Canine Round Cell Tumors

Elizabeth A. Nesbit, DVM; Perry J. Bain, DVM, PhD; Nicole C. Northrup, DVM, and Kenneth S. Latimer, DVM, PhD

Class of 2002 (Nesbit), Department of Pathology (Bain, Latimer), and Oncology Service, Department of Small Animal Medicine (Northrup), College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7388

Introduction

Cutaneous and subcutaneous masses account for a large percentage of chief complaints of animals presenting to small animal clinics. While many of these masses are abscesses, cysts, hematomas, or granulomas, the skin and subcutis are common locations for neoplasia in dogs. Common tumor types include epithelial neoplasms, lipomas, spindle cell tumors, melanocytic tumors, and round cell tumors. This manuscript discusses round cell tumors of dogs, with special emphasis on diagnostic cytology.

Round cell tumors exfoliate particularly well, which makes them easier to identify cytologically than other types of skin tumors (16). As a result, fine-needle aspiration can be quite rewarding and helpful in determining an appropriate course of action or discussion with the client. Canine round cell tumors consist of discrete cells that are round to oval in shape (8). They include mast cell tumor, histiocytoma, plasmacytoma, lymphoma, and transmissible venereal tumor.

MAST CELL TUMOR

Clinical Presentation

Mast cell tumor is a common neoplasm of dogs and is reported to account for approximately 21% of all canine skin tumors (13,23). These neoplasms usually occur in middle aged to older dogs with a mean of 8.5 years of age. A breed predilection exists for breeds of bulldog descent such as boxers and Boston terriers. Mast cell tumors also are common in Labrador retrievers, Golden retrievers, and Shar Peis (14). Neoplasms usually originate in the skin but rarely arise in other locations such as the spleen, kidney, gastrointestinal tract, oral cavity, and bone (19). Most dogs present with a single cutaneous lesion. A survey of 114 dogs with mast cell tumors found the thorax to be the most common location followed by the abdomen, hindlimb, forelimb, perineal area, head, and neck. Only 10% of the dogs had multiple tumors (24). The tumors can vary greatly in size, shape, and gross appearance. Dogs also may present with other systemic signs of disease resulting from histamine release by mast cells. The most common are gastrointestinal signs such as vomiting resulting from ulceration, bleeding, delayed wound healing, and hypotensive shock. Systemic disease also may be seen with metastasis to the lymph nodes, spleen, liver, and bone marrow (13).

Cytology

Mast cell tumors are easily diagnosed cytologically, but histopathology is required to accurately grade the neoplasms for prognostic purposes (please see "Mast Cell Disease in Dogs and Cats: An Overview" by Drs. Rebecca L. Dahm and Kenneth S. Latimer). Histologically, mast cell neoplasms are graded as well differentiated (grade I), intermediate differentiation (grade II), and poorly differentiated (III) (24). Grade I and grade II mast cell tumors are readily identified by the abundance of metachromatic (purple) cytoplasmic granules that sometimes obscure nuclear morphology (Fig. 1). Poorly differentiated or anaplastic mast cell tumors have fewer granules that are finer in appearance (8,16). They may have indistinct cytoplasmic boundaries, anisokaryosis, anisocytosis, and increased mitotic activity (Fig. 2). Due to cellular fragility, extracellular granules may be present in the background on the aspirates. Eosinophils may or may not be present.

Fig. 1. Mast cell tumor, well differentiated, Wright-Leishman stain. Well differentiated mast cells have numerous, purple, cytoplasmic granules that partially obscure nuclear morphology.	Fig. 2. Mast cell tumor, poorly differentiated, Wright-Leishman stain. Poorly differentiated mast cells exhibit anisocytosis and anisokaryosis. The cytoplasm contains fine but sparse purple granules. A few eosinophils also are present.

To accurately grade mast cell tumors for prognostic purposes, the neoplasms must be submitted for histopathology. Grading is based upon morphologic features in hematoxylin and eosin-stained sections as wells as AgNOR (silver nucleolar organizing regions) staining and scoring.

Treatment and Prognosis

Mast cell tumors should be considered malignant. Surgical resection is recommended, if possible, with wide margins of at least 3 inches in all surgical planes. Complete surgical excision is curative. It is important to identify specific surgical margins with sutures, India Ink, or another marking system so the adequacy of surgical excision can be evaluated critically.

