Pathology in Practice

Julia K. Ryseff Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523.

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Debra A. Kamstock Animal Cancer Center, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523.

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Katrina M. Hissam Sylvania Veterinary Hospital Inc, 4801 Holland-Sylvania Rd, Sylvania, OH 43560.

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Paul R. Avery Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523.

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History

A 12-year-old 3.86-kg (8.5-lb) neutered male domestic medium hair cat was evaluated because of multiple, bilateral nodular lesions of the nose and ear margins. Lesions were observed 24 to 48 hours before the evaluation; however, actual duration and initial progression of the lesions were uncertain because the cat was reclusive at home. Associated clinical signs included weight loss, lethargy, and eventual dyspnea associated with nares occlusion as a result of progressive enlargement of the nodules.

Clinical and Gross Findings

Physical examination revealed nodular facial lesions (Figure 1). Nodules were raised (approx 0.5 to 1.0 cm in diameter), firm, and alopecic with occasional ulceration. Results of a diagnostic test for circulating FeLV antigen and anti-FIV antibody were negative; a CBC revealed a regenerative left shift (2,944 band neutrophils/μL [reference range, 0 band neutrophils/μL] and 33,120 neutrophils/μL [reference range, 2.8 × 103 neutrophils/μL to 13.0 × 103 neutrophils/μL]) and lymphopenia (736 lymphocytes/μL; reference range, 1.8 × 103 lymphocytes/μL to 6.5 × 103 lymphocytes/μL). Serum biochemical analysis revealed hypocalcemia (8.1 mg/dL; reference range, 8.2 to 10.6 mg/dL), low total protein concentration (6.1 g/dL; reference range, 6.5 to 8.4 g/dL), and hypocholesterolemia (60 mg/dL; reference range, 95 to 200 mg/dL). Cystocentesis was performed, and urinalysis revealed a urine specific gravity of 1.050, with a large amount of blood and +2 protein (scale of 0 to +4). Kidneys were palpably irregular on physical examination. Radiography, ultrasonography, bone marrow evaluation, or other further diagnostic tests to establish the cat's true FeLV antigen status were not performed. At the time of the initial evaluation, fine-needle aspiration of the ear margin nodules was performed; slide preparations of the collected samples were submitted to the clinical pathology service at Colorado State University Veterinary Diagnostic Laboratory for evaluation. Treatment with prednisolone (2.5 mg, PO, q 12 h) was initiated for palliation of clinical signs, although the cat's condition continued to decline. Four days following initial evaluation, the cat was euthanized because of continued enlargement of the facial nodules, anorexia, and weight loss. A complete postmortem evaluation was not performed; however, tissue samples from the nose and ear margin nodules were collected and fixed in neutral-buffered 10% formalin for histologic evaluation.

Figure 1—
Figure 1—

Photographs of the face (A) and the caudal aspect of the right pinna margin (B) of a 12-year-old neutered male domestic medium hair cat that was evaluated because of multiple, progressively enlarging cutaneous nodules of the nose and ear margins. Notice the presence of the multiple, alopecic, raised nodules on the right ear margin; similar lesions were present on the left ear. Lesions were first noticed by the owner 24 to 48 hours prior to evaluation.

Citation: Journal of the American Veterinary Medical Association 241, 8; 10.2460/javma.241.8.1035

Cytologic and Histopathologic Findings

The fine-needle aspirate samples collected from the cat's ear margin nodules at the time of the initial evaluation were stained with a Wright-Giemsa stain (Figure 2). Slides were of high cellularity and comprised of a mixed lymphoid population. The predominant cell population (approx 60% of cells) consisted of large, immunoblastic cells. These cells were typically 2 to 2.5 times the size of neutrophils (approx 50 to 60 μm in diameter), with round nuclei, smooth chromatin, and markedly pleomorphic, prominent nucleoli of highly variable size. Nuclear-to-cytoplasmic ratios were high, and the cells had deeply basophilic cytoplasm and frequent small, indistinct, perinuclear clear zones. The remaining cells observed were small lymphocytes, scattered well-differentiated plasma cells, well-granulated mast cells, neutrophils, and leukophagocytic macrophages. The findings were interpreted as evidence of mixed inflammation and possible lymphoma; additional diagnostic testing was recommended at the time of the initial evaluation.

