Primary Care Medicine: Office Evaluation and Management of the Adult Patient
6th Edition
© 2009 Lippincott Williams & Wilkins
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Chapter 12
Evaluation of Lymphadenopathy
Of the nearly 600 lymph nodes throughout the body, only a few are normally palpable, including small nodes in the submandibular, axillary, and inguinal regions. Nevertheless, lymphadenopathy is a very common presenting symptom. Most often, adenopathy indicates benign, self-limited disease; this is particularly true in children and young adults, who are more prone to reactive lymphatic hyperplasia. Despite this, patient concern is often substantial because of worry about serious infectious processes (e.g., AIDS) on one hand and neoplastic diseases on the other. A systematic evaluation of lymphadenopathy will provide both reassurance and a correct diagnosis. A critical decision for the primary physician is when to refer the patient for a lymph node biopsy.
Pathophysiology and Clinical Presentation (1,2,3,4,5)
Pathophysiology
As part of the lymphoreticular system, normal lymph nodes play an essential role in host defense, often reacting to threat with a hyperplastic response that usually resolves within 1 month of resolution of the underlying stimulus. Sometimes, a degree of hyperplasia may persist leaving some residual enlargement, especially if the nodal response was marked or the stimulus was severe or prolonged. Pathologic enlargement ensues when inflammation or infiltration overtakes the node. If the underlying disease is well localized, the accompanying adenopathy tends to be focal and limited to the area of involvement. If the illness is widespread or systemic, generalized adenopathy may ensue.
Clinical Presentation
Size and Quality
Most nodes are not normally palpable in healthy individuals, except for the small lymph nodes in the neck, axilla, and groin. Palpable nodes in other regions or any node greater than 1 cm in size should be regarded as potentially abnormal, especially if they persist for more than 1 month in the absence of an obvious explanation. Size alone is not itself diagnostic of the underlying pathology, but nodes greater than 3 cm suggest neoplastic disease. The presentation of pathologic nodal enlargement can range from painless to tender, soft to hard, and mobile to fixed. Although soft, freely moveable nodes are more characteristic of nonmalignant nodal disease, early malignant involvement may present in similar fashion. Tenderness is not unique to adenopathy due to inflammation; rapidly expanding malignant nodes and those with intranodal hemorrhage may also be painful, as may the nodes of Hodgkin’s disease after intake of alcohol.
Accompanying Symptoms
“B” symptoms (recurrent fevers >38.3°C, night sweats, weight loss) are characteristic of the lymphomas, especially Hodgkin’s disease, and carry a worse prognosis (see Chapter 84). Such symptoms may also occur in systemic infections. Fever alone can occur across the full spectrum of etiologies of lymphadenopathy. Lymphangetic streaking is a hallmark of infection in the area of drainage. Accompanying splenomegaly is limited to infectious mononucleosis, lymphomas, and lymphocytic leukemias.
Distribution
The location of the adenopathy is directly related to etiology.
Generalized
Widespread lymph node enlargement results from systemic processes, such as infection, malignancy, hypersensitivity, and sometimes even metabolic disease with node infiltration. The adenopathy associated with infection may be caused by the disease itself (e.g., HIV infection) or to secondary infection (e.g., with cytomegalovirus). It may result from an illness that first produces localized adenopathy (e.g., cat-scratch disease). At the intersection of neoplastic and reactive lymphadenopathy is Castleman’s disease, a rare, idiopathic, atypical lymphoproliferative disease that can be localized or multicentric. Its clinical presentation can mimic that of lymphoma and HIV disease. Localized disease has a benign clinical course, but multicentric disease produces disseminated lymphadenopathy, systemic symptoms, and an increased risk for infection and cancer.
Cervical
Most cervical adenopathy is a consequence of head or neck infection, but lymphomas (especially Hodgkin’s disease) have a predilection for beginning in the cervical or supraclavicular nodes. Submandibular nodal enlargement, perhaps the most common type of adenopathy, typically results from pharyngitis (viral, streptococcal, gonococcal) or oral cavity infection. Preauricular adenopathy may be a component of “occuloglandular fevers” due to adenoviral conjunctivitis, sarcoidosis, tularemia, cat-scratch disease, and other processes. Posterior auricular or posterior cervical adenopathy frequently reflects infections of the scalp but may also be prominent in systemic processes, such as rubella or toxoplasmosis.
