Pathology in Practice

Jennifer L. Mumaw 1Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Lorelei Clarke 1Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Salman Latif Butt 1Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Elizabeth Uhl 1Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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History and Clinical Findings

A 7-year-old 15.9-kg (34.9-lb) spayed female Welsh Pembroke Corgi was evaluated because of respiratory difficulty of approximately 1 month's duration. On examination, the dog was tachycardic and tachypneic with harsh lung sounds and crackles that were loudest in the right ventral lung field. A CBC revealed regenerative anemia; hypercoagulability was suspected because multiple blood samples clotted immediately after they were collected and before a coagulation profile could be performed. Thoracic radiography revealed a mass of soft tissue density in the right caudal lung field that displaced the heart to the left and the remaining right lung lobes cranially. Intrathoracic lymph nodes did not appear enlarged. Abdominal radiography revealed hepatomegaly, and multiple hyperechoic hepatic nodules were identified ultrasonographically. The dog was sedated prior to liver biopsy, after which the dog developed respiratory distress. Resuscitation treatment included administration of aminocaproic acid, oxygen therapy, naloxone, fluid therapy with crystalloid and colloid solutions, and packed RBCs. Given that the dog was considered a poor surgical candidate, euthanasia was elected by the owner; necropsy was performed.

Gross Findings

At necropsy, there was diffuse, pitting, subcutaneous edema of the limbs and ventral aspect of the thorax. Approximately 20 mL of serosanguineous fluid was present in the thoracic cavity. A large (10 × 10 × 12-cm), pale, well-vascularized, firm mass effaced and expanded the majority (approx 80%) of the right caudal lung lobe (Figure 1). A similar, smaller (1 × 1 × 1.5-cm) mass was also present in the left caudal lung lobe. The liver was diffusely friable with rounded edges and a pronounced reticular pattern. Three firm, white masses were present in the liver, of which one (1 cm in diameter) was at the margin on the diaphragmatic surface, another (1 × 1 × 1.5 cm) was on the gastric surface of the right caudal liver lobe, and a third (2 × 1 × 1 cm) was in the right caudal liver lobe.

Figure 1—
Figure 1—

Photograph of the lungs of a 7-year-old Welsh Pembroke Corgi with a history of respiratory difficulty, tachycardia, and tachypnea. A 10 × 10 × 12-cm, firm, pale, vascularized mass has effaced much of the right caudal lung lobe. A smaller, similar 1.0 × 1.0 × 1.5-cm mass (arrow) is present in the left caudal lung lobe.

Citation: Journal of the American Veterinary Medical Association 254, 9; 10.2460/javma.254.9.1057

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

Histopathologic Findings

Sections of the lungs, liver, and various other tissues were fixed in neutral-buffered 10% formalin and routinely processed for microscopic evaluation. The grossly observed mass from the right caudal lobe was composed of a neoplastic cellular population that effaced and compressed the adjacent pulmonary parenchyma. The poorly demarcated, densely cellular, infiltrative, unencapsulated mass contained spindle-shaped to round pleomorphic cells that were haphazardly arranged in short streams and sheets within a fine fibrovascular stroma (Figure 2). Neoplastic cells had variably distinct cell borders and streaming, eosinophilic cytoplasm with basophilic stippling and several variably sized, clear to foamy vacuoles. The nuclei were round to reniform, with coarsely clumped nucleic acid and marked atypia. Randomly aggregated multinucleated cells containing 2 to 10 nuclei were common (Figure 3). There were 1 or 2 mitotic figures/hpf (400X). Immunohistochemical analysis for ionized calcium–binding adaptor molecule 1 revealed that neoplastic cells had strong positive membranous to cytoplasmic reactivity (Figure 4). There were large, multifocal to coalescing areas of necrosis within the mass, which were composed of karyorrhectic and proteinaceous cellular debris with foamy macrophages, cholesterol clefts, and multinucleated giant cells. Similar debris was present in the bronchi and bronchioles. The masses from the left caudal lung lobe and liver were composed of similar neoplastic cell populations.

Figure 2—
Figure 2—

Photomicrograph of a section of the lung mass from the dog in Figure 1. Air spaces and alveolar architecture have largely been obliterated by an infiltrate of spindle-shaped neoplastic cells with indistinct cell borders and abundant pale eosinophilic cytoplasm (asterisk). Several multinucleated cells are present (dagger). H&E stain; bar = 50 μm. Inset—Higher-magnification view of neoplastic cells in the lung mass. Notice the presence of cytoplasmic vacuoles. H&E stain; bar = 10 μm.

Citation: Journal of the American Veterinary Medical Association 254, 9; 10.2460/javma.254.9.1057

Figure 3—
Figure 3—

Photomicrograph of a section of the lung mass from the dog in Figure 1. Several neoplastic cells have marked nuclear pleomorphism (asterisk), and there are several multinucleated cells (dagger). These cells also have small, punctate cytoplasmic vacuoles that are consistent with histiocytic cellular morphology. H&E stain; bar = 50 μm.

