Non-Hodgkin Lymphoma

Catherine Lai

Mark Roschewski

Wyndham H. Wilson

I. INTRODUCTION

Non-Hodgkin lymphomas (NHLs) are a diverse group of malignant neoplasms involving lymphocytes of B-cell, T-cell, or natural killer (NK)-cell origin.¹ Significant variation exists across individual entities with respect to the natural history, underlying biology, and response to therapy, but in all lymphomas the malignant clones have acquired properties of uncontrolled proliferation coupled with dysfunctional apoptosis. Tumor clonality of the specimen is established by demonstrating immunoglobulin (Ig) gene rearrangement or lightchain restriction in B-cells, T-cell receptor rearrangement in T-cells, or methods that identify recurrent translocations by fluorescent in situ hybridization or polymerase chain reaction (PCR). Most lymphomas predominantly involve the lymphatic system, but they can arise in almost any extranodal site such as the spleen, bone marrow, bones, central nervous system (CNS), lung, gastrointestinal tract, and the skin.

It is now appreciated that NHLs arise from a combination of intrinsic genetic events that occur within the cell and favorable conditions in the tumor cell’s local microenvironment. The tumor cell and the local microenvironment both contribute to disease progression and both can be targeted with emerging novel therapies. Advances in the technology used to study the underlying biology of lymphoid tumors, such as gene-expression profiling (GEP) of tumors and next-generation sequencing, have improved our understanding of biologic differences across lymphomas.²,³,⁴,⁵,⁶,⁷ Despite these advances, a complete characterization of the genetic, epigenetic, and environmental events underlying lymphomagenesis has not been achieved.

II. EPIDEMIOLOGY AND RISK FACTORS OF NHL

A. Epidemiology

NHL is the seventh most common cancer overall and the most common hematologic malignancy. It is estimated that 70,800 cases of NHL will be diagnosed in the United States in 2014, and accounting for 4.3% of all new cancer diagnoses.⁸ Worldwide incidence of NHL also has important geographical distribution in certain subtypes of NHL (Table 23.1). B-cell lymphomas represent about 80% to 85% of all cases, with T-cell lymphomas being represented in the other 15% to 20% of cases and NK-cell lymphomas extremely rare. There is a male predominance in almost all subtypes for unknown reasons. Even though NHL occurs in persons of all ages, the incidence
rises steadily with age. The median age of patients at the time of diagnosis of NHL is between 65 and 74 years of age, which may affect therapeutic decisions. From the early 1970s to the late 1990s, the incidence of NHL in the United States dramatically rose at a rate of about 4% per year but since the early 2000s the incidence began to rise slower and appears to be stable in the last few years. Death rates from NHL overall have been decreasing by 2.6% per year between 2002 and 2011, but some subtypes such as T-cell lymphomas have a particularly dismal prognosis. Mortality rates are higher for patients living in lower socioeconomic neighborhoods, with the disparity being higher among younger patients.⁸

TABLE 23.1 Geographical Distribution of Certain NHLs

Lymphoma	Distribution
Adult T-cell lymphocytic leukemia	Caribbean, Southern Japan, Africa
Angioimmunoblastic T-cell lymphoma	Europe > North America
BL (endemic form)	Equatorial Africa
Gastric lymphoma	Northern Italy, Japan
T-/NK cell lymphomas, nasal-type	China, South America
BL, Burkitt lymphoma; NHL, non-Hodgkin lymphoma; NK, natural killer.
Source: Muller AM, Ihorst G, Mertelsmann R, et al. Epidemiology of non-Hodgkin’s lymphoma (NHL): trends, geographic distribution, and etiology. Ann Hematol. 2005;84:1-12.

B. Risk factors

Consistent with a model of acquired somatic mutations that accumulate throughout one’s life, an increased risk of NHL is associated with advanced age.⁹ Additional factors that increase one’s lifetime risk to develop NHL are important to recognize (Table 23.2).

