Lymphadenopathy may be an incidental finding in patients being examined for various reasons, or it may be a presenting sign or symptom of the patient's illness. The physician must eventually decide whether the lymphadenopathy is a normal finding or one that requires further study, up to and including biopsy. Soft, flat, submandibular nodes (<1 cm) are often palpable in healthy children and young adults; healthy adults may have palpable inguinal nodes of up to 2 cm, which are considered normal. Further evaluation of these normal nodes is not warranted. In contrast, if the physician believes the node(s) to be abnormal, then pursuit of a more precise diagnosis is needed.
Approach to the Patient: Lymphadenopathy
Lymphadenopathy may be a primary or secondary manifestation of numerous disorders, as shown in Table 59–1. Many of these disorders are infrequent causes of lymphadenopathy. In primary care practice, more than two-thirds of patients with lymphadenopathy have nonspecific causes or upper respiratory illnesses (viral or bacterial) and <1% have a malignancy. In one study, 84% of patients referred for evaluation of lymphadenopathy had a "benign" diagnosis. The remaining 16% had a malignancy (lymphoma or metastatic adenocarcinoma). Of the patients with benign lymphadenopathy, 63% had a nonspecific or reactive etiology (no causative agent found), and the remainder had a specific cause demonstrated, most commonly infectious mononucleosis, toxoplasmosis, or tuberculosis. Thus, the vast majority of patients with lymphadenopathy will have a nonspecific etiology requiring few diagnostic tests.
Table 59–1 Diseases Associated with Lymphadenopathy
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Table 59–1 Diseases Associated with Lymphadenopathy
|1. Infectious diseases|
|a. Viral—infectious mononucleosis syndromes (EBV, CMV), infectious hepatitis, herpes simplex, herpesvirus-6, varicella-zoster virus, rubella, measles, adenovirus, HIV, epidemic keratoconjunctivitis, vaccinia, herpesvirus-8|
|b. Bacterial—streptococci, staphylococci, cat-scratch disease, brucellosis, tularemia, plague, chancroid, melioidosis, glanders, tuberculosis, atypical mycobacterial infection, primary and secondary syphilis, diphtheria, leprosy|
|c. Fungal—histoplasmosis, coccidioidomycosis, paracoccidioidomycosis|
|d. Chlamydial—lymphogranuloma venereum, trachoma|
|e. Parasitic—toxoplasmosis, leishmaniasis, trypanosomiasis, filariasis|
|f. Rickettsial—scrub typhus, rickettsialpox, Q fever|
|2. Immunologic diseases|
|a. Rheumatoid arthritis|
|b. Juvenile rheumatoid arthritis|
|c. Mixed connective tissue disease|
|d. Systemic lupus erythematosus|
|f. Sjögren's syndrome|
|g. Serum sickness|
|h. Drug hypersensitivity—diphenylhydantoin, hydralazine, allopurinol, primidone, gold, carbamazepine, etc.|
|i. Angioimmunoblastic lymphadenopathy|
|j. Primary biliary cirrhosis|
|k. Graft-vs.-host disease|
|m. Autoimmune lymphoproliferative syndrome|
|3. Malignant diseases|
|a. Hematologic—Hodgkin's disease, non-Hodgkin's lymphomas, acute or chronic lymphocytic leukemia, hairy cell leukemia, malignant histiocytosis, amyloidosis|
|b. Metastatic—from numerous primary sites|
|4. Lipid storage diseases—Gaucher's, Niemann-Pick, Fabry, Tangier|
|5. Endocrine diseases—hyperthyroidism|
|6. Other disorders|
|a. Castleman's disease (giant lymph node hyperplasia)|
|c. Dermatopathic lymphadenitis|
|d. Lymphomatoid granulomatosis|
|e. Histiocytic necrotizing lymphadenitis (Kikuchi's disease)|
|f. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease)|
|g. Mucocutaneous lymph node syndrome (Kawasaki's disease)|
|h. Histiocytosis X|
|i. Familial Mediterranean fever|
|j. Severe hypertriglyceridemia|
|k. Vascular transformation of sinuses|
|l. Inflammatory pseudotumor of lymph node|
|m. Congestive heart failureAbbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus.|
The physician will be aided in the pursuit of an explanation for the lymphadenopathy by a careful medical history, physical examination, selected laboratory tests, and perhaps an excisional lymph node biopsy.
