Chapter 28. The Lymphoid System: I. Structure & Function; Infections & Reactive Proliferations

Circulation of Lymphocytes

The lymphoid system is the anatomic seat of the complex cellular and molecular interactions that make up the immune response (Chapter 4: The Immune Response). The cells of the lymphoid system must have access to all parts of the body, both for the detection of and the response to antigen (humoral and cellular immunity). As noted in Chapter 4: The Immune Response, lymphocytes bearing antigen receptors, both B and T cells, circulate extensively in the bloodstream. Immune cells that leave the blood in any tissue are collected in lymphatics and passed centrally, often through one or more series of lymph nodes, in which they may pause before reentering the blood. Lymphocytes also enter the lymph nodes directly from the blood through postcapillary venules (Figure 28-1).

Lymphoid Tissue

Within the lymphoid system there are several focal concentrations of immune cells (lymph nodes, spleen, tonsils, etc) wherein lymphocytes, macrophages, and other immune cells are arranged in a manner advantageous to the various interactions that make up the immune response. It is no accident that major accumulations of lymphoid tissue occur at portals of antigen entry: the tonsils (mouth and nose), the respiratory and gastrointestinal submucosa (for inhaled and ingested antigens), the lymph nodes (for lymph drainage of skin and organs), and the spleen (as the blood filter).

The thymus and bone marrow are often termed central lymphoid tissues in that they are central to the prenatal development of the immune system but do not participate in the immune response in the adult. The remaining lymphoid organs are actively involved in the immune response and constitute the peripheral lymphoid tissue.

The detailed microanatomic structure of the principal lymphoid organs has been described in Chapter 4: The Immune Response. The intimate juxtaposition of macrophages—which phagocytose and process antigen—and lymphocytes provides for an optimal immune response.

It is important to recognize that this microanatomic arrangement is subject to rapid modification in the presence of an active immune response. The histologic appearances of lymphoid tissue are largely dependent upon the degree of antigenic stimulation.

Note: Reactive follicles (foci of B cell proliferation) only appear following exposure to antigen. Likewise, immunoblasts are only present in the face of recent antigenic stimulation, while plasma cells indicate activity of some weeks' duration.

The cellularity of the lymph node (ie, the number of immune cells present) and the overall size of the node also depend upon the extent of antigenic stimulation—likewise for the spleen and other lymphoid tissues. A normal lymph node shows some degree of baseline activity owing to the normal low-level antigen load; in the face of an additional antigen load (eg, infection), these changes are greatly exaggerated, usually with a combination of B and T cell responses.

Immune Deficiency

(See also Chapter 7: Deficiencies of the Host Response)

Depletion of total lymphocytes in the tissues or in peripheral blood (lymphopenia) and abnormalities relating to specific subpopulations of lymphocytes may be associated with defective immunity, as described in Chapter 7: Deficiencies of the Host Response. Important causes include chemotherapy, corticosteroids, AIDS, and various congenital syndromes.

Perverted Immune Function

(See also Chapter 8: Immunologic Injury)

Immunologic hypersensitivity and autoimmunity are manifestations of an abnormal immune response that leads to disease. There may be some proliferation of lymphoid tissue in these conditions, but the primary pathologic features and clinical effects occur in the organs that are the target of the abnormal immune response.

Lymphadenopathy

(Table 28-1)

The term lymphadenopathy signifies enlarged lymph nodes. Lymphadenopathy may be localized to one lymph node group in the body or may be generalized, affecting multiple groups of lymph nodes all over the body. Conditions that cause generalized lymphadenopathy may also involve lymphoid tissues elsewhere (eg, splenomegaly). In the same way, because of the extensive circulation of lymphoid cells, the peripheral blood may also show increased numbers of lymphocytes (see Lymphocytosis, below).

Lymphocytosis

The number of circulating lymphocytes in the peripheral blood may be increased either as a function of the immune response (see Table 26-3) or as a result of neoplastic proliferation of lymphoid cells in lymphocytic leukemia and lymphoma (Chapter 29: The Lymphoid System: II. Malignant Lymphomas).

