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Evaluation of peripheral lymphadenopathy in adults

Evaluation of peripheral lymphadenopathy in adults
Literature review current through: Jan 2024.
This topic last updated: Apr 04, 2022.

INTRODUCTION — Peripheral lymphadenopathy without an obvious cause after the history and physical examination presents a diagnostic dilemma. There are many potential causes. Although biopsy is sometimes the best way to reach a definitive diagnosis, it should be used judiciously.

The general approach to the adult patient with peripheral lymphadenopathy is reviewed here. The evaluation and differential diagnosis of neck masses is presented separately. Evaluation and treatment of lymphadenopathy in children is also discussed separately. (See "Evaluation of a neck mass in adults" and "Differential diagnosis of a neck mass" and "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach" and "Cervical lymphadenitis in children: Diagnostic approach and initial management" and "Peripheral lymphadenopathy in children: Etiology" and "Evaluation of inguinal swelling in children".)

ANATOMY AND DEFINITIONS — The location of peripheral lymph node groups is shown schematically in the figures (figure 1 and figure 2). Normal lymph nodes are usually less than 1 cm in diameter and tend to be larger in adolescence than later in life.

A clinically useful approach is to classify lymphadenopathy as localized when it involves only one region, such as the neck or axilla, and generalized when it involves more than one region [1].

ETIOLOGIES — Lymphadenopathy can be caused by a vast array of diseases (table 1) and drugs (table 2) [2,3]. The location of lymphadenopathy can often be used to help identify specific etiologies (table 3).

Localized lymphadenopathy

Cervical — The anterior cervical lymph nodes are either superficial or deep to the sternocleidomastoid muscle and the posterior cervical nodes are posterior to the sternocleidomastoid muscle and anterior to the trapezius muscle (figure 2). The anterior cervical lymph nodes are often enlarged because of one of a variety of infections of the head and neck or due to some systemic infections such as Epstein-Barr virus (EBV), cytomegalovirus infection, or toxoplasmosis. Posterior cervical lymphadenopathy may occur with EBV infection, tuberculosis, lymphoma, or head and neck malignancy (either lymphomas or metastatic squamous cell carcinoma). (See "Clinical manifestations and treatment of Epstein-Barr virus infection" and "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults", section on 'CMV mononucleosis' and "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis", section on 'Clinical manifestations' and "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Lymphadenopathy'.)

Infection with Mycobacterium tuberculosis or atypical mycobacteria is suggested when multiple enlarged cervical nodes develop over weeks to months and become fluctuant or matted without significant inflammation or tenderness, and it is occasionally associated with fever. Tuberculous adenitis is usually regional (except in cases of miliary tuberculosis) and mainly affects nodes of the head and neck [4]. Infection with Bartonella henselae, the agent of cat scratch disease, can also present as multiple enlarged cervical lymph nodes. (See "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis" and "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease".)

Hard cervical lymph nodes, particularly in older patients and smokers, suggest metastatic head and neck cancer (eg, oropharynx, nasopharynx, larynx, thyroid, or esophagus).

Preauricular — The preauricular nodes drain the conjunctiva, portions of the auricle and external ear canal, and the anterior and temporal scalp. They are commonly enlarged in conjunctivitis caused by viral or bacterial pathogens. The “Parinaud oculoglandular syndrome” refers to an uncommon unilateral granulomatous conjunctivitis affecting the bulbar or palpebral conjunctivae. Cat scratch disease accounts for most cases, though other bacterial and fungal causes are less commonly identified [5].

Postauricular — These nodes (along with sub-occipital nodes) commonly enlarge and become tender in rubella infection. The adenopathy can precede the rash. Most commonly, however, enlargement of this node group is noted in bacterial or fungal infections of the parieto-temporal scalp.

Suboccipital — The nodes receive drainage from the posterior scalp and are commonly involved in bacterial or fungal infections [6].

Supraclavicular — Supraclavicular lymphadenopathy (figure 1) is associated with a high risk of malignancy. In two studies, malignancy was found in 34 and 50 percent of patients with this presentation; the risk was highest in those over the age of 40 [7,8]. Right supraclavicular adenopathy is associated with cancer in the mediastinum, lungs, or esophagus. Left supraclavicular adenopathy ("Virchow's node") suggests abdominal malignancy (eg, stomach, gallbladder, pancreas, kidneys, testicles, ovaries, lymphoma, or prostate) [9].