Figure 2—
Figure 2—

Photomicrograph of a fine-needle aspirate sample obtained from one of the ear margin masses in the cat in Figure 1. Notice the mixed inflammatory cell population with numerous immunoblastic cells (arrows). Wright-Giemsa stain; bar = 20 μm.

Citation: Journal of the American Veterinary Medical Association 241, 8; 10.2460/javma.241.8.1035

Histologic examination of postmortem tissue samples collected from the nose and ear margin nodules revealed similar-appearing, densely cellular, well-demarcated yet unencapsulated, multinodular masses, which expanded the superficial and deep dermis and elevated, yet did not infiltrate, the overlying epidermis, with the presence of a Grenz zone (Figure 3). Neoplastic cells were arranged in sheets. Individual cells were round to polygonal, large, and discrete, with mild to moderate amounts of eosinophilic cytoplasm and mildly pleomorphic, round to irregular, typically vesicular nuclei with a single prominent nucleolus. There was moderate anisocytosis and anisokaryosis. A subpopulation of the neoplastic cells, which were smaller in size with heterochromatic condensed basophilic nuclei, was identified. Five to 10 mitotic figures/ten 400× fields were noted. Low numbers of lymphocytes and occasional mast cells were scattered throughout. A histiocytic or lymphocytic neoplastic cell population was suspected. More specifically, based on cellular features, gross appearance, lesion distribution, and lack of epitheliotropism, feline progressive histiocytosis was considered.1 Additional round cell tumor histogenesis could not be ruled out.

Figure 3—
Figure 3—

Photomicrographs of sections of the right ear margin masses in the cat in Figure 1. A—In the affected areas, notice the expansion and effacement of the dermis with elevation, yet not infiltration, of the epidermis. H&E stain; bar = 1 mm. Inset—At higher magnification, sheets of discrete neoplastic cells are visible; the neoplastic cells spare follicular and epidermal epithelia, and a Grenz zone (zone of relatively normal collagen demarcating the boundary between unaffected epidermis and a dermal lesion) is present. H&E stain; bar = 100 μm. B—Within the masses, generalized staining for CD3 is supportive of a neoplastic T-cell population. Anti-CD3 immunohistochemical stain; bar = 1 mm. Inset—In a higher-magnification view, it is evident that immunopositive neoplastic cells have not infiltrated the follicular epithelium of an associated hair follicle. Anti-CD3 immunohistochemical stain; bar = 50 μm.

Citation: Journal of the American Veterinary Medical Association 241, 8; 10.2460/javma.241.8.1035

To assist in determining histogenesis, histochemical and immunohistochemical stains (Giemsa stain to detect mast cell granules and immunohistochemical stains for cell surface markers CD18, CD79a, and CD3 for histiocytes, B cells, and T cells, respectively) of the ear margin nodules were performed. For the neoplastic cells, results of Giemsa staining and staining for CD79a and CD18 were negative; therefore, feline progressive histiocytosis was ruled out as a differential diagnosis. However, the neoplastic cells did react uniformly when stained for CD3 (Figure 3), a finding considered consistent with T-cell lymphoma. There were a small number of CD79a-positive B cells, in addition to a few mast cells that reacted with Giemsa stain, likely representing a minimal, scattered reactive population. As an additional diagnostic test, an antigen receptor rearrangement PCR assay for lymphoma was performed on one of the previously submitted fine-needle aspirate samples and revealed the presence of a restricted population of T cells, thereby supporting the diagnosis of T-cell lymphoma.

Morphologic Diagnosis

Cutaneous, nonepitheliotropic T-cell lymphoma.