Supraclavicular
Isolated supraclavicular node enlargement is indicative of lymphoma or metastatic cancer. The right supraclavicular nodes drain the mediastinum, esophagus, and thorax, whereas the left supraclavicular system (Virchow’s node)
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serves the thoracic duct, which conducts flow from the abdomen.
Axillary
Breast cancer is the chief concern, but nodes in the axilla also become enlarged in response to infection of the upper extremities.
Hilar
Bilateral hilar adenopathy in an asymptomatic patient raises the possibilities of sarcoidosis and fungal exposure. Unilateral hilar disease suggests lymphoma, cancer, and granulomatous disease, as does bilateral disease in a symptomatic patient or one with abnormal physical findings.
Abdominal
Most isolated mesenteric lymph node enlargement is due to adenocarcinoma of the gut. Isolated retroperitoneal adenopathy is a manifestation of Hodgkin’s disease, other lymphomas, metastatic adenocarcinoma, tuberculosis, bladder cancer, and leukemias. A palpable periumbilical abdominal node (the Sister Joseph nodule) is a noted sign of metastatic gastric adenocarcinoma.
Inguinal
Nodes in this area are often palpable in healthy persons, especially if they walk barefoot, but these nodes can enlarge substantially in infections of the genitalia or perineum and in infections of the lower extremities. Cancers are also important causes of inguinal adenopathy, particularly lymphoma, melanoma, and squamous cell carcinomas of the genitalia.
Epitrochlear
Enlargement of these nodes traditionally suggested the generalized adenopathy of secondary syphilis—the proverbial sailor’s handshake supposedly included a check for epitrochlear nodes—but topping the list of modern etiologies are lymphoma, chronic lymphocytic leukemia, infectious mononucleosis, and HIV infection, usually in the setting of more-generalized nodal involvement. Local hand infections may also trigger epitrochlear enlargement.
Other Lymphatic Abnormalities
In addition to lymphadenopathy, abnormalities of the lymphatic system may present in other ways. Lymphangitis, appearing as red, warm streaks along the course of superficial lymphatic networks, suggests an acute inflammatory response to pyogenic infection in the drainage area; staphylococci and streptococci are frequently responsible. Lymphadenitis, presenting as a tender, warm, soft, rapidly enlarging node, has a similar significance and often reflects acute pyogenic infection of the node itself. An idiopathic variant, necrotizing lymphadenitis (Kikuchi’s disease), causes self-limited tender cervical adenopathy. Lymphedema results from the interruption of lymphatic drainage; surgical node dissection, radiotherapy, or fibrosis caused by chronic infections such as filariasis or lymphogranuloma venereum are causes of lymphedema.
Differential Diagnosis (1,6)
The causes of lymphadenopathy can be conveniently considered in terms of location of the enlarged nodes (Table 12.1). In children and young adults, most adenopathy is a result of reactive hyperplasia and is less likely to represent serious pathology than it is in adults. In persons less than the age of 30 years, the cause proves to be benign in 80% of cases; in persons greater than age 50 years, the rate of benign disease falls to 40%.
Workup (1,2,6,7,8,9,10,11,12,13)
History and Physical Examination
A number of basic questions arise in the evaluation of lymphadenopathy, which can be readily addressed by a careful history and physical examination:
  • Is the palpable mass indeed a lymph node? A variety of other structures, including enlarged parotid glands, cervical hygromas, thyroglossal and branchial cysts, hemangiomas, abscesses, lipomas, and other tumors, may on occasion be confused with lymphadenopathy.
  • Is the lymphadenopathy acute or chronic? Clearly, lymph node enlargement resulting from acute viral or pyogenic infection becomes less likely as the days and weeks pass, and granulomatous inflammation (sarcoidosis, tuberculosis, fungal infection) and neoplastic disease become greater worries. Even so, chronicity alone is not always a harbinger of serious disease because on occasion reactive hyperplasia can persist for many months.
