Differential Diagnosis of Lymphadenopathy
World Small Animal Veterinary Association World Congress Proceedings, 2004
Michael J. Day, BSc, BVMS(Hons), PhD, FASM, DECVP, MRC Path, FRCVS
School of Clinical Veterinary Science, University of Bristol
UK

INTRODUCTION

Enlargement of lymph nodes is a common clinical finding in dogs with a wide range of underlying disease states, but may sometimes be the primary presenting complaint. Technically, the term "lymphadenomegaly" is the correct description for lymph node enlargement, but "lymphadenopathy" (lymph node pathology) is generally used synonymously. Lymphadenopathy may involve peripheral (palpable) lymph nodes and/or internal visceral lymph nodes. Lymphadenopathy may be localised (solitary or regional) or generalized in distribution. "Lymphadenopathy" might also encompass situations where lymph nodes are reduced in size, for example in senility, cachexia, primary immunodeficiency disease or with viral infection or immunosuppression that depletes lymphoid tissue. Further, lymph nodes might display pathological change (e.g., the presence of metastatic tumour) without necessarily being enlarged.

PATHOGENESIS

Lymphadenopathy is not a specific disease entity, but is an important clinical finding, the cause for which should be ascertained whenever it is recognised. There are numerous differential diagnoses for canine lymphadenopathy1. The investigation of lymphadenopathy is generally one part of an overall clinical examination, and the interpretation of lymphadenopathy should always be made in light of knowledge of underlying local or systemic disease in the patient.

The first distinction that is made in the investigation of lymphadenopathy is whether the change is localised or generalised. Enlargement of a single lymph node, or unilateral enlargement of paired lymph nodes, most likely reflects pathological change in the tissue drained by that node. For example, oral infectious or neoplastic disease will often result in uni-or bilateral submandibular lymphadenopathy. Enlargement of multiple lymph nodes, particularly at distant sites not directly related to each other, is a potentially more significant clinical finding and suggests a multisystemic or multifocal disease process.

The single most common cause of lymphadenopathy in the dog is primary lymphoid neoplasia (lymphoma) affecting the node. However, approximately one third of enlarged lymph nodes in one large series of dogs presenting with primary lymphadenopathy were not due to lymphoma2. These differential diagnoses included:

 Reactive hyperplasia

 Primary or secondary inflammation of the node (lymphadenitis)

 Mineral-associated lymphadenopathy

 metastatic neoplasia

 Lymph node haemorrhage, infarction or oedema.

The pathogenesis of lymphoma is discussed elsewhere. Lymph node involvement might occur in most of the various anatomical forms of lymphoma in the dog, and lymphoma might be more likely to induce multiple or generalised lymphadenopathy3.

Reactive hyperplasia is the most common cause of benign lymphadenopathy, and reflects activity of the node as part of a local or general immune response. Hyperplasia (increased cell number) involves the cortical (follicular) and paracortical B and T lymphocytes respectively, and the plasma cells of the medullary cords. Reactive lymph nodes have increased lymphatic flow and there is evidence of this increased drainage from tissue from the presence of numerous phagocytic cells (macrophages and dendritic cells) within the medullary sinuses (sinus histiocytosis).

Lymphadenitis is inflammation of the lymph node. Most commonly, this is secondary to an inflammatory/infectious process in the tissue drained by the node. Some such processes will however have a primary focus within the node in the absence of local tissue changes. There is a wide range of infectious causes of lymph node enlargement, but in general pathogens that induce chronic inflammation (particularly intracellular pathogens) are most likely to induce this type of lymph node pathology. Leishmania and the range of systemic mycoses are good examples of this type of pathology. Increasingly, pathologists recognise a syndrome of "sterile granulomatous lymphadenopathy" where there is inflammatory change in an enlarged lymph node, but conventional methodology fails to demonstrate an infectious cause. This syndrome most likely represents infection with an unconventional pathogen that might require more sensitive molecular diagnostic approaches.

