Lymphatic System and Generalized Lymphadenopathy

Anatomy and Function of Lymphoid Tissue

The lymphoid system is composed of an extensive capillary network that drains lymph into elaborate systems of collecting vessels. The collecting vessels merge and empty lymph into the bloodstream by way of the thoracic duct at its entry into the left subclavian vein or by the right lymphatic duct, which empties into the right subclavian vein. Specialized lymphatic structures interspersed along the collecting vessels include the tonsillar tissues of the Waldeyer ring, the thymus, the spleen, mucosa-associated lymphoid nodules, and lymph nodes ( Table 16.1 ).

The Waldeyer ring of lymphoid tissue that surrounds the oropharyngeal isthmus and the opening of the nasopharynx into the oropharynx is uniquely positioned to interact with foreign material entering the nose or mouth. The ring is formed superiorly by the midline pharyngeal (adenoid) tonsil, found in the roof of the nasopharynx, and inferiorly by the lingual tonsils in the posterior third of the tongue. On either side of the pharynx, the lateral pharyngeal bands of lymphoid tissue connect the adenoid to the tubal tonsils of Gerlach at the openings of the eustachian tubes and to the faucial (palatine) tonsils. Smaller aggregates of lymphoid tissue in this area include the posterior pharyngeal granulations and the lymphoid tissue within the laryngeal ventricle.

Small submucosal lymphoid nodules located throughout the respiratory, gastrointestinal, and genitourinary tracts are composed of phagocytic and lymphoid cell collections without a connective tissue capsule. These nodules are ideally situated to respond to mucosal antigens.

The thymus, which is located over the superior vena cava in the anterior mediastinum, is relatively protected from antigens. Surrounded by a thin connective tissue capsule, the thymus is uniquely composed of epithelial and lymphatic elements.

The spleen is the largest lymphatic organ in the body and the only lymphatic tissue specialized to filter blood. Like the lymph nodes, the spleen is a component of the peripheral lymphoid system and is composed of red pulp (i.e., red blood cells) and an interior of white pulp, which contains lymphoid nodules with germinal follicles.

Normal lymph nodes are small oval or bean-shaped bodies that are strategically located along the course of lymphatic vessels to filter lymph on its way to the bloodstream. Lymphatic vessels enter around the periphery of the nodes. Lymph filters through the cortex to the medulla of the node and exits through the hilum. Blood vessels enter and leave through the hilum, which is connected to capillaries that course through the node. During this process, lymphocytes can leave the blood and re-enter the lymphatic circulation.

Nodes are densely packed with lymphocytes that are organized loosely into cortical nodules and medullary cords by connective tissue trabeculae and lymphatic sinuses. The juxtaposition of phagocytic cells, antigen-processing cells, and lymphocytes in an area of sluggish blood flow is ideally suited to provide the first line of defense against pathogens. As lymph slowly filters through the rich reticular network, organisms are trapped and can be ingested by phagocytic cells, stimulating the release of cytokines, which recruits lymphocytes for immunologic responses. The lymph node groups in the body can be divided into the superficial and peripheral nodes, which usually are easily palpable, and the deeper groups adjacent to major vessels and viscera ( Table 16.1 ).

Developmental Changes

Lymphoid tissue, including the thymus, forms a significantly larger percentage of total body weight in infants and children than in adults. Considerable lymphoid activity is present at birth, and continuing exposure to environmental antigens results in an increase in lymphoid mass that reaches a peak between the ages of 8 and 12 years. Atrophy of lymphoid tissue begins during adolescence. In children, the thymus can weigh 40 g; in adults, the thymus is replaced by fibrous and fatty tissue and can weigh only 10 g. By adult standards, almost all children have lymphadenopathy because palpable nodes, particularly in the cervical, axillary, and inguinal areas, are common in children of all ages, including neonates ( Table 16.2 ). Prominent palatine tonsils are common in preadolescent children, whereas in infants younger than 1 year of age and adults, the palatine tonsils usually are not visible.

