SEARCH

SEARCH BY CITATION

Keywords:

  • horse;
  • diagnostic;
  • thoracic;
  • neoplasia;
  • pulmonary

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Primary thoracic tumours
  5. Metastatic thoracic neoplasia
  6. Paraneoplastic syndromes
  7. Less common differentials
  8. Conclusion
  9. Authors' declaration of interests
  10. References
  11. Supporting Information

The diagnosis of thoracic neoplasia in the horse can be difficult due to the nonspecific nature of the clinical signs and their overlap with other pulmonary diseases. Haematological and serum biochemical evaluation, thoracic ultrasonography, radiography, endoscopic examination, and, where appropriate, thoracocentesis and pleural fluid cytology may all be helpful in reaching a diagnosis. Granular cell tumours are the most frequently reported primary pulmonary tumours of horses. They occur as single or multiple masses adjacent to bronchi and bronchioles, and the mass typically extends into the airway, resulting in partial or complete occlusion of the lumen. Thymic tumours are classified as benign or metastatic, based on evidence of tissue invasiveness, even though they uniformly appear benign histologically. These tumours are derived from epithelial reticular cells of the thymus and are rare in horses. Other primary thoracic neoplasms originate from various pulmonary tissues and are primarily reported as single case reports: pulmonary and bronchial carcinoma and adenocarcinoma, bronchogenic squamous cell carcinoma, bronchial myxoma, pulmonary chondrosarcoma, pulmonary leiomyosarcoma and pleuropulmonary blastoma. Clinical signs of these primary pulmonary neoplasms are dependent on the tumour type and location, but commonly include chronic cough, weight loss, anorexia, fever and respiratory difficulty; ventral oedema, pleural effusion and epistaxis are also frequently observed. Mesothelioma is a rare primary pleural tumour arising from the mesothelium of the pleura, pericardium and peritoneum. The clinical presentation in horses includes weight loss, respiratory difficulty and large volume pleural effusion. The tumour appears ultrasonographically as multiple small nodules on a thick serosal surface and pleural biopsy is diagnostic. Lymphoma is the most common haematopoietic neoplasm in horses, which can present with 4 main manifestations of lesions: mediastinal, multicentric, alimentary and cutaneous. Common clinical features include chronic weight loss, lethargy, anorexia, subcutaneous oedema, lymphadenopathy, colic, bleeding tendency and diarrhoea. Coughing and laboured respiratory effort are often apparent in individuals suffering from mediastinal masses. In such instances, pleural effusion may result in severe pulmonary atelectasis and pulmonary function is significantly compromised. Haemangiosarcoma is the second most common metastatic thoracic neoplasm in horses. Disseminated haemangiosarcoma is aggressive and rapidly progressive. The clinical presentation often includes tachypnoea, pale or icteric mucous membranes, respiratory distress, epistaxis, and subcutaneous, cutaneous or intramuscular masses. Other tumour types that metastasise to the thoracic cavity include adenocarcinoma, squamous cell carcinoma, fibrosarcoma, metastatic melanoma, mastocytoma and undifferentiated sarcoma. The clinical features of these tumours are generally nonspecific and often relate more to the primary site of tumour formation.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Primary thoracic tumours
  5. Metastatic thoracic neoplasia
  6. Paraneoplastic syndromes
  7. Less common differentials
  8. Conclusion
  9. Authors' declaration of interests
  10. References
  11. Supporting Information

Equine patients suffering from pulmonary neoplasia can present a diagnostic challenge. Case details, evidence of respiratory distress, depressed demeanour, pyrexia, ventral oedema and poor body condition collectively aid the clinician in establishing the presence of advanced pulmonary disease. However, allergic and infectious pulmonary diseases can present with overlapping clinical features. The majority of horses suffering from infectious pulmonary disease have a history of chronic, progressive respiratory disease characterised by pyrexia, cough, nasal discharge, travel history and/or respiratory disease among cohorts. Allergic airway disease is commonly accompanied by appropriate environmental factors that trigger the clinical manifestation of disease. Features of inflammation, including neutrophilia, monocytosis, hyperfibrinogenaemia and elevated globulins, often provide insight involving the magnitude andchronicity of the pulmonary disorder, yet these findings are not specific to establish an aetiological diagnosis.

Specific evaluation of pulmonary disease involves haematological and serum biochemical evaluations, thoracic ultrasound, radiography and, potentially, endoscopic examination. When pleural effusion is present, thoracocentesis and cytological examination may reveal diagnostic evidence that aids in making the distinction of septic vs. neoplastic disease. However, cytological evaluation of pleural effusion from a patient with nonexfoliative thoracic neoplasia may not provide definitive diagnostic information, which is the case with many primary metastatic thoracic neoplasms. Conversely, a neoplastic effusion may be colonised by a secondary bacterial pathogen, further masking the diagnosis of primary neoplasia.

Thoracic ultrasonography is a common diagnostic procedure used to examine equine patients with respiratory disease. A valuable component of this examination is the opportunity for the clinician to identify the presence of pleural fluid and establish whether pulmonary consolidation or atelectasis is present. Large volume anechoic effusion is frequently seen in horses suffering from thoracic lymphoma and mesothelioma (Reef 1991). Differentiation from septic exudate must be established in suspect individuals since pleuropneumonia may present with similar clinical features that include depression, respiratory distress, pyrexia and anorexia.

Haemothorax appears as echoic swirling fluid observed during imaging of the thoracic cavity (Reef 1991). The character of the pleural fluid will provide the clinician with an indication of the disease process; cytological analysis will be an important accompanying diagnostic modality to determine the aetiology of the disease process. Trauma or haemangiosarcoma are important differential considerations when haemorrhagic pleural effusion is present. Pleuropneumonia resulting from polymicrobial challenge will result in abundant hyperechoic echoes resulting from free gas within the pleural fluid, sometimes referred to as a composite effusion.

