Given the role of the lymphatic system in developing adaptive responses to numerous antigenic challenges and the rate at which the immune system is exposed to novel antigens early in life, enlarged lymph nodes are regularly encountered both incidentally and within the context of many childhood illnesses. The challenge for the clinician is determining when a change in the size or quality of a lymph node is physiologic and when such a change represents pathology. A thorough history, physical examination, and recognition of the anatomic drainage patterns of the lymphatic system will oftentimes sufficiently narrow the differential diagnosis of lymphadenopathy such that complicated or invasive diagnostic evaluations are unnecessary.
Mechanism of Lymphadenopathy
The lymphatic system is a network of vessels and tissues that collects excess fluid from the cellular interstitium and returns it to the peripheral circulation. This interstitial fluid is similar in composition to plasma, though it may contain additional proteins, pathogens, other antigens, and antigen-presenting cells. The collected fluid, termed lymph , enters the lymphatic system via specialized lymphatic capillaries and passes into nearby lymph nodes via afferent lymphatic vessels. The lymph nodes contain both B and T lymphocytes lying in a supportive framework within a connective tissue capsule ( Fig. 36.1 ). Additional lymphocytes may enter lymph nodes from the peripheral venous circulation via postcapillary high endothelial venules. Antigens, antigen-presenting cells, and pathogens present within the lymph interact with the lymphocytes, allowing for the production of B- and/or T-cell immune responses in an effort to clear the antigen or pathogen. Efferent lymphatic vessels then carry lymph and antigen-sensitized lymphocytes from the nodes back to the peripheral circulation via the thoracic duct.
(See Nelson Textbook of Pediatrics, p. 2413.)
Enlargement of lymph nodes can come about via several mechanisms. First, physiologic hyperplasia can occur as nodal and circulating lymphocytes proliferate within nodes in response to antigenic stimulation. Second, bacteria that have been transported to the nodes may stimulate the recruitment of polymorphonuclear cells and the elaboration of inflammatory mediators that can lead to the edema, erythema, and tenderness characteristic of bacterial lymphadenitis or to suppuration and abscess formation. Third, malignant cells may arise within the node itself and proliferate, causing enlargement, or arrive from distant cancerous sites and infiltrate the nodal tissue. Fourth, certain medications can cause lymphadenopathy either directly or as part of a serum sickness-like reaction. Finally, in rare genetic storage diseases (Niemann–Pick, Gaucher diseases), macrophages laden with abnormally metabolized lipids may lodge within lymph nodes, causing enlargement.
The regional drainage pattern of each lymph node group is important in determining the cause of lymphadenopathy, particularly when localized to an individual node or contiguous group of nodes ( Fig. 36.2 and Tables 36.1 and 36.2 ). The cervical lymph nodes drain lymph from distinct areas of the head, neck, and throat and may enlarge if a local infection is present. Consequently, because otitis media and pharyngitis are common infections in children, head and neck lymphadenopathy is one of the more frequently encountered regional lymphadenopathy patterns in small children. The axillary nodes drain lymph from the arms, lateral breasts, and superficial chest and upper abdomen, and isolated enlargement of these nodes may suggest pathology in these areas. The inguinal nodes drain the lower extremities, genitourinary system, and perineum, which may indicate lower extremity pathology or the presence of a sexually transmitted infection in patients with an exposure history. Supraclavicular lymphadenopathy is a concerning finding and should prompt concern for an underlying neoplasm, fungal infection, tuberculosis, or sarcoidosis. Generalized lymphadenopathy , defined as the presence of enlarged or abnormal lymph nodes in 2 or more noncontiguous lymph node groups (with or without hepatosplenomegaly), is often indicative of a systemic response to an infectious or otherwise inflammatory process but may also indicate malignant proliferation of lymphocytes ( Table 36.3 ).