Monoclonal Gammopathy

Neoplasms of B cell derivation that show evidence of plasmacytoid differentiation (myeloma, plasmacytoid lymphocytic lymphoma, heavy chain disease) may secrete sufficient amounts of monoclonal immunoglobulin for this to be detectable in the serum as a discrete spike or M (malignant) protein—a monoclonal gammopathy (Chapter 30: The Lymphoid System: III. Plasma Cell Neoplasms; Spleen & Thymus). The presence of such a monoclonal gammopathy provides a means of diagnosis and is of value in monitoring response to therapy of these neoplasms.

Splenomegaly

(See also Chapter 30: The Lymphoid System: III. Plasma Cell Neoplasms; Spleen & Thymus)

Splenomegaly is enlargement of the spleen beyond the normal adult range of 120–160 g. In a lean patient, a spleen weighing 300 g or more usually is palpable.

Splenomegaly is often a result of the same factors that cause lymphadenopathy (Table 28-1), particularly acute and chronic infections that have a blood-borne phase (infectious mononucleosis, malaria). However, the spleen also is a highly vascular organ and may become enlarged owing to simple congestion or involvement by proliferating hematopoietic cells, as in the leukemias.

Thymic Atrophy & Thymic Enlargement

The thymus reaches maximal size in relation to the whole body in fetal life and maximum absolute size in childhood. Thereafter, involution occurs, with gradual loss of lymphocytes and replacement by fibrofatty tissue. In the adult, the thymus weighs approximately 30 g, is essentially nonfunctional, and with rare exceptions does not participate in immunoproliferative responses.

Thymic agenesis or atrophy is characteristic of some of the immunodeficiency states described in Chapter 7: Deficiencies of the Host Response; cell-mediated (T cell) immunity is affected.

Thymic hyperplasia is a rare event but is characteristic of certain autoimmune diseases, most commonly myasthenia gravis. The only other notable causes of thymic enlargement relate to primary or secondary neoplasms in the thymus or the occasional presence of thymic cysts (Chapter 30: The Lymphoid System: III. Plasma Cell Neoplasms; Spleen & Thymus).

Nonspecific Reactive Hyperplasia

Reactive hyperplasia within lymphoid tissue represents the tissue manifestation of the immune response and consists of three interrelated elements:

1. Follicular hyperplasia (the B cell response).

2. Paracortical hyperplasia (the T cell response).

3. Sinus histiocytosis (the histiocyte [macrophage] response).

In practice, any one of these may predominate, but most responses represent an admixture of all three.

In B cell hyperplasia, the reactive follicles are usually large and conspicuous (Figure 28-2), consisting of actively proliferating B cells among which are scattered variable numbers of histiocytes and dendritic reticulum cells. The reactive follicles develop from small clusters of B cells, sometimes called primary follicles, in the outer part (cortex) of the lymph node. The first phase of follicular formation appears to be the trapping of antigen by dendritic reticulum cells, which then serve to stimulate local B cell proliferation, leading to development of a collection of actively transforming B lymphocytes (the secondary or reactive follicle).

A similar reaction occurs among T cells in the paracortex following trapping of antigen by interdigitating reticulum cells. In some instances, the T cell response may predominate; follicles may then be inconspicuous. This type of response particularly is seen in viral infections or postvaccination, eg, in lymph nodes draining the vaccination site.

Lymph nodes draining a malignant neoplasm frequently show reactive hyperplasia, and in many instances the most prominent component is marked expansion of the sinuses, which are filled with histiocytes (sinus histiocytosis).

Many cases of nonspecific reactive hyperplasia are localized in that the antigen source also is confined to a particular region of the body. An example is enlargement of lymph nodes in the neck in conjunction with streptococcal pharyngitis. Generalized reactive hyperplasia may occur with an antigen that is distributed throughout the body, eg, in the viremic phase of viral infections, of which rubella is an excellent example.

Specific Infections of Lymph Nodes

Infections of the lymph nodes combine (1) features of the immune response to microbial antigens, (2) features of inflammation, and (3) specific changes that may be produced by the infectious agent. The presence of the specific agent in the lymph nodes often permits diagnosis by culture of the node, which should be requested at the time of biopsy.

