Pathology in Practice

Annie S. H. Mi 1Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Janet A. Grimes 1Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Corry K. Yeuroukis 2Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Bridget C. Garner 2Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Elizabeth W. Howerth 2Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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History

A 2-year-old 19.1-kg (42.0-lb) spayed female English Bulldog was evaluated because of respiratory stertor and chronic vomiting. The dog was noted to have a mass in the left nostril (Figure 1) during the preceding 2 months. The mass had been gradually increasing in size and causing increasingly pronounced stertor. The dog had had a single syncopal episode.

Figure 1—
Figure 1—

Photograph of the nose of a 2-year-old spayed female English Bulldog with a nasal mass occluding the left nostril (A) and photomicrograph of a fine-needle aspirate specimen of the nasal mass (B). The mass had been present for 2 months; it had high cellularity and numerous plump to ovoid, individualized to aggregated cells. In panel B, modified Wright stain; bar = 20 μm.

Citation: Journal of the American Veterinary Medical Association 255, 5; 10.2460/javma.255.5.537

Clinical and Clinicopathologic Findings

On initial evaluation, the dog had marked upper respiratory stertor. A round, smooth, mildly ulcerated mass was associated with the axial surface of the wing of the left nostril; the mass completely filled the left nostril and occluded airflow. The remainder of the physical examination findings were within reference limits.

A CBC and serum biochemical analyses revealed mildly high Hct (60.3%; reference range, 36.6% to 59.6%), leukocyte count (16,300 WBCs/μL; reference range, 5,500 to 13,900 WBCs/μL), and concentrations of albumin (4.3 g/dL; reference range, 2.2 to 3.9 g/dL), glucose (116 mg/dL; reference range, 69 to 113 mg/dL), and cholesterol (298 mg/dL; reference range, 124 to 264 mg/dL). Results of urinalysis were unremarkable.

Three-view thoracic radiography and tracheal fluoroscopy were performed, and findings were within reference limits. Computed tomography of the skull was performed, revealing a well-defined, homogeneous, minimally contrast-enhancing soft tissue nodule measuring 1.4 × 1.4 × 1 cm in the lateral aspect of the left nostril with no evidence of osseous or lymph node involvement. Fine-needle aspiration of the mass yielded highly cellular samples with individualized to aggregated ovoid cells featuring a lightly basophilic cytoplasm (Figure 1). Nuclei were rounded to ovoid with coarsely stippled chromatin and prominent basophilic nucleoli. Multinucleated cells were frequently observed. Rarely, cells were observed in a circular arrangement of peripheralized nuclei suggestive of crown cells. Anisocytosis and anisokaryosis were moderate to marked, and occasional capillaries were coursing through the aggregated cells.

Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page→

Histopathologic, Immunohistochemical, and Electron Microscopic Findings

Biopsy of the nasal mass was performed, and multiple tissue samples were collected. Some samples were routinely processed and stained with H&E stain. Histologic examination of sections of the mass revealed an unencapsulated, poorly demarcated, densely cellular neoplasm composed of sheets of round to polygonal cells supported by fibrovascular stroma and dense bundles of preexisting collagen that extended from the epidermal-dermal junction and diffusely infiltrated and effaced the dermis. There was disruption of the epidermis with associated inflammation indicative of an ulcer overlying the mass.

Neoplastic cells had variably distinct cellular borders and moderate to abundant amounts of lightly granular, eosinophilic cytoplasm with occasional large, clear vacuoles. Nuclei were ovoid with lightly stippled chromatin and an occasional single small basophilic nucleolus. Anisocytosis and anisokaryosis were moderate, with binucleation of some cells. Mild, focal epithelial invasion by small aggregates of neoplastic cells was noted. No mitoses were observed in 10 hpfs (400× [equivalent to 2.4 mm2]). Small numbers of small lymphocytes and fewer plasma cells diffusely infiltrated the mass (Figure 2). Other sections of the mass underwent immunohistochemical staining for ionized calcium-binding adaptor molecule 1 (IBA-1), E-cadherin, PNL2 (melanoma-associated antigen), and CD3.

Figure 2—
Figure 2—

Photomicrographs of a section of the nasal mass in the dog in Figure 1. The neoplastic cells form diffuse sheets that extend from the epidermal-dermal junction into the deeper dermis. H&E stain; bar = 200 μm. Inset—The neoplastic cells have variably distinct cellular borders and moderate to abundant amounts of lightly granular, eosinophilic cytoplasm that contains large, clear distinct vacuoles. Ovoid nuclei contain stippled chromatin. Moderate anisocytosis and anisokaryosis are present. H&E stain; bar = 100 μm.