Comments

On the basis of cytologic, histopathologic, immunohistochemical, and PCR assay findings for the cat of the present report, a diagnosis of cutaneous, nonepitheliotropic T-cell lymphoma was made. Although a full necropsy was not performed, the clinicopathologic results and the lack of other abnormalities detected during physical examination suggested that the cutaneous lesions were the primary process. Initial cytologic examination of fine-needle aspirate samples from the ear margin nodules revealed a predominance of lymphoblastic cells, which was most consistent with lymphoma (variants of cutaneous, Hodgkin's-like lymphoma, and extranodal peripheral T-cell lymphoma were all considered), but the mixture of other inflammatory or reactive cell populations allowed for the inclusion of atypical lymphoid reactivity or hypersensitivity conditions as differential diagnoses.2

Although lymphoma is one of the most commonly diagnosed neoplasms in cats, the cutaneous form is rare, comprising only 1.9% of all feline lymphoid tumors.3 Affected cats are typically older, with a mean reported age of 10 to 12 years; there is no apparent breed or sex predilection. Lesions can be solitary, multifocal, or generalized with a variable gross appearance, which can include nodular, plaque-like, ulcerative, or exfoliative erythroderma.4 In general, these lesions are of primary origin and only very rarely develop secondary to multicentric disease. Cutaneous lymphoma can be classified into 2 categories on the basis of histologic and immunohistologic differentiation. The epitheliotropic form is characterized by the affinity of the neoplastic cells for the epidermal or mucosal epithelium and associated adnexal structures. This includes mycosis fungoides, pagetoid reticulosis, and Sézary syndrome and is typically of T-cell origin. The nonepitheliotropic form classically involves the dermis and subcutis, although vasotropic and intravascular forms may develop. Nonepitheliotropic neoplasms of either lymphocyte origin (B-cell or T-cell forms) have been reported.4–6 Extranodal peripheral T-cell lymphoma, mixed lymphoid, and mixed inflammatory types are additional nonepitheliotropic lymphomas, although these have been poorly characterized in cats.2

Infection with the retrovirus FeLV has long been associated as a cause of lymphoma in cats, with FeLV antigen–positive cats 62 times as at risk for developing the disease as FeLV antigen–negative cats.7 In recent years, the incidence of FeLV-associated forms of lymphoma (mediastinal and multicentric) in cats has decreased, due in great part to routine FeLV testing and vaccination. However, vaccination does not always prevent the integration of FeLV proviral DNA into the host genome.8 The direct association between nonproductive proviral integration and lymphoma is as yet unclear. However, it is interesting that in 1 study9 of lymphoma in cats, tumor cells in only 1 of 5 cats with cutaneous lymphoma were positive for FeLV antigen, whereas tumor cells in 4 of those 5 cats contained integrated proviral DNA. These findings suggest the possibility that FeLV exposure may still be an important cause of some forms of feline lymphoma, possibly secondary to insertional mutagenesis.9

Although the overall disease progression can be quite slow, extending over a period of months to years, the prognosis for cutaneous lymphoma in dogs and cats is generally considered to be guarded because of the local invasiveness and overall poor response to treatment. Excision may be considered curative in animals with solitary lesions; however, other treatments (radiation, topical administration of fibronectin and nitrogen mustard, and systemic administration of various chemotherapeutic agents such as prednisolone, vincristine, cyclophosphamide, methotrexate, or asparaginase) have been generally unsuccessful.10–15 In 1 case report12 involving a cat with nonepitheliotropic T-cell lymphoma, oral administration of lomustine was effective in resolving clinical signs and associated lesions for 3 months, prior to euthanasia because of unrelated renal issues.

References

  • 1. Affolter VK, Moore PF. Feline progressive histiocytosis. Vet Pathol 2006; 43:646655.

  • 2. Valli VE, Jacobs RM, Parodi AL, et al. Histological classification of hematopoietic tumors of domestic animals. In: World Health Organization International histological classification of tumors of domestic animals. Vol VIII. Second series. Washington DC: Armed Forces Institute of Pathology, 2002;4344.