Specific treatment depends upon the grade of the tumor (differentiated, intermediate differentiation, or poorly differentiated) as well as clinical stage of disease. Single, dermal, grade I mast cell tumors have an excellent prognosis. Grade II and III mast cell tumors require diagnostic staging to determine prognosis and post-surgical treatment. Histological grade is the most important prognostic factor (26). Other findings that imply a poor prognosis include systemic signs of disease, metastases to regional lymph nodes, and hepatic and / or splenic involvement.

Mast cell tumors in breeds of bulldog descent usually have a lower grade and, therefore, a better prognosis. The location of the tumor also provides some prognostic information. Mast cell tumors involving the inguinal, preputial, or perineal areas; mucous membranes; oral cavity; muzzle; and nailbed are associated with more malignant tumor behavior. Appropriate staging for any grade III neoplasm or a grade II mast cell tumor that was incompletely excised or lacked prognostic indicators should include: lymph node aspirates to detect regional metastases, buffy coat smears and bone marrow aspirates to detect systemic disease, and abdominal ultrasound to evaluate potential hepatic and/or splenic involvement.

Radiation therapy is effective against microscopic metastases. It can be used after surgery for any grade I or II mast cell tumor that was incompletely excised (1,9,12). For grade II mast cell tumors with indications of systemic disease or any grade III mast tumor, systemic chemotherapy has been shown to be effective. Prednisone in combination with vinblastine has a tumor response rate of almost 50%. Prednisone can also be used alone but with a lower tumor response rate (26). Other chemotherapeutic protocols also have been shown to be effective (10,21).

Symptomatic treatment is indicated whenever systemic signs of disease or a large tumor cell burden exists. Drug therapy with H-1 (i.e., diphenhydramine) and H2 (i.e., ranitidine) antagonists is recommended.

A study by Simoes, et al. evaluated several prognostic indicators in 122 dogs with confirmed mast cell tumors. The average survival time post-surgery was over 1.5 years. Mast cell tumor recurrence and death were significantly lower in dogs with grade I tumors than as opposed to those with grade III neoplasms. The incidence of tumor recurrence following surgery was 33.3%. Of these patients, 26.7% died or were euthanized as a result of the tumor. Approximately 20% of them also had metastases at the time of death (24). Although mast cell tumors are potentially metastatic and life threatening, they may be successfully treated following early diagnosis.

HISTIOCYTOMA

Clinical Presentation

Histiocytomas are fairly common skin tumors of dogs. One retrospective study over a 9-year period (1980 to 1989) showed that 5.5% of all cutaneous neoplasms were histiocytomas (23). These benign neoplasms are more common in certain breeds of dogs such as flat-coated retrievers that had a 25% incidence of histiocytomas (18). Histiocytomas are, however, the most common skin tumor in young dogs with the mean age of incidence being < 3 years (11). Histiocytomas are usually solitary tumors on the head (especially the pinnae), neck, hindlimbs, trunk, and feet. They appear well circumscribed, dome shaped, red, alopecic, and sometimes ulcerated (7,11). The dogs usually are not presented for other clinical signs related to the tumor, bu ulceration of the neoplasm can lead to secondary infection or bleeding.

Cytology

Fine-needle aspiration reveals a moderately cellular sample of discrete round cells (Fig. 3). Anisocytosis and anisokaryosis may be present but usually are not prominent. A few cells may be binucleate. Individual cells usually have a round to reniform nucleus with inapparent nucleoli. Folds or clefts in the nuclear membrane sometimes produce a unique appearance called a "butt cell" (wherein the nucleus resembles buttocks). The cytoplasm is typically light blue and lacks both vacuoles and granules. Mitotic figures are common. Inflammatory cells, especially lymphocytes and plasma cells, are often dispersed among the tumor cells, especially during regression of the neoplasm (7,8,16).

Fig. 3. Histiocytoma, Wright-Leishman stain. Neoplastic cells have a round to oval nucleus and light blue cytoplasm that lacks vacuoles and granules. A mitosis (bottom center) and "butt cell" (upper left) also are present.

Treatment and Prognosis

The prognosis for histiocytomas is good to excellent. These benign neoplasms commonly regress on their own; however, surgical excision may be considered for ulcerated or infected tumors. It is thought that the dog becomes immune after initial tumor growth; recurrence is seldom observed (7).

