Articles | Departments | Patient Information

Lymphadenopathy: Differential Diagnosis and Evaluation

ROBERT FERRER, M.D., M.P.H.,

University of Texas Health Sciences Center at San Antonio,

San Antonio, Texas

Although the finding of lymphadenopathy sometimes raises fears about serious illness, it is, in patients seen in primary care settings, usually a result of benign infectious causes. Most patients can be diagnosed on the basis of a careful history and physical examination. Localized adenopathy should prompt a search for an adjacent precipitating lesion and an examination of other nodal areas to rule out generalized lymphadenopathy. In general, lymph nodes greater than 1 cm in diameter are considered to be abnormal. Supraclavicular nodes are the most worrisome for malignancy. A three- to four-week period of observation is prudent in patients with localized nodes and a benign clinical picture. Generalized adenopathy should always prompt further clinical investigation. When a node biopsy is indicated, excisional biopsy of the most abnormal node will best enable the pathologist to determine a diagnosis.

The cause of lymphadenopathy is often obvious: for example, the child who presents with a sore throat, tender cervical nodes and a positive rapid strep test, or the patient who presents with an infection of the hand and axillary lymphadenopathy. In other cases, the diagnosis is less clear. Lymphadenopathy may be the only clinical finding or one of several nonspecific findings, and the discovery of swollen lymph nodes will often raise the specter of serious illness such as lymphoma, acquired immunodeficiency syndrome or metastatic cancer. The physician's task is to efficiently differentiate the few patients with serious illness from the many with self-limited disease. This article reviews the evaluation of patients with a central clinical finding of lymphadenopathy, emphasizing the identification of patients with serious illness.

Definition

Generalized lymphadenopathy is defined as two or more sites with abnormal lymph nodes.

The body has approximately 600 lymph nodes, but only those in the submandibular, axillary or inguinal regions may normally be palpable in healthy people.¹ Lymphadenopathy refers to nodes that are abnormal in either size, consistency or number. There are various classifications of lymphadenopathy, but a simple and clinically useful system is to classify lymphadenopathy as "generalized" if lymph nodes are enlarged in two or more noncontiguous areas or "localized" if only one area is involved. Distinguishing between localized and generalized lymphadenopathy is important in formulating a differential diagnosis. In primary care patients with unexplained lymphadenopathy, approximately three fourths of patients will present with localized lymphadenopathy and one fourth with generalized lymphadenopathy (Figure 1).^2,3

Figure 1. Presentation of lymphadenopathy by anatomic site (in percentages).

Epidemiology

Our understanding of the epidemiology of lymphadenopathy in family practice is limited by the scarcity of relevant literature. Only one study⁴ provides reliable population-based estimates. Findings from this Dutch study revealed a 0.6 percent annual incidence of unexplained lymphadenopathy in the general population. Of 2,556 patients in the study who presented with unexplained lymphadenopathy to their family physicians, 256 (10 percent) were referred to a subspecialist and 82 (3.2 percent) required a biopsy, but only 29 (1.1 percent) had a malignancy.

Findings from a Dutch study revealed that only 10 percent of patients with unexplained adenopathy required referral to a subspecialist, and only 1 percent had a malignancy.

This low prevalence of malignancy is supported by the results of two case series^2,3 from family practice departments in the United States, in which none of 80 patients and three of 238 patients with unexplained lymphadenopathy were diagnosed with malignancy. In contrast, the prevalence of malignancy in lymph node biopsies performed in referral centers is 40 to 60 percent,⁵ a statistic that has made its way into many textbooks (e.g., "In those more than 30 years of age, however, lymphadenopathy is due to a benign process only 40 percent of the time"⁶). Such assertions overestimate the probability of malignancy in patients with lymphadenopathy because they exclude the 97 percent of patients with lymphadenopathy who do not undergo a biopsy. In primary care settings, patients 40 years of age and older with unexplained lymphadenopathy have about a 4 percent risk of cancer versus a 0.4 percent risk in patients younger than age 40.⁴

Diagnostic Approach to Lymphadenopathy

The algorithm in Figure 2 provides a diagnostic framework for the evaluation of lymphadenopathy. The algorithm emphasizes that a careful history and physical examination are the core of the evaluation. In most cases, a careful history and physical examination will identify a readily diagnosable cause of the lymphadenopathy, such as upper respiratory tract infection, pharyngitis, periodontal disease, conjunctivitis, lymphadenitis, tinea, insect bites, recent immunization, cat-scratch disease or dermatitis, and no further assessment is necessary (see the "diagnostic" branch of the algorithm).

