Pathology in Practice

Ashley L. Leisering 1Marshfield Veterinary Lab, 1000 N Oak Ave, Marshfield, WI 54449.

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Mario F. Sola 2Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Lisbeth A. Ambrosius 4Advanced Veterinary Care, 1021 E 3300 S, Salt Lake City, UT 84106.

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Colleen F. Monahan 5New Hampshire Veterinary Diagnostic Laboratory, 21 Botanical Ln, Durham, NH 03824.

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Brian A. Meyer 2Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Pierre L. Deshuillers 6Ecole Nationale Vétérinaire d'Alfort, 94700 Maisons-Alfort, France.

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Abigail C. Durkes 2Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Deborah W. Knapp 3Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Dodd G. Sledge 7Veterinary Diagnostic Laboratory, Michigan State University, Lansing, MI 48910.

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Craig A. Thompson 2Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.
1Marshfield Veterinary Lab, 1000 N Oak Ave, Marshfield, WI 54449.
2Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.
3Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.
4Advanced Veterinary Care, 1021 E 3300 S, Salt Lake City, UT 84106.
5New Hampshire Veterinary Diagnostic Laboratory, 21 Botanical Ln, Durham, NH 03824.
6Ecole Nationale Vétérinaire d'Alfort, 94700 Maisons-Alfort, France.
7Veterinary Diagnostic Laboratory, Michigan State University, Lansing, MI 48910.

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History

A 14-year-old 6.3-kg (13.9-lb) spayed female domestic shorthair cat was taken to its primary care veterinarian for a cystectomy to remove a mass from the cranial aspect of the urinary bladder. Histologic evaluation of the excised mass was consistent with a urothelial carcinoma with narrow but clean margins. The following month, possible tumor recurrence in the bladder was detected during an ultrasonographic examination. The cat was then referred to a veterinary teaching hospital for further evaluation.

Clinical and Clinicopathologic Findings

On physical examination at the referral visit, there were no abnormal findings. Abdominal ultrasonography revealed mild focal apical thickening in the cranial aspect of the urinary bladder, bilateral medial iliac lymphadenomegaly, and multiple hypoechoic nodules adjacent to the spleen, in the pancreas, and in the caudoventrally located abdominal fat. Thoracic radiography revealed a mild bronchial lung pattern, but no evidence of tumor metastasis. Results of a CBC and serum biochemical panel indicated that the cat had mild lymphopenia, mildly high sodium and albumin concentrations, and mildly high amylase activity. No further diagnostic testing was pursued, and the cat was prescribed meloxicam as a palliative treatment for suspected metastatic urothelial carcinoma.

Three months later, the cat developed multiple cutaneous, coalescing nodules on the ventral aspect of the abdomen. In addition, it was anorexic, was urinating outside of the litter box, and had hind limb neurologic deficits. A fine-needle aspirate specimen of one of the cutaneous nodules was obtained, and smear preparations were submitted to the hospital's clinical pathology laboratory (Figure 1). Several days later, euthanasia (by IV injection of euthanasia solution) was elected because of the cat's rapidly deteriorating condition. A necropsy was performed.

Figure 1—
Figure 1—

Photomicrograph of an aspirate specimen from a skin nodule in a 14-year-old cat. Notice the abundant bare nuclei occasionally arranged in rosette-like structures (asterisk) and short rows (dagger) overlying a basophilic, granular-appearing cytoplasmic background. The nuclei are round to ovoid and have moderate anisokaryosis. The chromatin pattern is coarse; in some nuclei, a single, small to medium, prominent nucleolus is present. Modified Wright-Giemsa stain; bar = 20 μm.

Citation: Journal of the American Veterinary Medical Association 255, 4; 10.2460/javma.255.4.433

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

Cytologic, Necropsy, and Histopathologic Findings

Microscopic examination of the aspirate smears revealed that the cutaneous nodule was composed predominantly of bare nuclei overlying pools of blue, granular-appearing cytoplasm. The nuclei often appeared cohesively arranged, sometimes in short palisading formations and rarely in rosette-like arrangements. The nuclei were round to ovoid with moderate anisokaryosis. The chromatin pattern was coarse, sometimes with a single, small to medium-sized, round, prominent nucleolus. Very rarely, intact cells with similar nuclear features were identified singly and in small clusters. These intact cells were round to polygonal, had moderate anisocytosis, and contained small amounts of blue, granular-appearing cytoplasm. On the basis of these findings, the primary differential diagnosis was an endocrine or neuroendocrine tumor, possibly a Merkel cell tumor or metastatic endocrine or neuroendocrine tumor to the skin.