Radiographic imaging of the thorax provides little additional information in horses with a large volume of pleural effusion. However, after evacuation of pleural fluid, thoracic radiography may reveal abnormalities of the pulmonary parenchyma or mediastinum. Not all thoracic neoplasms are associated with pleural effusion. In cases of suspected thoracic neoplasia, due to chronic, unresponsive respiratory disease or evidence of hypertrophic osteopathy, thoracic radiography may be valuable to identify pulmonary and mediastinal masses.

Thoracoscopy is a valuable adjunct diagnostic procedure in horses with thoracic masses and nondiagnostic effusion. As described in the accompanying article (W. Lee et al., unpublished data) and in previous reports (Peroni et al. 2001), thoracoscopy is particularly safe, useful, efficient and cost-effective for the exploration of the pleural space including the mediastinum (Ford et al. 1987; Rossier et al. 1990; Vachon and Fischer 1998). Diagnostic information obtained from this procedure includes thorough visual inspection, as well as fluid and tissue sample collection. Thoracoscopy has been described for the ante mortem diagnosis of a variety of tumour types that include squamous cell carcinoma, haemangiosarcoma and cholangiocellular carcinoma (Ford et al. 1987; Mueller et al. 1993; Pollock and Russell 2006). Although lymphoma has been reported to be the most common thoracic neoplasm in horses (Mair and Lane 1989; Mair and Brown 1993), other lesions may be present within the pleural cavity and pulmonary parenchyma in equine patients. Thoracoscopy provides the clinician with a valuable additional diagnostic modality that may aid in establishing an accurate, efficient diagnosis.

Primary thoracic tumours

  1. Top of page
  2. Summary
  3. Introduction
  4. Primary thoracic tumours
  5. Metastatic thoracic neoplasia
  6. Paraneoplastic syndromes
  7. Less common differentials
  8. Conclusion
  9. Authors' declaration of interests
  10. References
  11. Supporting Information

Primary lung tumours are less common than metastatic pulmonary neoplasms and constitute <10% of all pulmonary tumours (Sweeney and Gillette 1989). Granular cell tumour is the most frequently reported primary pulmonary tumour of horses (Mair et al. 2004). Despite being the most common, only approximately 30 cases have been reported in the literature (Misdorp and van Gelder 1968; Parker et al. 1979; Nickels et al. 1980; Turk and Breeze 1981; Scarratt et al. 1993; Sutton and Coleman 1995; Goodchild et al. 1997; Pusterla et al. 2003). These tumours have been described as myoblastomas and appear to originate from Schwann cells (Bouchard et al. 1995). They occur as single or multiple masses adjacent to bronchi and bronchioles and are locally invasive with no reports of metastasis. The mass typically extends into a large calibre airway, resulting in partial or complete occlusion of the lumen (Fig 1). Some authors suggested a propensity for the right hemithorax, which is not supported by a cumulative review of the literature (Pusterla et al. 2003). Bilateral disease occurs in <20% of the case reports. There is no breed predilection and more females have been reported than males. Despite their size and propensity to occlude large airways, granular cell tumours may result in minimal clinical signs and represent an incidental necropsy finding in some horses.

image

Figure 1. Endoscopic examination identifying a granular cell tumour obstructing the right mainstem bronchus.

Download figure to PowerPoint

In clinically-affected horses, the presenting complaints are chronic cough, exercise intolerance, tachypnoea and weight loss. Horses with advanced disease demonstrate an increased effort of respiration during expiration. Depending on tumour size, auscultation may reveal decreased breath sounds over one hemithorax. Based on age (mean age 13 years) and clinical signs, horses with granular cell tumour are often assigned a presumptive diagnosis of reactive airway disease (heaves) (Pusterla et al. 2003). Failure to respond to therapy leads the clinician to more aggressive diagnostic testing. Focal pneumonia may develop in the pulmonary parenchyma distal to the mass due to poor clearance of respiratory secretions and inhaled particulate material. Horses with focal pneumonia present with fever, depression, abnormal lung sounds and leucocytosis, in addition to coughing. There are no reports of pleural effusion, epistaxis or mediastinal lymhadenapathy in horses with granular cell tumour. Hypertrophic osteopathy has been reported as a paraneoplastic complication of granular cell tumour in some horses (Alexander et al. 1965; Sutton and Coleman 1995; Mair et al. 1996; Heinola et al. 2001).

Routine blood work provides little evidence to advance the diagnosis of granular cell tumour. Thoracic radiography identifies a single, large mass or multiple pulmonary masses near or caudal to the hilus (Mair et al. 2004). Evaluation of magnification in left and right radiographic projections can identify the hemithorax affected by the tumour. Rarely, the tumour cannot be visualised via thoracic radiography. In some cases, the mass may be obscured by focal pneumonic lung (Fig 2a). Focal pneumonia in an atypical pulmonary location (i.e. central or dorsal lung fields) should trigger a suspicion of tumour or inhaled foreign body. Using the tracheobronchial map of the lung reported by Smith et al. (1994), the approximate location of the tumour in the pulmonary tree can be determined for endoscopic examination.

image

Figure 2. a) Thoracic radiograph demonstrating focal pneumonia in an atypical (perihilar) location obscuring the presence of a granular cell tumour in an 18-year-old mare. b) Thoracic radiograph obtained one year later. The granular cell tumour is readily apparent in this image without accompanying focal pneumonia. c) Endoscopic examination reveals near complete obstruction of a third generation bronchus, with minimal compression of pulmonary parenchyma.

Download figure to PowerPoint

There is no report of visualisation of the tumour mass via ultrasonographic examination; however, decreased movement of the pleural surface over the affected hemithorax has been reported in horses with large granular cell masses (Pusterla et al. 2003).