In other cases, a definitive diagnosis cannot be made on the basis of the history and physical examination alone; however, the clinical evaluation may strongly suggest a particular cause. Confirmatory testing should be performed in order to correctly identify the patient's illness (see the "suggestive" branch of the algorithm).

FIGURE 2 Algorithm for the evaluation of a patient with lymphadenopathy. (HIV=human immunodeficiency virus; CBC=complete blood count; PPD=purified protein derivative; RPR=rapid plasma reagin; ANA=antinuclear antibody; HBsAg=hepatitis B surface antigen)

TABLE 2 Medications That May Cause Lymphadenopathy Allopurinol (Zyloprim) Atenolol (Tenormin) Captopril (Capozide) Carbamazepine (Tegretol) Cephalosporins Gold Hydralazine (Apresoline) Penicillin Phenytoin (Dilantin) Primidone (Mysoline) Pyrimethamine (Daraprim) Quinidine Sulfonamides Sulindac (Clinoril) Adapted with permission from Pangalis GA, Vassilakopoulos TP, Boussiotis VA, Fessas P. Clinical approach to lymphadenopathy. Semin Oncol 1993; 20:570-82.

A subset of patients will either have unexplained lymphadenopathy after the initial clinical evaluation or have a presumptive diagnosis that is made in the "diagnostic" or "suggestive" branches of the algorithm and is not confirmed by test results or by the clinical course. In patients with unexplained localized lymphadenopathy and a reassuring clinical picture, a three- to four-week period of observation is appropriate before biopsy. Patients with localized lymphadenopathy and a worrisome clinical picture or patients with generalized lymphadenopathy will need further diagnostic evaluation that often includes biopsy (see the "unexplained" branch of the algorithm). Fine-needle aspiration is occasionally considered an alternative to excisional biopsy but often yields a high number of nondiagnostic results because of the small amount of tissue obtained and the inability to examine the architecture of the gland.⁷ In addition, there may be some risk of sinus tract formation, depending on the underlying pathology.⁸

History
The physician should consider four key points when compiling a patient's history.¹ First, are there localizing symptoms or signs to suggest infection or neoplasm in a specific site? Second, are there constitutional symptoms such as fever, weight loss, fatigue or night sweats to suggest disorders such as tuberculosis, lymphoma, collagen vascular diseases, unrecognized infection or malignancy? Third, are there epidemiologic clues (Table 1) such as occupational exposures, recent travel or high-risk behaviors that suggest specific disorders? Fourth, is the patient taking a medication that may cause lymphadenopathy? Some medications are known to specifically cause lymphadenopathy (e.g., phenytoin [Dilantin]), while others, such as cephalosporins, penicillins or sulfonamides, are more likely to cause a serum sickness-like syndrome with fever, arthralgias and rash in addition to lymphadenopathy (Table 2).

TABLE 1 Epidemiologic Clues to the Diagnosis of Lymphadenopathy Exposure Diagnosis General Cat Undercooked meat Tick bite Tuberculosis Recent blood transfusion or transplant High-risk sexual behavior Intravenous drug use Cat-scratch disease, toxoplasmosis Toxoplasmosis Lyme disease, tularemia Tuberculous adenitis Cytomegalovirus, HIV HIV, syphilis, herpes simplex virus, cytomegalovirus, hepatitis B infection HIV, endocarditis, hepatitis B infection Occupational Hunters, trappers Fishermen, fishmongers, slaughterhouse workers Tularemia Erysipeloid Travel-related Arizona, southern California, New Mexico, western Texas Southwestern United States Southeastern or central United States Southeast Asia, India, northern Australia Central or west Africa Central or South America East Africa, Mediterranean, China, Latin America Mexico, Peru, Chile, India, Pakistan, Egypt, Indonesia Coccidioidomycosis Bubonic plague Histoplasmosis Scrub typhus African trypanosomiasis (sleeping sickness) American trypanosomiasis (Chagas' disease) Kala-azar (leishmaniasis) Typhoid fever HIV=human immunodeficiency virus.