  • What is the character of the enlarged node itself? Tender, mobile nodes most often reflect lymphadenitis or lymphatic hyperplasia in response to acute inflammation. Firm, rubbery, nontender nodes may be found in lymphoma. Painless, stone-hard, fixed, matted nodes suggest metastatic carcinoma.
  • Is the adenopathy localized or generalized? Numerous systemic processes that include infections (e.g., infectious mononucleosis and other viral infections, toxoplasmosis, secondary syphilis), hypersensitivity reactions (serum sickness, reactions to phenytoin [Dilantin] and other drugs, and vasculitis, including systemic lupus erythematosus and rheumatoid arthritis), metabolic diseases (hyperthyroidism and various lipidoses), and neoplasia (especially leukemia) can produce generalized lymphadenopathy. However, Hodgkin’s disease is usually unicentric in origin and spreads to contiguous regional nodes, so that generalized adenopathy is rare except in very advanced disease. Although certain non-Hodgkin’s lymphomas may be multicentric, generalized adenopathy is also a late finding and is usually asymmetric, unlike the earlier and more symmetric adenopathy of some leukemias, such as chronic lymphocytic leukemia.
  • Are there associated systemic or localizing symptoms or signs? Fever, rash, weight loss, sore throat, dental pain, genital inflammation, and infections of the extremities are clues that may be particularly helpful. Of these symptoms, night sweats and weight loss suggest granulomatous and neoplastic disease. Ear, nose, and throat symptoms suggest reactive lymphatic hyperplasia secondary to viral or localized bacterial infection. A careful examination of the skin for a primary inoculation site may provide the clue to a diagnosis of cat-scratch disease or tularemia. A check for scalp infections, dermatophytes, and scabies is also needed. The liver and spleen are carefully examined; organomegaly may be an important clue for mononucleosis, sarcoidosis, or malignancy. Sternal tenderness may be present in leukemia.
  • Are there unusual epidemiologic clues? To cite some examples, in patients exposed to cats, cat-scratch disease or toxoplasmosis, which can also result from eating poorly cooked meat, may develop. Travel to the southwestern United States may suggest the possibility of plague. An appropriate travel history or exposure to bird droppings may suggest fungal infection, as may lacerations sustained during gardening in
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    the case of sporotrichosis. Contact with wild rodents can result in tularemia, as can tick bites. A history of exposure to tuberculosis may be an important clue to scrofula. More commonly, community outbreaks can provide clues to the diagnosis of streptococcal pharyngitis or rubella, whereas a history of sexual exposure may raise the question of gonorrhea, syphilis, genital herpes, or lymphogranuloma.
Table 12.1 Important Causes of Lymphadenopathy
Generalized Lymphadenopathy Localized Lymphadenopathy
Infections Anterior Auricular
   Mononucleosis    Viral conjunctivitis
   AIDS    Trachoma, posterior auricular
   AIDS-related complex    Rubella
   Toxoplasmosis    Scalp infection
   Secondary syphilis Submandibular or Cervical (Unilateral)
Hypersensitivity Reactions    Buccal cavity infection
   Serum sickness    Pharyngitis (can be bilateral)
   Phenytoin and other drugs    Nasopharyngeal tumor
   Vasculitis, lupus, rheumatoid arthritis    Thyroid malignancy
Metabolic Disease Cervical Bilateral
   Hyperthyroidism    Mononucleosis
   Lipidoses    Sarcoidosis
Neoplasia    Toxoplasmosis
   Leukemia    Pharyngitis
   Hodgkin’s disease (advanced stages) Supraclavicular, Right
   Non-Hodgkin’s lymphoma    Pulmonary malignancy
   Mediastinal malignancy
   Esophageal malignancy
Supraclavicular, Left
   Intraabdominal malignancy
   Renal malignancy
   Testicular or ovarian malignancy
Axillary
   Breast malignancy or infection
   Upper extremity infection
Epitrochlear
   Syphilis (bilateral)
   Hand infection (unilateral)
Inguinal
   Syphilis
   Genital herpes
   Lymphogranuloma venereum
   Chancroid
   Lower extremity or local infection
Any Region
   Cat-scratch fever
   Hodgkin’s disease
   Non-Hodgkin’s lymphoma
   Leukemia
   Metastatic cancer
   Sarcoidosis
   Granulomatous infections
Hilar Adenopathy, Bilateral
   Sarcoidosis
   Fungal infection (histoplasmosis, coccidioidomycosis)
   Lymphoma
   Bronchogenic carcinoma
   Tuberculosis
Hilar Adenopathy, Unilateral
   Lymphoma
   Bronchogenic carcinoma
   Tuberculosis
   Sarcoidosis
Laboratory Studies
Laboratory studies need not be very elaborate. A complete blood cell count with differential often provides useful information and is almost always indicated. For example, atypical lymphocytosis suggests mononucleosis, other viral infections, and toxoplasmosis; granulocytosis is indicative of pyogenic infection; eosinophilia raises the question of a hypersensitivity reaction; and pancytopenia is consistent with marrow suppression by tumor and HIV infection.
