Chapter 95: General Considerations for Lymphomas: Epidemiology, Etiology, Heterogeneity, and Primary Extranodal Disease

Lymphomas are a heterogeneous group of malignancies of B cells, T cells, and, rarely, natural killer (NK) cells that usually originate in the lymph nodes, but may affect any organ of the body. Lymphoma previously was referred to as lymphosarcoma and its two major subtypes designated reticulum cell sarcoma and giant follicular lymphoma (Brill-Symmers disease).^1,2,3 In 1966, Rappaport⁴ published a classification system based on the patterns of lymphoma cell growth, size, and shape that attempted to correlate morphology with clinical outcome. The classification proved to have some inaccuracies, such as the term histiocytic lymphoma to describe lymphoid tumors of large transformed lymphocytes that were not derived from the monocyte-macrophage lineage. Nonetheless, the Rappaport classification was an important milestone and became the most widely used classification in the United States. In 1974, Lukes and Collins proposed another classification system, which incorporated morphology with immunologic subtype, that was endorsed by the Committee on Nomenclature.⁴ Another scheme, the Kiel classification, introduced by Karl Lennert and colleagues, had been more popular in Europe.⁵ By the 1970s at least six classifications of lymphoma had been published, and the major ones included two in the United States, one in continental Europe, and one in the United Kingdom. There was no success in reaching a consensus classification that could be used worldwide. A National Cancer Institute study showed that there was poor reproducibility among different pathologists looking at the same slides and trying to classify the case of lymphoma using any existing scheme. In 1982, a Working Formulation sponsored by the National Cancer Institute attempted to reconcile the large number of competing classifications then in use.⁶ The Working Formulation was clinically useful and gained wide popularity. It divided the specific subtypes among high-grade, intermediate-grade, and low-grade lymphomas, focusing in part on the expected rate of progression, and not just on the phenotype of the case in question. With advances in our understanding of the immune system and lymphocyte progenitor developmental sequences, and the availability of monoclonal antibodies for subtyping lymphoid cells and lymphocyte gene profiling, a new classification schema became possible based on cell type, tissue of origin, immunophenotype, and genotype.

In 1994, a revised European-American classification of lymphoid neoplasms (the REAL classification) was proposed by the International Lymphoma Study Group (Chaps. 90 and 96).⁷ This group distinguished three major categories of lymphoid malignancies, which included B-cell, T-cell, and Hodgkin lymphoma. Lymphomas were defined by morphologic, immunologic, and genetic techniques. Many of the lymphomas were associated with distinct clinical presentations, and cases that did not fit into defined entities were left unclassified. Further subclassification⁸ divided each of the B-cell and T-cell lineages into (1) indolent lymphomas (low risk of rapid progression), (2) aggressive lymphomas (intermediate risk of progression), and (3) very aggressive lymphomas (high risk of progression). In 1995, a collaborative project of the European Association for Haematopathology and the Society for Hematopathology began to revise the REAL classification. In 2001, they published the World Health Organization (WHO) Classification of Tumors of the Haematopoietic and Lymphoid Tissues that is used in this chapter and represents the current worldwide consensus classification of malignancies that arise in a lymphocyte. In 2008, the WHO updated this classification (Chaps. 90 and 96).^9,10

Emerging concepts in the staging, therapy, and response evaluation of lymphomas evolved in parallel with the changing nomenclature. Initial efforts to define the extent of disease involvement were undertaken primarily for Hodgkin lymphoma (HL) and ultimately led to the Ann Arbor classification,¹¹ which subdivided patients into four stages, each subclassified into A and B groups based on the presence of fevers greater than 38.3°C, weight loss, and drenching night sweats. The Ann Arbor system proved useful for decades and was subsequently applied also to non-Hodgkin lymphomas (NHLs). The Cotswold modification of the Ann Arbor Classification¹² first formally incorporated computed tomography (CT) into clinical staging paradigms and introduced the terms “X” for bulky disease and “complete remission unconfirmed” (CRu) to describe patients with a residual mass after treatment that most likely represented fibrous scar tissue. The sensitivity and accuracy of CT imaging of the abdomen rendered the “staging laparotomy” for assessment of the abdomen obsolete. The first universally accepted response criteria for NHL were initially published in 1999 by the National Cancer Institute Working Group¹³ and later revised in 2007 to incorporate positron emission tomography (PET), marrow immunohistochemistry and flow cytometry for response assessment.¹⁴ PET/CT imaging rendered the CRu designation obsolete in 2007, because residual radiographic abnormalities could be accurately determined to be either residual active lymphoma or posttreatment fibrosis, based on the metabolic activity of the lesions. These criteria were critically reviewed and analyzed by working groups at the 11th and 12th International Conferences on Malignant Lymphoma in Lugano, Switzerland, in 2011 and 2013 and at the 4th International Workshops on Positron Emission Tomography in Lymphoma in Menton, France in 2012.^15,16 These international workshops were attended by leading hematologists, oncologists, radiation oncologists, pathologists, radiologists, and nuclear medicine physicians, representing all major lymphoma clinical trials groups and cancer centers in North America, Europe, Japan, and Australasia. Their deliberations culminated in the publication in 2014 of improved criteria for the initial evaluation, staging and response assessment for both HL and NHL¹⁷ that are relevant for community physicians, investigator-led trials, cooperative groups, and registration trials. These new rules, known as the “Lugano Classification,” depart substantially from older staging and evaluation systems as detailed later in this chapter.

Approximately 79,990 new cases of lymphoma were projected to be diagnosed and approximately 20,170 persons in the United States were expected to die of this disease in 2014.¹⁸ These numbers represent 4.8 percent of the annual incidence of all cancers and 3.4 percent of annual cancer-related deaths. The most recent age-adjusted incidence rates per 100,000 population provided by Surveillance, Epidemiology, and End Results (SEER) Program of the United States National Cancer Institute are: 24.9 for white males, 17.4 for black males, 17.2 for white females, and 11.9 for black females.¹⁹ The increased risk for men is similar to that found in other countries, although the incidence of NHL in the United States is approximately threefold that of several underdeveloped countries and twofold that of several comparable industrialized countries.²⁰ The risk of developing lymphoma is less in the United States among persons of African descent in comparison to those of European descent. An exponential increase in incidence in NHL among men and women occurs with increasing age (Fig. 95–1). There are some notable exceptions to this overall trend, however, with lymphoblastic lymphoma occurring most commonly in children, Burkitt lymphoma in the 20- to 64-year-old age group, and primary mediastinal B-cell lymphoma developing at a median age of 35 years.²⁰

Follicular lymphoma represents approximately 25 percent of NHL cases in the United States, but is very uncommon in many developing countries and in Asia, especially in Japan and China.^21,22 The United States has a higher incidence of all lymphomas than does Japan, whereas the incidence of extranodal lymphoma is higher in Japan.^21,22 Burkitt lymphoma occurs most frequently in sub-Saharan Africa, whereas T-cell leukemia/lymphoma is most common in southwest Japan, the southeastern United States, northeastern South America, and the Caribbean basin.