Acute Pyogenic (Bacterial) Lymphadenitis

Bacterial lymphadenitis is usually secondary to the spread of bacteria via lymphatics from a focus of infection in the area drained by the node. Acute inflammation with neutrophil infiltration of the node causes lymph node enlargement, pain, and tenderness. Fever is commonly present, as is a neutrophil leukocytosis in peripheral blood. Abscess formation is common. Precise diagnosis requires culture.

Infectious Mononucleosis

Infectious mononucleosis is characterized by a florid T cell hyperplasia, often so extensive that the follicles are totally obscured. In addition, the number of immunoblasts and T cells in intermediate stages of transformation is so high that the node may appear to be totally replaced by large cells (Figures 28-3 and 28-4), leading to possible misdiagnosis as malignant lymphoma. These large transformed lymphocytes are the same cells that appear in increased numbers in the peripheral blood (so-called Downey cells). (The term mononucleosis was used when the disease was first described because the nature of these large primitive-appearing mononuclear cells was unknown.)

Infectious mononucleosis is caused by the Epstein-Barr virus, which specifically infects B cells (which have a receptor for the Epstein-Barr (EB) virus on their surface). Infected B cells then express viral antigens on their surfaces to which the T cells mount a vigorous immune response (Figure 28-4). The histologic appearance of infectious mononucleosis may be mimicked closely by other acute viral illnesses, including infection with cytomegalovirus, hepatitis virus, herpes simplex (type 2), rubella, and adenovirus; or by vaccination with attenuated live viruses.

Infectious mononucleosis is more common in children and young adults and is transmitted via the upper respiratory tract (kissing disease). Patients present with acute onset of fever, sore throat, lymphadenopathy, and hepatosplenomegaly. Mild liver dysfunction may be present. The disease is often milder in young children and more severe in young adults.

Infectious mononucleosis may be diagnosed by the peripheral blood appearance (lymphocytosis with Downey cells) but should be confirmed serologically as described below. Lymph node biopsy is not necessary in the face of serologic confirmation unless there is continuing enlargement of lymph nodes in the face of clinical resolution of the viral infection.

The traditional serologic test for infectious mononucleosis is the detection of heterophil antibodies by the Paul-Bunnell test, of which the Monospot test is a well-known example. Heterophil antibodies are cross-reactive with a variety of different tissues in different species and are not specific for infectious mononucleosis. Their detection, however, does provide a useful screening test.

Recently, tests for specific antibodies against EB virus antigens have become available, and these now represent the most specific tests for infectious mononucleosis. IgM antibody to viral capsid antigen (VCA) appears early in the disease, followed by IgG antibodies that persist over a long period; antibodies to Epstein-Barr membrane antigen (MA) and nuclear antigen (EBNA) appear late but persist for life.

Toxoplasmosis

Toxoplasmosis is caused by a protozoan, Toxoplasma gondii, which commonly infects cats, rodents, and livestock. Human infection is usually acquired by ingestion of oocysts from soil contaminated by cat feces. As many as 50% of adults in the United States show evidence of having had the disease. (Changing cat litter boxes daily is an effective preventive measure because the oocysts only become infective for humans about a week after passage by the cat.) Less often, infection may be by ingestion of tissue cysts from undercooked pork. Because of the danger of transplacental infection of the fetus, pregnant women are advised to avoid contact with cats, kittens, and their excreta.

Acquired toxoplasmosis, which occurs in the adult, presents as an acute febrile illness with malaise and generalized lymphadenopathy resembling infectious mononucleosis. The illness may be so mild as to be asymptomatic. The presence of enlarged lymph nodes may lead to lymph node biopsy.

Histologically, the changes are quite characteristic, with extensive follicular hyperplasia and histiocytic proliferation; the histiocytes typically occur in clusters in the paracortex and within reactive centers (Figure 28-5). The pseudocysts of Toxoplasma may be seen occasionally; tachyzoites are almost never seen. Immunohistologic techniques using specific antibody are helpful in detecting the organisms.

