Non-Hodgkin Lymphoma in Adults

John P. Greer

Nishitha M. Reddy

Michael E. Williams

HISTORICAL PERSPECTIVE

Thomas Hodgkin was the first to recognize that lymphadenopathy could occur as a primary disorder rather than secondary to infection or carcinoma in his 1832 paper entitled, “On Some Morbid Appearances of the Absorbent Glands and Spleen.”¹ Since Hodgkin’s initial description, there have been four historical phases in the study of non-Hodgkin lymphoma (NHL): (1) clinical features, 1832 to 1900; (2) histopathology, 1900 to 1972; (3) immunopathology, 1972 to the present; and (4) molecular genetics, 1982 to the present. These phases naturally overlap and all contribute to the understanding of NHL.²

From 1863 to 1865, Virchow introduced the terms aleukemia and lymphosarcoma to distinguish lymphoproliferative diseases from leukemia³ and in 1871, Billroth used the term malignant lymphoma for a vague collection of primary lymphoid disorders.⁴ In 1893, Kundrat proposed that the term lymphosarcoma was more specific than the term originally used by Virchow and should be reserved for the sarcomatous tumors of lymph nodes.⁵

At the turn of the last century, Sternberg⁶ and Reed⁷ identified the giant cells characteristic of Hodgkin lymphoma (HL) and introduced histopathology as a method for diagnosis and classification of lymphoma. Brill⁸ and Symmers⁹ described follicular lymphoma (FL) in the 1920s and indicated it was a malignant, albeit indolent, disorder. Ewing (1914), Oberling (1928), and Roulet (1930) used the term reticulum cell sarcoma which came to be used for large cell lymphoma and was distinct from lymphosarcoma, mainly composed of small lymphocytes.¹⁰ In 1941, Gall and Mallory developed a classification scheme on NHL that had both clinical and histopathologic significance.¹¹ The histopathologic phase of NHL culminated in the 1956 classic work of Rappaport who developed a morphologic classification which stratified cases according to the pattern of growth with nodular replacing follicular and contrasting with diffuse.¹² There were four categories of lymphoma: well differentiated lymphocytic, poorly differentiated lymphocytic, mixed lymphocytic and histocytic, and histocytic.

In 1967, Good and Finstad discussed the relationship of B and T cells to lymphoid neoplasia, and Dameshek introduced the concepts that lymphomas were aberrations of immunologically competent cells and that transformation of lymphocytes to “blast” forms (immunoblasts) could occur secondary to antigenic stimulation.⁴ In 1972, the immunologic origin of lymphoid neoplasia was confirmed by the presence of monotypic immunoglobulin (Ig) on the cell surface (B cell) or by sheep erythrocyte rosette formation with neoplastic cells (T cell).¹³, ¹⁴ Lymphoblastic lymphoma (LBL) was determined to originate from thymocytes by Smith in 1973.¹⁵ Barcos and Lukes described the clinicopathologic features of “convoluted lymphocytic lymphoma” of thymic origin and used the term LBL, which was later preferred by Nathwani because of similarities to blasts of T cell acute lymphoblastic leukemia (ALL).¹⁴, ¹⁶

In 1974, Lennert in Kiel, Germany, and Lukes and Collins in the United States classified NHL on the basis of the cell of origin within the immune system (Fig. 88.1).¹⁷, ¹⁸ Subsequently, monoclonal antibodies to lymphocyte differentiation antigens have been able to detect sequential stages in the development of B and T cells and to identify subtypes of NHL. Recurrent cytogenetic translocations involving the IG gene locus on chromosome 14 were identified in Burkitt lymphoma (BL) in 1976 and in FL in 1979.¹⁹, ²⁰ In the 1980s, the lymphoid origin of NHL was confirmed at the molecular level with the identification of specific IG gene and T cell receptor (TCR) gene rearrangements in B and T cell lymphomas, respectively.²¹, ²²

In 1982, a Working Formulation (WF) of NHL separated diseases according to histologic grade and made correlations with survival; however, the WF lumped disparate diseases together by basing the diagnosis on morphology without utilizing immunophenotyping or molecular genetic techniques. The laboratories of Leder and Croce in 1982 identified MYC as the gene translocated from chromosome 8 to the IG genes in BL.²⁰, ²³, ²⁴ Subsequently, the genes defining FL, BCL2/IGH, and mantle cell lymphoma, CCND1/IGH, were described.²³, ²⁴ Recurrent translocations were less commonly seen in T cell lymphomas, but novel genes were translocated with the loci of T cell receptor genes in T-LBL/ALL. In 1989, a proportion of T-anaplastic large cell lymphomas (ALCL) were found to have t(2;5) (p23-, q35);²⁵ and in 1994, Morris identified the genes, ALK/NPM, involved in the translocation.²⁶

Issacson and Stein formed an international group of pathologists, International Lymphoma Study Group (ILSG), to develop a consensus about diagnosis and terminology of lymphoid neoplasms.² In 1994, a Revised European-American Lymphoma (REAL) classification was proposed to identify specific types of lymphomas of B and T cell origin.²⁷ The REAL classification dropped the grading schema of lymphomas and developed a diagnosis by identifying clinical features, morphology, immunophenotype, and genetic data when available. An International Lymphoma Classification Project organized by Armitage affirmed the clinical utility and the reproductibility of the REAL classification.²⁸ The World Health Organization (WHO) has adopted the diagnostic principles of the REAL classification, and the WHO classification is utilized as the schema for diagnosis of all hematopoietic neoplasms.

EPIDEMIOLOGY

There is a worldwide epidemic of NHL that varies according to gender, race, and geography. The rise in NHL has been faster than that of all other malignancies except lung cancer in women, melanoma, and prostate cancer.²⁹ The age-adjusted incidence of NHL in the United States increased from 11.1 per 100,000 people in 1975 to 19.3 in 2002; there has been a plateau in the incidence with 19.6 in 2009. There were approximately 484,000 people (250,000 men and 232,000 women) alive in 2009 with a history of NHL. More than 70,000 new cases will be diagnosed and nearly 19,000 will die of NHL in the United States (US) in 2012.³⁰ Worldwide, 356,000 new cases of NHL occurred in 2008 and over 191,000 deaths were due to NHL.³¹

Part of the increase was attributed to the development of NHL in patients with the acquired immunodeficiency syndrome (AIDS); however, there are a large number of other possible contributing factors to the epidemic (Table 88.1). Improvement in disease detection and cancer registration have likely played a role. Even before the AIDS crisis, there was a steady increase of 3% to 4% per year from the 1970s up until the early 1990s, when there was even a drop-off in some subgroups of patients (Fig. 88.2). Part of the drop-off is attributed to the introduction of highly active anti-retroviral therapy (HAART) for AIDS patients.³² The consensus is that the increase in NHL remains unexplained by either the AIDS crisis or improvements in diagnosis.

FIGURE 88.1. Cellular origins of non-Hodgkin lymphoma by B and T cell differentiation pathways. B and T cells originate in the marrow, where they are antigen independent. The follicular center is a normal site of antigen-dependent B cells which go through different stages: (a) proliferation of centroblasts (large noncleaved cells), (b) selection of centrocytes (small cleaved cells) or cell death via apoptosis, (c) differentiation into postgerminal center memory B lymphocytes or plasma cells, often in association with increased antigen affinity and an immunoglobulin isotope switch. The T cells depend upon the thymus for early differentiation before becoming peripheral T cells. The most immature T cell precursors are negative for both CD4 and CD8. Thymocytes can become committed to either the gamma-delta or alpha-beta lineage. As thymocytes within the alpha-beta lineage mature they gain CD4 and then CD8 to become double positive thymocytes. Normal thymocytes downregulate the expression of CD4 or CD8 to become mature peripheral T cells, which are subdivided into helper (CD4⁺) and suppressor/cytotoxic (CD⁸⁺) subsets. Corresponding lymphomas are based on stage of cellular differentiation and site(s) of nodal and/or extranodal origin. BCL, precursor B cell lymphoblastic lymphoma; SLL, small lymphocytic lymphoma; MZL, marginal zone lymphoma (MALT types, postgerminal center); MCL, mantle cell lymphoma (pre-germinal center); FL, follicular lymphoma; DLBCL, diffuse large B cell lymphoma; TCL, precursor T cell lymphoblastic lymphoma; ALCL, anaplastic large cell lymphoma (sinus involvement). Peripheral T/NK lymphomas tend to involve the interfollicular zone of lymph nodes or specific extranodal sites.

TABLE 88.1 EPIDEMIOLOGIC FACTORS THAT ARE ASSOCIATED WITH AN INCREASED RISK OF NON-HODGKIN LYMPHOMA

Immunodeficiency
	Congenital
	Acquired
Infectious agents
Male gender
Increasing age
Family history of non-Hodgkin lymphoma
Prior cancer history
Drug Exposure:
	Immunosuppressive agents
	Antiepileptic medication
Occupational History
Exposure to: herbicides
		pesticides
		wood dust
		epoxy glue
		solvents
Other possible etiologic factors
	Hair dye use
	Nutritional factors
	Blood transfusion

FIGURE 88.2. Temporal trends in the age-adjusted incidence rates of NHL in the United States (SEER data, 1979 to 2009).

Age, Race, and Sex Differences

The frequency of various lymphoid neoplasms is age-dependent, has a variable worldwide distribution, and is more common in males than females. Lymphomas represent approximately 10% of all childhood cancers in developed countries and are third in relative frequency behind acute leukemias and brain tumors. They are more common in adults than in children and have a steady increase in incidence from childhood through age 80 years (Fig. 88.3).³³ They are the fifth most common cancer in the United States and represent 4% of all cancers. The mean age at diagnosis is 45 to 55 years and the median age for 2005 to 2009 was 66 years. The annual incidence rate of NHL in 2005 to 2009 was 40% higher for males (23.8 per 100,000) than females (16.3 per 100,000). The median age of death was 75 years of age. The highest age-adjusted mortality in 2009 was in white males (8.7 per 100,000) and the lowest mortality has been in Asian/Pacific Islander females (3.4 per 100,000).³³ The incidence and mortality rates for NHL vary worldwide, with North America having the highest (Fig. 88.4).

A comparison of NHL in children and adults is outlined in Table 88.2. Lymphomas involving peripheral lymph nodes are usually of B cell origin in North America and Europe and are more common in adults than in children, who often present with gastrointestinal involvement (BL) or mediastinal widening (usually lymphoblastic lymphoma of T cell origin). The histologic appearance of NHL is more variable in adults, who frequently have low grade follicular or diffuse patterns in which the majority of malignant cells are small, dormant lymphocytes; children predominantly have high-grade diffuse patterns in which the malignant cells have a “blastic” or transformed appearance and a high mitotic rate. A possible explanation of the differences between childhood and adult NHL is that most childhood lymphomas arise from early cells that are antigen-independent, whereas many adult lymphomas arise from fully differentiated cells and are antigen-dependent.

Extranodal presentation of NHL occurs in 15% to 25% of adult patients in the United States, is higher in Europe, and is up to 40% to 50% in Asia.³⁴ Clinicopathologic features of the epidemic of NHL include a faster rise in extranodal than nodal disease, an increase in diffuse pattern over nodular, and in aggressive NHL than in indolent disease.³⁵ NHL of the brain has risen 4 times as rapidly as other extranodal sites and is partly due to AIDS, but the upward trend began before the AIDS crisis and continues to rise in immunocompetent hosts of all ages and in both genders.³⁶ The most common extranodal sites are the gastrointestinal tract and nasopharynx; other common sites include brain, skin, bone, thyroid, salivary glands, and testis.

FIGURE 88.3. Age-specific incidence rates of NHL according to race (SEER data, 1979 to 2009).

Familial aggregation of NHL plays a small role in the epidemic and accounts for a 1.5- to 4-fold increased risk for NHL in close relatives of patients with lymphoma or other hematopoietic neoplasm.³⁷ Aggregation has been reported to be stronger for siblings and male relatives.³⁸, ³⁹ Anticipation (earlier age of onset in subsequent generations) has been reported in NHL;⁴⁰ however, others have disputed the finding by suggesting that the studies do not account for the increasing incidence of NHL.⁴¹

There is an increased risk for both NHL and HL in families with an autoimmune lymphoproliferative syndrome (ALPS, also known as the Canale-Smith syndrome), which is characterized by chronic lymphadenopathy, splenomegaly, autoimmune features, and expanded T cells, negative for CD4 and CD8.⁴² Both NHL and HL, particularly nodular lymphocyte-predominant, may occur decades after recognition of the syndrome and are associated with germline FAS mutations and defective lymphocyte apoptosis. Somatic FAS mutations and CASP10 germline mutations are other subtypes of ALPS.⁴³

A prior history of cancer, Jewish ancestry, and small size families have been suggested as risk factors for lymphoma.⁴⁴ In families with a diagnosis of NHL, there are reports indicating an increased risk for melanoma and other cancers, including pancreas and stomach.³⁸ Patients who have both a family history of hematologic cancer and occupational exposures to certain substances (e.g., gasoline or benzene) appear to have an increased risk for NHL.⁴⁵

Infectious Agents

Infectious diseases have contributed to understanding the mechanisms of lymphomagenesis. The role infections play in specific lymphomas vary according to host factors, environment,
and geography.⁴⁶ There are at least two mechanisms in which infections contribute to lymphomagenesis. The best described is direct lymphocyte transformation by microbial agents. Lymphotropic viruses include Epstein-Barr virus (EBV), human T-leukemia virus-1 (HTLV-1), and human herpes virus 8 (HHV8). An alternative mechanism is an agent, such as Helicobacter pylori (H. pylori), infecting host tissues and eliciting a lymphoproliferation response that remains dependent upon the presence of the agent, or antigen. The former does not usually respond to antimicrobial therapy, while the latter does. There are an expanding number of infections associated with specific types of NHL (Table 88.3).

FIGURE 88.4. Age-adjusted incidence and mortality rates of NHL in selected world regions. From International Agency for Research on Cancer GLOBOCAN 2008 data, from Bassig BA, Lan Q, Rothman N, et al. Current understanding of life-style and environmental factors and risk of non-Hodgkin lymphoma: an epidemiological update. J Cancer Epidemiol 2012: 978930, with permission.