Other studies are based on the clinical presentation of the lymphadenopathy. A variety of blood chemistries may help in selected cases. Elevations of uric acid may reflect lymphoma or other hematologic malignancies. Serum liver chemistries (especially the alkaline phosphatase level) provide objective parameters to follow. Although such abnormalities are nonspecific, they do suggest liver involvement, which can be further evaluated by biopsy.
Localized Adenopathy
If pharyngitis and cervical or submandibular adenopathy are present, a throat culture is mandatory. It should be remembered that although these specimens are routinely processed for streptococci, a special Thayer–Martin medium also must be used if gonococci are suspected. Urethral or cervical cultures and smears should also be obtained if gonorrhea is a potential cause of inguinal lymphadenopathy. Blood cultures are indicated in the rare cases of suspected plague, tularemia, or brucellosis or if the clinical picture suggests staphylococcal or streptococcal lymphadenitis. Biopsy may be necessary to rule out lymphoma and Hodgkin’s disease if the adenopathy is progressive and the remainder of the workup is unrevealing (see later discussion).
On occasion, lymphomatous retroperitoneal or intraabdominal nodes may enlarge enough to present as an abdominal mass. When lymphoma is a serious possibility, or when staging is necessary in known lymphoma or Hodgkin’s disease, abdominal computed tomography (CT) can be used to detect enlargement of the retroperitoneal nodes; bone marrow biopsy may provide a tissue diagnosis (see Chapter 84).
Generalized Adenopathy
Serologic tests can be of great value. The heterophile test and serologic tests for syphilis are obvious examples. In addition, a serum sample from the acute phase of the illness can be frozen to be submitted with a later, convalescent-phase serum specimen for antibody titers against viruses, fungi, and toxoplasmosis. Brucellosis can also be diagnosed serologically. Serologic tests, including those for antinuclear antibodies and rheumatoid factor, may suggest a noninfectious process, such as collagen vascular disease.
Hilar Adenopathy
Tuberculin skin testing with purified protein derivative (PPD) and the angiotensin-converting enzyme (ACE) determination can facilitate the assessment. If the results of both are negative and the patient is white, then bronchoscopy and mediastinoscopy may be necessary to rule out lymphoma. If the patient is ACE-positive and PPD-negative, then the probability is very high that sarcoidosis is the cause, and there is little need for further evaluation. If the patient is ACE-negative and PPD-positive, then primary tuberculosis is likely. Reliable skin tests are also available for coccidioidomycosis and tularemia. On the other hand, cutaneous anergy may suggest sarcoidosis or lymphoma, but this is a nonspecific finding. Skin testing can be very helpful in the diagnosis of cat-scratch disease, but, as with the Kveim test, the necessary antigen is available only on a research basis in selected centers.
Among radiologic studies, the chest radiograph is particularly valuable because hilar adenopathy may be present in patients with enlargement of peripheral nodes. Hilar adenopathy may also be detected on chest radiograph in the absence of peripheral lymphadenopathy. Sarcoidosis, lymphoma, fungal infection, tuberculosis, or metastatic carcinoma (particularly from a lung primary) should be among the diagnostic considerations. CT can provide additional definition. Mediastinoscopy may be required for tissue diagnosis, although not in asymptomatic patients with bilateral hilar adenopathy and clear lung fields, who most likely have sarcoidosis or a fungal exposure.