Congenital toxoplasmosis is a much more serious condition in which infection is transmitted transplacentally from mother to fetus. It is characterized by necrosis in the brain, often severe, and retinal involvement. Organisms are seen in large numbers in both brain and retina. Congenital toxoplasmosis may cause stillbirth, microcephaly, hydrocephalus, and blindness in the neonatal period; or delayed neurologic and learning defects.

Diagnosis is by serologic techniques or isolation of the organism by animal inoculation (intraperitoneally into mice). The standard serologic test is the Sabin-Feldman dye test: serum containing anti-Toxoplasma antibody renders living Toxoplasma permeable to methylene blue. This test is being replaced by more sensitive fluorescence or enzyme-linked immunoassay (ELISA) tests, which do not require the use of live organisms.

Granulomatous Lymphadenitis

The immune response against facultative intracellular organisms is mediated by T cells, lymphokines, and macrophages and results in the formation of epithelioid granulomas (Chapter 5: Chronic Inflammation). Superimposed delayed hypersensitivity associated with the T cell response results in caseous necrosis.

The organisms most commonly responsible for caseous granulomatous lymphadenitis are Mycobacterium tuberculosis, atypical mycobacteria, Histoplasma capsulatum, and Coccidioides immitis, the relative frequency varying widely in different parts of the world. Lymphadenopathy usually effects only those nodes draining the sites of primary infection. Cervical nodes are most commonly affected. Lymphadenopathy may be the only manifestation of the disease, or lymph node involvement may be secondary to known disease elsewhere.

Histologically, the paracortical T cell response predominates. Granulomas may be small, or large and coalescent (Figures 28-6 and 28-7), with caseous necrosis replacing the entire lymph node. Marked fibrosis is commonly present.

Diagnosis is by culture. Mycobacteria may be demonstrated in histologic sections using special acid fast stains (Ziehl-Neelsen); in classic tuberculosis, organisms are few, but in atypical mycobacterial infections occurring in the elderly or immunodeficient host, numerous mycobacteria are present. Histoplasma (a dimorphic soil fungus) may be seen intracellularly as 2–4 μm yeasts by silver staining. Coccidioidomycosis typically forms refractile spherules (30–80 μm in diameter) packed with endospores (Figure 28-8).

Consistent with histologic evidence of delayed hypersensitivity, these infections are associated with delayed hypersensitivity type skin tests (Purified protein derivative (PPD) and tuberculin for M tuberculosis; histoplasmin for H capsulatum; coccidioidin for C immitis). Serologic (complement fixation) tests are available for the diagnosis of histoplasmosis and coccidioidomycosis.

Suppurative Granulomatous Lymphadenitis

In suppurative granulomatous lymphadenitis, the histologic appearances are much the same as for granulomatous lymphadenopathy, described above, but with the addition of acute inflammation and suppuration, with neutrophils in the center of the granulomas. The fully formed suppurative granuloma tends to be stellate (star-shaped). Several different organisms may produce this form of lymphadenopathy, which usually is localized to the site of infection (eg, in cat-scratch disease, the nodes draining the site of the skin scratch are involved; in lymphogranuloma venereum, groin nodes are involved).

Lymphogranuloma Venereum

Lymphogranuloma venereum (LGV) is a sexually transmitted disease, most common in tropical areas, caused by a strain of Chlamydia trachomatis. A local papule at the site of infection on the external genitalia is typically followed by marked regional lymphadenopathy, with suppuration and discharge of pus through multiple sinuses. The diagnosis may be suspected histologically (stellate granulomas) and confirmed serologically (complement fixation test) or by skin test (using heat-inactivated LGV for intradermal injection). Sulfonamides and tetracycline are effective treatment.

Cat-Scratch Disease

Cat-scratch disease is caused by a small gram-negative bacterium (Afipia felis) that stains positively with silver stains. The disease is manifested as acute onset of fever with lymphadenopathy. A history of a wound and exposure to cats is common. The diagnosis is clinical, confirmed by the pathologic features and demonstration of the organism by special stains and culture. A skin test utilizing heat-inactivated pus from known cases is positive in most individuals with the disease but also in about 10% of veterinarians with no history of the disease. The condition is self-limited.