The complex interplay of environmental and host factors in the pathogenesis of lymphoma was recognized through Dennis Burkitt’s description in 1958 of an aggressive tumor of young children that was characterized by frequent jaw and abdominal involvement (Fig. 88.5A). Using careful epidemiologic surveys, Burkitt identified a tumor belt across equatorial Africa that was associated with temperature, rainfall, and elevation (Fig. 88.5B).⁴⁷, ⁴⁸ Subsequently, the geographic distribution of this neoplasm was shown to correlate with that of endemic malaria. In 1964, Epstein, Achong, and Barr found viral particles in tumor cell lines derived from Burkitt’s patients.¹⁰ A direct causative role for the virus was subsequently questioned by its infrequency in BL occurring outside Africa; however, the EBV was shown to be trophic for B cells, to induce B cell proliferation and differentiation, and to be the etiologic agent for infectious mononucleosis. In 1965, Burkitt was the first to discover that the lymphoma could be cured with chemotherapy.⁴⁹

TABLE 88.2 CLINICOPATHOLOGIC DIFFERENCES BETWEEN CHILDHOOD AND ADULT NON-HODGKIN LYMPHOMAS

	Children		Adults
Incidence	Rare		Common
Median Age	10-15 years		55-70 years
Presentation	Extranodal > nodal		Nodal > extranodal
Most Common	B cell: Burkitt		B cell: Diffuse large cell (DLBCL)
Histologic		Diffuse large cell		Follicular
Diagnoses	T cell: Lymphoblastic		T cell: Peripheral T cell, not otherwise specified
		ALK + anaplastic large cell		Anaplastic large cell Angioimmunoblastic
Immunophenotype	60-70% B cell		85-90% B cell (United States, Europe); 20-35% T/NK cell (Asia)
Paraprotein	None		Rare (<5%)
Clinical Course	Aggressive		Variable—often indolent
Curability	70-95%		<30%, except 40% to 70% in aggressive subtypes, particularly DLBCL

TABLE 88.3 INFECTIONS AND ASSOCIATIONS WITH LYMPHOMA

Agent	Lymphoma Type(s)
Epstein-Barr virus (EBV)	Burkitt lymphoma (Africa) Posttransplant lymphoproliferative disorders Acquired immunodeficiency syndrome-related lymphoma (central nervous system, others) Natural killer/T cell nasal lymphoma Hodgkin lymphoma Diffuse large B cell lymphoma of the elderly
Human T-lymphotropic virus I (HTLV-1)	Adult T cell leukemia/lymphoma
Human herpes virus 8/Kaposi sarcoma-associated herpes virus	Primary effusion lymphoma Plasmablastic lymphoma
Helicobacter pylori	Gastric MALToma^a
Hepatitis B virus	Diffuse large B cell lymphoma
Hepatitis C virus	Splenic marginal zone lymphoma; other B cell lymphomas
Campylobacter jejuni	Immunoproliferative small intestinal disease^a
Borrelia burgdorferi	Primary cutaneous B cell lymphoma^a
Chlamydia psittaci	Ocular adnexal lymphoma^a
^aExtranodal marginal zone lymphoma, MALT-type.

The identification of a 14q+ cytogenetic abnormality in BL by Manalov and Manalova⁵⁰ in 1971 led to the description of the 8;14 chromosomal translocation by Zech¹⁹ in 1976. Subsequent molecular genetic studies showed that this translocation juxtaposed the MYC oncogene on chromosome 8 to the IG heavy chain gene sequences on chromosome 14.⁵¹ These observations suggest that the 8;14 translocation of endemic Burkitt NHL arises in a state of EBV-induced polyclonal B cell proliferation in the setting of immunodeficiency associated with chronic malaria.⁵² Support for this theory has been derived by the role of EBV in lymphoproliferation in other immunodeficient conditions. EBV has also been implicated in posttransplant lymphomas, AIDS-related lymphomas (mostly central nervous system [CNS] and variably with systemic), some T/NK lymphomas, particularly nasal; some HL, and several lymphomas that developed after chronic infectious mononucleosis.⁵³, ⁵⁴, ⁵⁵

Shortly after immunologic classifications for NHL were proposed, adult T cell leukemia/lymphoma (ATL) was described in Japan by Takatsuki and Uchiyama in 1977.⁵⁶ The clinical course of ATL was variable, but the majority of patients presented with an acute form, which was characterized by lymphadenopathy, organomegaly, skin lesions, hypercalcemia, and an elevated white count with multilobated lymphocytes, referred to as “cloverleaf” or “flower” cells (see Fig. 88.21D), and a rapidly fatal course. In 1980 to 1982, Poiesz et al. in Gallo’s lab in the United States and
Yoshida et al. in Hinuma’s lab in Japan independently discovered an unique retrovirus, HTLV-1, as the etiologic agent of ATL.⁵⁷, ⁵⁸ HTLV-1 was shown to be endemic to certain geographic areas: southwestern Japan, in which 6% to 20% of the population is seropositive for HTLV-1; the Caribbean Islands, New Guinea, parts of Central Africa and South America, parts of West Africa, the Middle East and Melanesia (Fig. 88.6).⁵⁹, ⁶⁰

FIGURE 88.5. A: Burkitt lymphoma involving mandible, maxilla, and orbit. From O’Conor GT. Significant aspects of childhood lymphomas in Africa. Cancer Res 1963;23:1514-1527. B: Lymphoma belt of Africa: Burkitt lymphoma occurred only in areas below 3,000 feet (above sea level), with mean temperature above 15.6°C, and with annual rainfall over 50 cm. Shaded area, where Burkitt lymphoma would be expected to occur; black squares, sites of cases identified by Burkitt. From Haddow AJ. An improved map for study of Burkitt lymphoma syndrome in Africa. E Afr Med J 1963;40:429-432.

HTLV-1 is an RNA-containing delta retrovirus that infects mature T cells, usually CD3⁺, CD4⁺, and HLA-DR⁺. The molecular pathogenesis revolves around TAX, a potent HTLV-1 transcription activator protein, and HTLV-1 basic ZIP factor, HBZ (Fig. 88.7).⁵⁹ T cell dysregulation may initially involve an autocrine interleukin (IL)-2 loop as well as paracrine effects from other cellular genes and cytokines. The TAX protein is prominent during the initial infection by increasing the expression of viral genes through viral long terminal repeats (LTRs) and by stimulating the transcription of cellular genes through signaling pathways of nuclear factor Kappa B (NFκB), serum response factor (SRF), cyclic AMP response element binding protein (CREB), and activated protein 1 (AP1).⁵⁹ The TAX protein induces proliferation and inhibits apoptosis of HTLV-1 cells through induction of IκB-alpha degradation, which activates the NFκB pathway, which in turn promotes expression of cell-cycle regulators (cyclin D2 and CDκ6) and leads to increased activation of PI3-kinase signaling.⁶¹ TAX deregulates the expression of cytokines (IL-2 and IL-15) and antiapoptotic genes, upregulates vascular cell adhesion molecules, activates osteoclasts, and alters interferon signaling, all of which contribute to the pathogenesis of ATL.

HBZ is transcribed from the 3′-LTR and is the only gene which is conserved and unmethylated in all ATL cases, while the TAX gene is often inactivated by epigenetic changes or the loss of 5′-LTR.⁶² Unlike TAX, which activates both the classical and alternative NFκB pathways and suppresses TGF-β signaling, HBZ suppresses the classical pathway without inhibiting alternative NFκB signaling and promotes TGF-β signaling, which leads to upregulation of forkhead box P3 (FOXP3) protein. By enhancing TGF-β and increasing FOXP3 expression, HBZ allows infected T cells to convert to Tregs, which contribute to viral persistence and leukemogenesis. HBZ promotes T cell proliferation in its RNA form by the regulation of E2F transcription factor 1 pathway; the HBZ protein interacts with CREB-2 and suppresses TAX-mediated viral transcription.⁶², ⁶³ Initially, the T lymphoproliferation is polyclonal and controlled by host defense mechanisms;⁶⁴ however, as TAX expression diminishes, an oligoclonal or monoclonal T cell proliferation that is IL-2-independent emerges, resulting in the clinical manifestations of ATL. HTLV-1 contributes to a multistep process of worsening genetic instability characterized by mutation of TP53, deletion of tumor suppressor genes CDKN2B/p15 and CDKN2A/p16, and DNA methylation.⁵⁹

HTLV-I can be transmitted by blood transfusions, needle sharing, sexual intercourse, and from mother to child through breast milk or through the placenta. Over 20 million people worldwide are estimated to be infected with HTLV-1, and over 90% will remain asymptomatic carriers.⁶⁰ The virus can have a prolonged latency period of decades before clinical syndromes appear⁶⁴, ⁶⁵ (see section on “Mature T/NK Leukemias”). Where the virus is endemic, ATL occurs at a rate of 20 to 86 cases per 100,000 population per year, with a lifetime risk of approximately 1% to 6% for those persons seropositive for HTLV-I antibodies.⁶⁴ In Japan, males are 3 times more likely to develop ATLL than females, with a peak age around 60 years, while in the Caribbean there is no gender difference and the peak age is 40 years.⁶⁶

HTLV-I infection induces the production of antibodies to various viral core proteins which can be used as serologic markers of infection.⁶⁷ The diagnosis is usually suggested by a screening enzyme-linked immunoabsorbent assay and confirmed by Western blot. Because of slow replication, seroconversion may take up to 2 years in HTLV-I infection compared to the 3 to 6 months for HIV. PCR utilizes primers and probes of the Pol (polymerase or reverse transcripter) and TAX (transactivator) regions and is the most sensitive and specific assay for detecting HTLV-I. HTLV-I can lead to other diseases, including myelopathy/tropical spastic paraparesis, uveitis, bronchopneumopathy, and arthropathy.⁶⁰, ⁶⁷

Other viruses have been implicated in lymphoid neoplasia and include HTLV-II, herpes virus (HHV-6), HHV-8, (Kaposi’s sarcoma-associated herpes virus [KSHV]), and hepatitis B and C. HTLV-2 was isolated in 1982 by Kalyanaraman et al. from a

patient with an unusual T cell variant of hairy cell leukemia.⁶⁸ It has subsequently been isolated only rarely in lymphoid neoplasia and in HTLV-I negative tropical spastic paraparesis, but it is prevalent in intravenous drug abusers.⁶⁹ Two other related viruses, HTLV-3 and HTLV-4, were reported in 2005 in Central Africa but have not been linked to human disease.⁷⁰ Salahuddin et al. identified HHV-6 in B lymphocytes from 6 patients with various lymphoproliferative disorders;⁷¹ it was identified subsequently as the etiologic agent for exanthem subitum (roseola infantum) and as a cause for pneumonia in immunocompromised hosts.⁷² A role for HTLV-2 or HHV6 in lymphoproliferation has not been detected. KSHV, also referred to as HHV-8, has been identified in AIDS-related body-cavity based B cell lymphomas and multicentric Castleman disease and has been associated with EBV genome in the absence of MYC rearrangement.⁷³, ⁷⁴ Theoretically, KSHV acts synergistically with EBV to transform B cells and causes a unique clinical presentation.

FIGURE 88.6. Geographic distribution of HTLV-1 in countries where the disease is endemic. The stars emphasize high-prevalence areas. The country boundaries shown in the map are not coincidental with the areas of endemicity, reflecting the cluster nature of HTLV infection. From Goncalves DU, Proietti FA, Ribas JG, et al. Epidemiology, treatment, and prevention of human T cell leukemia virus type 1-associated diseases. Clin Microbiol Rev 2010;23:577-589, with permission.

FIGURE 88.7. Course of HTLV-1 infection. After infection of a mature T helper cell, there is a long latency period (decades) which can be controlled by cytotoxic T cells and an autocrine IL-2 loop. Clonal proliferation is promoted by pleiotropic actions of Tax and other viral proteins that inhibit apoptosis and induce IκBα, which activates the NFκB pathway. HBZ promotes T cell proliferation and the HBZ protein suppresses TAX-mediated viral transcription. As TAX expression is lost, there is the emergence of a monoclonal T cell population that is independent of IL-2.CC chemokine receptor 4 (CCR4) and cutaneous lymphocyte antigen (CLA) on ATL cells interact with endothelial cells in the skin and contribute to epidermotropism. ATL follows a multistep process of worsening genetic instability and is subdivided into clinical syndromes characterized by immunodeficiency and chemoresistance.

There is conflicting data regarding the risk of NHL in patients infected with hepatitis B (HBV) and C (HCV), but the association appears valid, particularly in endemic areas. Meta-analyses have reported a 2- to 3- and a 2- to 4-fold risk of developing NHL in HBV and HCV-infected patients, respectively.⁷⁵,⁷⁶, ⁷⁷, ⁷⁸ The incubation time for lymphoma to occur in patients infected with hepatitis is estimated to be as long as 15 years.⁷⁹ DLBCL is the most common subtype associated with HBV.⁷⁵ Besides the association of HBV with NHL, cytotoxic therapy with or without rituximab can lead to HBV reactivation, resulting in hepatitis and even liver failure.⁷⁸, ⁸⁰ Screening HBV status prior to chemotherapy and prophylaxis with antiviral therapy for positive patients can decrease the rate of reactivation.⁸¹

The causative fraction of NHL by HCV varies widely according to country, but is estimated to be as high as 10% where HCV is endemic, such as Egypt, Italy, and South Korea.⁸² Chronic HCV infection is often (40% to 90%) present in patients with type II mixed cryoglobulinemia (MC); and 5% to 10% of MC patients have or will develop a B cell lymphoma (see Chapter 101).⁸³, ⁸⁴, ⁸⁵ Early studies stating that indolent B cell lymphomas, lymphoplasmacytic and marginal zone, were the most common subtypes associated with HCV have not been confirmed, but they were reported mainly in patients with MC who do have an increased risk for indolent lymphomas.⁷⁶, ⁸⁶ Spleen involvement is more common in DLBCL with HCV (34% vs. 13%); some of the DLBCL have undergone transformation from an indolent NHL.⁸⁷ Rearrangement of either IGH or the BCL2 genes occurs in up to three-fourths of patients with HCV and MC and can regress with antiviral therapy.⁸⁸ Complete responses to antiviral therapy, primarily peg-interferon and ribavirin, occur in 60% to 75% of patients with HCV-positive lymphomas.⁸⁹, ⁹⁰,⁹¹ Adding rituximab to antiviral therapy is well tolerated and improves responses.⁹², ⁹³ Proposed mechanisms of HCV’s role in lymphomagenesis include chronic antigenic stimulation, activation of B cells by an HCV E2 protein, and direct infection of B cells, a combination of which could lead to genetic aberrations.⁷⁶, ⁸⁵

FIGURE 88.8. MALToma of the stomach: model for lymphomagenesis. Helicobacter pylori infects the epithelial cells and there is recruitment of both T and B cells. Contact-dependent T cell help is mediated by CD40 and CD40 ligand interaction. B cells undergo a T cell-dependent polyclonal response which can develop into a postgerminal center monoclonal B cell lymphoma. Three-fourths of gastric MALTomas have allelic imbalance, methylator phenotype, and/or trisomies and respond to antibiotics that eradicate Helicobacter pylori. Alternatively, there can be clonal evolution that involves a specific translocation (i.e., t[11;18] or t[11;14]) and/or a loss of tumor suppressor genes (i.e., TP53, CDKN2B/p15, CDKN2A/p16), which are associated with dissemination of disease. The t(11;18) rarely is associated with transformation while the t(11;14) may progress to a diffuse large B cell lymphoma.