An inherited genetic susceptibility does not appear to account for most cases of NHL, but there is an increased risk for NHL in close relatives of patients with lymphoma. Lymphoma is often diagnosed in the setting of underlying immunodeficiency or autoimmunity highlighting the complex interplay between NHL and the immune system.¹⁰ These conditions can be divided into congenital (or primary) immunodeficiencies and acquired (or secondary) immunodeficiencies (Table 23.3).

Many lymphomas are associated with an underlying virus that either drives the lymphoma or impairs the immune surveillance of the host increasing the risk of developing NHL.¹¹ For example, the increased incidence of NHL in the 1970s to 1990s was due, in part, to the increase in human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). It is probable that defects in immune surveillance (particularly in T-cell immunity) result in unregulated B-cell proliferation in lymphoid tissue, often in association with
chronic antigen stimulation from infections such as the Epstein-Barr virus (EBV) or Human Herpesvirus-8 (HHV-8). Rare, extranodal T-cell lymphomas, such as enteropathy-associated T-cell lymphoma (EATCL), occur in the setting of celiac sprue, and hepatosplenic T-cell lymphoma (HSTCL) typically occurs in patients with a history of solid organ transplantation, inflammatory bowel disease, systemic lupus erythematosus, Hodgkin lymphoma, and malarial infection.¹²

TABLE 23.2 Factors Associated With an Increased Risk of NHL

▪	Immunosuppression, acquired
▪	Congenital immunodeficiency syndromes
▪	Increasing age
▪	Family history of NHL
▪	Silicone breast implants
▪	Drugs
	▪ Immunosuppressive agents
	▪ Phenytoin
	▪ Methotrexate
	▪ Tumor necrosis factor inhibitors
▪	Radiation therapy
▪	Occupational exposures
	▪ Exposure to herbicides, pesticides, wood dust, epoxy glue, solvents, Agent Orange
	▪ Farming, forestry, painting, carpentry, tanning
NHL, non-Hodgkin lymphoma.
Source: Zhang Y, Dai Y, Zheng T, et al. Risk factors of non-Hodgkin lymphoma. Expert Opin Med Diagn. 2011;5:539-550.

TABLE 23.3 Immune-Related Conditions that Predispose to NHL

Congenital	Acquired
Ataxia telangiectasia	Solid organ transplantation
Wiskott-Aldrich syndrome	Stem-cell transplantation (higher if T-cell depleted)
	AIDS
Severe combined immunodeficiency	Sjögren syndrome
Common variable immunodeficiency	Rheumatoid arthritis
Hyper immunoglobulin M (Job syndrome)	Hashimoto thyroiditis
X-linked hypogammaglobulinemia	Inflammatory bowel disease
X-linked lymphoproliferative syndrome	Celiac sprue
Autoimmune lymphoproliferative syndrome	Malarial infection Hodgkin lymphoma
NHL, non-Hodgkin lymphoma.
Source: Engels EA, Cerhan JR, Linet MS, et al. Immune-related conditions and immune-modulating medications as risk factors for non-Hodgkin’s lymphoma: a case-control study. Am J Epidemiol. 2005;162:1153-1161.

In addition to viruses, other infectious agents have specific clinical associations with subtypes of NHL (Table 23.4). Chronic
hepatitis C infection increases the risk of indolent B-cell lymphomas, and Helicobacter pylori infection can be identified in over 90% of cases of gastric mucosa-associated lymphoid tissue (MALT) lymphoma.¹³,¹⁴ In some cases of antigen-driven lymphomas, eradication of the infectious agent can result in remission of the lymphoma.

