Reactive Lymphoid Hyperplasia
Definition
Enlargement of lymph nodes or other lymphoid organs as a consequence of hyperplasia of some or all of the cellular components, reflecting stimulation of the lymphoid cells by a variety of antigens and representing a benign, reversible process.
Epidemiology
Lymphadenopathies, manifested clinically by the enlargement of lymph nodes, are a common occurrence. They represent the reaction of lymphoid tissues to some of the immense variety of intrinsic and environmental antigens. The vast majority of enlarged lymph nodes are non-neoplastic. Nevertheless, the challenge is to detect those lymph nodes affected by neoplastic processes in order to apply timely and efficient therapeutic measures. The ratio of non-neoplastic to neoplastic lymph node lesions varies greatly with the kind of medical practice in which they present. In family practice or general medical practice, malignancies represent only about 1.1% of lymph node lesions, whereas at referral centers their frequency is 40% to 60% (1,2,3). The age of patients is one of the most important factors in determining the nature of enlarged lymph nodes. In children, most lymphadenopathies are benign, whereas in adults, the probability of malignancy (metastatic carcinoma more so than lymphoma) increases with age (4). In a study of 628 lymph node biopsies, 79% were benign lymphadenopathies in patients younger than 30 years of age, 59% in those between 30 and 50 years, and 39% in patients older than 50 years (5). Additional epidemiologic data to be considered in the diagnosis of lymphadenopathies are environmental factors such as tobacco smoking, occupational exposure to silicon, beryllium or other pneumoconioses, close contact with animals particularly cats, travel to places of endemic infections (see Lymphadenitides), and high-risk sexual behaviors.
Etiology
The causes of reactive lymphoid hyperplasia (RLH) include a long list of bacteria, viruses, chemicals, environmental pollutants, drugs, altered tissue components, and numerous other substances acting as antigens or allergens. Iatrogenic agents, including various medications such as phenytoin, allopurinol, atenolol, gold, penicillins, quinidine, and others, also may be the cause of lymphadenopathies (6). The hyperplastic lymph node reaction to some of these noxious agents includes characteristic morphologic features, the recognition of which is helpful in determining the cause. The various lymphadenitides and lymphadenopathies described in the following chapters belong to this category.
In some cases, specific microorganisms can be detected on regular sections and identified by special stains, in situ hybridization, polymerase chain reaction (PCR), or other procedures, so that an etiologic diagnosis is possible. In others, characteristic morphologic patterns may suggest an etiologic diagnosis without proving it directly; such a situation must be clearly indicated in the final diagnosis. Still, the cases of RLH in which an etiologic agent is identified represent only a fraction, probably fewer than 10%, of all hyperplastic lymph nodes. Most enlarged lymph nodes involved by RLH or atypical lymphoid hyperplasia do not exhibit morphologic patterns indicative of specific agents, and therefore the cause of RLH is listed as unknown. Notwithstanding, in the search for specific etiologic agents in the investigation of lymphadenopathies, the prevailing objective in the majority of cases is to determine the presence or absence of a neoplastic process. For the etiologic investigation of lymphadenopathies, various algorithms have been proposed, including successive branches in which the various entities are ruled out depending on the response to laboratory tests, medications, and follow-up (1). To recall the main etiologic categories, some authors suggest using acronyms like MIAMI (malignancies, infections, autoimmune, miscellaneous, and iatrogenic) (3).
Pathogenesis
An essential function of lymph nodes is to filter the lymph drained from their tributary regions. Thus, a large variety of substances are carried to the lymph nodes. Some of these are amorphous foreign bodies, which are simply phagocytized and degraded; others are antigenic and therefore able to trigger an immune reaction. The reactions of lymph nodes to foreign substances are diverse and difficult to separate into specific patterns. Stansfeld distinguishes predominantly inflammatory reactions, caused mainly by bacteria and fungi, and predominantly immune reactions, which are more often the effects of viruses or drugs. The immune responses may be predominantly of B-cell type, characterized morphologically by either follicular hyperplasia or plasmacytosis, or predominantly of T-cell type, with a characteristic pattern of T-cell hyperplasia (7). Specific morphologic features of non-neoplastic lymph node lesions permit them to be distinguished from malignant lesions (8). Lymphadenitides and lymphadenopathies tend to exhibit one of four characteristic histologic patterns: follicular, sinusal, diffuse, or mixed (9). These represent expansions of the normal follicular, paracortical, medullary, and sinusal lymph node compartments (10). The histologic pattern seen on a tissue section captures only one point in time during the life of a lesion, reaction, or reparatory process. The patterns vary with the particular etiologic agent and the age of the lesion, as well as with the history and immune competence of the host. Therefore, combined, overlapping architectural features are a more common finding than clearly defined histologic patterns on biopsy specimens of non-neoplastic lymph nodes.