Citation: Journal of the American Veterinary Medical Association 255, 5; 10.2460/javma.255.5.537

Neoplastic cells had strong cytoplasmic staining for IBA-1, weak membranous and cytoplasmic staining for E-cadherin, and no staining for PNL2. Moderate numbers of CD3-positive lymphocytes were dispersed throughout the mass (Figure 3). Electron microscopic examination of sections of the mass was performed and revealed cells with lobulated, irregular, eccentric nuclei, perinuclear microfilaments, and prominent rough endoplasmic reticulum, consistent with Langerhans cells in cutaneous histiocytomas (Figure 4).

Figure 3—
Figure 3—

Photomicrographs of immunohistochemically stained sections of the nasal mass in the dog in Figure 1. A—The neoplastic cells are strongly positive for ionized calcium-binding adaptor molecule 1. Ionized calcium-binding adaptor molecule 1-specific stain; bar = 20 μm. B—Notice the moderate number of CD3-positive lymphocytes throughout the mass. CD3-specific stain; bar = 20 μm.

Citation: Journal of the American Veterinary Medical Association 255, 5; 10.2460/javma.255.5.537

Figure 4—
Figure 4—

Transmission electron micrograph of a single histiocytic cell of the mass in the dog in Figure 1. This cutaneous histiocytoma cell is characterized by an irregularly folded nucleus with perinuclear microfilaments and rough endoplasmic reticulum. Uranyl acetate and lead citrate stains; bar = 1 μm.

Citation: Journal of the American Veterinary Medical Association 255, 5; 10.2460/javma.255.5.537

Morphologic Diagnosis and Case Summary

Morphologic diagnosis and case summary: regressing cutaneous histiocytoma of the axial surface of the wing of the left nostril in a dog.

Comments

Neoplasia of the nasal planum in dogs is rare, with the most commonly reported tumor being squamous cell carcinoma.1 Other reported tumors of the nasal planum include lymphoma, fibrosarcoma, hemangioma, melanoma, mast cell tumor, fibroma, and eosinophilic granuloma.1 Although there have been a few descriptions2 of cutaneous histiocytoma on the nose of dogs, the authors are unaware of reports of this neoplasm on the nasal planum specifically.

Cutaneous histiocytoma is a benign neoplasm originating from intraepithelial dendritic cells known as Langerhans cells. These tumors generally develop as a single, small mass in dogs < 3 years of age but have been identified in older dogs.3 The tumors may develop in any region of the body but are frequently located on the head, particularly the pinnae.3 Initial growth of the mass is typically rapid, but lesions often spontaneously regress within 1 to 2 months. The trigger for tumor regression is poorly understood, but regression is typically mediated by CD8+ T cells with scant numbers of CD4+ T cells found within the tumor.4 A diagnosis of cutaneous histiocytoma can be supported by results of immunohistochemical staining for specific markers such as E-cadherin, which is expressed by Langerhans cells but not by dermal dendritic cells. Although expression of E-cadherin in the cutaneous histiocytoma of the dog of the present report was weak, it has been shown that intensity of E-cadherin expression is negatively correlated with the degree of lymphocyte infiltration, meaning that tumors undergoing regression have weaker E-cadherin expression, compared with findings for tumors that are not undergoing regression.5 Ionized calcium-binding adapter molecule 1 is a useful marker for histiocytic cell lineage in inflammatory, proliferative, and neoplastic conditions, but its detection alone does not help differentiate macrophages from dendritic antigen-presenting cells.6 In the case described in the present report, immunohistochemical analysis for PNL2 was performed to rule out the possibility of a melanocytic neoplasm; additional markers used for detection of melanoma include melan-A and Sox-10, but on the basis of the authors' experience, immunohistochemical analysis for PNL2 is typically sufficient to identify melanoma in dogs. The presence of large numbers of lymphocytes in the dog of the present report was most likely a feature of the regression phase of this tumor. Other immunohistochemical markers used to help identify cutaneous histiocytomas include CD204, CD4, and Thy-1; however, in the case described in the present report, analyses with these markers were not undertaken because of the unavailability of CD204-specific stain and the fact that frozen tissue sections are required for analysis of the latter 2 markers.4