At necropsy, > 30 individual or coalescing nodules were evident within the hilus of the left kidney, left adrenal gland, omentum, mesentery, skin, lungs, and abdominal wall. The adrenal nodule measured approximately 1 cm × 5 mm × 5 mm. On histologic evaluation of sections of the adrenal gland, there was a highly cellular, invasive neoplastic proliferation of round to polygonal cells with variably distinct cell borders (Figure 2). These cells were arranged in sheets and nests, separated by a fine fibrous stroma. The neoplastic population compressed the adrenal cortex, and low numbers of cells had invaded the adrenal capsule. The cells had moderate anisocytosis and contained moderate amounts of lightly basophilic to amphiphilic and finely granular cytoplasm. The nuclei were round to oval with a vesiculated chromatin pattern and 1 or 2 medium-sized, round, prominent nucleoli. There were 60 to 100 mitotic figures/10 hpf. Similar neoplastic cells were also present within the skin (Figure 3), left kidney, mesentery, abdominal musculature, lungs, and cerebellar peduncle.

Figure 2—
Figure 2—

Photomicrographs of sections of the left adrenal gland from the cat in Figure 1. The adrenal medulla contains a highly cellular, invasive proliferation of neoplastic cells arranged in nests and packets separated by a fine fibrous stroma. This population has invaded and compressed the adrenal cortex. H&E stain; bar = 500 μm. Inset—The neoplastic cells contain moderate amounts of amphiphilic to basophilic and finely granular cytoplasm. There is moderate anisocytosis and anisokaryosis. The nuclei are round to ovoid with a vesiculated chromatin pattern and 1 or 2 medium-sized, round, prominent nucleoli. H&E stain; bar = 50 μm.

Citation: Journal of the American Veterinary Medical Association 255, 4; 10.2460/javma.255.4.433

Figure 3—
Figure 3—

Photomicrographs of sections of a skin nodule from the cat in Figure 1. A well-demarcated, unencapsulated mass of neoplastic cells arranged in sheets and nests separated by a fine fibrous stroma has expanded the dermis and invaded the subcutis. H&E stain; bar = 500 μm. Inset—The neoplastic cells appear similar to those observed in the adrenal medulla. H&E stain; bar = 50 μm.

Citation: Journal of the American Veterinary Medical Association 255, 4; 10.2460/javma.255.4.433

Sections of the masses from the skin and adrenal medulla underwent immunohistochemical analysis for protein gene product (PGP) 9.5, chromogranin A, and synaptophysin at 1 of 2 laboratories.a,b The neoplastic cell population in both tissues had moderate to strong immunoreactivity for PGP9.5 and chromogranin A but had no immunoreactivity for synaptophysin. Immunohistochemical analyses for endorphin, met-enkephalin, and cytokeratin 20 were performed on sections of one of the skin masses. The neoplastic cell population had diffuse, weak to strong cytoplasmic immunoreactivity for endorphin and no immunoreactivity for met-enkephalin or cytokeratin 20 (Figure 4).

Figure 4—
Figure 4—

Photomicrographs of immunohistochemically stained sections of a skin nodule from the cat in Figure 1. The neoplastic cells have strong immunoreactivity for chromogranin A (A), moderate immunoreactivity for protein gene product 9.5 (B), variable immunoreactivity for endorphin (C), and no immunoreactivity for cytokeratin 20 (D). These findings are most consistent with chromaffin cells of the adrenal medulla, which confirms the suspected diagnosis of a pheochromocytoma with metastasis to the skin. Immunohistochemical stains for chromogranin A, protein gene product 9.5, endorphin, or cytokeratin 20; bar = 50 μm.

Citation: Journal of the American Veterinary Medical Association 255, 4; 10.2460/javma.255.4.433

Interpretation and Case Summary

Interpretation and case summary: malignant pheochromocytoma with widespread metastases to the skin, left kidney, mesentery, abdominal musculature, lungs, and brain in a cat.

Comments

Pheochromocytomas arise from chromaffin cells of the adrenal medulla. These tumors are uncommon in dogs and cattle and rare in domestic cats. The neoplastic chromaffin cells may secrete epinephrine, norepinephrine, or both.1 Clinical signs attributable to high circulating concentrations of tumor-secreted catecholamines or hemorrhage from or associated with the tumor may include weakness, episodic collapse, tachypnea, seizures, and systemic hypertension,2 although these problems were not evident in the case described in the present report.

To the authors’ knowledge, there are only 4 published case reports3–6 of pheochromocytomas in domestic cats. In a retrospective study7 that evaluated adrenal tumors in domestic animals, neoplastic lesions in feline adrenal glands included metastases (12/20 [60%] cases), adrenocortical adenomas (3/20 [15%] cases), adrenocortical carcinomas (3/20 [15%] cases), benign pheochromocytomas (1/20 [5%] cases), and malignant pheochromocytomas (1/20 [5%] cases).

