Lymphadenopathy - Diagnosis and Empiric Therapy

HISTORY

                The history in a patient with lymphadenopathy should focus upon demographic information (age, sex, race, ethnicity, occupation, location of residence), the clinical course (acute, subacute or chronic), constitutional symptoms (fever, night sweats, fatigue, weight loss, sore throat, cough), exposure history (pets, medications, infectious diseases), high-risk behavior (sexual behavior and drug abuse), family history (malignancy, tuberculosis and others).

PHYSICAL EXAMINATION

                If lymph nodes are palpated, the following five characteristics should be noted and documented in the history: size, tenderness, consistency, location, and fixation. Abnormal nodes are generally greater than 1cm in diameter. A lymph node size of 2.25 cm² (1.5 x 1.5cm) was the best discriminating limit for distinguishing malignant or granulomatous lymphadenopathy from other cause of lymphadenopathy. No patient with a lymph node smaller than 1 cm, 2 had cancer, compared with 8% and 38% of those with nodes 1 to 2.25 cm² and greater than 2.25 cm2, respectively.

               Hard nodes with fibrosis are usually associated with malignancy. Firm, rubbery nodes are found in lymphomas and chronic leukemia; nodes in acute leukemia tend to be softer. Tenderness occurs when the capsule is stretched during rapid enlargement, usually secondary to an on inflammatory process. Normal lymph nodes are freely movable in the subcutaneous space. Abnormal nodes can become fixed to adjacent tissues by invading cancers or inflammation in tissue surrounding the nodes.

               Localized lymphadenopathy should prompt a search for pathology in the area of node drainage, although some systemic diseases can present with local adenopathy (Table 1). Generalized adenopathy is usually a manifestation of systemic disease.

Table 1:  Lymph Node: Location, Lymphatic Drainage and Selected Differential Diagnosis  

LABORATORY TESTING

                Laboratory testing can be used to confirm a diagnosis that is suspected on the basis of the history and physical examination.

    General

Patients with generalized lymphadenopathy should have a CBC and chest radiograph. If these are normal, other test considerations include HIV antibody determination, RPR, ANA, and Monospot test, although these are often of low yield in the absence of a more specific indication.

    Serological Tests

Serological testing is useful for detection of antibodies for viral illness including EBV, CMV, measles, rubella, dengue and bacterial infections including Yersinosis, Cat Scratch Disease, tularemia, toxoplasmosis, and syphilis. For the diagnosis of acute infectious mononucleosis, the sensitivity of the heterophile test (Monospot) is 90%. Antibody to viral capsid antigen (VCA) and early antigen in diffuse pattern (EA-D) should be obtained for suspected cases of acute infectious mononucleosis. The VCA-EBV, IgM is the most sensitive test for acute EBV infection. Titers of IgM and IgG antibodies to VCA are elevated in more than 90% of patients at the onset of disease; the IgM antibodies are absent by 4-8 weeks following acute infection.

In the differential diagnosis of infectious mononucleosis, serology for hepatitis viruses (HBsAg, IgM anti HAV, IgM anti HBc, and anti-HCV), HIV, CMV, and toxoplasma should be ordered. For the diagnosis of primary syphilis, non-treponemal and treponemal tests are supportive (sensitivity 78% and 84%, respectively). The standard screening test for HIV infection is the ELISA with a sensitivity of > 99.5%. The most commonly used confirmatory test is the western blot. Serological tests are not reliable for rat-bite fever, sporotrichosis, lymphgranulmoa venereum (Chlamydia trachomatis).

    Microbiological

Fluctuant lymph nodes should be aspirated, while suppurative, ulcerative nodes should be biopsied for culture and microscopic evaluation. Characteristic findings of direct microscopic examination for lymphadenopathy includes intracellular gram-negative diplococci for Neisseria gonorrhoeae, “Chinese characters” on gram stain for Corynebacterium diphtheriae, bacilli in chains or clumps on Warthin-Starry Silver stains for Bartonella henselae, “safety-pin” shaped organisms on Wayson’s stain for Yersinia pestis, Giemsa, Wayson and gram stains for Streptobacillus moniliformis (rat-bite fever), “cigar-shaped organisms” on silver or PAS stain of histopathology for Sporotrichosis schenckii, multinucleated giant cell on Tzanck smear for HSV and VZV, Treponema pallidum by darkfield microscopy for primary syphilis, dark staining “Donovan bodies” on tissue crush preparation or biopsy for Klebsiella granulomatis (granuloma inguinale; donovanosis) (Table 4).