Physical Examination
When lymphadenopathy is localized, the clinician should examine the region drained by the nodes for evidence of infection, skin lesions or tumors (Table 3). Other nodal sites should also be carefully examined to exclude the possibility of generalized rather than localized lymphadenopathy. This is an important aspect of the examination, as a study of primary care physicians found that generalized lymphadenopathy was identified in only 17 percent of the patients in whom it was present.⁹ Careful palpation of the submandibular, anterior and posterior cervical, supraclavicular, axillary and inguinal nodes can be accomplished in a short time and will identify patients with generalized lymphadenopathy.

If lymph nodes are detected, the following five characteristics should be noted and described:

Fine-needle aspiration is occasionally considered an alternative to excisional biopsy but is often unhelpful.

Size. Nodes are generally considered to be normal if they are up to 1 cm in diameter; however, some authors suggest that epitrochlear nodes larger than 0.5 cm or inguinal nodes larger than 1.5 cm should be considered abnormal.^7,8 Little information exists to suggest that a specific diagnosis can be based on node size. However, in one series¹⁰ of 213 adults with unexplained lymphadenopathy, no patient with a lymph node smaller than 1 cm² (1 cm 3 1 cm) had cancer, while cancer was present in 8 percent of those with nodes from 1 cm² to 2.25 cm² (1 cm 3 1 cm to 1.5 cm 3 1.5 cm) in size, and in 38 percent of those with nodes larger than 2.25 cm² (1.5 cm 3 1.5 cm). In children, lymph nodes larger than 2 cm in diameter (along with an abnormal chest radiograph and the absence of ear, nose and throat symptoms) were predictive of granulomatous diseases (i.e., tuberculosis, cat-scratch disease or sarcoidosis) or cancer (predominantly lymphomas).¹¹ These studies were performed in referral centers, and conclusions may not apply in primary care settings.

Pain/Tenderness. When a lymph node rapidly increases in size, its capsule stretches and causes pain. Pain is usually the result of an inflammatory process or suppuration, but pain may also result from hemorrhage into the necrotic center of a malignant node. The presence or absence of tenderness does not reliably differentiate benign from malignant nodes.⁴

TABLE 3 Lymph Node Groups: Location, Lymphatic Drainage and Selected Differential Diagnosis Location Lymphatic drainage Causes Submandibular Tongue, submaxillary gland, lips and mouth, conjunctivae Infections of head, neck, sinuses, ears, eyes, scalp, pharynx Submental Lower lip, floor of mouth, tip of tongue, skin of cheek Mononucleosis syndromes, Epstein-Barr virus, cytomegalovirus, toxoplasmosis Jugular Tongue, tonsil, pinna, parotid Pharyngitis organisms, rubella Posterior cervical Scalp and neck, skin of arms and pectorals, thorax, cervical and axillary nodes Tuberculosis, lymphoma, head and neck malignancy Suboccipital Scalp and head Local infection Postauricular External auditory meatus, pinna, scalp Local infection Preauricular Eyelids and conjunctivae, temporal region, pinna External auditory canal Right supraclavicular node Mediastinum, lungs, esophagus Lung, retroperitoneal or gastrointestinal cancer Left supraclavicular node Thorax, abdomen via thoracic duct Lymphoma, thoracic or retroperitoneal cancer, bacterial or fungal infection Axillary Arm, thoracic wall, breast Infections, cat-scratch disease, lymphoma, breast cancer, silicone implants, brucellosis, melanoma Epitrochlear Ulnar aspect of forearm and hand Infections, lymphoma, sarcoidosis, tularemia, secondary syphilis Inguinal Penis, scrotum, vulva, vagina, perineum, gluteal region, lower abdominal wall, lower anal canal Infections of the leg or foot, STDs (e.g., herpes simplex virus, gonococcal infection, syphilis, chancroid, granuloma inguinale, lymphogranuloma venereum), lymphoma, pelvic malignancy, bubonic plague STDs=sexually transmitted diseases.

