostic Index for NHL¶

Five Clinical Risk Factors	Age ≥60 years	Serum lactate dehydrogenase levels elevated	Performance status ≥2 (ECOG) or ≤70 (Karnofsky)	Ann Arbor stage III or IV	>1 site of extranodal involvement
For Diffuse Large B-Cell Lymphoma	0, 1 factor = low risk	35% of cases; 5-year survival, 73%	2 factors = low-intermediate risk	27% of cases; 5-year survival, 51%	3 factors = high-intermediate risk	22% of cases; 5-year survival, 43%	4, 5 factors = high risk	16% of cases; 5-year survival, 26%
For Diffuse Large B-Cell Lymphoma Treated With R-CHOP	0 factor = good	10% of cases; 4-year survival, 94%	1, 2 factors = intermediate	45% of cases; 4-year survival, 80%	3, 4, 5 factors = poor	45% of cases; 4-year survival, 53%

7. MANAGEMENT & TREATMENT¶

NHL can be characterized into two broad groups—those that behave aggressively, require immediate or urgent treatment with combination chemotherapy regimens, and are potentially curable; and those that are more indolent in nature, can be observed and treated only when they cause symptoms or signs of organ function impairment, are very responsive to therapy, but are not ultimately curable in the vast majority of cases.
Among the aggressive diseases, the most common is DLBCL, and the most rapidly growing is BL.
FL is the second most common NHL and the most common indolent NHL.
Other indolent NHLs include MZL, lymphoplasmacytic lymphoma (LPL), and hairy cell leukemia (HCL).
MCL is an intermediate-grade lymphoma that shares some characteristics with the aggressive lymphomas (fairly urgent need for treatment and aggressive upfront combination chemotherapy regimens), but like the indolent lymphomas, it is not readily curable with conventional-dose therapies.
While exquisitely chemosensitive, it is imperative that treatment for BL be initiated quickly given the rapid doubling time and high morbidity of this disease.
There are several effective intensive combination chemotherapy regimens, all of which incorporate high doses of cyclophosphamide.
Prophylactic therapy to the CNS is mandatory.
Cure can be expected in 80–90% of patients when treated promptly and correctly.
Modified Magrath and dose-adjusted EPOCH-R (rituximab, infusional etoposide/vincristine/doxorubicin, cyclophosphamide, prednisone) are highly effective regimens.
Salvage therapy has been generally ineffective in patients whose disease progresses after upfront therapy, emphasizing the importance of the initial treatment approach and referral to a tertiary cancer center with experience treating this disease.
For patients in whom more aggressive therapy is an option, treatment for late relapsing patients is with combination chemotherapy using various combinations of drugs primarily in order to identify patients with chemosensitive disease.
Patients with chemosensitive disease have the greatest likelihood of benefiting from high-dose chemotherapy and autologous stem cell transplant, which improves response duration and survival.
For patients with poor performance status or certain comorbid conditions who are not candidates for such approaches are often managed with palliative intentions.
Radiation to symptomatic areas of disease can be transiently helpful.
Less intensive chemotherapy with drugs such as gemcitabine, cytarabine, or bendamustine can help control disease and symptoms for a limited period of time.
Newer drugs including the CD79b ADC polatuzumab in combination with bendamustine and rituximab (BR), the high-affinity CD19 monoclonal antibody (mAb) tafasitamab in combination with lenalidomide, the CD19 ADC loncastuximab, and the CD20-CD3 bispecific antibodies epcoritamab and glofitamab have been approved for use in these palliative settings as well as for patients who relapse after CAR-T therapy or autologous stem cell transplantation.
Some of these agents can be used as a bridge to a definitive allogeneic stem cell transplantation.