Axillary — The axillary nodes (figure 1) receive drainage from the arm, thoracic wall, and breast. Infections, including cat scratch disease, are common causes of axillary lymphadenopathy. (See "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease".)

In the absence of upper-extremity lesions, cancer is often found [10,11]. In one series of 31 patients with isolated axillary masses, nine had breast cancer (five in the contralateral breast) and nine had metastases from other sites [10]. Patients with a malignant pathology were older than those with a benign pathology.

Silicone breast implants can cause supraclavicular and axillary lymphadenopathy; regional nodes have an inflammatory, foreign body reaction to silicone particles [12].

Epitrochlear — The epitrochlear nodes (figure 1) are not normally palpable [13]. Palpable epitrochlear nodes are always pathologic. The differential diagnosis includes infections of the forearm or hand, lymphoma, sarcoidosis, tularemia, and secondary syphilis. (See "Tularemia: Clinical manifestations, diagnosis, treatment, and prevention", section on 'Clinical manifestations' and "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Secondary syphilis' and "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Lymphadenopathy' and "Overview of extrapulmonary manifestations of sarcoidosis".)

Inguinal — Lymph nodes are often palpable in the inguinal region in healthy people, perhaps because chronic trauma and infection is so common in the lower extremities. Inguinal lymphadenopathy (figure 1) is usually caused by lower-extremity infection, sexually transmitted diseases (such as chancroid, lymphogranuloma venereum, genital herpes, syphilis), or cancer. In one series of 2232 patients with malignant inguinal nodes, the primary site in descending order of frequency was skin of the lower extremities; cervix; vulva; skin of the trunk; rectum and anus; ovary; and penis [14]. (See "Chancroid", section on 'Lymphadenopathy' and "Lymphogranuloma venereum", section on 'Secondary infection' and "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Primary infection' and "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Secondary syphilis'.)

Generalized — Generalized lymphadenopathy may be a feature of a number of systemic diseases, many of which are recognized by other clinical findings. The following are some common or especially important diseases.

HIV infection Lymphadenopathy is common in primary human immunodeficiency virus (HIV) infection. Nontender adenopathy primarily involving the axillary, cervical, and occipital nodes develops in the majority of individuals during the second week of acute symptomatic HIV infection, concomitant with the emergence of a specific immune response to HIV [15]. The nodes decrease in size following the acute presentation, but a modest degree of adenopathy tends to persist. (See "Acute and early HIV infection: Pathogenesis and epidemiology".)

Mycobacterial infection Mycobacterial infections can present with lymphadenopathy alone, especially in the neck (scrofula). M. tuberculosis is the usual cause in adults; other mycobacteria, such as M. avium complex and M. scrofulaceum, account for most cases in children [16,17] (see "Tuberculous lymphadenitis"). Nodes are typically nontender, enlarge over weeks to months without prominent systemic symptoms, and can progress to matting and fluctuation.

Miliary tuberculosis is an important consideration in patients with generalized lymphadenopathy. This infection can be mistaken for malignancy. (See "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis" and "Epidemiology and pathology of miliary and extrapulmonary tuberculosis".)

Infectious mononucleosis Classic infectious mononucleosis is characterized by the triad of moderate to high fever, pharyngitis, and lymphadenopathy. Lymph node involvement is typically symmetric and involves the posterior cervical more than the anterior chain (figure 2).

Lymphadenopathy may also be present in the axillary and inguinal areas, which helps to distinguish infectious mononucleosis from other causes of pharyngitis. Nodes are kidney-shaped and may be large. Lymphadenopathy peaks in the first week and then gradually subsides over two to three weeks. (See "Infectious mononucleosis".)

Infectious causes of heterophile-negative, mononucleosis-like illnesses include cytomegalovirus, human herpesvirus 6, HIV, adenovirus, herpes simplex virus, Streptococcus pyogenes, and Toxoplasma gondii [18].