Other Causes

Other infections that may produce suppurative granulomatous lymphadenitis include (1) mesenteric lymphadenitis in young children due to Yersinia enterocolitica and Yersinia pseudotuberculosis; (2) brucellosis, caused by various species of Brucella; (3) tularemia, due to Pasteurella tularensis; (4) plague, due to Yersinia pestis (the bubonic form of the disease affects lymph nodes draining the site of the flea bite); and (5) glanders and melioidosis, caused by Pseudomonasmallei and Pseudomonas pseudomallei.

All of these organisms are short gram-negative rods; in all, there may be a septicemic phase, and lymphadenopathy with suppuration (bubo formation) may occur. The severity of disease is variable, with plague the most severe.

Persistent Generalized Lymphadenopathy

Acquired immunodeficiency syndrome (AIDS) has been described elsewhere in relation to immunodeficiency states (Chapter 7: Deficiencies of the Host Response). Patients who are at risk for AIDS commonly show persistent enlargement of lymph nodes, often generalized and often associated with fever. These patients, who do not have AIDS as defined by the clinical criteria for the disease, nonetheless have antibodies for the human immunodeficiency virus (HIV), and the virus can often be isolated from involved lymph nodes. The T helper:suppressor cell ratio is reversed in blood.

At present in the United States, it is estimated that there are at least 2,000,000 people who have contracted the virus and give a positive serum test for HIV antibody. Of these, 10% have evidence of persistent generalized lymphadenopathy, while 1–3% have AIDS. The percentage of HIV antibody-positive individuals without overt disease who proceed to develop persistent generalized lymphadenopathy or AIDS is not known, but it is believed that about 25% of persistent generalized lymphadenopathy patients progress to AIDS within 1 year, and up to 50% in 5 years.

Histologically, the lymph nodes in persistent generalized lymphadenopathy show follicular and paracortical hyperplasia, with very large conspicuous follicles in the early stages. Irregular loss or fragmentation of the mantle zone (the rim of small lymphocytes around the follicle) is characteristic. The helper: suppressor ratio typically is reversed in the nodes. (In other forms of reactive hyperplasia, T helper cells predominate in the lymph node.) In later stages, there is progressive depletion of lymphoid cells, and 10% develop aggressive B cell lymphomas.

It should be emphasized that lymph nodes from patients with AIDS have identical histologic appearances with the only difference that patients in the latter group have in addition the criteria for AIDS as defined by the Centers for Disease Control (see Chapter 7: Deficiencies of the Host Response).

Reactive Lymphoid Hyperplasia with Specific Features

Dermatopathic Lymphadenopathy

Dermatopathic lymphadenopathy is a form of reactive hyperplasia occurring in lymph nodes draining skin that has suffered chronic damage, such as chronic radiation dermatitis, psoriasis, and exfoliative dermatitis. The most conspicuous feature is the presence of numerous pale histiocytes containing lipid material and melanin released by the damaged epidermis.

Lymphangiography-Altered Lymph Nodes

Lymph nodes may show florid hyperplasia of histiocytes following lymphangiographic examination with lipid-containing contrast media. The histiocytes contain globules of the oily dye in the cytoplasm. This is of importance only in that it may obscure underlying pathologic processes.

Lymphadenopathy of Uncertain Cause

Sarcoidosis

Sarcoidosis is a systemic disease characterized by the presence of noninfectious epithelioid cell granulomas in many tissues, particularly lung, liver, lymph nodes, and skin. It ranges from asymptomatic to a severe febrile debilitating illness with cough and dyspnea, characterized by a chronic course with remissions and relapses. It is more common in men than in women, in blacks than in whites, and in the age group from 20 to 30 years. The incidence is high in Scandinavia, Western Europe, and North America.

Histologically, the granulomas resemble those occurring in tuberculosis except for the absence of caseous necrosis in sarcoid granulomas. Sarcoid granulomas frequently contain calcified bodies called Schaumann bodies. These are not specific for sarcoidosis. No etiologic agent has been identified.

Immunologically, patients with sarcoidosis show depressed cell-mediated immunity (eg, loss of positive skin tests to tuberculin, mumps antigen). The Kveim test (a skin test utilizing an extract of known sarcoid tissue) is usually positive.