TABLE 23.4 Infectious Agents Associated With NHL

Infectious Agent	Lymphoma
EBV	Burkitt lymphoma, EBV+ DLBCL of the elderly, extranodal NK/T-cell lymphoma, lymphomatoid granulomatosis, PTLD, systemic EBV+ T-cell lymphoproliferative disorder of childhood, hydroa vacciniformelike T-cell lymphoma
Human T-cell lymphotropic virus type I	ATLL
Helicobacter pylori	Gastric MALT
Hepatitis C	Marginal zone lymphoma; lymphoplasmacytic lymphoma, nodal
Human herpesvirus 8 (formerly KSHV)	Primary effusion lymphoma, plasmablastic lymphoma
Human immunodeficiency virus (HIV)	DLBCL, Burkitt lymphoma, PCNSL, primary effusion lymphoma, plasmablastic lymphoma
Borrelia burgdorferi	Cutaneous B-cell lymphoma
Chlamydia psittaci	Ocular adnexal MALT
Chlamydia trachomatis	Pulmonary MALT
Chlamydia pneumonia	Pulmonary MALT
Campylobacter jejuni	Small intestine MALT
EBV, Epstein-Barr virus; NK, natural killer cell; PTLD, post-transplant lymphoproliferative disorder; ATLL, adult T-cell leukemia/lymphoma; MALT, mucosa-associated lymphoid tissue; KSHV, Kaposi’s sarcoma-associated herpesvirus; DLBCL, diffuse large B-cell lymphoma; PCNSL, primary central nervous system lymphoma.
Source: Engels EA. Infectious agents as causes of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2007;16:401-404.

Increased scrutiny has recently been placed on the risks of repeated exposure to ionizing radiation in the form of contrast-enhanced imaging scans as well as the risk of therapeutic radiation.¹⁵,¹⁶ It is clear that exposure to radiation increases the lifetime risk of developing NHL, especially in younger patients. Modern radiotherapy treatment protocols attempt to mitigate this risk by delivering lower doses of radiation or using alternative modalities such as proton therapy, but the long-term risk reduction is currently unknown.

III. CLASSIFICATION OF NHL

The classification systems for lymphomas have changed frequently since they were first introduced in the 1950s. Ideally, a classification system should identify types of NHL that are scientifically and clinically meaningful as well as those that are relatively homogeneous from a clinical, morphologic, immunologic, and genetic perspective. The systems have evolved along with available technology and scientific discovery from ones that rely heavily on morphologic descriptions to the current working system that incorporates morphology, immunophenotypic characteristics, cytogenetic and molecular abnormalities, and clinical variables.

In 1956, Henry Rappaport of the U.S. Armed Forces Institute of Pathology proposed a very simple and reproducible classification system on the basis of the growth pattern of the disease (nodular vs. diffuse) as well as the appearance of the predominant cell as well differentiated, poorly differentiated, undifferentiated, or histiocytic. This was followed in the 1970s by the Lukes-Colins-Lennert classification system that related morphology to lymphocyte lineage by dividing entities into B-cell and T-cell disorders on the basis of their cell-surface markers; however, they still did not address clinical concerns and were not uniformly utilized internationally.¹⁷

In the 1980s, the New Working Formulation defined broad categories of lymphoma on the basis of general clinical prognosis of either low grade, intermediate grade, or high grade in order to assist the clinician in treating the lymphoma. The system, however, did not include information regarding immunophenotype, and therefore was difficult to reproduce and did not foster recognition of new entities.

In 1994, the International Lymphoma Study Group developed a consensus list of diseases that could be recognized by pathologists and that appeared to be distinct clinical entities called the Revised European-American Classification of Lymphoid Neoplasms classification system, which ultimately became the World Health Organization (WHO) classification system: the first international consensus on the classification of hematologic malignancies.¹⁸ The original classification system, published in 2001, defined diseases by four features: morphology, immunophenotype, genetics, and clinical information. The updated 2008 version (Table 23.5) increases the use of both molecular profiles and clinical presentations to define separate clinicopathologic entities.¹

Newly recognized entities in the WHO 2008 classification system include “gray-zone” lymphomas, which are intermediate between two distinct lymphomas. The inclusion of these entities demonstrates that, in some cases, the ability to distinguish between lymphomas is difficult.