Systemic lupus erythematosus Enlargement of lymph nodes occurs in approximately 50 percent of patients with systemic lupus erythematosus (SLE). The nodes are typically soft, nontender, and discrete, varying in size from 0.5 to several centimeters, and are usually detected in the cervical, axillary, and inguinal areas. Lymphadenopathy is more frequently noted at the onset of disease or in association with an exacerbation. Lymph node enlargement can also be the result of infection or a lymphoproliferative disease in SLE; when infections are present, the enlarged nodes are more likely to be tender. (See "Hematologic manifestations of systemic lupus erythematosus".)

Medications – A number of medications can cause serum sickness that is characterized by fever, arthralgias, rash, and generalized lymphadenopathy (table 2). Phenytoin can cause generalized lymphadenopathy in the absence of a serum sickness reaction. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)

Sarcoidosis Sarcoidosis most frequently involves the lung, but up to 30 percent of patients present with extrathoracic manifestations of sarcoidosis (table 4) [19-22]. Peripheral lymphadenopathy is present in up to 40 percent of patients. Patients with sarcoidosis also often have lymphadenopathy seen on imaging (most often hilar and/or paratracheal mediastinal). Common presenting respiratory symptoms include cough, dyspnea, and chest pain; these are frequently accompanied by fatigue, malaise, fever, and weight loss. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Typical presentations' and "Overview of extrapulmonary manifestations of sarcoidosis".)

Lymphoma Hodgkin or non-Hodgkin lymphoma may present with painless, firm, peripheral lymphadenopathy, although most patients with Hodgkin lymphoma present with neck (cervical and/or supraclavicular) lymphadenopathy. Waxing and waning peripheral lymphadenopathy may represent indolent lymphomas. Many patients with lymphoma present with isolated adenopathy on exam; other sites of nodal involvement may be identified on subsequent imaging. (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults", section on 'Lymphadenopathy' and "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Lymphadenopathy'.)

Uncommon causes — Lymphadenopathy is a central feature of a number of rare systemic diseases. The clinical presentation may suggest one of the following diseases, but biopsy is usually required for diagnosis.

Castleman’s disease Angiofollicular lymph node hyperplasia (Castleman's disease) is an uncommon lymphoproliferative disorder characterized by massive lymphadenopathy and systemic features such as fever, hepatomegaly, splenomegaly, polyclonal hypergammaglobulinemia, and, rarely, amyloidosis [23,24]. Localized disease is successfully treated by excision; the multicentric form is usually fatal without some form of chemotherapy. (See "HHV-8/KSHV-associated multicentric Castleman disease".)

Kikuchi’s disease – Kikuchi's disease is a rare, benign condition of unknown cause occurring most commonly in young women, and it is usually characterized by cervical lymphadenopathy (although it may be more generalized) and fever [25-27]. Histologic examination of pathologic nodes shows a broad spectrum of abnormalities that can be confused with lymphoma [28]. (See "Kikuchi disease".)

Kawasaki disease – Kawasaki disease, though an uncommon illness, is the most frequent cause of childhood vasculitis. This syndrome is associated with fever, cervical lymphadenopathy, and a variety of other symptoms including conjunctivitis, mucositis, rash, and coronary artery aneurysms [29]. (See "Kawasaki disease: Epidemiology and etiology".)

Angioimmunoblastic T cell lymphoma Angioimmunoblastic T-cell lymphoma (also called angioimmunoblastic lymphadenopathy) is a systemic disease characterized by generalized lymphadenopathy, fever, hepatosplenomegaly, hemolytic anemia, and polyclonal hypergammaglobulinemia [30]. Most cases (80 percent) follow an aggressive course. Lymph nodes show neovascularization and infiltration with immunoblasts and plasma cells. (See "Clinical manifestations, pathologic features, and diagnosis of angioimmunoblastic T cell lymphoma".)

Inflammatory pseudotumor Inflammatory pseudotumor of lymph nodes is a syndrome of lymphadenopathy in one or more node groups, often with systemic symptoms. Nodes show a fibrosing and inflammatory process [31].

Amyloidosis Amyloid can be deposited in lymph nodes and is a rare cause of lymphadenopathy in the absence of amyloid infiltration of other organs [32,33]. (See "Overview of amyloidosis".)

