Pathology in Practice

Paula A. Schaffer Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523.

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Suzanne Barnes Eagle Valley Pet Hospital, 550 Grand Ave, Eagle, CO 81631.

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History

An adult 3.7-kg (8.1-lb) neutered male domestic longhair cat was evaluated at the Eagle Valley Pet Hospital because of lethargy and lameness of the left forelimb of approximately 1 week's duration.

Clinical and Gross Findings

The soft tissues of multiple digits on all 4 paws were very firm and severely thickened up to 2 times their expected dimensions. There was ulceration and thick serocellular crusting around the nail beds of affected digits, which were discolored dark red to purple. A CBC revealed leukocytosis (WBC count, 22,700 WBCs/μL; reference range, 4,200 to 15,600 WBCs/μL) with neutrophilia (17,933 neutrophils/μL; reference range, 2,500 to 12,500 neutrophils/μL), and reactive lymphocytes were detected on examination of a blood smear. The cat tested negative for circulating FeLV antigen and anti-FIV antibody by means of an ELISA. Serum biochemical analysis revealed low alanine aminotransferase activity (21 U/L; reference range, 28 to 100 U/L) and mild hypokalemia (3.6 mEq/L; reference range, 3.9 to 5.3 mEq/L), both attributed to anorexia. Serum concentrations of thyroxine (1.7 μg/dL; reference range, 0.8 to 4.7 μg/dL) and N-terminal pro B-type natriuretic peptide (28 pmol/L; reference range, 0 to 100 pmol/L) were within reference ranges.

A diagnosis of paronychia (nail bed infection) was made, and the cat was treated with amoxicillin-clavulanic acid drops (1 mL, PO, q 12 h), once-daily warm water antibacterial soaks (diluted betadine solution) of the distal portions of the limbs, and application of a fentanyl patch (providing 25 μg of fentanyl/h). Six days later, the cat remained lethargic and all affected digits remained swollen, caused pain, and were exudative. The owners declined additional diagnostic testing, including examination of cytologic or biopsy specimens and radiography. At that time, the cat was given an SC injection of prednisolone acetate (10 mg). Treatment with prednisone (5 mg, PO, q 24 h for 1 week, then 2.5 mg, PO, q 24 h for 1 week) and enrofloxacin (22.7 mg, PO, q 24 h) was initiated. The owners initially reported that the cat's appetite and activity levels were improved and that the digital swelling had decreased.

The cat was briefly lost to follow-up. Six weeks after the initial evaluation, the cat was brought to the hospital for euthanasia. The cat was weak, nonambulatory, and mentally dull with fixed mydriasis and lateral strabismus of the left eye. Digits of all 4 limbs remained markedly swollen and multifocally ulcerated. Several claws were absent. Multiple skeletal muscles, including the left triceps brachii and right and left gastrocnemius muscles, were asymmetrically firm and swollen; signs of pain were elicited on palpation. The left stifle joint was contracted with limited range of motion. There was moderate edema of the distal portion of the left hind limb. The cat was euthanized by IV administration of pentobarbital sodium solution owing to poor prognosis and declining quality of life.

Gross postmortem lesions included severe soft tissue swelling of the distal digits on all 4 paws with serocellular crusting, exudation from the nail beds, and multifocal loss of claws (Figure 1). Many patchy, poorly demarcated zones of pallor were present within the bodies of multiple skeletal muscles, including the left triceps brachii and both gastrocnemius muscles. There were multiple chronic renal infarctions characterized by radiating, irregular to wedge-shaped areas of cortical depression and parenchymal loss. Multiple small (≤ 1-cm-diameter), nodular, discrete gray foci were present within the lung tissues. The CNS was not evaluated at necropsy.

Figure 1—
Figure 1—

Photograph of the forelimb digits of an adult domestic longhair cat that was evaluated because of lethargy and lameness of the left forelimb of approximately 1 week's duration. Notice that the soft tissues of multiple digits on the forelimbs are palpably expanded with surface ulceration and serocellular crusting around the nail beds.