The incidence of NHL increased dramatically in the last half of the 20th century in Europe, Asia, and in the United States.^20,21,22 From 1973 to 1990, inclusive, the increase in the United States was slightly more than 80 percent, or approximately 4 to 5 percent per year (Fig. 95–2). The increase in incidence started after World War II, but the best data in the United States were acquired after 1972. The increase affected men and women, all age groups except children, and most histologic types examined, though the greatest increase was in diffuse large B-cell lymphoma (DLBCL). The increased incidence per year reached a plateau in the early 1990s, except among women and older men where the incidence continued to rise.²¹ Hardell has hypothesized that new chemicals synthesized during and after World War II accounted for increased incidence trends, with subsequent improvements in safety gear and regulatory restrictions resulting in stabilization in the last decade.²³ HIV was not prevalent in the human population when the increase first became apparent, although in later years HIV-related lymphoma may have played a part in increasing incidence rates. Orbital adnexal lymphoma and mantle cell lymphoma are exceptions to the recent plateau, with each still increasing at approximately 6 percent a year.^24,25

Several occupations and industries and several potentially hazardous exposures, such as pesticides, herbicides, dyes, engine exhausts, and solvents, have been found in one study or another to be more frequent in lymphoma patients than “matched” healthy comparison groups.^21,26,27 The results often have been inconsistent from study to study. Expert opinion indicates that no workplace exposure has been conclusively linked to lymphoma,²⁸ although farming or living in a community in which farming is prevalent has been a frequent association with higher lymphoma incidence.^21,26,27

Many publications have reported a slightly increased familial predisposition to the development of NHL, with an odds ratio of 1.5 in first-degree relatives of patients with NHL in a pooled analysis of 17 case control studies.^20,29,30,31 Nonsyndromic familial lymphoma refers to apparently healthy family members, unlike syndromic familial lymphoma in which immunodeficiency syndromes are the predisposing phenotype (e.g., Wiskott-Aldrich syndrome; see “Immunosuppression” below). The familial cases occur in different generations and among enough family members to strongly suggest that a predisposing unidentified gene results in an incidence above that in the population at large. Li-Fraumeni syndrome is such an example, involving germline mutations in p53. Alternatively, it is possible that family members inherit a susceptibility to an unidentified environmental lymphomagen.

HISTOPATHOLOGIC HETEROGENEITY

Unlike other cancers, the malignancy referred to as “lymphoma” consists of nearly 80 phenotypes.⁹ Because each subtype of lymphoma exhibits unique nuances in its natural history, therapeutic considerations, and prognosis, unequivocal establishment of the precise subtype of lymphoma is of paramount importance in a newly diagnosed patient. The single most important test in a lymphoma patient is an adequate biopsy of affected tissue. In most cases, this should be an excisional lymph node biopsy, or generous incisional biopsy of an extranodal site. When the only sites of disease involvement are deep in the thorax or pelvis, rendering excisional node biopsy difficult, a core needle biopsy obtained with the assistance of ultrasound or CT guidance may be adequate. Fine-needle aspiration alone should never be used as the sole method of establishing the initial diagnosis of lymphoma,^17,32,33 because the precise subtyping of lymphomas requires examination of tissue architecture, not merely cytologic examination of isolated cells. Biopsies should be subjected to microscopic examination, flow cytometry of fresh cells, immunohistochemical examination of fixed tissue sections, and cytogenetic/interphase fluorescence in situ hybridization (iFISH) analysis.³³ In the near future, it is likely that genomic analyses using ribonucleic acid sequencing (RNA-seq) technology will also become important to define specific mutations permitting personalized selection of targeted agents capable of inhibiting deranged intracellular pathways.³⁴

Table 95–1 lists the most prevalent phenotypes distinguishable by pathologists according to the current WHO classification system.^9,10 Approximately 88 percent of lymphomas originate in a cell that exhibits features most consistent with B lymphocyte derivation (B-cell CD surface antigens or immunoglobulin gene rearrangement). The remaining cases are lymphomas in which the phenotype and genotype are most closely related to T cells or NK cells (T-cell receptor [TCR] chain rearrangements or specific immunophenotypes). This heterogeneity is problematic for histopathologic diagnosis, classifying patients in clinical trials, and selecting therapy. It also makes studies of epidemiology and etiology more difficult. To understand acquired (environmental) or genetic causes of the type of lymphoma in question, the latter studies, to be insightful, must stratify the study group by specific histopathologic diagnosis. This requirement can be difficult if one is studying uncommon phenotypes.

The histopathologic diversity of lymphoma is the result of the complexity of the immune system; its wide distribution through many organs with highly specialized sites, such as mucosa-associated lymphatic tissue (MALT); its differentiation into T-lymphocyte, B-lymphocyte, and NK-lymphocytic lineages; its complex maturation through many progenitor cell levels; the concomitant sequential alterations in expression of immune complex genes and the myriad opportunities for transforming mutations; and the transforming effects of mutations in the many genes encoding immunoglobulin chains or the TCR. Thus, studies in prevalent subtypes of lymphoma such as follicular and DLBCL are more common than in uncommon or rare subtypes. In addition, epidemiologic or etiologic findings relevant to one subtype may not be relevant to another subtype or to lymphoma in general.

ENVIRONMENTAL FACTORS

An increased incidence of lymphoma has been observed, especially among farmers and gardeners but also in printers, woodworkers, dry cleaners, barbers and hairdressers, possibly from organic solvent exposure, especially to trichloroethylene (TCE), a solvent used in many industries.^{20,21,22,26,27,28} The increased incidence in agricultural workers may be attributed to exposure to a variety of agents, including organochlorines, organophosphates, and phenoxyacid herbicides.^21,22 Despite many studies, an association with lymphoma incidence with herbicide or pesticide exposure has not reached the level of scientific certainty.²¹ Indeed, evidence indicates that modest exposure to herbicides by adults who use such products in and around their homes is not likely to increase lymphoma risk,³⁵ although heavy occupational exposures remain under study. Large studies of two pesticides, chlorpyrifos³⁶ and glyphosate³⁷ showed no association with lymphoma incidence. In the former case, the relative risk of death from all causes, from any cancer, or from lymphoma was significantly less in the 22,000 applicators exposed to chlorpyrifos than in the 33,000 applicators not so exposed. It is possible that subsets of individuals may be susceptible to different exposures based on genetic differences (see “Interaction of Environment and Genotype” below) Indeed, preliminary studies using single nucleotide polymorphism–based analysis have linked lymphomagenesis with normal variations (polymorphisms) in genes involved in apoptosis, cell cycle regulation, lymphocyte development, and inflammation.^38,39,40 In some cases, polymorphic genes have been associated with specific morphologic subsets of lymphoma.⁴¹ Dark hair dyes have also been associated with a moderately increased risk of follicular lymphoma in women.⁴² A meta-analysis has demonstrated a dose–response relationship of NHL with cigarette smoking, with increasing NHL risk in heavy or long-duration smokers, possibly from a suppressive effect of smoking on the immune system.²⁰ Increased body mass index is associated with an increased risk of many cancers,^43,44 including lymphoma.^44,45,46,47 Indexes above 30 to 35 kg/m² (normal = 8.5 to 25 kg/m²) are associated with an increased risk of lymphoma and a worse outcome after treatment. The risk factors discussed in this section have not been found uniformly in all studies of their association with lymphoma and should be considered provisional associations. In addition, as larger populations of patients with lymphoma, stratified by histologic type, are studied, it may become possible to dissect out etiologic relationships of exogenous exposures with specific subtypes of lymphoma but not others.