For the dog of the present report, additional cytologic differential diagnoses included histiocytic sarcoma, amelanotic melanoma, and, less likely, a poorly cohesive carcinoma. Because the location and cytologic appearance of the mass were not classic for cutaneous histiocytoma and its immunohistochemical staining properties were consistent with a histiocytic origin but not specifically confirmatory of cutaneous histiocytoma, electron microscopic examination of biopsy specimens was performed to distinguish cutaneous histiocytoma from cutaneous histiocytosis. Cutaneous histiocytosis is a nonneoplastic disease associated with dysregulation of the immune system that causes proliferation of reactive dermal dendritic cells. Lesions of cutaneous histiocytosis appear as nonpruritic plaques or nodules in the skin and subcutaneous tissues and may extend into the deep portions of the dermis.3 Lesions of cutaneous histiocytosis on the nasal planum were detected in 10 of 32 (31%) dogs in 1 study.7 There is no E-cadherin expression associated with cutaneous histiocytosis, but given the weak expression in the dog of the present report, electron microscopic examination of mass specimens was recommended to be certain of the diagnosis of cutaneous histiocytoma.5,7–9 Electron microscopy revealed that the cutaneous histiocytoma Langerhans cells had eccentric irregularly folded nuclei commonly surrounded by microfilaments, and the cytoplasm contained rough endoplasmic reticulum along with numerous cytoplasmic vesicles, characteristics consistent with cutaneous histiocytoma.9,10 However, most vesicles were likely artifacts because the ultrastructural samples were extracted from paraffin.

The dog of the present report was discharged from the hospital after the owner received recommendations to monitor for regression or recurrence of the residual mass lesion. Five months after hospital discharge, the owners reported the mass had regressed and both the stertor and chronic vomiting had resolved. The resolution of vomiting was consistent with previous reports of a link between upper respiratory obstructive disease and gastrointestinal tract signs in brachycephalic dogs.11–13

The case described in the present report highlighted the challenging nature of diagnosis of histiocytic diseases in dogs. For this dog, cytologic findings were not consistent with a typical cutaneous histiocytoma. The presence of multinucleated crown cells typically indicates a perivascular wall tumor; however, the degree of multinucleation and atypical cells observed in this case were inconsistent with the cellular features that are characteristic of perivascular wall tumors. Because a definitive cytologic diagnosis could not be made, samples of the mass underwent histologic examination, immunohistochemical analyses, and electron microscopy. In most cases of cutaneous histiocytoma, diagnostic testing other than cytologic or histologic examination of samples of the mass is not required. For the dog of the present report, disparity between the cytologic and histopathologic findings and the unusual location of the mass warranted additional testing to definitively diagnose a regressing cutaneous histiocytoma.

References

  • 1. Withrow S. Cancer of nasal planum. In: Withrow SJ, Vail DM, Page RL, eds. Withrow & MacEwen's small animal clinical oncology. 5th ed. St Louis: Elsevier Saunders, 2013;432435.

    • Search Google Scholar
    • Export Citation
  • 2. Taylor DO, Dorn CR, Luis OH. Morphologic and biologic characteristic of the canine cutaneous histiocytoma. Cancer Res 1969;29:8392.

  • 3. Moore PF. A review of histiocytic diseases of cats and dogs. Vet Pathol 2014;51:167184.

  • 4. Moore PF, Schrenzel MD, Affolter VK, et al. Canine cutaneous histiocytoma is an epidermotropic Langerhans cell histiocytosis that expresses CD1 and specific beta 2-integrin molecules. Am J Pathol 1996;148:16991708.

    • Search Google Scholar
    • Export Citation
  • 5. Paździor-Czapula K, Rotkiewicz T, Otrocka-Domagała I, et al. Morphology and immunophenotype of canine cutaneous histiocytic tumors. Vet Res Commun 2015;39:717.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Pierezan F, Mansell J, Ambrus A, et al. Immunohistochemical expression of ionized calcium binding adapter molecule 1 in cutaneous histiocytic proliferative, neoplastic and inflammatory disorders of dogs and cats. J Comp Pathol 2014;151:347351.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Palmeiro BS, Morris DO, Goldschmidt MH, et al. Cutaneous reactive histiocytosis in dogs: a retrospective evaluation of 32 cases. Vet Dermatol 2007;18:332340.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Affolter VK, Moore PF. Canine histiocytic proliferative disease, in Proceedings. 15th Am Acad Vet Dermatol & Am Coll Vet Dermatol Meet, 1999;7986.

    • Search Google Scholar
    • Export Citation
  • 9. Marchal T, Dezutter-Dambuyant C, Fournel C, et al. Immunophenotypic and ultrastructural evidence of the Langerhans cell origin of the canine cutaneous histiocytoma. Acta Anat (Basel) 1995;153:189202.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10. Glick AD, Holscher M, Campbell GR. Canine cutaneous histiocytoma: ultrastructural and cytochemical observations. Vet Pathol 1976;13:374380.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11. Poncet CM, Dupre GP, Freiche VG, et al. Prevalence of gastrointestinal tract lesions in brachycephalic dogs with upper respiratory syndrome: clinical study in 73 cases. J Small Anim Pract 2005;46:273279.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. Poncet CM, Dupre GP, Freiche VG, et al. Long term results of upper respiratory syndrome surgery and gastrointestinal tract medical treatment in 51 brachycephalic dogs. J Small Anim Pract 2006;47:137142.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13. Roedler FS, Pohl S, Oechtering GU. How does severe brachycephaly affect dog's lives? Results of a structured preoperative owner questionnaire. Vet J 2013;198:606610.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Figure 1—

    Photograph of the nose of a 2-year-old spayed female English Bulldog with a nasal mass occluding the left nostril (A) and photomicrograph of a fine-needle aspirate specimen of the nasal mass (B). The mass had been present for 2 months; it had high cellularity and numerous plump to ovoid, individualized to aggregated cells. In panel B, modified Wright stain; bar = 20 μm.