7.1 Treatment of DLBCL¶

DLBCL is the most common histologic subtype of NHL diagnosed, representing about one-third of all cases.
It is slightly more common in Caucasians and men, and the median age at diagnosis is 64.
The relative risk (RR) of DLBCL is higher among people with affected first-degree relatives (RR 3.5-fold), and patients with congenital or acquired immunodeficiency, patients on immunosuppression, and patients with autoimmune disorders also have a higher risk of developing DLBCL, often EBV-related.
The majority of patients present with advanced-stage disease, with only 30–40% of patients having stage I or II disease.
~40% of patients will have "B" symptoms, and 50% of patients will have an elevated LDH.
Up to 40% of patients will have involvement of non–lymph node sites including bone marrow, CNS, gastrointestinal tract, thyroid, liver, and skin.
Patients with extensive bone marrow involvement or involvement of the testes, breast, kidney, adrenal gland, paranasal sinus, or epidural space are at increased risk of CNS dissemination.
The tumor consists of a diffuse proliferation of large, atypical lymphocytes with a high proliferative index.
These cells typically express the B-cell antigens CD19, CD20, and CD79a.
Expression of CD10 and BCL6 is consistent with the tumor cell being of germinal center origin (GCB), while the expression of MUM1 corresponds with the non–germinal center or ABC subtype.
BCL2 is overexpressed in anywhere from 25 to 80% of DLBCLs, whereas BCL6 is positive in more than two-thirds of cases, as the result of translocations, gain of copy number, or promoter mutations.
MYC is rearranged in 10% of DLBCLs, and ~20% of MYC-rearranged cases have a concurrent BCL2 rearrangement, a combination referred to as "double-hit lymphoma."
These double-hit lymphomas constitute one subtype of high-grade B-cell lymphoma (HGBL) and are associated with an extremely poor performance status or certain comorbid conditions who are not candidates for such approaches are often managed with palliative intentions.
Radiation to symptomatic areas of disease can be transiently helpful.
Less intensive chemotherapy with drugs such as gemcitabine, cytarabine, or bendamustine can help control disease and symptoms for a limited period of time.
Newer drugs including the CD79b ADC polatuzumab in combination with bendamustine and rituximab (BR), the high-affinity CD19 monoclonal antibody (mAb) tafasitamab in combination with lenalidomide, the CD19 ADC loncastuximab, and the CD20-CD3 bispecific antibodies epcoritamab and glofitamab have been approved for use in these palliative settings as well as for patients who relapse after CAR-T therapy or autologous stem cell transplantation.
Some of these agents can be used as a bridge to a definitive allogeneic stem cell transplantation.
For patients in whom more aggressive therapy is an option, treatment for late relapsing patients is with combination chemotherapy using various combinations of drugs primarily in order to identify patients with chemosensitive disease.
Patients with chemosensitive disease have the greatest likelihood of benefiting from high-dose chemotherapy and autologous stem cell transplant, which improves response duration and survival.

8. PROGNOSIS & COMPLICATIONS¶

The International Prognostic Index (IPI) is perhaps the best predictor of outcome (Table 113-7).
The IPI was developed based on the analysis of >2000 patients with aggressive NHLs treated with an anthracycline-containing regimen.
Age (≤60 vs >60), serum LDH (≤ normal vs > normal), performance status (0 or 1 vs 2–4), stage (I or II vs III or IV), and extranodal involvement (1 site) were identified as independently prognostic for overall survival (OS).
A point is awarded for each risk factor and then summed, defining four risk groups: low (0 or 1); low-intermediate (2); high-intermediate (3); and high (4–5).
The 5-year OS rates for patients with scores of 0–1, 2, 3, and 4–5 were 73, 51, 43, and 26%, respectively.
The age-adjusted IPI separates patients ≤60 from patients >60.
For the age-adjusted IPI, only stage, LDH, and performance status were important.
Younger patients with 0, 1, 2, or 3 risk factors had 5-year survival rates of 83, 69, 46, and 32%, compared to 56, 44, 37, and 21% for older patients.
When factoring in the introduction and clinical benefit of rituximab, the 4-year progression-free survival rates are 94, 80, and 53% for 0–1, 2, or 3 or more risk factors, respectively.
The Follicular Lymphoma International Prognostic Index (FLIPI) is a similar predictive model for FL, derived from the analysis of >4000 patients.
The presence of >4 nodal sites, an elevated serum LDH concentration, and a hemoglobin <12 were identified as independent prognostic variables, and summation of each variable identified three risk groups.
The median 10-year survival rates for patients with zero to one (low risk), two (intermediate risk), or three or more (high risk) of these adverse factors were 71, 51, and 36%, respectively.
Similar disease-specific IPIs have been developed for MCL and peripheral T-cell lymphoma (PTCL) as well.
These prognostic indices take into account the proliferative index and cell-surface markers, respectively.
Finally, as mentioned previously, gene expression profiling has identified DLBCLs with differential prognoses: GCB and ABC, where GCB-like DLBCL is associated with a significantly better OS.
A more readily accessible immunohistochemical algorithm has been developed, based on the presence or absence of CD10, BCL6, and MUM1, that correlates closely with gene expression profiles and can differentiate the majority of GCB from non–GCB-like DLBCL.
These profiles have prognostic importance but, to date, do not alter treatment recommendations for the primary treatment of DLBCL.
Current clinical trials do stratify by DLBCL subtype, and it appears that agents like the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and lenalidomide are most active in non-GCB DLBCL in the relapsed setting.
Treatment may then be differentiated by these subtypes in the future.

