Mesothelioma in Dogs

Laurena A. Kavula, DVM; Kenneth S. Latimer, DVM, PhD; Perry J. Bain, DVM, PhD

Class of 2003 (Kavula), Department of Pathology (Latimer, Bain), College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7388

Introduction

Mesotheliomas are rare neoplasms that originate from ectodermal cells that line the body cavities.¹ Healthy mesothelium is composed of a flattened monolayer of mesothelial cells that line the pleural, pericardial, and peritoneal cavities. These cells also cover the tunica albuginea of the testes.² Mesothelial cells are characterized by the presence of microvilli and desmosomes. They also have the potential to phagocytose cells and particulate matter. When mesothelial cells are perturbed following inflammation or irritation, they may increase in size (hypertrophy) and number (hyperplasia). Following fluid accumulation within the body cavities, mesothelial cells may exfoliate and implant on serosal surfaces. Mesotheliomas are malignant neoplasms. Their exfoliated cells also can seed the body cavities. Although multiple tumors often are present, distant metastases are rare.¹ Non-neoplastic mesothelial cells affected by inflammation, irritation, or malignancy may have a similar cytologic appearance to mesothelioma cells. Thus, cytologic distinction of neoplastic and reactive mesothelial cells can be challenging to impossible.²

Signalment

Mesotheliomas usually occur in older dogs, with an average onset at 8 years of age. However, documented cases of mesothelioma have been reported in patients from as young as 7 weeks to as old as 15 years.^2-4 Extremely early age of onset (7 weeks old) suggests that congenital mesothelioma may occur infrequently in the dog.¹ Bouvier des Flandres, Irish Setters, and German Shepherd Dogs appear to be at greater risk for tumor development,² and mesotheliomas are more common in male than in female dogs.

Etiology

In humans, mesotheliomas have been directly correlated with exposure to asbestos.² A history of exposure to asbestos crystals is present in > 70% of human cases. Occupations with a greater risk for the development of mesotheliomas from asbestos exposure include welding, construction, asbestos mining, automotive machinery, and shipbuilding. Family members of these types of workers are also at an increased risk for neoplasia due to exposure to asbestos fibers on the clothing of workers. Humans with asbestos exposure usually have an increased number of asbestos fibers in their lungs (Fig. 1). Asbestos exposure results in genetic damage giving rise to a population of mesothelial cells that begin to secrete growth factors and experience uncontrolled growth. The loss of tumor suppressor gene products aids in the malignant transformation of mesothelial cells. Immunosuppression also has been documented in people with mesothelioma and may play an important role in the development of this cancer.¹

Fig. 1. Microscopic appearance of asbestos fibers (photo from Mesothelioma Help Network)

Asbestos exposure also is believed to contribute significantly to the development of mesotheliomas in dogs. Dogs with mesotheliomas often belong to people who have a lifestyle or occupation with higher asbestos exposure.¹ Dogs with mesotheliomas, like their human counterparts, have been proven to have higher levels of asbestos fibers in their lungs.³

Asbestos fibers are divided into two forms, designated chrysotile and amphibole. In humans, a greater risk of mesothelioma is associated with amphibole asbestos.¹ Ferruginous bodies are fibers that are covered with ferritin and amorphous protein. Typical ferruginous bodies have cores of amphibole asbestos. These bodies are found in human lungs and are evidence of asbestos exposure. In a study involving urban dogs and the incidence of mesotheliomas, dogs with mesotheliomas had an increased number and type of ferruginous bodies when compared with control dogs. Atypical ferruginous bodies also have been found in dogs with mesotheliomas; they were rarely present in control dogs. Thus, dogs in urban settings may have a higher risk for the development of mesothelioma.³ Finally, evidence also suggests that exposure to certain chemicals may increase the risk of mesothelioma.² An example is pentachlorophenol (used as a, herbicide, algaecide, defoliant, wood preservative, germicide, fungicide, and molluscicide), which has been shown to cause mesothelioma in rats.⁵

Clinical Signs

The greatest incidence of mesotheliomas occurs in the pleural cavity, followed by the peritoneal and pericardial cavities.² More than one body cavity may be involved in the neoplastic process.¹ Clinical signs of disease usually are evident for up to one month prior to diagnosis. The major clinical sign of mesothelioma in the dog is dyspnea secondary to body cavity effusions or a large, space-occupying mass.^1,2 Effusion is the result of fluid exudation from the surface of the tumor or from blocked lymphatic channels.¹ Effusion often results in abdominal discomfort, respiratory distress, cough, tachypnea, and exercise intolerance.