Kimura disease Kimura disease is an inflammatory condition involving the subcutaneous tissue and lymph nodes of the head and neck, often with associated elevations in serum immunoglobulin E levels and eosinophilia [34]. (See "Eosinophil biology and causes of eosinophilia", section on 'Disorders with eosinophilic involvement of specific organs'.)

Progressive transformation of germinal centers – Progressive transformation of germinal centers (PTGC) is an uncommon condition, often presenting as unexplained, asymptomatic, persistent or recurrent lymphadenopathy. It is more common in men (3:1), presenting most often in the head and neck area [35-37]. (See "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging", section on 'Progressive transformation of germinal centers'.)

PTGC is characterized by the presence in a lymph node of one or more nodules three to five times the size of a typical reactive follicle, with a predominance of small mantle zone B cells, as well as disruption and eventual replacement of the germinal center [37,38]. While PTGC and nodular lymphocyte predominant Hodgkin lymphoma are often associated, and some patients with PTGC may develop lymphoma at a later date, PTGC is not considered to be a premalignant condition. It may be associated with chronic inflammatory or autoimmune conditions.

Rosai-Dorfman disease Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) is a condition characterized by massive accumulation of histiocytes in lymph nodes, usually in the neck. Histiocytes may accumulate outside lymph nodes as well (eg, in bone, lungs, skin). The disease is usually self-limited but can cause complications related to pressure at the site of accumulation and hemolytic anemia [39]. (See "Peripheral lymphadenopathy in children: Etiology", section on 'Rosai-Dorfman disease'.)

IgG4-related disease – Immunoglobulin G4 (IgG4)-related disease is a multi-organ immune-mediated condition that involves tumor-like swelling of involved organs and characteristic histologic findings upon biopsy, including infiltration with IgG4-positive plasma cells and a specific pattern of fibrosis. It most commonly occurs in middle-aged and older men. Lymphadenopathy associated with IgG4-related disease is usually either generalized or localized to an adjacent involved organ. Diagnosis of IgG4-related disease from a lymph-node biopsy can be difficult because the lymph nodes often lack the degree of fibrosis seen in other affected organs.

EVALUATION — A history and focused physical examination will most often lead to a differential diagnosis of peripheral lymphadenopathy, which will then inform the need for further evaluation (eg, laboratory evaluation, imaging, and/or biopsy).

History — The history in a patient with lymphadenopathy should focus upon the following [1]:

Localizing signs or symptoms suggesting infection or malignancy.

Exposures likely to be associated with infection (eg, cat scratches [cat scratch disease], undercooked meat [toxoplasmosis], tick bite [Lyme disease]), travel to areas with high rates of endemic infection, high-risk behavior (eg, sexual behavior, injection drug use) (table 5).

Constitutional symptoms such as fever, night sweats, or weight loss suggesting tuberculosis, lymphoma, or other malignancy; fever typically accompanies lymphadenopathy for the majority of the infectious etiologies. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Systemic "B" symptoms'.)

Use of medications that can cause lymphadenopathy (table 2).

Foreign travel, which should extend the differential diagnosis to diseases that do not otherwise occur locally (table 5).

The time course of the adenopathy also can help narrow the diagnostic possibilities. However, patients may not notice when enlargement first occurs, even in obvious places like the neck.

Physical examination — Evaluating nodes’ symmetry from left and right sides is helpful in distinguishing enlarged nodes in a given patient. It is important, after identifying abnormal nodes in one location, to examine other locations to exclude generalized adenopathy (figure 1 and figure 2). All lymph node groups should be examined with the following characteristics in mind:

Location – Localized lymphadenopathy suggests local causes and should prompt a search for pathology in the area of node drainage, although some systemic diseases such as plague, tularemia, and aggressive lymphomas can present with local adenopathy. Generalized adenopathy is usually a manifestation of systemic disease. (See "Clinical manifestations, diagnosis, and treatment of plague (Yersinia pestis infection)" and "Tularemia: Clinical manifestations, diagnosis, treatment, and prevention" and "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Hodgkin lymphoma: Epidemiology and risk factors".)