The medical history should reveal the setting in which lymphadenopathy is occurring. Symptoms such as sore throat, cough, fever, night sweats, fatigue, weight loss, or pain in the nodes should be sought. The patient's age, sex, occupation, exposure to pets, sexual behavior, and use of drugs such as diphenylhydantoin are other important historic points. For example, children and young adults usually have benign (i.e., nonmalignant) disorders that account for the observed lymphadenopathy such as viral or bacterial upper respiratory infections; infectious mononucleosis; toxoplasmosis; and, in some countries, tuberculosis. In contrast, after age 50, the incidence of malignant disorders increases and that of benign disorders decreases.
The physical examination can provide useful clues such as the extent of lymphadenopathy (localized or generalized), size of nodes, texture, presence or absence of nodal tenderness, signs of inflammation over the node, skin lesions, and splenomegaly. A thorough ear, nose, and throat (ENT) examination is indicated in adult patients with cervical adenopathy and a history of tobacco use. Localized or regional adenopathy implies involvement of a single anatomic area. Generalized adenopathy has been defined as involvement of three or more noncontiguous lymph node areas. Many of the causes of lymphadenopathy (Table 59–1) can produce localized or generalized adenopathy, so this distinction is of limited utility in the differential diagnosis. Nevertheless, generalized lymphadenopathy is frequently associated with nonmalignant disorders such as infectious mononucleosis [Epstein-Barr virus (EBV) or cytomegalovirus (CMV)], toxoplasmosis, AIDS, other viral infections, systemic lupus erythematosus (SLE), and mixed connective tissue disease. Acute and chronic lymphocytic leukemias and malignant lymphomas also produce generalized adenopathy in adults.
The site of localized or regional adenopathy may provide a useful clue about the cause. Occipital adenopathy often reflects an infection of the scalp, and preauricular adenopathy accompanies conjunctival infections and cat-scratch disease. The most frequent site of regional adenopathy is the neck, and most of the causes are benign—upper respiratory infections, oral and dental lesions, infectious mononucleosis, or other viral illnesses. The chief malignant causes include metastatic cancer from head and neck, breast, lung, and thyroid primaries. Enlargement of supraclavicular and scalene nodes is always abnormal. Because these nodes drain regions of the lung and retroperitoneal space, they can reflect lymphomas, other cancers, or infectious processes arising in these areas. Virchow's node is an enlarged left supraclavicular node infiltrated with metastatic cancer from a gastrointestinal primary. Metastases to supraclavicular nodes also occur from lung, breast, testis, or ovarian cancers. Tuberculosis, sarcoidosis, and toxoplasmosis are nonneoplastic causes of supraclavicular adenopathy. Axillary adenopathy is usually due to injuries or localized infections of the ipsilateral upper extremity. Malignant causes include melanoma or lymphoma and, in women, breast cancer. Inguinal lymphadenopathy is usually secondary to infections or trauma of the lower extremities and may accompany sexually transmitted diseases such as lymphogranuloma venereum, primary syphilis, genital herpes, or chancroid. These nodes may also be involved by lymphomas and metastatic cancer from primary lesions of the rectum, genitalia, or lower extremities (melanoma).