Citation: Journal of the American Veterinary Medical Association 254, 9; 10.2460/javma.254.9.1057

Figure 4—
Figure 4—

Photomicrograph of a section of the lung mass from the dog in Figure 1 following immunohistochemical staining for ionized calcium–binding adaptor molecule 1. Notice that the cytoplasm and plasma membrane of neoplastic cells have strong reactivity for ionized calcium–binding adaptor molecule 1. Ionized calcium–binding adaptor molecule 1–specific stain with 3,3′-diaminobenzidine chromagen and hematoxylin counterstain; bar = 20 μm.

Citation: Journal of the American Veterinary Medical Association 254, 9; 10.2460/javma.254.9.1057

Morphologic Diagnosis and Case Summary

Morphologic diagnosis and case summary: pulmonary histiocytic sarcoma with hepatic and pulmonary metastasis in a dog.

Comments

The term histiocyte encompasses cells of macrophage and dendritic cell lineages derived from CD34+ stem cell precursors.1 Histiocytes are potent antigen-presenting cells that have an integral role in T-cell activation, phagocytic functions, and innate immunity.1,2 Dendritic cell lineages are present in the interstitium of many organs, particularly the skin (eg, Langerhans cells and epidermal dendritic cells) and peripheral lymphoid organs (eg, interdigitating dendritic cells).1,2 Tissue macrophages may potentially originate from circulating monocytes released from the bone marrow or from self-renewing local macrophage populations. Tissue macrophages have specialized functions in the skin, spleen, lungs (alveolar macrophages), and liver (Kupffer cells).1,2

Neoplastic diseases of histiocytes in dogs include histiocytoma, cutaneous histiocytosis, cutaneous Langerhans cell histiocytosis, systemic histiocytosis, histiocytic sarcoma, and dendritic cell leukemia.1 With the exception of hemophagocytic-type histiocytic sarcoma, which originates from CD11d+ splenic macrophages,3 histiocytic sarcoma generally originates from interstitial dendritic cells. Localized tumors can develop in the lymph nodes, spleen, lungs, bone marrow, skin, subcutis, brain, and periarticular and articular tissues of joints. Primary tumors may develop in a single organ and then rapidly disseminate to other tissues, commonly the liver, lungs, and lymph nodes.1 In the dog of the present report, the large pulmonary mass was likely the primary tumor that then metastasized to other lung lobes and the liver. Because interstitial dendritic cells are present ubiquitously in tissues, histiocytic sarcomas can potentially develop in almost any tissue location. Histiocytic sarcomas are more common in dogs than in cats; among dogs, there is a higher frequency of histiocytic sarcoma development in Bernese Mountain Dogs,4 Rottweilers, Golden Retrievers, and Flat-Coated Retrievers,5 although all breeds are thought to be susceptible.1,2 A study6 of dogs in Japan also found an increased incidence of histiocytic sarcoma in Welsh Pembroke Corgis. In another report7 of dogs in Japan, it was speculated that Welsh Pembroke Corgis may have a predilection for development of pulmonary histiocytic sarcomas.

Neoplastic cells of histiocytic sarcomas have characteristic morphological features and immunophenotypes.1 Grossly, these tumors are typically destructive, multinodular, and white to tan with a smooth cut surface. Histologically, the tumors are composed of solitary or multiple nodules of large, pleomorphic, mononuclear, round to spindle-shaped cells with indistinct cell borders that may be admixed with multinucleated neoplastic giant cells.1 Frequently, there is a high degree of cellular atypia and bizarre mitotic figures, which may necessitate the use of immunohistochemical analysis to reach a diagnosis. Most histiocytic sarcomas are positive for CD1a, MHCII, and CD11c/CD18 and negative for CD3, CD4, and CD79a, a staining pattern that can distinguish this type of neoplasm from lymphoma.1,2 More recently, ionized calcium–binding adaptor molecule 1 has gained popularity as a histiocytic immunohistochemical marker, because it is expressed by all subpopulations of the monocyte-macrophage lineage, including macrophages, dendritic cells, and microglia.8

For the case described in the present report, the macroscopic appearance of the lesion led to formulation of several potential differential diagnoses, including pulmonary carcinoma, lymphoma, a metastatic neoplasm, and granulomatous disease. Histologic and immunohistochemical findings were used to determine the cell type of origin. The diagnosis of histiocytic sarcoma was made on the basis of the morphology (spindle shape), frequent multinucleation, and ionized calcium–binding adaptor molecule 1 positivity of the neoplastic cells.

The dog's respiratory distress was attributed to both a mass effect in the lungs and reduced gas exchange in the lung lobe occupied by the tumor. This eventually led to hypoxemia and resulted in the observed tachycardia and tachypnea. Blood clotting analysis was prevented because of the clotting of multiple blood samples immediately after they were collected, which indicated that the dog was likely in a hypercoagulable state. The production of prothrombotic factors by neoplastic cells and effects of inflammatory cytokines, acute-phase proteins, and hemodynamic derangements would all potentially contribute to hypercoagulability secondary to the malignant neoplasia.9

References

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

  • 2. Fulmer AK, Mauldin GE. Canine histiocytic neoplasia: an overview. Can Vet J 2007;48:10411043.