Lymph Node Biopsy
Biopsy is the most direct approach to the diagnosis of lymphadenopathy. Sometimes, careful observation for a period of time may be diagnostically useful before biopsy is undertaken. In many cases of benign lymphadenopathy, the nodes will regress spontaneously even if no etiologic diagnosis has been made. However, some lymphomas may regress transiently and simulate a more benign etiology.
Indications
If undiagnosed adenopathy persists during a period of weeks to months, especially if the nodes are enlarging or if neoplastic disease remains a concern, then consideration of node biopsy is indicated. In one retrospective study, weight loss, night sweats, nodes greater than 2 cm, and abnormal chest radiographic findings were the strongest predictors of important disease before biopsy. In radiologic series, nodes greater than 1 cm in the thoracic and retroperitoneal regions that persisted for more than 1 month were likely to be pathologic.
Approaches and Yield
When possible, excisional biopsy is preferred. It is more accurate than needle biopsy and higher yielding. Fine-needle aspiration has an accuracy of 75% for non-Hodgkin’s lymphoma and 85% for metastatic carcinoma compared to excisional biopsy. In persons with an accessible peripheral node, excision is preferred to skinny-needle aspiration, especially when it is necessary to distinguish lymphoid hyperplasia from lymphoma. However, skinny-needle sampling can be helpful in settings in which surgical biopsy may be problematic, such as with pancreatic or thyroid disease. When possible, core-needle biopsy is preferred to skinny-needle aspiration. Suspicious nodes revealing atypical hyperplasia require consideration of follow-up examination; a small but substantial percentage of such cases eventually prove to be due to lymphoma. In the case of fluctuant nodes, needle aspiration can be used to diagnose infectious processes in some cases.
Choice of Node
The node to be sampled should be selected with care. When multiple nodes are enlarged, the largest node is the preferred target. If generalized adenopathy is present, it is best to avoid inguinal or axillary nodes if possible because
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reactive hyperplasia in these areas may make interpretation difficult. In general, enlarged supraclavicular nodes have the highest diagnostic yield.
Complications
The majority of excisional biopsies are not technically demanding and can be accomplished under local anesthesia. Nonetheless, this is an invasive procedure and should be employed only when simpler approaches have failed to give a diagnosis and suspicion of a therapeutically important cause remains (e.g., tuberculosis, lymphoma, cancer, sarcoidosis, cat-scratch disease). Complications include spinal accessory nerve injury in posterior cervical biopsy and facial nerve injury in biopsy of the parotid area.
Processing of Biopsy Specimen
Proper processing is essential to maximizing diagnostic yield. Alerting the pathologist to the diagnostic considerations is essential to assuring optimal processing. Immunohistochemical staining of frozen tissue and flow cytometry improve the detection of lymphoma, Hodgkin’s disease, and other malignancies. When infection is a concern, tissue should be submitted for appropriate bacteriologic smears and cultures in addition to histologic study. Touch preparations may be useful. Special stains for bacteria, mycobacteria, and fungi may be helpful, as may specific stains for unusual processes, such as periodic acid-Schiff stains for Whipple’s disease or lipidosis and Congo red stains for amyloid. The interpretation of lymph node pathology can be quite difficult and requires careful study by experienced observers. With such study, benign processes such as toxoplasmosis or cat-scratch disease can be suspected histologically, and detailed analysis of serial sections may reveal lymphomas that are not diagnosed with less intensive pathologic study.
Follow-up/Empiric Treatment
Empiric therapy with antibiotics or steroids is not recommended unless there is a diagnosis of high probability that is evident and the treatment is specific to it. If pathologic study reveals reactive hyperplasia or is nondiagnostic, patients should be followed carefully because up to 25% may eventually exhibit an illness responsible for the lymphadenopathy, most often lymphoma.