Physical Findings

Upon thoracic auscultation, dogs with marked pleural effusion will have muffled heart sounds, decreased lung sounds, and weak peripheral pulse. Pulmonary edema and/or enlarged to globoid heart also may be present. If abdominal mesothelioma is present, effusion will be associated with abdominal distension and lethargy.² Hepatomegaly also may be apparent. Sclerosing mesothelioma is seen in male dogs, especially German Shepherd Dogs. This form of mesothelioma is associated with thick fibrous linings of the abdominal or pleural peritoneum. Movement of the abdominal viscera often is restricted secondary to fibrosis, resulting in vomiting and urinary abnormalities.¹

Diagnosis

A definitive diagnosis of mesothelioma can be challenging, especially in the early stages of disease. If effusion is detected upon physical examination, a complete blood cell count, biochemical profile, urinalysis, radiographs, and ultrasound can provide critical staging criteria. Ultrasound is often useful to evaluate any visceral involvement in the neoplastic process. However, mesotheliomas not visible with ultrasound or CT because they often fail to penetrate the surface of the viscera and may not form discrete masses. In such instances, mesotheliomas may appear only as a diffusely thickened surface.²

In diagnosing mesotheliomas, it must be demonstrated that the neoplasm has originated in the coelomic cavity and has metastasized via transcoelomic implantation. Whenever the majority of neoplastic tissue is located on the coelomic surface, mesothelioma must be considered in the differential diagnosis.¹

Cytology

Cytological evaluation of effusion fluid may be helpful for the diagnosis of cardiac disease, bacterial infection, or other neoplasms such as lymphoma. However, cytological evaluation may not be diagnostic for mesothelioma.¹ Primary cytomorphologic criteria of malignancy include cellular aggregates, pleomorphism (variable cellular appearance), anisocytosis (variation in cell size), anisokaryosis (variation in nuclear size), multinucleation, prominent to irregular nucleoli, increased nuclear to cytoplasmic ratio, monomorphic cellular appearance, and increased mitotic figures.⁶ Hyperplastic mesothelial cells also may exhibit anisocytosis, anisokaryosis, increased nuclear to cytoplasmic ratio, binucleate and multinucleate, and scattered mitoses. Any situation that results in fluid accumulation within the body cavities can induce mesothelial cell hyperplasia and exfoliation with an abnormal cellular morphology (Fig. 2). Therefore, the differentiation between mesothelial cell hyperplasia and mesothelioma may be difficult or impossible (Fig. 3).¹ Furthermore, carcinomatosis (seeding of the body cavities by malignant carcinoma cells) of any type may difficult or impossible to distinguish from mesothelial cell hyperplasia and mesothelioma (Fig. 4).

Cytologic examination of pericardial effusions is less often diagnostic compared to routine abdominocentesis or thoracocentesis. In a recent study, fifty pericardial effusions were analyzed to determine the medical disorder. Approximately 74% of neoplastic effusions (n = 19) were diagnosed correctly, while 13% of nonneoplastic effusions (n = 31) were falsely positive for neoplasia. Based on these results, it was concluded that analysis of pericardial fluid for cytological characteristics did not distinguish neoplastic and nonneoplastic conditions.⁷

Fig. 2. Mesothelial cell hyperplasia and hemorrhage in an abdominocentesis specimen from a dog following blunt trauma (Wright stain).	Fig. 3. Pleomorphic mesothelial cells, nondegenerative neutrophils, and erythrocytes are present in thoracic fluid of a dog with mesothelioma (Wright stain).	Fig. 4. Pleomorphic epithelial cells in the thoracic fluid of a dog with carcinomatosis (Wright stain).