Consistency. Stony-hard nodes are typically a sign of cancer, usually metastatic. Very firm, rubbery nodes suggest lymphoma. Softer nodes are the result of infections or inflammatory conditions. Suppurant nodes may be fluctuant. The term "shotty" refers to small nodes that feel like buckshot under the skin, as found in the cervical nodes of children with viral illnesses.

Matting. A group of nodes that feels connected and seems to move as a unit is said to be "matted." Nodes that are matted can be either benign (e.g., tuberculosis, sarcoidosis or lymphogranuloma venereum) or malignant (e.g., metastatic carcinoma or lymphomas).

Location. The anatomic location of localized adenopathy will sometimes be helpful in narrowing the differential diagnosis. For example, cat-scratch disease typically causes cervical or axillary adenopathy, infectious mononucleosis causes cervical adenopathy and a number of sexually transmitted diseases are associated with inguinal adenopathy (Table 4).

TABLE 4 Evaluation of Suspected Causes of Lymphadenopathy Disorder Associated findings Test Mononucleosis-type syndromes Fatigue, malaise, fever, atypical lymphocytosis Epstein-Barr virus* Splenomegaly in 50% of patients Monospot, IgM EA or VCA Toxoplasmosis* 80 to 90% of patients are asymptomatic IgM toxoplasma antibody Cytomegalovirus* Often mild symptoms; patients may have hepatitis IgM CMV antibody, viral culture of urine or blood Initial stages of HIV infection* "Flu-like" illness, rash HIV antibody Cat-scratch disease Fever in one third of patients; cervical or axillary nodes Usually clinical criteria; biopsy if necessary Pharyngitis due to group A streptococcus, gonococcus Fever, pharyngeal exudates, cervical nodes Throat culture on appropriate medium Tuberculosis lymphadenitis* Painless, matted cervical nodes PPD, biopsy Secondary syphilis* Rash RPR Hepatitis B* Fever, nausea, vomiting, icterus Liver function tests, HBsAg Lymphogranuloma venereum Tender, matted inguinal nodes Serology Chancroid Painful ulcer, painful inguinal nodes Clinical criteria, culture Lupus erythematosus* Arthritis, rash, serositis, renal, neurologic, hematologic disorders Clinical criteria, antinuclear antibodies, complement levels Rheumatoid arthritis* Arthritis Clinical criteria, rheumatoid factor Lymphoma* Fever, night sweats, weight loss in 20 to 30% of patients Biopsy Leukemia* Blood dyscrasias, bruising Blood smear, bone marrow Serum sickness* Fever, malaise, arthralgia, urticaria; exposure to antisera or medications Clinical criteria, complement assays Sarcoidosis Hilar nodes, skin lesions, dyspnea Biopsy Kawasaki disease* Fever, conjunctivitis, rash, mucous membrane lesions Clinical criteria Less common causes of lymphadenopathy Lyme disease* Rash, arthritis IgM serology Measles* Fever, conjunctivitis, rash, cough Clinical criteria, serology Rubella* Rash Clinical criteria, serology Tularemiala* Fever, ulcer at inoculation site Blood culture, serology Brucellosis* Fever, sweats, malaise Blood culture, serology Plague Febrile, acutely ill with cluster of tender nodes Blood culture, serology Typhoid fever* Fever, chills, headache, abdominal complaints Blood culture, serology Still's disease* Fever, rash, arthritis Clinical criteria, antinuclear antibody, rheumatoid factor Dermatomyositis* Proximal weakness, skin changes Muscle enzymes, EMG, muscle biopsy Amyloidosis* Fatigue, weight loss Biopsy *--Causes of generalized lymphadenopathy. EA=early antibody; VCA=viral capsid antigen; CMV=cytomegalovirus; HIV=human immunodeficiency virus; PPD=purified protein derivative; RPR=rapid plasma reagin; HBsAg=hepatitis B surface antigen; EMG=electromyelography.