The size and texture of the lymph node(s) and the presence of pain are useful parameters in evaluating a patient with lymphadenopathy. Nodes <1.0 cm2 in area (1.0 cm × 1.0 cm or less) are almost always secondary to benign, nonspecific reactive causes. In one retrospective analysis of younger patients (9–25 years) who had a lymph node biopsy, a maximum diameter of >2 cm served as one discriminant for predicting that the biopsy would reveal malignant or granulomatous disease. Another study showed that a lymph node size of 2.25 cm2 (1.5 cm × 1.5 cm) was the best size limit for distinguishing malignant or granulomatous lymphadenopathy from other causes of lymphadenopathy. Patients with node(s) ≤1.0 cm2 should be observed after excluding infectious mononucleosis and/or toxoplasmosis unless there are symptoms and signs of an underlying systemic illness.
The texture of lymph nodes may be described as soft, firm, rubbery, hard, discrete, matted, tender, movable, or fixed. Tenderness is found when the capsule is stretched during rapid enlargement, usually secondary to an inflammatory process. Some malignant diseases such as acute leukemia may produce rapid enlargement and pain in the nodes. Nodes involved by lymphoma tend to be large, discrete, symmetric, rubbery, firm, mobile, and nontender. Nodes containing metastatic cancer are often hard, nontender, and nonmovable because of fixation to surrounding tissues. The coexistence of splenomegaly in the patient with lymphadenopathy implies a systemic illness such as infectious mononucleosis, lymphoma, acute or chronic leukemia, SLE, sarcoidosis, toxoplasmosis, cat-scratch disease, or other less common hematologic disorders. The patient's story should provide helpful clues about the underlying systemic illness.
Nonsuperficial presentations (thoracic or abdominal) of adenopathy are usually detected as the result of a symptom-directed diagnostic workup. Thoracic adenopathy may be detected by routine chest radiography or during the workup for superficial adenopathy. It may also be found because the patient complains of a cough or wheezing from airway compression; hoarseness from recurrent laryngeal nerve involvement; dysphagia from esophageal compression; or swelling of the neck, face, or arms secondary to compression of the superior vena cava or subclavian vein. The differential diagnosis of mediastinal and hilar adenopathy includes primary lung disorders and systemic illnesses that characteristically involve mediastinal or hilar nodes. In the young, mediastinal adenopathy is associated with infectious mononucleosis and sarcoidosis. In endemic regions, histoplasmosis can cause unilateral paratracheal lymph node involvement that mimics lymphoma. Tuberculosis can also cause unilateral adenopathy. In older patients, the differential diagnosis includes primary lung cancer (especially among smokers), lymphomas, metastatic carcinoma (usually lung), tuberculosis, fungal infection, and sarcoidosis.
Enlarged intraabdominal or retroperitoneal nodes are usually malignant. Although tuberculosis may present as mesenteric lymphadenitis, these masses usually contain lymphomas or, in young men, germ cell tumors.
The laboratory investigation of patients with lymphadenopathy must be tailored to elucidate the etiology suspected from the patient's history and physical findings. One study from a family practice clinic evaluated 249 younger patients with "enlarged lymph nodes, not infected" or "lymphadenitis." No laboratory studies were obtained in 51%. When studies were performed, the most common were a complete blood count (CBC) (33%), throat culture (16%), chest x-ray (12%), or monospot test (10%). Only eight patients (3%) had a node biopsy, and half of those were normal or reactive. The CBC can provide useful data for the diagnosis of acute or chronic leukemias, EBV or CMV mononucleosis, lymphoma with a leukemic component, pyogenic infections, or immune cytopenias in illnesses such as SLE. Serologic studies may demonstrate antibodies specific to components of EBV, CMV, HIV, and other viruses; Toxoplasma gondii; Brucella; etc. If SLE is suspected, antinuclear and anti-DNA antibody studies are warranted.
The chest x-ray is usually negative, but the presence of a pulmonary infiltrate or mediastinal lymphadenopathy would suggest tuberculosis, histoplasmosis, sarcoidosis, lymphoma, primary lung cancer, or metastatic cancer and demands further investigation.
