Etiology and Pathogenesis

In this chapter lymphadenopathy is defined as lymph node enlargement. According to the distribution, the following terms are used to characterize lymphadenopathy. Solitary lymphadenopathy refers to the enlargement of a single lymph node. Regional lymphadenopathy is an enlargement of a chain of lymph nodes draining a specific anatomic area. Generalized lymphadenopathy is a multicentric lymph node enlargement affecting more than one anatomic area. Lymphadenopathies can also be classified as superficial or deep (or visceral) according to their anatomic location.

Lymph nodes enlarge as a consequence of the proliferation of normal cells that normally reside in the node, or infiltration with normal or abnormal cells. Rarely, lymph nodes enlarge as a result of vascular changes (e.g., hyperemia, congestion, neovascularization, edema).

When normal cells proliferate within a lymph node in response to antigenic stimuli (e.g., vaccination, infection), the term reactive lymphadenopathy (or lymph node hyperplasia) is used. Lymphoid and MP/AP cells proliferate in response to immunologic and infectious stimuli, although occasionally a clinician evaluates a dog or cat in which a cause for the reactive lymphadenopathy cannot be identified. Because these lymphoid structures are usually presented with many antigens simultaneously, the cell proliferation that occurs in reactive lymphadenopathies is polyclonal (i.e., a wide variety of morphologic types of lymphoid and MP/AP cell types are present in a cytologic or histopathologic specimen).

When polymorphonuclear leukocytes or macrophages predominate in the cellular infiltrate, the term lymphadenitis is used. This is usually, but not always, a result of infectious processes. Depending on the predominant cell type in the infiltrate, lymphadenitides are classified as suppurative (neutrophils predominate), granulomatous (macrophages predominate), pyogranulomatous (macrophages and neutrophils predominate), or eosinophilic (eosinophils predominate). A focal area of suppurative inflammation with marked liquefaction (i.e., pus) is referred to as a lymph node abscess. The etiologic agents that commonly cause the different types of lymphadenitis are listed in Table 88-1.

TABLE 88-1 Classification of Lymphadenopathies in Dogs and Cats

D, Dogs; C, cats; RMSF, Rocky Mountain spotted fever.

Modified from Hammer AS et al: Lymphadenopathy. In Fenner NR, editor: Quick reference to veterinary medicine, ed 2, Philadelphia, 1991, JB Lippincott.

Infiltrative lymphadenopathies usually result from the displacement of normal lymph node structures by neoplastic cells and, more rarely, from extramedullary hematopoiesis. Neoplasms affecting the lymph nodes can be either primary hematopoietic tumors or secondary (metastatic) neoplasms. Lymph node infiltration by hematopoietic malignancies (i.e., lymphoma) constitutes one of the most common causes of generalized lymphadenopathy in dogs.

Clinical Features

From the clinical standpoint, familiarization with the location and palpation characteristics of normal lymph nodes, which should always be evaluated during a routine physical examination, is important. The following lymph nodes are palpable in normal dogs and cats: the mandibular, prescapular (or superficial cervical), axillary (in approximately half of animals), superficial inguinal, and popliteal (Fig. 88-2). Lymph nodes that are palpable only when markedly enlarged include the facial, retropharyngeal, mesenteric, and iliac (sublumbar) lymph nodes.

FIG 88-2 Anatomic distribution of clinically relevant lymph nodes in a dog. The nodes are in the same general location in cats. The lymph nodes depicted by the darkened circles include, from cranial to caudal, the mandibular, prescapular, axillary, superficial inguinal, and popliteal lymph nodes. The lymph nodes depicted by the open circles include, from cranial to caudal, the facial, retropharyngeal, and iliac or sublumbar lymph nodes.

(Reprinted from Couto CG: Diseases of the lymph nodes and spleen. In Ettinger SJ, editor: Textbook of veterinary internal medicine—diseases of the dog and cat, ed 3, Philadelphia, 1989, WB Saunders.)

When evaluating dogs and cats with lymphadenopathy or diffuse splenomegaly, the clinician can glean important information from the history. Certain diseases have a defined geographic or seasonal prevalence, including leishmaniasis in the Mediterranean region of Europe, salmon poisoning in the Pacific Northwest, and some systemic mycoses, such as histoplasmosis in the Ohio River Valley. Systemic (constitutional) clinical signs are usually present in dogs with systemic mycoses, salmon poisoning, Rocky Mountain spotted fever (RMSF), ehrlichiosis, bartonellosis, leishmaniasis, and acute leukemia. Clinical signs are rare or absent in dogs and cats with chronic leukemias, anaplasmosis, most lymphomas, and reactive lymphadenopathies occurring after vaccination; cats with idiopathic reactive lymphadenopathy (see the following section) are usually asymptomatic.