Supraclavicular lymphadenopathy has the highest risk of malignancy, estimated as 90 percent in patients older than 40 years and 25 percent in those younger than age 40.⁴ Having the patient perform a Valsalva's maneuver during palpation of the supraclavicular fossae increases the chance of detecting a node. Lymphadenopathy of the right supraclavicular node is associated with cancer in the mediastinum, lungs or esophagus. The left supraclavicular (Virchow's) node receives lymphatic flow from the thorax and abdomen, and may signal pathology in the testes, ovaries, kidneys, pancreas, prostate, stomach or gallbladder. Although rarely present, a paraumbilical (Sister Joseph's) node may be a sign of an abdominal or pelvic neoplasm.¹²

In patients with generalized lymphadenopathy, the physical examination should focus on searching for signs of systemic illness. The most helpful findings are rash, mucous membrane lesions, hepatomegaly, splenomegaly or arthritis (Table 4). Splenomegaly and lymphadenopathy occur concurrently in many conditions, including mononucleosis-type syndromes, lymphocytic leukemia, lymphoma and sarcoidosis.

Clinical Evaluation for Algorithm's 'Suggestive' Branch

Laboratory tests that may be useful in confirming the cause of lymphadenopathy are listed in Table 4. The presence of certain characteristic clinical syndromes may help the physician determine a suspected cause of lymphadenopathy.

Mononucleosis-Type Syndromes
Patients with these syndromes present with lymphadenopathy, fatigue, malaise, fever and an increased atypical lymphocyte count. Mononucleosis is most commonly due to Epstein-Barr virus infection. The presence of the typical syndrome and positive results on a heterophilic antibody test (Monospot test) confirms the diagnosis. The most common cause of heterophil-negative mononucleosis is early Epstein-Barr virus infection. False-negative results on heterophilic antibody tests are especially common in patients younger than four years of age. Epstein-Barr virus infection may be confirmed by repeating the Monospot test in seven to 10 days. Rarely is it necessary to confirm the diagnosis with IgM viral capsid antigen or early antigen antibody titers.

If Epstein-Barr virus antibodies are absent, other causes of the mononucleosis syndrome should be considered. These include toxoplasmosis, cytomegalovirus infection, streptococcal pharyngitis, hepatitis B infection and acute human immunodeficiency virus (HIV) infection. Acute infections with cytomegalovirus and Toxoplasma may be identified with IgM serology for those organisms.

Ulceroglandular Syndrome
This syndrome is defined by the presence of a skin lesion with associated regional lymphadenopathy. The classic cause is tularemia, acquired by contact with an infected rabbit or tick; more common causes include streptococcal infection (e.g., impetigo), cat-scratch disease and Lyme disease.

Oculoglandular Syndrome
This syndrome involves the combination of conjunctivitis and associated preauricular nodes. Common causes include viral keratoconjunctivitis and cat-scratch disease resulting from an ocular lesion.

HIV Infection
Enlargement of the lymph nodes that persists for at least three months in at least two extrainguinal sites is defined as persistent generalized lymphadenopathy and is common in patients in the early stages of HIV infection. Other causes of generalized lymphadenopathy in HIV-infected patients include Kaposi's sarcoma, cytomegalovirus infection, toxoplasmosis, tuberculosis, cryptococcosis, syphilis and lymphoma.

Unexplained Lymphadenopathy

When, after the initial evaluation and after exploration of the "diagnostic" and "suggestive" branches of the algorithm (Figure 2), a cause for the lymphadenopathy remains unexplained, the physician must decide whether to pursue a specific diagnosis. The decision will depend primarily on the clinical setting as determined by the patient's age, the duration of the lymphadenopathy and the characteristics and location of the nodes.

Generalized lymphadenopathy almost always indicates the presence of a significant systemic disease.

Generalized Lymphadenopathy
Because generalized lymphadenopathy almost always indicates that a significant systemic disease is present, the clinician should consider the diseases listed in Table 4 and proceed with specific testing as indicated. If a diagnosis cannot be made, the clinician should obtain a biopsy of the node. The diagnostic yield of the biopsy can be maximized by obtaining an excisional biopsy of the largest and most abnormal node (which is not necessarily the most accessible node). If possible, the physician should not select inguinal and axillary nodes for biopsy, since they frequently show only reactive hyperplasia.