Clinical Syndrome
Enlarged lymph nodes may be the expression of a local lesion or of systemic disease, and the clinical symptoms will reflect the underlying disorder accordingly. A number of clinical features are significantly important in the diagnosis of lymphadenopathies.
Location. The etiology is often suggested by location. Cervical lymph nodes are often affected in infectious mononucleosis; posterior cervical lymph nodes in toxoplasmosis; cervical and axillary lymph nodes in cat-scratch disease; inguinal lymph nodes in sexually transmitted diseases (1); and parotid, submaxillary, epitrochlear lymph nodes are frequently involved in human immunodeficiency virus (HIV) infection (11,12). Supraclavicular lymph nodes are of particular importance, being associated with malignant disease in 25% of patients younger than 40 years and in 90% of patients older than 40 years of age (2). An enlarged right supraclavicular lymph node may indicate cancer of the lung or esophagus, whereas enlargement of the left supraclavicular lymph nodes may indicate cancer of the stomach, pancreas, or gallbladder (the Virchow sign) (1). In general, supraclavicular lymph nodes produce the highest and inguinal lymph nodes the lowest yields of diagnoses (13). Localized lymph node enlargement in the absence of other symptoms may be followed-up for 3 to 4 weeks, whereas generalized lymphadenopathies—defined as two or more noncontiguous areas of involvement—require further investigation (1).
Size. In general, lymph nodes with a diameter of 1 cm or larger are considered abnormal; however, in relation to their location, 0.5 cm should be considered the upper limit for epitrochlear and l.5 cm for inguinal lymph nodes (l).
Consistency. The affected lymph node may be stone-hard in metastatic cancer, firm or rubbery in lymphoma, soft in inflammation, or fluctuant in suppuration. Small, “shotty” lymph nodes can be seen in viral diseases of children; matted lymph nodes are common in tuberculosis, lymphogranuloma venereum, or cancer (1).
Pain. Pain is caused by the stretching of the lymph node capsule and is more often related to inflammation or hemorrhage (1).
Fever, weight loss, pallor, and malaise are important general symptoms and must be taken into consideration in the evaluation of lymph nodes in both children and adults.
Duration. The duration of a lymphadenopathy is important but not specific (14).
Age. The age of the patient is a key factor. Older patient age is a key risk factor for neoplasia. A firm, fixed lymph node in a supraclavicular location is a clear indication for biopsy (3).
In the elderly, RLH is uncommon because the humoral immune response is subdued (15) and the proliferation and expansion of germinal centers is less apparent than in younger persons (16). In a study of Japanese patients age 60 years or older, florid reactive follicular hyperplasia was accompanied by immunologic abnormalities (most often resulting from rheumatoid arthritis or multicentric Castleman disease) in 16 of 23 cases (70%), and malignant lymphoma developed in none (17). In contrast, in a U.S. study of 58 lymph node biopsy specimens from patients age 60 years or older, reactive follicular hyperplasia was associated with an inflammatory cause (rheumatoid arthritis, thrombophlebitis, or skin infection) in only 12 cases (20%), whereas lymphoma was present concurrently or subsequently in 18 cases (31%) (16). Reactive lymphadenopathies in older patients may have an occult neoplastic cause, so that careful study is required to rule out lymphoma. In children, enlarged lymph nodes are not uncommon. Non-neoplastic diagnoses were made in 68% of peripheral lymph node biopsy specimens from 85 children, and almost half were benign reactive hyperplasia (18). In a child up to 12 years of age, a palpable lymph node not exceeding 10 mm in diameter can be considered a normal finding, whereas lymph nodes larger than 3 mm in diameter in newborns or children past the age of 12 years are potentially abnormal and must be explored further (19). Nondiagnostic biopsies, most often with a follicular pattern, are frequent. In one study, these biopsy findings accounted for 37 of 100 cases, and 74% of the patients were alive and well 5 to 20 years after the biopsy (20). In children between 1 and 6 years of age, only 28% of cervical lymph nodes infected with atypical mycobacteria were detected with Ziehl-Neelsen or auramine O stain (18). Lymph nodes that are firm to hard, sometimes adherent to deep tissues, suggest malignancy, whereas soft or fluctuant nodes indicate inflammation. Axillary, epitrochlear, and inguinal lymph nodes in children are frequently enlarged as a result of trauma and infections that result from play habits or exposure to animals (21). Cervical nodes may be enlarged because of upper respiratory infection, and enlarged cervical nodes are less cause for alarm than enlarged nodes in the supraclavicular area or lower neck, which may indicate mediastinal disease (21). The indications for biopsy in 239 lymphadenopathies of children found that the number of lymph nodes enlarged, consistency, and duration were nonspecific whereas age, location, and fixation were specific (14). In children in developing countries, the majority of chronic lymphadenopathies have an infectious cause and of these Mycobacterium tuberculosis is predominant. In a study of 1,877 cervical lymphadenopathies in South African children, the mean age was 7 years; 48% had nonspecific reactive lymphoid hyperplasia and 37% had granulomatous lesions, of which 25% were tuberculous. Of those with neoplastic disease, more than two-third had lymphoma
(22). In 242 lymph node biopsies in children in Nigeria, the diagnosis was tuberculosis in 33% and lymphoma in 31.4% (23).