H. pylori is a gram-negative rod which was discovered by Warren and Marshall in 1983 and was shown to be associated with peptic ulcer disease, gastric carcinoma, and NHL.⁹⁴, ⁹⁵,⁹⁶ Gastric lymphoma was found to have a high frequency in certain parts of Europe, such as the Veneto region of Italy, and was usually an indolent B cell lymphoma of mucosa-associated lymphoid tissue (MALToma), a term proposed by Isaacson and Wright.⁹⁷,⁹⁸ Parsonett recognized that H. pylori infection preceded the development of lymphoma,⁹⁹ and Wotherspoon reported in 1993 that antibiotic treatment for H. pylori caused regression of the lymphoma in over two-thirds of patients.¹⁰⁰ Over one-half of H. pylori large B cell gastric lymphoma will also respond to antibiotics.¹⁰¹

MALToma of the stomach serves as a model for lymphomagenesis secondary to antigenic stimulation (Fig. 88.8).¹⁰² Both B and T cells are recruited to the gastric mucosa following H. pylori infection. Proliferation of B cells are dependent upon reactive T cells.¹⁰³ There is a continuous spectrum of pathologic lesions during the transition from gastritis to low grade MALToma to the less frequent large B cell.¹⁰² PCR may be helpful in identifying a malignant B cell clone which may persist after histologic regression following antibiotic therapy.¹⁰⁴ Somatic hypermutation is characteristic of the B cell clone of MALToma and, along with the observation of plasmacytic differentiation, indicates a post germinal center origin. Translocation-positive gastric MALTomas lead to activation of the NFκB pathway which causes overexpression
of BCL2, blocks apoptosis of B cells, and leads to antibiotic resistance, while translocation-negative cases involve inflammatory and immune responses, which maintain B and T cell interaction and respond to H. pylori eradication.¹⁰⁵ The oncoprotein of the CAGA gene has been shown to be directly delivered into B cells by H. pylori, and it likely contributes to lymphomagenesis.¹⁰⁶

The most common genetic abnormality in gastric MALToma is the t(11;18)(q21;q21) which is present in one-quarter to one-third of cases, and up to one-half of H. pylori negative cases.¹⁰⁷, ¹⁰⁸ The genes involved at t(11;18) are an apoptosis inhibitor-2 gene (API2) and a novel 18q gene, MALT, and are more likely to result in disseminated disease but less likely to undergo histologic transformation than other genetic abnormalities.¹⁰⁹ The t(14:18) in MALToma involves IGH/MALT2 and may coexist with trisomies 3, 12, or 18; occurs in 5% gastric MALTomas; and is more common in nongastrointestinal sites.¹⁰⁸ The t(1;14)(p22;q32) and t(1;2)(p22;q12) involve the BCL10 gene¹⁰², ¹¹⁰ and are present in 1% to 3% of gastric MALTomas.¹⁰², ¹⁰⁸, ¹¹⁰ BCL1 and BCL2 gene rearrangements are usually not present in MALTomas, and BCL-6 has rarely (1% to 2%) been reported.¹⁰², ¹¹¹ There is controversy whether the B cell clones remain dependent upon antigen stimulation or expand through autonomous (antigen-independent) growth. Loss of tumor suppressor genes and amplification of 3q27 have been associated with histologic progression and dissemination of MALTomas.¹⁰⁹, ¹¹²

Other infections associated with specific MALTomas include Borrelia burgdorferi with primary cutaneous B cell lymphoma, Chlamydia psittaci with ocular adnexal MALTomas, and Campylobacter jejuni with immunoproliferative small intestinal disease (also called alpha heavy chain disease or Mediterranean lymphoma).⁴⁶, ¹¹³ Their frequency varies according to endemic geography and have been found more commonly in Europe than in North America or Asia. The ability to diagnose the association depends upon either immunohistochemistry using a monoclonal antibody detecting the agent or, preferably, targeted polymerase chain reaction (PCR) that detects the DNA of the infectious agent. When the infections are present in these MALTomas, the lymphomas will regress in the majority of patients treated with antibiotics.¹¹⁴, ¹¹⁵

Environmental Factors

Environmental associations implicated in the pathogenesis of NHL include not only infections, but also drug exposure and toxic chemical exposure. Immunosuppressive agents contribute to lymphomagenesis through interaction with EBV, particularly in organ transplants. Phenytoin and carbamazepine have been associated with both pseudolymphoma and malignant lymphoma, with the former condition presenting with fever, rash, and adenopathy that regress after drug withdrawal.¹¹⁶ Methotrexate and the tumor necrosis factor (TNF) alpha inhibitors (adalimumab, certolizumab, etanercept, golimumab, and infliximab) have been associated with an increased risk of lymphoma in some but not all studies in rheumatoid arthritis, which itself may have an increased risk (see section on “Prelymphomatous Conditions”).¹¹⁷ In a meta-analysis of randomized controlled studies, there was a trend for an increased risk of B-NHL in patients receiving anti-TNF therapy, but it did not reach statistical significance.¹¹⁸ Hepatosplenic T cell lymphoma has been reported in patients with Crohn disease receiving anti-TNF therapy usually with other immunomodulators.¹¹⁹ Although epidemiologic studies are flawed by methodologic weaknesses, other drugs possibly associated with NHL include analgesics, antibiotics, steroids, digitalis, estrogen, and tranquilizers.⁴⁴, ¹²⁰, ¹²¹, ¹²² A Danish study found no increased risk of NHL in women using postmenopausal hormone replacement.¹²³

Occupational exposures have been suggested as factors in the epidemic, but studies are often flawed because of small numbers and being retrospective. An increased risk of NHL has been reported among people employed in agriculture, forestry, fishing, construction, motor vehicles, telephone communication, and leather Industries.¹²⁴, ¹²⁵ Specific jobs at risk include plant and poultry farmers, butchers, gardeners, painters and plasterers, car repair and gasoline station workers, carpenters, brick and stone masons, plumbers, welders and solderers, roofers, and teachers. The associations tend to increase with longer duration of employment, and studies have correlated specific jobs with histologic types.¹²⁵

Chemicals that have been implicated in the epidemic include organochlorines and phenoxyacetic acids that are commonly found in pesticides and herbicides.¹²⁶, ¹²⁷, ¹²⁸, ¹²⁹ A number of organochlorine compounds have been banned in the United States, including dichlorodiphenyl-trichloroethane (DDT, used from 1939 to 1972), polychlorinated biphenyls (PCBs, 1929 to 1977), and chlordane (1947 to 1988); however, studies have correlated the presence of these and similar chemicals in carpet dust and in adipose tissue with a higher risk of developing NHL. An excess risk for NHL has also been suggested for exposure to organic solvents, such as benzene, xylene, toluene and trichloroethylene, fertilizers, epoxy glues, and wood dust.¹³⁰ Variations in immune genes or DNA repair genes may affect an individual’s risk of developing NHL after exposure to solvents,¹³¹, ¹³² which may also directly impair cell-mediated immunity.

Hair dyes, ultraviolet light (UV), and nutritional factors have been implicated in some epidemiologic studies and negated in others.¹³³, ¹³⁴, ¹³⁵, ¹³⁶ Hair dye is more likely to be a factor in women than in men because of greater use in women. There has been an increased risk for NHL in women who used hair dyes before 1980, but not among women after 1980, probably related to removal of carcinogenic compounds.¹³⁶, ¹³⁷

Several studies noted an increase in NHL among patients with melanoma or squamous cell skin cancer and suggested a role for UV suppressing the immune system;¹³³ however, there was no correlation between NHL mortality and increased UV light exposure in the southern United States or in Scandinavia.¹³⁴, ¹³⁸ Additionally, a reduced risk of NHL has been reported with higher sun exposure.¹³⁸, ¹³⁹ A hypothesis is that reduced risk in midlatitudes arises from vitamin D production with UVB light, while an increased risk arises from immunosuppression by more UVA light in higher latitudes.¹⁴⁰ Other studies have found no protective effect of UV radiation and no association between vitamin D and NHL risk.¹⁴¹, ¹⁴²

Nutritional factors, including milk, butter, liver, meat, coffee, and cola consumption, have been identified as possible risk factors.¹⁴³, ¹⁴⁴, ¹⁴⁵, ¹⁴⁶, ¹⁴⁷ A high-meat diet and a high intake of fat from animal sources have been associated with an increased risk of NHL; there was a decreased risk with increased ingestion of fruits.¹³⁵ Other studies have reported a lower risk for NHL with higher intakes of vegetables, lutein and zeaxanthin, and zinc.¹⁴⁸ Milk consumption has had conflicting reports.¹³⁵, ¹⁴⁷ Obesity and lack of exercise have been suggested as contributing to the epidemic in some studies and refuted in others.¹⁴⁷, ¹⁴⁹, ¹⁵⁰

Blood transfusion has been implicated as contributing to the increased incidence of NHL.¹⁵¹, ¹⁵², ¹⁵³ The use of blood products beginning in the 1950s has coincided with the epidemic. Transmission of infectious agents through blood transfusion could suppress the immune system, and make a patient susceptible to the development of lymphoma. Blood transfusion has been associated with all types of histologies, but a meta-analysis found a higher risk for CLL/SLL.¹⁵², ¹⁵³ While cohort studies have supported the connection between blood transfusion and lymphoma, case-control studies have not consistently confirmed the association.¹⁵¹, ¹⁵³, ¹⁵⁴

A number of other factors have been mentioned as possibly contributing to the epidemic, including ionizing radiation, electromagnetic fields, alcohol, tobacco, and chronic fatigue syndrome, but the data is weak to support an association of any of these factors
with an increased risk of NHL.¹⁵⁵, ¹⁵⁶, ¹⁵⁷, ¹⁵⁸ The epidemiology of NHL continues under investigation and requires carefully designed studies with large cohorts and prolonged follow-up to determine the validity of an association between a factor and NHL. InterLymph, an international consortium of NHL studies, is providing large databases to assess the impact of environmental risk factors.¹⁵⁹

PRELYMPHOMATOUS CONDITIONS

The mechanism of developing lymphomas has been best studied in those occurring in immunodeficiency states. These disorders can be subdivided into congenital, or primary, immunodeficiencies, and acquired, or secondary, immunodeficiencies (Table 88.4). Common components to all these disorders are defects in immunoregulation, particularly in T cell immunity, resulting in decreased cytokines, and uncontrolled B cell growth in lymphoid tissue, often in association with the EBV genome. Since 1973, cases of malignant disease in children with immunodeficiency have been recorded by immunodeficiency cancer registries, and NHL constitutes the majority of the cases.¹⁶⁰, ¹⁶¹ The median age of onset is 7 years and there is a predominance of males over females, due in part to the contribution of X-linked disorders.¹⁶⁰ The importance of EBV in the pathogenesis of lymphoproliferation in immunodeficiency was suggested by Purtilo et al. in 1974, when they described an X-linked disorder in which 6 boys in a single family died of infectious mononucleosis, agammaglobulinemia, or malignant lymphoma.¹⁶² The role of EBV in lymphomas developing in patients with immunodeficiencies is addressed in Chapters 62, 63 and 64.

Organ Transplants

In the early 1980s, a range of lymphoproliferative lesions was described that occurred in patients receiving chronic immunosuppressive therapy after solid organ transplantation. The clinical and pathologic spectrum of diseases included primary infectious mononucleosis, polymorphic B cell hyperplasia, and intermediate-to high-grade B cell lymphomas in which necrosis, cytologic atypia, monotypic Ig expression, and cytogenetic abnormalities are harbingers of neoplastic transformation and aggressive behavior.¹⁶³ Serologic and molecular studies linked many of these lymphoproliferations to primary or secondary EBV infection.¹⁶⁴ The risk of developing lymphoproliferation after transplantation is dependent upon age, EBV status, type of transplant, and amount of immunosuppression.¹⁶⁵ A lower chance occurs in older as opposed to younger age, sibling over cadaver donor, and single over multiple transplants. Early reports from Stanford University indicated that up to 40% of patients surviving cardiac transplantation developed a malignant lymphoma.¹⁶⁶ With less immunosuppression, the incidence is 1% to 15% after solid organ transplants, which is a 30- to 60-fold increase in lymphomas compared to the general population.¹⁶⁷, ¹⁶⁸ The diagnosis and management of posttransplant lymphoproliferative disease (PTLD) is described in Chapter 62.

TABLE 88.4 PRELYMPHOMATOUS CONDITIONS

Congenital	Acquired
Ataxia telangiectasia	Immunodeficiency
Wiskott-Aldrich syndrome		Organ transplants Acquired immunodeficiency syndrome
Severe combined immunodeficiency
Common variable immunodeficiency	Autoimmune disorders
		Sjögren syndrome
Hyper IgM syndrome		Hashimoto thyroiditis
Hyper IgE syndrome		Rheumatoid arthritis Systemic lupus erythematosus
X-linked hypogammaglobulinemia	Inflammatory bowel disease
X-linked lymphoproliferative syndrome	Castleman disease Hodgkin lymphoma
Autoimmune lymphoproliferative syndrome	Lymphomatoid granulomatosis Predisposition to T cell lymphoma
		Nontropical sprue Angioimmunoblastic lymphadenopathy Lymphomatoid papulosis

Acquired Immunodeficiency Syndrome

AIDS was recognized as a disease in 1981 and the first case of lymphoma in an AIDS patient was reported in 1982.¹⁶⁹ This was followed by a series of 90 homosexual patients with NHL reported by Ziegler et al. in 1984.¹⁷⁰ In 1985, the diagnosis of NHL in association with positive serologic evidence for human immunodeficiency virus (HIV) became a criterion for the diagnosis of AIDS.¹⁷¹ In Ziegler’s series, presenting features included generalized adenopathy and opportunistic infections in one-third of patients.¹⁷⁰ Extranodal sites of disease and advanced stage occur in three-fourths of patients with AIDS-related lymphoma (ARL). The most common extranodal sites are the meninges, gastrointestinal tract, bone marrow, liver, and lung/pleura; unusual sites include rectum, oral cavity, heart/pericardium, common bile duct, and skin.¹⁷² NHLs in AIDS patients are usually of B cell origin and include diffuse large B cell (DLBCL: immunoblastic, or large transformed) and BL. Unique presentations of ARL include plasmablastic lymphoma of the oral cavity¹⁷³ and primary effusion lymphoma.⁷³ Differences in the histology of ARL have not impacted survival;¹⁷⁴ however, they are likely to become more important with improved survival in AIDS.

The prevalence of NHL in AIDS is 3% to 6%, and before the era of highly active antiretroviral therapy (HAART) there were projected increased risks over time.¹⁷⁵ The risk of lymphoma is increased 60- to 650-fold among HIV-infected patients compared to the general population and is associated with older age, severe immunodeficiency (defined by CD4 count and HIV viral load), and prolonged HIV infection.¹⁷⁶,¹⁷⁷ Since the introduction of HAART in 1996, epidemiologic studies in developed countries are reporting an increase in ARL as the first AIDS-defining illness but decreased overall incidence in ARL, particularly in primary CNS NHL and in DLBCL (immunoblastic) histology.¹⁷²,¹⁷⁷, ¹⁷⁸, ¹⁷⁹ Additionally, survival for ARL has improved.¹⁷⁷, ¹⁸⁰ Prognostic factors and therapy of ARL are addressed in Chapter 64.

