History

A 16-year-old 4.4-kg (9.7-lb) spayed female domestic longhair cat was examined by a referring veterinarian because of ptyalism. Upon examination, a left-sided oral swelling or mass was identified. Skull radiography revealed a lytic and proliferative lesion associated with the left mandible; findings of thoracic radiography were unremarkable. Additional patient history included hyperthyroidism; inflammatory bowel disease; cutaneous mast cell tumors with hepatic and splenic metastases, which had been treated with 8 doses of vinblastine-based chemotherapy and splenectomy; chronic kidney disease (International Renal Interest Society¹ stage 2); and hypertrophic cardiomyopathy. Medical management of the cat's concurrent maladies had maintained control of those diseases without clinical signs. Medications that the cat was receiving at the time included methimazole, atenolol, budesonide, and chlorambucil.

Clinical and Clinicopathologic Findings

A week after the initial examination, the cat was taken to a veterinary teaching hospital for further evaluation and treatment. A CBC and serum biochemical panel revealed mild normocytic normochromic anemia, mild hyperglycemia, mild hypermagnesemia, mild azotemia, and minimally high alkaline phosphatase activity. Mild hypercalcemia (10.8 mg/dL; reference interval, 8.2 to 10.4 mg/dL) was also detected. Physical examination revealed moderate dental calculus accumulation, ptyalism, and a firm mass associated with the left mandible. No ocular or nasal discharge was noted, and regional lymph nodes were soft and symmetrical during palpation. Lung sounds were clear in all fields, and a grade 3/6 heart murmur was auscultated on both the right and left sides of the thorax. Abdominal palpation yielded no remarkable findings. For further assessment and possible surgical planning, the cat underwent a CT scan of the head and neck, which revealed an irregular osseous proliferative and moth-eaten lytic lesion (2.0 × 2.3×1.5 cm) centered on the left mandibular body with concurrent tooth loss, suggestive of an aggressive process. Two fine-needle aspirate specimens of the lesion were obtained by a veterinary student and a surgical oncologist; 1 slide preparation was stained for microscopic examination in the clinic. The stained slide preparation had a moderately atypical population of cells. The cells were present singly as well as arranged in variably sized, tightly cohesive sheets throughout the preparation, along with several large multinucleated cells (Figure 1). The cat was anesthetized for a hemimandibulectomy procedure and placement of an esophagostomy tube. Surgical removal of the mass was uneventful. Unfortunately, the cat had cardiopulmonary arrest the morning after surgery, and resuscitation was unsuccessful; the owners declined a postmortem examination.

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Photomicrograph of a fine-needle aspirate specimen obtained from a left-sided mass associated with the mandible of a 16-year-old cat. The preparation contained a moderately atypical population of cells arranged singly as well as in tightly cohesive sheets, along with several large multinucleated cells (black arrows). Modified Romanowsky stain; bar = 200 μm.

Citation: Journal of the American Veterinary Medical Association 255, 3; 10.2460/javma.255.3.309

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

Cytologic Findings

The previously stained and remaining unstained slide preparations were submitted for review by a clinical pathologist. On microscopic examination of all slides, the fine-needle aspirate preparations appeared disparate. A subset of the slides, including the previously evaluated stained slide, contained a moderately atypical squamous cell population (Figure 2). The pleomorphic cells were in various stages of maturation, typically seen as individual cells but also in variably sized, tightly cohesive sheets. They were oval to polyhedral, with variably distinct cytoplasmic borders and a moderate to abundant amount of pale to moderately basophilic to aqua blue cytoplasm that occasionally contained a few ill-defined perinuclear clear vacuoles. The round or oval nucleus in each cell was paracentral to eccentric, measured approximately 1.5 to 3 times the size of an erythrocyte, had coarse to open lacey chromatin, and rarely contained 1 or 2 discernible nucleoli. Asynchrony of maturation between nucleus and cytoplasm was a common feature of these cells; the overall anisocytosis and anisokaryosis were moderate to occasionally marked, and the nucleus-to-cytoplasm ratio was generally low. A subset of these cells was arranged in small, variably sized clusters; these cells were of immature morphology, had a higher nucleus-to-cytoplasm ratio and greater cytoplasmic basophilia, and often contained multiple prominent nucleoli of variable size.