| Abdominal and Pelvic |
| Abdomen, lower extremity, pelvic organs |
| Axillary |
| Arm, breast, chest wall, hand, upper and lateral abdominal wall |
| Cervical |
| External ear, larynx, parotid, superficial tissues of the scalp, head, and neck, thyroid, tongue, trachea |
| Epitrochlear |
| Forearm, hand |
| Iliac |
| Bladder, lower abdomen, part of the genitalia, urethra |
| Inguinal |
| Gluteal region, lower anal canal, lower extremity, perineum, vulva and vagina in females, scrotum and penis in males, skin of the lower abdomen |
| Mediastinal |
| Thoracic viscera |
| Occipital |
| Posterior scalp |
| Popliteal |
| Knee joint, skin of the lateral lower leg and foot |
| Preauricular |
| Cheek, conjunctivae, eyelid, temporal scalp |
| Submaxillary/Submental |
| Buccal mucosa, gums, teeth, tongue |
| Supraclavicular |
|
| Cervical |
| Oropharyngeal infection (viral, group A streptococcal, or staphylococcal) |
| Scalp infection (tinea) |
| Mycobacterial lymphadenitis (tuberculous and nontuberculous mycobacteria) |
| Viral infection (EBV, CMV, HHV-6, measles) |
| Cat-scratch disease |
| Kawasaki disease |
| Thyroid disease |
| Kimura disease |
| Periodic fever, aphthous stomatitis, pharyngitis, cervical adenopathy (PFAPA) syndrome |
| Kikuchi-Fujimoto disease |
| Anterior Auricular |
| Conjunctivitis or other eye infections |
| Oculoglandular tularemia, cat-scratch disease, EBV, adenovirus |
| Posterior Auricular |
| Otitis media |
| Viral infection (especially rubella, parvovirus) |
| Supraclavicular |
| Malignancy or infection in the mediastinum (right) |
| Metastatic malignancy from abdomen (left) |
| Lymphoma |
| Tuberculosis |
| Epitrochlear |
| Hand infection, arm infection * |
| Lymphoma † |
| Sarcoidosis |
| Syphilis |
| EBV |
| HIV |
| Inguinal |
| Urinary tract infection |
| Sexually transmitted infection (especially syphilis or lymphogranuloma venereum) |
| Lower extremity suppurative infection |
| Plague |
| Hilar (Not Palpable, Found on Chest Radiograph or CT) (see Table 36.4 ) |
| Tuberculosis † |
| Histoplasmosis † |
| Blastomycosis † |
| Coccidioidomycosis † |
| Leukemia/lymphoma † |
| Hodgkin disease † |
| Metastatic malignancy * |
| Sarcoidosis † |
| Castleman disease |
| Axillary |
| Cat-scratch disease |
| Arm infection |
| Malignancy of chest wall |
| Leukemia/lymphoma |
| Brucellosis |
| Neonate | Child | Adolescent |
|---|---|---|
| Common Causes | ||
| CMV | Nonspecific viral infections | Viral Infections |
| HIV | EBV | EBV |
| Syphilis | CMV | CMV |
| Toxoplasmosis | HIV | HIV |
| Toxoplasmosis | Measles | |
| Measles | Toxoplasmosis | |
| Syphilis | ||
| Rare Causes | ||
| Chagas disease (congenital) | Serum sickness | Serum sickness |
| Congenital leukemia | SLE, JIA | SLE, JIA |
| Congenital tuberculosis | Leukemia/lymphoma | Leukemia/lymphoma |
| Reticuloendotheliosis | Tuberculosis (miliary) | Tuberculosis |
| Metabolic storage disease | Sarcoidosis | Sarcoidosis |
| Histiocytic disorders | Fungal infections | Fungal infections |
| Listeria sepsis | Plague | Plague |
| Leptospirosis | Leptospirosis | |
| Brucellosis | Brucellosis | |
| Langerhans cell histiocytosis | Drug reaction (immune) | |
| Macrophage activating syndrome | Castleman disease | |
| Hemophagocytic lymphohistiocytosis | Rickettsial infection | |
| Castleman disease (very rare in the this age group) | ||
| Chronic granulomatous disease | ||
| Sinus histiocytosis (Rosai–Dorfman disease) | ||
| Kikuchi-Fujimoto disease | ||
| Autoimmune lymphoproliferative disease (ALP) | ||
| Rickettsial infection | ||
History
History should be aimed at establishing the time course of the development of lymphadenopathy, whether the lymphadenopathy is restricted to a particular anatomic region or is generalized, and if there are any associated signs, symptoms, or exposures that may suggest an etiology.
