The lymphatic system plays a critical role in regulating body fluid volume and immune function. Lymphatics originate within the interstitium as specialized endothelial-lined capillaries transporting fluid, solutes, and macromolecular particles back into the venous system. Fluid, protein, cells, and macro-molecular particles from the interstitial space empty into the initial lymphatics composed of a series of small lymphatic capillaries that begin blindly in the tissues. The lymph then flows through a system of lymphatic vessels that progressively increase in diameter. As lymph flows centrally it passes through at least one lymph node before emptying into larger lymphatic trunks. The deep trunks unite to form two major lymphatic vessels: (1) the thoracic and (2) right lymphatic duct. The thoracic duct drains most of the body and returns fluid into the venous system at the brachycephalic vein or the left subclavian vein. The right lymphatic duct drains the right side of the head and neck and right forelimb.
Lymphatic vessels contain many junctions between individual endothelial cells that are connected to the surrounding extracellular matrix by reticular fibres and collagen. These junctions open when tissue hydrostatic pressure becomes elevated and the anchoring filaments stretch, allowing fluid to move into the vessel. As the fluid is cleared from the interstitium, the connecting fibers contract and the junctions between the endothelial cells close. The opening and closing of these junctions allow them to act as inlet valves, preventing the backflow of lymph into the interstitium. The larger vessels of the lymphatic system have progressively fewer open junctions, increasingly muscular walls, and frequent intralymphatic valves that also prevent backflow of lymph. The action of external muscular contraction along with intrinsic contractility of the lymphatic vessels aid in the movement of lymph through the lymphatic system. Lymph is filtered by at least one lymph node before entering the venous circulation. While in the lymph node, the lymph is in contact with the blood circulation and approximately half of the fluid is drained before leaving into the larger lymphatic ducts.
In addition to its transport function, the lymph system plays a major role in the immunologic responses to infectious agents. It serves as a filtering system to impede the spread of microorganisms and neoplastic cells. The cellular components, in particular the lymphocytes, are indispensable for immunologic reactions and antibody formation.
Lymphatic disorders can be subdivided into those of internal organs, such as intestinal lymphangiectasis, and peripheral lymphatic disorders. Several lymphatic diseases have been recognized in animals, including lymphedema, intestinal lym-phangiectasia, chylothorax, lymphadenitis, lymphocysts, lymphoma, lymphangioma, and lymphangiosarcoma. Types and causes of peripheral lymphatic disorders are summarized in Box Causes of Peripheral Lymphatic Disorders.
Causes of Peripheral Lymphatic Disorders
Lymphangitis, Lymphedema, Lymphadenitis, Lymphadenopathy
- Reactive hyperplasia
- Primary developmental abnormality of lymphatics
- Secondary acquired abnormalities of lymphatics
- Surgical excision of lymphatics or lymph nodes
- Posttraumatic lymphangiopathy
- Neoplastic invasion
- Extrinsic compression of lymph vessels or tissue
- Acute obstructive lymphadenitis
- Chronic sclerosing lymphadenitis/lymphangitis
- Lymphatic atrophy with interstitial fibrosis
- Radiation therapy
- Cystic hygroma, lymphoceles, pseudocyst
Inflammatory Lymphatic Disorders (Lymphangitis and Lymphadenitis)
Lymphangitis and lymphadenitis often occur secondary to local inflammation, particularly involving the skin, mucous membranes, and subcutaneous tissues. Lymphangitis can also result from bacterial or fungal infection or adjacent neoplastic and inflammatory disease. Lymphatics may be affected and occluded as they drain inflammatory agents and their by-products from tissue spaces. In lymph nodes, microorganisms are phagocytized and inactivated or killed by humoral and cellular mechanisms. During this process, lymph nodes may become obstructed, enlarged, warm, and painful. Affected limbs may be locally swollen, and lameness can result. Pyrexia, anorexia, and depression are common, and leukocytosis may be present with acute, severe lymphangitis.
Lymphangitis may become chronic when associated with a granulomatous or static lesion, such as a foreign body, or with unsuccessfully treated acute inflammation. Persistence of inflammatory edema results in mesenchymal cell proliferation, which in turn can cause irreversible thickening of skin and subcutis.
The prognosis is favorable with early treatment. Therapy consists of moist, warm, local compresses or soaks, which reduce swelling and promote drainage. Aggressive local and systemic antibiotic therapy usually promotes recovery in animals with fever and anorexia. Bacterial culture and sensitivity testing should be performed if acute lymphangitis fails to respond to treatment and in cases of chronic lymphangitis. Contrast studies and surgical exploration may be indicated if fistulous tracts or abscesses are present or if a foreign body is suspected.
