What do matted lymph nodes feel like

Dr. Saul Rosenberg

Dr. Saul Rosenberg is a Stanford University Emeritus Professor and a luminary in the research and treatment of Hodgkin's Disease and other lymphomas. He is also a skilled bedside examiner and has wonderful tips for examining the spleen and lymph nodes. During the department’s Osler Evening forum, Dr. Abraham Verghese interviewed Dr. Rosenberg about his career and inspiring life story.

Clinical Pearl

Enlarged inguinal lymph nodes are very common. Usually, they are shotty lymph nodes which are small, often hard, lymph nodes that are usually of no clinical concern. The term "shotty" comes from that fact that they have a similar feel to buckshot or pellets.

Answer: How to tell whether your lymph node that is swollen is a good lymph node or a bad lymph node -- two major ways to find out. One, is where they are located and how they feel. Where they are located, oftentimes with sore throats, you'll get some lymph node enlargement here in the front, what we call the anterior area of your neck. Occasionally you'll get a few in the back, particularly with mono, but the ones in the back if you get large lymph nodes in the back, they certainly are concerning.

The lymph nodes location most commonly like I said is in the neck, or sometimes in the groin. Now, what about how they feel? A normal lymph node that's reacting to just an infection is small, it's well-defined and a little rubbery, and usually moves.

The lymph nodes that you got to worry about, however ,are going to be the ones that are matted, that are large, more than say maybe a half-inch around and they don't move very well. Also, these lymph nodes will be in areas that you don't traditionally see lymph nodes, such as in the elbow area, the knee area, in the back of the neck as I mentioned before. So those are the ones that you want to be concerned about. Also, you can find lymph nodes in the front of the collar bone area and those too are concerning lymph nodes that you certainly want to have your physician check.

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.[1][2][3]

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.[4][5][6]

Algorithmic Analysis of Lymphadenopathy

After a history and physical examination are completed, lymphadenopathy is placed into 3 categories: 

1. "Diagnostic" such as strep pharyngitis or upper respiratory tract disease, in which case the course of action is to treat the condition
2. "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
3. "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: 

1. Infectious disease exposure
2. Animal exposure
3. Insect bites
4. Recent travel
5. Complete medication history
6. Personal habits-smoking, consumption of alcohol, consumption of drugs-special attention to a history of IVTA, high-risk sexual behavior
7. Consumption of under-cooked food/untreated water[7][8]

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.[9][10][11][12]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.[13]

Etiology

The etiology of lymphadenopathy includes the following:

• Infectious disease
• Neoplasm
• Inflammatory disease
• Autoimmune disease
• Inborn metabolic storage disorder
• Exposure to toxic/medication[7][14]

Infectious disease can be of viral, bacterial, mycobacterial, fungal, or parasitic etiology:

• Viral etiologies of lymphadenopathy include HIV, mononucleosis caused by EBV or CMV, roseola, HSV, varicella, and adenovirus.
• Bacterial etiologies of lymphadenopathy include Staphylococcus, Streptococcus, Salmonella,  Syphilis, and Yersinia.
• Mycobacterial etiology of lymphadenopathy include tuberculosis and Mycobacterium avium intracellulare (MAI)
• Fungal etiology of lymphadenopathy includes coccidioidomycosis, histoplasmosis, and Candida.
• Parasitic etiology of lymphadenopathy includes toxoplasmosis, Chagas, and many ectoparasites.
• Neoplastic causes of lymphadenopathy include both primary malignancies and metastatic malignancies: Acute lymphoblastic leukemia (ALL), Hodgkin lymphoma, non-Hodgkin lymphoma, neuroblastoma, pediatric acute myelocytic leukemia, rhabdomyosarcoma, metastatic carcinoma of the lung, metastatic carcinoma of the viscera of the gastrointestinal (GI) tract, metastatic breast cancer, and metastatic thyroid cancer and metastatic renal cancer.
• Autoimmune disease these causes of lymphadenopathy include sarcoidosis, juvenile rheumatoid arthritis (JRA), serum sickness, systemic lupus erythematosus (SLE)
• Exposures to toxins and medications that are common causes of lymphadenopathy include the medications allopurinol, atenolol, captopril, carbamazepine, many of the cephalosporins, gold, hydralazine, penicillin, phenytoin, primidone, para methylamine, quinidine, the sulfonamides, and sulindac. Lifestyle exposures to alcohol, ultraviolet (UV) radiation, and tobacco can cause cancers with secondary lymphadenopathy.
• Inborn metabolic storage disorders (including Niemann-Pick disease and Gaucher disease) are possible additional causes of lymphadenopathy[15][16][17][18][17]

