Enlarged lymph nodes can be seen in patients presenting for a variety of reasons and can also be detected as a symptom of the patient’s own disease. The clinician must ultimately be able to determine whether it is a normal finding or whether it requires further examination or even biopsy. Soft, flat submandibular lymph nodes (<1 cm) are often palpable in healthy children and young adults, and inguinal lymph nodes of 2 cm may be palpable in healthy adults. Therefore, further evaluation of these normal lymph nodes is not necessary. Conversely, if the clinician considers the lymph node enlargement to be abnormal, a more definitive diagnosis is needed.
Lymph node enlargement can be a primary or secondary manifestation of many diseases, as shown in Table 1. Many of these disorders are rarer causes of lymph node enlargement. In more than 2/3 of patients initially diagnosed, lymph node enlargement is due to a nonspecific cause or an upper respiratory tract disease (viral or bacterial). In one study, of 220 patients with enlarged lymph nodes, 186 (84%) had benign disease and 34 (16%) had malignancy (lymphoma or metastatic cancer). 63% (112) of the 186 benign patients had nonspecific or reactive factors (no clear cause identified), while the rest had a proven specific cause, most commonly infectious mononucleosis, toxoplasmosis or tuberculosis. The most common of these are infectious mononucleosis, toxoplasmosis, or tuberculosis. Thus, the majority of patients with lymphadenopathy are due to nonspecific factors.
Table 1 Diseases associated with lymph node enlargement
. Infectious diseases
. Viral – infectious mononucleosis (EBV, CMV), infectious hepatitis, herpes simplex virus, herpes virus type 6, varicella-zoster virus, rubella, measles, adenovirus, HIV, epidemic keratoconjunctivitis, cowpox, herpes virus type 8
. Bacterial – streptococcus, staphylococcus , cat scratch fever, brucellosis, rabbit fever, plague, soft chancre, rhinophyma, rhinophyma, tuberculosis, atypical mycobacteria, primary and secondary syphilis, diphtheria, leprosy
. Fungal-histoplasmosis, coccidioidomycosis, paracoccidioidomycosis
. Chlamydia – lymphogranuloma venereum, trachoma
. Parasitic – toxoplasmosis, leishmaniasis, conidiosis, filariasis
. Rickettsiosis – Scrub typhus, rickettsial pox
. Immunological diseases
. Rheumatoid arthritis
. Juvenile rheumatoid arthritis
. Mixed connective tissue disease
. Systemic lupus erythematosus
. Dermatomyositis
. Dry syndrome
. Serum sickness
. Drug allergy – phenytoin, hydrazidiazide, alobigine, paromomid, gold, carbamazepine
. Primary biliary cirrhosis
. Graft-versus-host disease
. Silicon-related diseases
. Malignant Diseases
Hematologic – Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, acute or chronic lymphocytic leukemia, hairy cell leukemia, malignant histiocytosis, amyloidosis
Metastatic – various primary cancers
Lipid deposition disease – Gaucher disease, Niemann-Pick disease, Fabry disease, Tangier disease
Endocrine disorders – hyperthyroidism
Other diseases
Diseases
Nodular diseases
Dermatologic lymphadenopathy
Lymphomatoid granulomatosis
Histiocytic necrotizing lymphadenopathy (Kikuchi’s disease)
Sinus histiocytic hyperplasia with giant lymph node enlargement
Cutaneous mucosal lymph node syndrome
Histiocytic hyperplasia
Familial Mediterranean fever
Severe hyperlipidemia
Inflammatory pseudotumors of the lymph nodes
Clinical evaluation In the search for the cause of lymph node enlargement the physician must rely on a detailed history, a thorough physical examination, selective laboratory tests and, if necessary, lymph node biopsy.
The history should describe the pathogenesis of the enlarged lymph nodes. Symptoms such as sore throat, cough, fever, night sweats, fatigue, weight loss, and lymph node pain should be sought. The patient’s age, gender, occupation, pet exposure, sexual history, and medication history such as phenytoin are also important components of the history. For example, children and young adults are susceptible to benign diseases such as viral or bacterial upper respiratory infections, infectious mononucleosis, toxoplasmosis and, in some countries, tuberculosis. In contrast, the incidence of malignant diseases increases after the age of 50.
Physical examination can provide useful clues such as the extent of lymph node enlargement (local or generalized), size and texture of the lymph nodes, the presence of pressure, signs of inflammation in the lymph nodes, skin lesions, and splenomegaly. Adult patients with swollen lymph nodes in the neck and a history of smoking should undergo a complete ENT examination. Local or regional lymph node enlargement suggests involvement of a single anatomic region, while generalized lymph node enlargement refers to involvement of three or more discontinuous lymph node areas. Many diseases that cause lymph node enlargement (Table 1) can result in local or generalized lymph node enlargement, so the role of this difference in the differential diagnosis is limited. Nevertheless, systemic lymphadenopathy is mostly associated with benign diseases such as infectious mononucleosis (EBV or CMV), toxoplasmosis, AIDS and other viral infections, systemic lupus erythematosus, and mixed connective tissue disease. In adults, acute and chronic lymphocytic leukemia and malignant lymphoma can also cause generalized lymph node enlargement.