The drainage basin (figure 1) of the affected lymph node(s) should be carefully examined for a skin lesion. The differential diagnosis of a skin lesion with associated adenopathy can usually be narrowed on the basis of context (eg, environmental exposures from a patient’s activities or area of residence). Examples include exposure to cats (cat scratch disease), gardening (Sporotrichosis), mites in urban areas (Rickettsialpox), tick bites (ulceroglandular tularemia), and water exposures (Mycobacterium marinum). (See "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease", section on 'Clinical manifestations' and "Rickettsialpox", section on 'Clinical manifestations' and "Tularemia: Clinical manifestations, diagnosis, treatment, and prevention", section on 'Ulceroglandular disease' and "Soft tissue infections following water exposure", section on 'Clinical evaluation' and "Clinical features and diagnosis of sporotrichosis", section on 'Nodular lymphangitis'.)

Size – Abnormal nodes are generally greater than 1 cm in diameter. In one series, no patient with a lymph node smaller than 1 cm2 had cancer, compared with 8 and 38 percent of those with nodes 1 to 2.25 and greater than 2.25 cm2, respectively [40]. The term "shotty" is sometimes used to describe multiple, small nodes, but has no particular diagnostic significance.

Consistency – Hard nodes are found in cancers that induce fibrosis (scirrhous changes) and when previous inflammation has left fibrosis. Firm, rubbery nodes are found in lymphomas and chronic leukemia; nodes in acute leukemia tend to be softer.

Fixation – Normal lymph nodes are freely movable in the subcutaneous space. Abnormal nodes can become fixed to adjacent tissues (eg, deep fascia) by invading cancers or inflammation in tissue surrounding the nodes. They can also become fixed to each other ("matted") by the same processes.

Tenderness – Tenderness suggests recent, rapid enlargement that has put pain receptors in the capsule under tension. This typically occurs with inflammatory processes but can also result from hemorrhage into a node, immunologic stimulation, and malignancy.

A complete physical examination should also be performed to look for signs of systemic disease. For example, associated splenomegaly suggests lymphoma, chronic lymphocytic leukemia, acute leukemia, or infectious mononucleosis.

Laboratory testing — Laboratory studies may be helpful to evaluate or confirm suspected diagnoses based on the history and physical. (See 'Diagnostic approach' below.)

Imaging — Radiologic tests can define node size and distribution more precisely than physical examination. Imaging tests are helpful if it is not clear after physical examination that there is lymphadenopathy and/or to evaluate surrounding structures for abnormalities. Imaging by computed tomography (CT), ultrasound, Doppler technology, or magnetic resonance imaging (MRI) can help distinguish enlarged lymph nodes from other structures and define the pathologic process, especially cystic changes [41-43]. Imaging can provide clues to diagnosis but usually cannot replace biopsy [44].

Additionally, specific imaging studies may be appropriate to assess for malignancy in certain patients. For example, in an older woman with axillary lymphadenopathy, evaluation for breast cancer may be appropriate. (See 'Concern for malignancy' below and "Diagnostic evaluation of suspected breast cancer".)

Lymph node biopsy — The need for biopsy will vary depending on the suspected etiology/etiologies based on the history and physical examination and whether or not the peripheral lymphadenopathy is localized or generalized. (See 'Diagnostic approach' below.)

Several options are available for direct examination of abnormal lymph nodes. The mode of biopsy will depending on where the lymphadenopathy is located and suspected diagnoses.

Open biopsy – Open biopsy allows histologic examination of intact tissue and provides information about both the presence of abnormal cells (carcinoma, microorganisms) and abnormal node architecture, which is useful for the diagnosis of lymphomas. False negative results occur when the wrong node is taken. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Lymph node and tissue biopsy'.)

Biopsy is usually performed without hospital admission and under local anesthesia. The most abnormal node is selected if multiple node groups are involved. If no single node predominates, the choice in descending order of preference is supraclavicular, neck, axilla, and groin since the chances of a nonspecific result are greatest with axillary and inguinal nodes, and the frequency of the main complications of lymph node biopsy, infection, and damage to the neurovascular structures is higher in the groin and axilla. There are more vital structures in the neck, but they are relatively easily identified and avoided during surgery.

