스크랩 Mast Cell Disease in Dogs and Cats: An Overview

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Veterinary Clinical Pathology Clerkship Program

Mast Cell Disease in Dogs and Cats: An Overview

Rebecca L. Dahm, DVM and Kenneth S. Latimer, DVM, PhD

Class of 2001 (Dahm) and Department of Pathology (Latimer), College of Veterinary Medicine, The University of Georgia, Athens, GA 30602

Structure and Function of Normal Mast Cells in Healthy Animals

Mast cells originate in the bone marrow from the same pluripotential stem cell (CD34+) as basophils. They subsequently are distributed to the tissues via the blood as nongranulated mononuclear cells. Within tissues, mast cells continue to differentiate, develop granules, and may have a lifespan ranging from weeks to months.

The cytoplasmic granules of mast cells contain many biologically active substances which contribute to their roles in health and which cause many of the pathologic syndromes in neoplasia. Mast cell secretory products include biogenic amines like histamine and serotonin, proteoglycans such as heparin, numerous enzymes, arachidonic acid products like prostaglandins and leukotrienes, and many cytokines including interleukins that attract eosinophils.⁴

Mast cells are integral in host defense mechanisms. These cells are involved in hypersensitivity reactions, acute and chronic inflammation, T-cell stimulation, and tissue defense against parasites.⁴

Mast cells are classified cytologically as round cells. Individual mast cells typically contain a round to oval nucleus and a variable amount of cytoplasm that is filled with metachromatic granules (Fig. 1A). The granules may partially obscure nuclear morphology. Sometimes the cytoplasmic granules have such high affinity for Romanowsky stain that the nucleus does not stain or stains only faintly (Fig. 1B). With inadequate fixation, the granules may not stain or may be dissolved with aqueous-based stains such as Diff-Quik, a modified Romanowsky stain. Other traditional Romanowky stains, such as Wright, Giemsa, or Leishman stain, are best for mast cell visualization.⁴ The longer fixation time appears to be responsible for maintenance of granule integrity in stained hematologic and cytologic preparations.

Fig. 1A. Cutaneous mast cell tumor (well differentiated), dog, Wright-Leishman stain. The mast cells have numerous purple granules that partially obscure nuclear morphology.	Fig. 1B. Cutaneous mast cell tumor (well differentiated), dog, Wright-Leishman stain. Numerous mast cells are present. Numerous purple cytoplasmic granules obscure nuclear detail. Many mast cells also have poorly stained (pale blue) nuclei.

Mast cells rarely circulate in blood, but they inhabit most tissues of the body. Therefore, it is important to understand tissue preval‎!ence of mast cells in order to diagnose abnormal conditions such as mast cell tumor or metastasis. In a study of clinically normal dogs, 1-16 mast cells per slide were found in 24% of the lymph node slides eval‎!uated. In contrast, less than 4% of the bone marrow slides had a single mast cell. Mast cells were not observed within buffy coat smears from these healthy dogs.¹ Because of their involvement with allergic inflammation, lymph nodes may be involved with such conditions as flea allergy dermatitis wherein a slight increase in mast cell number would be expected. Similarly, mastocytemia has been associated with inflammatory diseases in dogs without mast cell tumors. Conditions associated with mastocytemia in dogs include enteritis (especially parvovirus), fibrinous pericarditis and pleuritis, bacterial peritonitis, aspiration pneumonia, acute pancreatic necrosis, immune-mediated hemolytic anemias, renal failure associated with acute inflammation, inflammatory skin diseases, hemorrhage secondary to hemophilia, and gastric torsion.⁴

Mast Cell Neoplasia

Cutaneous mast cell tumors - Mast cell tumors are most preval‎!ent in the skin and represent the most common cutaneous tumor of dogs and the second most common cutaneous tumor of cats.⁶ Middle-aged (about 8 years old) dogs and cats usually are affected,² although neoplasms have been observed in young kittens and Shar Pei dogs. Cutaneous tumors are most common on the trunk and hind limbs of dogs and the head of cats, but may occur in any location.² Mast cell neoplasms are usually solitary lesions, but multiple cutaneous tumors also occur.⁶ Grossly, tumors vary widely in size, shape, and texture,² thus making cytological examination essential for diagnosis. Because of the eosinophil chemotactic factors elaborated by mast cells, these neoplasms frequently have mild to marked infiltrates of eosinophils (Fig. 2). Occasionally, manipulation of the tumor causes degranulation of mast cells, resulting in local erythema and wheal formation that is known as Darier's sign.² Metastasis, when it occurs, initially involves regional lymph nodes, followed by neoplastic cell dissemination to liver, spleen, and bone marrow (Figs. 3A & 3B).² The more widespread the metastasis, the poorer the clinical prognosis.⁶

Fig. 2. Cutaneous mast cell tumor (intermediate differentiation), dog, Wright-Leishman stain. Pleomorphic mast cells with sparse metachromatic (purple) granulation are scattered among eosinophils.

