Lymph Node Disorders 

The lymphatic system is an important component of the immune system. It includes lymphatic fluid, lymphatic vessels, lymph nodes, spleen, tonsils, adenoids, Peyer patches, and the thymus. Lymphatic fluid consists of an ultrafiltrate of blood collected within lymphatic channels, which run throughout the entire body. The fluid is slow-moving and is transported from the head and extremities to larger vessels, which then drain into the venous system. Along these channels reside approximately 600 lymph nodes.

Lymph nodes are composed of follicles and contain and abundance of lymphocytes. Lymph is filtered through the lymph node sinuses, where particulates and infectious organisms are detected and removed. Because of the exposure to immune challenges, antibody and cell-mediated immunity is mediated. As a result of such normal processes, the lymph nodes can enlarge by proliferation of normal cells or infiltration by abnormal cells.

A child with an enlarged lymph node is a common situation faced by clinicians. The challenge is to satisfy the parents' fears of malignancy and to do so in a safe, timely, and cost-effective manner. Organizing the possible causes of lymphadenopathy by anatomic location and origin aids the clinician in the evaluation. In this article, a rational approach is provided to determine the etiology of the lymph node disorder, and various disorders are highlighted to consider when treating a child with lymphadenopathy. Furthermore, various means are discussed for obtaining a tissue diagnosis when the cause of lymphadenopathy is uncertain.

The removal of lymph nodes to determine the etiology of their enlargement has been practiced for many years, but it is unknown when it was first performed. The removal of lymph nodes is a procedure that is performed by almost general adult and pediatric surgeons. Because children often present with enlarged lymph nodes, pediatric surgeons are often the ones who treat these children primarily or as a referral.

Lymphadenopathy is defined as the enlargement of one or more lymph nodes as a result of normal reactive effects or a pathologic occurrence. While size is the most common reference, others include an abnormal number or alteration in consistency as a pathologic change that requires investigation.

It is important to differentiate true enlarged lymph nodes from what are often referred to as "shotty" lymph nodes. Such descriptions refer to small mobile lymph nodes that are often palpable and that usually represent a benign change, usually following a viral illness.

Frequency

Lymphadenopathy is a common presentation in children; it is so common that the exact frequency may be difficult to establish. The likelihood of enlarged lymph nodes increases with age and exposure.

Five broad etiologic categories lead to lymph node enlargement, as follows:^[1]

• An immune response to infective agents (eg, bacteria, virus, fungus)
• Inflammatory cells in infections involving the lymph node
• Infiltration of neoplastic cells carried to the node by lymphatic or blood circulation (metastasis)
• Localized neoplastic proliferation of lymphocytes or macrophages (eg, leukemia, lymphoma)
• Infiltration of macrophages filled with metabolite deposits (eg, storage disorders)

The pathophysiology of lymphadenopathy differs based on etiology. If it is a reactive process, a physiologic increase in the number of lymphocytes and macrophages causes the size of the node to increase. Alternatively, in increases in size related to pathologic processes, the node may increase in size because bacteria, fungus, virus, or metastatic cells may fill the node.

History

In most situations, performing a thorough history, a review of symptoms, and a physical examination can establish the likely etiology of the lymphadenopathy and prevent any further tests.

Evaluation of the child with lymphadenopathy may begin with specific aspects of the enlarged lymph node or nodes and then expand to encompass the various aspects that may have caused it. The duration of lymph node enlargement often guides therapy. In general, benign lymphadenopathy resolves over 4-6 weeks, whereas persistent or progressive lymphadenopathy raises the possibility of malignancy.

In addition to duration, the clinician must evaluate for any associated symptoms. Other general questions include recent or past illnesses, infections, local trauma, or bites. Exposure to drugs and specifically antibiotics is also important because it may shrink the lymph nodes. If no obvious sources of infection are present, the presence of constitutional symptoms such as fever, weight loss, and night sweats are potential signs of malignancy. These are commonly referred to as "B" symptoms. If the patient has recurrent infections, immunodeficiencies such as HIV infection must be considered.

Information regarding family and social history is helpful to exclude associated malignancies and is useful to allay fears that cancer can run in the family. Social history may elicit potential sources of lymphadenopathy, including drinking of unsanitized water, exposure to animals that may carry unique infections, exposure to tuberculosis (TB), exposure to typhoid, and exposure to trypanosomiasis. Activities such as sexual contact are also important to obtain. If the history is otherwise unremarkable, a thorough review of symptoms may establish other aspects of cause.

Physical examination

The physical examination of a child with lymphadenopathy begins as a complete examination and then focuses on the enlarged node(s). The skin and the soft tissue drained by the enlarge node should be carefully examined for signs of inflammation, skin breakdown, and trauma. The character of the lymph node should be noted. Normal lymph nodes are described as soft, easily compressible, and freely mobile. Hyperplastic lymph nodes that develop as a response to viral infections are small, discrete, mobile, nontender, and bilateral. Usually, no accompanying cellulitis or inflammation is present.