The location of local or regional enlarged lymph nodes can provide useful clues to the etiology. Swollen occipital lymph nodes often suggest infection of the scalp, and swollen preauricular lymph nodes are associated with conjunctival infection and cat-scratch fever. The neck is the most common site of regional lymph node enlargement, mostly due to benign diseases such as upper respiratory tract infections, oral and dental disorders, infectious mononucleosis, and other viral diseases. Metastases from primary tumors of the head and neck, breast, lung, and thyroid are the main malignant causes. Enlarged supraclavicular and oblique lymph nodes are usually abnormal. Because they drain the lung and retroperitoneal regions, they suggest lymphoma or other tumors or infections occurring within the area. The enlarged left supraclavicular lymph node is known as Virchow’s lymph node and is caused by metastatic infiltration of the primary gastrointestinal cancer. Metastases to the supraclavicular lymph nodes can also be seen in lung, breast, testicular or ovarian cancers. Non-neoplastic disorders such as tuberculosis, tuberculosis, and toxoplasmosis can also cause supraclavicular lymph node enlargement. Axillary lymph node enlargement is usually due to injury or local infection of the medial upper extremity. Malignant causes include melanoma, lymphoma, and breast cancer in women. Inguinal lymph node enlargement is usually secondary to infection or injury to the lower extremity and can also be associated with sexually transmitted diseases such as lymphogranuloma venereum, primary syphilis, genital herpes, or soft chancre. Lymphomas, metastases from primary cancers of the rectum, external genitalia, or lower extremities (melanoma) may also involve the lymph nodes in this area.
Size, texture, and painful presentation are useful parameters in the evaluation of lymph node enlargement. Lymph nodes <1.0 cm2 (<1.0×1.0 cm) are usually secondary to benign nonspecific reactive disease. In a retrospective study, lymph node biopsies performed in young patients aged 9 to 25 years were found to be >2 cm in maximum diameter as a discriminating point to predict whether the biopsy was malignant or granulomatous disease. Another study showed that lymph nodes of 2.5 cm2 (1.5 × 1.5 cm) in size were the best discriminating point between malignant or granulomatous lymph node enlargement and other causes of lymph node disease. Patients with lymph nodes ≤1.0 cm2 should be observed after exclusion of infectious mononucleosis and/or toxoplasmosis, unless the patient has signs and symptoms of systemic disease.
The texture of lymph nodes may be described as soft, firm, rubbery, hard, separated, fused, indurated, mobile, or fixed. Compression of the lymph nodes may occur when their envelope is stretched during rapid enlargement, usually secondary to an inflammatory process. Some malignant diseases such as acute leukemia can cause rapid enlargement of lymph nodes resulting in pain. In lymphomas, lymph nodes tend to be large, isolated, symmetrical, rubbery, firm, mobile and painless. Lymph nodes in metastatic carcinoma are often firm, non-pressurized, and immobile because they are fixed to surrounding tissue. Co-magnification of the spleen and lymph nodes suggests a systemic disease such as infectious mononucleosis, lymphoma, acute or chronic leukemia, systemic lupus erythematosus, nodular disease, toxoplasmosis, cat-scratch fever, or other less common blood disorders. A medical history can provide useful clues to these systemic diseases.
Deep lymph node (chest or abdomen) enlargement is often found when a diagnostic test is made for symptoms. Enlarged thoracic lymph nodes may be detected during a routine chest radiograph or during a condition-based examination of superficial lymph nodes. Deep lymph node enlargement may also be found in patients with complaints of coughing and wheezing due to airway compression, hoarseness due to involvement of the recurrent laryngeal nerve, dysphagia due to esophageal compression, or swelling of the neck, face, or upper extremities secondary to compression of the superior vena cava or subclavian vein. The differential diagnosis of mediastinal and hilar lymph node enlargement includes disorders of primary origin in the lungs and systemic diseases characterized by mediastinal and hilar lymph node involvement. In young adults, mediastinal lymph node enlargement is associated with lymphoma, infectious mononucleosis, and nodular disease. In endemic areas, histoplasmosis may involve unilateral paratracheal lymph nodes and is similar to lymphoma. In older patients, the differential diagnosis should include primary lung cancer (especially in smokers), lymphoma, metastatic cancer (usually lung cancer), tuberculosis, fungal infection, and nodular disease.
Enlarged abdominal or retroperitoneal lymph nodes are usually malignant. Although tuberculosis can present as tethered lymphadenitis, these masses are usually lymphomas or germ cell tumors in young adults.