 Special culture media for fastidious organisms includes Loffler’s or Tindale’s media for Corynebacterium diphtheriae, Cefsulodin-Irgasan-Novobiocin (CIN) agar for Yersinia spp., Thayer-Martin media for Neisseria gonorrhoeae, Cysteine-enriched media for Fransicella tularensis, Sabouraud’s agar for fungi (Sporotrichosis, Histoplasmosis), and cell culture or mouse inoculation for Toxoplasma gondii. Primary cutaneous coccidioidomycosis, nocardiosis, and blastomycosis may be diagnosed by biopsy with appropriate stains and cultures. Sporotrichosis is definitively diagnosed by culture of the nodules, since neither serology nor scrapings of the lesions of staining are especially helpful.

Table 4. Microbiological Findings of Lymphadenopathy

Tests for M. tuberculosis

A positive tuberculin skin test, although suggestive, is not diagnostic of tuberculosis because a positive test can occur in individuals without active disease. Moreover, a negative tuberculin skin test may be observed in active tuberculosis (15-25% in tuberculosis lymphadenitis). A PPD may assist in differentiating tuberculosis from sarcoidosis when the lymph node histology is nonspecific. Tuberculin skin is the first step in the diagnosis of cervicofacial lymphadenitis in children without a history of tuberculosis exposure or BCG vaccination. Among total 112 nontuberculous mycobacterial infections (83 of Mycobacterium avium, 21 of Mycobacterium haemophilum, and 8 of other nontuberculous mycobacterial species); tuberculin skin testing had a sensitivity and specificity of 70% and 98%, respectively, and a positive predictive value and a negative predictive value of 98% and 64% at the optimal cutoff for a positive test (5mm).

The QuantiFERON®-TB Gold test (QFT-G) is a whole-blood test for use in diagnosing Mycobacterium tuberculosis infection, including latent tuberculosis infection (LTBI) and tuberculosis (TB) disease. Results are not affected by exposure to BCG or other mycobacterial species. If the patient is infected with M. tuberculosis, their white blood cells will release IFN-gamma in response to contact with the TB antigens. The QFT-G results are based on the amount of IFN-gamma that is released in response to the antigens. Results are reported as positive, negative or indeterminate and do not require the subjective evaluation of reading a PPD. Positive results do not vary based on patient risk factors as do the PPD. Caution must be employed when interpreting results of QFT-G in immunocompromised patients since data is lacking.

    Imaging Studies

Chest radiograph, although seldom positive, should be performed in every patient because it may show the presence of mediastinal lymph node enlargement observed in malignant lymphomas, sarcoidosis, tuberculosis, histoplasmosis, and metastatic cancer. Chest radiograph may also disclose parenchymal lesions compatible with granulomatous fungal diseases, tuberculosis sarcoidosis, metastatic tumors, or lymphomas. The computed tomography (CT) and ultrasonography of the involved area may be useful to differentiate lymphadenopathy from other nonlymphatic enlargements, to show lymph node enlargement of the mediastinum or abdomen, and to determine the exact anatomic location of the enlarged node before its surgical excision (particularly in the cervical area).

    Invasive Diagnostic Methods

Lymph node may be biopsied by excisional methods or needle aspiration. Although fine-needle aspiration is simple, safe, and inexpensive, lymph node disorders such as reactive hyperplasia, Hodgkin disease, and non-Hodgkin lymphoma may be extremely difficult to distinguish from one another with fine-needle aspiration alone. In patients without an established diagnosis and with accessible peripheral adenopathy, excisional biopsy is preferred over fine-needle aspiration to ensure adequate sampling.

The changes of chronic inflammation seen on lymph node biopsy may also be nonspecific. Even the presence of epitheloid granulomatous with caseous necrosis and giant-cell formation is not in itself diagnostic of tuberculosis, since the same findings may be seen in tularemia, LGV, cat scratch disease, brucellosis, and even sarcoidosis. With appropriate cultures and stains such as Ziehl-Neelsen, PAS, and the Gomori silver stain, a specific microorganism may occasionally be identified.