Small but significant increases in lymphoma are associated with radiation exposure. An increased incidence of lymphoma was reported in survivors of the atomic bombings in Hiroshima and Nagasaki who were near the hypocenter of the detonation.^48,49,50,51 An increased incidence of lymphomas also has been reported for individuals at the Chernobyl accident site who received radiation equivalent to that of the atomic bomb exposures in Japan.⁵² Individuals treated a half century ago with radiation for ankylosing spondylitis also had a small increase in lymphoma incidence.⁵³ The relative risk of lymphoma with high-dose radiation is low and some still question the causal relationship.⁵⁴ Several studies have found an inverse relationship between an individual’s exposure to ultraviolet light and lymphoma incidence (especially DLBCL).⁵⁵

INTERACTION OF ENVIRONMENT AND GENOTYPE

Polymorphic immune gene variations have been identified as significant factors in the association of organochloride exposure with increased incidence of lymphoma in a large population of patients and matched controls.⁵⁶ Associations between all exposures and NHL risk were limited to the same genotypes for interferon-γ, IFNG (C-1615T) TT, and interleukin-4, IL4 (5′-UTR, Ex1–168C→T) CC. Associations between PCB180 in plasma and dust and NHL risk were limited to the same genotypes for interleukin-16, IL16 (3′-UTR, Ex22+871A→G) AA, interleukin-8, IL8 (T-251A) TT, and interleukin-10, IL10 (A-1082G) AG/GG. This result indicates that the relation between organochlorine exposure and NHL risk may be modified by particular variants in immune genes, supporting the concept of a gene-environment interaction for induction of NHL.

INFECTIOUS AGENTS

Human T-Cell Leukemia/Lymphoma Virus I

Adult T-cell leukemia/lymphoma (ATLL) provides the most compelling evidence for a viral etiology of lymphoma.⁵⁷ Human T-cell leukemia/lymphoma virus-1 (HTLV-1) is a C-type RNA tumor virus, isolated from patients with ATLL.⁵⁸ HTLV-1 is an acquired retrovirus that is not related to other known animal retroviruses. HTLV-1 can immortalize lymphoid cells in culture and induce malignancy in an infected human host. The incidence of infection with HTLV-1 in endemic areas is very high, yet few of these infected patients develop ATLL. HTLV-1 also leads to a neurologic disorder called tropical spastic paraparesis.⁵⁹ Host determinants affect transformation of lymphocytes by HTLV-1, and these may be genetic factors.⁵⁸ Development of ATLL is associated with infection by the virus.⁶⁰ Serum specimens from Japanese patients with ATLL are positive for HTLV-1, as are serum samples from ATLL patients in the Caribbean, where ATLL is endemic.⁶¹ The highest prevalence of ATLL in Japan is in the southern island of Kyushi, where 10 to 15 percent of the population has antibody to HTLV-1.⁶² On the Japanese islands where ATLL is rare, the rate is less than 1 percent. These and additional data from the Caribbean, the southeastern United States, South America, and Africa indicate that ATLL clusters in regions where HTLV-1 is prevalent.^60,61 How these regions are linked is not known. One hypothesis is that HTLV-1 was brought to the Americas from Africa by the slave trade and then to the southern islands of Japan by trade between Japan and Africa.^61,63

Host susceptibility, a shared environmental exposure, or both contribute to HTLV-1 infection. The prevalence of HTLV-1 antibodies in close family members is three to four times higher than in the corresponding normal population.^63,64 In some instances, cell cultures of antibody-positive, clinically normal patients yield HTLV-1 isolates.⁶⁴ Blood donors are routinely screened for antibodies to HTLV-1 to prevent transmission by this route.

Epstein-Barr Virus

Some B-cell lymphomas, including Burkitt lymphoma, posttransplantation lymphoma, and HIV-associated lymphomas (immunodeficiency-related Burkitt lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, the immunoblastic-plasmacytoid type of DLBCL, and oral cavity plasmablastic lymphoma) may be caused by Epstein-Barr virus (EBV; Chaps. 98 and 102).⁶⁵ EBV is a DNA virus in the herpesvirus family that first was described in cultured lymphoblasts from patients with African Burkitt lymphoma.⁶⁶ EBV binds to the CD21 antigen (also the receptor for the C3d component of complement) on B lymphocytes.⁶⁷ It is capable of transforming B lymphocytes into lymphoblastoid cells that may proliferate perpetually in cell culture.⁶⁸ EBV is present in greater than 95 percent of cases of endemic Burkitt lymphoma and in approximately 20 percent of cases of nonendemic Burkitt lymphoma.^69,70 Malaria is holoendemic in regions where endemic Burkitt lymphoma exists.⁷¹ A three-step process in the development of this lymphoma has been proposed^72,73: (1) EBV initiates a polyclonal proliferation of B cells; (2) malaria or other infections further stimulate the proliferating B cells; and (3) the transforming B cells incur specific reciprocal translocations of chromosome 8 with chromosome 2, 14, or 22, resulting in a clonal expansion of B lymphocytes.

Extranodal NK/T-cell lymphoma, nasal type is mostly endemic to East Asia and is usually associated with EBV infection (Chap. 104). The EBV genome is typically detected in the lymphoma cells.^74,75 Geographic localization of extranodal NK/T-cell lymphoma matches the endemic distribution of EBV, suggesting the role of EBV in lymphomagenesis.