Because of their normally hyperplastic nodes, the response of children to antigenic, infectious, or neoplastic stimuli is much more rapid, prolific, and exaggerated than that in adults. Lymph nodes can increase in size as much as 15-fold within 5–10 days of antigen exposure. Increased size of mediastinal and mesenteric nodes can be particularly pronounced.

Characteristics of Lymphadenopathy

Lymphadenopathy (i.e., enlarged lymph nodes) can be characterized by size, location, consistency, rate of growth, tissue inflammation, and fixation. In all ages and lymph node groups, a node is considered enlarged if it measures (in the longest diameter) greater than 10 mm. There are two exceptions to this rule. In the epitrochlear region, nodes greater than 5 mm are abnormal, and in the inguinal region, only nodes greater than 15 mm are considered abnormal.

Most children examined when healthy have palpable lymph nodes. In healthy neonates, lymph nodes ranging from 3 to 12 mm in the longest diameter can be found in the cervical, axillary, and inguinal regions. In children younger than 2 years, palpable nodes can be found at any peripheral location, except in the epitrochlear, supraclavicular, and popliteal areas, where palpable lymph nodes always are abnormal. In children older than 2 years, palpable lymph nodes in these areas and in the posterior auricular and suboccipital areas are considered abnormal.

Characteristics of lymph nodes are determined by palpation ( Table 16.3 ). Soft, discrete, nontender, small (<2 cm) nodes that are found bilaterally or usually with no periadenitis, cellulitis, or abscess formation typically result from hyperplasia due to viral infection. Unilateral, large (>2 cm), warm, tender, poorly defined nodes with surrounding edema, erythema, or abscess formation usually are infected with pyogenic bacteria. Moderately large, unilateral nodes with discrete margins and minimal inflammation that progress slowly to become erythematous (but not warm), fluctuant, and adherent to overlying skin are characteristic of chronic, usually bacterial, infections.

Enlarged nodes resulting from lymphoma usually are firm, discrete, freely movable, nontender, and rubbery, and they have no surrounding inflammation. Nodes increase in size over time, and adjacent nodes can become matted together and lose individual characteristics. Suppuration and fixation to skin or deeper structures, as seen in inflammatory lymphadenopathy, are not expected in lymphoma. Lymphomatous nodes can wax and wane in size over weeks to months, and lymphomatous changes can develop or become more apparent in nodes for which a biopsy specimen initially showed only hyperplasia. Enlarged nodes that result from metastatic tumors are hard and bound to each other and to surrounding tissues.

Enlarged nodes can be single or multiple and contiguous. When confined to one region, the condition is referred to as regional lymphadenopathy . Enlargement of a single node or regional nodes can be the result of localized disease or the first manifestation of generalized lymphadenopathy. Generalized lymphadenopathy is defined as the simultaneous occurrence of two or more enlarged nodes in noncontiguous groups; enlargement need not be identified at every body site. Concurrent mesenteric and hilar adenopathy is considered generalized lymphadenopathy. Splenomegaly also can occur but is not included in the definition.

Pathogenesis of Lymphadenopathy and Lymphadenitis

Microorganisms reach lymph nodes directly by lymphatic flow from the inoculation site or by lymphatic spread from adjacent nodes. If initial involvement of regional nodes does not contain infection adequately, organisms can reach noncontiguous nodes by hematogenous spread. Lymph node enlargement can result from a variety of mechanisms ( Box 16.1 ).

In acute pyogenic lymphadenitis, the initial inflammatory response in the node, including complement activation and cytokine release, causes recruitment of neutrophils and mononuclear phagocytes. Vascular engorgement, intranodal edema, and cellular replication in response to the antigenic stimulus lead to rapid enlargement of the node. Involvement of adjacent lymph nodes and surrounding soft tissues, including skin, can result in cellulitis, suppuration, necrosis, and fixation to adjacent tissues. After purulence occurs, lymph node architecture and antibiotic access are destroyed. Healing occurs by fibrosis.