Autoimmune and Other Immunologic Disorders

Chronic inflammation, immune hyperactivity, and/or immunosuppression are elements of autoimmune disorders that predispose patients to lymphoma.⁹⁸, ¹⁸¹, ¹⁸² Many of these lymphomas arise in extranodal sites where there is sparse lymphoid tissue; they are usually localized, low grade B cell lymphomas arising from mucosa-associated lymphoid tissue (MALT). Isaacson and Wright initially recognized MALTomas in the gastrointestinal tract and indicated they were a subset of immunoproliferative small intestinal disease, or Mediterranean lymphoma; however, they subsequently identified similar lymphomas occurring in the lung and salivary gland.¹⁸³ Multiple other extranodal sites have been involved with MALTomas and include thyroid gland, thymus, breast, conjunctiva, gallbladder, skin, cervix, larynx, and trachea. Although the term MALToma is misleading due to the fact that not all of the lesions arise in mucosal tissue, two common features are chronic inflammation and the presence of glandular epithelium that is destroyed by progressive lymphocytic infiltration.

Lymphomas associated with Sjögren syndrome (SS) and Hashimoto thyroiditis (HT) are of B cell origin and tend to occur in elderly females. The presumed pathogenesis of lymphomas in these patients is associated with chronic antigenic stimulation causing polyclonal B cell growth with eventual development of a monoclonal B cell lymphoma. Bunim and Talal reported the first association of lymphoma and SS in 1963,¹⁸⁴ and Kassan et al. subsequently reported a greater than 40-fold risk for lymphomas in these patients.¹⁸⁵ Approximately 5% of patients with primary SS will develop lymphoma.¹⁸⁶, ¹⁸⁷

The histologic lesion of SS is a myoepithelial sialoadenitis (MESA) characterized by lymphoid infiltration of the salivary gland along with acinar atrophy and proliferation of ductal cells to form myoepithelial islands.¹⁸⁸ Although the initial clinical course of SS usually is benign, clonally rearranged IG genes can be detected in the biopsy of MESA.¹⁸⁹ Furthermore, the finding of light chain restriction in minor salivary glands of the lip by in situ hybridization techniques correlates with development of lymphoma.¹⁹⁰ These findings suggest, as in many other prelymphomatous conditions, that the “benign” lesion actually represents either a monoclonal population of unknown significance or malignant lymphoma in situ. B-lymphocyte activator of the TNF-family (BAFF) is overexpressed in SS salivary glands, induces BCL-2 which impairs apoptosis, and likely contributes to lymphomagenesis.¹⁹¹ Overt lymphoma tends to occur in those lesions with extensive, confluent areas of monotypic B cell proliferation, and the lymphomas most commonly seen are marginal zone, lymphoplasmacytic, or DLBCL types.

Lindsay and Dailey described an association between lymphoma of the thyroid and HT in 1957.¹⁹² Subsequent studies indicate that over 75% of thyroid lymphomas are preceded by HT, made evident by thyroiditis in the nonlymphomatous portion of the pathologic specimens and by antithyroid antibodies in most patients.¹⁹³ There is a 60- to 80-fold increase in thyroid lymphoma after thyroiditis, but the lifetime risk is only 1% to 2%.¹⁹⁴ Unlike the lesion of SS, which has IG gene rearrangement, the lesion of HT does not usually have a clonal population of cells identified by DNA analysis;¹⁹⁵ however, similar IGH bands have been detected in a minority of HT patients and subsequent thyroid lymphoma, supporting the hypothesis of clonal evolution of NHL from HT.¹⁹⁶ Most thyroid lymphomas express surface IgG rather than the IgM characteristic of follicular center cell (FCC) lymphomas, suggesting that thyroid lymphomas involve B cell progenitors with the ability to differentiate further from IgM to IgG production.¹⁹⁷

Lymphomas have been reported in patients with other autoimmune disorders, including rheumatoid arthritis (RA), systemic lupus erythematosis (SLE), scleroderma, inflammatory bowel disease, and dermatomyositis; however, the increased incidence in these disorders are complicated by the use of immunosuppressive therapy and by possible methodologic flaws in the epidemiologic studies.¹⁹⁸ The increased risk for lymphoma in RA varies from 2- to 15-fold and is higher in patients with more severe disease or with Felty syndrome.¹⁹⁹ A large study reported an increased NHL risk (2.9[1.7 to 4.9]) in RA patients treated with any biologic agent and a greater risk with anti-TNF agents than methotrexate.²⁰⁰ A meta-analysis of randomized clinical trials in RA reported no increased risk of malignancy with biologic therapy, but did find an increased risk for NHL of 2.1 (0.55 to 8.4) in patients receiving anti-TNF therapy compared with controls.²⁰¹ A wide spectrum of lesions have been described in RA patients, ranging from lesions that resemble posttransplant polymorphous lymphoproliferation to large B cell lymphomas, the most common type, HL, and, rarely, PTCL.¹⁹⁸, ²⁰² EBV may be present in tumor cells, and the lymphoproliferations may regress with discontinuation of immunosuppression.²⁰², ²⁰³ T-large granular lymphocyte leukemia is often associated with rheumatoid arthritis and neutropenia.²⁰⁴ The risk of NHL in SLE is increased 3- to 4-fold and DLBCL is the most common type.²⁰⁵

Castleman disease (CD) (giant lymph node hyperplasia, angiofollicular lymph node hyperplasia) was first recognized in the 1920s and was further described as a clinicopathologic entity in 1954.²⁰⁶, ²⁰⁷ It has two types of clinical presentations (localized and multicentric) and three types of histologic subtypes (hyaline vascular, plasma cell, and mixed).²⁰⁸, ²⁰⁹ The hyaline vascular type is the most common subtype and presents as localized adenopathy, often in the mediastinum. It can be amenable to surgical resection; and although it was initially reported to be radioresistant, it has been successfully treated with radiation as well.²¹⁰

The plasma cell variant is associated with systemic symptoms, anemia of chronic disease, hypergammaglobulinemia, and a variety of unusual syndromes, including myasthenia gravis, nephrotic syndrome, peripheral neuropathy, amyloidosis, and temporal arteritis.²¹¹ A plasmablastic subvariant is associated with HIV infection. Increased expression of the gene coding for IL-6 has been identified in CD, and retroviral transduction of the gene into mice has reproduced histology and symptoms.²¹² Moreover, antibodies to IL-6 or its receptor have ameliorated the disease.²¹³ The plasma cell variant tends to be either a local form, more commonly occurring in a young adult and amenable to local therapy, or a multicentric form occurring in an older adult or in an HIV-infected patient with diffuse adenopathy and a variable, but often fatal, clinical course in which 20% to 30% of patients develop either Kaposi sarcoma or B cell lymphoma.²¹¹, ²¹⁴, ²¹⁵ Immunophenotyping and IG gene rearrangements of the plasma cell variant in CD indicate that patients usually have polyclonal lesions;²¹⁶ however, monoclonal IG gene rearrangements have been identified in patients with the multicentric form and in patients developing B cell lymphoma.²¹⁷ KSHV (HHV8) has been identified in HIV-associated multicentric CD cases and levels of KSHV DNA correlate with symptomatic disease.²¹⁵, ²¹⁸ KSHV positive plasmablasts have lambda light chain restriction, are localized to the mantle zone of germinal centers, and can coalesce to form microscopic lymphomas.²¹⁹ The lymphomas have had a variable histologic pattern but they are usually of B cell origin with mantle cell the most common subtype and have a poor prognosis.²²⁰ Plasmablastic lymphoma and primary effusion lymphoma have also been reported.⁷⁴ There is no standard of treatment for multicentric CD, and anecdotal cases have utilized rituximab, interferon, thalidomide, tocilizumab (anti-IL6), antiviral therapy, and chemotherapy with variable success.²⁰⁷, ²¹⁵, ²²¹, ²²²

NHL may follow HL, with prior therapy and the cell-mediated immune defect characteristic of HL serving as possible contributing factors. Krikorian et al. reported 6 cases from Stanford University of intermediate- to high-grade lymphoma developing after HL.²²³ In subsequent series, authors estimated that 1% to 5% of patients with HL will develop NHL;²²⁴ some studies have indicated a greater risk in the nodular variant of lymphocyte predominant HL (LPHL), which has a unique CD20⁺ B cell immunophenotype.²²⁵, ²²⁶ The large B cell lymphomas associated with LPHL generally are regarded as a progression of LPHL rather than as secondary neoplasms. Single cell analysis of the lymphocytic and histiocytic cells of LPHL have proven a clonal relation to large B cell lymphoma developing in the same patient.²²⁷ There are rare patients with intermediate clinical and pathological features between DLBCL and classical HL that have been referred to as “mediastinal gray zone lymphoma,” or “large B cell lymphoma with Hodgkin-like features.”²²⁸ Most NHL that occur after all subtypes of HL are of B cell origin,²²⁵, ²²⁹ but those of T cell immunophenotype have followed HL as well.²³⁰The EBV genome has been found in some cases of NHL developing after HL.²³¹

T cell lymphomas commonly do not occur in the setting of immunodeficiencies, with the exception of ataxia telangiectasia; however, some disorders appear to predispose to PTCL, and up to one-tenth of lymphomas in organ transplants are of T cell origin. PTLD of T cell origin tend to occur late and have a poor prognosis.²³² Hepatosplenic γδ T cell lymphoma can occur late
after solid organ transplantation and in patients with Crohn disease, the majority of whom were on anti-TNF therapy.¹¹⁹, ²³³ PTCL comprise only 3% of all AIDS lymphomas.²³⁴ Patients with gluten-sensitive enteropathy or celiac disease have an increased incidence of intestinal T cell lymphoma.²³⁵ Although Isaacson et al. initially reported that these lymphomas were variants of malignant histiocytosis, subsequent studies with gene rearrangement techniques indicated a T cell origin and they are referred to as enteropathy-associated T cell lymphoma (EATL).²³⁶ Primary anaplastic large cell lymphoma has been reported after breast implant surgery.²³⁷

Skin disorders may also evolve into a malignant CTCL (Chapter 92). Clonality, as evidenced by TCR gene rearrangements, has been detected in some patients with lymphomatoid papulosis²³⁸ as well as in those with other cutaneous T cell processes of uncertain malignant potential, such as pityriasis lichenoides et varioliformis acuta,²³⁹ granulomatous slack skin disease,²⁴⁰ and pagetoid reticulosis.²⁴¹ The latter two disorders are considered variants of mycosis fungoides.

CLINICAL FEATURES AT PRESENTATION

The majority of patients with NHL present with painless adenopathy, more commonly in the cervical or supraclavicular regions;²⁴² however, extranodal disease can be detected at presentation in up to 40% of patients and varies depending upon immune status and geographic differences. Systemic symptoms occur in less than 25% of patients in most large series.²⁴², ²⁴³ When present, however, they usually are associated with advanced stages of disease and a poor prognosis. Significant cytopenias are rare unless marrow involvement is extensive or there are associated immune mediated cytopenias, hypersplenism, or rarely, hemophagocytosis. Leukemia presentations in NHL are rare and variably impact prognosis.²⁴⁴, ²⁴⁵

The gastrointestinal tract is the most common extranodal site at presentation and is involved in 5% to 20% of adults with NHL.²⁴⁶ The stomach is most frequently involved followed by the small intestine, the colon, and the esophagus. Approximately 90% of primary gastrointestinal lymphomas are of B cell origin. Certain subtypes have a site predilection: MALToma in the stomach, Burkitt (non-African) in the terminal ileum; mantle cell in the terminal ileum, jejunum, and colon; T cell (EATL) in the jejunum; follicular in the duodenum.

Gastrointestinal symptoms are often nonspecific with vague abdominal pain the most common presenting symptom. Epigastric pain, dyspepsia, nausea and, less often, early satiety, suggest stomach involvement. Frank bleeding occurs in less than 30% of patients with gastrointestinal lymphomas, and usually is from either a gastric (melanotic stool) or large bowel source.²⁴⁷ Patients with rectal involvement usually present with hematochezia or a change in bowel habits.²⁴⁸ Obstruction, specifically intussusception, or perforation are associated with aggressive small bowel lymphomas, particularly BL and EATL. Mantle cell lymphoma presents with gastrointestinal symptoms in 20% to 30% of patients, and multiple polyposis may be found on colonoscopy (Fig. 88.9). Lymphomatous polyposis of the gastrointestinal tract is not restricted to MCL and has also been detected in FL and MALToma.²⁴⁶, ²⁴⁹ Although the mucosa may appear normal, abnormal histology in the gastrointestinal tract is found in over 80% of MCL patients.²⁵⁰ Dysphagia, airway obstruction, and eustachian tube blockage with or without cervical adenopathy are symptoms suggesting Waldeyer’s ring involvement. Epistaxis and nasal obstruction usually with facial edema are common signs of involvement of nasal lymphomas.

FIGURE 88.9. Mantle cell lymphoma. A: Intestine involved by multiple lymphomatous polyposis. Multiple small nodules extensively involve the bowel mucosa. Image provided by Dr. Lawrence Weiss, City of Hope National Medical Center. B: Aggregates of small B cells from multiple nodules just beneath the mucosa express CD5 and cyclin D1. Image provided by Dr. Dan Arber, Stanford University, Palo Alto, CA.

Hepatosplenomegaly is a common feature of advanced indolent B cell lymphoma, including small B lymphocytic lymphoma, and splenic marginal zone lymphoma (SZML), and can be the predominant clinical feature of hepatosplenic T cell lymphoma. Subclinical secondary involvement of the liver has been reported in 26% to 40% of NHL, while primary hepatic lymphoma (PHL) is extremely rare, representing 0.05% of extranodal lymphoma.²⁵¹, ²⁵² Primary splenic lymphoma is similarly rare, and splenectomy may be considered for diagnosis and therapy.²⁵³ Primary NHL of the liver usually is a large B cell type, can be associated with hepatitis C (40% to 60%), and can arise in immunodeficient hosts. Presenting features include right upper quadrant pain, anorexia, nausea, coagulopathy, and elevated liver enzymes without significant jaundice.²⁵¹, ²⁵², ²⁵⁴ Hypercalcemia is present in 40% of patients. Hypodense, nonenhancing (possible rim enhancement) masses on CT imaging are characteristic of primary liver NHL. Solitary masses occur in approximately two-thirds, multiple masses in one-third, and diffuse infiltration is unusual.²⁵¹, ²⁵⁴ Obstructive jaundice can occur in NHL secondary to periportal lymphadenopathy or to primary lymphoma of the bile duct or pancreas. Rarely, liver involvement with NHL may present with hepatic failure.²⁵⁵

The skin is another common extranodal presentation of NHL, and the most common primary cutaneous type is the cerebriform T cell of mycosis fungoides/Sezary syndrome (Chapter 92). While mycosis fungoides tends to be confined to the skin with characteristic stages, B cell lymphomas involving the skin represent only 15% to 25% of primary cutaneous lymphoma and usually present
as nodules involving head, neck, or trunk.²⁵⁶, ²⁵⁷ The major types of primary cutaneous B cell lymphomas and their distinguishing immunotypes include marginal zone (MALT-type) (CD20+, CD5^–, CD10^–), primary cutaneous follicular lymphoma (PCFL) (CD20⁺, CD10⁺), and primary cutaneous large B cell lymphoma (PCBCL) (CD20⁺; usually CD10^–). Other T cell lymphomas with unique skin involvement include anaplastic large cell lymphoma (ALCL), which can be a primary cutaneous type or a systemic disease;²⁵⁸ subcutaneous panniculitis-like PTCL, αβ subtype; and 3 provisional entities, cutaneous γδ T cell lymphoma (TCL), aggressive epidermotropic CD8⁺ cytotoxic TCL, and primary cutaneous CD4⁺ small/medium-sized pleomorphic TCL.

