Chapter 58: General Considerations of Lymphoma: Epidemiology, Etiology, Heterogeneity, and Primary Extranodal Disease

Approximately 72,000 cases of non-Hodgkin lymphoma (NHL) will be diagnosed in 2015 and approximately 20,000 persons will die of the disease in the United States.

NHL represents approximately 4.5% of cancers in the United States and 3.5% of cancer deaths, annually.

The age-adjusted incidence rates per 100,000 persons for NHL in the United States are 25 for white males, 18 for black males, 17 for white females, and 12 for black females.

The risk of NHL in the United States is approximately three times that of several underdeveloped countries and two times that of several comparable industrialized countries.

There is a logarithmic increase in annual incidence in both men and women from late teenagers to octogenarians in the United States: males 15 to 19 years of age, 2.3 cases/100,000 persons; males 80 to 84 years of age, 147 cases/100,000 persons; females 15 to 19 years, 1.2 cases/100,000 persons; and females 80 to 84 years, 102 cases per 100,000 persons.

Follicular lymphoma represents approximately 25% of NHL cases in the United States but is uncommon in many developing countries and in Asia, especially China and Japan.

Diffuse large B-cell lymphoma represents approximately 30% of NHL cases in the United States.

The annual incidence of NHL, but not Hodgkin lymphoma, increased significantly between 1972 and 1995 in the United States and western European countries. The increase probably started before 1972 based on European data, but the United States National Cancer Institute did not track specific-site cancer incidence before that date.

The rate is still increasing slightly for women and older men in the United States. Orbital adnexal lymphoma and mantle cell lymphoma are increasing at a rate of approximately 5% per year.

The evidence that benzene, other solvents, pesticides, herbicides, dyes, various occupations, and other industrial exposures increase the relative risk of lymphoma is disputed and, at this time, is insufficient to reach a level of medical or scientific certainty, according to the International Agency on Research in Cancer.

There are instances of familial clustering and an increase in the relative risk of lymphoma in siblings of patients with lymphoma or related hematologic malignancies (eg, myeloma). These so-called nonsyndromic examples of increased familial risk are likely explained by as yet undefined predisposition genes, akin to the Li-Fraumeni syndrome, which is the result of germline inheritance of mutated p53.

Several syndromic immunodeficiency states increase the relative risk of lymphoma in family members (see “Immunosuppression and Autoimmunity,” below).

The World Health Organization has categorized more than 30 unique histopathologic types of NHL and these are shown in Table 58–1 with their approximate relative frequency. Approximately 88% are B-cell lymphomas and approximately 12% are T-cell lymphomas. There are striking variations in the incidence of various subtypes of NHL in different geographic areas throughout the world.

Single nucleotide polymorphism base analysis has indicated that lymphomagenesis may be linked to polymorphic genes that are involved in apoptosis, cell cycle regulation, lymphocyte development, and inflammation. The polymorphisms could also be linked to individual susceptibility to certain environmental exposures.

Adult T-cell leukemia-lymphoma is caused by human T-cell lymphocytotrophic virus- (HTLV)-1 (see Chap. 66).

The Epstein-Barr virus genome has been found with a high prevalence in the neoplastic lymphocytes of African Burkitt lymphoma, post-transplantation lymphoma, human immunodeficiency virus (HIV)–related lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, immunoblastic plasmacytoid B-cell lymphoma, oral cavity plasmablastic lymphoma, and extranodal natural killer (NK) cell/T-cell lymphoma. The precise role of this virus in lymphomagenesis has not been defined, but it is likely to be an important facilitating factor in some of these lymphoma types.

Human herpesvirus-8 is associated with Kaposi sarcoma, Castleman disease, and primary effusion lymphoma found most frequently in immunodeficiency associated with HIV infection.

Hepatitis B and C virus have been implicated in the pathogenesis of lymphoma based on the seropositivity of cases compared with controls. Hepatitis C virus has a predilection for lymphocytes, and it has been specifically associated with diffuse large B-cell lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma, but not follicular lymphoma. The etiologic role of and the pathogenetic mechanisms attributed to these viruses have not been established.

Helicobacter pylori can cause marginal zone B-cell lymphomas of mucosa-associated lymphatic tissue (MALT lymphoma), notably of the stomach. This organism is the first bacterium shown to be capable of inducing a human neoplasm (see Chap. 63).