The surface of granular cell tumours is smooth pink to white in colour and occludes or nearly occludes a large calibre airway (Video S1). A main stem bronchus is the most commonly affected airway (Kelley et al. 1995). Biopsy confirmation is difficult and may not be necessary, since the endoscopic appearance of the tumour is distinctive. The external surface of the mass consists of normal respiratory epithelium; therefore, a biopsy sample obtained via endoscopy may be nondiagnostic due to insufficient size and depth (Facemire et al. 2000; Pusterla et al. 2003). To obtain a larger tissue sample, with a greater chance of achieving a diagnosis, a biopsy instrument (such as uterine biopsy forceps) can be passed through a tracheotomy incision at the level of the thoracic inlet (Facemire et al. 2000).

On histopathological examination, neoplastic cells are benign and appear rounded to polyhedral with hyperchromatic nuclei, numerous eosinophilic cytoplasmic granules and indistinct cytoplasmic margins (Kelley et al. 1995; Pusterla et al. 2003). Histochemical and immunohistochemical staining results of these tumours are well-described and suggest that they are composed primarily of neural crest cells, probably myelinating Schwann cells (Bouchard et al. 1995). Morphological features of the equine pulmonary granular cell tumours are similar to those of human endobronchial granular cell tumours (Bouchard et al. 1995; Kelley et al. 1995). In other species (dogs, cats and man), granular cell tumours are reported to occur at many other sites besides the thoracic cavity, including the oral cavity and central nervous system.

Granular cell tumours are presumably slow growing and may be an incidental finding at post mortem examinations. Conservative treatment may produce an acceptable clinical outcome for years in horses with stable clinical signs (Pusterla et al. 2003). The presenting complaint for the horse shown in Figure 2a reflected focal pneumonia, including cough, fever and depression. The granular cell tumour obscured a third generation bronchus (Fig 2c) and compressed only a small portion of pulmonary parenchyma. The mare was treated with a 2 week course of broad-spectrum antibiotics and managed for several years with minimal clinical signs (Fig 2b). Ohnesorge et al. (2002) removed the intraluminal portion of a granular cell tumour mass via transendoscopic electrosurgery. The remaining tumour surface was irradiated using a neodymium:yttrium-aluminium-garnet (Nd-YAG) laser to coagulate and kill residual tumour cells. In most cases, the tumour observed in the airway represents only a small proportion of the total tumour mass. Horses with large tumour masses require more aggressive therapy. Facemire et al. (2000) removed the entire right lung that was affected by multiple large masses. In the reports by Ohnesorge et al. (2002) and Facemire et al. (2000), there was no tumour recurrence after 2 years.

Necropsy examination reveals a single large mass or, more commonly, a large mass with multiple small nodular masses that compress the surrounding parenchyma and invade the lumen of a large airway. There are no reports of metastasis to other organs, primary neoplasia originating from other sites, metastasis to regional lymph nodes or invasion of nonpulmonary tissue (Mair et al. 2004).

Thymic tumours are classified as benign or metastatic, based on evidence of tissue invasiveness, even though they uniformly appear benign histologically. These tumours are derived from epithelial reticular cells of the thymus. Tumour classification has historically included those with a lymphocytic component, epithelial or mixed composition. More recently, the World Health Organization (WHO) has provided classification recommendations to include: A, AB, B1, B2 and B3 (Dadmanesh et al. 2001). The equine case report that utilised this classification scheme describes a type A tumour characterised by proliferation of spindle cells without nuclear atypia that contain no more than a few non-neoplastic lymphocytes and inconspicuous nuclei (Shahriar and Moore 2010). Thymic tumours are rare in horses. In an original report of 2 cases, they were considered incidental post mortem findings without evidence of metastasis (Migaki 1969).

Malignant thymoma has rarely been reported to affect horses (Whiteley et al. 1986; Furuoka et al. 1987; Shahriar and Moore 2010). A mediastinal mass, associated lymphadenopathy and marked pericardial involvement was reported in one case (Furuoka et al. 1987). In addition to cranial thoracic disease, the affected Percheron mare had evidence of pulmonary lymph node involvement, extensive parenchymal pulmonary disease, abdominal and retroperitoneal lesions. A separate report described a mixed breed mare affected by a squamous cell thymoma, which demonstrated a markedly more aggressive nature (Whiteley et al. 1986). This latter report described the lesions to extend from the intermandibular space to the thoracic inlet. Post mortem examination revealed the mass to involve the mediastinum and pericardial sac. Pulmonary nodules were diffusely present and were confirmed on histopathology.

A recent report describes an 18-year-old Tennessee Walking Horse which died suddenly while on a trail ride (Shahriar and Moore 2010). Post mortem examination revealed the pleural cavity and pericardial sac to contain a combined volume of 300–500 ml of serosanguineous fluid. A large mass was found to occupy the cranial thoracic cavity and was adherent to the thoracic wall. The architecture of the right atrium was significantly distorted, which also involved the tricuspid valve. Histopathological evaluation of the mass revealed few characteristics of neoplasia, consistent with previous reports of thymic tumours in horses. This tumour was classified in accordance with the WHO classification system as a type A thymoma with proliferation of spindle-shaped cells with oval to elongated nuclei, lack of nuclear atypia and a lack of neoplastic lymphocytes with inconspicuous nuclei. A predominant feature of this neoplasm and the findings in this reported case is the lack of neoplastic nature identified on histopathology, despite the aggressive behaviour of the tumour in the host. In the reported case, cardiac invasion was attributed to lymphatic drainage or direct local invasion, although haematogenous spread was also considered a possibility (Shahriar and Moore 2010).