Lymphadenopathy that develops rapidly over several days is more suggestive of an acutely inflammatory, often infectious process, whereas more indolently developing lymphadenopathy may suggest malignancy, chronic disease, or an atypical infection. The sudden onset of unilateral inguinal adenopathy shortly following lower extremity trauma suggests an infection in the traumatized extremity. In contrast, progressive enlargement of multiple noncontiguous nodal groups over the course of weeks or months that is accompanied by weight loss, fevers, or night sweats, suggests a systemic illness such as lymphoma or tuberculosis. When establishing the time period over which the lymphadenopathy developed, the clinician should clarify both when the node was first noted to be abnormal, as well as the last time the node was felt to be normal. This information is particularly essential if associated symptoms, overlying skin changes, and tenderness are absent, since more slowly developing lymphadenopathy may not be noticed until the node or nodes are quite enlarged, or if lymphadenopathy was noted only incidentally when dressing, grooming, or bathing.
The age of the child with lymphadenopathy is similarly important in the consideration of the cause (see Table 36.3 ). Neonatal lymphadenopathy is typically indicative of exposure to an infectious agent in utero, such as cytomegalovirus (CMV), syphilis, human immunodeficiency virus (HIV), rubella, or toxoplasmosis, though may less frequently be associated with congenital malignancy or storage diseases. In contrast, toddlers and children with adenopathy tend to have either focal infections that drain into the affected nodal chain, or systemic viral infections, resulting in diffusely enlarged nodes. Adolescents may acquire exposures that place them at risk for sexually transmitted infections and inguinal adenopathy. Just as exposure to certain infectious agents may vary with age, the risk of hematologic malignancy varies as well: acute leukemias are more common in toddlers and young children; non-Hodgkin lymphoma is more common is school-aged children, and Hodgkin lymphoma is more common in adolescents.
The past medical history and review of systems should be explored for conditions that may either cause lymphadenopathy directly or place the patient at increased risk for opportunistic infections, such as congenital or acquired immunodeficiency. The clinician should inquire about any signs or symptoms that would suggest an acute infectious process or more slowly progressive constitutional symptoms that may suggest malignancy or indolent infection. The quality of oral hygiene practices and dentition should be assessed as odontogenic infections may not readily be appreciated as a source of cervical lymphadenopathy. The use of any prescription medications, over-the-counter medicines, or traditional remedies should be ascertained. In addition to medications that may directly cause lymphadenopathy, other substances may provoke lymphadenopathy as a component of a serum sickness-like reaction or be associated with autoimmune or rheumatologic conditions that cause generalized lymphadenopathy (see Table 36.3 ).
After determining the timing and distribution of the lymphadenopathy and placing these findings within the context of the child’s age and past medical history, the clinician should inquire about any exposures that may have led to the development of lymphadenopathy, focusing in particular on diet, travel history, and contact with individuals, animals, or environments that may pose a risk for disease transmission. Contact with or consumption of raw or undercooked meats, particularly pork, lamb, and venison, may transmit Toxoplasma gondii , leading to toxoplasmosis. Similarly, contact with agricultural animals or ingestion of unpasteurized dairy products may place patients at risk for acquiring certain pathogens, such as Brucella species or Mycobacterium bovis ; infection with either of which may lead to generalized lymphadenopathy. Potential exposures in the home environment should be assessed, including the risk of contaminated drinking water and whether there are concerns for mold exposure, particularly in immunocompromised patients. The presence of pets, either within the home or in the area, should be determined. Cats or kittens that may scratch the child and transmit Bartonella henselae , the etiologic agent of cat-scratch disease , are often omitted from the history unless such questions are specifically asked. Furthermore, some families may deny the presence of household pets but forget to mention that the child plays with a pet present in a barn or around the neighborhood. Travel history should determine whether the child is from or has been exposed to geographic areas associated with a higher risk for acquiring certain infections, such as tuberculosis in developing nations or histoplasmosis in the Ohio River valley. The clinician should inquire whether any family members or close contacts are ill or taking medications, whether any have recently traveled to or immigrated from other countries, and whether any have recently been incarcerated. Adolescents should be questioned about risk factors for HIV and sexually transmitted infections, such as syphilis or lymphogranuloma venereum, which may cause generalized or inguinal lymphadenopathy, respectively.