Increased age (>40 years) suggests malignancy. At younger ages, individuals are more likely to have nonspecific lymphadenitis, infectious mononucleosis, rubella, and toxoplasmosis. Lymph node size is generally determined by palpation and external measurement. It should be conceded that this parameter is not easily measured or reproducible by physical examination. Location is pertinent. Palpable lymph nodes in the cervical axillary and inguinal areas are often observed in normal individuals. In one study, 56% of patients examined for other causes had palpable cervical nodes. In another study of individuals older than 13 years, palpable nodes were found in the cervical (80%), axillary (70%), and inguinal (90%) areas. On the other hand, supraclavicular lymphadenopathy is considered suggestive of serious disease. Tenderness or painful lymph nodes are usually benign, while painless hard nodes can be malignant. Duration of lymphadenopathy is also useful. A duration of several days is usually infection. Interestingly, a long history (>1 year) is also suggestive of a benign condition (although tuberculosis and lymphoma can have a prolonged course). Duration proved not to be a useful parameter in assessing the lymph node biopsy.

In summary, we recommend that the following studies be performed for most patients in whom lymph node biopsy is considered: 1) Monospot test and VCA (viral capsid antigen)-EBV, IgM. 2) Serology for toxoplasmosis. 3) Quantiferon-TB Gold test or PPD skin test for tuberculosis, and 4) chest radiograph to search for pulmonary infiltrates and mediastinal lymphadenopathy.

Clinical parameters favoring malignancy and are increased age (>40 years), large size of the lymph node (>4.0 cm²), supraclavicular location, and hardness of the node. The presence of constitutional symptoms (fever, weight loss, night sweats) is suggestive of a lymphoma or tuberculosis. Excisional biopsy may be warranted.

In general, lymph nodes that have been present outside the inguinal region for longer than 1 month and measure 1×1 cm or larger without an obvious diagnosis should be considered for biopsy. The purpose of the biopsy is to rule out malignancy or treatable infectious diseases, especially tuberculosis and disseminated fungal disease. Most patients who present with lymphadenopathies have acute, localized process. Invasive evaluation of these nodes is not generally warranted. The biopsy of these involved nodes shows nonspecific histology, i.e., regional nonspecific lymphadenitis. If the underlying cause of lymphadenopathy is suspected to be a viral infection, lymph node biopsy can be deferred.

    Prediction Models

Clinical prediction rules have been developed that use key elements of history and physical examination to predict the utility of lymph node biopsy. Centor’s criteria is a simple 4-item clinical prediction rule used to predict the probability of Group A streptococcus infection. Tonsillar exudate, swollen tender anterior cervical nodes, absence of cough, and a history of fever are the key parameters. The rule is accurate, with an area under the receiver operating characteristic (ROC) curve of 0.79. The presence of 3 or 4 findings increases the probability of streptococcal pharyngitis.

A mathematical model has been formulated for the prediction of the need of lymph node biopsy develop based on the medical history (age) and the physical findings. The lymph node parameters were tenderness and size of the affected lymph node, supraclavicular location and texture of the lymph nodes (soft, semi-hard, hard). Surprisingly, generalized pruritus was one of the parameters; presence of pruritis correlated with presence of lymphoma, especially Hodgkins disease. This model was developed in a university hospital in Greece. A study in a Japanese hospital showed that the results of a model developed in Greece could not readily be extrapolated elsewhere. In the Japanese study, tuberculosis and toxoplasmosis were extremely rare as compared to the Greece study. In contrast, Kikuchi’s lymphadenopathy was common in Japan, but rare in Greece. This disparity illustrates how the differences in epidemiology and patient population will affect the incidence of the diverse causes of lymphadenopathy.

EMPIRIC ANTIBIOTICS

                Antibiotics are not indicated for lymphadenopathy unless there is unusually strong evidence of a bacterial infection and the patient is toxic. Glucocorticosteroids should not be used to treat lymphadenopathy because their lympholytic effect was obscure some diagnoses (lymphoma, leukemia, Castleman's disease). Moreover, corticosteroids can contribute to delayed healing or activation of underlying infections. An exception is the life-threatening pharyngeal obstruction by enlarged lymphoid tissue in Waldeyer’s ring that is occasionally seen in infectious mononucleosis.

ENDPOINTS FOR MONITORING

                Most patients with lymphadenopathy do not require a biopsy. If the patient's history and physical findings point to a benign cause for lymphadenopathy, then careful follow-up at a 2- to 4-week interval can be employed. The watch-and-wait policy is generally applied when lymph node enlargement may be caused by a viral infection for which no specific therapy is available. Close follow-up of the patient at monthly intervals, or earlier if the size of the enlargement is increasing, is necessary.