The Lymphoid System

By | April 21, 2016

The Lymph Nodes

In dogs, the primordial structure of the largest lymph nodes is present at 35 to 38 days of gestation, and lymphocytic colonization of the nodes is prominent at 52 to 53 days of gestation (). At birth, puppies and kittens have readily recognizable lymph nodes with a loose reticular structure, low lymphocyte density, and limited organization into cortex and medulla that rapidly proliferates into cortical nodules and medullary cords. Lymph nodes and lymphatic vessels vary in location and number, but their primary function is to participate in immunologic reactions by filtering lymph and recirculating the lymphocytes (). Antigens that gain access to particular body tissues are ultimately found in lymphatic vessels that drain these tissues, making it logical that elements of the immune system are strategically positioned along lymphatic vessels. Although lymph node architecture is relatively uniform throughout the body, nodes near portals of entry of external antigens (mandibular and mesenteric lymph node areas) are often more reactive than nodes in other locations.

Lymph Node Disorders

As a major site of immunologic recognition, lymph nodes are expected to respond to various local and systemic inflammatory, infectious, and neoplastic stimuli. Lymphadenopathy may be characterized by enlargement of lymph nodes that are normally palpable, the presence of nodes that are not usually apparent on examination, or nodes that are simply altered in texture on palpation. Lymph nodes that are typically palpable in dogs and cats are the mandibular, superficial cervical, superficial inguinal, and popliteal lymph nodes. More than one lymph node may be palpable at each anatomic location. The tonsils may be visualized in the oral cavity, and buccal or facial lymph nodes may be found in some normal healthy puppies. Pathology is indicated if the axillary, accessory axillary, cervical, femoral, or retropharyngeal lymph nodes are palpable. Sublumbar and mesenteric lymph nodes must be enlarged to be detected on rectal or abdominal palpation ().

Puppies and kittens are presented with many new antigenic stimuli early in life, and increased lymph node size is an expected part of the immunologic response. Indeed, lymphadenopathy is often noted after routine vaccination. As the animal ages, lymph node size often decreases. Two basic mechanisms result in lymphadenopathy. First, and most commonly, there can be increased number and size of lymphatic follicles with proliferation of lymphocytes and reticuloendothelial elements (immune stimulation). Disease processes causing reactive changes in lymph nodes are listed in Table Diseases Associated with Lymphadenopathy. Second, infiltration of cells that are not normally found in the lymph node (neoplasia) could produce lymphadenopathy. Fortunately, neoplasia is a rare cause of nodal enlargement in puppies and kittens.

Diseases Associated with Lymphadenopathy

Causes of Reactive Hyperplasia

Infectious

Bacterial

  • Staphylococcus species
  • Streptococcus species
  • Pasteurella species
  • Corynebacterium species
  • Bartonella species
  • Brucellosis
  • Salmonellosis
  • Actinomyces species
  • Nocardia species
  • Mycobacterial infection
  • Septicemia

Viral

  • Feline leukemia virus
  • Feline immunodeficiency virus
  • Feline infectious peritonitis
  • Canine distemper
  • Infectious canine hepatitis

Parasitic

  • Demodicosis
  • Sarcoptes
  • Flea infestation
  • Tick infestation

Fungal

  • Histoplasmosis
  • Blastomycosis
  • Cryptococcosis
  • Coccidioidomycosis
  • Sporotrichosis
  • Aspergillosis
  • Zygomycosis

Rickettsial

  • Ehrlichiosis
  • Rocky Mountain spotted fever
  • Salmon poisoning

Protozoal

  • Toxoplasmosis
  • Hepatozoonosis
  • Leishmaniasis

Algal

  • Protothecosis

Noninfectious

Postvaccination

Allergic skin disease

Immune-mediated disorders

Eosinophilic granuloma complex

Dermatopathic lymphadenopathy

Localized inflammation

Idiopathic lymphadenopathy of young cats

Tumor-related reactive hyperplasia

Extramedullary hematopoiesis

Primary Lymphoid Neoplasia (rare)

Lymphoma

Leukemias

Systemic mast cell disease

Metastatic Neoplasia (rare)

Mast cell tumor

Transmissible venereal tumor

Malignant melanoma

Carcinomas

Evaluation of lymphadenopathy should include a detailed history and physical examination. Distribution of the adenopathy is important in determining the type of underlying disease process. If one lymph node or regional group of lymph nodes is involved, the sites drained by these lymph nodes should be carefully examined for evidence of inflammation, infection, or neoplasia. If lymph node involvement is more widespread, primary lymphoid neoplasia or diseases causing systemic antigenic stimulation should be considered.