Human Herpesvirus-8

Human herpesvirus-8 (HHV-8) is associated with Kaposi sarcoma, Castleman disease, and primary effusion lymphoma, found most commonly in immunodeficient individuals infected with HIV.^{65,76,77,78,79} HHV-8 is not a ubiquitous virus. It is mainly endemic in areas where classical or Kaposi sarcoma is of high prevalence, including the Mediterranean basin and East and Central Africa. In the latter areas, the HHV-8 seroprevalence can reach 80 percent in the adult population.⁷⁹ In the homosexual population (mainly in the United States and Europe), HHV-8 is principally transmitted during repeated sexual contacts, whereas in Africa it is mainly transmitted from mother to child and among siblings. Saliva seems to play a major role in HHV-8 transmission.⁷⁹ Posttransplantation primary effusion lymphoma is associated with HHV-8.⁷⁶

Hepatitis Viruses B and C

Hepatitis B and C have been implicated in the pathogenesis of lymphoproliferative diseases.⁸⁰ In one study, 334 newly diagnosed lymphoma patients and 1014 controls had a serologic evaluation for the presence of prior hepatitis virus B or C infection.⁸¹ The results suggested that hepatitis B seropositivity was significantly higher in patients with DLBCL and follicular lymphoma, and seropositivity for hepatitis C was significantly higher in DLBCL patients. A similar result was found in another study in Taiwan, an area with a high frequency of hepatitis B virus infection.⁸² In two other studies, seropositivity for hepatitis C was significantly higher in patients with B-cell lymphomas.^83,84 Hepatitis C virus has a predilection for B cells. Hepatitis C virus RNA levels are significantly higher in B cells than CD4+ or CD8+ T cells or other cells in infected patients, and the virus is associated with immunopathologic reactions, such as cryoglobulinemia, and, not infrequently, clonality of infected B lymphocytes.⁸⁵ Hepatitis C virus infection may be associated with the onset of DLBCL, marginal zone lymphoma, and lymphoplasmacytic lymphoma, but not follicular lymphoma.⁸³

Helicobacter pylori

Helicobacter pylori can cause marginal zone B-cell MALT lymphomas of the stomach and probably causes some of the higher-grade lymphomas, either from transformation of a MALT or de novo large cell lymphoma.^86,87,88 This spiral Gram-negative bacillus is the first bacterium demonstrated to cause a human neoplasm. It had been thought that the stomach was sterile because of the acid environment, but H. pylori had evolved to tolerate the environment, perhaps in part, because it secretes urease, an enzyme that converts urea to ammonia, making the microenvironment around the organism less acidic. Although the stomach has no endogenous lymphoid tissue, the latter develops in response to the organism, and ultimately the chronic inflammatory reaction can result in the transformation and selection of a mutant lymphocyte with a growth and survival advantage leading to a lymphoma (Chap. 101). Eradication of H. pylori with antibiotics early in the course of gastric MALT lymphoma can lead to regression of the lymphoma and permanent cure of the majority of afflicted patients.⁸⁹

Chlamydophila psittaci

Ocular adnexal lymphomas are the most common tumor of the eye.^90,91 The majority of ocular adnexal lymphomas are extranodal, mucosa-associated lymphoid tissue lymphomas and have been linked to Chlamydophila psittaci infection in several reports. In one study, this organism was detected in lymphoma tissue in 75 percent of cases.⁹² DNA was detected in conjunctional swabs and/or blood mononuclear cells from 50 percent of patients. Mononuclear phagocytes were the carriers of C. psittaci in this population of patients.⁹³ Confirmatory reports of the association of C. psittaci with adnexal ocular lymphoma have been published,^94,95 but other studies report no association.^96,97,98 These discrepant reports may be explained by the association of different organisms with ocular lymphoma in different geographic regions of the world.^99,100

Other Bacteria

Other bacterial infestations have been found in association with lymphomas of MALT. Campylobacter jejuni and Borrelia burgdorferi have been connected to the onset of immunoproliferative disease of the small intestine and B-cell lymphoma of the skin.¹⁰¹

IMMUNOSUPPRESSION

Inherited

A number of the rare immunodeficiency syndromes tabulated in Table 95–2^82,102–123 result from gene mutations leading to deficiencies in cellular or humoral immunity or both. These syndromes have a paradoxically high frequency of autoantibodies but, more relevant to this discussion, an increased probability of developing a lymphoma. Because these syndromes are so uncommon, reliable assessment of the increased risk of lymphoma often has to be inferred. The increased risk of approximately 0.5 to 10 percent of patients, depending on the immunodeficiency disease in question, is several orders of magnitude above the risk in the general population (age-adjusted incidence rate in the United States younger than 65 years of age: males = 0.011 percent and females = 0.008 percent). With the exception of common variable immunodeficiency, the syndromes present in childhood and because several are X-chromosome-linked, males are affected more commonly than females. The lymphomas induced may result from a susceptibility to EBV and the lymphoproliferation may initially be polyclonal before evolving to a monoclonal tumor. Extranodal involvement appears to be more common than in persons with lymphoma who are immunocompetent. The initial manifestations of the immunodeficiency are usually infections or autoimmune abnormalities, such as immune cytopenias, and lymphoma is a later complication. We have included Li-Fraumeni syndrome in this cluster for convenience of presentation. This germline predisposition syndrome does not have an immunodeficiency phenotype as do all the other entries in Table 95–2. Rather, it is a nonsyndromic familial cancer syndrome transmitting susceptibility to mutations in p53. The cancers that occur in these families include lymphoma.

Acquired

A variety of types of immunosuppressed individuals develop lymphoma. Chapter 81 discusses AIDS-related lymphoma.¹²⁴ Posttransplantation lymphoproliferative diseases generally display B-cell lineage derivation, involvement of extranodal sites, aggressive histology and clinical behavior, and frequent association with EBV infection. The occurrence of immunoglobulin (Ig) V mutations in the overwhelming majority of posttransplantation lymphoproliferative disease indicates that malignant transformation targets germinal center B cells and their descendants, both in EBV-positive and EBV-negative cases.^125,126,127 Posttransplantation T-cell lymphomas may occur and often arise in extranodal sites, such as skin or central nervous system.^128,129

The incidence and severity of lymphomas have increased with the introduction of immunosuppressive agents such as cyclosporine, infliximab, and etanercept for treatment of autoimmune diseases.