Other primary thoracic neoplasms originate from various pulmonary tissues and are primarily reported as single case reports: pulmonary and bronchial carcinoma and adenocarcinoma (Dill et al. 1986; Uphoff and Lyncoln 1987; van Rensburg et al. 1989; Anderson et al. 1992; Mair and Brown 1993); bronchogenic squamous cell carcinoma (Schultze et al. 1988); bronchial myxoma (Murphy et al. 1978); pulmonary chondrosarcoma (Clem et al. 1986); pulmonary leiomyosarcoma (Rossdale et al. 2004); and pleuropulmonary blastoma (Pérez-Écija et al. 2009; Woolford et al. 2010).

Clinical signs of primary pulmonary neoplasms are dependent on the tumour type and location. Chronic cough, weight loss, anorexia, fever and respiratory difficulty are common clinical findings in horses with pulmonary neoplasia regardless of the tissue of origin. Ventral oedema, pleural effusion and epistaxis are not unusual in horses with pulmonary neoplasia. Most case reports involve aged horses (>12 years), although pleuropulmonary blastoma has been reported in a neonate and a young mature horse (Pérez-Écija et al. 2009). As in human patients, this tumour is characterised by mixed epithelial and mesenchymal elements and aggressive malignancy. The clinical presentation of pulmonary leiomyosarcoma is similar to granular cell tumour, with the exception of the presence of epistaxis (Rossdale et al. 2004).

Mesothelioma is a rare primary pleural tumour arising from the mesothelium of the pleura, pericardium and peritoneum. In man, this malignancy is associated with asbestos exposure. The clinical presentation in horses includes weight loss, respiratory difficulty and large volume pleural effusion. Differentiation of neoplastic mesothelial cells from reactive mesothelial cells is difficult on cytological examination of pleural effusion. The tumour appears ultrasonographically as multiple small nodules on a thick serosal surface, and pleural biopsy is diagnostic. There is no treatment and the prognosis is grave (Straub et al. 1974; Kramer et al. 1976; Carnine et al. 1977; Wallace et al. 1987; Colbourne et al. 1992; Mair et al. 1992; Fry et al. 2003).

Most cases of primary thoracic neoplasia have an extended history of cough and nonspecific signs of weight loss and anorexia (Mair et al. 2004). The most common first-opinion diagnosis in horses with pulmonary neoplasia is heaves, followed by low-grade pneumonia and pleuropneumonia. In some cases, the definitive diagnosis is not identified for months to years. With the exception of granular cell tumour, there are limited options for therapeutic intervention and the prognosis is grave at the time of diagnosis (Sweeney and Gillette 1989).

Metastatic thoracic neoplasia

  1. Top of page
  2. Summary
  3. Introduction
  4. Primary thoracic tumours
  5. Metastatic thoracic neoplasia
  6. Paraneoplastic syndromes
  7. Less common differentials
  8. Conclusion
  9. Authors' declaration of interests
  10. References
  11. Supporting Information

Equine lymphoma is the most common haematopoietic neoplasm in horses, which can present with a variety of clinical signs that have been previously described (Neufeld 1973a,b; Cotchin 1977; van den Hoven and Franken 1983; Platt 1988; Mair and Brown 1993; East and Savage 1998; Taintor and Schleis 2011). Classification involves 4 main manifestations of lesions: mediastinal, multicentric, alimentary and cutaneous. When present in the thoracic cavity, this manifestation of lymphoma is not considered a true primary neoplasm, since it originates from an extrathoracic site (Mair and Brown 1993). Lymphoma is most commonly a disease of mature horses without a tendency toward breed or gender (Platt 1988).

Clinical signs of lymphoma typically relate to the primary organ system involvement. Common clinical features of the disease include chronic weight loss, lethargy, anorexia, subcutaneous oedema, lymphadenopathy, colic, bleeding tendency and diarrhoea (Rebhun and Bertone 1984; Reef et al. 1984; Adams et al. 1988). Although the disease has an insidious progression, it is not uncommon for cases to present with a relatively acute change or deterioration in condition. It is likely that the time of presentation relates to a stage of disease where the clinical manifestation has become pronounced.

Ventral oedema is a common clinical finding in association with lymphoma, resulting from lymphatic obstruction. Coughing and laboured respiratory effort are often apparent in individuals suffering from mediastinal masses. In such instances, pleural effusion may result in severe pulmonary atelectasis and pulmonary function is significantly compromised.

Haematological and serum biochemical testing are nonspecific with regard to provision of diagnostic evidence for the presence of thoracic lymphoma. Thoracic radiography may identify a pleural fluid line and, in some instances, reveals the presence of a mediastinal mass. Thoracic ultrasonography provides specific evidence regarding the presence, depth and character of pleural fluid. Thoracocentesis is an important diagnostic procedure that will provide the clinician with evidence of the nature of fluid. Cytological examination provides evidence of lymphoma, when the tumour is exfoliative. In some instances, concurrent sepsis may be identified; therefore, careful examination of lymphocyte morphology should be performed. When overlapping conditions exist, such as sepsis with mediastinal lymphoma, a lack of response to appropriate medical therapy should alert the clinician to the potential for complicating factors rather than a primary pleuropneumonia. Thoracoscopy may be particularly helpful in these cases. When enlarged peripheral lymph nodes are present, biopsy is strongly recommended to aid in diagnostic confirmation of lymphoma (Fig 3). Fine needle aspirates do not provide information regarding (disrupted) nodal architecture and are difficult to cytologically differentiate from reactive lymph nodes.

image

Figure 3. Submandibular lymphadenopathy in a 13-year-old mare suffering from lymphoma.