Lymph nodes that are acutely infected with bacteria, most often Staphylococcus aureus or group B streptococci,^{[2, 3]} tend to be large, warm, and tender and have surrounding erythema and edema. Chronically infected nodes tend to have discrete margins and are adherent to underlying tissues and have minimal signs of inflammation. Nodes that are associated with malignancy tend to be larger than 2 cm, involve several groups of nodes, and occur in children older than 8 years.^{[4, 5]} Lymphadenopathy associated with malignancy has been described as firm or rubbery, discrete, nontender, and fixed to the skin or underlying structures.^{[2, 5]}

With a thorough physical examination, the clinician is able to broadly classify whether the lymphadenopathy is a local or a general phenomenon. A localized lymphadenopathy usually results from abnormalities of the area in which the lymph node drains (eg, infection), although it cannot be excluded as the first sign of a precocious clinical manifestation in the course of a progressive systemic process. The appearance of a generalized lymphadenopathy suggests a systemic disease and orients the clinician more directly toward serologic and hematologic testing.

Of the regional lymphadenopathies, occipital and preauricular locations are rarely malignant; the former are often related to scalp and outer-ear infections, exanthematous diseases, and toxoplasmosis, whereas the latter are associated with infections of superficial tissue of the orbit, the middle ear, and the parotid glands. Submental lymphadenopathy requires a search for disorders in the anterior portion of the mouth and the lower lip, the submandibular portion of the face, the nose, the maxillary sinus, the mucosa of the oral cavity, the floor of the mouth, and the submental salivary gland.

Laterocervical lymphadenopathy in the upper portion of the neck can be associated with inflammatory or neoplastic disorders of the hypopharynx, the larynx, or the thyroid gland, whereas those in the lower part of the neck are related to disorders of the hypoglottic larynx, the thyroid, and the upper portion of the esophagus. Supraclavicular and epitrochlear enlargement must be considered as red flags for the potential of malignancy.

Enlarged axillary and inguinal lympha nodes are usually of benign etiology. Axillary lymphadenopathy is seen with infections of the upper extremity, chest wall, breast tissue, and intrathoracic lesions. Inguinal lymphadenopathies are caused by sexually transmitted diseases of the genitalia and other infections of the perineum and pelvis.

Enlarged popliteal lymph nodes are generally associated with infections of the foot and leg. Lymphadenopathies of the mediastinum, retroperitoneum, and mesentery usually go undetected during physical examination but are sometimes suspected by compression of the surrounding structures.

The presence of general lymphadenopathy should alert the clinician to the presence of significant pathology. Any of the common viral illnesses may produce generalized lymphadenopathy (eg, Epstein-Barr virus [EBV], cytomegalovirus [CMV], HIV). Even more concerning are the hematogenous malignancies (eg, leukemia, lymphomas) and other malignancies (eg, neuroblastoma, rhabdomyosarcoma). Some rare causes of generalized lymphadenopathy include autoimmune connective tissue diseases and use of certain drugs, particularly phenytoin and carbamazepine.

Lymphadenopathy in children generally occurs following benign etiologies. A thorough history usually points the clinician in this direction. Further, the physical examination guides the physician to the correct etiology by focusing on whether the enlarged nodes are regional or systemic, the exact characteristics of the involved nodes, and any other suspicious findings. Alternatively, if the etiology is still unclear, further investigations such as laboratory and radiographic tests are warranted and are based on the presumed diagnosis. Ultimately, if malignancy is suspected, a definitive biopsy will need to be performed.

Lymph node distribution

Lymph nodes are organized in groups that drain specific regions of the body. This knowledge guides the clinician to inspect particular areas of anatomy when lymphadenopathy occurs.

Lymphatic drainage of the head and neck is traditionally divided into 6 regions. The most important nodes in this grouping are around the internal jugular lymph nodes. The superior aspect is termed region II; it receives lymph from the supraglottic larynx, anterior nasopharynx, and oropharynx via submental and submandibular lymph nodes (region I). The middle portion of the internal jugular chain is region III; it collects drainage from the superior hypopharynx and superior larynx via direct drainage through lymphatic capillaries.

The inferior part of the internal jugular chain is region IV; it collects drainage from the inferior hypopharynx, inferior larynx, and thyroid and supraclavicular regions. Region VI sits in the anterior aspect of the neck; it contains supraclavicular, pretracheal, and thyroid nodes, which drain into region IV. Region IV of the internal jugular chain is the common collecting point for regions I-III and VI. Region V collects lymph from the scalp and posterior nasopharynx. All lymphatic drainage from region V and region IV on the internal jugular chain collect into the jugular trunk (ie, a group of nodes positioned at the internal jugular anterior brachiocephalic veins) and then subsequently into the thoracic duct on the left or directly into the brachiocephalic vein on the right.

The thoracic cavity maintains a distinct collection of lymph nodes, with a slightly complex drainage route that parallels bronchi, arteries, and veins. Each major bronchi division has a collection of nodes called the intrapulmonary lymph nodes, which lie within the lungs and drain each of the lung's corresponding segments. The intrapulmonary nodes drain into a set of nodes, the left and right bronchopulmonary (hilar) lymph nodes, which are located at the junction of each lung and its main bronchi. These nodes collect the lymphatic drainage from the segments of their respective lung.