Fig. 3A. Lymph node, cat, Wright-Leishman stain. Metastatic mast cells exhibit anisocytosis and anisokaryosis with a variable degree of fine metachromatic granulation.	Fig. 3B. Spleen, dog, Wright-Leishman stain. Two metastatic mast cells with coarse purple granules are present.

Paraneoplastic syndromes- Because of the biologically active substances within mast cell granules, degranulation or hyperactivity of neoplastic mast cells may be associated with an array of secondary syndromes including gastrointestinal ulceration, local and systemic coagulopathies, delayed wound healing, vascular damage, and, occasionally, shock-like signs (hypotensive events). These syndromes may occur after tumor manipulation.^2,6

Systemic mastocytosis- Systemic mastocytosis, or disseminated mast cell neoplasia, is more common in cats than in dogs and most often involves the liver, spleen, lymph nodes, and bone marrow (Fig. 4).^2,3 A leukemic blood profile (the presence of neoplastic cells in the blood) is sometimes a feature of this disease (Fig. 5A).³ However, degranulation of the mast cells in stained blood smears occasionally may make the diagnosis of mast cell neoplasia more difficult because the cells may be mistaken for monocytes (Figs. 5B). Initial presentation of dogs and cats with systemic mastocytosis often reflects the presence of various paraneoplastic syndromes including signs such as vomiting, hematemesis, diarrhea, and melena.³ Additional findings on physical examination may include lymphadenopathy, abdominal masses, hemorrhage, dyspnea, hypotensive shock, and pale mucous membranes.³ Laboratory abnormalities may include mastocytemia, eosinophilia, and basophilia.³

Fig. 4. Bone marrow, dog, Wright-Leishman stain. Metastatic mast cells exhibit anisocytosis and anisokaryosis. Neutrophil segmenters and myelocytes also are present.

Fig. 5A. Blood smear, dog, Wright-Leishman stain. Mast cell is present in the blood smear of a dog with cutaneous neoplasms.	Fig. 5B. Blood smear, dog, Wright-Leishman stain. A degranulated mast cell (right) is present in the blood smear of a dog with systemic mastocytosis.

Mast cell leukemia- Mast cell leukemia originates in the bone marrow; it is unaccompanied by more typical cutaneous, splenic, or gastrointestinal mast cell tumors. The diagnosis of mast cell leukemia is based upon a moderate to marked leukocytosis composed of a significant proportion of mast cells (3-74%) on the complete blood cell count as well as diffuse bone marrow infiltration with these cells (Figs. 6A & B).³

Fig. 6A. Blood smear, dog, mast cell leukemia, Wright-Leishman stain. Moderate numbers of mast cells (similar to the cell illustrated here) were present in the stained blood smear of this dog with mast cell leukemia. Cutaneous neoplasms were not present.	Fig. 6B. Bone marrow, dog, mast cell leukemia, Wright-Leishman stain. Numerous mast cells were present in the stained bone marrow.

Prognosis in Mast Cell Neoplasia

Prognostic factors dictate the approach to treatment of mast cell tumors. Traditionally, this process has involved clinical staging of disease, cytologic eval‎!uation, and histologic grading of the neoplasms. Clinical staging of disease is also associated with tumor location and growth rate. More recently, improved histologic grading of neoplasms is associated with AgNOR (Argyrophilic Nucleolar Organizing Region) scoring.

• Clinical staging- The clinical staging of cutaneous mast cell neoplasms assesses the number of tumors, lymph node involvement, distant metastasis, recurrence, and presence or absence of systemic signs of disease.⁶ Tumor recurrence and systemic signs of disease are associated with more aggressive mast cell tumors and poorer clinical prognosis.⁶

• Tumor location- The location of cutaneous mast cell tumors around mucocutaneous junctions is associated with a poorer prognosis.⁶

• Growth rate- The growth rate of mast cell tumors is predictive of metastatic behavior. Slow-growing tumors tend to be benign, while rapidly enlarging neoplasms are more malignant.⁶

• Cytologic eval‎!uation- Cytologic eval‎!uation of mast cell tumors is based upon the presence of anisocytosis, anisokaryosis, nuclear pleomorphism, and degree of cytoplasmic granulation. In general, poorly differentiated mast cells have a bizarre appearance compared to the uniform appearance of well differentiated mast cells. Well differentiated tumors consist of round to oval cells with a uniform appearance in cell and nuclear size. The cytoplasm contains an abundance of basophilic granules (Fig. 7A). In contrast, intermediate (Fig. 7B) to poorly differentiated (Fig. 7C) or anaplastic tumors exhibit pleomorphism, anisocytosis including giant cells, anisokaryosis, and fewer cytoplasmic granules that are smaller in size.^5,6

Fig. 7A. Well differentiated mast cells, cutaneous neoplasm, dog, Wright-Leishman stain. The neoplastic cells are of relatively uniform size and appearance with numerous fine purple granules.