Laboratory tests The history and physical examination of the patient with enlarged lymph nodes are used to infer the possible etiology and to further select laboratory tests purposefully. A clinical study investigated 249 young patients with swollen lymph nodes that were not infected or lymphadenopathy, of which 51% did not undergo laboratory testing. If laboratory tests were used, the most common were complete blood count (33%), pharyngeal swab culture (16%), and chest x-ray (12%). Lymph node biopsies were performed in only 8 patients (3%), half of which were normal or reactive. A complete blood count can provide useful clues for the diagnosis of acute or chronic leukemia, EBV or CMV mononucleosis, leukemic-phase lymphoma, septic infection, or systemic lupus erythematosus, which cause immunocytopenia. Serological tests can detect specific antibodies to EBV, CMV, HIV and other viruses; Toxoplasma gondii, Borrelia burgdorferi and others. If SLE is suspected, anti-nuclear and anti-DNA antibodies must be checked.
Chest X-rays are usually negative, but in tuberculosis, histoplasmosis, nodal disease, lymphoma, primary lung cancer, or metastatic cancer pulmonary invasion or mediastinal lymph node enlargement may be present and require further investigation.
A variety of imaging techniques (CT, MRI, ultrasound, Doppler ultrasonography) have been used to identify benign and malignant lymph nodes, especially in patients with head and neck cancer. CT and MRI have equal accuracy (65% to 90%) for the diagnosis of cervical lymph node metastases. Ultrasound is used to measure the long axis, short axis, and long-short axis ratio (L/S) of cervical lymph nodes. The L/S ratio <2.0 has 95% sensitivity and specificity in differentiating benign and malignant lymph nodes in patients with head and neck tumors. This ratio has a higher sensitivity and specificity than palpation and simple measurement of long or short axis.
Although the indications for lymph node biopsy are unclear, it is a valuable diagnostic tool. Biopsy may be performed at the time of initial diagnosis or delayed until 2 weeks, and should be performed immediately if the history and physical examination suggest malignancy, such as isolated, firm, painless cervical lymph node enlargement in an elderly patient who is a long-term smoker; supraclavicular lymph node enlargement; and isolated or generalized lymph node enlargement that is firm and mobile, suggesting lymphoma. If an isolated, hard cervical lymph node is suspected to be a primary head and neck cancer, a careful ear, nose and throat examination should be performed. Any mucosal lesion suspected to be cancerous should be biopsied first. If no mucosal lesion is found, the largest lymph node should be taken for biopsy. Fine needle aspiration should not be chosen for the initial diagnosis. Most diagnoses require more tissue than fine needle aspiration, and fine needle aspiration often delays the diagnosis. Fine needle aspiration may still be indicated in patients with a clear primary diagnosis of thyroid nodules and in patients with recurrence. If the first physician is unsure whether to perform a biopsy, a hematologist or clinical oncologist can be consulted for assistance. Less than 5% of patients with enlarged lymph nodes require biopsy at the time of initial consultation. The percentage of lymph node biopsies in clinical patients in hematology, oncology, or otolaryngology is quite high.
Two groups reported methods to more accurately determine the need for biopsy in patients with enlarged lymph nodes. They were both retrospective analyses of clinics. The first study selected patients aged 9 to 25 years who had undergone biopsy and identified 3 variables to predict these patients with enlarged peripheral lymph nodes who were ready for biopsy; lymph node diameter >2 cm or radiographic abnormalities were positive predictors, while recent ear, nose, and throat symptoms were negative predictors. The second study examined 220 patients with enlarged lymph nodes and identified five variables [lymph node size, location (supraclavicular or non-supraclavicular), age (≥40 or <40 years), texture (not hard or hard) and tenderness]. They were determined by a mathematical model for these patients requiring biopsy. Positive predictive values were age ≥40 years, located on the supraclavicular bone, lymph nodes >2.25 cm2, hard, and without tenderness; negative predictive values were age <40 years, lymph nodes <1.0 cm2, not hard, and with tenderness or pain. Ninety-one percent of these patients requiring biopsy could be correctly classified by this model. Because both studies were retrospective analyses and one study was limited to young adults, the utility of applying these models to first-time patients has yet to be further determined.
Most patients with enlarged lymph nodes do not require biopsy, and at least half of them do not require laboratory testing. If the history and physical examination suggest benign lymph node enlargement, the patient can be followed for 2 to 4 weeks. Patients should be advised to follow up if their lymph nodes increase in size. Antibiotics are not indicated for lymphadenopathy unless there is strong evidence of bacterial infection. Because the lympholytic effect of glucocorticoids can interfere with the diagnosis of some diseases (lymphoma, leukemia, Castleman’s disease) and delay treatment or activate potential infection, they are not used in the treatment of enlarged lymph nodes. An exception to this is the life-threatening condition of enlarged lymphoid tissue in Waldeyer’s ring that obstructs the pharynx, which occurs most often in infectious mononucleosis.