9. SPECIAL CONSIDERATIONS¶

Patients with both primary and secondary immunodeficiency states are predisposed to developing NHL.
These include patients with HIV infection, patients who have undergone organ transplantation, and patients with inherited immune deficiencies and autoimmune conditions.
The NHLs that occur in the context of immunosuppression or immunodeficiency, including HIV infection, are frequently associated with EBV.
Histologically, DLBCLs are most frequently associated with immunosuppression and autoimmune diseases, although almost all histologies can be seen, especially MALT lymphomas in the context of autoimmune diseases such as Sjögren's syndrome and Hashimoto's thyroiditis.
The rare inherited immunodeficiency diseases X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, Chédiak-Higashi syndrome, ataxia-telangiectasia, and common variable immunodeficiency syndrome are complicated by highly aggressive lymphomas.
Since HIV and hepatitis B and C infection can be risk factors for developing NHL, and since treatment for some NHLs can result in the potentially life-threatening reactivation of hepatitis B, patients with a new diagnosis of NHL should be screened for these viruses as well.
Treatment for some NHLs can result in the potentially life-threatening reactivation of hepatitis B.

9.1 Immunodeficiency¶

Patients with both primary and secondary immunodeficiency states are predisposed to developing NHL.
These include patients with HIV infection, patients who have undergone organ transplantation, and patients with inherited immune deficiencies and autoimmune conditions.
The NHLs that occur in the context of immunosuppression or immunodeficiency, including HIV infection, are frequently associated with EBV.
Histologically, DLBCLs are most frequently associated with immunosuppression and autoimmune diseases, although almost all histologies can be seen, especially MALT lymphomas in the context of autoimmune diseases such as Sjögren's syndrome and Hashimoto's thyroiditis.
The rare inherited immunodeficiency diseases X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, Chédiak-Higashi syndrome, ataxia-telangiectasia, and common variable immunodeficiency syndrome are complicated by highly aggressive lymphomas.