Neurologic symptoms and signs, including headache, confusion, lethargy, dysphasia, hemiparesis, seizures, and cranial nerve palsies, and rarely, multifocal leucoencephalopathy, may be presenting features of CNS involvement.²⁵⁹ Cognitive and personality changes are more common in primary CNS lymphoma (PCNSL) due to a predilection for involvement in the frontal lobes, corpus callosum, and periventricular areas. Approximately 90% of PCNSL are DLBCL; the remainder are indolent B cell lymphomas, BLs, and peripheral T cell lymphomas.²⁵⁹, ²⁶⁰

The detection of a single lesion on MRI favors PCNSL, but multifocal lesions can occur in approximately one-third of normal hosts and formerly more frequently in AIDS patients (Fig. 88.10). The differential in AIDS patients with intracranial mass lesions includes not only CNS lymphoma, but also toxoplasmosis, progressive multi- focal leukoencephalopathy, and other opportunistic infections. CT scanning of CNS lymphoma usually identifies a contrast enhancing lesion or lesions with a mass effect and edema which may have ring enhancement, a common finding in toxoplasmosis. The definitive diagnostic procedure is CT-guided stereotactic biopsy.²⁶¹ Positron emission tomography (PET) scanning may distinguish lymphoma and toxoplasmosis and obviate the need for biopsy in some AIDS patients.²⁶²

FIGURE 88.10. Primary CNS lymphoma. This FLAIR sequence MRI demonstrates a small periventricular mass lesion in the left thalamus. The lesion displays a signal intensity that is isointense compared with normal gray matter structures. This feature is consistent with a highly cellular lesion, a finding that suggests lymphoma but is not specific for that diagnosis. In addition, there are multiple areas of high signal intensity with ill-defined borders, most pronounced in the left frontal region. This appearance is also nonspecific, reflecting increased water content or decreased myelin in those regions, as may occur with any cause of inflammation. It is consistent with a multifocal, widely infiltrative process, and supportive of the diagnosis of lymphoma. Description provided by Dr. Paul Moots, Vanderbilt University, Nashville, TN.

Lymphomatous meningeal infiltration may be detected in up to 15% of patients with parenchymal PCNSL or may occur as an early or late complication in patients with specific sites of disease, including nasopharynx through local extension, testicular, or extensive marrow involvement.²⁶³ The histologies involving the spinal fluid are usually aggressive and include Burkitt, lymphoblastic, and DLBCL. Primary leptomeningeal lymphoma is when there is no systemic lymphoma or parenchymal disease and occurs in 7% of presentations with CNS disease.²⁶³ Neurolymphomatosis is a rare syndrome characterized by a clinical neuropathy with variable pain and is due to lymphomatous infiltration of peripheral nerve(s), nerve root or plexus, or cranial nerves.²⁶⁴Intravascular B cell lymphoma usually has subcutaneous skin lesions, but can present with a wide variety of neurological symptoms, including neuropathies, myopathy, dementia, and stroke.²⁶⁵

Because of the risk of leptomeningeal disease in PCNSL, ARL, Burkitt, lymphoblastic, and DLBCL with the specific sites noted above, the CSF should be examined by cytology and flow cytometry, and prophylaxis should be considered in these patients. Elevated LDH and more than one extranodal site have been associated with CNS disease in patients with intermediate to high-grade histologies.²⁶⁶

Symptoms of spinal cord compression may include back pain, paresthesias, weakness, and incontinence, and requires emergent recognition and therapy. Compression occurs through extension of a paravertebral mass or direct involvement of a vertebral body. MRI of the entire spine is recommended to exclude multiple sites of involvement. The thoracic spine is the most common area, followed by lumbar and then cervical.²⁶⁷

Primary ocular lymphoma is part of the spectrum of CNS lymphoma, usually with DLBCL histology; and is defined by infiltration by lymphoma cells in the visual tract, retina, vitreous, or optic nerve head. Approximately 5% to 15% of PCNSL have ocular involvement at diagnosis while CNS involvement may follow isolated ocular lymphoma in 50% to 80% of patients.²⁵⁹ Ocular symptoms include blurred vision and loss of visual acuity, or “floaters,” but patients can be asymptomatic. Slit lamp examination is recommended for patients with CNS or ocular lymphoma. The external eye usually is normal, and the diagnosis can be confused with uveitis, vitritis, or glaucoma.²⁶⁸

Lymphomas of the extraocular space are more common than ocular lymphomas and can arise in the superficial conjunctiva or eyelids or deeper in the lacrimal gland or retrobulbar tissues.²⁶⁹, ²⁷⁰ Blurred vision, ptosis, chemosis, epiphora, and proptosis can occur depending upon the orbital site involved. Most orbital lymphomas are of B cell origin and are low grade, particularly in the conjunctiva or eyelids, but can be a large B cell lymphoma in the lacrimal gland or retrobulbar area. Bilateral involvement occurs in 10% to 15% of patients, mostly in conjunctival forms. CNS involvement rarely occurs, and the risk of distant spread is less with conjunctival lesions.

Other symptoms and signs depend on unusual extranodal presentations. Bone pain is uncommon unless the lymphoma has a leukemic component or the patient has extranodal bone lymphoma, which accounts for 3% to 5% of extranodal NHL.²⁷¹ The long bones are most commonly affected and there may be soft tissue swelling.²⁷² The lesions may be lytic, sclerotic, or mixed with periosteal erosion, and are best evaluated by MRI. Genitourinary presentations include renal mass, ureteral obstruction, testicular mass, ovarian mass, and vaginal bleeding. The most common cause of a testicular mass in an elderly male is NHL. Primary breast lymphoma is rare, accounts for 0.04% to 0.5% of all malignant breast tumors, and has a bimodal presentation. Breast lymphoma in young women is associated with pregnancy and lactation and often has diffuse involvement of both breasts.²⁷³ Older women tend to have discrete masses with unilateral involvement. Large B cell lymphoma is the most common type of the above extranodal NHL.

Lung and heart are rarely involved in NHL, but patients commonly present with cardiopulmonary symptoms. Cough, dyspnea, and chest pain usually of a short duration of a few weeks may be the presenting symptoms of mediastinal nodal involvement. The superior vena caval syndrome can occur with either T-lymphoblastic lymphoma or large B cell lymphoma of the mediastinum. Pleural effusions require cytology and immunophenotyping by flow cytometry to determine if there is lymphomatous involvement. The most common primary lung lymphoma is a MALToma, a small B cell bronchus-associated lymphoid tissue (BALT) lymphoma which more commonly presents as localized opacities.²⁷⁴, ²⁷⁵ Bronchoscopy may reveal bronchial narrowing and biopsy can identify submucosal involvement. Open thoracotomy or video-assisted thoracoscopy is required in the majority of cases because bronchoscopy is diagnostic in approximately one-third of patients.²⁷⁵ Primary lymphoma of the pleura has been associated with chronic tuberculosis pyothorax or empyema.²⁷⁶ Primary cardiac lymphoma is extremely rare, usually occurs as a large B cell NHL in an immunocompromised host, and may present with heart failure, pericardial effusion, or arrhythmia, including heart block.²⁷⁷

NHL occasionally will present with metabolic and endocrine problems, which tend to be more prominent following introduction of therapy, particularly in the setting of a large tumor volume or aggressive histologies. Hypercalcemia, hyperuricemic renal failure, and severe hypoglycemia are unusual metabolic presentations. Hypercalcemia is present in approximately one-fifth of patients with ATL at diagnosis and occurs in up to 70% during the course of the illness.⁵⁹ A few cases of primary adrenal lymphoma have been reported and the initial presentation is usually due to the mass effect.²⁷⁸ Rarely, adrenal insufficiency may be the initial presentation of NHL and is rapidly fatal if unrecognized.²⁷⁹

STAGING

The Ann Arbor staging classification (Table 88.5) developed for HL in 1971 has been the standard scheme for NHL;²⁸⁰ however, it does not account for tumor burden and does not correlate well with prognosis. Other staging systems have been developed for NHL, particularly in children (Chapter 89), specific pathologies, and extranodal sites of disease, including gastrointestinal (Table 88.5). Prognosis and therapy depend not only on stage, but also on the pathologic features of the lymphoma and by a variety of clinical parameters which reflect tumor bulk and kinetics (e.g., size of mass, LDH level, number of extranodal sites).²⁸¹, ²⁸²

The International Prognostic Index (IPI) (Table 88.5) was developed to correlate clinical parameters with prognosis and appears more useful than the Ann Arbor staging system in predicting survival.²⁸³ When the REAL classification was under evaluation for clinical utility, an early report indicated that a high IPI did not predict an adverse outcome for ALCL; however, subsequent studies have indicated that the IPI correlates with prognosis for all histologies.²⁸⁴, ²⁸⁵ There are situations where the IPI may be less useful, such as large B cell lymphoma of the mediastinum, for which prognosis depends upon the extent of local disease.
Modification in clinical prognostic indices have been made for different types of NHL and biologic parameters can further subdivide groups (see section on “Prognostic Factors”).

TABLE 88.5 STAGING OF NON-HODGKIN LYMPHOMA

Staging System	Stage	Definition
Ann Arbor	I	Involvement of a single lymph node region or of a single extranodal organ or site (I_E)
	II	Involvement of two or more node regions on the same side of the diaphragm, or localized involvement of an extranodal site or organ (II_E) and one or more lymph node regions on the same side of the diaphragm
	III	Involvement of lymph node regions on both sides of the diaphragm which may also be accompanied by localized involvement of an extranodal organ or site (III_E) or spleen (III_S) or both (III_SE)
	IV	Diffuse or disseminated involvement of one or more distant extranodal organs with or without associated lymph node involvement
	B symptoms	Fever >38°C, night sweats, and/or weight loss >10% of body weight in the 6 months preceding admission are defined as systemic symptoms
Staging Modification		The E designation is used when extranodal lymphoid malignancies arise in tissues separate from, but near, the major lymphatic aggregates. Stage IV refers to disease that is diffusely spread throughout an extranodal site, such as the liver. If pathologic proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed. Sites are identified by the following notation: H, Liver, S, spleen; L, Lung; P, pleura; M, bone marrow; O, bone; D, skin. Current practice assigns a clinical stage (CS) based on the findings of the clinical evaluation and a pathologic stage (PS) based on the findings made as a result of invasive procedures beyond the initial biopsy
	International Prognostic Index
Adverse Factor	Risk Group	Number of Factors
Performance status ≥ 2^*	Low	0, 1
LDH > normal^*	Low-intermediate	2
Extranodal sites ≥ 2	High-intermediate	3
Stage III/IV disease^*	High	4.5
Age > 60
Age-adjusted factors^*
Follicular Lymphoma International Prognostic Index (FLIPI)
Adverse Factor	Risk Group	Number of Factors
Age > 60 years	Low	0,1
Stage III/IV	Intermediate	2
Hemoglobin <120 g/L	High	≥ 3
Number of nodal areas >4
LDH > normal
FLIPI2: Adverse Factor
β-2 Microglobulin elevated
Age >60 y
Bone marrow positive for lymphoma
Anemia, hemoglobin < 120 g/L
One or more nodes > 6 cm
Proposed Staging System for Gastrointestinal Non-Hodgkin Lymphoma^a
Stage	Description
Stage I	Tumor confined to gastrointestinal tract without serosal penetration Single primary site
Stage II	Tumor extending into abdomen from primary site—nodal involvement II₁ Local (gastric/mesenteric) II₂ Distant (para-aortic/para-caval)
Stage II_E	Penetration of serosa to involve adjacent “structures”; enumerate actual site of involvement, such as Stage II_E (large intestine) Perforation/peritonitis
Stage IV	Disseminated extranodal involvement or a gastrointestinal tract lesion with supradiaphragmatic nodal involvement
^aFrom Rohatiner A. Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma. Ann Oncol 1994;5:397-400.

Table 88.6 outlines the clinical evaluation and staging studies to consider when evaluating patients with NHL. Bone marrow evaluation detects disease in 20% to 40% of all patients with NHL and from 50% to 70% of patients with indolent lymphomas.²⁸⁶ Flow cytometry (FC) can increase the overall percent involvement; but morphology can be positive when FC is negative, as well as vice versa.²⁸⁷ Immunoperoxidase techniques may identify isolated tumor cells not visualized on routine hematoxylin and eosin stains. Because NHL can have focal involvement, there may be a slight advantage in performing bilateral posterior iliac crest biopsies.²⁸⁸ MRI is a sensitive technique to identify marrow involvement in patients whose biopsies have been negative.²⁸⁹ Molecular studies, particularly PCR, are more sensitive than morphology and further increase the percentage of marrow involvement; however, there is an ongoing debate about the impact of molecular markers on prognosis in NHL.²⁹⁰

Positron emission tomography (PET) using 18F-fluorodeoxyglucose (18F-FDG) has replaced 67-gallium (67Ga) scintigraphy as a nuclear medicine imaging technique to diagnose disseminated disease and to assess response (see section on “Functional Imaging in Prognostic Factors”). Patients with a tumor that remains 18F-FDG avid during therapy are more likely to develop progressive disease than those patients with lesions that become FDG negative.²⁹¹ 18F-FDG uptake varies according to histology and proliferative activity, with less uptake in the indolent lymphomas than in the aggressive lymphomas. Although there is increasing reliance on PET scans, there is no substitute for tissue diagnosis to confirm the presence of disease.