Download figure to PowerPoint

Peripheral lymphadenopathy is an uncommon clinical feature of disease (Meyer et al. 2006), yet when lymphadenopathy develops, the prescapular or submandibular nodes are most commonly enlarged. Post mortem examination typically reveals conclusive evidence of lymphoid pathology (Fig 3). When examining a patient with suspected lymphoma, rectal palpation is an important component of the physical examination to determine whether abdominal lymphadenopathy is present. A recent report of lymphoma described an 18-year-old mare with a presenting complaint of severe pruritus, alopecia, pyrexia, mammary gland enlargement and lymphadenopathy (Mendes et al. 2011). This mare was determined to be suffering from primary T cell lymphoma that primarily affected the mammary gland. Haematological dyscrasias that may be present in lymphoma cases include hyperglobulinaemia, hypercalcaemia and anaemia. Rarely, leukaemia may be identified, which typically represents bone marrow involvement. The mare reported by Mendes et al. (2011) suffered from pyrexia and anaemia, which resulted from paraneoplastic complications. Pruritus has been previously described to occur as a paraneoplastic condition in horses (Finley et al. 1998) and has been identified in approximately 25% of human patients suffering from Hodgkin's lymphoma.

A recent report described a mare with significant submandibular lymphadenopathy and respiratory distress that was later diagnosed with lymphomatoid granulomatosis (Keen et al. 2004). Although the mare had clinical findings to suggest a more typical case of lymphoma, this mare had evidence of marked lymphocytosis on haematological examination. Morphological evaluation of these cells revealed that approximately 98% of the cells were classified as atypical T cells. Additional clinical findings included anaemia and thrombocytopenia. On post mortem examination, unencapsulated nodules were scattered throughout all the lung lobes, without obvious involvement of other organs. However, microscopic examination of the skin revealed perivascular and mural infiltrates of neoplastic mononuclear cells closely associated with affinity for vascular elements. Neoplastic cells were characterised to have oval or cleaved nuclei with characteristics of neoplasia represented by multiple nucleoli and evidence of mitosis among cells. Lymphomatoid granulomatosis is a rare form of lymphoma that has been previously identified in man (Liebow et al. 1972), dogs (Lucke et al. 1979; Postorino et al. 1989; Berry et al. 1990; Leblanc et al. 1990; Fitzgerald et al. 1991) and cats (Valentine et al. 2000). The findings in this mare were supportive of this diagnosis for the first time in a horse. Interestingly, her lesions involved primarily the submandibular lymph nodes, pulmonary tissue and skin. The leukaemic nature of disease in this horse was believed to represent a consequence of the angioinvasive progression of disease. This differential consideration should be considered for clinical disease that presents in a similar fashion with clinical and histopathological findings to support this diagnosis.

Classification of tumour type has become a routine component of the clinical evaluation of lymphoma. Specifically, diagnostic modalities utilised for tumour classification include immunophenotypic examination with flow cytometry and immunohistochemical staining on tissue samples. Immunophenotypic evaluation of pleural fluid can be performed to determine lymphocyte surface marker expression, which can aid with the characteristic nature of neoplasia. Flow cytometry of fluid effusions is analysed for surface expression of major histocompatibility II (MHC II), CD4, CD5, CD8α or CD8/α/β (Roberts 2008). When tissue samples are available, immunohistochemistry is utilised to establish cell surface expression, which provides criteria for tumour classification (Kelley and Mahaffey 1998; Meyer et al. 2006). Cellular staining provides diagnostic evidence for the distinction between T and B cell lineage neoplasms. Standard staining protocols involve identification of CD3 for T cell lesions and CD20, CD21 and/or CD79α for B lymphocyte surface marker. Several veterinary laboratories offer diagnostic services that can aid in the specific identification of tumour type. Examination of DNA ploidy may aid in characterisation of neoplastic cell populations in some clinical investigations (Ross 1996; Davis et al. 2002).

Classification of equine lymphoma has been hindered by documentation of relatively few cases. An original report examined 31 horses with diagnostic confirmation of lymphoma. Among these cases, 24 (77%) horses had lymphoma derived from B lymphocytes with an infiltration of non-neoplastic T lymphocytes, therefore termed T cell rich B cell lymphoma (TCRBCL) (Kelley and Mahaffey 1998). This investigation concluded that not all equine lymphomas can be classified; however, among equine tumours that can be classified, there is an apparent tendency towards TCRBCL.

In contrast, a more recent investigation that utilised immunophenotyping, classified 37 cases of equine lymphoma (Meyer et al. 2006). Among all tumours, 34 (91%) of the neoplasms involved multiple lymphoid tissues in addition to abdominal or thoracic organs. Twenty-six (70%) of the cases were identified to be of T cell origin, 7 of B cell origin and 4 were not able to be classified. Immunophenotyping was performed on effusions and were found to be consistent with the immunohistochemical findings in 6 tumours (Meyer et al. 2006). The investigation of this population concluded that most horses had large T cell tumours, a concurrent inflammatory response was common and many horses had mediastinal masses. This population of affected horses was uncharacteristically young, aged <5 years. Anaemia was the most common cytopenia and was frequently associated with agglutination and hyperglobulinaemia. Thrombocytopenia and neutropenia were identified in association with myelopthesis (Meyer et al. 2006). Although equine lymphoma is relatively uncommon, an effort to establish a diagnosis early in the course of disease would be expected to enhance the chance for a favourable case outcome should chemotherapy be a therapeutic option.

Post mortem examination typically reveals large volume pleural effusion and associated ventral pulmonary atelectasis. Cranial mediastinal masses are commonly present and are often composed of coalescing enlarged lymph nodes. Such masses may occlude the thoracic inlet contributing to obstruction of blood flow and lymphatic drainage. Regional and local lymph nodes are commonly enlarged. In some instances the pulmonary parenchyma may be infiltrated with neoplastic lesions as well as other organs that may be involved including: liver, kidney, spleen and, potentially, gastrointestinal tract (Mair and Brown 1993; Scarratt and Crisman 1998).