10. KEY PEARLS & CLINICAL TRAPS¶

The incidence of NHL has nearly doubled over the past 20–40 years and continues to rise by 1.5–2% each year.
Patients with both primary and secondary immunodeficiency states are predisposed to developing NHL.
The 5-year survival rate for NHL is 74% and is higher for Caucasians than it is for African Americans.
The incidence of NHL and the patterns of expression of the various subtypes differ geographically and across age groups.
T-cell lymphomas are more common in Asia than in Western countries, whereas certain subtypes of B-cell lymphomas such as follicular lymphoma (FL) are more common in Western countries.
A specific subtype of NHL known as the angiocentric nasal T/NK-cell lymphoma has a striking geographic occurrence, being most frequent in southern Asia and parts of Latin America.
Another subtype of NHL associated with infection by human T-cell lymphotropic virus (HTLV) 1 is seen particularly in southern Japan and the Caribbean.
The association between immunosuppression and induction of NHLs is compelling because if the immunosuppression can be reversed, a percentage of these lymphomas regress spontaneously.
The incidence of NHL is nearly a hundredfold increased for patients undergoing organ transplantation necessitating chronic immunosuppression and is greatest in the first year posttransplant.
About 30% of these arise as a polyclonal B-cell proliferation that evolves into a clonal B-cell malignancy.
The NHLs that occur in the context of immunosuppression or immunodeficiency, including HIV infection, are frequently associated with EBV.
Histologically, DLBCLs are most frequently associated with immunosuppression and autoimmune diseases, although almost all histologies can be seen, especially MALT lymphomas in the context of autoimmune diseases such as Sjögren's syndrome and Hashimoto's thyroiditis.
The rare inherited immunodeficiency diseases X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, Chédiak-Higashi syndrome, ataxia-telangiectasia, and common variable immunodeficiency syndrome are complicated by highly aggressive lymphomas.
An increased risk of NHL has been observed in first-degree relatives with NHL, HL, or chronic lymphocytic leukemia (CLL).
In large database studies, ~9% of patients with lymphoma or CLL have a first-degree relative with a lymphoproliferative disorder.
The duration of symptoms and pace of symptomatic progression are important in distinguishing aggressive from more indolent lymphomas.
As are the presence or absence of "B" symptoms, such as fevers, night sweats, or unexplained weight loss.
Patients should be asked about localizing symptoms that may point toward lymphomatous involvement of specific sites, such as the chest, abdomen, or CNS.
Comorbid diagnoses that may impact therapy or monitoring on therapy should be reviewed and acknowledged, including a history of diabetes or congestive heart failure.
A physical examination should pay close attention to all the peripherally accessible sites of lymph nodes; the liver and spleen size; Waldeyer's ring; whether there is a pleural or pericardial effusion or abdominal ascites; whether there is an abdominal, testicular, or breast mass; and whether there is cutaneous involvement because all of these findings may influence further evaluation and disease management.
Laboratory studies should include a complete blood count, routine chemistries, liver function tests, and serum protein electrophoresis to document the presence of circulating monoclonal paraproteins.
The serum β-microglobulin level and serum lactate dehydrogenase (LDH) are important independent prognostic factors in NHL.
Staging of certain diseases may involve a bone marrow biopsy; results of other laboratory and staging studies may also warrant a marrow evaluation.
A lumbar puncture for evaluation of lymphomatous involvement may be indicated in the setting of concerning neurologic signs or symptoms or diseases that are high risk for CNS involvement.
The latter may include disease involving the paranasal sinuses, testes, breast, kidneys, adrenal glands, and epidural space, as well as highly aggressive histologies like BL.
Since HIV and hepatitis B and C infection can be risk factors for developing NHL, and since treatment for some NHLs can result in the potentially life-threatening reactivation of hepatitis B, patients with a new diagnosis of NHL should be screened for these viruses as well.
Lymphoma histology and clinical presentation dictate which imaging studies should be ordered.
Chest, abdominal, and pelvic computed tomography (CT) scans are essential for accurate staging to assess lymphadenopathy for indolent lymphomas.
Whereas positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG-PET) is useful for aggressive lymphomas, including BL, DLBCL, plasmablastic lymphoma, and the aggressive T-cell NHLs.
FDG-PET is highly sensitive for detecting both nodal and extranodal sites involved by NHL.
The intensity of FDG avidity, or standardized uptake value (SUV), correlates with histologic aggressiveness, and may be useful in cases when disease transformation from early-stage disease limited to a radiation field where local therapy with radiation is an option, all other disease is treated the same regardless of stage.
PET scanning can also differentiate between treated disease and active disease at the end of therapy in patients with residual masses on CT scans.
Consensus recommendations regarding PET scanning were published as a result of an International Harmonization Project and state that PET should only be used for DLBCL and HL, that scanning during therapy should only be done as part of clinical trials, and that the end-of-treatment scan should not be done before 3 weeks but preferably 6–8 weeks after chemotherapy and 8–12 weeks after radiation or chemoradiotherapy.
There is no evidence that long-term follow-up should include PET scanning.