IV. STAGING OF NHL

A. Making the diagnosis

The most critical initial step in a patient with suspected NHL is ensuring the accuracy of the pathologic diagnosis. The adequacy of

the original biopsy procurement procedure is essential and should be representative of the disease (not necessarily the most accessible). In general, fine-needle aspiration is not sufficient to accurately classify NHLs, and excisional lymph-node biopsies are preferred. In situations where involved nodes are not easily accessible, multiple core biopsies can substitute. When T-cell lymphomas are suspected, expertise is essential as the discordant rate can be as high as 15%.¹⁹

TABLE 23.5 WHO 2008 Classification of Lymphoid Neoplasms

Precursor Lymphoid Neoplasms
▪	B lymphoblastic leukemia/lymphoma NOS
▪	B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
	▪	t(9:22)(q34;q11.2); BCR-ABL1
	▪	t(v;11q23); MLL rearranged
	▪	t(12:21)(p13;q22); TEL-AML1 (ETV6-RUNX1)
	▪	With hyperdiploidy
	▪	With hypodiploidy
	▪	t(5:14)(q31;q32); IL3-IGH
	▪	t(1:19)(q23;p13.3); E2A-PBX1(TCF3-PBX1)
▪	T lymphoblastic leukemia/lymphoma
Mature B-Cell Neoplasms
▪	SLL/CLL
▪	B-cell prolymphocytic leukemia
▪	Splenic B-cell MZL
▪	Hairy cell leukemia
▪	Splenic B-cell lymphoma/leukemia, unclassifiable
	▪	Splenic diffuse red pulp small B-cell lymphoma
	▪	Hairy cell leukemia-variant
▪	Lymphoplasmacytic lymphoma
▪	Heavy-chain diseases
	▪	Gamma heavy-chain disease
	▪	Mu heavy-chain disease
	▪	Alpha heavy-chain disease
▪	Plasma cell neoplasms
	▪	Monoclonal gammopathy of undetermined significance
	▪	Plasma cell myeloma
	▪	Solitary plasmacytoma of bone
	▪	Extraosseous plasmacytoma
	▪	Monoclonal immunoglobulin deposition diseases
▪	Extranodal marginal zone B-cell lymphoma of MALT
▪	Nodal marginal zone B-cell lymphoma
▪	FL
▪	Primary cutaneous follicle center lymphoma
▪	Mantle cell lymphoma
▪	DLBCL, NOS
	▪	T-cell/histiocyte-rich large B-cell lymphoma
	▪	Primary DLBCL of the CNS
	▪	Primary cutaneous DLBCL, leg type
	▪	EBV-positive DLBCL of the elderly
▪	DLBCL associated with chronic inflammation
▪	Lymphomatoid granulomatosis
▪	Primary mediastinal (thymic) large B-cell lymphoma
▪	Intravascular large B-cell lymphoma
▪	ALK+ large B-cell lymphoma
▪	Plasmablastic lymphoma
▪	Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease
▪	Primary effusion lymphoma
▪	BL
▪	B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL
▪	B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma
Mature T- and NK-Cell Neoplasms
▪	T-cell prolymphocytic leukemia
▪	T-cell large granular lymphocyte leukemia
▪	Chronic lymphoproliferative disorder of NK cells
▪	Aggressive NK-cell leukemia
▪	EBV-positive T-cell lymphoproliferative diseases of childhood
	▪	Systemic EBV+ T-cell lymphoproliferative disease of childhood
	▪	Hydroa vacciniforme-like lymphoma
▪	Adult T-cell lymphoma/leukemia
▪	Extranodal NK-/T-cell lymphoma nasal type
▪	Enteropathy-associated T-cell lymphoma
▪	Hepatosplenic T-cell lymphoma
▪	Subcutaneous panniculitis-like T-cell lymphoma
▪	Mycosis fungoides (CTCL)
▪	Sézary syndrome
▪	Primary cutaneous CD30-positive T-cell lymphoproliferative disorders
▪	Primary cutaneous PTCLs, rare subtypes
	▪	Primary cutaneous gamma-delta T-cell lymphoma
	▪	Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma
	▪	Primary cutaneous CD4-positive small/medium T-cell lymphoma
▪	PTCL-NOS
▪	Angioimmunoblastic T-cell lymphoma
▪	Anaplastic large-cell lymphoma, ALK⁺
▪	Anaplastic large-cell lymphoma, ALK^–
Immunodeficiency-Associated Lymphoproliferative Disorders
▪	Lymphoproliferative diseases associated with primary immune disorders
▪	Lymphomas associated with HIV infection
▪	PTLD
	▪	Plasmacytic hyperplasia and infectious-mononucleosis-like PTLD
	▪	Polymorphic PTLD
	▪	Monomorphic PTLD
	▪	Classical Hodgkin lymphoma-type PTLD
▪	Other iatrogenic immunodeficiency-associated lymphoproliferative disorders
BL, Burkitt lymphoma; CLL, chronic lymphocytic leukemia; CNS, central nervous system; CTCL, cutaneous T-cell lymphomas; DLBCL, diffuse large B-cell lymphoma; EBV, Epstein-Barr virus; FL, follicular lymphoma; HHV8, human herpesvirus 8; HIV, human immunodeficiency virus; MZL, marginal zone lymphoma; NK, natural killer; NOS, not otherwise specified; PTCL, peripheral T-cell lymphomas; PTLD, posttransplant lymphoproliferative disorder; SLL, small lymphocytic lymphoma; WHO, World Health Organization.