Chlamydophila psittaci has been associated with a majority of cases of a specific extranodal mucosa-associated lymphoid tissue lymphoma, ocular adnexal lymphoma.

Campylobacter jejuni and Borrelia burgdorferi have been associated with immunoproliferative diseases of the small intestines and B-cell lymphoma of the skin.

A number of inherited immunodeficiency syndromes listed in Table 58–2 are associated with a predisposition to lymphoma.

Acquired immunodeficiency states, including acquired immunodeficiency syndrome (AIDS)–related lymphoma and post-transplantation–related lymphoma, usually have a B-cell lineage immunophenotype and often involve extranodal sites (eg, skin or central nervous system), are aggressive in behavior, and often associated with Epstein-Barr virus infection of the neoplastic B lymphocytes.

The occurrence of Ig (V) mutations in acquired immunodeficiency-related lymphoma strongly suggests a germinal center B lymphocyte transformation.

The incidence and severity of immunodeficiency-related lymphoma have increased in relationship to the use of more powerful immunosuppressive agents, such as cyclosporine and in the setting of mismatched T-cell–depleted allogeneic hematopoietic stem cell grafts.

Several autoimmune disorders are associated with an increased relative risk of lymphoma. These include systemic lupus erythematosus, Sjögren syndrome, autoimmune thyroid disease, and, perhaps, rheumatoid arthritis. For example, lymphoma is increased 6.5-fold and MALT lymphoma of the parotid gland 1000-fold in Sjögren syndrome.

Chromosome abnormalities involving all 22 autosomes and the sex chromosomes can occur with lymphoma.

Lymphomas have a high frequency of fusion genes usually one of two types: oncogenes activated by juxtaposing with immunoglobulin or T cell receptor genes or by forming chimeric genes that activate mutant kinases or transcription factors.

Approximately 85% of cases of follicular lymphoma have a t(14;18)(q32;q21)(IgH;BCL-2) in the lymphoma cells. Presumably the overexpression of BCL-2 contributes to an antiapoptotic effect favoring an accumulation of long-lived centrocytes (see Chap. 61).

In patients with Burkitt lymphoma, t(8;14)(q24;q32), principally, or t(2;8)(p13;q24) or t(8;22)(q24;q11) is present in the lymphoma cell. The common feature is the formation of a fusion gene involving the MYC gene at band q24 on chromosome 8 with either the IgH or Igκ or Igλ genes (see Chap. 64).

The t(2;5)(p23;q35) in the cells of anaplastic large cell lymphoma (ALCL) involves the NPM gene at 5p35 and the ALCL tyrosine kinase (ALK) gene at 2p23, resulting in a novel oncoprotein, p80. The translocation occurs in about 50% of cases in adults and a higher proportion of children.

Four translocations, t(11;18)(API2;MALT1), t(1;14)(IgH-BCL10), t(14;18)(IgH;Malt1), and t(3;14)(IgH;FOXP1) have been associated with marginal zone lymphomas of the MALT type at different sites. In the first three translocations shown, the oncogenic product targets the nuclear factor-κB pathway (see Chap. 63).

Most cases of mantle cell lymphoma have t(11;14)(q13;q32) in the lymphoma cells. This translocation juxtaposes CCND1 and the IgH genes and results in upregulation of cyclin D1, used as a marker in the diagnosis of this disease (see Chap. 62).

Complete history and physical examination to determine extent of superficial lymphadenopathy, evidence of extranodal involvement, and presence of B symptoms (fever to > 38°C, night sweats, weight loss > 10% body weight in past 6 months).

Staging should be carried out to determine extent of disease as shown in Table 58–3.

The Lugano staging system for lymphoma is shown in Table 58–4.

Lymphomas involving extranodal sites most commonly occur simultaneously with nodal involvement at time of diagnosis or during course of the disease.

Lymphoma only found in extranodal sites after staging procedures (see Table 58–4) is called primary extranodal lymphoma.

Solitary extranodal lymphoma can occur in any organ. Lymphoma should be considered in the differential diagnosis of any solitary mass.