Useful diagnostic tests include aspiration cytology, biopsy for histologic evaluation, bacterial culture, laboratory testing including serology, survey radiographs, and ultrasonography. Aspiration cytology can be a particularly useful and cost-effective screening test when evaluating animals with lymphadenopathy. The largest lymph node is usually not ideal for the aspiration procedure because it may have a necrotic center and areas of hemorrhage. Mandibular lymph nodes are also not ideal because they typically have reactive changes associated with regional drainage from the oral cavity. Cytology may provide a definitive diagnosis when microorganisms (i.e., bacteria or fungi) are identified and in the rare circumstance of large cell lymphoma. It can also provide a supportive picture of reactive changes that can occur secondary to local or systemic antigenic stimulation with increased numbers of inflammatory cells, including plasma cells, neutrophils, eosinophils, and macrophages.

Several specific disorders affecting lymph nodes in puppies and kittens deserve particular attention. Canine juvenile cellulitis (commonly known as puppy strangles) is a granulomatous and pustular disorder of the face, pinnae, and mandibular lymph nodes of puppies (). Typical affected puppies are between 3 and 16 weeks of age; one or several in a litter may have the condition. Clinical signs include an acutely swollen face with papules and pustules progressing to ulceration and striking mandibular lymphadenopathy. The puppies may also exhibit lethargy, anorexia, pyrexia, and joint pain. Cytologic examination reveals pyogranulomatous inflammation with no microorganisms identified or cultured. Daily treatment with corticosteroids is indicated until the disease is inactive. If there is clinical evidence of secondary bacterial infection, bactericidal antimicrobial agents should be administered simultaneously.

Reactive lymphoid hyperplasia in young cats can present as a transient generalized lymphadenopathy that can develop in the initial viremic stage of many viral infections, including feline leukemia virus and feline immunodeficiency virus. However, in a retrospective study of 132 feline lymph node biopsy specimens, many cases of lymphadenopathy () were not associated with a specific cause and were designated as idiopathic (). Fourteen cats in this study had lymph node hyperplasia with unique histologic features including severely distorted nodal architecture, making differentiation from lymphoma difficult. The cats were young (5 to 24 months old), and lymph nodes were judged to be two to three times normal size. Six of nine cats tested for feline leukemia virus were positive. Prominent generalized peripheral lymphadenopathy was also identified in six cats with biopsy specimens that had histo-logic features compatible with lymphoma. One cat was euthanized, but in the remaining five cats the lymph nodes regressed in size without therapy within 1 to 17 weeks. These studies emphasize the importance of careful interpretation of lymph node biopsy results, particularly for young cats. Infections in young cats with one of the Bartonella species may also contribute to a palpable lymphadenopathy, and can be reported by the veterinary pathologist as reactive lymphoid hyperplasia.

Lymphoma is rare in dogs and cats younger than 12 months (). In one study, the hematopoietic system, brain, and skin were the most frequently affected sites for neoplasia in immature dogs younger than 6 months (). The age-specific incidence for lymphoma for dogs younger than 1 year old was estimated to be 1.5/100,000 dogs per year (). The multicentric form is the most common form of canine lymphoma, making chemotherapy the optimal therapy. Remission rates and survival times vary with the chemotherapy protocol used.

When neoplasia is diagnosed in young cats, hematopoietic neoplasms and lymphoma predominate (). Cats with lymphoma should be tested for feline leukemia virus and feline imunodeficiency virus, as both viruses may be associated with an increased incidence of lymphoproliferative disease. In very young animals, anterior mediastinal and multicentric are the most frequent forms and are often associated with positive retrovirus status. The stage of disease is significantly related to response to chemotherapy, with less advanced stages being more likely to achieve a complete response (). The stage of disease and feline leukemia virus status are both significantly related to survival time, even though feline leukemia virus status does not affect response to therapy (). Combination chemotherapy is recommended for multifocal lymphoma, but radiation can be effective for the limited number of cases with localized disease ().

