Benign conditions of lymphoid organs

Key points

Lymph nodes are composed of four major compartments: the cortical B cell–rich follicles, the paracortical T cell–rich interfollicular zone, the medullary region, and the sinusoidal compartment.
Lymphoid hyperplasia may be classified according to the compartment and major cell type that is affected: B-cell follicular hyperplasia, T-cell paracortical hyperplasia, or histiocytic sinusoidal hyperplasia.
Lymphadenopathy refers to any lymph node enlargement, whether caused by lymphoma, metastatic cancer, lymphoid or histiocytic hyperplasia, granulomatous disease, or infection.
Lymphadenitis often refers to an acute painful form of lymph node enlargement (lymphadenopathy) seen with infection or necrosis.
Clues as the cause of granulomatous lymphadenitis include the presence or absence of necrosis, the type of necrosis (caseating or noncaseating), the presence or absence of multinucleated giant cells, and the detection of microorganisms by a variety of techniques (including immunohistochemistry, polymerase chain reaction, culture, and serology).
Benign causes of splenic enlargement (splenomegaly) include chronic passive congestion, infection, chronic hemolytic anemia, storage diseases, and vascular defects.
Hypersplenism refers to any form of peripheral blood cytopenia caused by increased splenic sequestration or destruction of blood cells and is often accompanied by splenomegaly.
Conditions leading to thymic enlargement include thymic hyperplasia (often seen in myasthenia gravis), hyperthyroidism, thymoma (usually benign tumor of thymic epithelium), and malignant lymphoma.

Lymph nodes constantly respond to antigens arriving from lymph and blood. However, in most instances, the antigen load is small and triggers only minimal transient enlargement of responding lymph nodes. Immune reactions that take place within lymph nodes often lead to follicular, paracortical, or both types of hyperplasia. Follicular hyperplasia results from proliferation of germinal center (GC) B cells within secondary follicles ( Fig. 17.1 ), whereas paracortical hyperplasia results from proliferation of T cells within the interfollicular zone ( Fig. 17.2 ). In some cases, reaction to antigen leads instead to a proliferation of histiocytes that remain confined to lymphoid sinuses, a process termed sinus histiocytosis ( Fig. 17.3 ).

Significant enlargement of lymph nodes (>1 cm ³ ) is generally considered abnormal and is termed lymphadenopathy . The most common causes of lymphadenopathy are infection, cancer (most commonly lymphoma), autoimmune disorders (rheumatoid arthritis and systemic lupus erythematosus [SLE]), and drug hypersensitivity (e.g., Dilantin). Lymphadenopathy may be classified as either localized or generalized.

Painful lymphadenopathy, often referred to as lymphadenitis , most often results from acute inflammation related to infection. Lymphadenitis is seen with all types of infection, including viruses ( Epstein-Barr virus [EBV] , cytomegalovirus, and human immunodeficiency virus [HIV]), bacteria ( Mycobacteria, Bartonella, and Treponema spp.) , fungi ( Histoplasma and Cryptococcus spp.), and protozoa (Toxoplasma gondii).

Granulomatous lymphadenitis is characteristic of some infectious diseases; of the idiopathic condition sarcoidosis; and as a reaction to foreign materials such as talc, silica, and nylon suture. Granulomas are collections of activated macrophages (histiocytes) and CD4+ T lymphocytes that form in response to certain microbes, microbial products, foreign material, or keratinaceous debris ( Fig. 17.4 ). The general idea is that granulomas form in response to antigenic material that cannot be effectively cleared from tissues. Granuloma formation has been shown in some experimental models to depend on a Th2 response and a variety of cytokines, including interferon-γ, transforming growth factor β, and tumor necrosis factor α. In many cases, fusion of macrophages leads to the formation of multinucleated giant cells ( Fig. 17.5 ). Granulomas are generally classified as either necrotizing (as in tuberculosis and cat scratch disease) or non-necrotizing (as in sarcoidosis and toxoplasmosis). Necrosis can be further defined as either caseous or noncaseous necrosis. Caseous necrosis is devoid of identifiable cellular and nuclear debris and is particularly characteristic of tuberculous lymphadenitis . In tuberculosis, the caseous necrosis is accompanied by multinucleated giant cells with horseshoe-shaped arrangements of the nuclei known as Langhans-type giant cells . In contrast to infection with Mycobacterium tuberculosis, infection with atypical mycobacteria such as Mycobacterium avium-intracellulare is more often chara cterized by non-necrotizing granulomas devoid of giant cells.

It is important to recognize that necrotizing lymphadenitis can also be seen in the absence of granulomas. Examples include bacterial and fungal infection, SLE lymphadenitis , and Kikuchi-Fujimoto disease (a rare idiopathic condition that is seen most commonly in young females) ( Fig. 17.6 ).