Haemangiosarcoma appears to be the second most common metastatic thoracic neoplasm in horses. In a series of 35 cases, pulmonary parenchyma and pleura were involved in 77% of the horses (Southwood et al. 2000). The age distribution of affected horses is clustered around middle-aged (mean age 12 years, range 3–27 years). Pulmonary haemangiosarcoma is not unusual in horses aged 6–7 year (Valentine and Ross 1986; Johnson et al. 1988; Rossier et al. 1990). Disseminated haemangiosarcoma is aggressive and rapidly progressive. Most horses present in good body condition with an abbreviated history of anorexia and depression. The clinical presentation often includes tachypnoea, pale or icteric mucous membranes, respiratory distress, epistaxis, and subcutaneous, cutaneous or intramuscular masses (Fig 4) (Jean et al. 1994). Anaemia, thrombocytopenia and neutrophilia are the most common abnormalities on routine blood work (Southwood et al. 2000). A large volume of haemorrhagic pleural effusion is present in approximately 20% of the cases (Fig 5), accompanied by ventral oedema and marked respiratory distress. Thoracocentesis provides relief for horses with large volume pleural effusion. Pleural fluid is typically serosanguinous and may be characterised as haemothorax. Cytological examination may or may not reveal neoplastic cells. Trauma is the most common first opinion diagnosis in horses with haemothorax due to haemangiosarcoma (Southwood et al. 2000).

image

Figure 4. Subcutaneous mass on the lateral thorax of a patient with haemangiosarcoma and large volume haemorrhagic pleural fluid.

Download figure to PowerPoint

image

Figure 5. Large volume of haemorrhagic pleural effusion (approximately 60 l) collected from a patient with haemangiosarcoma.

Download figure to PowerPoint

Ante mortem diagnosis is uncommon (Southwood et al. 2000), but has been achieved via cytological evaluation of pleural fluid (Fig 6) and pleuroscopic guided biopsy (Rossier et al. 1990). Biopsy of a haemangiosarcomatous mass can result in further haemorrhage. Plans to manage haemostasis should be considered prior to completing a biopsy in cases of suspected haemangiosarcoma. At post mortem examination, neoplastic tissue is widely distributed to many tissues including the heart, spleen, kidney, skeletal muscle and central nervous system. The spleen is the most common organ of origin, although many other tissues have been reported to be the site of primary tumour formation. Occasionally, the thoracic cavity is considered the primary tumour site with disseminated metastasis to distant sites.

image

Figure 6. Cytological evaluation of sarcoma-type cells identified from pleural effusion from a patient with haemangiosarcoma. Ante mortem diagnosis based on identification of neoplastic cells in pleural effusion is uncommon.

Download figure to PowerPoint

Disseminated haemangiosarcoma should be differentiated from focal haemangiosarcoma of the distal limb in horses aged <3 years (Johnson et al. 2005). These tumours do not demonstrate the same aggressive biological activity and are unlikely to metastasise at the same rate. Surgical resection can be curative and in some cases, the tumour may resolve spontaneously.

Other tumour types that metastasise to the thoracic cavity include adenocarcinoma (Prater et al. 1989; East et al. 1998), squamous cell carcinoma (Ford et al. 1987), fibrosarcoma (Jorgensen et al. 1997), metastatic melanoma (Murray et al. 1997; MacGillivray et al. 2002), mastocytoma (Tan et al. 2007) or undifferentiated sarcoma (Sweeney and Gillette 1989; Mair and Brown 1993). The clinical features of these tumours are generally nonspecific and often relate more to the primary site of tumour formation. Some metastatic tumours will produce a neoplastic effusion and/or damage to intrathoracic structures (Jorgensen et al. 1997; Murray et al. 1997). Cytological evaluation may or may not identify neoplastic cells. Thoracoscopy is an important diagnostic tool to obtain a tissue sample to confirm neoplasia and identify the tissue type (Peroni et al. 2001; Vachon and Fischer 1998).

Paraneoplastic syndromes

  1. Top of page
  2. Summary
  3. Introduction
  4. Primary thoracic tumours
  5. Metastatic thoracic neoplasia
  6. Paraneoplastic syndromes
  7. Less common differentials
  8. Conclusion
  9. Authors' declaration of interests
  10. References
  11. Supporting Information

Paraneoplastic conditions develop in association with neoplasia yet are often unrelated to the primary site of tumour development. Recent reviews will provide the reader with a comprehensive understanding of this condition and specific manifestations in equine cases (Hollis 2011; Johnson and Axiak 2011).

Fever is a common paraneoplastic disorder observed in association with equine lymphoma resulting from cytokine production by the tumour. Interleukin (IL)1, IL6 and tumour necrosis factor are pyrogens that are believed to increase prostaglandin E production by hypothalamic endothelial cells. When pyrexia is identified in combination with anaemia, the differential list must include potential infectious aetiologies such as equine infectious anaemia and piroplasmosis. Immune mediated disorders should also be considered as a primary disease or manifestation of paraneoplastic disease that may also involve intermittent or persistent fevers.

Pruritus has been clearly demonstrated to develop as a paraneoplastic condition associated with equine lymphoma (Finley et al. 1998). Altered T cell function is believed to result in modified cytokine synthesis and secretion. Additional aetiologies for pruritus include nerve entrapment or compression, tumour growth and hepatic involvement leading to bile duct obstruction (Hollis 2011).