Lymphedema refers to an accumulation of fluid in the interstitial space resulting from abnormal lymphatic drainage. This term should not be used for other forms of edema, such as circulatory edema related to venous obstruction or generalized edema related to hypoproteinemia. Lymphedema may result when capillary filtration exceeds the resorptive capacity of the veins and lymphatics. The protein rich fluid (2 to 5 g/dL) causes a high osmotic gradient and exacerbates fluid accumulation. Numerous classification schemes have been used to categorize lymphedema. Commonly used causative categories of lymphedema include: overload, inadequate collection into lymphatic capillaries, abnormal lymphatic contractility, insufficient lymphatics, lymph node obstruction, and main lymphatic ductal defects.
Traditionally, clinical effort is undertaken to differentiate primary versus secondary lymphedema. Primary lymphedema refers to an abnormality of the lymphatic vessels or lymph nodes. Secondary lymphedema refers to disease in the lymphatic vessels or lymph nodes due to a different disease process. Secondary lymphedema can occur as a result of neoplasia, surgery, trauma, parasites, radiation therapy, or infection and is more common than primary lymphedema. Distinguishing between primary and secondary lymphedema is often difficult. A disease process involving a lymph node can result in fibrosis and obstruction with secondary lymphedema developing.
Primary lymphedema can result from three principle morphologic and functional abnormalities including (1) abnormalities of large vessels including aplasia or hypoplasia of the thoracic duct and cistema chyli, (2) aplasia of the peripheral lymphatics or congenital valvular incompetence, and (3) lymph node fibrosis or a deficient lymph node size and number.
Lymphedema caused by aplasia, hypoplasia, or dysplasia of proximal lymph channels or popliteal lymph nodes (or dysplasia of both) occurs most often in the hindlimbs of young dogs (). The edema can be transient, observed only during the juvenile period, or permanent. Mild cases are restricted to the hindlimbs, whereas severe cases may progress to whole body edema. Although the condition is frequently bilateral, one limb is often more swollen than the other. A number of cases of suspected congenital lymphedema have been reported. Reported breeds include bulldogs, poodles, Old English sheepdogs, and Labrador retrievers, although it is not dear whether these breeds are at increased risk.
The history may identify chronic limb swelling since birth or edema appearing later in life. The swelling represents a pitting edema of varying magnitude that is neither too warm nor cold. The edema is not usually accompanied by lameness or pain unless massive enlargement or cellulitis occurs. Growth and activity are usually normal, but rest and limb massage do not typically reduce the severity of edema. Total plasma protein, serum protein electrophoresis, hemogram, and blood chemistry are generally unremarkable The diagnosis of primary lymphedema is based on history (age of onset, disease progression, affected limbs, and distribution of edema), and clinical signs. Previous surgery, trauma, or infections should also be noted. Radiographic lymphography may be needed to confirm the diagnosis in subtle cases and is helpful in determining morphology of anomalous lymphatic systems.
The prognosis for resolution of congenital lymphedema is guarded and depends on the cause. Occasionally, dogs that develop hindlimb edema during the neonatal period may improve spontaneously. More frequently, dogs with severe edema of the limbs and trunk succumb during the first few weeks after birth. Chronic lymphatic vessel dilation leads
to loss of contractility and permanent lymphatic valvular dysfunction. Metabolic by-products accumulate and lead to collagen deposition and fibrosis. Complications such as abrasions and infection often develop. Dogs with primary lymphedema should not be used for breeding. Test matings of dogs with congenital lymphedema support the hypothesis of autosomal dominant inheritance with variable expression.
Persistent lymphedema occurs only after destruction or blockage of a considerable number of major lymph channels (or several sequential lymph nodes with their afferent or efferent lymphatics). Factors that can delay or prevent edema formation include opening of collateral vessels, rerouting of lymph flow through peripheral lymphaticovenous anastomoses and perilymphatic routes of lymph drainage, and increased venous fluid uptake. Secondary lymphedema is often related to a combination of lymphatic and venous obstruction. Inhibited venous return increases lymphatic flow by altering Starling’s forces toward increased tissue fluid accumulation. This overloads the lymphatic capillaries and results in the accumulation of fluid in the interstitial space. Distal lymphatics may become more distended, causing loss of valvular competency, stagnation of lymph flow, mural insufficiency, and further accumulation of proteinaceous fluid in subcutaneous tissues. Other common causes include posttraumatic or postsurgical interruption of lymphatics or lymph node excision and blockage of lymph nodes and lymph vessels by compression or invasive neoplasms. Lymphedema resulting from local neoplasia is usually a sign of a widely disseminated and highly invasive malignant process.