For microorganisms that cause subacute or chronic granulomatous changes, the increase in node size and tenderness and adjacent inflammatory response usually are modest. Formation of granulomas and, in some cases, caseating necrosis also destroy nodal architecture; drainage or removal may be required to relieve pain or hasten resolution.

With local or generalized viral infections, the nodal response primarily is one of hyperplasia without necrosis. This resolves as infection abates without sequelae.

Enlarged lymph nodes, lymphoid nodules, or lymphoid tissue such as the Waldeyer ring can result in obstruction, compression, or erosion of important structures, rupture of nodal contents, or inflammation of adjacent structures. Generalized hyperplasia of the Waldeyer ring can result in obstruction of the posterior nares, eustachian tube, or oropharynx. Extensive mediastinal lymphadenopathy can lead to obstruction or erosion of the airways, esophagus, superior vena cava, recurrent laryngeal nerve, or lymphatics ( Table 18.3 ). Gastrointestinal inflammation of Peyer patches (e.g., Salmonella Typhi infection) can lead to intestinal perforation and hemorrhage or serve as the lead point for intussusception. Infectious mesenteric lymphadenitis can lead to an intra-abdominal abscess. Perinodal inflammation of muscles in the neck results in torticollis and spread of infection in the neck can lead to deep fascial space infections.

Histopathology of Lymphadenitis

Nonspecific hyperplasia is the most common histopathologic finding in biopsy specimens of enlarged lymph nodes. The cause is not determined in most children, and the condition usually resolves. For 17%–25% of cases, however, a pathologic process ultimately develops, most often a lymphoreticular disease.

In acute pyogenic infection, lymph nodes are filled with neutrophils, microorganisms, edema, and necrotic debris. Granuloma formation along with caseating necrosis is typical of infections caused by Mycobacterium tuberculosis, Histoplasma capsulatum, Coccidioides immitis, and some nontuberculous mycobacteria. Stellate abscesses surrounded by palisading epithelioid cells are typical for lymphogranuloma venereum (caused by Chlamydia trachomatis ) and infections caused by Bartonella henselae and Francisella tularensis (with more extensive granuloma formation in the latter). Toxoplasmosis produces characteristic nodal histologic findings of reactive follicular hyperplasia with scattered clusters of epithelioid histiocytes in cortical and paracortical zones, blurring of margins of germinal centers, and focal distention of subcapsular and trabecular sinuses by monocytoid cells. Yersinia spp. can cause necrotizing lymphadenitis in cervical, mediastinal, and mesenteric nodes. Brucellosis is characterized by noncaseating granulomas that are indistinguishable from those of sarcoidosis.

Lymphocutaneous and Oculoglandular SyndromeS

For several infections resulting in regional and, with extension, generalized lymphadenopathy, a characteristic and often granulomatous inflammatory reaction develops at the site of inoculation. Regional adenopathy often develops from lymphatic spread of organisms before the inoculation site has healed. When the initial inoculation site is in the conjunctiva, the constellation is the Parinaud oculoglandular syndrome, and when in the skin, it is the lymphocutaneous syndrome. Organisms that cause these syndromes are shown in Box 17.1 .

Infectious Causes of Generalized Lymphadenopathy

Local or generalized lymph node enlargement due to self-limited conditions must be differentiated from potentially life-threatening disorders such as a neoplasm, histiocytic proliferation, or autoimmune disease. ^, The distinctions usually can be made on the basis of history, lymph node examination ( Table 16.3 ), other systemic manifestations, and a limited number of laboratory tests ( Box 16.2 ).

Systemic infections are the most common causes of generalized lymphadenopathy. Many conditions characterized by generalized adenopathy also cause hepatic or splenic enlargement or initially cause regional adenopathy. Differentiating features of characteristic syndromes are listed in Table 16.4 .