Anaemia may result from immune-mediated mechanisms or reduction of bone marrow production, such as with myelophthisis. Anaemia of chronic disease is well-recognised and occurs secondary to a variety of inflammatory conditions. Changes in bone marrow function occur secondary to altered cytokine synthesis. Cytokines that have been implicated in this mechanism include transforming growth factor B, IL1, IL6 and interferon gamma, which upregulate hepcidin synthesis. Hepcidin will antagonise gastrointestinal iron uptake and utilisation. In addition, erythropoietin antagonism results from tumour necrosis factor affecting bone marrow production and function (Hollis 2011).

Hypercalcaemia (calcium >140 mg/l) may result from a paraneoplastic syndrome, although the clinician should consider other differential possibilities as well such as: chronic renal failure, iatrogenic hypervitaminosis D, consumption of wild or day-blooming jasmine (Estrum diurnum) particularly in the south eastern USA, rapid administration of calcium containing solutions, laboratory error and hyperparathyroidism.

The mechanisms of hypercalcaemia occurring in patients suffering from neoplastic disease may include lytic bone metastases, malignant hyperparathyroidism, ectopic tumour production of parathyroid hormone-like hormone (PTHLH, PTHrP), tumour produced prostaglandins (PGE1 and PGE2) and tumour produced osteoclast activating factor (Blackman et al. 1978; Weir et al. 1988; Dascanio et al. 1992). The cDNA sequence for equine PTHLP has been reported (Accession NP_001157453). Although this protein has been clearly defined to result in hypercalcaemia associated with canine tumours such as with lymphoma and anal sac adenocarcinoma (Weir et al. 1986), further investigations are required to more clearly define the relationship of PTHLH in the horse. Reported cases of hypercalcaemia in equine cases suffering from neoplasia are somewhat limited to include disseminated lymphoma and lymphoid leukaemia (Jaeschke and Rudolph 1991, 1992; Finley et al. 1998).

Hypertrophic osteopathy (aka Marie's disease, HO) has been reported in domestic species and is most commonly associated with primary and metastatic pulmonary tumours (Brodey et al. 1958; Brodey 1971; Fawthrop and Russell 1993). The pathogenesis of HO remains incompletely understood. The primary syndrome involves periosteal proliferation on the cortices of long bones (Fig 7). The condition is classically described to occur secondary to an intrathoracic mass, yet may also develop secondary to extrathoracic lesions. Although HO is more common in man and dogs, it also occurs in horses, where it has been reported in association with a variety of pulmonary conditions including infection, neoplasia and trauma (Mair et al. 1996; Mair and Tucker 2004). Thoracic neoplasia is an uncommon disease in horses with HO being rarely reported in affected individuals. This finding is in contrast to the findings in man where up to 10% of patients with thoracic neoplasia develop HO, often characterised by clubbing of the fingers, dermal changes, limb swelling and arthropathy (Fawthrop and Russell 1993). In canine patients suffering from HO, the most common predisposing factor is consistently pulmonary neoplasia (Brodey 1971). The presence of HO in an equine patient should alert the clinician to be aware of the potential for intrathoracic disease to exist.

image

Figure 7. Radiograph of the distal limb of a mare with hypertrophic osteopathy. Note the periosteal proliferation on the first phalanx.

Download figure to PowerPoint

Although HO is a relatively uncommon condition in horses, it has been described to occur in association with pulmonary and extrapulmonary disease. Previous retrospective reports that described HO in horses include a total of 42 cases (Sweeney et al. 1989; Mair et al. 1996, 2004). These reports are divided among individual case reports that date back to 1944 and a more recent retrospective that describes the clinical features of 24 cases (Mair et al. 1996). In this report 71% of the horses were ultimately diagnosed with pulmonary disease. Among those with pulmonary lesions, 40% were neoplastic in origin. In cases with a treatable pulmonary condition, resolution of HO occurred following clearance of the primary pulmonary disease. Limb swellings were present on all 4 limbs and typically occurred in a bilaterally symmetric fashion. In some instances the limbs were cool and comfortable while in others they were warm and sensitive to palpation. Head lesions were present in 2 of the cases that involved the mandible and maxilla (Mair et al. 1996). Stiffness and pain were commonly reported in affected individuals (Fig 7). When intrathoracic disease was present, clinical signs also included cough and dyspnoea. The radiographic findings associated with HO included periosteal new bone formation that was in a palisade fashion. Similar to findings in human and canine cases, in those individuals with a treatable condition, clinical signs resolved upon resolution of the primary disorder. Interestingly, in this report, 3 cases were not identified to have a primary disorder, yet clinical signs resolved following symptomatic therapy with phenylbutazone. In man, indomethacin is a nonsteroidal anti-inflammatory drug that has been reported to provide clinical benefit when used as the primary therapy for the management of HO (Leung et al. 1985).

Less common differentials

  1. Top of page
  2. Summary
  3. Introduction
  4. Primary thoracic tumours
  5. Metastatic thoracic neoplasia
  6. Paraneoplastic syndromes
  7. Less common differentials
  8. Conclusion
  9. Authors' declaration of interests
  10. References
  11. Supporting Information

Differentiating a thoracic tumour from a number of infectious conditions of the thorax can be surprisingly difficult. The accompanying article (W. Lee et al., unpublished data) demonstrates a common dilemma for clinicians in differentiating neoplastic effusion from pleuropneumonia or a mediastinal abscess. Middle-aged and aged horses with solid pulmonary tumours are often mistaken as being affected with heaves. Hydatid cysts and fungal pneumonia are less common conditions that may mimic signs of thoracic neoplasia.

Equine cases of hydatid cyst may present with a large volume of pleural effusion. In Europe, hydatidosis (Echinococcus equinus) is generally well tolerated in horses, and cysts in the liver and lung may be an incidental finding at post mortem examination (Blutke et al. 2010). In the USA, Echinococcus spp. and an unidentifiable aberrant, acephalic metacestode have been identified in the liver and lungs of horses. Occasionally the cyst will rupture, resulting in clinical respiratory difficulty due to large volume pleural effusion. In the USA, this clinical syndrome has been associated with the acephalic metacestode.