Evaluation of Lymphadenopathy in the HIV-Infected Patient
In most patients who are HIV-positive, the lymphadenopathy represents follicular hyperplasia in response to HIV infection. However, the list of possible causes includes lymphoma, mycobacterial and viral infections, Kaposi’s sarcoma, and other cancers (see Chapter 13). The principles for evaluation and biopsy are similar to those for the non-HIV patient, with the proviso that the probability of serious underlying pathology is increased. Suggested criteria for lymph node biopsy in these patients include a diameter greater than 2 cm, rapidly enlarging or asymmetric adenopathy, constitutional symptoms, and intrathoracic adenopathy on chest radiograph. When these rather restrictive criteria are used and needle aspiration is the mode of biopsy, yields of less than 50% have been reported, with most patients having follicular hyperplasia.
Indications for Referral
Any patient suspected of harboring a malignancy should have a consultation with an oncologist or oncologic surgeon to consider further the need for biopsy and to determine the best approach to obtaining a tissue diagnosis. Simply arranging for the biopsy of an accessible node may fail to achieve a diagnosis and will subject the patient to an unnecessary invasive procedure. Consultation may also be useful if one is thinking about a period of observation and wants to be sure that this represents a reasonable approach.
A.G.M.
Annotated Bibliography
1. Habermann TM, Steensma DP. Lymphadenopathy. Mayo Clin Proc 2000;75:723. (Excellent traditional review, especially as regards differential diagnosis and workup; 154 references.)
2. Pangalis GA, Vassilakopoulos TP, Boussiotis VA, et al. Clinical approach to lymphadenopathy. Semin Oncol 1993;20:570. (Finds that nodes >1.5 cm in diameter deserve evaluation.)
3. Dorfman RE, Alpern MB, Gross BH, et al. Upper abdominal lymph nodes: criteria for normal size determined with CT. Radiology 1991;180:319. (Nodes >1.0 cm are likely to be pathologic.)
4. Tompkins DC, Steigbigel RT. Rochalimaea’s role in cat-scratch disease and bacillary angiomatosis. Ann Intern Med 1993;118:388. (Editorial useful for its terse review of the criteria for diagnosis of cat-scratch disease, an important infectious cause of localized and diffuse lymphadenopathy.)
5. Herrad J, Cabanillas F, Rice L, et al. The clinical behavior of localized and multicentric Castleman disease. Ann Intern Med 1998;128:657. (Best review of this idiopathic condition, which has both reactive and neoplastic characteristics and can mimic lymphoma.)
6. Greenfield S, Jordan MC. The clinical investigation of lymphadenopathy in primary care practice. JAMA 1978;240:1388. (A still-useful algorithm for the workup of peripheral lymphadenopathy in the ambulatory setting.)
7. Slap GB, Brooks JSJ, Schwartz JS. When to perform biopsies of enlarged peripheral lymph nodes in young patients. JAMA 1984;252:1321. (A retrospective study of 123 patients up to the age of 25 years who underwent lymph node biopsy. A predictive model was developed to determine before biopsy which patients were likely to have “treatable” causes of adenopathy.)
8. Slap GB, Connor JL, Wigton RS, et al. Validation of a model to identify young patients for lymph node biopsy. JAMA 1986;255:2768. (Follow-up study testing the model in ref. 7 found that it performed well.)
9. Gupta AK, Nayar M, Chandra M. Reliability and limitations of fine needle aspiration cytology of lymphadenopathies: an analysis of 1261 cases. Acta Cytol 1991;35:777. (Finds utility, but not as high yielding as excision.)
10. Battista AF. Complications of biopsy of the cervical lymph nodes. Surg Gynecol Obstet 1991;173:142. (Biopsy is not without its risks, which are reviewed here.)
11. Pinkus GS. Needle biopsy in malignant lymphoma. J Clin Oncol 1996;14:2415. (An editorial arguing that excisional biopsy is preferred.)
12. Knowles DM. Immunophenotypic and immunogenotypic approaches useful in distinguishing benign and malignant lymphoid proliferation. Semin Oncol 1993;20:583. (Summary of modern methods.)
13. Schroer KR, Fransilla KO. Atypical hyperplasia of lymph nodes: a follow-up study. Cancer 1979;44:115. (Cohort study; 6% to 25% of participants were found within a few months to have lymphoma, cancer, connective tissue disease, or infection.)
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