Noncaseous necrosis, on the other hand, contains identifiable cell fragments and nuclear debris, often neutrophilic debris. Cat scratch disease presents as fever and painful localized lymphadenitis caused by infection by Bartonella henselae, a bacterium carried by healthy domestic cats. The infection is usually acquired by cat scratch or cat bite, with involvement of draining lymph nodes (often axillary). The lymph node contains numerous large confluent granulomas with noncaseous necrosis and neutrophilic abscesses ( Fig. 17.7 ). Aggregates of bacteria may be detected in tissue sections with the Warthin-Starry silver stain or by immunostaining with specific antibody ( Fig. 17.8 ). In syphilis ( Treponema pallidum infection), the necrosis is usually accompanied by increased plasma cells and capsular fibrosis. Silver staining of tissue sections highlights the characteristic elongated spiral-shaped bacteria.

Sarcoidosis is an idiopathic, often asymptomatic systemic condition commonly associated with hilar and mediastinal lymphadenopathy, as well as lung involvement. Affected lymph nodes contain numerous non-necrotizing granulomas with multinucleated giant cells ( Fig. 17.9 ). It is important to exclude all other known infectious causes of granulomatous disease before making this diagnosis.

Toxoplasmosis , caused by infection by the protozoan parasite Toxoplasma gondii, leads in most cases to non-necrotizing granulomatous lymphadenitis, particularly involving cervical lymph nodes. T. gondii infection is often acquired by contact with infected cats (the definitive host), cat feces, or contaminated soil. The infection may also be acquired from other animals (mammals and birds) or from undercooked meats. Toxoplasma infection is widespread, with a seroprevalence rate in the United States of about 22%. The histology of Toxoplasma lymphadenitis is marked by follicular (B-cell) lymphoid hyperplasia, monocytoid B-cell aggregates, and clusters of epithelioid histiocytes often within or adjacent to GCs ( Fig. 17.10 ). Monocytoid B cells are marginal zone–like B cells with oval nuclei and abundant clear cytoplasm that resemble monocytes. Epithelioid histiocytes are large, activated macrophages with enlarged oval nuclei that often cluster together to form granulomas. Toxoplasma cysts may rarely be detected in hematoxylin and eosin–stained lymph nodes, and individual organisms can sometimes be detected by immunohistochemistry with Toxoplasma -specific antibody.

Acid-fast bacteria (mycobacteria and Nocardia spp.), fungi, and non–acid-fast bacteria can be identified in tissue sections by special histochemical stains (acid-fast bacilli stain; silver stain or periodic acid–Schiff; and tissue Gram stain, respectively) ( Figs. 17.11 to 17.13 ). Other infectious agents can be identified in tissue by immunohistochemical staining with specific antibody. In many cases, however, identification of the infectious agent requires culture and serology. Foreign materials (talc, silica, suture) that induce granuloma formation can often be identified as refractile material with the use of a microscope equipped with a polarizing filter.

Dermatopathic lymphadenitis is a relatively common cause of lymph node enlargement (often axillary or inguinal) that results from proliferation of Langerhans cells and T cells in the lymph node paracortex. Langerhans cells are immature CD1a+ dendritic cells located within the epidermis and mucosal epithelium that, upon encounter with antigen, migrate to regional lymph nodes, where they present antigen to paracortical T cells, leading to paracortical lymphoid hyperplasia ( Figs. 17.14 and 17.15 ). Recent data indicate that Langerhans cells, unlike classic dendritic cells, may not be derived from bone marrow precursors and maintain their number by local proliferation in the skin and mucosa. Virtually any inflammatory (particularly exfoliative) dermatologic process can lead to dermatopathic lymphadenitis. Dermatopathic lymphadenitis is also seen in cutaneous T-cell lymphoma (mycosis fungoides). The diagnosis of mycosis fungoides can be confirmed by detection of a monoclonal population of T cells with an aberrant CD3+ CD7− immunophenotype. In contrast to mycosis fungoides, the T cells in dermatopathic lymphadenitis are polyclonal, with CD3 and CD7 coexpression.

In infectious mononucleosis , cervical lymph nodes are marked by florid follicular and interfollicular B-cell hyperplasia with numerous large, EBV-positive immunoblasts ( Fig. 17.16 ). Castleman disease is a rare benign idiopathic condition that in most cases (hyaline vascular variant) is associated with markedly enlarged lymph nodes with many small atretic GCs surrounded by concentric layers of mantle zone B cells ( Fig. 17.17 ). The less common plasma cell variant of Castleman disease, commonly seen in HIV-infected patients, is marked by interfollicular plasmacytosis. Progressive transformation of germinal centers (PTGC) is another rare benign idiopathic form of lymphadenopathy marked histologically by significantly enlarged CD20+ lymphoid follicles with infiltration and disruption of GCs by mantle zone B cells ( Fig. 17.18 ). PTGC is sometimes seen in association with nodular lymphocyte–predominant Hodgkin lymphoma. Kimura disease is an idiopathic condition marked by large interfollicular aggregates of eosinophils that may sometimes undergo necrosis ( Fig. 17.19 ).