TABLE 88.6 STAGING STUDIES IN NON-HODGKIN LYMPHOMA

Complete history and physical examination, inquiring about B symptoms, HIV risk, infections, autoimmune diseases, immunosuppressive therapy

Complete blood count, including leukocyte count with differential, platelet count

Chemistry profile, particularly lactate dehydrogenase: also alkaline phosphatase, uric acid, creatinine, calcium, and albumin

Computerized tomography of chest, abdomen, pelvis and neck

Bone marrow aspiration and biopsy – cytogenetics [+fluorescent in situ hybridization (FISH) in specific lymphomas: BCL2, BCL1, MYC, ALK, others] and consider molecular tests and gene rearrangement studies in selected patients

Lumbar puncture with cytology in selected patients: all patients with Burkitt and lymphoblastic lymphomas; patients with non-Hodgkin lymphoma in certain sites: nasopharynx, epidural space, testes, and large cell with marrow involvement; HIV+ patients

Gastrointestinal endoscopy for patients with Waldeyer ring involvement or abdominal symptoms

Cytologic assessment of third space fluids (pleura, peritoneum)

Immunophenotype of pathology specimen (cytogenetics/gene rearrangement data in selected patients)

Selected radiologic procedures as clinically appropriate (e.g. PET scan, MRI, ultrasound, bone scan)

Other blood evaluations: levels of β₂-microglobulin and cytokines (IL-2 receptor, tumor necrosis factor)

PROGNOSTIC FACTORS

The broad spectrum of NHL is reflected by a highly variable prognosis among and within individual subtypes of the disease. Recent advances in clinical scoring systems, molecular and immunophenotypic markers, and functional imaging techniques such as PET scans have improved the ability to predict therapeutic response and clinical outcome for individual patients. Table 88.7 outlines clinical, laboratory, and biologic features that affect prognosis in NHL. Prognostic biomarkers specific to individual NHL subtypes are also discussed with these entities in this chapter. An important aim of ongoing studies of prognostic markers is to identify approaches for rational and effective risk-adapted therapy that takes into account the marked heterogeneity within individual NHL entities and among patients with otherwise histologically identical diseases.

Histologic Type

The WHO classification separates disorders into B, T, and NK cell neoplasms, with the B and T cell lymphomas further subdivided into precursor versus mature subtypes. The B cell lymphomas represent about 85% of NHL in Western countries, whereas T-cell subtypes are more prevalent in Asia. B cell NHL are clinically stratified as indolent (e.g., follicular, marginal zone, and small lymphocytic) versus aggressive (e.g., DLBCL, mantle cell, and Burkitt) subtypes. Patients with follicular grade 1 to 2 lymphoma typically experience prolonged survival despite a continuous rate of relapse, while FL grade IIIa may have prolonged disease-free survival following anthracycline-based induction therapy.²⁹², ²⁹³ Discordant lymphoma is encountered when DLBCL presents with a coexisting indolent lymphoma in the marrow or lymph node; in most cases this represents an aggressive component that has transformed from a preexisting indolent B cell clone. These patients show lower rates of complete response and freedom from progression than de novo DLBCL, although the overall survival (OS) does not differ.²⁹⁴ Concordant involvement of the marrow has an inferior OS compared to DLBCL with discordant involvement or a negative marrow.²⁹⁵

Since the initial recognition of T cell lymphomas in the 1970s, there has been controversy about the effect of recognizing the cell of origin on prognosis. Large, prospective trials have indicated a worse prognosis for PTCL than for DLBCL except for ALCL of Tcell origin, which has a survival equivalent or superior to DLBCL (Fig. 88.11).²⁹⁶, ²⁹⁷ Within B and T cell lymphoma subtypes there are clinical, immunophenotypic, and genetic markers that further predict prognosis. Randomized pediatric trials for the most aggressive lymphomas (Burkitt and T-lymphoblastic) have identified the effects of pathology and different therapies on outcome.²⁹⁸ The improved response and survival with anti-CD20 monoclonal antibody plus chemotherapy compared to chemotherapy alone in DLBCL is additional evidence supporting the importance of recognizing the cell of origin.²⁹⁹

TABLE 88.7 CLINICAL AND PATHOLOGIC FEATURES THAT AFFECT TREATMENT OUTCOME IN NON-HODGKIN LYMPHOMA

Clinical Features
	Stage (I/II vs. III/IV)
	Age (≤60 vs. >60 years)
	Performance status (ECOG 0, 1 vs. ≥2)
	B symptoms
	Mass size (<10 cm vs. ≥10 cm)
	Number of extranodal sites (< 2 vs. ≥ 2)
	Bone marrow involvement
	Functional imaging (PET)
	Treatment courses to CR (≤ 3 vs. > 3)
Laboratory Parameters
	Lactate dehydrogenase
	β₂– Microglobulin
Biologic Characteristics
	Histology
	Lineage (B cell vs. T cell)
	Proliferative rate
	Tumor-infiltrating T lymphocyte response
	Lymphocyte-associated macrophage content
	Karyotype
	Genotype

FIGURE 88.11. Overall survival of 228 PTCL (non-ALCL) and 60 T-ALCL compared with 1,595 DLBCL patients. From Gisselbrecht C, Gaulard P, LePage E, et al. Prognostic significance of T cell phenotype in aggressive non-Hodgkin’s lymphoma. Blood 1998;92:76-82, with permission.

Clinical Scoring Systems

The International Prognostic Index (IPI) score has utility in predicting survival for DLBCL based on readily available clinical and laboratory parameters (Table 88.5).³⁰⁰ Revisions to the IPI have been based on the improved outcomes observed for patients treated with the R-CHOP immunochemotherapy regimen incorporating rituximab as opposed to earlier chemotherapy-only regimens.³⁰¹ Whereas the original IPI identified 4 prognostic subgroups, the revised IPI found that patients could be stratified into 3 groups, defined as very good (0 risk factors) (10% of patients, 4-year overall survival [OS] 94%), good (1 or 2 factors) (45% of patients, 4-year OS 79%), and poor (≥3 factors) (45% of patients, 4-year OS 55%) (Fig. 88.12).

As a component of the IPI, serum LDH represents a surrogate quantitative measure for tumor burden. Other serologic markers, particularly β₂ microglobulin (β₂m), have been identified as prognostic factors. β₂m is a low-molecular-weight polypeptide noncovalently linked to the heavy chain of Class I histocompatibility antigens that is shed with cell turnover.³⁰² Combined with serum LDH, β₂m provides a reliable serologic system for predicting freedom from relapse and survival in large cell lymphoma.³⁰³ Patients at low risk for disease recurrence have normal levels of both markers, whereas elevations in levels of both LDH and β-2m (>3.0 mg/L) predict shortened remission and survival.³⁰³ The IPI also is predictive in FL, but its discriminatory value is limited because most patients fall into low- or low-intermediate-risk groups. A scoring system designated the FLIPI stratifies patients into low-, intermediate-, or high-risk groups based on the number of nodal groups involved, age, Ann Arbor stage, hemoglobin level, and LDH (Table 88.5).³⁰⁴ The FLIPI has been validated as a useful prognostic tool, and provides a means of comparing relative patient risk distribution among clinical trials. The FLIPI2 scoring system (Table 88.5)
is more relevant to current patients, however, as it is based on initial therapy with rituximab-containing regimens (Fig. 88.13). The acronym “BABA6” can be used for the 5 FLIPI2 markers: Beta-2 microglobulin > normal, Anemia with hemoglobin <120 g/L, Bone marrow positive for lymphoma, Age > 60 years, and one or more nodal masses ≥⁶ cm in diameter. Five- and ten-year overall survival rates had a strong inverse correlation with low-, intermediate-, and high-risk FLIPI2 scores.³⁰⁵

FIGURE 88.12. Progression-free survival according to the revised International Prognostic Index. From Sehn LH, Berry B, Chhanabhai M, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B cell lymphoma treated with R-CHOP. Blood 2007;109:1857-1861, with permission.

FIGURE 88.13. Progression-free survival are overall survival according to the Follicular Lymphoma International Index 2. A and B are the PFS and OS for the training sample (832 patients) and C and D are for the validation sample (231 patients). FLIPI2: low risk (blue line), score 0; intermediate risk (yellow line), score 1-2; high risk (grey line), score 3-5. From 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, with permission.

A mantle cell lymphoma IPI (MIPI) score has also been validated that utilizes the clinical parameters of age, LDH, white blood cell count, and performance status, and has been further refined to include the proliferation marker Ki-67.³⁰⁶ Similarly, a prognostic index for PTCL (PIT) includes 4 variables:bone marrow involvement, age, performance status, and LDH.³⁰⁷

Immunophenotypic and Molecular Markers

Advances in the molecular and cellular biology of lymphoma have contributed to better understanding of tumor-specific variables that affect clinical behavior and therapeutic response. Cell kinetics (low-growth vs. high-growth fraction), tumor microenvironment (e.g., monocyte/macrophage vs. T cell predominance), and cell adhesion molecules are biologic parameters that contribute to lymphomagenesis and may correlate with prognosis. In DLBCL and mantle cell lymphoma, a high proliferative fraction as defined by expression of the nuclear proliferation antigen Ki-67 (MIB1; >30% to 60% of malignant cells) has identified patients at risk for early relapse and short survival.³⁰⁶, ³⁰⁸, ³⁰⁹

Correlations between acquired molecular abnormalities and specific lymphoma entities are a central part of the WHO classification and the understanding of lymphomagenesis. Immunophenotyping further identifies protein expression patterns that correlate with specific cytogenetic abnormalities and with prognosis (Table 88.8). Examples include nuclear cyclin D1 expression with the t(11;14)(q13;q32) of mantle cell lymphoma, and anaplastic lymphoma kinase (ALK) expression with
the t(2;5) and its variants in ALCL.³¹⁰ BCL-6 expression has been associated with an improved outcome in DLBCL, but its absence may be less deleterious in the rituximab era.³¹¹

TABLE 88.8 PROGNOSTIC BIOMARKERS BY IMMUNOHISTOCHEMISTRY IN AGGRESSIVE LYMPHOMA

Biomarker	Pathway/Function	Correlation	Reference
ALK	Proliferation (tyrosine kinase)	Improved survival if positive in T-ALCL	310, 561, 562
BCL-2	Apoptosis	Decreased survival in activated B-cell-like (ABC) expressing BCL-2	506
Ki-67	Proliferation	Expression associated with increased proliferative rate and decreased survival in MCL, PTCL, and DLBCL	306, 309
FOX P1	Transcription factor	Poor survival in cases with strong expression (DLBCL)	317, 521
BCL-6	Transcriptional repressor, marker of germinal center origin	Improved response and survival in BCL-6 positive DLBCL	311
CD10+; or CD10-, BCL-6+, MUM1-	Markers for Germinal center B-like (GCB) subtype	Improved survival vs. non-GCB (DLBCL)	315, 316
CD10-, BCL-6-; or CD10-, BCL-6+, MUM1+	Markers for non-GCB subtypes	Decreased survival vs. GCB (DLBCL)	315, 316
MYC plus BCL-2	Proliferation and apoptosis	Double hit DLBCL, poor prognosis	319, 320
TP53⁺, CDKN1A-	Proliferation and apoptosis	TP53 mutation, poor prognosis DLBCL and PTCL	517, 586
ALCL, anaplastic large cell lymphoma;DLBCL, diffuse large B cell lymphoma; MCL, mantle cell lymphoma;PTCL, peripheral T cell lymphoma.

Gene expression profiling using cDNA microarrays has been a powerful tool for dissecting pathogenetically relevant mutations and therapeutically targetable pathways in lymphomas. For example, DLBCL may be stratified into prognostic subtypes based upon molecular profile.³²³, ³²⁴ These include primary mediastinal Bcell lymphoma (PMBL), germinal center Bcell-like (GCB), activated Bcell-like (ABC), and a fourth type with a microarray signature distinct from the other types. PMBL and GCB have better prognoses than the others in patients treated with CHOP-like chemotherapy (Fig. 88.14).³²⁵ Since molecular profiling is not currently practical for routine clinical use, efforts have been made to use immunophenotypic expression patterns to stratify DLBCL into GCB or non-GCB subtypes. One of these systems, the Hans algorithm, uses immunostains for CD10, BCL-6, and MUM1, with good correlation with gene expression profile analysis.³¹⁷, ³¹⁸

A modification, the Choi algorithm, also uses these markers plus GCET1 and FOXP1 to stratify patients into GCB vs. ABC DLBCL, again with good correlation with patient overall survival.³¹⁵ To further enhance this scoring system, the Choi algorithm was integrated with immunohistochemical staining for a marker of the DLBCL tumor microenvironment and stromal-1 signature (SPARC: secreted protein, acidic, and rich in cysteine), a good prognostic marker when expressed;and markers of angiogenesis and microvessel density within the tumor stroma, a poor prognostic marker when increased. The resulting “biologic prognostic model” assigned 1 point each for each adverse prognostic marker; those patients with 0 or 1 marker designated “low-risk” and those ≥ 2 as intermediate- or high-risk.³²⁶ All patients had de novo DLBCL treated with R-CHOP or R-CHOP-like regimens in this multicenter study. A highly significant correlation was found for improved event-free and overall survival for those in the low-risk group.

FIGURE 88.14. Gene expression arrays can stratify diffuse large B cell lymphoma (DLBCL) into at least three subtypes, primary mediastinal B cell lymphoma (PMBL), germinal center B cell (GCB), and activated B cell-like (ABC). This Kaplan-Meier curve indicates differing survival among the groups. From Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med 2003;198:851-862, with permission.

About 5% to 8% of DLBCL carry translocations in the MYC oncogene, often with coexisting BCL2 and/or BCL6 translocations (“doublehit” or “triplehit”). MYC protein expression identifies MYC deregulation not detected by FISH; and coexpression with BCL-2 is present in 21% to 29% of DLBCL.³¹⁹, ³²⁰ Double hit DLBCL has a poor outcome with standard R-CHOP chemotherapy; as such, testing for these markers using immunohistochemistry or FISH analysis and applying alternative treatment strategies for these patients is now being assessed.³²⁷, ³²⁸

Whereas molecular and phenotypic features of the tumor cells themselves have prognostic relevance in DLBCL, gene expression profiling in FLs revealed prognostic subsets correlating with survival based on the type of tumor-infiltrating immune cells.³²⁹ FL patients with a predominant T cell signature had improved outcome versus those patients with an immune response signature reflecting a predominant monocyte/macrophage infiltrate. An immunophenotypic correlate was shown by analysis of lymphoma-associated macrophage (LAM) content, wherein FL patients with >15 LAM per high-power field had inferior survival compared to those with fewer LAM.³³⁰ Similarly, a high number of regulatory T cells in the tumor microenvironment as assessed by FOXP3 expression was associated with improved survival.³³¹, ³³²

It should be recognized that prognostic markers for treatment response and patient outcome are defined within the context of specific regimens and thus may become irrelevant when newer therapeutics are applied. As such, it is essential to revalidate these markers with new regimens and targeted therapies.

Treatment-associated Parameters

The ability to deliver a prescribed treatment regimen is a recognized prerequisite to optimal patient outcome in any area of oncology. Treatment delays, dose reductions, or eliminating one or more agents during a patient’s therapy—i.e., a reduction in doseintensity or dose-density—may lead to a lower likelihood of achieving durable remission or cure. While tumor-associated features correlate with outcome, as described above, patientassociated variability in pharmacokinetics may have an important impact even with strict adherence to a treatment regimen. The dose-adjusted R-EPOCH regimen (rituximab, continuous-infusion etoposide, doxorubicin, and vincristine plus cyclophosphamide and prednisone) was designed to address potential underdosing by integrating scheduled incremental dose increases based upon interim neutrophil counts between cycles for treatment of DLBCL.³³³ Phase II studies have shown improved progression-free survival as compared with historic R-CHOP data; a U.S. Intergroup trial led by CALGB is directly comparing DA-R-EPOCH with R-CHOP. This study is also correlating GCB vs. non-GCB DLBCL subtype with the treatment regimen and patient outcome. Looking forward, it is anticipated that methods for pharmacogenomic assessment and dose-optimized delivery of chemotherapy and targeted agents will become available to improve treatment response and to decrease treatment-associated toxicities.