Lymphedema

Congenital lymphedema usually becomes evident at a young age, often at birth (). Primary lymphedema is caused by an abnormality or disease of the lymph conduction elements of the lymph vessels or nodes. Lymphedema usually has an insidious onset, is initially pitting in nature, painless, and typically begins in the distal part of the limb and progresses proximally (). Lameness and pain are uncommon unless there is massive enlargement or cellulitis. The primary differential diagnosis is an abnormality of the venous system such as venous stasis or arteriovenous fistula. If the edema is bilateral, systemic causes of edema including hypoproteinemia and heart failure must be ruled out.

The Thymus

The thymus is a pale, lobulated organ occupying a portion of the cranial mediastinum. Organ size can vary considerably, with its relative size being greatest in the newborn and its absolute size greatest at puberty. Gradual and continuing thymic involution accelerates after puberty and often coincides with the loss of deciduous teeth. The thymus atrophies, and its cortex is gradually replaced with loose connective tissue and fat. Remnants of the organ do, however, persist until old age (). In the young animal, the thymus can frequently be identified on ventrodorsal or dorsoventral thoracic radiographs as it lies in the cranioventral mediastinal reflection. It is not easily seen on lateral views as it may silhouette with and obscure the cranial margin of the heart ().

In mammals, the thymus is a primary lymphoid organ that is essential for development of T lymphocytes (). Lymphocytes differentiating in the thymus leave and populate secondary lymphoid organs (lymph nodes, spleen, and bone marrow) and other aggregates of scattered lymphoid nodules with T cells. Continual circulation of T cells through the spleen and lymph nodes is important in immune recognition and stimulation. The role of the thymus in immunity is demonstrated by neonatal thymectomy that leads to an impaired ability to mount a delayed hypersensitivity response. The ability to produce an antibody-mediated response is also impaired because antibody production requires T-cell assistance ().

Developmental disorders of the thymus have been reported in both dogs and cats. The organ grossly appears rudimentary; the decreased size may be from reduced numbers of lymphocytes, decreased epithelial framework, or both. The thymus may be involved in cases of wasting syndrome in puppies and kittens that cannot be attributed to a specific etiology (). Other than viral-induced disease, thymic hypoplasia is rare, and presenting clinical signs are likely to be related to immunosuppression (). Recognized congenital abnormalities include an X-linked, severe combined immunodeficiency in a colony of basset hounds established from a single affected female, growth hormone deficiency resulting in immunodeficient dwarfism in a family of Wei-maraners, a syndrome of thymic atrophy in Mexican hairless dogs, acrodermatitis with immunodeficiency in bull terriers, and thymic aplasia associated with a syndrome of hair-lessness in Birman cats ().

Infectious agents, toxins, neoplasia, or malnutrition may cause injury to the thymus resulting in variable degrees of immunodeficiency. Infection with feline leukemia virus, feline immunodeficiency virus, feline infectious peritonitis, canine distemper virus, canine parvovirus, and feline panleukopenia can be associated with thymic and lymph node atrophy at necropsy (). Canine distemper virus, canine parvovirus, and feline panleukopenia are lympholytic and result in thymic necrosis. Feline leukemia virus induces thymocyte apoptosis (a programmed cell death), but thymic hypoplasia does not always occur with feline immunodeficiency virus. Thymic function may be impaired in young animals with severe protein malnutrition resulting in diminished immunoglobulin synthesis, and zinc deficiency in pups has also been shown to result in severe atrophy of the thymus (). Thymic involution is part of the normal process of aging and may be accelerated by any toxic insult.

Thymic neoplasia is usually identified as lymphoma or thymoma. Lymphoma has a higher incidence in cats than dogs and is often associated with feline leukemia virus in this age group. Benign cysts of the ventral mediastinum are uncommon congenital defects and can arise from diverse cell lines including thymic (). Puppies and kittens are typically asymptomatic, and the cysts are incidental findings on thoracic radiographs. After aspiration, benign cysts should be radiographically diminished in size. A mediastinal cystic lymphangioma associated with progressive dyspnea was diagnosed and successfully surgically resected in an 8-week-old puppy ().