The pathologist should know in advance that there will be a lymph node biopsy, so that the proper smears, stains and cultures will be done. Many of these techniques require unfixed specimens, and it may be difficult for pathologists to distinguish benign follicular hyperplasia from lymphoma without them [45]. As an example, when lymphoma is suspected, special studies using immunohistochemical, cytogenetic, and molecular genetic techniques should be anticipated before obtaining the specimen. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Lymph node and tissue biopsy'.)

Fine-needle aspiration for cytology – Fine-needle aspiration for cytology is most useful when searching for recurrence of cancer. False-positive results are uncommon, but there is a substantial false-negative rate because of sampling error [8,46]. Lack of information on tissue architecture is a specific problem with this technique when lymphoma is suspected. In one study, only 27 of 93 (27 percent) fine-needle aspiration attempts for initial diagnosis of lymphoma yielded a specific and complete histologic diagnosis [47].

Core needle biopsy – Classification of lymphoma increasingly depends on immunophenotypic, genetic, and molecular features of the tumor, in addition to tissue architecture. Core needle biopsy provides tissue for special studies and some information on nodal architecture and is a relatively low-morbidity, inexpensive alternative to open biopsy in patients with suspected lymphoma in whom an intact node is not easily accessible [48]. Open biopsy may be needed if the core biopsy suggests lymphoma.

DIAGNOSTIC APPROACH — The cause of lymphadenopathy is often obvious or suspected after a complete history and physical examination. The diagnostic approach will differ depending on the concerns or suspected diagnosis based on the history and physical examination. (See 'Etiologies' above and 'History' above and 'Physical examination' above.)

Non-malignant cause likely — The cause of lymphadenopathy is often obvious after a complete history and physical examination (table 5). When history and physical examination suggests a non-malignant cause, appropriate testing may be used to confirm a suspected diagnosis. However, some patients may not need any testing (eg, patients with cervical lymphadenopathy in the setting of a viral upper respiratory infection). Patients with specific or suspected non-malignant cause can be advised to follow up if the lymphadenopathy persists after resolution of illness/appropriate treatment.

Concern for malignancy — In patients with lymphadenopathy, the probability of an underlying carcinoma, especially head, neck, and breast, rises rapidly with age. In one study, the risk of malignancy was 4 percent in patients older than 40 and 0.4 percent in younger patients [7]. In a population-based, case-control study of teenagers and young adults, the risks of leukemia and lymphoma in patients with lymphadenopathy were 0.15 and 0.28 percent respectively [49].

However, patients of any age in whom there is a concern for malignancy based on characteristics of the lymph node (eg, firm node, rapid increase in size of the node, or location such as supraclavicular nodes), symptoms (eg, systemic complaints of fever, night sweats, weight loss), and/or patient characteristics (eg, firm cervical nodes in older patients who are smokers, axillary nodes in older women) should have appropriate evaluation for malignancy.

These patients should have imaging for further evaluation (specific imaging will depend on suspected malignancy) and should be referred for biopsy (of the lymph node and/or other suspicious structure). (See 'Lymph node biopsy' above.)

Unexplained lymphadenopathy — Peripheral lymphadenopathy without an obvious cause after the history and physical examination presents a diagnostic dilemma. When lymphadenopathy is unexplained after the history and physical, the subsequent workup depends upon whether the adenopathy is localized or generalized. (See 'Localized lymphadenopathy' below and 'Generalized lymphadenopathy' below.)

Localized lymphadenopathy — In patients with localized lymphadenopathy without history or physical examination findings to suggest malignancy, we check a complete blood count (CBC), as well as targeted laboratory studies based upon the patient’s age, history, and risk factors or exposures (table 5). As examples:

In a young patient with recent fever, adenopathy, and sore throat, a CBC with differential, heterophile Ab, and immunoglobulin M for cytomegalovirus and toxoplasmosis would be ordered.

An adult with adenopathy, fever, weight loss, and night sweats would be initially evaluated with a CBC with differential, chest radiograph, and tuberculin skin test.

Adenopathy in the drainage area of an associated skin ulcer would trigger specific tests depending on the circumstances: sporotrichosis in a gardener, tularemia in a hunter or hiker, or Mycobacterium marinum in a fisherman.