Epidemiology

Broad generalities can safely be made about the epidemiology of lymphadenopathy.[19][20][21]

First, both generalized and localized lymphadenopathies are fairly equally distributed without regard to gender.

Second, lymphadenopathy is more prevalent in the pediatric population than in the adult population, secondary to the more significant number of viral infections. It would follow that the majority of the time, lymphadenopathy in the pediatric population is of less consequence again secondary to the prevalence of viral and bacterial infections in that age group. Three-quarters of all lymphadenopathy observed are localized, and of those three-quarters, half of these are localized to the head and neck area. All remaining localized lymphadenopathy is found in the inguinal area, and the remaining lymphadenopathy is located in the axilla in the supraclavicular area. Of note, the differential diagnosis of lymphadenopathy changes significantly with the patient's age.

Third, the patient's location and circumstance are very revealing and lymphadenopathy. For example, in the developing world (sub-Saharan Africa, Southeast Asia, Indian subcontinent), exposure to parasites, HIV, and miliary TB are far more likely to be causes of generalized lymphadenopathy than in the United States and Europe. Whereas, Epstein-Barr virus, streptococcal pharyngitis, and some neoplastic processes are more likely candidates to cause lymphadenopathy in the United States and the remainder of the localized industrial world. An exposure history is significant for diagnosis.

• Exposure to blood and blood-borne products either through transfusion, unsafe sexual practices, intravenous drug abuse, or vocation
• Exposure to infectious disease, whether it be travel, in the workplace, or the home
• Medication exposure-prescription, nonprescription, or supplements
• Exposure to animal-borne illness either via pets or the workplace
• Exposure to arthropod bites[22]

Pathophysiology

Lymphatic fluid represents the totality of the interstitial fluid of the body, and the lymphatic channels conduct this fluid and label antigens with antigen-presenting cells. As the lymphatic channel's progress, they converge regionally to form discreet lymph nodes. The function of the lymph node is to evaluate and, when possible, process and initiate the immune response to the presented antigens. Lymph nodes can be thought of like a mesh of reticular cells containing lobules wherein the antigens are presented to the immune system. Lobules anatomically contain three discreet compartments (cortex, paracortex, and medulla) in which B-cells, T-cells, and macrophages are separately sequestered.

The appropriate cell line responds to the presented antigen by increasing its numbers. Commonly the cell lines can multiply by 3 to 5 times in 6 to 24 hours. The reticular network can stretch to contain the cell-swollen lobules. This increases the size of the lymph node and causes the clinical phenomenon of lymphadenopathy.

Lymph nodules are integrated with afferent and efferent blood vessels which allow a rich interface between intravascular and extravascular spaces. Macroscopically, the result is antigenic "policing" of both intravascular and interstitial fluids and ready immune response to threats. Microscopically, the decentralized hubs of antigen presentation and response allow for prompt action with an economy of lymphoid resources.[23]

History and Physical

A history and physical examinations are the cornerstones of time and cost-effective diagnosis of adenopathy. The depth and the extent of the H&P conducted are proportional to the obscurity of the etiology of the adenopathy. The obvious presence of strep pharyngitis and its related localized anterior cervical adenopathy requires far less clinical brainpower than generalized adenopathy secondary to sarcoidosis or a Gaucher disease.

The history itself involves gathering 5 important components: chronicity, localization, concomitant symptoms, patient epidemiology, and pharmacological exposure.