B. Recommended workup and imaging

Accurate assessment of tumor burden prior to therapy is a prognostic tool and serves as a baseline for determining treatment response. The staging evaluation of NHL begins with a history focused on the pace of the disease at presentation, the presence or absence of B symptoms (fevers, drenching night sweats, unintentional weight loss greater than 10% of body weight over 6 months or less), possible sites of nodal and extranodal involvement, and signs suggestive of a possible underlying immunodeficiency. When performing the physical examination, special care must be given to examining the Waldeyer ring, epitrochlear nodes, and popliteal nodes, which may be difficult to measure on radiographic imaging, as well as examining for sites of extranodal involvement such as the skin and abdomen for signs of hepatosplenomegaly. Recommended tests that supplement the history and physical examination at the time of diagnosis are listed in Table 23.6.

C. Ann Arbor staging

The Cotswold modification of the Ann Arbor classification is generally used to stage patients with newly diagnosed NHL and is shown in Table 23.7.²⁰ Anatomy-based imaging such as contrast-enhanced
computed tomography (CT) scans (or magnetic resonance imaging for patients with contrast allergies) is the gold standard for determining which nodal chains are involved with lymphoma. Lymph nodes are considered involved if the long axis is ≥1.5 cm (regardless of short axis) or if the long axis is ≥1.1 cm and the short axis is >1.0 cm. Lymph nodes that are ≤1.0 cm in both axes are considered uninvolved.²¹ Determining the stage of lymphomatous involvement on the basis of anatomic imaging alone misses nodes that are involved but not enlarged and can easily miss extranodal sites of disease such as bony involvement, which may affect treatment recommendations.

TABLE 23.6 Recommended Workup of Newly Diagnosed NHL

▪ Adequate biopsy specimen with tissue sent for flow cytometry and molecular studies

▪ Complete blood count

▪ LDH

▪ Comprehensive metabolic panel

▪ Uric acid

▪ Beta-2 microglobulin

▪ HIV

▪ Hepatitis B surface antigen

▪ Chest-abdominal-pelvic CT with contrast

▪ ¹⁸Fluoro-2-deoxy-D-glucose PET/CT scan

▪ Lumbar puncture with flow cytometry of CSF (in select cases)

▪ Unilateral bone marrow biopsy with aspirate

▪ Assessment of ejection fraction with multigated acquisition scan or echocardiogram

▪ Pregnancy testing in women

▪ Discussion of pregnancy and fertility issues

CSF, cerebro-spinal fluid; CT, computed tomography; LDH, lactate dehydrogenase; NHL, non-Hodgkin lymphoma; PET, positron emission tomography.

TABLE 23.7 Staging System for NHL

Ann Arbor Staging Classification for NHLs
Stage	Description
I	Involvement of a single lymph-node region (I) or involvement of a single extralymphatic organ or 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 site (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
A	Asymptomatic
B	Unexplained persistent or recurrent fever with temperature higher than 38°C or recurrent drenching night sweats within 1 month or unexplained loss of more than 10% body weight within 6 months
E	Limited direct extension into extralymphatic organ from adjacent lymph node
X	Bulky disease (mediastinal tumor width greater than one-third transthoracic diameter at T5-T6 or tumor diameter larger than 10 cm)
NHL, non-Hodgkin lymphoma.
Source: Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the committee on Hodgkin’s disease staging classification. Cancer Res. 1971;31:1860-1861.