More recently, though, PET scan results at the end of therapy for FL have been associated with prognosis, with patients with residual PET-avid disease at the end of treatment having a poorer prognosis than those who are PET negative, and so it may be used for this prognostic purpose.
Finally, magnetic resonance imaging (MRI) is useful in detecting bone, bone marrow, and CNS disease in the brain and spinal cord.
The staging evaluation is outlined in Table 113-5.
The International Prognostic Index (IPI) is perhaps the best predictor of outcome (Table 113-7).
The IPI was developed based on the analysis of >2000 patients with aggressive NHLs treated with an anthracycline-containing regimen.
Age (≤60 vs >60), serum LDH (≤ normal vs > normal), performance status (0 or 1 vs 2–4), stage (I or II vs III or IV), and extranodal involvement (1 site) were identified as independently prognostic for overall survival (OS).
A point is awarded for each risk factor and then summed, defining four risk groups: low (0 or 1); low-intermediate (2); high-intermediate (3); and high (4–5).
The 5-year OS rates for patients with scores of 0–1, 2, 3, and 4–5 were 73, 51, 43, and 26%, respectively.
The age-adjusted IPI separates patients ≤60 from patients >60.
For the age-adjusted IPI, only stage, LDH, and performance status were important.
Younger patients with 0, 1, 2, or 3 risk factors had 5-year survival rates of 83, 69, 46, and 32%, compared to 56, 44, 37, and 21% for older patients.
When factoring in the introduction and clinical benefit of rituximab, the 4-year progression-free survival rates are 94, 80, and 53% for 0–1, 2, or 3 or more risk factors, respectively.
The Follicular Lymphoma International Prognostic Index (FLIPI) is a similar predictive model for FL, derived from the analysis of >4000 patients.
The presence of >4 nodal sites, an elevated serum LDH concentration, and a hemoglobin 95% of the cases.
The most common partners are chromosomes 14, 2, or 22, rearrangements that produce fusions of MYC with either the IgH (80%), kappa (15%), or lambda (5%) light chain genes, respectively.
While exquisitely chemosensitive, it is imperative that treatment for BL be initiated quickly given the rapid doubling time and high morbidity of this disease.
There are several effective intensive combination chemotherapy regimens, all of which incorporate high doses of cyclophosphamide.
Prophylactic therapy to the CNS is mandatory.
Cure can be expected in 80–90% of patients when treated promptly and correctly.
Modified Magrath and dose-adjusted EPOCH-R (rituximab, infusional etoposide/vincristine/doxorubicin, cyclophosphamide, prednisone) are highly effective regimens.
Salvage therapy has been generally ineffective in patients whose disease progresses after upfront therapy, emphasizing the importance of the initial treatment approach and referral to a tertiary cancer center with experience treating this disease.
Diffuse Large B-Cell Lymphoma (DLBCL) is the most common histologic subtype of NHL diagnosed, representing about one-third of all cases.
It is slightly more common in Caucasians and men, and the median age at diagnosis is 64.
The relative risk (RR) of DLBCL is higher among people with affected first-degree relatives (RR 3.5-fold), and patients with congenital or acquired immunodeficiency, patients on immunosuppression, and patients with autoimmune disorders also have a higher risk of developing DLBCL, often EBV-related.
The majority of patients present with advanced-stage disease, with only 30–40% of patients having stage I or II disease.
~40% of patients will have "B" symptoms, and 50% of patients will have an elevated LDH.
Up to 40% of patients will have involvement of non–lymph node sites including bone marrow, CNS, gastrointestinal tract, thyroid, liver, and skin.
Patients with extensive bone marrow involvement or involvement of the testes, breast, kidney, adrenal gland, paranasal sinus, or epidural space are at increased risk of CNS dissemination.
The tumor consists of a diffuse proliferation of large, atypical lymphocytes with a high proliferative index.
These cells typically express the B-cell antigens CD19, CD20, and CD79a.
Expression of CD10 and BCL6 is consistent with the tumor cell being of germinal center origin (GCB), while the expression of MUM1 corresponds with the non–germinal center or ABC subtype.
BCL2 is overexpressed in anywhere from 25 to 80% of DLBCLs, whereas BCL6 is positive in more than two-thirds of cases, as the result of translocations, gain of copy number, or promoter mutations.
MYC is rearranged in 10% of DLBCLs, and ~20% of MYC-rearranged cases have a concurrent BCL2 rearrangement, a combination referred to as "double-hit lymphoma."
These double-hit lymphomas constitute one subtype of high-grade B-cell lymphoma (HGBL) and are associated with an extremely poor performance status or certain comorbid conditions who are not candidates for such approaches are often managed with palliative intentions.
Radiation to symptomatic areas of disease can be transiently helpful.
Less intensive chemotherapy with drugs such as gemcitabine, cytarabine, or bendamustine can help control disease and symptoms for a limited period of time.
Newer drugs including the CD79b ADC polatuzumab in combination with bendamustine and rituximab (BR), the high-affinity CD19 monoclonal antibody (mAb) tafasitamab in combination with lenalidomide, the CD19 ADC loncastuximab, and the CD20-CD3 bispecific antibodies epcoritamab and glofitamab have been approved for use in these palliative settings as well as for patients who relapse after CAR-T therapy or autologous stem cell transplantation.
Some of these agents can be used as a bridge to a definitive allogeneic stem cell transplantation.
For patients in whom more aggressive therapy is an option, treatment for late relapsing patients is with combination chemotherapy using various combinations of drugs primarily in order to identify patients with chemosensitive disease.
Patients with chemosensitive disease have the greatest likelihood of benefiting from high-dose chemotherapy and autologous stem cell transplant, which improves response duration and survival.