Citation: Journal of the American Veterinary Medical Association 249, 2; 10.2460/javma.249.2.157

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

Histopathologic Findings

Sections of the lungs, kidneys, heart, skeletal muscles, and 1 digit were fixed in neutral-buffered 10% formalin and submitted for histologic evaluation. Evaluation of the lung tissue revealed that the alveolar parenchyma was multifocally expanded by multiple unencapsulated, well-demarcated masses consisting of neoplastic epithelial cells (Figure 2). The neoplastic cells were cuboidal to columnar in shape and formed compact glandular structures supported by scant fibro-vascular stroma. Each cell had an indistinct cell border, a modest amount of eosinophilic cytoplasm, and a basally located oval nucleus with stippled to vesicular chromatin and a single small nucleolus. There was moderate anisocytosis and anisokaryosis, and mitotic figures were common (10 mitotic figures/10 hpf). Glandular lumina occasionally contained mucoid material and small numbers of foamy alveolar macrophages. Luminal mucoid material was strongly periodic acid–Schiff (PAS) stain positive, consistent with mucin-containing material, and many neoplastic cells contained granular PAS stain–positive cytoplasmic contents.

Figure 2—
Figure 2—

Photomicrographs of sections of lung tissue from the cat in Figure 1. A—Neoplastic epithelial cells have replaced the pulmonary parenchyma. Adjacent alveoli are moderately atelectic (x). H&E stain; bar = 200 μm. B—Neoplastic cells are columnar with indistinct borders and modest amounts of cytoplasm; each cell has an ovoid nucleus with stippled chromatin and a single small nucleolus. Mitotic figures are fairly common (arrows). Glandular lumina contain mucoid material (asterisk). H&E stain; bar = 75 μm. C—Mucoid material within glands is strongly periodic acid–Schiff (PAS) stain positive (asterisk), and neoplastic cells contain granular PAS stain–positive material in the apical cytoplasm (arrows). PAS stain; bar = 75 μm.

Citation: Journal of the American Veterinary Medical Association 249, 2; 10.2460/javma.249.2.157

One digit was evaluated histologically (Figure 3). The dermis of the digit was infiltrated, expanded, and disrupted by large numbers of neoplastic epithelial cells that effaced dermal collagen, entrapped and distorted adnexal structures, and eroded into the cortex and marrow cavity of the distal phalanx (not shown). The neoplastic cells formed densely packed lobules, glands, and tubular structures that occasionally contained mucoid debris and small numbers of inflammatory cells. Anisocytosis and anisokaryosis were more marked in the dermis of the digit than within the pulmonary mass. The overlying epidermis was multifocally ulcerated and replaced by thick serocellular crusts. Mucoid material within neoplastic glands was strongly PAS stain positive, and scattered neoplastic cells contained granular PAS stain–positive cytoplasmic contents.

Figure 3—
Figure 3—

Photomicrographs of digital skin from the cat in Figure 1. A—Neoplastic cells, similar to those in the lung tissue, have effaced the dermis and surround hair follicles (F) and adnexa. There is focal ulceration and cellular crusting (arrow). Glandular spaces contain mucoid material (asterisk). H&E stain; bar = 200 μm. B—Mitotic figures are common (arrows). H&E stain; bar = 75 μm. C—Mucoid material within glands is strongly PAS stain positive (asterisk) and neoplastic cells contain granular PAS stain–positive material in the apical cytoplasm (arrows). PAS stain; bar = 75 μm.

Citation: Journal of the American Veterinary Medical Association 249, 2; 10.2460/javma.249.2.157

Neoplastic cells similar to those previously described multifocally formed small lobules, glands, and tubular structures throughout the interstitium of the left triceps brachii and gastrocnemius muscles (not shown). There was extensive subacute to chronic infarction of myocytes with myocyte atrophy and loss and extensive replacement fibrosis adjacent to the metastatic lesions. In the kidneys (not shown), invasive neoplastic cells formed lobules and glandular structures throughout all levels of the cortex and also expanded the renal capsule. Multiple large corticomedullary vessels were occluded by rafts of neoplastic cells (tumor emboli) that partially to fully occluded the vascular lumina, leading to infarction and fibrosis of cortical tissue. Large numbers of lymphocytes and plasma cells were dispersed throughout the interstitium between tumor cells and remnant renal tubules, which were commonly atrophied or degenerated.

Morphologic Diagnosis and Case Summary

Morphologic diagnosis: pulmonary adenocarcinoma with disseminated metastasis.

Case summary: digital metastasis of pulmonary adenocarcinoma (feline lung-digit syndrome) in an adult domestic longhair cat.