Mineral-associated lymphadenopathy (mineral-associated disease, MAD) was first documented in the UK in the late 1980s, and is now commonly recognised in that country as a significant cause of canine lymph node enlargement4. Affected dogs present with a range of non-specific clinical signs (e.g., malaise, pyrexia, inappetence) in conjunction with multiple lymphadenopathy5. The diagnosis is made histopathologically, and is characterised by granulomatous lymphadenitis with the accumulation of large quantities of crystalline, mineral material within the node. Electron microprobe analysis of this mineral reveals it to comprise a complex mixture of elements. Many of these comprise extraneous environmental elements (e.g., aluminium, silicon, titanium, nickel) that are presumed to have an environmental origin, but the precise source and means of entry to the body and deposition within peripheral lymph nodes has not yet been determined.

Lymph node enlargement secondary to metastatic spread of neoplasia can involve any lymph node draining malignant neoplastic tissue. Lymph node enlargement due to a range of other causes (haemorrhage, infarction, oedema) might occur--but again often reflects changes in local or surrounding tissues.

Predispositions to lymphadenopathy

There is no particular geographical prevalence for the various causes of canine lymphadenopathy. There are few data suggesting that lymphoma has geographical distribution in the dog. Some systemic infectious diseases associated with lymphadenopathy (e.g., leishmaniasis) do have distinct geographical distribution largely related to that of the arthropod vector of infection6. Canine mineral-associated lymphadenopathy is widely recognised in the United Kingdom, but does not appear to be often reported elsewhere.

Lymphadenopathy can occur at any age, but there may be some age predilections. Lymph node enlargement post vaccination (draining the site of vaccine administration) might be more commonly observed in pups. Lymphadenopathy due to lymphoma, autoimmune disease or mineral deposition might be more commonly documented in middle aged to adult dogs.

Lymphadenopathy due to some specific causes might have a breed predisposition. For example, lymph node enlargement as part of lymphoma will follow the breed distribution for that neoplasm and might be more common in breeds such as the boxer. Lymphadenopathy occurring as part of histiocytic neoplasia (localised or disseminated histiocytic sarcoma) may be more common in breeds such as the Bernese Mountain Dog or Flat Coat Retriever7. Mineral-associated lymphadenopathy has been more commonly documented in the Doberman and Rottweiler.

DIAGNOSIS

Important historical information for the investigation of lymphadenopathy would include the duration of the process, recent vaccination, trauma, infection or travel to areas endemic for particular infectious diseases. The pathology that underlies lymph node enlargement is generally of insidious onset and the changes occur slowly over time. However, in general terms lymphadenopathy associated with neoplasia may be of longer duration than enlargement due to inflammation or infection.

By definition a dog with lymphadenopathy will have enlargement of one or more lymph nodes. External nodes should be palpably enlarged, and internal lymph node enlargement will be visualized by imaging examination or identified on laparotomy/ laparoscopy. Palpation of most enlarged lymph nodes reveals them to be firm to touch, mobile within surrounding tissues, painless and of normal temperature. The exception to this rule is dogs with lymphadenitis where the nodes are more likely to be soft, warm and tender. Lymph nodes affected by lymphadenitis, or where neoplastic cells infiltrate through the node capsule, are more likely to be adherent to surrounding tissue than mobile within it. The size of the enlarged lymph nodes might also be informative. Extreme enlargement (five to ten times greater than normal) is more likely to occur with lymphoma, metastatic neoplasia or lymphadenitis, than a benign reactive process.

Dogs presenting with lymphadenopathy as a primary clinical problem will often display a range of non-specific clinical signs such as pyrexia, anorexia/anorexia or malaise. The effect of gross lymphadenomegaly will be compromise of adjacent structures--for example enlargement of retropharyngeal nodes might lead to dysphagia, or of cervical/ bronchial nodes might cause dyspnoea. Lymphadenopathy which disrupts the flow of afferent lymph from tissues will be associated with oedema of that tissue site.