Functional Imaging

The use of 18F-FDG-PET scans has improved the sensitivity for initial staging and posttreatment restaging of NHL.³³⁴ Assessment of treatment response by anatomic staging with routine CT scans, especially in aggressive lymphomas, reveals that many patients have measurable residual abnormalities. The significance of such findings is often problematic as to whether they represent fibrous tissue only versus residual lymphoma, and biopsy of these residual masses may be inconclusive or falsely negative due to sampling error or necrosis. Properly performed and interpreted PET scans have a high discriminatory value in identifying residual lymphoma in patients with incomplete therapeutic response. Several studies have correlated posttreatment PET positivity with relapse and poor survival, and prospective clinical trials are ongoing to assess the use of PET imaging to stratify patients for early institution of dose-intensive therapy.³³⁵

TABLE 88.9 2007 RESPONSE CRITERIA FOR NON-HODGKIN LYMPHOMA

Response Category	Definition	Nodal Masses	Spleen/Liver	Bone Marrow
Complete response	Disappearance of all evidence of disease	a) FDG-avid or PET positive prior to therapy becomes negative; a post treatment mass of any size is permitted if PET negative b) If variably FDG-avid or PET positive, all lymph nodes should regress to normal size on CT	Not palpable; nodules disappear	Infiltrate cleared on repeat biopsy; if indeterminate by morphology, immunohistochemistry should be negative
Partial Response	Regression of measurable disease and no new sites	a) ≥ 50% decrease in SPD of up to 6 largest masses; no increase in size of other nodes b) One or more persistently FDG-avid or PET positive sites c) Regression on CT if variably FDG-avid or PET negative	≥ 50% decrease in SPD of nodules; no increase in size of liver or spleen Irrelevant if positive prior to therapy and partial response at other sites
Stable Disease	Failure to attain CR/PR, but does not meet criteria for progressive disease	a) FDG-avid or PET positive at prior sites of disease and no new sites on PET or CT b) Variably FDG-avid or PET negative; no change in size of previous lesions on CT
Relapsed or Progressive Disease	Any new lesion or increase by ≥50% of previously involved sites from nadir	Appearance of a new lesion(s) > 1.5 cm in any axis, ≥ 50% increase in SPD of more than one node, or ≥50% increase in longest diameter of a previously identified node > 1 cm in short axis. Lesions PET positive if FDG-avid lymphoma or PET positive prior to therapy	>50% increase from nadir in the SPD of any previous lesions	New or recurrent involvement
CT, computed tomography; FDG (18F)fluorodoxyglucose; PET, positron emission tomography; PR, partial remission; SPD, sum of the product of the diameters.
Adapted from Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579-586.

The use of interim PET imaging following two to three cycles of chemotherapy has shown a strong correlation with outcome in HL; however, interim PET in DLBCL remains controversial. Interim 18-FDG-PET/CT failed to predict outcome in diffuse large Bcell lymphoma patients treated at diagnosis with rituximab-CHOP.³³⁶, ³³⁷ Retrospective data in mantle cell lymphoma suggested an improved outcome for negative posttreatment PET/CT but not for interim scans.³³⁸ Pre- and postinduction PET/CT imaging was performed in 122 patients with FL who took part in a prospective clinical trial of rituximab-chemotherapy followed by maintenance rituximab versus observation.³³⁹ Patients remaining PET-positive after induction therapy had significantly inferior progression-free survival and increased risk of death compared to PET-negative individuals. Interestingly, response by traditional posttreatment restaging including CT scans did not correlate with outcome.

Response criteria for NHL now include recommendations for incorporation of functional imaging by PET in patients with DLBCL and HL (Table 88.9).³⁴⁰ In addition, guidelines for standardization and interpretation of PET scans have been recommended for use in clinical trials and in prospective registries assessing treatment outcomes and prognosis.³⁴¹

THERAPEUTIC PRINCIPLES

Therapy follows assessment of the patient, pathology, and stage of disease. The ability of the patient to tolerate therapy is dependent upon age, performance status, and, if present, immunodeficiency due to a prelymphomatous condition. How advanced age
adversely affects outcome in therapy is controversial, but comorbid illnesses and biologic differences of lymphomas can contribute to higher mortality in the elderly. Treatment-related toxicities are greater in elderly patients, but deaths from unrelated causes are also increased.³⁴², ³⁴³ Biologic differences of NHL between young and old patients are implicated by a greater lymphomarelated mortality in some series of elderly patients compared with younger cohorts³⁴⁴ (see section on “Therapy in the Elderly”).

The type of therapy is based on pathology. One of the clinical disadvantages of the WHO/REAL classifications was deleting the WF grading system. Clinical schemas have been proposed to recognize the biologic behavior along with the cell of origin of the lymphoid neoplasm (Table 88.10).

The intensity of therapy is based on pathology and stage of disease. Advanced stage, tumor bulk as reflected by size (usually greater than 10 cm) and LDH, and number of extranodal sites of involvement were recognized early as independent prognostic determinants in NHL and contribute to the IPI. The IPI has correlated clinical features into prognostic groups for both indolent and aggressive lymphomas.³⁴⁵, ³⁴⁶

TABLE 88.10 CLINICAL SCHEMA FOR LYMPHOID NEOPLASMS

B Cell Lineage		T/NK Cell Lineage
Indolent Lymphomas/Leukemia
Chronic lymphocytic leukemia/small lymphocytic lymphoma		Large granular lymphocytic leukemia, T and NK cell types
Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia		Mycosis fungoides/Sezary syndrome Primary cutaneous anaplastic large cell
Follicular lymphoma (grade I/II) Marginal zone B cell lymphoma		Smoldering and chronic adult T cell leukemia/lymphoma (HTLV1⁺)
	Splenic marginal zone lymphoma Extranodal (MALT-B cell lymphoma) Nodal (monocytoid)
Aggressive Lymphomas
Mantle cell lymphoma (can be indolent)		Prolymphocytic leukemia (can be indolent)
Follicular (large cell)-grade III		Peripheral T cell lymphoma, not otherwise specified
Diffuse large B cell lymphoma		Anaplastic large cell lymphoma (ALK +/ALK-)
Primary mediastinal large B cell lymphoma		Angioimmunoblastic lymphoma
Large B cell lymphoma with intermediate features between DLBCL and Hodgkin lymphoma		Enteropathy-associated T cell lymphoma Nasal type NK/T cell lymphoma Hepatosplenic γδ T cell lymphoma Subcutaneous panniculitis-like T cell lymphoma, αβ (can be indolent)
Highly Aggressive Lymphomas/Acute Leukemias
Precursor B-lymphoblastic lymphoma/leukemia		Precursor T-lymphoblastic lymphoma/leukemia
Burkitt lymphoma/B cell acute leukemia Large B cell lymphoma with intermediate features between DLBCL and Burkitt lymphoma		Adult T cell lymphoma/leukemia (HTLV-1+) (lymphoma and acute leukemia subtypes)
		Natural killer cell leukemia
ALK, anaplastic lymphoma kinase; DLBCL, diffuse large B cell lymphoma ; HTLV-1, human T-leukemia virus-1; NK, natural killer.

After therapy is instituted, response formerly was assessed according to standardized criteria developed in 1999;³⁴⁷ however, new criteria based on PET scans, immunohistochemistry and flow cytometry are now being used³⁴⁰ (Table 88.9). Previously, nodal masses should be ≤1.5 cm to be considered normal but should be ≤1.0 cm if initially clinically abnormal in the 1.0 to 1.5 cm range.³⁴⁷ A common problem particularly in large cell NHL is a residual mass after therapy. A designation of unconfirmed complete response (CRu) was given if there was a greater than 75% reduction in tumor size after therapy; but the criteria utilizing PET scans eliminates the CRu category.³⁴⁰ Persistently positive PET scans after therapy suggest residual disease, but biopsy should be performed if a therapeutic decision is going to be made. The end points of clinical trials should be well defined, and their importance may vary according to type of lymphoma. For example, PFS is more important in aggressive lymphomas than in indolent lymphomas, for which OS or time to next treatment may be more relevant. The problem with the latter endpoint is that guidelines for initiation of treatment need to be standardized as well.

INDOLENT LYMPHOMAS

Indolent lymphomas are characterized by a long median survival and by a slow but continuous decline in survival. They are usually advanced stage at presentation; respond to therapy, but relapse; over time, may transform to a more aggressive course; and rarely, spontaneously regress. With the availability of new chemotherapy agents and the advent of immunotherapy, the therapeutic options for indolent lymphomas are increasing in number and prognosis is improving (Table 88.11). While the expansion of therapies represents a major advancement, the decisions of when to initiate therapy and what type of therapy to select are often controversial and confusing for the individual patient.

Indolent B cell lymphomas include FL, small lymphocytic lymphoma, lymphoplasmacytoid lymphoma, and marginal zone lymphoma. Indolent T/NK cell lymphomas are less common and are less well recognized, other than mycosis fungoides (Chapter 92).
T/NK lymphomas/leukemias which can have an indolent phase include large granular T/NK leukemia, smoldering and chronic HTLV-1+ ATL, T-prolymphocytic leukemia, and, more controversially, some types of PTCL. FLs formerly included follicular small cleaved (FSCL), mixed (FML), and large cell (FLCL), and roughly correlated with cytologic grades 1, 2, and 3, respectively. Cytologic grading of FL is under scrutiny due to poor reproducibility among pathologists.

TABLE 88.11 THERAPEUTIC OPTIONS FOR INDOLENT LYMPHOMA

Watchful waiting
Local radiation for limited stage disease
Chemotherapy
	Alkylating agent
	Nucleoside analogue
	Bendamustine
	Combination chemotherapy
Immunotherapy
	Unconjugated monoclonal antibody
	Radioimmunotherapy
	Interferons
	Cellular
	Vaccines
Combined modality
	Chemotherapy and immunotherapy
	Chemotherapy and radiation
Transplantation
	Autologous ± purging
	Allogeneic:
		Myeloablative
		Nonmyeloablative
Selected therapies
	Antibiotics in selected MALTomas
	Splenectomy

FL (grades I and II) is the second most common NHL behind DLBCL and is the most common indolent lymphoma in North America and Europe, usually comprising 25% to 35% of lymphomas, compared to 5% to 12% in Asia and developing countries.³⁴⁸, ³⁴⁹, ³⁵⁰ Most patients present with asymptomatic lymphadenopathy; B symptoms occur in approximately one-fourth of patients.²⁹² The disease occurs primarily in the elderly (median age, 55 to 65 years), has a near equal male:female ratio, and usually is disseminated at diagnosis (stage III/IV ≥ 70%).²⁹², ³⁵¹, ³⁵² Marrow involvement occurs in 30% to 60% of FL.³⁵¹, ³⁵², ³⁵³ Evaluating the marrow or blood for the BCL-2 translocation will often identify occult disease and can upstage patients by molecular criteria.³⁵⁴, ³⁵⁵

Prior to the recognition of different types of lymphomas by immunophenotyping and the prevalence of BCL-2 translocation in FL, extensive descriptions were made about pathologic differences among FLs. The degree of nodularity was associated with a better prognosis in grade I FL, but it was not of major significance without near complete absence of follicles, as in diffuse small cleaved cell lymphoma (DSCL).³⁵¹ With present—day immunophenotyping, most DSCL are more aggressive diseases than FL and include mantle cell NHL and PTCL. FL immunophenotyping is characterized by the presence of CD10⁺, CD20⁺, BCL2⁺, CD23^+/-, CD43^–, CD5^–, CCND1^–, and BCL6⁺.

Cytologic grading further subclassifies FL into grades 1 to 3. Histologic grades 1 and 2 are treated as indolent disease, while grade 3b is usually excluded from clinical trials involving FL due to its similar behavior to that of intermediate-grade lymphoma. Identification of BCL2 translocations and Ki-67 may add to the prognosis of FL. Approximately 70% of patients have translocations at the major breakpoint region (MBR) located in the untranslated region 3′ of the last exon of the BCL2 gene, and 10% to 15% of patients have translocations in the minor cluster region (mcr) which is 30 kb downstream of the BCL2 gene.³⁴⁸ Lopez-Guillermo correlated survival with BCL2 rearrangements: the 3-year failure-free survival (FFS) for mcr, MBR, and germline cases were 95%, 76%, and 57%, respectively (P< 0.001).³⁵⁶ The impact of persistence of BCL2 rearrangement in FL after therapy is controversial, because there is data indicating its presence adversely affects clinical progression after therapy and, alternatively, other series indicate that it has no effect on long-term survival.³⁵⁵, ³⁵⁷ Patients with low grade and a high proliferation index (Ki-67 > 30%) appear to have clinically aggressive behavior.³⁵⁸, ³⁵⁹ Median survivals for FL were static in the range of 8 to 12 years for several decades, but are now improving due, in part, to monoclonal antibody therapy and better supportive care.³⁵¹, ³⁵², ³⁶⁰, ³⁶¹

The microenvironment and gene expression profiling in FL are likely to add prognostic information and potential therapeutic targets. There has been conflicting data about the presence of tumor-associated CD68⁺ macrophages (TAM) and T-reg cells, with initial reports indicating a poor prognosis for the former and a favorable prognosis for the latter. Subsequent studies have not confirmed these findings.³³⁰, ³³², ³⁶⁴ Gene profiling identified a favorable “immune response 1” signature encoding T cells (CD7, CD8B1, ITK, LEF1, and STAT4) and macrophages. (ACTN1 and TNFSF3B) and an unfavorable “immune response 2” signature of genes in macrophages and/or dendritic cells (TLR5, FCGR1A, SEPT10, CCR1, LGMN, and C3AR1). Future studies will incorporate genetic, molecular, and biologic data into prognostic models which will influence the selection of therapy.