Comments

Pulmonary carcinomas are relatively uncommon in cats.1–3 Geriatric cats are most commonly affected (mean age, 12.3 years; range, 6 to 18 years), and Persians may be overrepresented.3 These tumors are typically aggressive with metastasis occurring in 75% to 80% of cases.3,4 Common metastatic sites include adjacent pulmonary parenchyma, pleura, lymph nodes, skin, uvea, skeletal muscles, bones, and internal viscera.1,3

Metastasis of pulmonary carcinoma to the dermis of the digits of cats is a rare but classic sequela sometimes referred to as feline lung-digit syndrome. Cats reportedly have a higher digital blood flow than other species as a mechanism to facilitate heat loss; thus, a relatively higher blood flow to the digits may predispose to metastasis to this area.1 In addition, it has been suggested that metastatic cells may have specific receptors or ligands that result in tropism for digital dermal tissues or that other factors of the digital microenvironment, such as relative hypoxia, could play a role in recruiting metastatic cells.1 Metastatic lesions originate in the dermis adjacent to the nail bed or within the footpad and frequently erode into bone of the distal phalanx. Invasion into the intra-articular space and erosion of the middle phalanx are also reported.2

In a study5 of amputated feline digits, metastatic pulmonary carcinoma in the digits and primary digital squamous cell carcinoma were the only epithelial tumors identified, and metastatic pulmonary carcinomas were approximately as common as primary digital squamous cell carcinomas and primary digital fibrosarcomas. In a separate retrospective study,6 metastatic carcinoma was the most common carcinoma of feline digits. Other primary tumors of the digit, such as osteosarcoma, mast cell tumor, and hemangiosarcoma, are relatively rare.6 Interestingly, digital metastasis occurs in humans with pulmonary squamous cell carcinoma as well as renal and mammary carcinomas.7,8 Digital metastasis is not a recognized phenomenon in domestic species other than cats.

Cats with digital metastasis of pulmonary adenocarcinoma typically develop lameness. The gross lesion associated with metastatic cells in a digit can be easily mistaken for acute or chronic nail bed infection, especially in cats that are evaluated early in the course of disease (eg, when only 1 or 2 digits are affected) or in cats that have no respiratory tract signs. In 2 studies2,6 of cats with digital metastasis of pulmonary carcinoma, 16.7% (6/36 cats) and 62.5% (40/64 cats) had multiple digit involvement at the first evaluation. The forelimb digits appear to be slightly more likely to be affected than the hind limb digits, and weight-bearing digits appear to be more likely affected than non–weight-bearing digits.2 Additional clinical signs in cats with digital metastasis of pulmonary carcinomas commonly include weight loss, lethargy, and inappetence. Less than half of affected cats have clinical signs directly related to the pulmonary neoplasm, such as cough or dyspnea.4

Although rare, digital metastasis of pulmonary adenocarcinoma should be considered an important differential diagnosis for nail bed infections or any unexplained swellings of digits in cats, especially when multiple digits on multiple limbs are affected and lesions are nonresponsive or are progressive in the face of antimicrobial treatment. Radiographic evidence of bony lysis of the distal phalanges is very common and may also help raise the index of clinical suspicion for a neoplastic process, especially when osteolysis involves both the middle and distal phalanges. Thoracic radiography may be useful to establish the presence of a pulmonary mass. Cytologic evaluation of fine-needle aspirates from digital masses can also be useful for identification of neoplastic epithelial cells in the dermis. Examination of a biopsy specimen of an affected digit or an entire amputated digit in combination with clinical features and radiographic findings may sometimes be necessary for definitive diagnosis. Histologically, biopsied tissue typically has neoplastic epithelial cells arranged in tubular or tubulopapillary patterns within the dermis with extension into bones of the digit. The neoplastic epithelium may contain goblet cells, and some cells may bear cilia. Neoplastic cells within metastatic lesions often contain and secrete mucins that stain with PAS stain. Thus, PAS stain positivity supports a diagnosis of metastatic pulmonary carcinoma and helps to distinguish metastatic pulmonary carcinoma from primary adenocarcinomas of the digit that do not produce mucins (such as eccrine or apocrine tumors).

Early diagnosis of digital metastasis of pulmonary adenocarcinoma is critical because the prognosis is very poor and treatment options are extremely limited. The reported median survival time of affected cats is 58 days.1

References

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  • 2. Gottfried SD, Popovitch CA, Goldschmidt MH, et al. Metastatic digital carcinoma in the cat: a retrospective study of 36 cats (1992–1998). J Am Anim Hosp Assoc 2000; 36: 501509.

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  • 3. D'Costa S, Yoon BI, Kim DY, et al. Morphologic and molecular analysis of 39 spontaneous feline pulmonary carcinomas. Vet Pathol 2012; 49: 971978.

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  • 8. Cohen PR. Metastatic tumors to the nail unit: subungual metastases. Dermatol Surg 2001; 27: 280293.

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