The family history should also focus on potentially heritable conditions, such as autoimmune or rheumatologic disorders, certain hematologic and soft tissue malignancies as well as storage diseases that may be associated with noninfectious forms of lymphadenopathy.
Physical Examination
Physical examination should assess general appearance and look for signs or symptoms that may reveal the underlying cause of lymphadenopathy. Examination of the lymphatic system should establish the size, quality, and distribution of any abnormal lymph nodes and should assess for the presence of tenderness or changes in the overlying skin or surrounding tissues.
Size
The threshold beyond which a particular node is considered enlarged varies by nodal group. In general, nodes over 1 cm in diameter are considered enlarged; exceptions include epitrochlear nodes greater than 0.5 cm in diameter and inguinal nodes greater than 1.5 cm in diameter.
Quality
The quality of the nodes often yields some clues as to the cause of the adenopathy. The clinician should assess consistency, mobility, shape, tenderness, and whether any changes to the overlying skin or soft tissues are present. The following general patterns are worth noting:
- •
Erythematous, tender, and warm: acute bacterial infection with suppurative adenitis
- •
Tender, nonerythematous, and soft: viral infection or other systemic infection
- •
Firm, hard, rubbery, and nontender: lymphoma or other infiltrating tumor
- •
Hard, matted, immobile, and nontender: tumor, metastatic or local; fibrosis that follows acute infection
Distribution
All areas in which lymphadenopathy is commonly present should be palpated, including the cervical, auricular, axillary, epitrochlear, inguinal, and supraclavicular areas, because lymphadenopathy in certain regions is linked to systemic or local illness. If more than 2 noncontiguous nodal groups are abnormal, without evidence of distinct focal infections inciting the lymphadenopathy within each group, the lymphadenopathy is generalized.
Regional lymphadenopathy usually reflects pathologic processes within the lymphatic drainage distribution of that particular nodal chain (see Table 36.2 ). Several patterns of regional lymphadenopathy should prompt further evaluation. The presence of palpable supraclavicular nodes is often a red flag for a serious illness such as malignancy. Supraclavicular nodes that are palpated on the right side often reflect a mediastinal tumor or invasive mediastinal infection, such as histoplasmosis. Supraclavicular nodes on the left side are often the result of metastatic spread of an abdominal tumor. The presence of either type of node mandates an urgent evaluation, including computed tomography (CT) or magnetic resonance imaging. Epitrochlear nodes , if unilateral, commonly indicate the hand or arm as a source of distal infection; however, palpable bilateral epitrochlear lymph nodes usually reflect systemic illness, such as syphilis, sarcoidosis, or lymphoma. Inguinal node enlargement is common and is usually caused by the frequent occurrence of minor trauma and infections in a child’s legs and feet. Significantly enlarged inguinal nodes may also be present with sexually transmitted infections, such as syphilis, chlamydial urethritis, lymphogranuloma venereum, or with urinary tract infection, lymphoma, or abdominal tumors.
Mediastinal adenopathy (or mass) may be detected incidentally, or secondary to chest symptoms, or during the evaluation of peripheral but generalized lymphadenopathy. The differential diagnosis is noted in Table 36.4 .
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