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Photomicrographs of fine-needle aspirate preparations obtained from the mandibular lesion in the cat in Figure 1 illustrating the disparate cytologic populations in different slide preparations. A—In this slide preparation, there is a predominance of a moderately atypical squamous cell population. The cells are present singly and in cohesive sheets. Wright-Giemsa stain; bar = 200 μm. Inset—The cells are pleomorphic and have a variable nucleus-to-cytoplasm ratio, variably distinct cytoplasmic borders, and a moderate to abundant amount of pale to moderately basophilic to aqua blue cytoplasm. The round or oval nuclei are paracentral to eccentric with coarse to open lacey chromatin and rarely contain 1 or 2 discernible nucleoli. Wright-Giemsa stain; bar = 50 μm. B—In this slide preparation, there is a moderately to markedly atypical population of mesenchymal cells (osteoblasts). Cells are oval to stellate to fusiform and have variably indistinct cytoplasmic borders and a moderate amount of medium basophilic cytoplasm that frequently contain a small paranuclear clear zone. The variably placed, oval nucleus of each cell has finely to coarsely stippled chromatin and 1 to 4 round or oval, discernible nucleoli of variable size. Wright-Giemsa stain; bar = 50 μm.

Citation: Journal of the American Veterinary Medical Association 255, 3; 10.2460/javma.255.3.309

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Examination of the remaining slide preparations revealed a moderately to markedly atypical population of mesenchymal cells, which were interpreted as osteoblasts; these cells were typically present individually or, less frequently, arranged in variably sized, loosely cohesive clusters occasionally admixed with a small amount of bright eosinophilic extracellular matrical material, possibly osteoid. These cells were oval to stellate to fusiform and had variably indistinct cytoplasmic borders and a moderate amount of medium basophilic cytoplasm that frequently formed wispy projections and contained a small paranuclear clear zone. The round to oval nucleus was variably placed, measured approximately 2 to 3 times the size of an erythrocyte, had finely to coarsely stippled chromatin, and usually contained 1 to 4 round or oval, discernible nucleoli of variable size. Overall, anisocytosis, anisokaryosis, and nucleus-to-cytoplasm ratio for this population were moderate. Large multinucleated cells, compatible with osteoclasts, were frequently detected. Additionally, non-to mildly vacuolated macrophages, often containing phagocytized cellular debris, were occasionally noted. Mature, nondegenerate neutrophils were present in a low to moderate number, often in close association with the squamous epithelial cells and occasionally within their cytoplasm (emperipolesis).

In the absence of observable tissue architecture, the cytologic diagnosis was confounded because of the presence of 2 atypical cell populations of apparently different origins, but neoplasia was considered most likely. The neoplastic differential diagnoses were a primary bone tumor (eg, osteosarcoma) with secondary reactive squamous cell hyperplasia or dysplasia or an aggressive squamous cell carcinoma with secondary bone lysis and bone reactivity. Both cell populations had moderate to marked atypia, although neutrophilic inflammation, which typically accompanies squamous cell carcinomas, was not prominent. Regardless of the type of neoplasia and given the potential aggressive behavior of either top disease consideration, surgical excision was the recommended treatment with follow-up histologic examination of removed tissues to provide additional prognostic information. Collection and examination of samples of regional lymph nodes was also suggested. On the basis of the diagnosis of neoplasia, surgical excision and histologic evaluation of the mass and affected portion of the mandible were elected.

Histopathologic Findings

Histologic examination of sections of the excised tissue revealed a multifocal, unencapsulated, infiltrative, densely cellular mass that had filled > 50% of the mandibular marrow spaces, replaced medullary components, surrounded and replaced trabeculae, and moderately disrupted and replaced the cortex (Figure 3). The mass was composed of cells that formed nests separated by abundant fibrous connective tissue (desmoplasia). The cells were medium to large and polygonal with variably distinct cellular borders, pale eosinophilic cytoplasm, and frequent intercellular bridging. The round or oval nuclei were medium to large, had coarsely clumped chromatin, and often contained 1 or 2 nucleoli. The mitotic rate was estimated at 20 mitotic figures/10 hpf (400×). The mass had infiltrated the bone, forming Howship lacunae with large numbers of multinucleated giant cells (osteoclasts).

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Photomicrograph of a section of the mandibular lesion excised from the cat in Figure 1. The unencapsulated, infiltrative mass is composed of medium to large and polygonal cells, which have replaced medullary components (white arrows). The cells have variably distinct cellular borders, pale eosinophilic cytoplasm, and frequent intercellular bridging. The mass has infiltrated the bone, forming multiple Howship lacunae with several osteoclasts (black arrows). H&E stain; bar = 200 μm.