The histology of primary extranodal lymphoma is usually marginal zone lymphoma of mucosa associated lymphoid tissue or diffuse large B-cell lymphoma. Other lymphoma types may occasionally be the histologic diagnosis.

Therapy is usually a combination of excision, radiotherapy, multidrug chemotherapy, and a lymphocyte-directed monoclonal antibody. Rituximab, cyclophosphamide, hydroxydoxorubicin (Adriamycin), vincristine (Oncovin), and prednisone (R-CHOP) is one commonly used regimen for extranodal B-cell malignancies.

The pathobiology underlying a propensity of primary extranodal lymphoma to arise simultaneously in paired organs (kidneys, ovaries, breasts, eyes, adrenals, and others) is unknown.

Specific anatomical sites include:

— Bone. Primary lymphoma may affect any bone but usually the long bones are involved. If the skull is involved, central nervous system invasion may occur.

— Breast. Primary lymphoma of the female breast mimics carcinoma. Staging finds lymph node, marrow, or other extranodal sites of involvement in half the cases.

— Central nervous system. Involvement of the leptomeninges may produce headache, stiff neck, and cranial nerve impairment. Brain involvement can result in headache, lethargy, papilledema, focal neurologic signs, or seizures. Spinal cord involvement can result in back pain, extremity weakness, paresis, and paralysis. This is a usually aggressive type of diffuse large B-cell lymphoma. Intracerebral lymphoma is a feature of AIDS.

— Chest and lung. Primary pulmonary lymphoma may present as a solitary mass in the lung and require lung biopsy for diagnosis. Primary chest wall lymphoma can be accompanied by fever, sweating, and dyspnea and require excisional biopsy for diagnosis. Primary endobronchial lymphoma may follow lung transplantation and cause airway obstruction.

— Endocrine glands. Primary adrenal lymphoma usually presents bilaterally and may lead to adrenal insufficiency. Primary thyroid lymphoma often develops on the background of autoimmune (Hashimoto) thyroiditis. Primary pituitary lymphoma can result in pituitary insufficiency, including diabetes insipidus.

— Eye. Ophthalmic lymphoma is the most common orbital malignancy and includes lymphoma involving the eyelids, conjunctiva, lacrimal sac, lacrimal gland, orbit, or intraocular space. Ophthalmic lymphoma accounts for approximately 7% of primary extranodal lymphoma cases.

— Gastrointestinal tract. This is the most common form of primary extranodal lymphoma, accounting for approximately one-third of cases. The most common site of involvement is the stomach, followed by the ileum, cecum, colon, and rectum. The liver, pancreas, and gallbladder may also be the site of extranodal lymphoma. Symptoms are related to the site involved (eg, nausea, vomiting, diarrhea, bleeding).

— Genitourinary tract. Primary lymphoma of the testes presents as painless enlargement and may be bilateral. Primary lymphoma of the ovary is often bilateral and presents as abdominal masses sometimes felt on abdominal or pelvic examination. Cases limited to the uterus, uterine cervix, vagina, or vulva may occur. Lymphomatous involvement of both kidneys usually presents with renal failure. Bilateral ureteral involvement presents with obstructive renal failure. Primary lymphoma of the bladder or of the prostate may occur.

— Heart. Primary cardiac lymphoma may involve the heart or pericardium. Patients may present with dyspnea, edema, arrhythmia, or pericardial effusion with tamponade. Masses may occur in the right atrium (most common), pericardium, right ventricle, left atrium, or left ventricle.

— Paranasal sinuses. Lymphoma may present with local pain, upper airway obstruction, rhinorrhea, facial swelling, or epistaxis. It is usually diffuse large B-cell lymphoma in the United States and western Europe and T-cell and NK cell lymphoma in Asia.

— Skin. The three main types of cutaneous B-cell lymphoma are primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicular center B-cell lymphoma, and primary cutaneous large B-cell lymphoma (leg type). The first two are indolent lymphomas and the last type is an aggressive lymphoma. These lymphomas may present as soft tissue masses, mimicking sarcoma, until a biopsy and histopathologic diagnosis is obtained.

— Spleen. Primary splenic lymphoma is rare because concomitant marrow involvement is present in most cases. The issue of whether splenic lymphoma is extranodal arises but because lymphoma is usually confined to the red pulp and not the white pulp, it can be considered extranodal.