AUTOIMMUNITY

Several autoimmune disorders are risk factors for lymphoma, probably as a result of chronic immune stimulation leading to excessive B-cell proliferation as well as depressed regulatory T-cell function. The strongest associations are for primary Sjögren syndrome, systemic lupus erythematosus, and rheumatoid arthritis with relative risks of 18.8, 7.4, and 3.9, respectively.²⁰ Patients with Sjögren syndrome are especially susceptible to development of parotid gland marginal zone lymphoma (1000-fold increased risk), DLBCL and follicular lymphomas (Fig. 95–3). Similarly, marginal zone lymphoma and DLBCL are the subtypes most likely to develop in patients with lupus.¹³⁰ DLBCL has also been reported in association with autoimmune hemolytic anemia. The risk of developing a T-cell lymphoma is increased for patients with celiac disease and psoriasis. Hashimoto thyroiditis is associated with an increased risk of thyroid marginal zone lymphoma, but may also have a higher risk of marginal zone lymphoma in other locations.¹³¹ Sarcoidosis is an inflammatory (granulomatous) disorder that may predispose to lymphoma.¹³²

Chromosomal abnormalities involving all chromosomes may occur in lymphomas (Chap. 11). Lymphoid malignancies have a high frequency of translocation-inducing fusion genes. Usually they are of two types: one involving oncogenes that are activated by juxtaposition with IgH or TCR genes, or by formation of chimeric genes that constitutively activate mutant kinases or mutant transcription factors. The molecular alterations leading to translocations involving nonimmune genes are not known, whereas there is strong evidence that mistakes in V(D)J (variable diversity joining) recombinase activity are responsible for those translocations involving IgH or the TCR genes.¹³³

As in translocations associated with childhood acute lymphocytic leukemia and adult chronic myelogenous leukemia (CML) and acute myelogenous leukemia, translocations involving t(14;18)(IgH;BCL-2) are found in healthy persons. Presumably, additional genetic events are required for transformation of a lymphocyte to occur. Alternatively, cells containing these translocations may be entering an apoptotic process, destined to be eliminated.¹³³

FOLLICULAR LYMPHOMA

Approximately 85 percent of follicular lymphomas carry the chromosomal translocation t(14;18)(q32;q21) in which the BCL-2 oncogene on chromosome 18q21 is brought in continuity with the immunoglobulin heavy-chain loci on 14q32,¹³⁴ resulting in overexpression of the BCL-2 protein.¹³⁵ The accumulation of the BCL-2 protein permits accumulation of long-lived centrocytes, because the BCL-2 protein inhibits programmed cell death (apoptosis), leading to a longer cell life (Chap. 99).¹³⁶ The BCL-2 rearrangement can be detected by the polymerase chain reaction or by iFISH testing (Chap. 99).

BURKITT LYMPHOMA

In Burkitt lymphoma, the common genetic abnormality is the translocation of the MYC oncogene from chromosome 8 to either the immunoglobulin heavy-chain region on chromosome 14, t(8;14)(q24;q32), or, less commonly, the κ region on chromosome 2, t(2;8)(p13;q24), or the λ region on chromosome 22, t(8;22)(q24;q11). In the African endemic cases, the breakpoint on chromosome 14 includes the heavy-chain joining region, suggesting translocation occurs before complete immunoglobulin gene rearrangement in an early B cell (Chap. 102). In nonendemic cases, the translocation involves the immunoglobulin heavy-chain switch region, suggesting translocation occurs at a later stage of B-cell development.¹³⁷ EBV genomes are demonstrated in the tumor cells in most of the African cases, in approximately one-third of the cases associated with AIDS,^138,139 but less frequently in non-African, nonimmune-deficient cases (Chap. 102).

ANAPLASTIC LARGE CELL LYMPHOMA

The translocation t(2;5)(p23;q35) of anaplastic large cell lymphoma (ALCL) involves the nucleophosmin (NPM) gene at 5p35 and the ALCL tyrosine kinase (ALK) gene at 2p23,¹⁴⁰ leading to expression of the novel fusion protein p80 that can be identified by immunohistochemical studies.¹⁴¹ This translocation has been identified in approximately 50 percent of systemic cases in adults and in a majority of pediatric cases of ALCL.^142,143 The t(2;5) translocation is rare in primary cutaneous ALCL, which is generally considered to be a different disease than systemic ALCL (Chap 2. 103 and 104.)¹⁴⁴

MARGINAL ZONE LYMPHOMA OF MUCOSA-ASSOCIATED LYMPHATIC TISSUE

t(11;18)(API2-MALT1), t(1;14)(IGH-BCL10), t(14;18)(IGH-MALT1), and t(3;14)(IGH-FOXP1) occur in marginal zone B-cell lymphoma of MALT of different sites. The first three chromosome translocations are specifically associated with the marginal zone lymphoma of MALT lymphomas and the oncogenic products of these translocations target the nuclear factor-κB pathway (Chap. 101).¹⁰¹

MANTLE CELL LYMPHOMA

t(11;14)(q13;q32) is present in the cells of most cases of mantle cell lymphoma and results in cyclin D1 upregulation. iFISH is the most useful test to identify the juxtaposition of the CCND1 and IGH genes in mantle cell lymphoma (Chap. 100).¹⁴⁵

HISTORY AND PHYSICAL EXAMINATION

A complete history and physical examination are required in all patients with lymphoma to ascertain the distribution of lymphadenopathy, extranodal disease, and functional disturbances of affected organ systems. It is also important to document whether the patient has fever (i.e., temperature >38°C for 3 consecutive days), drenching night sweats, or metabolic wasting resulting in loss of more than 10 percent of body weight within the preceding 6 months. The presence of such “B” symptoms has unfavorable prognostic significance in HL, but recent analyses have shown that these “B symptoms” do not have independent prognostic significance for NHL, and current staging criteria no longer recommend assigning “A” or “B” designations when staging patients with NHL.¹⁷ Fatigue, rash, pruritus, and alcohol-induced pain in patients with HL should also be noted, as their recurrence after treatment may herald disease relapse. During the physical examination, all enlarged lymph nodes (>1.5 cm) should be recorded. Involved nodes typically are nontender, firm, and rubbery. The throat should be examined for involvement of the oropharyngeal lymphoid tissue (Waldeyer ring). Aggressive lymphomas more likely involve extranodal sites, such as the skin and CNS (see “Primary Extranodal Lymphoma” below). Liver and spleen size should be assessed as well as palpation of the abdomen for evidence of enlargement of deep nodes (e.g., paraaortic, iliac).

STAGING

Optimal management of a patient with lymphoma relies not only on knowledge of the precise histopathologic subtype of lymphoma, but also on an appreciation of the degree of disease dissemination, determined by a sequence of diagnostic tests known as “staging.” The 2014 recommendations from an international working group for the evaluation, staging and response assessment of lymphomas emphasize the emerging dominance of 2-fluorodeoxyglucose (FDG)-PET/CT for initial staging and “end of treatment” response assessment of all FDG-avid lymphomas (including HL, DLBCL, follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma, ALCL, and most subtypes of peripheral T-cell lymphoma) (Fig. 95–4).^16,17 Contrast-enhanced CT imaging remains the standard for lymphoma subtypes that are not reliably FDG-avid (e.g., most marginal zone lymphomas, chronic lymphocytic leukemia/small lymphocytic lymphoma, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, angioimmunoblastic T-cell lymphoma, mycosis fungoides, and cutaneous B-cell lymphomas). For FDG-avid lymphomas, PET/CT imaging has been shown to improve the accuracy of staging for both nodal and extranodal sites compared with CT imaging, leading to a change in stage in 10 to 30 percent of patients, usually as a result of upstaging. Alterations in the therapeutic plan occur in fewer patients and no impact on overall survival as a result of PET/CT imaging has been demonstrated; however, improved staging assures that fewer patients are undertreated or overtreated.¹⁷ PET/CT is particularly important before consideration of radiation therapy for apparently localized disease, because identification of disease sites outside the radiation field by PET/CT entirely alters the treatment plan. The CT portion of a PET/CT scan may be performed with contrast enhancement at a full radiation dose to obtain a high-quality CT examination or without contrast using a lower radiation dose, which merely allows correction for the attenuation of radioactivity within the patient and to localize abnormalities seen on PET.