  • Figure 2—

    Photomicrographs of a section of the nasal mass in the dog in Figure 1. The neoplastic cells form diffuse sheets that extend from the epidermal-dermal junction into the deeper dermis. H&E stain; bar = 200 μm. Inset—The neoplastic cells have variably distinct cellular borders and moderate to abundant amounts of lightly granular, eosinophilic cytoplasm that contains large, clear distinct vacuoles. Ovoid nuclei contain stippled chromatin. Moderate anisocytosis and anisokaryosis are present. H&E stain; bar = 100 μm.

  • Figure 3—

    Photomicrographs of immunohistochemically stained sections of the nasal mass in the dog in Figure 1. A—The neoplastic cells are strongly positive for ionized calcium-binding adaptor molecule 1. Ionized calcium-binding adaptor molecule 1-specific stain; bar = 20 μm. B—Notice the moderate number of CD3-positive lymphocytes throughout the mass. CD3-specific stain; bar = 20 μm.

  • Figure 4—

    Transmission electron micrograph of a single histiocytic cell of the mass in the dog in Figure 1. This cutaneous histiocytoma cell is characterized by an irregularly folded nucleus with perinuclear microfilaments and rough endoplasmic reticulum. Uranyl acetate and lead citrate stains; bar = 1 μm.

  • 1. Withrow S. Cancer of nasal planum. In: Withrow SJ, Vail DM, Page RL, eds. Withrow & MacEwen's small animal clinical oncology. 5th ed. St Louis: Elsevier Saunders, 2013;432435.

    • Search Google Scholar
    • Export Citation
  • 2. Taylor DO, Dorn CR, Luis OH. Morphologic and biologic characteristic of the canine cutaneous histiocytoma. Cancer Res 1969;29:8392.

  • 3. Moore PF. A review of histiocytic diseases of cats and dogs. Vet Pathol 2014;51:167184.

  • 4. Moore PF, Schrenzel MD, Affolter VK, et al. Canine cutaneous histiocytoma is an epidermotropic Langerhans cell histiocytosis that expresses CD1 and specific beta 2-integrin molecules. Am J Pathol 1996;148:16991708.

    • Search Google Scholar
    • Export Citation
  • 5. Paździor-Czapula K, Rotkiewicz T, Otrocka-Domagała I, et al. Morphology and immunophenotype of canine cutaneous histiocytic tumors. Vet Res Commun 2015;39:717.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Pierezan F, Mansell J, Ambrus A, et al. Immunohistochemical expression of ionized calcium binding adapter molecule 1 in cutaneous histiocytic proliferative, neoplastic and inflammatory disorders of dogs and cats. J Comp Pathol 2014;151:347351.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Palmeiro BS, Morris DO, Goldschmidt MH, et al. Cutaneous reactive histiocytosis in dogs: a retrospective evaluation of 32 cases. Vet Dermatol 2007;18:332340.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Affolter VK, Moore PF. Canine histiocytic proliferative disease, in Proceedings. 15th Am Acad Vet Dermatol & Am Coll Vet Dermatol Meet, 1999;7986.

    • Search Google Scholar
    • Export Citation
  • 9. Marchal T, Dezutter-Dambuyant C, Fournel C, et al. Immunophenotypic and ultrastructural evidence of the Langerhans cell origin of the canine cutaneous histiocytoma. Acta Anat (Basel) 1995;153:189202.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10. Glick AD, Holscher M, Campbell GR. Canine cutaneous histiocytoma: ultrastructural and cytochemical observations. Vet Pathol 1976;13:374380.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11. Poncet CM, Dupre GP, Freiche VG, et al. Prevalence of gastrointestinal tract lesions in brachycephalic dogs with upper respiratory syndrome: clinical study in 73 cases. J Small Anim Pract 2005;46:273279.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. Poncet CM, Dupre GP, Freiche VG, et al. Long term results of upper respiratory syndrome surgery and gastrointestinal tract medical treatment in 51 brachycephalic dogs. J Small Anim Pract 2006;47:137142.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13. Roedler FS, Pohl S, Oechtering GU. How does severe brachycephaly affect dog's lives? Results of a structured preoperative owner questionnaire. Vet J 2013;198:606610.

    • Crossref
    • Search Google Scholar
    • Export Citation

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