    • Search Google Scholar
    • Export Citation
  • 3. Valli VE, Jacobs RM, Norris A, et al. The histiologic classification of 602 cases of feline lymphoproliferative disease using the National Cancer Institute working formulation. J Vet Diagn Invest 2000; 12:295306.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Ihrke PJ, Walder EJ, Affolter VK. Lymphocytic tumors. In: Gross TL, ed. Skin diseases of the dog and cat. 2nd ed. Oxford, England: Blackwell Science Ltd, 2005;876890.

    • Search Google Scholar
    • Export Citation
  • 5. Ginn PE, Mansell JEKL, Rakich PM. Skin and appendages. In: Maxie MG, ed. Jubb, Kennedy, and Palmer's pathology of domestic animals. 5th ed. Philadelphia: Elsevier Saunders, 2007;773775.

    • Search Google Scholar
    • Export Citation
  • 6. Schick R, Murphy G, Goldschmidt M. Cutaneous lymphosarcoma and leukemia in a cat. J Am Vet Med Assoc 1993; 203:11551158.

  • 7. Withrow SJ, Vail DM. Cancer biology and metastasis. In: Withrow and MacEwen's Small animal clinical oncology. 3rd ed. St Louis: Saunders Elsevier, 2007;2325.

    • Search Google Scholar
    • Export Citation
  • 8. Hofmann-Lehmann R, Cattori V, Tandon R, et al. Vaccination against the feline leukaemia virus: outcome and response categories and long-term follow-up. Vaccine 2007; 25:5531e9.

    • Search Google Scholar
    • Export Citation
  • 9. Weiss A, Klopfleisch R, Gruber A. Prevalence of feline leukemia provirus DNA in feline lymphomas. J Feline Med Surg 2010; 12:929935.

  • 10. Baker JL, Scott DW. Mycosis fungoides in two cats. J Am Anim Hosp Assoc 1989; 25:97101.

  • 11. Caciolo PL, Nesbitt GH, Patnaik AK, et al. Cutaneous lymphosarcoma in the cat: a report of nine cases. J Am Anim Hosp Assoc 1984; 20:491496.

    • Search Google Scholar
    • Export Citation
  • 12. Komori S, Nakamura S, Takahashi K, et al. Use of lomustine to treat cutaneous nonepitheliotropic lymphoma in a cat. J Am Vet Med Assoc 2005; 226:237239.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13. McKeever PJ, Grindem CK, Stevens JB, et al. Canine cutaneous lymphoma. J Am Anim Hosp Assoc 1982; 180:531536.

  • 14. Neta M, Naigamwalla D, Bienzle D. Perforin expression in feline epitheliotropic cutaneous lymphoma. J Vet Diagn Invest 2008; 20:831835.

  • 15. Tobey J, Houston D, Breur G, et al. Cutaneous T-cell lymphoma in a cat. J Am Vet Med Assoc 1994; 204:606609.

  • Figure 1—

    Photographs of the face (A) and the caudal aspect of the right pinna margin (B) of a 12-year-old neutered male domestic medium hair cat that was evaluated because of multiple, progressively enlarging cutaneous nodules of the nose and ear margins. Notice the presence of the multiple, alopecic, raised nodules on the right ear margin; similar lesions were present on the left ear. Lesions were first noticed by the owner 24 to 48 hours prior to evaluation.

  • Figure 2—

    Photomicrograph of a fine-needle aspirate sample obtained from one of the ear margin masses in the cat in Figure 1. Notice the mixed inflammatory cell population with numerous immunoblastic cells (arrows). Wright-Giemsa stain; bar = 20 μm.