Full-dose, contrast-enhanced CT scans may identify additional findings, improve detection of abdominal or pelvic disease, permit radiation therapy planning in the treatment position, and are required for accurate nodal measurements on clinical trials. However, full-dose, contrast-enhanced CT scans entail additional radiation exposure and expense, and uncommonly change the overall management plan. Several international consensus groups have recommended that PET/CT with full-dose, contrast-enhanced CT scans be done at the time of initial diagnosis, but that if contrast-enhanced CT scans do not divulge additional sites of disease, that only low-dose, noncontrast PET/CT imaging be done at the end of treatment.¹⁶

Although marrow aspiration and biopsy have been standard in lymphoma staging in the past, the high sensitivity of PET/CT for marrow involvement has rendered this procedure unnecessary for patients with HL and DLBCL who have negative PET/CT imaging of the bones and marrow. Data for other histologies are currently insufficient and a single 2.5-cm core biopsy with flow cytometry and cytogenetics are still recommended for full staging of other subtypes.^16,17 Standard blood testing should also be performed, including a complete blood count (CBC) and chemistries. Lactate dehydrogenase and β₂-microglobulin are important serum prognostic markers that should be assessed at baseline for most lymphomas.^33,146 Table 95–3 lists the staging procedures that are currently recommended and the criteria used to assign a patient’s stage (Table 95–4).¹⁷

At the completion of therapy, all diagnostic studies performed at baseline detecting evidence of disease are repeated for response evaluation. Current recommendations suggest that PET/CT imaging be interpreted using visual inspection according to a 5-point “Deauville scale” (Table 95–5).¹⁵ Deauville scores of 1 to 2 on FDG-PET scans indicate metabolic activity in tumor sites less than in the mediastinal blood pool, signifying complete metabolic response and complete remission. In contrast, Deauville scores of 4 or 5 at the end of treatment, indicate residual abnormal metabolic activity, representing treatment failure (Table 95–6). A Deauville score of 3, indicating metabolic activity greater than the mediastinum but less than the liver, is indeterminant. Most patients with HL or DLBCL who have a Deauville score of 3 at the end of treatment have good outcomes, but careful followup of such patients is important.

The International Working Group (IWG) and the National Cancer Center Network (NCCN) have published recommendations for followup of patients in remission that vary by histology, whether a patient is on a clinical trial or not, and by the clinical setting (e.g., initial vs. relapsed/refractory disease; complete response or not). For curable histologies such as HL and DLBCL, the likelihood of relapse decreases over time and visits are reduced from every 3 months during the first 2 years, to every 6 months for the next 3 years, and then annually thereafter. Incurable histologies are observed every 3 to 6 months, determined by pretreatment risk factors, whether the patient is being managed conservatively, and whether treatment has achieved a complete remission or not. At each visit, a history, physical examination, CBC, metabolic panel, and serum lactate dehydrogenase are performed. The role, if any, of surveillance radiographic imaging for patients in remission is controversial. All groups strongly discourage surveillance monitoring with PET/CT imaging for patients in remission because of the high rate of false-positive findings in this setting, which lead to unnecessary anxiety, expense, and biopsy procedures.^15,16,17,33 The Lugano IWG guidelines also discourage surveillance CT imaging for patients with HL and DLBCL in complete remission at the end of therapy. In contrast, NCCN guidelines recommend that contrast-enhanced CT imaging be performed no more frequently than every 6 months for 2 years after the end of therapy for DLBCL and HL, and then be discontinued.

Lymphomas involving extranodal sites most commonly occur simultaneously with nodal involvement, either at the time of diagnosis or during the course of the disease. Extranodal involvement that occurs as the only initial evidence of lymphoma after staging procedures is referred to as primary extranodal lymphoma. The presence of a tumor or mass outside of the lymph nodes is usually not considered lymphoma until a biopsy is done and the histopathology establishes the diagnosis. On the other hand, solitary extranodal lymphomas can occur in virtually any organ or tissue and should be considered in the differential diagnosis of a solitary mass lesion anywhere. The histopathology of primary extranodal lymphoma is usually either marginal zone lymphoma of MALT or DLBCL. Follicular lymphoma and several other histologic subtypes of lymphoma may also occur. Therapy usually involves a combination of multidrug chemotherapy and a lymphocyte-directed monoclonal antibody, such as rituximab-cyclophosphamide, hydroxydoxorubicin, vincristine (Oncovin), and prednisone (R-CHOP). Selection of the best regimen depends on the histopathologic subtype of lymphoma and the location of the disease. Radiotherapy is used less commonly in the management of lymphoma than in the past because of concerns about induction of secondary malignancies and delayed cardiopulmonary toxicities, although it still has a role in treatment of localized, stages I to II lymphomas, and for consolidation of bulky adenopathy (>10 cm) in selected settings.

An unanswered pathogenetic question concerning primary extranodal lymphoma is the propensity for both sites of paired organs (e.g., ovaries, testicles, breasts, ocular adnexa, adrenal glands, kidneys, and ureters) to be affected simultaneously. It is also curious that several of these sites (e.g., kidney) are normally devoid of significant accumulations of lymphatic tissue. If the transformed lymphocyte arises outside these tissues, it must have a tropism for both paired organs, perhaps because of expression of site-specific adhesion molecules or addressins.¹⁴⁷

CENTRAL NERVOUS SYSTEM

Primary lymphomas originating in and confined to the leptomeninges,¹⁴⁸ brain,^149,150,151 or spinal cord¹⁵² are uncommon. They almost always are of an aggressive histologic subtype, usually DLBCL.^151,153 Spinal cord compression typically presents with back pain, followed by extremity weakness, paresis, and paralysis. Leptomeningeal spread may present with cranial nerve palsies and signs of meningeal irritation, for example, headache and stiff neck. Intracerebral mass lesions may present with headaches, lethargy, papilledema, focal neurologic signs, or seizures. Intracerebral lymphoma increased dramatically after the onset of the human immunodeficiency virus epidemic as a result of the association with AIDS-related aggressive lymphomas (Chap. 81). The incidence of intracerebral lymphoma has slowed in AIDS patients because of more successful antiviral therapy. Primary pituitary (or hypothalamic) extranodal lymphoma may result in hypopituitarism. Diabetes insipidus or anterior pituitary failure may occur. The lesion may invade the sella turcica or other neighboring bone and nervous tissue.^154,155,156