Biopsy and Immunohistochemistry

Due to the fact that cytology of effusion fluid frequently does not confirm a diagnosis of mesothelioma, a definitive diagnosis must be made via biopsy (Fig. 5). Furthermore, immunohistochemical staining often is necessary to differentiate a mesothelioma from other neoplasms.² With the advancement of thoracoscopy and laparoscopy guided biopsies, samples of diagnostic value can be obtained with minimal invasiveness to the patient. Histopathologically, mesotheliomas can be epithelial, mesenchymal or mixed morphologic types. The epithelial form is most common in animals and resembles carcinoma or adenocarcinoma on histopathology.¹ Sclerosing mesothelioma is a variation of the mesenchymal form. This form is similar to sarcoma on histopathology.¹ Based on histopathology of the tumor cells, common differentials include mesothelioma, metastatic squamous cell carcinoma, adenocarcinoma, and sarcomas.^1,7

Fig. 5. Histologic section of a mesothelioma invloving the pleura. A solid nodule (left) is present on the pleural surface. Pleomorphic mesothelial cells (center) are present on the surface and extend into the subjacent tissue as nodules are formed (right).

Immunohistochemical staining can be useful in differentiating mesotheliomas and carcinomas.^1,7,10 Mesotheliomas have been shown to express both vimentin and cytokeratin (high and low molecular weight) intermediate filaments. Pulmonary adenocarcinomas should express cytokeratins but not vimentin. Therefore, immunohistochemical staining may be useful to differentiate carcinomas from mesotheliomas.^1,7

Immunohistochemical staining for antibody 3B5 reactivity, vimentin, and cytokeratins may be useful in the diagnosis of canine mesotheliomas.¹⁰ Experimentally, a monoclonal antibody (designated 3B5) has been developed using canine mesothelioma cells as the immunogen. This monoclonal antibody has been found to bind with high sensitivity to a cytoplasmic antigen that is expressed in canine mesothelial cells. This antibody can be used to identify reactive mesothelial cells in proliferative lesions. Although the monoclonal antibody can distinguish mesothelial cells from carcinoma cells, it cannot differentiate mesothelioma cells from normal or hyperplastic mesothelial cells. The antibody does not stain fibroblasts, fibrosacromas, or stroma; therefore, it may be useful in differentiating sarcomatoid mesotheliomas from sarcomas or reactive fibroplasia.

Ultrastructure

Ultrastructurally, mesotheliomas often have long microvilli with primary and secondary branching that surrounds the entire cell circumference. Neoplastic cells are connected by desmosomes with prominent intracellular spaces. Neoplastic mesothelial cells also have a large volume of cytoplasm with several bundles of tonofilaments around the nucleus, profiles of rough endoplasmic reticulum, scattered glycogen granules, and mitochondria.^3,7

Treatment

Both surgical and medical management have been employed in the treatment of canine mesotheliomas. Surgical excision often is not feasible in dogs with mesotheliomas because the neoplasms are multifocal, locally invasive, metastasize via implantation and lymphatics, and may surround vital structures.^1,2,11 Surgical excision may benefit some patients but by the time of diagnosis there usually is significant local involvement and metastasis of the disease via implantation.^1,2

Marked effusion from the neoplasm or from lymphatic blockage can be managed by repeated thoracocentesis or pericardiocentesis.¹¹ Patients may tolerate these procedures for several months with an improvement in dyspnea, cardiac tamponade, or abdominal distention. However, it eventually may be necessary to perform thoracocentesis or pericardiocentesis every few days.⁴ Pericardectomy may serve as palliative treatment in selected patients with pericardial effusion. Pericardectomy may prolong the survival time of some dogs approximately 4 to 9 months. Partial pericardectomy via thoracic endoscope resulted in a median survival time of only 38 days in dogs with malignant pericardial effusions.²

A proper chemotherapeutic regimen is best chosen in consultation with a veterinary oncologist. In general, vincristine, cyclophosphamide, and prednisone treatment have not resulted in remission of mesotheliomas. In contrast, chemotherapy with mitoxantrone and doxorubicin have resulted in complete remission of mesothelioma in some dogs.