  • Figure 3—

    Photomicrographs of sections of the right ear margin masses in the cat in Figure 1. A—In the affected areas, notice the expansion and effacement of the dermis with elevation, yet not infiltration, of the epidermis. H&E stain; bar = 1 mm. Inset—At higher magnification, sheets of discrete neoplastic cells are visible; the neoplastic cells spare follicular and epidermal epithelia, and a Grenz zone (zone of relatively normal collagen demarcating the boundary between unaffected epidermis and a dermal lesion) is present. H&E stain; bar = 100 μm. B—Within the masses, generalized staining for CD3 is supportive of a neoplastic T-cell population. Anti-CD3 immunohistochemical stain; bar = 1 mm. Inset—In a higher-magnification view, it is evident that immunopositive neoplastic cells have not infiltrated the follicular epithelium of an associated hair follicle. Anti-CD3 immunohistochemical stain; bar = 50 μm.

  • 1. Affolter VK, Moore PF. Feline progressive histiocytosis. Vet Pathol 2006; 43:646655.

  • 2. Valli VE, Jacobs RM, Parodi AL, et al. Histological classification of hematopoietic tumors of domestic animals. In: World Health Organization International histological classification of tumors of domestic animals. Vol VIII. Second series. Washington DC: Armed Forces Institute of Pathology, 2002;4344.

    • Search Google Scholar
    • Export Citation
  • 3. Valli VE, Jacobs RM, Norris A, et al. The histiologic classification of 602 cases of feline lymphoproliferative disease using the National Cancer Institute working formulation. J Vet Diagn Invest 2000; 12:295306.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Ihrke PJ, Walder EJ, Affolter VK. Lymphocytic tumors. In: Gross TL, ed. Skin diseases of the dog and cat. 2nd ed. Oxford, England: Blackwell Science Ltd, 2005;876890.

    • Search Google Scholar
    • Export Citation
  • 5. Ginn PE, Mansell JEKL, Rakich PM. Skin and appendages. In: Maxie MG, ed. Jubb, Kennedy, and Palmer's pathology of domestic animals. 5th ed. Philadelphia: Elsevier Saunders, 2007;773775.

    • Search Google Scholar
    • Export Citation
  • 6. Schick R, Murphy G, Goldschmidt M. Cutaneous lymphosarcoma and leukemia in a cat. J Am Vet Med Assoc 1993; 203:11551158.

  • 7. Withrow SJ, Vail DM. Cancer biology and metastasis. In: Withrow and MacEwen's Small animal clinical oncology. 3rd ed. St Louis: Saunders Elsevier, 2007;2325.

    • Search Google Scholar
    • Export Citation
  • 8. Hofmann-Lehmann R, Cattori V, Tandon R, et al. Vaccination against the feline leukaemia virus: outcome and response categories and long-term follow-up. Vaccine 2007; 25:5531e9.

    • Search Google Scholar
    • Export Citation
  • 9. Weiss A, Klopfleisch R, Gruber A. Prevalence of feline leukemia provirus DNA in feline lymphomas. J Feline Med Surg 2010; 12:929935.

  • 10. Baker JL, Scott DW. Mycosis fungoides in two cats. J Am Anim Hosp Assoc 1989; 25:97101.

  • 11. Caciolo PL, Nesbitt GH, Patnaik AK, et al. Cutaneous lymphosarcoma in the cat: a report of nine cases. J Am Anim Hosp Assoc 1984; 20:491496.

    • Search Google Scholar
    • Export Citation
  • 12. Komori S, Nakamura S, Takahashi K, et al. Use of lomustine to treat cutaneous nonepitheliotropic lymphoma in a cat. J Am Vet Med Assoc 2005; 226:237239.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13. McKeever PJ, Grindem CK, Stevens JB, et al. Canine cutaneous lymphoma. J Am Anim Hosp Assoc 1982; 180:531536.

  • 14. Neta M, Naigamwalla D, Bienzle D. Perforin expression in feline epitheliotropic cutaneous lymphoma. J Vet Diagn Invest 2008; 20:831835.

  • 15. Tobey J, Houston D, Breur G, et al. Cutaneous T-cell lymphoma in a cat. J Am Vet Med Assoc 1994; 204:606609.

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