EYE

Ophthalmic lymphoma, the most common orbital malignancy, includes lymphoma localized to the eyelid, conjunctiva, lacrimal sac, lacrimal gland, orbit, or intraocular space.^157,158,159 This location accounts for approximately 7 percent of all extranodal lymphomas.¹⁶⁰ The most frequent subtype is extranodal marginal zone lymphoma of MALT. Bilateral involvement occurs in 10 percent of cases. The most common site of ocular lesions is the periorbital soft tissues, particularly the conjunctival mucosal surfaces and the area surrounding the lacrimal gland. These lesions typically have a low-risk of progression and commonly have the histology of a marginal zone lymphoma of MALT or follicular center cell lymphoma and may be associated with C. psittaci (see “Infectious Agents” above). In a Danish study, approximately 50 percent of orbital and ocular adnexal lymphomas were of the marginal zone lymphoma of MALT subtype; DLBCL was the most common intraocularly.^91,160 Lymphoma arising in the lacrimal sac was usually DLBCL. There has been a striking increase in incidence rates for lymphoma of the eye over the past 30 years.^{24,157,158,159,161} Patients with marginal zone lymphoma of MALT of the ocular orbit may relapse or have progression of disease after initial therapy and relapses can be found at extraocular sites.⁹¹ Overall survival, however, was not significantly worse for patients with relapse. The frequency of translocations involving the MALT1 and IGH gene loci is low in orbital marginal zone lymphoma of MALT (approximately 5 percent), but may predict increased risk of relapse.¹⁶⁰ The therapy for orbital marginal zone lymphoma is usually radiotherapy, which is curative in the majority of patients.¹⁵⁷ Anecdotal reports of responses to rituximab or rituximab postradiation suggest that rituximab may have a therapeutic role in low-grade lymphomas involving the eye. In the rare situation where DLBCL involves the periorbital soft tissue, treatment is determined by the distribution of the disease, but R-CHOP chemotherapy either alone or combined with local radiotherapy is standard.

Intraocular lymphomas are a rare presentation of lymphoma of the eye. Most cases are DLBCL. The diagnosis is established by a vitrectomy. There is an approximately 50 percent chance that the disease will be bilateral and the disease is frequently associated with brain or leptomeningeal involvement. The mainstay of therapy in the past has been local radiotherapy or intraocular injections of methotrexate or rituximab, but most patients treated in this manner relapse within the eye or brain. Standard chemotherapeutic agents administered intravenously (e.g., R-CHOP) typically do not penetrate the eye or brain, rendering these regimens ineffective. In recent years, many neuro-oncologists have advised treating intraocular lymphomas similarly to primary DLBCL of the brain with high-dose methotrexate based-chemotherapy with or without intrathecal treatment and/or whole-brain and eye radiotherapy. A large study conducted at 17 European centers has not confirmed the expected efficacy of this aggressive approach for vitreoretinal lymphoma, however.¹⁵⁸

PARANASAL SINUSES

Localized NHL involving the nasal cavity and/or paranasal sinuses may be DLBCL, T-cell lymphoma, or NK/T-cell lymphoma.^{74,162,163,164,165,166,167,168} The nasal cavity is the predominant site of involvement in T-cell and NK/T-cell lymphoma, whereas sinus involvement without nasal disease is common in B-cell lymphoma. Systemic B symptoms are more frequently observed in NK/T-cell lymphoma. Based on in situ hybridization studies, there is a strong association of EBV with NK/T-cell lymphoma. These lymphomas may involve the frontal, maxillary, ethmoid, and sphenoid sinuses and typically involve bone. They present with local pain, upper airway obstruction, rhinorrhea, facial swelling, or epistaxis. They may extend into the periorbital area causing proptosis, visual loss, or diplopia. These lymphomas typically are DLBCL in the United States and Western Europe and more often T- and NK-cell lymphomas in Asia. Nasal NK/T lymphomas are typically treated with combination chemotherapy including l-asparaginase plus radiotherapy.^162,169 In contrast, patients with primary sinus lymphoma usually have DLBCL. A series of 80 patients with primary sinonasal DLBCL treated with R-CHOP chemotherapy demonstrated a long-term progression-free survival rate of 50 to 60 percent, with only a single patient experiencing CNS relapse.¹⁷⁰

SKIN

The three main types of cutaneous B-cell lymphomas are primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicular center lymphoma, and primary cutaneous large B-cell lymphoma (leg type) as defined by the WHO–European Organization for Research and Treatment of Cancer.¹⁷¹ Primary cutaneous marginal zone B-cell and primary cutaneous follicle center lymphoma are indolent types with an excellent prognosis that should be treated primarily with nonaggressive therapies, including simple excision, glucocorticoid injections or local radiotherapy. Primary cutaneous large B-cell lymphoma (leg type) is a diffuse dermal infiltrate of neoplastic B cells with extension to both the papillary dermis and the subcutaneous fat.^172,173 It typically presents as a solitary soft-tissue mass and mimics a soft-tissue sarcoma until biopsy clarifies the diagnosis. It is an aggressive lymphoma that should be treated primarily with aggressive chemotherapy (Chap. 98). Chap. 103 discusses classical T-cell cutaneous lymphomas, particularly mycosis fungoides.

CHEST AND LUNG

Primary pulmonary lymphoma may present as a pulmonary nodule or mass and may be associated with hilar lymph node enlargement. The histopathology is usually marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue or DLBCL, though lymphomatoid granulomatosis may also present in this fashion.^174,175 Lung biopsy is usually required to make a definitive diagnosis. Pleural effusions may occur as a result of either central lymphatic obstruction or pleural seeding.

Primary chest wall lymphoma may present as local pain or may be accompanied by fever, sweating, and dyspnea. These masses usually require excisional or incisional biopsy. They may be associated with pleural effusions and involvement of neighboring ribs.¹⁷⁶

Primary endobronchial lymphoma is a rare occurrence and may follow lung transplantation. It can lead to airway obstruction as an early sign.