PLASMACYTOMAS

Clinical Presentation

Extramedullary plasmacytomas are tumors of plasma cells that occur outside the bone marrow cavity. The most common location of these neoplasms is the skin or mucous membranes, especially the lip, digits, trunk, ears, and face. Plasmacytomas are not very common tumors in dogs, but it is thought that they may be underrepresented due to misclassification as different tumor types (2,20). They usually occur on older dogs, with a mean age between 9 and 10 years (2,5,20). There appears to be no sex predilection although some studies found that more males than females were affected. While many breeds were represented in these reports, one study found that Cocker Spaniels were more commonly affected (20). Plasmacytomas are usually solitary raised nodules that appear red and sometimes ulcerated, especially neoplasms on the digits (1). Cutaneous and mucocutaneous plasmacytomas usually lack clinical signs of disease; however, oral and rectal plasmacytomas have been associated with gagging or rectal prolapse, respectively. If signs of generalized illness are present concurrently, the possibility of multiple myeloma should be excluded (6,20).

Cytology

Fine-needle aspirates of plasmacytomas are moderately cellular. Prominent cytologic features include marked anisocytosis and anisokaryosis with scattered binucleated and trinucleated cells (Fig. 4). Individual cells have a round to oval nucleus with inapparent nucleoli. The nucleus is often eccentrically placed and has a coarse chromatin pattern. The cytoplasm is blue and lacks vacuoles and granules; a paranuclear clear zone may be observed (2,20). Infrequently, aspirates of plasmacytomas may contain amyloid that appears pink and finely fibrillar in Wright-stained preparaions.

Fig. 4. Plasmacytoma, Wright-Leishman stain. Neoplastic plasma cells exhibit anisocytosis and anisokaryosis, but retain plasmacytoid features such as blue cytoplasm and a Golgi zone. A trinucleated cell also is present (center).

Treatment and Prognosis

Surgical excision is the treatment of choice for plasmacytomas and generally results in a favorable prognosis. When the surgical margins still contain neoplastic cells, treatment with radiation therapy or chemotherapy has been shown to have a good response (6). In a survey of 131 dogs treated by surgical excision alone, an 8% rate of local tumor recurrence and 3.5% incidence of distant tumor spread were documented. These recurrences were most common when the surgical margins contained neoplastic cells and the primary tumor was located in the oral mucosa (6).

TRANSMISSIBLE VENEREAL TUMORS

Clinical Presentation

Transmissible venereal tumors (TVT) are contagious, sexually transmitted tumors of dogs. They are usually seen in young, sexually active dogs from an environment with a high concentration of free roaming dogs with poor control of reproduction. Females are more susceptible than males, but there does not appear to be a breed predilection (5,14,22). TVT is most common in sub-tropical to tropical urban areas. It is enzootic in many areas of the world including the southern United States (22).

TVTs are transmitted by direct contact wherein viable tumor cells are seeded onto mucous membranes (especially when associated with trauma) or implanted subcutaneously in bite wounds. Due to their sexually transmitted nature they are most commonly found on the external genitalia. However, they also have been observed in other locations such as the nasal and oral cavities. In these instances the neoplasm is spread by social behaviors including sniffing and licking (5,22).

TVTs are single to multiple, pink-red, cauliflower-shaped lesions that can vary greatly in size. Neoplasms are relatively firm but fragile, especially those tumors involving the external genitalia. Because of a rich blood supply, TVTs appear pink to bright red. Hemorrhage is associated with tumor fragility. Other associated clinical signs may include genital discharge, abnormal odor, and excessive licking. If metastasis is present, local or distant lymphadenopathy may be observed (22).

Cytology

Aspirates from TVTs are highly cellular and often bloody. Individual neoplastic cells have a round nucleus, fine to granular chromatin pattern, and often a single, prominent nucleolus. Mitotic figures are frequently observed. The cytoplasm is pale blue and moderately abundant. The most prominent cytological feature of TVTs is the presence of distinct, clear, cytoplasmic vacuoles (8,22, Fig. 5). TVT cells that lack cytoplasmic vacuoles may be easily confused with other round cell tumors. The morphological appearance and location of the tumor, however, are helpful in the diagnosis. A variety of inflammatory cells may be observed, especially in traumatized neoplasms.

