Lymphadenopathy is a common abnormal finding during the physical exam in general medical practice. Patients and physicians have varying degrees of associated anxiety with the finding of lymphadenopathy as a small number of cases can be caused by neoplasm or infections of consequence, for example, HIV or tuberculosis (TB). However, it is generally recognized that most lymphadenopathy, both localized and generalized, is of benign, self-limited etiology. A clear understanding of lymph node function, location, description, and the etiologies of their enlargement is important in the clinical decisions of which cases need rapid and aggressive workup and which need only be observed.
The lymph node functions as an antigen filter for the reticuloendothelial (RE) system of the body. It consists of a multi-layered sinus that sequentially exposes B-cell lymphocytes, T-cell lymphocytes, and macrophages to an afferent extracellular fluid. In this way, the immune system can recognize and react to foreign proteins and mount an immune response or sequester these proteins as appropriate. In this reaction, there is some multiplication of the responding resistant cell line, and thus, the node itself increases in size. It is generally held that a node size is considered enlarged when it is more significant than 1 cm. However, the reality is that "normal" and "enlarged" criteria vary depending on the location of the node and the age of the patient. For example, children younger than ten have more hypertrophic immune systems, and nodes up to 2 cm can be considered normal in some clinical situations. However, an epitrochlear node of above 0.5 cm is deemed to be pathological in an adult.
The pattern, distribution, and quality of the lymphadenopathy can provide much clinical information in the diagnostic process. Lymphadenopathy occurs in 2 patterns: generalized and localized. Generalized lymphadenopathy entails lymphadenopathy in 2 or more non-contiguous locations. Localized adenopathy occurs in contiguous groupings of lymph nodes. Lymph nodes are distributed in discrete anatomical areas, and their enlargement reflects the lymphatic drainage of their location. The nodes themselves may be tender or non-tender, fixed or mobile, discreet or "matted" together. Concomitant symptomatology and the epidemiology of the patient and the illness provide further diagnostic cues. A thorough history of any prodromal illness, fever, chills, night sweats, weight loss, and localizing symptoms can be very revealing. Additionally, the demographic particulars of the patient, including age, gender, exposure to infectious disease, toxins, medications, and their habits, may provide further cues.
As evidenced above, the critical step in evaluation for adenopathy is a careful history and focused physical exam. The extent of the history and physical is determined by the clinical presentation of the patient. For example, a patient with posterior cervical adenopathy, sore throat, and tremendous fatigue need only a careful history, cursory examination, and a mono test. In contrast, a person with generalized lymphadenopathy and fatigue would require more extensive investigation. Generally, the majority of the lymphadenopathy is localized (some site a 3:1 ratio), with the majority of that being represented in the head and neck region (again, some site a 3:1 ratio). It also is accepted that all generalized lymphadenopathy merits clinical evaluation, and the presence of "matted lymphadenopathy" is strongly indicative of significant pathology.Examination of the patient's history, physical examination, and the demographic in which they fall can allow the patient to be placed into 1 of several different accepted algorithms for workup of lymphadenopathy. The use of these cues and selection of the correct arm of the algorithm allows for a fairly rapid and cost-effective diagnosis of lymphadenopathy, including determination when it is safe to observe.
Algorithmic Analysis of Lymphadenopathy
After a history and physical examination are completed, lymphadenopathy is placed into 3 categories:
"Diagnostic" such as strep pharyngitis or upper respiratory tract disease, in which case the course of action is to treat the condition
"Suggestive" such as mononucleosis lymphoma or HIV wherein the history and physical strongly suggestive diagnosis-specific testing is performed and if positive the action is to treat the condition
"Unexplained" where the lymphadenopathy is divided into generalized lymphadenopathy and localized lymphadenopathy
For unexplained localized lymphadenopathy, a review of history, a regional exam, and epidemiological clues are used to separate patients into lower (no risk of malignancy or serious disease) versus higher risk for serious disease or malignancy categories. If the patient is at no risk for malignancy or serious illness, the reasonable course is to observe the patient for 3 to 4 weeks to see if the lymphadenopathy resolves or improves. In which case, the clinician is safely cleared to follow the patient. If the lymphadenopathy does not resolve or improve, the next step is to obtain a biopsy. If the patient is judged to have a risk for malignancy or serious illness, the procedure is to proceed immediately to biopsy.
For unexplained generalized lymphadenopathy, the key to diagnosis is a history to evaluate for suspected causes. The initial search would be questioning for a mononucleosis-type syndrome evidenced by fever atypical lymphocytosis and malaise included in these differentials would be Epstein-Barr virus, cytomegalovirus, toxoplasmosis, and (especially in the case of a flu-like illness and her rash) the initial stages of an HIV infection. The second step in evaluating unexplained generalized lymphadenopathy involves a careful review of epidemiological cues. Included in the epidemiological cues would be:
Infectious disease exposure
Animal exposure
Insect bites
Recent travel
Complete medication history
Personal habits-smoking, consumption of alcohol, consumption of drugs-special attention to a history of IVTA, high-risk sexual behavior
Consumption of under-cooked food/untreated water
Although there is no "cookbook" for the laboratory evaluation of generalized unexplained lymphadenopathy, the initial steps are to obtain a complete blood count (CBC) with a manual differential and EBV serology. If non-diagnostic, the next steps would be PPD placement, RPR, chest x-ray, ANA, hepatitis B surface antigen, and HIV test. Again if any of the above are positive, appropriate treatment can be initiated. In the presence of negative serological examinations and radiological examinations, and or significant symptomology, a biopsy of the abnormal node is the gold standard for diagnosis.Statistics concerning lymphadenopathy are not accurate as the great majority of lymphadenopathy is caused by a non-reportable illness and thus not reported or taken into account. This results in a statistical bias, or skew, toward the reportable causes of lymphadenopathy: malignancies, HIV, tuberculosis, and sexually transmitted infections (STIs). Citations in the recent literature for general medical practice indicate that less than 1% of people with lymphadenopathy have malignant disease most often due to leukemia and younger children Hodgkin disease in adolescence non-Hodgkin disease and chronic lymphocytic leukemia (CLL) in adults. It has been reported the general prevalence of malignancy is 0.4% in patients under 40 years and around 4% in those older than 40 years of age seen in a primary care setting. It is reported that the prevalence rate of neoplastic disease rises to near 20% in referral centers and rises to 50% or more in patients with initial risk factors.
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