Berylliosis produces a histologic picture identical to that of sarcoidosis, and a history of beryllium exposure should be excluded before a diagnosis of sarcoidosis is made. Similar granulomas may be found in intravenous drug users due to contaminants (especially talc) in the materials injected.

Lymphadenopathy of Autoimmune Disease

Lymphadenopathy is not a conspicuous feature of most autoimmune diseases (Chapter 8: Immunologic Injury). However, significant lymph node enlargement may be seen in systemic lupus erythematosus, rheumatoid arthritis—particularly the juvenile form (Still's disease; Chapter 68: Diseases of Joints & Connective Tissue)—and Sjögren's syndrome (Chapter 33: The Eye).

In systemic lupus erythematosus and rheumatoid arthritis, affected lymph nodes show nonspecific follicular hyperplasia, with occasional evidence of vasculitis. In Still's disease, the lymphadenopathy may be the presenting clinical feature. Sjögren's syndrome may occur alone or in conjunction with systemic lupus erythematosus (SLE) or rheumatoid arthritis. Lymphadenopathy is frequently present and typically shows a diffuse hyperplasia with inconspicuous follicles. Immunoblasts may be so numerous as to lead to a mistaken diagnosis of lymphoma. True lymphoma rarely supervenes.

Hypersensitivity states such as serum sickness and chronic drug reactions (eg, reactions to aminosalicylic acid [PAS], an antituberculous drug) may also produce lymphadenopathy, with features of mixed B and T cell response.

Sinus Histiocytosis with Massive Lymphadenopathy

This condition is uncommon outside North Africa. In the United States, it occurs mainly in blacks. The cause is unknown. Children are mainly affected, and clinical presentation is with massive cervical lymphadenopathy, often bilateral. Affected children may have fever and mild anemia but do not appear ill. The disease is self-limited.

The histologic picture is remarkable in that affected lymph nodes contain large numbers of cytologically benign-appearing histiocytes filling the sinuses. The histiocytes contain normal-appearing lymphocytes within their cytoplasm (this phenomenon of live cell ingestion is called emperipolesis); its significance is unknown.

Giant Lymph Node Hyperplasia (Castleman-Iverson Disease)

Giant lymph node hyperplasia is an uncommon condition characterized by benign nonprogressive lymphadenopathy, usually in the mediastinum or retroperitoneum. There has been debate about whether this disease represents a hamartoma (developmental abnormality) or some form of chronic immune response to an agent or agents unknown. Two variants are recognized: plasmacellular and angiofollicular. It is unclear whether these variants represent two separate diseases or are two ends of a spectrum of changes.

In the plasmacellular form of giant lymph node hyperplasia, the lymph nodes show large follicles with numerous plasma cells in the remainder of the lymph node. The plasma cells are polyclonal (ie, reactive) in almost all cases. There is often an associated polyclonal hyperglobulinemia and low-grade fever; both return to normal on resection of the involved nodes. A significant number of cases progress to malignant lymphoma.

In the angiofollicular form of giant lymph node hyperplasia, there are numerous small follicles associated with excessive numbers of peculiar hyalinized vessels. This form is not believed to be associated with an increased incidence of malignant lymphoma.

Angioimmunoblastic Lymphadenopathy

Angioimmunoblastic lymphadenopathy (or immunoblastic lymphadenopathy, which represents a narrower definition of the same process) is a relatively uncommon condition primarily affecting older patients (over 50 years of age). Patients are debilitated, with weight loss, fever, hepatosplenomegaly, skin rashes, and generalized lymphadenopathy. In most studies, 50% of patients have died within 3 years, either of infection or because of development of an aggressive malignant lymphoma (immunoblastic sarcoma) in 15–20%. The cause is unknown.

Histologically, the lymph nodes show progressive depletion of lymphoid cells with obliteration of normal architecture and loss of follicles. Immunoblasts (both B and T) are conspicuous among the residual cells, along with a variable admixture of histiocytes, plasma cells, and eosinophils. There is amorphous cellular debris in the background.

In many instances, some but not all of these features are present. Such cases are said to show an abnormal immune response or atypical hyperplasia. The outcome in such patients is unpredictable.