A variety of imaging techniques (CT, MRI, ultrasound, color Doppler ultrasonography) have been employed to differentiate benign from malignant lymph nodes, especially in patients with head and neck cancer. CT and MRI are comparably accurate (65–90%) in the diagnosis of metastases to cervical lymph nodes. Ultrasonography has been used to determine the long (L) axis, short (S) axis, and a ratio of long to short axis in cervical nodes. An L/S ratio of <2.0 has a sensitivity and a specificity of 95% for distinguishing benign and malignant nodes in patients with head and neck cancer. This ratio has greater specificity and sensitivity than palpation or measurement of either the long or the short axis alone.
The indications for lymph node biopsy are imprecise, yet it is a valuable diagnostic tool. The decision to biopsy may be made early in a patient's evaluation or delayed for up to two weeks. Prompt biopsy should occur if the patient's history and physical findings suggest a malignancy; examples include a solitary, hard, nontender cervical node in an older patient who is a chronic user of tobacco; supraclavicular adenopathy; and solitary or generalized adenopathy that is firm, movable, and suggestive of lymphoma. If a primary head and neck cancer is suspected as the basis of a solitary, hard cervical node, then a careful ENT examination should be performed. Any mucosal lesion that is suspicious for a primary neoplastic process should be biopsied first. If no mucosal lesion is detected, an excisional biopsy of the largest node should be performed. Fine-needle aspiration should not be performed as the first diagnostic procedure. Most diagnoses require more tissue than such aspiration can provide, and it often delays a definitive diagnosis. Fine-needle aspiration should be reserved for thyroid nodules and for confirmation of relapse in patients whose primary diagnosis is known. If the primary physician is uncertain about whether to proceed to biopsy, consultation with a hematologist or medical oncologist should be helpful. In primary care practices, <5% of lymphadenopathy patients will require a biopsy. That percentage will be considerably larger in referral practices, i.e., hematology, oncology, or ENT.
Two groups have reported algorithms that they claim will identify more precisely those lymphadenopathy patients who should have a biopsy. Both reports were retrospective analyses in referral practices. The first study involved patients 9–25 years of age who had a node biopsy performed. Three variables were identified that predicted those young patients with peripheral lymphadenopathy who should undergo biopsy; lymph node size >2 cm in diameter and abnormal chest x-ray had positive predictive values, whereas recent ENT symptoms had negative predictive values. The second study evaluated 220 lymphadenopathy patients in a hematology unit and identified five variables [lymph node size, location (supraclavicular or nonsupraclavicular), age (>40 years or <40 years), texture (nonhard or hard), and tenderness] that were used in a mathematical model to identify those patients requiring a biopsy. Positive predictive value was found for age >40 years, supraclavicular location, node size >2.25 cm2, hard texture, and lack of pain or tenderness. Negative predictive value was evident for age <40 years, node size <1.0 cm2, nonhard texture, and tender or painful nodes. Ninety-one percent of those who required biopsy were correctly classified by this model. Because both of these studies were retrospective analyses and one was limited to young patients, it is not known how useful these models would be if applied prospectively in a primary care setting.
Most lymphadenopathy patients do not require a biopsy, and at least half require no laboratory studies. If the patient's history and physical findings point to a benign cause for lymphadenopathy, careful follow-up at a 2- to 4-week interval can be employed. The patient should be instructed to return for reevaluation if there is an increase in the size of the nodels). Antibiotics are not indicated for lymphadenopathy unless strong evidence of a bacterial infection is present. Glucocorticoids should not be used to treat lymphadenopathy because their lympholytic effect obscures some diagnoses (lymphoma, leukemia, Castleman's disease) and they contribute to delayed healing or activation of underlying infections. An exception to this statement is the life-threatening pharyngeal obstruction by enlarged lymphoid tissue in Waldeyer's ring that is occasionally seen in infectious mononucleosis.