Fig. 7B. Intermediate differentiation of mast cells, cutaneous neoplasm, dog, Wright-Leishman stain. The mast cells are large with pleomorphic cytoplasmic granulation that varies in size and abundance.	Fig. 7C. Poorly differentiated mast cells, cutaneous neoplasm, dog, Wright-Leishman stain. The mast cell (left) is large and has sparse cytoplasmic granulation.

• Histologic grading and AgNOR counts of neoplasms- Histologic grading of mast cell tumors historically has been based upon cellular pleomorphism. Typical characteristics have included anisocytosis, anisokaryosis, vesicular nuclei with prominent nucleoli, degree of cytoplasmic granulation, and mitotic activity (Figs. 8A & C). More recently, AgNOR staining and scores have been employed because of better prognostic value (Figs. 8B & D). The term "AgNOR" refers to the argyrophilic nucleolar organizing regions within individual nuclei. The AgNOR staining technique uses a silver nitrate solution that makes the AgNORs appear as dark brown to black dots within the nucleus (Figs. 8B & 8D). The AgNOR score is computed by counting the total number of AgNORs in 100 mast cells and then dividing by 100. Thus, the resulting score is the average AgNOR count per nucleus or per mast cell. The AgNOR score is predictive of metastatic potential, post-surgical tumor recurrence, and predicted survival period.^5,6 The higher the AgNOR score, the more malignant the neoplasm. As a general guideline, neoplasms with an AgNOR score >2.25 have a greater probability of metastasis.

Fig. 8A. Well differentiated cutaneous mast cell tumor, dog, hematoxylin & eosin stain. The mast cells have a relatively uniform appearance with heavy cytoplasmic granulation.	Fig. 8B. Well differentiated cutaneous mast cell tumor, dog, AgNOR stain. The mast cells have 1-2 AgNORs per cell with an overall score of 1.8. The potential for metastasis is low.

Fig. 8C. Intermediate differentiation, cutaneous mast cell tumor, dog, hematoxylin & eosin stain. The mast cells exhibit mild anisocytosis, anisokaryosis, decreased granulation, and increased mitotic activity.	Fig. 8D. Intermediate differentiation, cutaneous mast cell tumor, dog, AgNOR stain. The mast cells have 1-7 AgNORs per cell with an overall score of 3.19. The potential for metastasis is very high.

Treatment

Note: Treatment of animals should only be performed by a licensed veterinarian. Veterinarians should consult the current literature and current pharmacological formularies before initiating any treatment protocol.

Surgical excision with wide and deep margins is the treatment of choice, with ancillary radiation therapy providing successful treatment of microscopic tumor.⁶ Presurgical treatment with histamine blockers is recommended to prevent complications of mast cell degranulation.² Chemotherapy for metastatic mast cell neoplasia does not offer consistent results, and the prognostic factors already discussed must be considered in the decision to pursue tratment.⁶ Other treatment methods which have been tried include cryotherapy, intralesional injection of deionized water, and hyperthermia.² These latter forms of treatment are promising, but are not uniformly curative.

Selected References

1. Bookbinder PF, Butt MT, Harvey HJ: Determination of the number of mast cells in lymph node, bone marrow, and buffy coat cytologic specimens from dogs. J Am Vet Med Assoc 200:1648-1650, 1992.

2. Lemari? RJ, Lemari? SL, Hedlund CS: Mast cell tumors: Clinical management. Compend Cont Edu Pract Vet 17:1085-1101, 1995.

3. Plier ML, MacWilliams PS: Systemic mastocytosis and mast cell leukemia. Schalm's Veterinary Hematology, 5th ed. Feldman BF, Zinkl JG, Jain NC (eds). Lippincott Williams & Wilkins, 2000, pp. 747-753.

4. Scott MA, Stockham SL: Basophils and mast cells. Schalm's Veterinary Hematology, 5th ed. Feldman BF, Zinkl JG, Jain NC (eds). Lippincott Williams & Wilkins, 2000, pp. 308-315.

5. Simoes JPC, Schoning P, Butine M: Prognosis of canine mast cell tumors: A comparison of three methods. Vet Pathol 31:637-647, 1994.

6. Vail DE: Mast cell tumors. Small Animal Clinical Oncology, 2nd ed. Withrow SJ, MacEwen EG. Saunders, 1996, pp. 192-208.

Acknowledgement

"Cats" a colour etching by Lucy Wills is from The Image Gallery | Animals section of her web site Lucy Willis: Painter and Printmaker (www.lucywillis.com) and is used with the kind permissiom of the artist.

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