Clinical signs associated with secondary lymphedema vary depending on the underlying systemic causes Lymphedema may be localized to the periphery of an extremity () or extend proximally to the subcutaneous tissues. The location and severity of obstruction determine the extent of edema formation. For example, sublumbar or intrapelvic obstruction induces bilateral hindlimb edema and edema of the thighs and external genitalia. Mediastinal masses and thrombosis of the cranial vena cava induce bilateral edema of the front limbs and tissue of the ventral thorax, neck, and head. The clinician must palpate all lymph nodes carefully for enlargement and pain. With bilateral hindlimb edema, it is important to perform rectal or abdominal palpation to assess sublumbar lymph nodes. The prostate and anal region or mammary glands and vaginal area should be carefully inspected for neoplasms, which can lead to obstructive intrapelvic processes. Intrapelvic masses should be suspected in all dogs with hindlimb edema and vague signs of sublumbar pain, discomfort during ambulation, or difficulties with defecation or urination. Depending on the type and extent of underlying systemic illness, limb edema may be the only detectable abnormality or may be accompanied by fever, anorexia, and weight loss. Clinicopathologic findings depend on the underlying primary disorder.
Diagnosis is based largely on history and clinical examination and is facilitated by diagnostic imaging. Survey radiographs should be taken of suspicious areas, which often include the pelvis or cranial thorax. In a substantial number of cases, soft tissue masses or destructive bony lesions can be detected. Abdominal ultrasonography can provide information about soft tissue masses and readily identifies enlarged lymph nodes and other structures. Lymphography or other imaging techniques may be indicated if the diagnosis remains unclear. Lymphography is often relied upon for definitive diagnosis of lymphatic disorders. In some cases the lymphatics are hypoplastic throughout their course. When aplastic, lymphatics suitable for cannulation and injection of radiocontrast agent may not be found. Failure to outline a lymph node after lymphography is not absolute proof of its absence. Lymphographic features of primary lymphedema include lymph node aplasia and small lymphatics that end blindly or anastomose into collateral vessels around (instead of into) lymph nodes where they would be normally found.
Lymphoscintigraphy is an alternative approach for imaging peripheral lymphatics. This technique requires a gamma-camera system and intradermal injection of high molecular weight-radiolabeled colloids. Such equipment and specialized training are not widely available. When compared with conventional lymphography, lymph nodes only appear as hot spots, preventing adequate assessment of nodal structure.
Differential diagnoses for dogs with edema confined to one limb include inflammation, trauma, vascular obstruction, hemorrhage, cellulitis, phlebitis, and A-V fistula. Diagnostic considerations for dogs with edema involving both forelimbs include thrombosis or compression or invasion of the cranial cava by a mediastinal mass. With the latter, edema usually involves the head and neck regions and the limbs. Causes of only bilateral hindlimb edema include obstruction of sublumbar lymph nodes by neoplastic infiltration. If all four limbs are involved, the differential diagnoses should include hypoproteinemia, CHF, renal failure, or portal hypertension. The close association of lymphatic and venous structures can make it difficult to distinguish between lymphatic and venous obstruction, and both can occur at the same time. Ulceration, dermatitis, cyanosis, weeping varices, and fat necrosis are signs of venous obstruction rather than lymph stasis.
Therapy is usually unrewarding. In the early stages of lymphedema, medical management is directed to maintaining the patient’s comfort and reducing swelling. Infectious disorders require long-term antimicrobial therapy. Some neoplastic conditions may benefit from chemotherapy or radiation therapy. Long-term heavy bandage application (e.g. Robert Jones splint) may encourage lymphatic flow and reduce subcutaneous lymph accumulation. Local topical skin care and intermittent antibiotic therapy are helpful in reducing cellulitis. With the exception of isolated instances, pharmacologic therapies are generally unrewarding. The benzopyrones (e.g. rutin) are a group of drugs that have been advocated to reduce high-protein lymphedema by stimulating macrophages, promoting proteolysis, and enhancing absorption of protein fragments. Long-term diuretic administration may be contraindicated, because after reduction of interstitial fluid, proteins in the residual interstitial space proteins may promote tissue injury. Surgical options may include (1) procedures to facilitate lymph drainage from affected limbs (lymphangio-plasty, bridging procedures, shunts, omental transposition), and (2) procedures to excise abnormal tissue. Surgical excision of the subcutaneous edematous tissue should be staged to decrease devascularization. Short-term administration of anti-inflammatory agents or diuretics, bandaging, and physical therapy may be helpful in cases of traumatic and postsurgical induced lymphedemas.