In general, negative or nondiagnostic lymph node biopsy results showing only a general reactive pattern that does not indicate a specific diagnosis constitute a frequent problem for pathologists and clinicians. In review studies of lymph node biopsies, 37% to 59% were nondiagnostic, but during follow-up of these same patients, a disease related to the initial indication for lymph node biopsy, usually lymphoma, developed in 25% within 8 months and in 50% within 5 years (24,25). These results suggest that clinicians should not hesitate to recommend a repeated biopsy when systemic symptoms and nonlocalized adenopathies persist (25).
Histopathology
A pathologic entity as heterogeneous and loosely defined as RLH may, not unexpectedly, exhibit a variety of morphologic patterns. This is because each of the major lymph node tissue components may be involved in the reactive process, resulting in effacement of the original architecture and the formation of new histologic structures. Although clearly defined patterns are not usually observed, several attempts have been made to classify the variants of RLH. According to the predominance of various lymph node components, four major histologic patterns—follicular, diffuse, sinusal, and mixed—have been described in the reactive process (9).
Reactive Follicular Hyperplasia
Follicular patterns are characteristically expressed in reactive follicular hyperplasia, which is the B-cell response to various antigens, mainly bacterial. The lymph node follicles are numerous and enlarged (Fig. 32.1), located not only in one row in the cortex but in two and three rows in the paracortex, corticomedullary junction, and even medulla (26). They vary considerably in size and shape, occasionally coalesce, and display dumbbell, hourglass, or other bizarre configurations (Figs. 32.2 and 32.3). The mantle zone and germinal center are sharply demarcated in a reactive follicle. The germinal centers are prominent and hyperplastic (Figs. 32.2 and 32.4) and comprise a mixture of small and large lymphoid cells, centrocytes, and centroblasts. The centroblasts accumulate at the medial pole of the germinal center, forming a darker zone in contrast to a lighter zone toward the peripheral pole occupied by centrocytes (Figs. 32.5 and 32.6). The centroblasts representing the activated lymphocytes are three to four times the size of inactivated lymphocytes with a narrow rim of basophilic cytoplasm and large, round vesicular nuclei with one to three fairly large peripheral nucleoli and frequent mitoses. The centrocytes representing a later stage of activation are smaller and less basophilic, with scant cytoplasm, cleaved nuclei, small nucleoli, and no apparent mitoses. Scattered among the centroblasts, and alternating with the cells in mitosis in the dark zone, are numerous tingible-body macrophages (i.e., macrophages with engulfed nuclear debris resulting in the characteristic starry-sky pattern; Figs. 32.5 and 32.6). Surrounding the activated germinal centers are concentric, thick, darkly staining layers of small inactivated lymphocytes forming the mantle zone of the secondary follicles. Silver staining reveals a slightly compressed reticulin network around the expanding reactive lymphoid follicles, but not as much compression as is seen in follicular lymphoma (FL). Large numbers of lymphocytes may infiltrate
the capsule and perinodal fat or surround the lymphatics and blood vessels (Fig. 32.7); occasionally, the appearance resembles the invasion of extranodal tissues seen in lymphomas and leukemias.
the capsule and perinodal fat or surround the lymphatics and blood vessels (Fig. 32.7); occasionally, the appearance resembles the invasion of extranodal tissues seen in lymphomas and leukemias.
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