Citation: Journal of the American Veterinary Medical Association 255, 3; 10.2460/javma.255.3.309

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Morphologic Diagnosis and Case Summary

Morphologic diagnosis and case summary: mandibular squamous cell carcinoma (SCC) with concurrent prominent bone reactivity and remodeling in a cat.

Comments

For the cat of the present report, the final diagnosis was mandibular SCC with prominent invasion of adjacent bone; however, the cytologic and radiographic characteristics of the neoplasm mimicked an osteosarcoma (OSA). Although primary bone tumors in cats are rare, OSA is the most common type.² Among 145 feline cases of OSA in 1 study,³ 7 (4.8%) were mandibular OSAs.

Squamous cell carcinoma is a malignant neoplasm of epithelial cells with differentiation into keratinocytes. It is the most common oral tumor in cats⁴ and the third most common oral tumor in dogs.⁵ In cats, oral SCC is a locally invasive neoplasm with the potential to metastasize in approximately a third of cases^6,7; however, most cats develop illness related to the primary tumor site before metastatic disease becomes clinically relevant.⁸

In cats, the development of SCCs is likely multifactorial; predisposing factors such as exposure to UV radiation or environmental tobacco smoke, usage of flea collars, and consumption of canned foods have been proposed, and there is a possible association with papillomavirus infection.⁹ Similar to humans, oral SCC often develops in older cats with no apparent breed or sex predisposition.⁷ In cats with oral SCC, the most commonly affected sites are the gingivae, followed by sublingual locations and the tongue.¹⁰ Cats and humans may develop lingual SCC, which is one of the less common locations of oral SCC in other species.¹¹ Cats with oral SCC may have hyporexia or anorexia, lethargy, weight loss, ptyalism, and halitosis; mandibular SCCs usually appear as a firm, diffuse swelling with or without ulceration and tooth loss in the affected area.⁸

Oral SCCs frequently invade bone in cats and dogs. In cats, SCC-related bone invasion is usually severe and extensive, promotes destruction of oral tissues, and often is associated with tooth loss, ulceration, and secondary bacterial infections.¹² Bone invasion is most commonly found in cases of gingival SCC, likely because of the proximity of the gingivae to the underlying bone.¹⁰ However, oral SCCs can cause new bone formation as well as bone destruction.¹³

Bone invasion associated with oral SCC is dependent on osteoclast activation and function. Increased amounts of parathyroid hormone-related protein and the receptor activator of nuclear factor kB ligand are involved in osteolytic properties of both human and feline oral SCCs.^{10,11,14–16} Hypercalcemia, as evident in the cat of the present report, may have been associated with high serum concentration of parathyroid hormone-related protein; it could also have been a direct result of bone lysis by the tumor^10,17 or possibly a consequence of the cat's comorbidities.

Treatment of oral SCC is curative only for a small percentage of affected cats in which complete surgical removal of the lesion is possible.⁸ Treatment methods for cats with oral SCC include surgery, radiation therapy, chemotherapy, adjunctive treatments, and different combinations of these methods.¹⁸ In 1 study,¹⁹ cats with oral SCC that underwent mandibulectomy and radiation therapy had a median survival time of 14 months, although the survival time of cats with oral SCC is usually brief because most cats are euthanized after the diagnosis has been made.²⁰ In cats treated surgically, tumor recurrence is common and may be attributed to challenges in defining the extent of tumor invasion and subsequent failure to obtain clean margins in all dimensions around the tumor.⁸

Given the milieu of bone resorption, new bone formation, stromal fibroblastic response, and squamous epithelial neoplastic invasion in cases of oral SCC, it is not surprising that a sample of the mass obtained by fine-needle aspiration may yield a mixture of cell populations and preclude establishing a definitive cytologic diagnosis. In the case described in the present report, the collection of specimens by both a veterinary student and a surgical oncologist may have influenced the attempted cytologic diagnosis. The disparity between findings for the slide preparations may have been related to differences in operator collection method or experience, sample site choice, or random chance. Although cytologic assessment of fine-needle aspirate specimens provides important clinical information (which was consistent with a neoplastic process for the cat of the present report), histologic examination of sections of the mass allows structural and architectural evaluation, which is often required to determine a definitive diagnosis.

Oral SCCs in any species are a diagnostic challenge to practitioners and clinical pathologists alike. Although an SCC may be suspected on the basis of the tumor's gross appearance and location, the lesion must be differentiated from other malignancies with similar clinical features because biological behavior, typical survival time of an affected animal, routes of metastasis, and other variables are likely to differ among tumor types.