When adenopathy of scalp-draining nodes occurs in the setting of patchy or diffuse alopecia, secondary syphilis should be considered [50].

If no etiology is identified, patients can be observed for three to four weeks. They should be advised to return sooner if they develop new symptoms, notice rapid changes in the lymph node, or develop other lymphadenopathy during this time.

Biopsy is appropriate if an abnormal node has not resolved after four weeks. This approach is safe and avoids unnecessary biopsies since the adenopathy will resolve or the cause will become obvious in many patients during that time. Even with "can't miss" diagnoses such as Hodgkin lymphoma, head and neck cancer, or tuberculosis, the window of opportunity for effective treatment is likely to remain open during this period of observation.

Many patients with unexplained lymphadenopathy (and their clinicians) are concerned about the possibility of malignancy. Many such studies from referral centers are based on case series of node biopsies, however, and therefore overestimate the risk of malignancy in patients presenting to primary care, only a small fraction of whom are sent for biopsy. The prevalence of malignancy in lymph node biopsies performed in referral centers approaches 60 percent [51-53]. In a setting where patients were referred from primary care providers, the prevalence of malignancy was 17 percent [8]. However, in a typical primary care practice, the prevalence is much lower. As an example, a retrospective study of patients presenting to a family clinician with unexplained lymphadenopathy found that only 1.1 percent of nodes were malignant [7]. This Dutch study estimated the annual incidence of unexplained lymphadenopathy at 0.6 percent in the general population, of whom 10 percent were referred to a subspecialist, 3.2 percent required a biopsy, and 1.1 percent were diagnosed with a malignancy. Two case series of patients with adenopathy from primary care support this low prevalence [54,55].

Generalized lymphadenopathy — The evaluation of patients with generalized lymphadenopathy without suspected diagnosis based on history and physical examination should start with a CBC, chest radiograph, and human immunodeficiency virus (HIV) testing. If these are normal, other considerations include testing for tuberculosis and syphilis, antinuclear antibody (ANA), and heterophile test, although these are often of low yield in the absence of a more specific indication. If the diagnosis is still uncertain, a biopsy of the most abnormal node should be obtained. (See 'Lymph node biopsy' above.)

SUMMARY AND RECOMMENDATIONS

Definition and classification of lymphadenopathy – The location of peripheral lymph node groups is shown schematically in the figures (figure 1 and figure 2). A clinically useful approach is to classify lymphadenopathy as localized when it involves only one region (such as the neck or axilla) and generalized when it involves more than one region. Normal lymph nodes are usually less than 1 cm in diameter and tend to be larger in adolescence than later in life. (See 'Anatomy and definitions' above.)

Etiologies – Lymphadenopathy can be caused by a vast array of diseases (table 1) and drugs (table 2). The location of lymphadenopathy can often be used to help identify specific etiologies (table 3). (See 'Etiologies' above.)

Evaluation – A history and focused physical examination will most often lead to a differential diagnosis of peripheral lymphadenopathy, which will then inform the need for further evaluation (eg, laboratory evaluation, imaging, and/or biopsy). (See 'Evaluation' above.)

Diagnostic approach – The diagnostic approach will differ depending on the concerns or suspected diagnosis based on the history and physical examination.

When history and physical examination suggests a non-malignant cause, appropriate testing may be used to confirm a suspected diagnosis (table 5). (See 'Non-malignant cause likely' above.)

Patients in whom there is a concern for malignancy should have appropriate evaluation for malignancy. (See 'Concern for malignancy' above.)

Peripheral lymphadenopathy without an obvious cause after the history and physical examination presents a diagnostic dilemma.

Patients with localized lymphadenopathy can be observed for three to four weeks if there is nothing else in the history, physical examination, and laboratory screening to suggest malignancy. Biopsy is appropriate if an abnormal node has not resolved after four weeks. (See 'Localized lymphadenopathy' above.)

The evaluation of patients with generalized lymphadenopathy without suspected diagnosis based on history and physical examination should start with a complete blood count (CBC), chest radiograph, and human immunodeficiency virus (HIV) testing. (See 'Generalized lymphadenopathy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert Fletcher, MD, who contributed to an earlier version of this topic review.

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Topic 8386 Version 33.0

References

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