HEART

Primary cardiac lymphoma may involve the heart or pericardium or both. Patients may present with dyspnea, edema, arrhythmia, or pericardial effusion. The effusion may result in cardiac tamponade. Lymphomatous masses may be found in the right atrium (most common), pericardium, right ventricle, left atrium, or left ventricle. Most cases are a B-cell lymphoma; less than 5 percent are of T-cell lineage.^177,178,179

GASTROINTESTINAL TRACT

Gastrointestinal lymphoma is the most common form of extranodal lymphoma, accounting for one-third of cases.¹⁸⁰ The most commonly involved site is the stomach, followed by the small bowel, ileum, cecum, colon, and rectum. Lymphoma of the stomach typically causes dyspeptic symptoms and sometimes anorexia or early satiety. Hemorrhage is unusual but if present suggests a high-grade lymphoma. Diagnosis typically is made by endoscopic biopsy.^180,181 H. pylori infection has been implicated in the pathogenesis of MALT gastric lymphoma.⁸⁸ At endoscopy, mild to severe gastritis is common. Multiple biopsies are important to obtaining adequate material to determine the presence of H. pylori. MALT lymphoma is common, but DLBCL also may arise de novo or may be found in the background of a MALT lymphoma.¹⁸¹ If both subtypes of lymphoma are present, the treatment should be directed at the large B-cell lymphoma.

In the bowel, the small intestine, rectum, and colon may be involved, in that order of frequency.^88,182 The intestinal location most often involved is the ileocecal region followed by small bowel, large bowel, and multiple intestinal sites.¹⁸² Primary esophageal lymphoma is rare.¹⁸³ Primary colonic lymphoma is associated with symptoms of diarrhea, lower gastrointestinal bleeding, and nausea and vomiting secondary to low-grade obstruction. The most common disease location is the cecum, followed by the right colon, and the sigmoid colon.¹⁸⁴

Rare cases of lymphoma may be confined to the liver. Right upper quadrant pain is the most common symptom. In about half of cases there is a history of previous inflammatory liver disease, such as hepatitis C.^{185,186,187,188}

Primary extranodal lymphoma of the pancreas may present with abdominal pain, nausea, vomiting, obstructive jaundice, and weight loss, and very rarely signs of pancreatitis.^189,190,191

The gallbladder may be the site of primary extranodal lymphoma and may present with right upper quadrant pain or other symptoms and signs consistent with cholecystitis.^192,193 It may extend into the bile ducts with jaundice and other signs of bile duct obstruction.¹⁹⁴

GENITOURINARY

Testicular

Primary lymphoma of the testes typically presents as a painless enlargement of the testis in an older man (Fig. 95–5). A hydrocele may also be present.^{195,196,197,198} The histologic type usually is a DLBCL. At presentation, two-thirds of cases are localized to the testicle or to the testicle and pelvic or abdominal lymph nodes. After orchiectomy has established the diagnosis, patients are staged with a special focus on the remaining testicle. If sonography of the remaining testicle demonstrates a solid mass, it should be assumed to be lymphoma. Patients presenting with testicular lymphoma have historically experienced a poorer prognosis compared to patients with other presentations of DLBCL, with relapses commonly occurring in either the CNS or contralateral testicle.¹⁹⁹ The current international standard of care consists of orchiectomy, R-CHOP chemotherapy given every 21 days for six cycles, intrathecal methotrexate, and locoregional radiotherapy to the contralateral testicle.^195,196 This combined modality approach has been shown to render an excellent 5-year progression-free survival rate of 74 percent.¹⁹⁶

Ovary

Primary lymphoma of the ovary is often bilateral and presents as an abdominal mass with abdominal pain or palpation of a mass on physical examination.^{200,201,202,203,204,205}

Uterus, Cervix, Genitalia

Cases of lymphoma limited to the uterus,^206,207,208 uterine cervix,^209,210 vagina, or vulva²¹¹ can occur. Uterine and cervical lymphoma usually presents with an abdominal mass or vaginal bleeding. Lymphoma can develop within a uterine leiomyoma.²⁰⁸

Kidney

Lymphomatous involvement of both kidneys usually presents with renal insufficiency, which can be reversed with multidrug chemotherapy, or radiotherapy. Bilateral enlargement of the kidneys without obstruction and other organ or nodal involvement and absence of other causes of renal failure are characteristic of primary renal lymphoma.^{212,213,214,215,216} The origins of the lymphoma are perplexing as the kidney is thought to be devoid of lymphoid tissue. Both careful staging and postmortem examination have verified the absence of lymphoma in other sites. An increased association of renal cell carcinoma and primary renal lymphoma may exist.²¹⁵ Rarely, the lymphomatous involvement, although still solely extranodal, involves only the perirenal space.²¹⁷

Ureter, Bladder, Prostate

Bilateral ureteral involvement with obstructive renal failure may occur.²¹⁸ Primary lymphoma of the bladder may rarely extend to the kidney. Usually it is localized and responds well to treatment.^219,220,221 Primary extranodal lymphoma may involve the prostate.^222,223

SPLEEN

Primary splenic lymphoma is rare.^224,225 Concomitant marrow involvement is present in most cases. When primary to the spleen, the lymphoma may be principally confined to the red pulp and is usually consistent histopathologically with DLBCL or marginal zone lymphoma.²²⁴ In the absence of lymph node involvement or splenic white pulp involvement at the time of diagnosis or during the course of the disease, it can be considered an “extranodal” splenic lymphoma.²²⁵

BONE

Primary bone lymphoma may involve any bone but usually affects the long bones.^{226,227,228,229} The presentation is usually bone pain and the lesions are usually lytic when imaged.^226,228 When the skull is involved the lymphoma may invade the central nervous system.²²⁷ Most patients exhibiting skeletal involvement are due to aggressive lymphomas, particularly DLBCL. Management generally involves R-CHOP chemotherapy with consolidative radiotherapy.²²⁶

BREAST

The clinical presentation of primary lymphoma of the female breast often mimics carcinoma of the breast. A small proportion of cases may be bilateral. The pathologic diagnosis is DLBCL in approximately 85 percent of cases.²³⁰ BCL-2 expression is frequently present in the tumor cells. Small lymphocytic lymphoma, follicular lymphoma, and marginal zone lymphoma of mucosa-associated lymphoid tissue may also be the histopathologic diagnosis.^231,232 Staging may uncover either nodal involvement, marrow involvement or other extranodal sites with lymphoma in as many as half of cases. Approximately 10 percent of cases of primary breast lymphoma relapse in the central nervous system.^230,232

ENDOCRINE GLANDS

Primary adrenal lymphoma usually present bilaterally and thus may lead to adrenal insufficiency. In the latter case, the presenting symptoms may be fatigue, asthenia, and other signs of hypoadrenocorticism.^{233,234,235,236} Primary thyroid lymphoma often occurs in a gland afflicted by Hashimoto thyroiditis. Thus, it occurs more frequently in women than men. The patient may present with an enlarged thyroid (goiter) or have symptoms as a result of tracheal compression.^237,238,239 The histopathology may be DLBCL or marginal zone B-cell MALT lymphoma. Primary pituitary lymphoma is discussed under “Central Nervous System” above.