1. Chronicity: The accepted definition of "chronic adenopathy" is a duration of greater than 3 weeks and the observation that duration of fewer than 2 weeks or greater than 1 year is usually associated with benign causality.
2. Localization: The first determination is if the adenopathy can be viewed as localized or generalized. The accepted definition of generalized lymphadenopathy is clinical lymphadenopathy in 2 or more non-contiguous areas. Generalized adenopathy may be indicative of systemic illness, and the workup is typically more laboratory and imaging-intensive and pursued more rapidly. Localized beds of enlarged nodes reflect possible localized pathology in the areas in which they drain.
3. Physical characterization of the node itself 
4. Concomitant symptoms: The presence or absence of constitutional symptoms is a major cue in the determination of the pace and depth of the workup in lymphadenopathy when taken in the clinical context. For example fever, chills, night sweats, weight loss, and fatigue are worrisome in the setting of generalized lymphadenopathy. However, similar symptoms are acceptable in the setting of localized cervical lymphadenopathy and a concomitant Flu or Strep.
5. Epidemiology: Included in the epidemiological search for lymphadenopathy, will be questions pertaining to Dietary exposure, pet exposure, insect bite, recent blood exposure, high-risk sexual behavior or intravenous drug use, occupational exposure to animals, and travel-related epidemiology especially attention to travel to third world or the Southwest in the United States.
6. Pharmacological exposure: A thorough medical history is necessary including prescription medications, over-the-counter medications, supplements, and herbal medicines.[7][24]

The physical examination can be quite revealing, especially with the location of the adenopathy and consideration of the lymphatic drainage of the related areas. Once the determination has been made that the lymphadenopathy is either localized or general, strict attention to the localized area must be paid. For example:

• Submandibular nodes typically drain the tongue the lips and the mouth and the conjunctiva
• Submental nodes typically drain the lower lip portions of the oropharynx and the cheek
• Jugular lymphadenopathy typically drains the tongue, the tonsils, the pinna, and the parotid gland
• Posterior cervical adenopathy typically is indicative of scalp, neck, skin of the arms and legs
• Pectoral thoracic cervical and axillary drainage
• Suboccipital nodes reflect drainage of the scalp in the head, and preauricular nodes reflect drainage of the eyelids, conjunctiva temporal region, and pinna.
• Postauricular nodes reflect drainage at the scalp in the external auditory meatus.
• The right supraclavicular node represents drainage of the mediastinum the lungs in the esophagus
• Axillary nodes typically create the arm at the thoracic wall and the breast.
• The epitrochlear nerve roots typically drain the ulnar aspect of the forearm and the hand.
• Inguinal nodes drain the penis, the scrotum, the vulva, vagina, the perineum, the gluteal region, and the lower abdominal wall and portions of the lower anal canal[25]

Characterization of the node morphology itself:

• Tenderness or pain may result from an inflammatory process or perforation and also may result from hemorrhage into the necrotic center of a malignant node. (Presence or absence of pain is not a reliable differentiating factor for malignant nodes though.)
• Consistently firm rubbery nodes may suggest lymphoma; softer nodes are usually the result of infection or inflammatory conditions; hard stonelike nodes are typically a sign of cancer more commonly metastatic than primary.
• "Shotty" nodes refer to very small, scattered nodes that feel like shotgun pellets under the skin. This configuration is typically is found in cervical nodes of children with viral illnesses
• The designation of a "matting" configuration of nodes describes the pattern of clustered, seemingly conjoined lymph nodes. This is indicative of, but not pathognomonic, malignancy.[26]