Affected horses may have intermittent fever, depression, rapid shallow respiration, pectoral oedema and nonspecific laboratory findings indicative of inflammation (Blutke et al. 2010). A large volume of pleural effusion is a consistent finding in horses with pulmonary and pleural metacestode infection. The effusion has low to moderate cellularity (5–80 x109 cells/l), 20–80% neutrophils, markedly increased protein concentration (50–80 g/l) and may be difficult to differentiate from neoplastic effusion (Rush and Mair 2004). Bacterial and fungal culture of the pleural fluid is negative. Ultrasound examination may reveal a large fluid-filled cyst within the pulmonary parenchyma, on the surface of the diaphragm (Fig 8), and/or within the hepatic parenchyma. Metacestodes may be attached to a thickened pleural surface, or hypoechoic cysts (1 × 4 mm) may be seen floating within the pleural or peritoneal fluid.

image

Figure 8. Ultrasound examination that revealed a large fluid-filled cyst within the pulmonary parenchyma on the surface of the diaphragm in a patient with a metacestode cyst.

Download figure to PowerPoint

The authors treated one horse with an unidentified aberrant, acephalic metacestode using albendazole (10 mg/kg bwt per os s.i.d. × 30 days), thoracic drainage, and surgical debridement of the pleura and cyst (10 × 10 × 17 cm) on the surface of the diaphragm. Disruption of a cyst by centesis or surgery may result in an anaphylactic reaction or seeding of daughter metacestodes within the thoracic cavity. Surgical intervention was performed in this case after 2 weeks of antiparasitic therapy. The horse was asymptomatic 6 weeks after treatment, and remained athletic for years.

The radiographic appearance of fungal pneumonia can be similar to disseminated pulmonary neoplasia. The most common isolate from horses with fungal pneumonia is Aspergillus sp., and the majority of cases occur in horses as a complication of severe gastrointestinal disease. Prolonged neutropenia is a primary risk factor. Clinical signs of fungal pneumonia include tachypnoea, fever, nasal discharge, epistaxis, nasal plaques or erosions, abnormal lung sounds, and pleural friction rubs. Most horses have a history of progression of respiratory disease despite aggressive antimicrobial therapy. A miliary or reticulonodular interstitial pattern is common with multifocal, coalescing nodules visualised in peripheral lung fields in both fungal pneumonia and metastatic neoplasia. Low volume pleural effusion can be detected by thoracic ultrasound, and fibrin plaques may occur on visceral and parietal pleural surfaces. If pleural effusion is identified, pleural fluid samples should be submitted for cytological evaluation and culture. Observation of fungal spores on cytological evaluation and/or culture of fungal elements from transtracheal aspirate samples are not strong indicators of a diagnosis of fungal pneumonia in horses. Culture and histological evaluation of lung biopsy samples provide definitive evidence of fungal pneumonia and differentiation from neoplasia. Fungal mediastinal granuloma appears similar to mediastinal lymphoma on radiographic examination (Fig 9) (Rush Moore et al. 1993). The site is difficult to biopsy percutaneously and is best identified via thoracoscopy.

image

Figure 9. Gross findings of a fungal mediastinal granuloma, which appeared radiographically similar to mediastinal lymphoma.

Download figure to PowerPoint

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Primary thoracic tumours
  5. Metastatic thoracic neoplasia
  6. Paraneoplastic syndromes
  7. Less common differentials
  8. Conclusion
  9. Authors' declaration of interests
  10. References
  11. Supporting Information

Diagnosis of thoracic neoplasia may be delayed because the clinical signs of disease are non-specific. Horses with solid intrapulmonary tumours typically present with chronic cough and weight loss, and are often treated for heaves for a period of months before performing additional diagnostic tests. Neoplastic conditions that produce pleural effusions may mimic the clinical signs of infectious pleuropneumonia, and secondary bacterial infections further complicate the diagnosis of thoracic neoplasia. Pleural effusion and intrathoracic masses are readily visualized using thoracic radiography and ultrasonography; however, the diagnosis of neoplasia may not be apparent based on imaging alone. Pleural cytology does not always reveal neoplastic cells. Endoscopic examination of the lower airway and thorascopic biopsy are valuable tools to definitively diagnose thoracic neoplasia. Early diagnosis of thoracic neoplasia may improve the outcome for horses with granular cell tumour, and timely diagnosis of neoplasia in horses with a grave prognosis will minimize patient suffering and reduce client costs.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Primary thoracic tumours
  5. Metastatic thoracic neoplasia
  6. Paraneoplastic syndromes
  7. Less common differentials
  8. Conclusion
  9. Authors' declaration of interests
  10. References
  11. Supporting Information

Supporting Information

  1. Top of page
  2. Summary
  3. Introduction
  4. Primary thoracic tumours
  5. Metastatic thoracic neoplasia
  6. Paraneoplastic syndromes
  7. Less common differentials
  8. Conclusion
  9. Authors' declaration of interests
  10. References
  11. Supporting Information

Video S1. Videoendoscopy of the right bronchus of an 18-year-old mare with chronic cough. The mare is intermittently coughing during the procedure. A granular cell tumour was identified obscuring a third generation bronchus. The approximate location of this mass (region of interest) was determined using lateral radiographic projections obtained from the right and left hemithorax and the trachobrnchial map of the lung, reported by Smith et al. (1994). Transendoscopy biopsy was successful in identifying the tumour type in this mare. Because the mass is covered with normal respiratory epithelium, this method is not always successful in obtaining a representative biopsy.

FilenameFormatSizeDescription
eve326_sm_VideoS1.avi3842KSupporting info item

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.