Accurate assessment of disease involvement can be improved with the use of functional imaging such as positron emission tomography (PET) scans. ¹⁸Fluorodeoxyglucose (FDG)-PET scans and PET/CT scans exploit the enhanced rate of glucose utilization (both uptake and phosphorylation) seen in many tumor cells as compared with normal surrounding cells (the Warburg effect).²² Thus, ¹⁸FDG-PET scans can provide a semiquantitative measurement of tumor involvement in NHLs, and have improved sensitivity to identify extranodal and bony lesions.

V. PROGNOSIS OF NHL

A. Clinical prognostic index scores

The prognosis of patients with newly diagnosed NHL involves more than just Ann Arbor staging, and clinical prognostic index scores were developed as a means to better understand pretreatment prognosis beyond stage alone. The first example was the International Prognostic Index (IPI) score that was developed in diffuse large B-cell lymphoma (DLBCL) to stratify patients into quartiles with differing probabilities of both complete response as well as 5-year disease-free survival (DFS).²³ The IPI score uses the five variables of age, stage, performance status, number of extranodal sites of disease, and lactate dehydrogenase (LDH) level. For all patients, 5-year survival was 73% for low-risk patients, 51% for low/intermediaterisk patients, 43% for high/intermediate-risk patients, and 26% for high-risk patients (Table 23.8). For patients under the age of 60 years, a slightly modified age-adjusted prognostic system was developed, in which the 5-year survival was 83% for low-risk patients, 69% for low/intermediate-risk patients, 46% for high/intermediate-risk patients, and 32% for high-risk patients (Table 23.9).

TABLE 23.8 International Prognostic Index for NHL

Risk Factors	Definition		Risk Category	Number of Risk Factors
Age	>60 years		Low	0-1
LDH	>1 × normal	Predictive model	Low intermediate	2
		→
ECOG performance status	>1	Aggressive NHL	High intermediate	3
Stage	III/IV		High	4-5
Extranodal sites	>1
Risk Category	% Cases	CR (%)	Five-Year DFS of CR (%)	*Overall Survival^ (%)**
Low	35	87	70	73
Low/intermediate	27	67	51	51
High/intermediate	22	55	49	43
High	16	44	42	26
CR, complete remission; DFS, disease-free survival; ECOG, Eastern Cooperative Oncology Group; NHL, non-Hodgkin lymphoma.
^Histologies: Diffuse mixed, diffuse large, and immunoblastic. Source: A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med*. 1993;329:987-994.

TABLE 23.9 Age-Adjusted International Prognostic Index for DLBCL^*

Patients Aged <60 Years	0 points	1 point
Stage	I or II	III or IV
Performance status	0 or	1 ≥2
LDH	Normal	Elevated
DLBCL, diffuse large B-cell lymphoma.
^*Risk category: Low risk, 0 points; low/intermediate risk, 1 point; high/intermediate risk, 2 points; high risk, 3 points.

The IPI cannot be extrapolated to other NHL subtypes, so other clinical prognostic scores have been created to account for other variables that affect outcomes in indolent lymphomas. Follicular lymphoma (FL) is typically a widespread disease at presentation that frequently involves multiple nodal chains and the bone marrow, even in cases in which the natural history of the tumor growth will be slow. Also, it is common for patients to experience no symptoms attributable to the disease despite the widespread amount of tumor burden. On the basis of multivariate analysis collected on over 4,000 patients and ultimately validated on almost 1,000 patients, a five-variable prognostic index was constructed: the Follicular Lymphoma International Prognostic Index (FLIPI; Table 23.10).²⁴ Despite its widespread use in clinical trials, however, the FLIPI does not define for clinicians which patients should be treated at time of diagnosis.

In an attempt to improve on the FLIPI, an international project was conducted on over 1,000 patients with newly diagnosed FL; all were treated with rituximab-based regimens. A prognostic score was also determined from this data set of five variables that could also separate patients into three separate risk groups, termed the F2 (Table 23.11).²⁵ The strengths of the F2 score are that it includes readily available clinical variables and was derived from patients treated with rituximab.