Evaluation

Laboratory Evaluation of Lymphadenopathy

• CBC with manual differential: This is a foundational test in diagnosing both generalized and regional lymphadenopathy. The number and differential of the white blood cells can indicate bacterial, viral, or fungal pathology. In addition, characteristic white blood cell (WBC) patterns are observed with several hematological neoplasms producing lymphadenopathy.
• EBV serology: Epstein-Barr viral mono is present, causing regionalized lymphadenopathy
• Sedimentation rate: A measure of inflammation though not diagnostic, can contribute to diagnostic reasoning.
• Cytomegalovirus titers: This viral serology is indicative of possible CMV mononucleosis
• HIV serology: This serology can be used to diagnose acute HIV syndrome-related lymphadenopathy or to infer the diagnosis of secondary HIV-elated pathologies causing lymphadenopathy. 
• Bartonella henselae serology: Serology that may be indicative of the diagnosis of cat-scratch lymphadenopathy
• FTA\RPR: These tests can establish if syphilis is a cause of lymphadenopathy
• Herpes simplex serology: Serological testing to discern if the herpes-related, mononucleosis-like syndrome is present or if regionalized inguinal adenopathy is secondary to herpes simplex exposure
• Toxoplasmosis serology: These serological tests can lead to a diagnosis of acute toxoplasmosis as a cause of lymphadenopathy
• Hepatitis B serology: Serological tests for hepatitis B to establish it as a contributing factor for lymphadenopathy
• ANA: A serological screening test for SLE that can help establish it as a cause for generalized lymphadenopathy

Diagnostic Radiological Testing

• Chest x-ray: This radiological imaging modality can reveal tuberculosis, pulmonary sarcoidosis, and pulmonary neoplasm.
• Chest CAT scan: This radiological imaging modality can define the above processes and reveal hilar adenopathy.
• Abdominal and pelvic CAT scan: These images, in combination with chest CAT scan, can be revealed in cases of supraclavicular adenopathy and the diagnosis of secondary neoplasm.
• Ultrasonography: This imaging modality can be used to assess number, size, size, shape, marginal definition, and internal structures in patients with lymphadenopathy. Of note, color Doppler ultrasonography is used to distinguish the vascular pattern between older pre-existing lymphadenopathy and recent (newly active) lymphadenopathy. Studies have indicated that a low long axis to short axis ratio of lymphadenopathy as measured by ultrasound can be a significant indicator of lymphoma and metastatic cancer as a cause of lymphadenopathy.
• MRI scanning: As with CAT scanning, this modality of diagnostic imaging has great utility in evaluating thoracic, abdominal, and pelvic masses.[27]

PPD

Tuberculosis is among the leading cause of both regional and generalized adenopathy in the non-industrialized world[28]

Differential Diagnosis

The differential diagnosis of the etiology of lymphadenopathy can be thought of in the following algorithm:After a thorough history and physical examination, lymphadenopathy can be initially categorized as:

• Diagnostic-where in the practitioner has a proximal cause for the lymph nodes and can treat them. Examples would be strep pharyngitis or localized cellulitis.
• The lymphadenopathy pattern history and physical examination can be suggestive; an example would be mononucleosis wearing the practitioner has a strong clinic index of suspicion can perform a confirmatory test which if positive he can go on and treat the patient.
• Unexplained lymphadenopathy.
• Unexplained lymphadenopathy can be generalized into localized or generalized lymphadenopathy.[7]

Unexplained localized lymphadenopathy (after careful review of the history and epidemiology) is further divided into patterns at no risk for malignancy or severe illness, in which case the patient can be observed for 3 to 4 weeks and if response or improvement can be followed. The other alternative is if the patient is found to have a risk for malignancy or serious illness, a biopsy is indicated.[30]

Unexplained generalized lymphadenopathy can be approached after review of epidemiological clues and medications with initial testing with a CBC with manual differential and mononucleosis serology; if either is positive and diagnostic, proceed to treatment. If both are negative, the second workup approach would be a PPD, and RPR, a chest x-ray, ANA, hepatitis BS antigen serology, and HIV. Additional testing modalities and lab tests may be indicated depending on clinical cues. If the results of this testing are conclusive, the practitioner can proceed on to diagnosis and treatment at the illness. If the results of the testing are still not clear, proceed onto biopsy of the most abnormal of the nodes.The most functional way to investigate the differential diagnosis of lymphadenopathy is to characterize it by node pattern and location, obtain pertinent history, including careful evaluation of epidemiology, and place the patient in the appropriate arm of the algorithm to evaluate lymphadenopathy.

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