Fig. 5. Transmissible venereal tumor, Wright-Leishman stain. Neoplastic cells have a round nucleus, single nucleolus, and thin rim of basophilic, vacuolated cytoplasm. Aspirates often are bloody.

Treatment and Prognosis

The prognosis for TVTs is very good. Less than 5% of TVTs ultimately metastasize to other sites (14). Vincristine administration is the treatment of choice, with the majority of dogs being cured (5). Even in the case of metastasis, the cure rate for TVTs is over 90% (5,22). Dogs generally tolerate vincristine administration well; fewer than 15% of treated dogs experience drug-related side effects. For tumors that are resistant to vincristine, doxorubicin is the most effective chemotherapeutic agent (5). TVTs have also been shown to be very sensitive to radiation therapy (14).

CUTANEOUS LYMPHOMA

Clinical Presentation

While lymphoma is a common cancer in dogs, the cutaneous form is very rare and accounts for only 3-8% of all canine lymphomas (3,17). Cutaneous lymphoma usually is seen in middle aged to older dogs ranging from 5 and 11 years of age (25). Unlike other round cell tumors, cutaneous lymphoma usually presents as multiple tumors on the skin as opposed to a solitary mass. Cutaneous lymphoma is divided into epitheliotropic and nonepitheliotropic forms. Epitheliotropic lymphoma is also known as mycosis fungoides (MF), so named because of the mushroom-like morphology of the tumors in humans (3). Early stages of epitheliotropic lymphoma can resemble inflammatory skin disease including erythema, scaling, pruritis, depigmentation, alopecia, plaques, ulceration, and crusting. Many dogs are presented with a history of chronic skin disease. The skin lesions may be focal or generalized. Dogs presented with advanced epitheliotropic lymphoma usually have multiple tumors that can occur anywhere, but appear to have a predilection for mucocutaneous junctions and the oral cavity (3,17). Metastasis to lymph nodes and other organs occurs, so dogs may present with lymphadenopathy and other signs of systemic disease (17).

Nonepitheliotropic lymphoma is extremely rare in dogs (but is the more common form of cutaneous lymphoma in cats). It may represent metastatic disease to the skin or a primary skin neoplasm. Multiple, ulcerated, skin nodules are usually observed in this form of the disease. Nonepitheliotropic lymphoma is generally unassociated with erythema, pruritus, and scaling (17).

Cytology

Early stages of epitheliotropic lymphoma usually contain a mixture of small- and medium-sized lymphocytes, while the later stages of neoplasia contain mostly large, immature lymphocytes (17). Individual cell nuclei may be round or have irregular margins that are indented or cleaved. The chromatin pattern is fine and prominent nucleoli are observed (8, Figure 6). Nonepitheliotropic lymphoma is not as morphologically consistent; neoplastic cells sometimes may be mistaken for poorly differentiated mast cell tumors or histiocytes (17). Neoplastic lymphocytes are fragile and easily lysed during aspiration and smear preparation. Biopsy often is required for definitive diagnosis.

Fig. 6. Cutaneous lymphoma, Wright-Leishman stain. Neoplastic lymphocytes are large cells with a round nucleus, fine chromatin pattern, multiple nucleoli, and thin rim of dark blue, finely vacuolated cytoplasm. A mitotic figure is present (upper left).

Treatment and Prognosis

The prognosis is poor for both forms of cutaneous lymphoma (3,17). Recurrence of disease is very common despite various treatment protocols (17). Generalized epitheliotropic lymphoma is often treated with a five-drug chemotherapy protocol. Palliative therapy, such as glucocorticoid and antibiotic administration as well as antiseborrheic and antibacterial shampoos, can temporarily improve the patient’s quality of life. Retinoids may retard malignant progression, induce remission, and extend life expectancy somewhat.

Focal mycosis fungoides can be treated with surgery or radiation treatment with or without chemotherapy. This form of cutaneous lymphoma has a slightly better prognosis.

Radiation treatment may be helpful, with or without systemic chemotherapy, depending on the stage of disease. In human patients without evidence of systemic disease, total skin electron-beam radiation therapy is very successful in retarding the progression of cutaneous lymphoma (15).

References

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Acknowledgement

Print of Golden Retrievers found at The Art Monk

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