An uncommon syndrome of spontaneous thymic hemorrhage has been reported in the canine, often as a cause of death (). Although it is unlikely to be a specific pathogenic entity, spontaneous hemorrhage appears to be confined to the age of thymic involution, as most dogs are younger than 1 year. Some investigators feel that the syndrome may be related to specific histologic changes associated with thymic involution (). During involution, blood vessels within the stroma of the thymus lose their tissue support, dilate, and become thin walled. In one study, some form of trauma was often noted in the immediate history (). Thirteen of 20 dogs had a history that involved a major or minor trauma such as being hit by a car or having the head suddenly pulled back by the owner when running at the end of a leash. The authors speculated that trauma resulting in sudden overstretching of the relaxed neck could be followed by rupture of small vessels in loose tissues like thymus. At necropsy, diffuse thymic hemorrhage, cranial hemomediastinum, and hemothorax are seen. Treatment of spontaneous thymic hemorrhage is immediate blood replacement therapy and other supportive care. Surgical removal of the thymus is seldom needed.

The Spleen

The normal spleen may be palpable in most puppies and infrequently in kittens as a flat structure oriented dorsoventrally in the left anterior abdominal quadrant (). The spleen is one of the major hematopoietic organs during fetal development, although this activity diminishes before or shortly after birth. Although normal adult canine and feline spleens have no hematopoietic activity, the ability to initiate extramedullary hematopoiesis is retained. The spleen, which is the largest mass of lymphatic tissue in the body, has multiple functions including blood cell formation, hemoglobin and iron metabolism, red blood cell destruction, blood filtration, blood storage, phagocytosis, and immune response ().

The spleen has a unique vascular structure through which blood circulates in close contact with macrophages, allowing for ample biologic filtration of cells and particles (). Just as lymph nodes filter lymph, the spleen filters blood (). It is an organ of great immunologic significance because it is a major site for production of antibodies and effector T cells. Formation and storage of red blood cells and antigen trapping occur in the red pulp, whereas the immune response occurs in the white pulp. The spleen helps clear poorly opsonized bacteria and remains a critical line of defense against bloodborne bacteria (). Sepsis after splenectomy and hyposplenism, however, appears to be rare in the puppy and kitten. Postoperative sepsis is more likely to occur in animals that are already immunosuppressed. An intact spleen does provide protection from parasitemia in animals with hemoparasitic infections.

The spleen is a target for many pathologic processes because it is located between the portal and systemic circulation (). The spleen may be a primary disease site, but it can also be affected secondarily by systemic disease and may act as a sentinel organ for an underlying disease process. Diseases that may be associated with splenomegaly in puppies and kittens are listed in Table Diseases Associated with Splenomegaly. Diagnostic evaluation for the specific splenic disorder may include the history, physical examination, hematology, serology, imaging (radiography, ultrasonography), aspiration cytology, and biopsy and would be done in a similar manner for the adult dog and cat.

Diseases Associated with Splenomegaly

Inflammatory

Infectious

  • Bacterial (sepsis, pyometra, peritonitis, endocarditis, brucellosis)
  • Fungal (histoplasmosis, blastomycosis, sporotrichosis)
  • Rickettsial (ehrlichiosis, haemobartonellosis)
  • Viral (feline infectious peritonitis, infectious canine hepatitis)
  • Protozoal (toxoplasmosis, leishmaniasis)

Noninfectious

  • Hemolytic disorders
  • Eosinophilic gastroenteritis
  • Hypereosinophilic syndrome

Other

  • Splenic torsion
  • Penetrating abdominal wounds
  • Migrating foreign body

Noninflammatory

Congestive

  • Splenic torsion
  • Pharmacologic (tranquilizers, anticonvulsants)
  • Portal hypertension (right-sided heart failure, intrahepatic obstruction)

Infiltrative

  • Extramedullary hematopoiesis
  • Neoplasia (lymphoma, leukemias, mastocytosis)

Other

  • Hematoma
  • Splenic rupture secondary to trauma

 

Selections from the book: “Veterinary pediatrics: dogs and cats from birth to six months”. Johnny D. Hoskins. (2001)