In the cat of the present report, cytologic examination of aspirate specimen smears of a cutaneous nodule initially raised the suspicion for an endocrine or neuroendocrine tumor, which was confirmed by the findings of histologic evaluation. Given the involvement of the adrenal medulla, a pheochromocytoma was the primary consideration. This diagnosis was corroborated by the neoplastic cells’ immunoreactivity for PGP9.5, chromogranin A, and endorphin. In general, pheochromocytomas have variable immunoreactivity for leu-enkephalin, met-enkephalin, phenylethanolamine N-methyltransferase, endorphin, chromogranins A and B, synaptophysin, vimentin, PGP9.5, and S-100.8

Given the cutaneous involvement in the case described in the present report, a Merkel cell tumor with widespread metastasis was also considered. Merkel cells are neuroendocrine cells of the epidermis and follicular epithelium that are involved in mechanoreception. These tumors are typically immunoreactive for chromogranin A, synaptophysin, and cytokeratin 20.9 There are only 2 reported cases of Merkel cell tumors in cats; in one cat, the tumor was benign,10 and in the other cat, the tumor was malignant with pulmonary and mediastinal metastasis.11 For the cat of the present report, a malignant Merkel cell tumor was ultimately considered unlikely because of the lack of immunoreactivity for cytokeratin 20 among the neoplastic cells.

Acknowledgments

Dr. Deshuillers was funded by a Morris Animal Veterinary Fellowship for Advanced Study and Frederick N. Andrews Fellowship (Purdue University).

The authors thank Dr. Ramos-Vara for the histologic interpretation of the urothelial carcinoma and Dr. Matti Kiupel for immunohistochemistry recommendations.

Footnotes

a.

Indiana Animal Disease Diagnostic Laboratory, Purdue University, West Lafayette, Ind.

b.

Veterinary Diagnostic Laboratory, Michigan State University, Lansing, Mich.

References

  • 1. Maxie MG, Jubb KV, Kennedy PC, et al. Endocrine glands. Jubb, Kennedy, and Palmer's pathology of domestic animals. 6th ed. Edinburgh: Elsevier Saunders, 2015;349356.

    • Search Google Scholar
    • Export Citation
  • 2. Ettinger AJ, Feldman EC. Endocrine disorders. Textbook of veterinary internal medicine. 7th ed. St Louis: Elsevier Saunders, 2010;1867.

    • Search Google Scholar
    • Export Citation
  • 3. Calsyn JD, Green RA, Davis GJ, et al. Adrenal pheochromocytoma with contralateral adrenocortical adenoma in a cat. J Am Anim Hosp Assoc 2010;46:3642.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Patnaik AK, Erlandson RA, Lieberman PH, et al. Extra-adrenal pheochromocytoma (paraganglioma) in a cat. J Am Vet Med Assoc 1990;197:104106.

    • Search Google Scholar
    • Export Citation
  • 5. Henry CJ, Brewer WG Jr, Montgomery RD, et al. Clinical vignette. Adrenal pheochromocytoma. J Vet Intern Med 1993;7:199201.

  • 6. Chun R, Jakovljevic S, Morrison WB, et al. Apocrine gland adenocarcinoma and pheochromocytoma in a cat. J Am Anim Hosp Assoc 1997;33:3336.

  • 7. Labelle P, De Cock HEV. Metastatic tumors to the adrenal glands in domestic animals. Vet Pathol 2005;42:5258.

  • 8. Kiupel M, Capen C, Miller M, et al. Tumors of the adrenal glands. In: Histological classification of tumors of the endocrine system of domestic animals. Washington, DC: Armed Forces Institute of Pathology in cooperation with the CL Davis DVM Foundation and the World Health Organization Collaborating Center for Worldwide Reference on Comparative Oncology: Armed Forces Institute of Pathology in cooperation with the CL Davis DVM Foundation and the World Health Organization Collaborating Center for Worldwide Reference on Comparative Oncology, 2008;4647.

    • Search Google Scholar
    • Export Citation
  • 9. Meuten DJ, Moulton JE. Epithelial and melanocytic tumors of the skin. In: Tumors in domestic animals. 5th ed. Ames, Iowa: Wiley Blackwell, 2017;123125.

    • Search Google Scholar
    • Export Citation
  • 10. Bagnasco G, Properzi R, Porto R, et al. Feline cutaneous neuroendocrine carcinoma (Merkel cell tumour): clinical and pathological findings. Vet Dermatol 2003;14:111115.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11. Patnaik AK, Post GS, Erlandson RA. Clinicopathologic and electron microscopic study of cutaneous neuroendocrine (Merkel cell) carcinoma in a cat with comparisons to human and canine tumors. Vet Pathol 2001;38:553556.

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

    Photomicrograph of an aspirate specimen from a skin nodule in a 14-year-old cat. Notice the abundant bare nuclei occasionally arranged in rosette-like structures (asterisk) and short rows (dagger) overlying a basophilic, granular-appearing cytoplasmic background. The nuclei are round to ovoid and have moderate anisokaryosis. The chromatin pattern is coarse; in some nuclei, a single, small to medium, prominent nucleolus is present. Modified Wright-Giemsa stain; bar = 20 μm.