Clinical signs in dogs and cats with lymphadenopathy or splenomegaly are vague and nonspecific and are usually related to the primary disease rather than the organ enlargement; they include anorexia, weight loss, weakness, abdominal distention, vomiting, diarrhea, polyuria-polydipsia (PU/PD) (the latter in dogs with lymphoma-associated hypercalcemia), or a combination of these. Enlarged lymph nodes can occasionally result in obstructive or compressive signs (e.g., dysphagia resulting from enlarged retropharyngeal nodes, coughing resulting from enlarged tracheobronchial nodes, edema).

The distribution of the lymphadenopathy is also of diagnostic relevance. In patients with solitary or regional lymphadenopathy, the area drained by the lymph node(s) should be examined meticulously because the primary lesion is generally found there. Most cases of superficial solitary or regional lymphadenopathy in dogs and cats result from localized inflammatory or infectious processes or from metastatic neoplasia (less commonly), whereas most cases of deep (i.e., intraabdominal, intrathoracic) solitary or regional lymphadenopathy result from metastatic neoplasia or systemic infectious diseases (e.g., systemic mycoses). Most cases of generalized lymphadenopathy are caused by systemic fungal or bacterial infections (dogs), nonspecific hyperplasia (mainly cats), or lymphoma (dogs) (Table 88-2).

TABLE 88-2 Correlation between Clinical Presentation and Etiology in Dogs and Cats with Lymphadenopathy in the Midwestern United States (in Relative Order of Importance)

A, Abdomen; T, thorax.

The characteristics of the lymph nodes on palpation are also important. In most dogs and cats with lymphadenopathy, regardless of the distribution, the lymph nodes are firm, irregular, and painless; their temperature is normal to the touch (cold lymphadenopathies); and they do not adhere to the surrounding structures. However, in patients with lymphadenitis the lymph nodes may be softer than usual and more tender and warmer than normal; they may also adhere to surrounding structures (fixed lymphadenopathy). Fixed lymphadenopathies may also be the presenting feature in dogs and cats with metastatic lesions, lymphomas with extracapsular invasion, or ceratin infectious diseases (e.g., mycobacteriosis).

The size of the affected lymph nodes is also important. Massive lymphadenopathy—lymph node size five to 10 times normal—occurs almost exclusively in dogs with lymphoma or lymphadenitis (lymph node abscess formation). In cats the syndrome of distinctive lymph node hyperplasia usually results in massive lymphadenopathy. Rarely, metastatic lymph nodes exhibit this degree of enlargement; the main example of massive metastatic lymphadenopathy is the apocrine gland adenocarcinoma metastases to the sublumbar lymph nodes. Recognizing that lymph nodes of normal size may contain metastatic neoplasia is important. Dogs with salmon poisoning may also have marked generalized lymphadenopathy as the presenting feature, preceded by or in conjunction with bloody diarrhea. Mild to moderate lymph node enlargement (two to four times the normal size) occurs mostly in a variety of reactive and inflammatory lymphadenopathies (e.g., ehrlichiosis, bartonellosis, anaplasmosis, RMSF, systemic mycoses, leishmaniasis, immune-mediated diseases, skin diseases) and in leukemias.

As previously discussed, the area draining the enlarged lymph node(s) should always be thoroughly examined, paying particular attention to the skin, subcutis, and bone. In dogs and cats with generalized lymphadenopathy, evaluation of other hemolymphatic organs is important, including the spleen, liver, and bone marrow.

Clinical Features

The history-taking and physical examination in dogs with splenomegaly are similar to those in dogs with lymphadenopathy. The clinical signs in dogs with splenomegaly are vague and nonspecific and include anorexia, weight loss, weakness, abdominal distention, vomiting, diarrhea, PU/PD, or a combination of these. PU/PD is relatively common in dogs with marked splenomegaly, particularly in those with splenic torsion. Although the pathogenesis of the PU/PD is unclear, psychogenic polydipsia provoked by abdominal pain and distention of the splenic stretch receptors may be a contributory mechanism. Splenectomy in these dogs usually results in prompt resolution of the signs. Other signs associated with splenomegaly result from the hematologic consequences of the splenic enlargement and include spontaneous bleeding caused by thrombocytopenia, pallor caused by anemia, and fever caused by neutropenia or the primary disorder.