At the bifurcation of the trachea and beginning of each bronchus, 3 sets of nodes reside, the right and left tracheobronchial lymph nodes and the inferior tracheobronchial lymph nodes. An unusual feature of this anatomy is that the inferior tracheobronchial nodes, also known as the carinal nodes, collect lymph from the left lower lobe but drain that fluid into the right tracheobronchial lymph nodes. This is significant because a suspicious-appearing lymph node in the right hilar region should prompt evaluation of the left lower lobe and the right lung.

Aligned with the sides of the trachea are groups of nodes known as the right and left paratracheal lymph nodes, which collect lymphatic fluid from the right and left tracheobronchial nodes, respectively. The posterior thoracic cavity is drained via the intercostal lymph nodes and into the posterior mediastinal lymph nodes. The anterior thoracic cavity is drained through the parasternal lymph nodes, which are located next to the sternum in the intercostal space. The parasternal lymph nodes collect lymph from the anterior mediastinum and communicate with the medial aspect of the anterior chest wall. The common drainage site for all of the aforementioned lymph nodes is into the jugular trunk and then into the thoracic duct on the left or directly into the brachiocephalic vein on the right.

The thoracic duct is the final common lymphatic drainage system for the lower extremities, pelvis, mesentery, most of the thoracic cavity, left upper extremity, and left head and neck. The thoracic duct is positioned on the right side of the aorta in the abdomen and receives lymph from the cisterna chyli. It ascends up through the thorax in the posterior mediastinum while receiving lymphatic drainage from the intercostal nodes. It crosses over to the left just below the carina and ascends to the level of the junction of the left internal jugular and left subclavian vein, where it connects into the venous system. The upper intercostal nodes and right apical axillary nodes drain directly into the right brachiocephalic vein via the right bronchomediastinal trunk, and lymphatic drainage from the right side of the head and neck drain directly into the right brachiocephalic vein via the right jugular trunk.

The upper extremity lymph node distribution consists of the cubital fossae and axillary region. The axillary group is subdivided into 5 subgroups. The lateral axillary group drains the upper extremity and receives lymph from the posterior axillary group, which in turn drains the posterior chest wall. The anterior axillary nodes drain lymph from the anterior chest wall. The lateral and anterior groups drain into the central axillary group, which in turn drains into the apical axillary (or subclavian) group. The apical axillary nodes drain into the thoracic duct on the left or directly into the brachiocephalic vein on the right.

The intra-abdominal lymphatic drainage parallels the arterial system. Lymph nodes lie in the mesentery, adjacent to an arterial counterpart. Each artery has a cluster of nodes that receives lymph from its corresponding arterial supply: celiac, superior, inferior mesenteric lymph nodes. These nodal groups eventually drain into the cisterna chyli, the beginning of the thoracic duct. The additional role of the mesenteric lymphatic system is to absorb and transport long-chain fatty acids via chylomicrons. Intestinal mucosal immunity is primarily the responsibility of Peyer patches, which are unencapsulated collections of lymphatic tissue in lamina propria located on the antimesenteric side of the ileum. Mesenteric lymph nodes may become enlarged in mesenteric adenitis, a common cause of abdominal pain in children. A recent study that examined CT scans of the abdomen showed that abdominal lymph nodes measuring up to 8 mm may be considered normal.^[6]

The 2 groups that serve the lower extremities are the popliteal nodes and the inguinal nodes. The inguinal nodes are grouped into external and internal subtypes. The external group drains the lower extremity and lymph from the anterior abdominal wall and external genitalia. The internal inguinal nodes then drain into the external iliac nodes, which join the lymphatic drainage of the pelvis, via the internal iliac nodes, to come together in the common iliac nodes. The 2 groups of common iliac nodes drain into the left and right lumbar nodes, beginning just proximal to the bifurcation of the aorta and eventually draining into the cisterna chyli, via left and right lumbar trunks. The cisterna chyli is the beginning of the thoracic duct. The kidneys and adrenal glands drain into lymph nodes around the renal vessels and subsequently into the lumbar nodes.

In most instances, lymph nodes up to 1 cm can still be considered normal. The 2 exceptions to this rule include the epitrochlear node, in which up to 0.5 cm is allowed, and the inguinal nodes, in which up to 1.5 cm is allowed.

An absolute contraindication to lymph node biopsy is recognized if the etiology is clear and if the lymphadenopathy is expected to improve with no further management.

A relative contraindication is recognized if the suspected etiology can be treated expectantly (eg, in cases of bacterial infection of the node in which the use of antibiotics is expected to improve the clinical scenario without a need for biopsy).

Another relative contraindication is acknowledged if an anterior mediastinal mass is noted on chest radiography and considered to be a high anesthetic risk. In this situation, the anesthetic risks need to be balanced with the need for obtaining tissue.