Flowcharts & Algorithms¶

Reproduced from Harrison's 22nd Edition.

Flowchart 1¶

Pathway of normal B-cell differentiation and relationship to B-cell used...

Caption: FIGURE 113-2 Pathway of normal B-cell differentiation and relationship to B-cell used to distinguish stages of development. Terminal transferase (TdT) is a cellular rearrangement or deletion (κR or D, λR or D) occur early in B-cell development. The shown. ALL, acute lymphoid leukemia; CLL, chronic lymphocytic leukemia; SL, small

Flowchart 2¶

Pathway of normal T-cell differentiation and relationship to T-cell lymphomas

Caption: FIGURE 113-3 Pathway of normal T-cell differentiation and relationship to T-cell lymphomas. CD1, CD2, CD3, CD4, CD5, CD6, CD7, CD8, CD38, and CD71 are cell markers used to distinguish stages of development. T-cell antigen receptors (TCR) rearrange in the thymus, and mature T cells emigrate to nodes and peripheral blood. ALL, acute lymphoid leukemia; CTCL, cutaneous T-cell lymphoma; NHL, non- Hodgkin’s lymphoma; T-ALL, T-cell ALL; T-CLL, T-cell chronic lymphocytic leukemia; T-LL, T-cell lymphoblastic lymphoma. translocations produce fusion genes that encode chimeric oncogenic proteins. Examples of this include the (2;5)(p23;q35) translocation involving the ALK and NPM1 genes in anaplastic large-cell lymphoma

Figures & Illustrations¶

Reproduced from Harrison's 22nd Edition.

Figure 1¶

Relative frequency of lymphoid malignancies

Caption: FIGURE 113-1 Relative frequency of lymphoid malignancies. ALL, acute lymphoid — FIGURE 113-1 Relative frequency of lymphoid malignancies. ALL, acute lymphoid leukemia; CLL, chronic lymphocytic leukemia; MALT, mucosa-associated lymphoid tissue.

Figure 2¶

Burkitt’s lymphoma

Caption: FIGURE 113-4 Burkitt’s lymphoma. The neoplastic cells are homogeneous, medium- sized B cells with frequent mitotic figures, a morphologic correlate of high growth fraction. Reactive macrophages are scattered through the tumor, and their pale cytoplasm in a background of blue-staining tumor cells gives the tumor a so-called starry sky appearance. — FIGURE 113-2 Pathway of normal B-cell differentiation and relationship to B-cell lymphomas. HLA-DR, CD10, CD19, CD20, CD21, CD22, CD5, and CD38 are cell markers used to distinguish stages of development. Terminal transferase (TdT) is a cellular enzyme. Immunoglobulin heavy chain gene rearrangement (HCR) and light chain gene rearrangement or deletion (κR or D, λR or D) occur early in B-cell development.

Figure 3¶

Follicular lymphoma

Caption: FIGURE 113-6 Follicular lymphoma. The normal nodal architecture is effaced by nodular expansions of tumor cells. Nodules vary in size and contain predominantly small lymphocytes with cleaved nuclei along with variable numbers of larger cells of with vesicular chromatin and prominent nucleoli. of While >85% of FLs will harbor a t(14;18) and overexpress the anti- apoptotic protein BCL2, this genetic event is necessary but not suffi- cient for malignant transformation of the B lymphocytes, and multiple genetic events are required for the development of FL. Studies have — FIGURE 113-3 Pathway of normal T-cell differentiation and relationship to T-cell lymphomas. CD1, CD2, CD3, CD4, CD5, CD6, CD7, CD8, CD38, and CD71 are cell markers used to distinguish stages of development. T-cell antigen receptors (TCR) rearrange in the thymus, and mature T cells emigrate to nodes and peripheral blood.

Figure 4¶

Diffuse large B-cell lymphoma

Caption: FIGURE 113-5 Diffuse large B-cell lymphoma. The neoplastic cells are heterogeneous but predominantly large cells with vesicular chromatin and prominent nucleoli. — FIGURE 113-4 Burkitt's lymphoma. The neoplastic cells are homogeneous, medium-sized B cells with frequent mitotic figures, a morphologic correlate of high growth fraction. Reactive macrophages are scattered through the tumor, and their pale cytoplasm in a background of blue-staining tumor cells gives the tumor a so-called starry sky appearance.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.