B. GEP as prognostic tools

As opposed to clinical variables that may be dominated by extent of disease burden, there has been great interest in attempting to define and predict the clinical behavior of lymphomas on the basis of the expression of genes on tissue microarray.²⁶ With the advent of GEP, which can simultaneously analyze the relative expression of thousands of genes at one time on an individual’s tissue sample, it has become possible to predict outcomes on the basis of the molecular profile of the tissue. One example of this exists in DLBCL, which can be subdivided into three categorical subtypes: germinal center
B-cell (GCB) subtype, activated B-cell (ABC) subtype, and primary mediastinal B-cell lymphoma (PMBL).²,³,²⁷ All three of these subtypes have a widely different prognosis (independent of IPI score), with the GCB subtype responding more favorably to standard chemotherapy regimens than the ABC subtype and the mediastinal B subtype with the best overall prognosis (59%, 30%, and 64% 5-year survivals, respectively). GEP was first developed using frozen tissue, which is not always readily available. More recently, a new digital gene-expression technique has been developed that can be used on formalin-fixed paraffin-embedded tissue, potentially making this means of risk stratification more readily available in the future.²⁸

TABLE 23.10 Follicular Lymphoma International Prognostic Index (FLIPI)

▪ Score one point for each factor:
▪ Age ≥60 years
▪ Ann Arbor stage III-IV
▪ Hemoglobin level <12 g/dL
▪ Serum LDH level > upper limit of normal
▪ Number of nodal sites ≥5
Score	Risk Group	Five-Year OS (%)
0-1	Low	90.6
2	Intermediate	77.6
≥3	High	52.5
OS, overall survival.
Source: Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. 2004;104:1258-1265.

TABLE 23.11 F2 Prognostic Model

▪ Score one point for each factor:
▪ Age >60 years
▪ Hemoglobin level <12 g/dL
▪ Serum B2 microglobulin > upper limit of normal
▪ Longest diameter of the largest involved lymph node longer than 6 cm
▪ Bone marrow involvement
Score	Risk Group	Three-Year PFS (%)	Five-Year PFS (%)
0	Low	90.9	79.5
1-2	Intermediate	69.3	51.2
3-5	High	51.3	18.8
PFS, progression-free survival.
Source: Federico M, Bellei M, Marcheselli L, et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol. 2009;27:4555-4562.

C. Interim imaging scans performed during therapy

In addition to providing a tool for staging patients, ¹⁸FDG-PET scanning also has the potential to serve as an interim functional biomarker during therapy for aggressive lymphomas to predict which patients are responding to therapy and which ones are likely to fail induction.²⁹,³⁰ Patients who achieve a negative PET scan during therapy have a better prognosis than those who remain PET positive on interim imaging scans. Thus, risk-adapted or response-adapted approaches were developed on the basis of the premise that early identification of the patients who are failing therapy allows for an earlier switch to alternative treatment. Unfortunately, the clinical results from such response-adapted approach in DLBCL have not shown that changing therapy can overcome the poor prognosis of a positive interim PET scan. Future research likely will continue to test these and other biomarkers during therapy, but treatment decisions based on interim PET scanning cannot be recommended.

D. Response assessment at the end of therapy

The International Working Group published guidelines in 1999 for response assessment and outcomes measurement rely mainly on CT scans. However, the widespread use of PET scans prompted another revision in 2007, referred to as the Revised Response Criteria for Malignant Lymphoma.³¹ The guidelines included recommendations on definition of a positive PET scan, timing of PET scans, and measurement of response. The most recent modernization of recommendations for initial evaluation, staging, and response assessment called The Lugano Classification was published in 2014.³² The major changes included the following: PET is used to assess response in FDG-avid histologies using the 5-point scale, with CT being preferred in low or variable FDG avid lymphomas; a complete remission is defined by negative PET even in the presence of a persistent mass; and surveillance PET scans after remission are discouraged in aggressive lymphomas.

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Sep 16, 2016 | Posted by drzezo in ONCOLOGY | Comments Off

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