  • Figure 2—

    Photomicrographs of sections of the left adrenal gland from the cat in Figure 1. The adrenal medulla contains a highly cellular, invasive proliferation of neoplastic cells arranged in nests and packets separated by a fine fibrous stroma. This population has invaded and compressed the adrenal cortex. H&E stain; bar = 500 μm. Inset—The neoplastic cells contain moderate amounts of amphiphilic to basophilic and finely granular cytoplasm. There is moderate anisocytosis and anisokaryosis. The nuclei are round to ovoid with a vesiculated chromatin pattern and 1 or 2 medium-sized, round, prominent nucleoli. H&E stain; bar = 50 μm.

  • Figure 3—

    Photomicrographs of sections of a skin nodule from the cat in Figure 1. A well-demarcated, unencapsulated mass of neoplastic cells arranged in sheets and nests separated by a fine fibrous stroma has expanded the dermis and invaded the subcutis. H&E stain; bar = 500 μm. Inset—The neoplastic cells appear similar to those observed in the adrenal medulla. H&E stain; bar = 50 μm.

  • Figure 4—

    Photomicrographs of immunohistochemically stained sections of a skin nodule from the cat in Figure 1. The neoplastic cells have strong immunoreactivity for chromogranin A (A), moderate immunoreactivity for protein gene product 9.5 (B), variable immunoreactivity for endorphin (C), and no immunoreactivity for cytokeratin 20 (D). These findings are most consistent with chromaffin cells of the adrenal medulla, which confirms the suspected diagnosis of a pheochromocytoma with metastasis to the skin. Immunohistochemical stains for chromogranin A, protein gene product 9.5, endorphin, or cytokeratin 20; bar = 50 μm.

  • 1. Maxie MG, Jubb KV, Kennedy PC, et al. Endocrine glands. Jubb, Kennedy, and Palmer's pathology of domestic animals. 6th ed. Edinburgh: Elsevier Saunders, 2015;349356.

    • Search Google Scholar
    • Export Citation
  • 2. Ettinger AJ, Feldman EC. Endocrine disorders. Textbook of veterinary internal medicine. 7th ed. St Louis: Elsevier Saunders, 2010;1867.

    • Search Google Scholar
    • Export Citation
  • 3. Calsyn JD, Green RA, Davis GJ, et al. Adrenal pheochromocytoma with contralateral adrenocortical adenoma in a cat. J Am Anim Hosp Assoc 2010;46:3642.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Patnaik AK, Erlandson RA, Lieberman PH, et al. Extra-adrenal pheochromocytoma (paraganglioma) in a cat. J Am Vet Med Assoc 1990;197:104106.

    • Search Google Scholar
    • Export Citation
  • 5. Henry CJ, Brewer WG Jr, Montgomery RD, et al. Clinical vignette. Adrenal pheochromocytoma. J Vet Intern Med 1993;7:199201.

  • 6. Chun R, Jakovljevic S, Morrison WB, et al. Apocrine gland adenocarcinoma and pheochromocytoma in a cat. J Am Anim Hosp Assoc 1997;33:3336.

  • 7. Labelle P, De Cock HEV. Metastatic tumors to the adrenal glands in domestic animals. Vet Pathol 2005;42:5258.

  • 8. Kiupel M, Capen C, Miller M, et al. Tumors of the adrenal glands. In: Histological classification of tumors of the endocrine system of domestic animals. Washington, DC: Armed Forces Institute of Pathology in cooperation with the CL Davis DVM Foundation and the World Health Organization Collaborating Center for Worldwide Reference on Comparative Oncology: Armed Forces Institute of Pathology in cooperation with the CL Davis DVM Foundation and the World Health Organization Collaborating Center for Worldwide Reference on Comparative Oncology, 2008;4647.

    • Search Google Scholar
    • Export Citation
  • 9. Meuten DJ, Moulton JE. Epithelial and melanocytic tumors of the skin. In: Tumors in domestic animals. 5th ed. Ames, Iowa: Wiley Blackwell, 2017;123125.

    • Search Google Scholar
    • Export Citation
  • 10. Bagnasco G, Properzi R, Porto R, et al. Feline cutaneous neuroendocrine carcinoma (Merkel cell tumour): clinical and pathological findings. Vet Dermatol 2003;14:111115.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11. Patnaik AK, Post GS, Erlandson RA. Clinicopathologic and electron microscopic study of cutaneous neuroendocrine (Merkel cell) carcinoma in a cat with comparisons to human and canine tumors. Vet Pathol 2001;38:553556.

    • Crossref
    • Search Google Scholar
    • Export Citation

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