Intracavitary cisplatin is currently the treatment of choice for canine mesothelioma and seems to provide to most clinical benefit. Effusion fluid accumulation is reduced quickly if cisplatin is effective. If the dog fails to respond to one or two intracavitary treatments of cisplatin, further treatment is not indicated. Intravenous doxirubicin can be administered concurrently with cisplatin for optimal response.² Due to the fact that the penetration of intracavitary chemotherapy is shallow (only 2-3 mm), large masses will not be significantly reduced. In these cases, surgical debulking of the mesothelioma combined with chemotherapy may be necessary.¹ If pericardectomy is combined with chemotherapeutic agents, survival may be greatly extended (one dog treated with pericardectomy, intrathoracic and intravenous cisplatin, and intravenous doxorubicin was free of disease at 27 months post treatment).¹

The median survival time for untreated animals with mesotheliomas in any location is difficult to determine. This is because mesotheliomas are rare and affected animals often are euthanized when the neoplasm is diagnosed.¹ Canine mesotheliomas are similar to human mesotheliomas in their clinical and morphologic appearance. Humans with mesotheliomas usually die from secondary complications of mesothelioma rather than the tumor per se. However, mesothelioma in humans and dogs usually is rapidly progressive and has a grave prognosis.³

References

1. Withrow SJ, MacEwen EG: Small Animal Clinical Oncology, 3^rd ed. Philadelphia, W.B. Saunders Co., 2001, pp.656-660.

2. Ogilvie GK, Moore AS: Managing the Veterinary Cancer Patient, 1^st ed. Trenton, Veterinary Learning Systems Co., Inc, 1995, pp. 441-444.

3. Harbison ML, Godleski JJ: Malignant mesothelioma in urban dogs. Vet Pathol 20:531-540, 1983.

4. Kim J-H, Choi Y-K, Yoon H-Y, Kweon O-K, Kim D-Y: Juvenile malignant mesothelioma in a dog. J Vet Med Sci 64:269-271, 2002.

5.Chhabra RS, Maronpot RM, Bucher JR, Haseman JK, Toft JD, Hejtmancik MR: Toxicology and carcinogenesis studies of pentachlorophenol in rats. Toxicol Sci 48:14-20, 1999.

6. Rakich PM, Latimer KS: Cytology. In: Latimer KS, Mahaffey EA, Prasse KW (eds): Duncan and Prasse's Veterinary Laboratory Medicine: Clinical Pathology, 4^th ed. Ames, Iowa State Press, 2003, pp 304-330.

7. McDonough SP, MacLachlan NJ, Tobias AH: Canine pericardial mesothelioma. Vet Pathol 29:256-260,1992.

8. Sisson D, Thomas WP, Ruehl WW, Zinkl JG: Diagnostic value of pericardial fluid analysis in the dog. J Am Vet Med Assoc 184:51-55, 1984.

9. DiPinto MN, Dunstan RW, Lee C: Cystic, peritoneal mesothelioma in a dog. J Am Anim Hosp Assoc 31:385-389, 1995.

10. Liu KX, Bird, AE, Lenz SD, McDonough SP, Wolfe LG: Antigen expression in normal and neoplastic canine tissues defined by a monoclonal antibody generated against canine mesothelioma cells. Vet Pathol 31:663-673, 1994.

11. Ikede Bo, Zubaidy A, Gill CW: Pericardial mesothelioma with cardiac tamponade in a dog. Vet Pathol 17:496-500,1980.

Acknowledgement

"Fire Talk" ^© by Suzanne Adams, CT (ASCP) is used with permission of the artist. Her website sare Welcome to Fine Art Images! and The Art of Cytology.

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