  • 3. Moore PF, Affolter VK, Vernau W. Canine hemophagocytic histiocytic sarcoma: a proliferative disorder of CD11d+ macrophages. Vet Pathol 2006;43:632645.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Abadie J, Hedan B, Cadieu E, et al. Epidemiology, pathology, and genetics of histiocytic sarcoma in the Bernese mountain dog breed. J Hered 2009;100(suppl 1):S19S27.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. Constantino-Casas F, Mayhew D, Hoather TM, et al. The clinical presentation and histopathologic-immunohistochemical classification of histiocytic sarcomas in the Flat Coated Retriever. Vet Pathol 2011;48:764771.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Takahashi M, Tomiyasu H, Hotta E, et al. Clinical characteristics and prognostic factors in dogs with histiocytic sarcomas in Japan. J Vet Med Sci 2014;76:661666.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Kagawa Y, Nakano Y, Kobyashi T, et al. Localized pulmonary histiocytic sarcomas in Pembroke Welsh Corgi. J Vet Med Sci 2016;77:16591661.

    • Search Google Scholar
    • Export Citation
  • 8. Pierezan F, Mansell J, Ambrus A, et al. Immunohistochemical expression of ionized calcium binding adaptor 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
  • 9. Caine GJ, Stonelake PS, Lip GY, et al. The hypercoagulable state of malignancy: pathogenesis and current debate. Neoplasia 2002;4:465473.

  • Figure 1—

    Photograph of the lungs of a 7-year-old Welsh Pembroke Corgi with a history of respiratory difficulty, tachycardia, and tachypnea. A 10 × 10 × 12-cm, firm, pale, vascularized mass has effaced much of the right caudal lung lobe. A smaller, similar 1.0 × 1.0 × 1.5-cm mass (arrow) is present in the left caudal lung lobe.

  • Figure 2—

    Photomicrograph of a section of the lung mass from the dog in Figure 1. Air spaces and alveolar architecture have largely been obliterated by an infiltrate of spindle-shaped neoplastic cells with indistinct cell borders and abundant pale eosinophilic cytoplasm (asterisk). Several multinucleated cells are present (dagger). H&E stain; bar = 50 μm. Inset—Higher-magnification view of neoplastic cells in the lung mass. Notice the presence of cytoplasmic vacuoles. H&E stain; bar = 10 μm.

  • Figure 3—

    Photomicrograph of a section of the lung mass from the dog in Figure 1. Several neoplastic cells have marked nuclear pleomorphism (asterisk), and there are several multinucleated cells (dagger). These cells also have small, punctate cytoplasmic vacuoles that are consistent with histiocytic cellular morphology. H&E stain; bar = 50 μm.

  • Figure 4—

    Photomicrograph of a section of the lung mass from the dog in Figure 1 following immunohistochemical staining for ionized calcium–binding adaptor molecule 1. Notice that the cytoplasm and plasma membrane of neoplastic cells have strong reactivity for ionized calcium–binding adaptor molecule 1. Ionized calcium–binding adaptor molecule 1–specific stain with 3,3′-diaminobenzidine chromagen and hematoxylin counterstain; bar = 20 μm.

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

  • 2. Fulmer AK, Mauldin GE. Canine histiocytic neoplasia: an overview. Can Vet J 2007;48:10411043.

  • 3. Moore PF, Affolter VK, Vernau W. Canine hemophagocytic histiocytic sarcoma: a proliferative disorder of CD11d+ macrophages. Vet Pathol 2006;43:632645.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Abadie J, Hedan B, Cadieu E, et al. Epidemiology, pathology, and genetics of histiocytic sarcoma in the Bernese mountain dog breed. J Hered 2009;100(suppl 1):S19S27.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. Constantino-Casas F, Mayhew D, Hoather TM, et al. The clinical presentation and histopathologic-immunohistochemical classification of histiocytic sarcomas in the Flat Coated Retriever. Vet Pathol 2011;48:764771.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Takahashi M, Tomiyasu H, Hotta E, et al. Clinical characteristics and prognostic factors in dogs with histiocytic sarcomas in Japan. J Vet Med Sci 2014;76:661666.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Kagawa Y, Nakano Y, Kobyashi T, et al. Localized pulmonary histiocytic sarcomas in Pembroke Welsh Corgi. J Vet Med Sci 2016;77:16591661.

    • Search Google Scholar
    • Export Citation
  • 8. Pierezan F, Mansell J, Ambrus A, et al. Immunohistochemical expression of ionized calcium binding adaptor 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
  • 9. Caine GJ, Stonelake PS, Lip GY, et al. The hypercoagulable state of malignancy: pathogenesis and current debate. Neoplasia 2002;4:465473.

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