Small B lymphocytic lymphoma (SLL) comprises 3% to 10% of all NHL and is part of the spectrum of diffuse small B cell lymphomas which includes lymphoplasmacytoid lymphoma, marginal zone lymphomas, and mantle cell lymphoma (Chapter 86).³⁶⁵, ³⁶⁶ There is extensive clinical overlap with chronic lymphocytic leukemia (CLL) (Chapter 90), although there is more prominent lymphadenopathy and less lymphocytosis in SLL than in CLL.³⁶⁷, ³⁶⁸, ³⁶⁹, ³⁷⁰ The WHO considers SLL and CLL different clinical presentations of the same disease. An initial lymphocyte count greater than 5 × 10⁹/L is considered diagnostic of CLL. Over time, 10% to 20% of patients develop a lymphocytosis consistent with CLL. SLL represents 4% to 6% of NHL in the West, is a disease of the elderly (median age, 55 to 65 years), and has a male:female ratio of approximately 2:1.³⁶⁷, ³⁶⁸ Patients usually present with generalized adenopathy, and marrow involvement is found in most patients (70% to 80%). Median survivals have been variable from a low of 4 to 6 years to 10+ years, may depend upon prognostic factors and the criteria utilized to separate SLL from CLL, but are similarly improving in the rituximab era.³⁷¹ Deletion at chromosome 6q is the most common cytogenetic abnormality in SLL, but has had no effect on prognosis,³⁷² whereas del(17p) and del(11q) are associated with poorer prognosis.³⁷³ Both unmutated genes as opposed to hypermutated genes and expression of CD38 or ZAP 70 have been associated with a worse prognosis in CLL.³⁷⁴ Between 2% and 8% of SLL and CLL evolve into an aggressive large cell process known as Richter syndrome, which is characterized by bulky retroperitoneal adenopathy, rising LDH, and survival usually less than 1 year.³⁷⁵, ³⁷⁶ Prognosis is better if transformation occurs in previously untreated patients.³⁷⁰

Lymphoplasmacytic lymphoma (LPL) largely overlaps with Waldenström macroglobulinemia (WM) (Chapter 100). LPL represents 1% to 2% of NHL, usually occurs in the elderly (median age 60 to 70 years), and presents with lymphadenopathy (15% to 20%), splenomegaly (10% to 20%), and marrow involvement in most patients.³⁷⁷, ³⁷⁸ A paraprotein is found in 29% to 50% of patients, with IgM the most prevalent type, and can contribute to hyperviscosity (6% to 20%), neuropathy, and glomerular disease.³⁷⁷ A positive Coombs’ test, cold agglutinin disease, cryoglobulinemia, autoimmune diseases, and positive hepatitis C serology can be associated with LPL and WM.³⁷⁹, ³⁸⁰ Mutation of the myeloid differentiation primary response gene⁸⁸ (MYC88) is nearly universal in WM and can be useful in differentiating it from other disorders.³⁸¹ Translocation (9;14) involving the paired box gene PAX5 can be detected in LPL, but its frequency and significance are a matter of debate.³⁷⁸ Deletion of 6q is the most common cytogenetic abnormality but it is not specific for LPL/WM.³⁷⁸ Median survivals have been variable, usually in the 7- to 10-year range, and are worse with advanced age, cytopenias, organomegaly, elevated B2 M, and hypoalbuminemia.³⁷⁸, ³⁸², ³⁸³

Marginal zone B cell lymphomas (MZL) usually account for between 5% and 7% of all NHL and include extranodal MALToma, nodal based disease, and SMZL.³⁸⁴ Extranodal MALTomas represent the most common MZL (50% to 70%) and are discussed in the section “Management of Extranodal Lymphomas”. Nodal MZL occurs in the elderly (median age, 59 to 65 years) and preferentially in women (up to 2:1 female:male ratio), may present with localized lymphadenopathy, and has less marrow involvement (28% to 45%) than other indolent lymphomas.³⁷¹, ³⁸⁴, ³⁸⁵, ³⁸⁶ Cytopenias or a paraprotein (10%) are rarely present. The most frequent cytogenetic abnormalities are gains in chromosomes 3 and 18q23.³⁸⁷ Median survival has been variable due to limited numbers of patients but has been recorded in the 9- to 12-year range.³⁷¹

SMZL occurs in the elderly (median age, 61 to 70 years), has a slight female predominance, and usually presents because of symptoms of splenomegaly.³⁸⁴, ³⁸⁸, ³⁸⁹ Cytopenias are common (46% to 60%); peripheral adenopathy is rare (10% to 15%); and marrow involvement is usually detected (73% to 100%).³⁹⁰, ³⁹¹
A paraprotein may be present and is usually IgM. Despite disseminated disease, splenectomy can alleviate symptoms and improve cytopenias.³⁸⁹, ³⁹⁰ Median survival has been recorded to be 10.5 years, but is shorter in the presence of a paraprotein, elevated β-2m, or lymphocytosis (>9 × 10⁹/L).³⁹¹, ³⁹² A simple prognostic scoring system is based on 3 factors: hemoglobin <120 g/L, LDH level greater than normal, and albumin <35 g/L. The 5-year cause-specific survival was subdivided into 3 groups: 88% for no adverse factor, 73% (one factor), and 50% (two or more factors).³⁸⁸ Complete or partial trisomy 3 is the most frequent (˜85%) cytogenetic abnormality.³⁹³ The abnormality characteristic of SMZL is a deletion or translocation of chromosome 7q32, present in 40% of patients.³⁸⁴ Adverse cytogenetics include del(17p), del(8p), and del(7q) with unmutated genes.³⁹⁴, ³⁹⁵

Special Clinicopathologic Features

Clinicopathologic features unique to indolent lymphomas are histologic transformation (HT) and spontaneous regression. The forerunner and counterpart of HT is the Richter syndrome of CLL/SLL.³⁷⁵, ³⁷⁶, ³⁹⁶, ³⁹⁷ HT of indolent lymphomas usually is associated clinically with increasing adenopathy and LDH levels. All of the indolent lymphomas can undergo transformation, but the most common lymphoma to do so is grade I FL; the transformation is characterized pathologically by a loss of a follicular pattern and an increase in the number of large noncleaved cells.³⁹⁷, ³⁹⁸, ³⁹⁹, ⁴⁰⁰ Predictive factors for HT of FL have included no prior CR, hypoalbuminemia, an elevated B2m (>3 mg/L), and a high FLIPI score at diagnosis.³⁹⁶, ⁴⁰¹ The median time from initial diagnosis to HT is 4 to 6 years.³⁹⁸, ³⁹⁹, ⁴⁰⁰ Historically, the incidence of HT is uncertain, but has been estimated to be between 10% and 70% of indolent lymphomas. Discrepancies among studies are related to methodological differences, including the definition of transformation.³⁹⁷ The risk of HT in FL is estimated at 2% to 4% per year, and it appears to increase over time, but some series have suggested a plateau at 20 years (Fig. 88.15A).⁴⁰¹, ⁴⁰², ⁴⁰³ Autopsy series of nodular lymphomas have identified diffuse morphologic changes, usually with increased large cells, in more than two-thirds of patients.⁴⁰⁴ HT may involve the expression of additional cytogenetic abnormalities and oncogenes.⁴⁰⁵, ⁴⁰⁶, ⁴⁰⁷ The disease course usually progresses rapidly after HT, with median survival usually less than 1 year and ranges from 2.5 to 22 months (Fig. 88.15B).³⁹⁸, ⁴⁰¹, ⁴⁰³ Patients with limited stage disease, low FLIPI, and no prior chemotherapy at the time of histologic transformation are more likely to have prolonged survival.³⁹⁷, ⁴⁰⁰, ⁴⁰³

FIGURE 88.15. Histologic transformation of follicular lymphoma. A: Cumulative incidence of transformation. B: Survival (median = 1.2 years) in patients after transformation. From Montoto S, Davies AJ, Matthews J, et al. Risk and clinical implications of transformation of follicular lymphoma to diffuse large B cell lymphoma. J Clin Oncol 2007;25:2426-2433, with permission.

Spontaneous regression has occurred in the indolent lymphomas, but its exact incidence is uncertain. Horning and Rosenberg reported regression in 19 (23%) of 83 untreated FL patients, including complete regression in 6 patients.⁴⁰² Spontaneous regression occurs in approximately one-fourth of primary cutaneous ALCL (see section on “ALCL”). Spontaneous remission in DLCL has rarely been observed.⁴⁰⁸

Additional clinicopathologic terms that are often misnomers are discordant histology, composite lymphoma, and gray zone lymphoma. Discordant histology refers to identifying different histologic grades of lymphoma in the same patient. The most commonly identified discordant histology is a peripheral node with predominantly large cells and a marrow with small cleaved cells (see section on “Prognostic Factors”).²⁹⁵, ⁴⁰⁹ Composite lymphoma has been used to describe a mixture of histologic grades but probably should be restricted to lymphomas that have two distinct histopathologic types, i.e., two distinct diseases, preferably with both immunophenotypic and molecular genetic differences.⁴¹⁰ Gray zone lymphomas are intermediate between two diseases with DLBCL having overlap features with either Hodgkin or BL.²²⁸, ⁴¹¹

Stages I and II Indolent Lymphoma

Limited stage disease in indolent lymphomas is infrequent and may be as low as 6%, as reported by the National Cancer Institute (NCI) series of pathologically staged patients;⁴¹² most series that involve clinical staging report between 10% and 20% of patients with limited stage disease.³⁵¹, ⁴¹³ Immunophenotyping and molecular genetic studies may identify more advanced stage disease as well as predict the clinical course, but their impact on therapeutic decisions is controversial. Radiation therapy has achieved disease-free survival (DFS) in 31% to 85% of limited stage FL patients with follow-up over 10 years, including reports from Stanford University of relapse-free survival (RFS) of 44% and 37% at 10 and 20 years, and from Dana Farber Cancer Institute of freedom from treatment failure (FFTF) of 47% and 43% at 10 and 15 years.⁴¹⁴, ⁴¹⁵ The median survival in the latter study involving predominantly stage I FL (only grades 1 and 2) was 19 years.⁴¹⁵ While these reports suggest that some limited stage patients may be curable, there is not a clear plateau on the survival curves. Most relapses have occurred outside the radiation field. The best results have been in young patients (less than 50 years), with stage I and nonbulky disease (less than 2.5 cm).⁴¹³ Observation alone can be considered in patients with clinically insignificant disease and has no adverse effect on prognosis even
in the rituximab era.⁴¹⁶, ⁴¹⁷ In a study that evaluated the role of reduced field of radiation (involved regional field or involved nodal radiation therapy), the 10-year PFS and OS were 49% and 66%, respectively. By reducing the field of radiation, there was no difference in the recurrence rate.⁴¹⁸

Rituximab (anti-CD20 monoclonal antibody) (see section on “Immunotherapy”) was initially approved for relapsed indolent lymphomas with response rates in the 50% range, but is now being used as front-line single agent therapy with response rates of 47% to 76%.⁴¹⁹, ⁴²⁰ The rationale for its use in limited stage patients includes its efficacy with low tumor burden, better PFS with molecular responses, and the fact that most limited stage patients actually have advanced stage disease.⁴²¹

Stages III and IV Indolent Lymphoma

Many investigators advocate initial “watchful waiting” for asymptomatic patients with advanced stage indolent lymphomas, because of a continual risk of relapse; early chemotherapy has not improved overall survival (OS).⁴²², ⁴²³ Although stages III and IV usually are considered together, stage III has a tendency toward better survival than stage IV.³⁵¹, ⁴¹³ Among the most controversial aspects in the management of indolent lymphomas are the initiation of therapy and the selection of type of therapy (Table 88.11). The choices of therapy are multiple and vary widely from no initial therapy, rituximab alone, to various chemotherapy agents (single or in combination) with or without monoclonal antibody therapy, to radioimmunotherapy, and to transplantation.⁴²², ⁴²⁴

The number of choices are increasing but there is general agreement that once a decision has been made to start therapy, combination chemotherapy with rituximab offers the best response.³⁵⁰, ⁴²⁵ Clinical features which usually warrant therapy include B symptoms, bulky lymphadenopathy, nodal encroachment on vital organs, massive organomegaly, cytopenias, or transformation.³⁶³, ⁴²², ⁴²⁶, ⁴²⁷ Age of the patient, histologic grade, performance status, comorbid illnesses, patient preference, and physician training and bias influence therapeutic decisions. A number of clinical scoring systems, including the FLIPI and subsequent modifications have been devised not only to predict prognosis, but also to select patients for therapy (see section on “Prognostic Factors”). Because indolent lymphomas usually have long median survivals, prolonged follow-up is required and randomized trials are needed to determine optimal therapy.

Watchful waiting can be psychologically difficult for both patient and physician, but remains a valid approach based on initial observations and randomized trials before the availability of rituximab. There are 3 randomized trials that compared watchful waiting to some form of initial therapy.⁴²³, ⁴²⁸, ⁴²⁹ The NCI group used an aggressive combined modality regimen ProMACE (prednisone, methotrexate, Adriamycin [doxorubicin], cyclophosphamide, and etoposide) and MOPP (mustard, Oncovin [vincristine], procarbazine, and prednisone) plus total lymphoid irradiation; the French used interferon or prednimustine; and the British used chlorambucil. There was no difference in overall survival between observation and therapy in all these reports. In the latter study, the median follow-up was 16 years; and the median length of time until chemotherapy was started in the observation group was 31 months. The actuarial chance of not requiring chemotherapy at 10 years was 19%.⁴²⁹ In a phase III trial evaluating the role of immediate treatment with rituximab versus watchful waiting for advanced stage disease, the median PFS was significantly longer in patients receiving rituximab therapy (NR vs.24 months; P< 0.001); but there was no difference in OS.⁴³⁰

There is no standard of care treatment recommendation for upfront therapy of FL. Rituximab is uniformly incorporated with chemotherapy at the time of treatment initiation. Multiple randomized trials comparing chemotherapy plus rituximab to chemotherapy alone have shown improved response rates and PFS with the rituximab arm.⁴²⁵ Due to the lack of randomized trials, disparate therapeutic approaches have been adopted worldwide. The most commonly used regimens for advanced indolent lymphoma, particularly FL, were formerly alkylator based and included single agents, chlorambucil or cyclophosphamide, with or without prednisone; and CVP (cyclophosphamide, vincristine, prednisone);⁴³¹ however, the addition of doxorubicin in R-CHOP is the most commonly used regimen. Nucleoside analogs, bendamustine, and mitoxantrone are all being used in different upfront regimens as well. In a multicenter longitudinal study by the National LymphoCare in the United States, the initial chemotherapeutic regimen of choice was R-CHOP (55%), followed by R-CVP (23%) and R-fludarabine based (15.5%).⁴³²

Nucleoside analogs are well tolerated, with few gastrointestinal side effects and no alopecia, but cause prolonged decrease in T cell immunity and contribute to immune mediated cytopenias. Responses with single agent nucleoside analogs are 40% to 50% (10% to 20% CR) in previously treated patients, and 60% to 90% (37% to 50% CR) in untreated patients.⁴³³, ⁴³⁴, ⁴³⁵ Adding rituximab to fludarabine yielded a response rate of 90% with 80% CR.⁴³⁶

Combination of nucleoside analogs with other agents are being used in indolent lymphomas. In phase I and II trials of fludarabine plus cyclophosphamide in untreated indolent lymphomas and SLL/CLL, the response rates have been 92% to 100%, including CR rates of 47% to 89%.⁴³⁷, ⁴³⁸ The addition of rituximab to this combination has similarly high response rates and can achieve molecular remission.⁴³⁹ Despite these encouraging results, opportunistic infections are increased with the combination; there may be increased incidence of myelodysplasia; and stem cells may be difficult to collect after its use.

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