The diagnostic approach to lymphadenopathy should always involve a consideration of the entire animal, with view to the identification of any underlying primary disease.8,9 Routine diagnostic procedures such as haematology, serum biochemistry, urinalysis and imaging (survey radiography and ultrasound) may provide valuable diagnostic information that help to refine a differential diagnosis list for lymphadenopathy. Assessment of serum globulins is of particular relevance, as either monoclonal or polyclonal gammopathy might occur in dogs with lymphadenopathy due to lymphoma or infections such as leishmaniasis or monocytic ehrlichiosis6. Possible infectious aetiologies might be confirmed by culture, serology or PCR testing. Similarly, note should be taken of serum calcium concentration, as lymphoma may be associated with the "hypercalcaemia of malignancy".

A specific diagnosis of lymphadenopathy will require either (or both) cytological and histopathological examination of the lymph node. Fine needle aspiration of peripheral nodes (or internal nodes by ultrasound guidance) is simply performed. Cytological examination may provide a definitive diagnosis, but a greater chance of achieving a diagnosis would be obtained by taking a tissue sample for histopathology. Biopsy of a lymph node might be restricted to a needle core of tissue, a partial incisional biopsy, or an excisional biopsy of the entire enlarged node might be considered. The greater the quantity of tissue submitted to the pathologist, the more likely it is that a diagnosis will be achieved. Diagnosis might be refined by the application of panels of special histochemical stains (e.g., for detection of infectious agents) or immunohistochemical stains (e.g., for infectious agents or tumour types).10. Where an infectious cause for lymphadenopathy is possible, a portion of the lymph node biopsy might be submitted freshly for culture. Where a patient has multiple lymphadenopathy, sampling of more than one node is appropriate--the popliteal and axillary nodes are often chosen for their relative accessibility. In general, the single largest node should not be sampled through choice as such nodes may have a necrotic centre and not provide a representative sample. Similarly, the submandibular node should not be sampled through choice as these nodes will often be reactive if a dog has any evidence of gingival disease.

References

1.  Day, MJ. 1999. Diseases of lymphoid tissue. In: MJ Day. Clinical Immunology of the Dog and Cat. Manson Publishing, London. pp. 250-265.

2.  Day MJ, Whitbread TJ. A review of pathological diagnoses in dogs with lymph node enlargement. Vet Rec 1995; 136: 72-73.

3.  Day MJ, Pearson GR, Lucke VM et al. Lesions associated with mineral deposition in the lymph node and lung of the dog. Vet Pathol 1996; 33: 29-42.

4.  Day MJ. Expression of interleukin-1b, interleukin-6 and tumour necrosis factor-a by macrophages in canine lymph nodes with mineral-associated lymphadenopathy, granulomatous lymphadenitis or reactive hyperplasia. J Comp Pathol 1996; 114: 31-42.

5.  Dobson JM, Gorman NT. Canine multicentric lymphoma. 1. Clinicopathological presentation of the disease. J Small Anim Pract 1993; 34: 594-598.

6.  Shaw SE, Day MJ, Birtles RJ, Breitschwerdt EB. Tick-borne infectious diseases of dogs. Trends Parasitol2001; 17: 74-80.

7.  Affolter VK, Moore PF. Localized and disseminated histiocytic sarcoma of dendritic cell origin in dogs. Vet Pathol 2002; 39: 74-83.

8.  Rogers KS, Barton CL, Landis M. Canine and feline lymph nodes. Part I. Anatomy and function. Comp Cont Educ Pract Vet 1993; 15: 397-409.

9.  Rogers KS, Barton CL, Landis M. Canine and feline lymph nodes. Part II. Diagnostic evaluation of lymphadenopathy. Comp Cont Educ Pract Vet 1993; 15: 1493-1503.

10. Day MJ, Kyaw-Tanner M, Silkstone MA et al. T-cell-rich B-cell lymphoma in the cat. J Comp Pathol 1999; 120: 155-167.

Speaker Information
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Michael J. Day, BSc, BVMS(Hons), PhD, FASM, DECVP, MRC Path, FRCVS
School of Clinical Veterinary Science, University of Bristol
UK


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