During a routine physical examination in pups and cats, the normal spleen is easily palpated as a flat structure oriented dorsoventrally in the left anterior abdominal quadrant. In some deep-chested dogs (e.g., Irish Setters, German Shepherd dogs), the normal spleen is also easily palpated during routine examination, either in the ventral midabdomen or in the left anterior quadrant. This is also the case in Miniature Schnauzers and in some Cocker Spaniels. The fullness of the stomach determines to what extent a normal spleen is palpable in other breeds of dogs. It is easily palpated postprandially because its contour conforms to the greater curvature of the stomach, such that it lies parallel to the last rib. However, not all enlarged spleens are palpable, and not every palpable spleen is abnormal. The characteristics of the spleen on palpation vary. In dogs an enlarged spleen can be either smooth or irregular (“lumpy-bumpy”). In most cats with marked splenomegaly, the surface of the organ is smooth; a diffusely enlarged, lumpy spleen in a cat suggests systemic mast cell disease. As previously discussed, animals with hematologic abnormalities secondary to splenomegaly may also have pallor, petechiae, or ecchymoses.

Clinicopathologic Features

A complete blood count (CBC) and a serum biochemistry profile should be obtained, particularly in dogs and cats with generalized or regional lymphadenopathies and those with diffuse splenomegaly. Changes in the CBC may indicate a systemic inflammatory process (e.g., leukocytosis with neutrophilia, left shift, monocytosis) or hemolymphatic neoplasia (e.g., circulating blasts in acute leukemia or lymphoma, marked lymphocytosis suggestive of chronic lymphocytic leukemia or ehrlichiosis). Occasionally the etiologic agent may be identified during examination of a blood smear (e.g., histoplasmosis, mycoplasmosis, trypanosomiasis, babesiosis). Polymerase chain reaction for clonality and immunophenotyping with flow cytometry are commonly used in our clinic in patients with lymphadenopathy or splenomegaly and circulating abnormal cells or lymphocytosis.

The spleen exerts a marked influence on the CBC, resulting in two patterns of hematologic changes in dogs and cats with splenomegaly: hypersplenism and hyposplenism, or asplenia. Hypersplenism results from increased MP activity, is rare, and is characterized by cytopenias in the presence of a hypercellular bone marrow; these changes resolve after splenectomy. Hyposplenism is more common and results in hematologic changes similar to those seen in splenectomized animals, such as thrombocytosis, schistocytosis, acanthocytosis, Howell-Jolly bodies, and increased numbers of reticulocytes and nucleated RBCs.

Anemia in dogs and cats with lymphadenopathy or splenomegaly can occur as a result of the several mechanisms already mentioned. In brief, anemia of chronic disease can be seen in inflammatory, infectious, or neoplastic disorders; hemolytic anemia is usually present in patients with hemoparasitic lymphadenopathies or splenomegaly and in some dogs with malignant histiocytosis or hemophagocytic syndrome. Severe nonregenerative anemia may be seen in dogs with chronic ehrlichiosis, in cats with feline leukemia virus–related disorders or feline immunodeficiency virus–related disorders, and in dogs and cats with primary bone marrow neoplasms (e.g., leukemias, multiple myeloma).

Thrombocytopenia is a common finding in patients with ehrlichiosis, RMSF, anaplasmosis, sepsis, lymphomas, leukemias, multiple myeloma, systemic mastocytosis, or some immune-mediated disorders. Pancytopenia is common in dogs with chronic ehrlichiosis or systemic immunemediated disorders; in dogs and cats with lymphoma or leukemia; and in cats with disorders associated with retroviral infections.

Two major serum biochemical abnormalities are of diagnostic value in dogs and cats with lymphadenopathy or diffuse splenomegaly: hypercalcemia and hyperglobulinemia. Hypercalcemia is a paraneoplastic syndrome that occurs in approximately 10% to 20% of dogs with lymphoma and multiple myeloma, although it may also occur in dogs with blastomycosis. It is extremely rare in cats with these diseases. Monoclonal hyperglobulinemia commonly occurs in dogs and cats with multiple myeloma and occasionally in dogs with lymphoma, ehrlichiosis, or leishmaniasis (see Chapter 89). Polyclonal hyperglobulinemia commonly occurs in dogs and cats with systemic mycoses; in cats with feline infectious peritonitis; and in dogs with ehrlichiosis, anaplasmosis, or leishmaniasis (see Chapter 89).

Serologic and microbiologic studies should always be conducted in dogs and cats with suspected infectious lymphadenopathy-splenomegaly. Serologic tests or polymerase chain reaction for canine ehrlichiosis, RMSF, brucellosis, and systemic mycoses may help diagnose regional or systemic lymphadenopathies. Lymph node specimens for bacterial and fungal cultures should also be obtained if necessary.

Imaging

Radiographic abnormalities in dogs with lymphadenopathy can be related to the primary disorder, or they can reflect the location and degree of lymphadenopathy. In general, plain radiographs or computed tomography (CT) are beneficial in dogs and cats with solitary lymphadenopathy to search for primary bone inflammation or neoplasia, in those with generalized peripheral (superficial) lymphadenopathy to detect intrathoracic or intraabdominal lymph node enlargement, and in those with deep regional lymphadenopathy involving the thoracic cavity to determine the distribution and size of the affected nodes and the changes in the pulmonary parenchyma and pleural space.

The spleen is normally well visualized on plain abdominal radiographs, but its appearance can vary widely. On dorsoventral or ventrodorsal views, the spleen is seen between the gastric fundus and the left kidney. The size and location of the spleen are more variable on lateral radiographs than on ventrodorsal or dorsoventral projections. In some breeds, such as Greyhounds, the spleen appears to be large on plain radiographs and ultrasonography. On plain radiographs, large splenic masses usually appear in the caudal abdomen or the midabdomen. Tranquilization or anesthesia usually results in a diffuse congestive splenomegaly, making radiographic interpretation of splenic size extremely difficult. CT is a useful diagnostic tool in dogs with focal or diffuse splenomegaly.

Ultrasonography is the noninvasive procedure of choice to evaluate intraabdominal lymphadenopathy and splenomegaly because it can accurately image and show the size of both enlarged lymph nodes and the spleen so that the patient’s response to therapy can be monitored. In addition, ultrasound-guided FNA or biopsies can be performed with minimal complications. Abdominal ultrasonography can reveal diffuse splenomegaly, splenic masses, splenic congestion, hepatic nodules, or other changes; in addition, color-flow Doppler allows evaluation of splenic blood flow. A major issue a clinician frequently must deal with is the incidental splenic nodule in an older dog; these lesions are common and usually clinically irrelevant, but they tend to cloud the clinical picture in a patient with intraabdominal neoplasia. If possible, splenic nodules should be aspirated and evaluated cytologically. Of note, however, is that the presence of hepatic nodules in a dog with a splenic mass does not constitute a valid reason for an owner to decline treatment or request euthanasia because regenerative liver nodules are indistinguishable from metastatic lesions. Moreover, hypoechoic splenic nodules are frequently found in normal dogs.

Radionuclide imaging of the spleen (and less commonly of lymph nodes) using technetium-99m–labeled sulfur colloid has become an accepted method of splenic imaging in human beings and small animals. However, this technique only evaluates the spleen’s ability to clear particulate matter and rarely provides a morphologic diagnosis.

Additional Diagnostics

Evaluation of bone marrow aspirates or core biopsy specimens may be beneficial in dogs and cats with generalized lymphadenopathy or splenomegaly caused by hemolymphatic neoplasia or systemic infectious diseases. For example, acute or chronic leukemia in dogs may be difficult to diag nose on the basis of lymph node cytologic findings alone because the diagnosis is usually that of lymphoma (with the presence of well-differentiated or poorly differentiated lymphoid cells). In those cases, the combination of hematologic and bone marrow findings is usually diagnostic. Bone marrow evaluation should always be done before splenectomy in patients with cytopenias because the spleen may assume the primary hematopoietic function in dogs and cats with primary bone marrow disorders such as hypoplasia or aplasia. Splenectomy in these animals could remove the sole source of circulating blood cells, leading to death.

Cytologic evaluation of lymph node and splenic aspirates provides the clinician with a wealth of information and often constitutes the definitive diagnostic procedure in animals with lymphadenopathy or diffuse splenomegaly. In my experience, cytologic evaluation of appropriately collected specimens yields diagnostic findings in approximately 80% to 90% of dogs and 70% to 75% of cats with lymphadenopathy and in approximately 80% of dogs and cats with diffuse splenomegaly.

Although superficial lymph nodes can be aspirated with minimal difficulty, the successful aspiration of intrathoracic or intraabdominal lymph nodes or spleen requires some expertise and occasionally must be done under the guidance of imaging techniques (e.g., fluoroscopy, ultrasonography, CT) (see Chapter 75). To obtain an FNA of a superficial node, the area does not have to be surgically prepared. However, the aspiration of intrathoracic and intraabdominal structures (e.g., spleen) requires surgical preparation of the area and adequate restraint of the animal. Certain intraabdominal lymph nodes (e.g., markedly enlarged mesenteric or iliac nodes) are easily aspirated transabdominally by using manual isolation of the mass. Iliac lymph nodes can also be aspirated transrectally with a 2- to 3-inch (5 to 7.5cm) needle. Splenic aspirates are obtained with the animal in right lateral or dorsal recumbency with manual restraint or mild sedation. Transabdominal splenic FNA in dogs or cats chemically restrained with phenothiazine tranquilizers or barbiturates usually yields blood-diluted specimens as a result of splenic congestion.

In a patient with generalized lymphadenopathy, the clinician must decide which lymph node to aspirate. Obviously aspiration of a node in which the tissue changes are representative of the ongoing disease is important. Therefore do not obtain a specimen from the largest lymph node because the central necrosis in such a node usually pre-cludes a definitive diagnosis. Because clinical and subclinical gingivitis are common in older dogs and cats, mandibular lymph nodes should not be routinely aspirated because they are usually reactive and findings may obscure the primary diagnosis. The techniques of FNA are described in Chapter 75.

Several reviews of the cytologic evaluation of lymphoid tissues have appeared in the veterinary literature (see Suggested Readings). In brief, normal lymph nodes are composed primarily of small lymphocytes (80% to 90% of all cells); a low number of macrophages, medium or large lymphocytes, plasma cells, and mast cells can also be found. Normal spleens are similar except that RBCs are in high concentration given this organ’s vascularity. Reactive lymph nodes and hyperplastic spleens are characterized by variable numbers of lymphoid cells in different stages of development (small, medium, and large lymphocytes; plasma cells); hematopoietic precursors are common in dogs and cats with splenic hyperplasia. The cytologic features of lymphadenitis-splenitis vary with the etiologic agent and the type of reaction elicited. Etiologic agents can frequently be identified in cytologic specimens from nodes with lymphadenitis. Metastatic neoplasms have different cytologic features depending on the degree of involvement and the cell type. Carcinomas, adenocarcinomas, melanomas, and mast cell tumors are easily diagnosed on the basis of cytologic findings. However, the cytologic diagnosis of sarcomas may be difficult because the neoplastic cells that comprise this tumor do not exfoliate easily. Primary lymphoid neoplasms (lymphomas) are characterized by a monomorphic population of lymphoid cells, which are usually immature (showing a fine chromatin pattern, one or more nucleoli, basophilic cytoplasm, vacuolation) (Fig. 88-3). For a more detailed description of cytologic changes, see Chapter 75.

FIG 88-3 Cytologic characteristics of a lymph node aspirate from a dog with massive generalized lymphadenopathy (lymphoma). Note a monomorphic population of large, round cells with a lacy chromatin pattern (neoplastic cells) intermixed with small, darker, normal lymphocytes. (Wright-Giemsa stain, ×1000.)

When the cytologic examination of an enlarged lymph node or spleen does not yield a definitive diagnosis, excision of the affected node or incisional or even excisional splenic biopsy to obtain a specimen for histopathologic examination is indicated. Excision of the whole node is preferable because core biopsy specimens are difficult to interpret because the lymph node architecture is often poorly preserved. A wedge of tissue can be obtained during a splenic biopsy or, if the surgeon deems it necessary, a splenectomy can be performed. Care should be taken in handling the tissues during surgical manipulation because trauma may induce considerable artifactual changes, which would preclude interpretation of the specimen. The popliteal lymph nodes are easily accessible and are the ones usually excised in dogs and cats with generalized lymphadenopathy.

Once a node is excised, it should be sectioned in half lengthwise, impression smears made for cytologic analysis, and the node fixed in 10% buffered formalin in a proportion of one part of tissue to nine parts of fixative. The specimen is then ready to be sent to a laboratory for evaluation. Samples can also be saved for cytochemical or immunohistochemical evaluation, ultrastructural studies, or microbiologic evaluation, including polymerase chain reaction. The same guidelines apply to the preparation of splenic specimens.