Localized Lymphadenopathy
If the lymphadenopathy is localized, the decision about when to biopsy is more difficult. Patients with a benign clinical history, an unremarkable physical examination and no constitutional symptoms should be reexamined in three to four weeks to see if the lymph nodes have regressed or disappeared. Patients with unexplained localized lymphadenopathy who have constitutional symptoms or signs, risk factors for malignancy or lymphadenopathy that persists for three to four weeks should undergo a biopsy. Biopsy should be avoided in patients with probable viral illness because lymph node pathology in these patients may sometimes simulate lymphoma and lead to a false-positive diagnosis of malignancy.

Initial Management

Many patients worry about the cause of their abnormal lymph nodes. To adequately address their fears, the physician should ask the patient about his or her concerns and respond to questions about specific diagnoses. When biopsy is deferred, the physician should explain to the patient the rationale for waiting. Patients should be cautioned to remain alert for the reappearance of the nodes because lymphomatous nodes have been known to temporarily regress.

Final Comment

In most patients, lymphadenopathy has a readily diagnosable infectious cause. A diagnosis of less obvious causes can often be made after considering the patient's age, the duration of the lymphadenopathy and whether localizing signs or symptoms, constitutional signs or epidemiologic clues are present. When the cause of the lymphadenopathy remains unexplained, a three- to four-week observation period is appropriate when the clinical setting indicates a high probability of benign disease.

Figure 1 adapted from Allhiser JN, McKnight TA, Shank JC. Lymphadenopathy in a family practice. J Fam Pract 1981;12:27-32, and Williamson HA Jr. Lymphadenopathy in a family practice: a descriptive study of 249 cases. J Fam Pract 1985;20:449-58.

Each year members of a different family practice department develop articles for "Problem-Oriented Diagnosis." This series is coordinated by the Department of Family Practice at the University of Texas Health Science Center at San Antonio. Guest editors of the series are David A. Katerndahl, M.D., and Clinton Colmenares.

---

The Author

ROBERT FERRER, M.D., M.P.H.,
is an assistant professor of family practice at the University of Texas Health Sciences Center at San Antonio. He received his medical degree from Hahnemann University School of Medicine in Philadelphia and completed a residency in family medicine at Duke University School of Medicine, Durham, N.C., and a fellowship in family medicine at the University of Washington School of Medicine, Seattle.

Address correspondence to Robert Ferrer, M.D., M.P.H., Department of Family Practice, University of Texas Health Sciences Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78284-7795; e-mail: ferrerr@uthscsa.edu. Reprints are not available from the author.

REFERENCES

1. Goroll AH, May LA, Mulley AG Jr. Primary care medicine: office evaluation and management of the adult patient. 2d ed. Philadelphia: Lippincott, 1987.
2. Allhiser JN, McKnight TA, Shank JC. Lymphadenopathy in a family practice. J Fam Pract 1981;12: 27-32.
3. Williamson HA Jr. Lymphadenopathy in a family practice: a descriptive study of 249 cases. J Fam Pract 1985;20:449-58.
4. Fijten GH, Blijham GH. Unexplained lymphadenopathy in family practice. An evaluation of the probability of malignant causes and the effectiveness of physicians' workup. J Fam Pract 1988;27: 373-6.
5. Lee Y, Terry R, Lukes RJ. Lymph node biopsy for diagnosis: a statistical study. J Surg Oncol 1980;14: 53-60.
6. Bennett JC, Plum F, eds. Cecil textbook of medicine. 20th ed. Philadelphia: Saunders, 1996.
7. Libman H. Generalized lymphadenopathy. J Gen Intern Med 1987;2:48-58.
8. Morland B. Lymphadenopathy. Arch Dis Child 1995; 73:476-9.
9. Paauw DS, Wenrich MD, Curtis JR, Carline JD, Ramsey PG. Ability of primary care physicians to recognize physical findings associated with HIV infection. JAMA 1995;274:1380-2.
10. Pangalis GA, Vassilakopoulos TP, Boussiotis VA, Fessas P. Clinical approach to lymphadenopathy. Semin Oncol 1993;20:570-82.
11. Slap GB, Brooks JS, Schwartz JS. When to perform biopsies of enlarged peripheral lymph nodes in young patients. JAMA 1984;252:1321-6.
12. Sapira JD. The art and science of bedside diagnosis. Baltimore: Urban & Schwarzenberg, 1990:139-44.

Copyright © 1998 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP.