History
A 12-year-old 24.86-kg (54-lb) spayed female mixed-breed dog was evaluated because of polyuria and polydipsia that had persisted over a 3-month period. At the initial evaluation, the dog was found to be hypercalcemic (serum total calcium concentration, 12.8 mg/dL [reference interval, 9.2 to 11.3 mg/dL]; serum ionized calcium concentration, 1.77 mmol/L [reference interval, 1.12 to 1.40 mmol/L]). Other pertinent biochemical abnormalities detected at the time of hypercalcemia diagnosis included low-normal serum phosphorus concentration (2.1 mg/dL; reference interval, 2 to 5 mg/dL), low-normal serum parathyroid hormone concentration (0.60 pmol/L; reference interval, 0.50 to 5.80 pmol/L), and unmeasurably high plasma parathyroid hormone–related peptide concentration (reference interval, 0 pmol/L). Additional comprehensive diagnostic testing included collection of a fine-needle aspirate specimen from a mildly thickened anal sac that was performed during subsequent visits to the hospital. Cytologic examination of the anal sac aspirate specimen revealed no overt abnormalities (no abnormal or potentially neoplastic cells were observed). The dog's polyuria, polydipsia, and hypercalcemia did not respond to alendronate treatment (1.4 mg/kg [0.6 mg/lb], PO, every other day).
Clinical and Clinicopathologic Findings
On physical examination 3 months after the first evaluation, the dog's inguinal lymph nodes were enlarged and firm bilaterally. No other abnormalities were noted. A positron emission tomography (PET) and CT scan performed after injection of a radioactive tracer (2-deoxy-2-[18F]fluoro-d-glucose) revealed increased radioisotope uptake in the dog's inguinal lymph nodes (maximum standardized uptake value, 2.5) and ventral aspect of the vaginal wall (clitoral fossa; maximum standardized uptake value, 2.7). In addition, the diagnostic imaging revealed bilaterally enlarged sublumbar lymph nodes that had increased radioisotope uptake. A vaginal mass within the clitoral fossa was subsequently palpated; grossly, it was broad based, firm, highly vascularized, and multilobular. A fine-needle aspirate specimen of the vaginal mass was obtained for cytologic evaluation.
Cytologic Findings
Cytologic examination of the aspirate specimen of the vaginal mass revealed that it was highly cellular and composed of cohesive epithelial cells that had mild anisocytosis and anisokaryosis (Figure 1). The cells were arranged in clusters, sheets, and occasional acini. They had indistinct borders and moderate amounts of lightly basophilic cytoplasm. The nuclei were round to ovoid and 1.5 to 2 times the diameter of a mature erythrocyte; they contained finely stippled chromatin. Nucleoli were indistinct, and no mitotic figures were seen.
Low- (A) and high- (B) magnification photomicrographs of a fine-needle aspirate specimen from a vaginal mass in a 12-year-old spayed female mixed-breed dog. The specimen contains clusters of epithelial cells that have a neuroendocrine appearance, with mild pleomorphism. Wright-Giemsa stain; in panels A and B, bar = 100 μm and 20 μm, respectively.
Citation: Journal of the American Veterinary Medical Association 254, 10; 10.2460/javma.254.10.1167
Low- (A) and high- (B) magnification photomicrographs of a fine-needle aspirate specimen from a vaginal mass in a 12-year-old spayed female mixed-breed dog. The specimen contains clusters of epithelial cells that have a neuroendocrine appearance, with mild pleomorphism. Wright-Giemsa stain; in panels A and B, bar = 100 μm and 20 μm, respectively.
Citation: Journal of the American Veterinary Medical Association 254, 10; 10.2460/javma.254.10.1167
Low- (A) and high- (B) magnification photomicrographs of a fine-needle aspirate specimen from a vaginal mass in a 12-year-old spayed female mixed-breed dog. The specimen contains clusters of epithelial cells that have a neuroendocrine appearance, with mild pleomorphism. Wright-Giemsa stain; in panels A and B, bar = 100 μm and 20 μm, respectively.
Citation: Journal of the American Veterinary Medical Association 254, 10; 10.2460/javma.254.10.1167
Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page→
Additional Clinicopathologic Findings
At the time of the PET-CT scan, serum biochemical analysis revealed that the dog had moderate hypercalcemia (total calcium concentration, 16.6 mg/dL) and mild hypophosphatemia (1.6 mg/dL). Ionized calcium concentration was markedly elevated (2.34 mmol/L). Plasma parathyroid hormone–related peptide concentration was markedly elevated (8.9 pmol/L), and serum parathyroid hormone concentration was at the lower reference limit (0.50 pmol/L).
Representative low- (A) and high- (B) magnification photomicrographs of a section of a clitoral adenocarcinoma surgically removed from the dog in Figure 1. —The mass is densely cellular, and contains cells arranged in tubules, acini, and sheets. H&E stain; bar = 100 μm. B—The epithelial cells contain abundant eosinophilic cytoplasm and ovoid nuclei with finely stippled chromatin. H&E stain; bar = 50 μm.
Citation: Journal of the American Veterinary Medical Association 254, 10; 10.2460/javma.254.10.1167
Representative low- (A) and high- (B) magnification photomicrographs of a section of a clitoral adenocarcinoma surgically removed from the dog in Figure 1. —The mass is densely cellular, and contains cells arranged in tubules, acini, and sheets. H&E stain; bar = 100 μm. B—The epithelial cells contain abundant eosinophilic cytoplasm and ovoid nuclei with finely stippled chromatin. H&E stain; bar = 50 μm.
Citation: Journal of the American Veterinary Medical Association 254, 10; 10.2460/javma.254.10.1167
Representative low- (A) and high- (B) magnification photomicrographs of a section of a clitoral adenocarcinoma surgically removed from the dog in Figure 1. —The mass is densely cellular, and contains cells arranged in tubules, acini, and sheets. H&E stain; bar = 100 μm. B—The epithelial cells contain abundant eosinophilic cytoplasm and ovoid nuclei with finely stippled chromatin. H&E stain; bar = 50 μm.
Citation: Journal of the American Veterinary Medical Association 254, 10; 10.2460/javma.254.10.1167
Histopathologic and Additional Cytologic Findings
The dog underwent surgery, and both inguinal lymph nodes, the right sublumbar lymph node, right iliac lymph node, and vaginal mass were excised and submitted for histologic evaluation. Samples of the left inguinal lymph node underwent cytologic examination, which revealed the presence of cells with neuroendocrine-like features similar to those of the cells in the aspirate specimen of the vaginal mass. On the basis of the cytomorphologic features of the predominant cell population and the distribution of the cells in the lymph node and the vaginal mass, a neuroendocrine neoplasm was considered a strong possibility. Samples of the right inguinal lymph node were also examined cytologically, which revealed evidence of reactive lymphoid hyperplasia.
On histologic examination of the vaginal mass, polygonal epithelial cells predominated and were arranged in sheets, packets, tubules, acini, and rosette-like arrangements, all of which were surrounded by fibrovascular stroma (Figure 2). The cells had an abundant amount of eosinophilic cytoplasm. Ovoid nuclei had a maximum dimension of 10 to 12 μm and contained finely stippled chromatin. Eosinophilic amorphous material was present within some acinar structures. There were 22 mitoses/10 hpf (400×). Additionally, erectile tissue (poorly cornifying stratified squamous mucosa with small areas of blood-filled spaces) was present within the mass. Immunohistochemical analyses revealed that the neoplastic cells in the vaginal mass had strong cytoplasmic immunoreactivity for pancytokeratin and were negative for cytoplasmic chromogranin A and membranous synaptophysin. These findings confirmed the cells’ epithelial origin and decreased the suspicion of neuroendocrine origin, respectively. All of the lymph node specimens (examined prior to evaluation of the vaginal mass) contained populations of similar neoplastic epithelial cells that effaced 80% to 100% of the normal tissue architecture.
Morphologic Diagnosis and Case Summary
Morphologic diagnosis and case summary: clitoral adenocarcinoma with metastases to all evaluated regional lymph nodes and associated hypercalcemia of malignancy in a dog.
Comments
To our knowledge, there are reports1–3 of clitoral adenocarcinoma with or without secondary hypercalcemia of malignancy in 3 other dogs. In those other 3 reported cases of clitoral adenocarcinoma, gross and histopathologic findings were similar to those for the dog of the present report, with hypercalcemia identified in 2 of the 3 cases. In the case described in the present report, hypercalcemia improved following surgical excision of the malignant mass (similar to findings in the case2 involving a 10-year-old spayed female Basset Hound), and the dog was normocalcemic at the last recheck evaluation.
The cytologic appearance, likelihood of metastasis to regional lymph nodes, and associated paraneoplastic hypercalcemia of clitoral adenocarcinoma are similar to characteristics of apocrine gland anal sac adenocarcinomas.4 However, the dog of the present report did not have any perianal masses detected during physical examination or diagnostic imaging, which excluded the possibility of metastasis of a perianal neoplasm. The dog underwent conformal radiation therapy directed at the vaginal mass, sublumbar lymph node, and inguinal lymph node surgical sites. The dog also received 3 IV doses of mitoxantrone (mean dose, 4.6 mg/m2; range of doses, 4.3 to 5 mg/m2) at 3-week intervals. The dog continued to do well 16 months after treatment was initiated. Results of the aggressive treatment for metastatic clitoral adenocarcinoma administered to the dog of the present report suggested that the prognosis for dogs with this type of tumor can be good with adequate local and systemic treatment. Other carcinomas that have neuroendocrine-like differentiation are well documented and include papillary and mucinous breast carcinomas,5,6 clear cell basal cell carcinoma,7 prostate carcinoma,8 and thymic carcinoma in humans9 and apocrine gland anal sac adenocarcinoma in dogs.10 Although anal sac gland carcinomas with neuroendocrine differentiation and, thus, chromogranin A positivity have been described in dogs,10 only 28 of 69 (40%) samples of anal sac gland carcinomas evaluated in 1 study10 had chromogranin A positivity. Of note, apocrine glands are present in the vulva of dogs4; however, upon subsequent histologic evaluation of the clitoral mass in the dog of the present report, the anatomic location of the mass and the microscopic presence of erectile tissue raised the suspicion of clitoral gland adenocarcinoma.
Anatomically, the vulva includes the vestibule, labia, and clitoris.11 There are bilateral major vestibular glands (mucus-secreting tubuloacinar glands) as well as minor vestibular glands within the vestibular mucosa (tubular mucous glands) of most domestic animals.11 The labia contain both sebaceous and tubular apocrine glands.11 The clitoris consists of variable amounts of erectile tissue (corpus cavernosum) as well as a glans and a prepuce.11 To the authors’ knowledge, it has not been reported that the canine clitoris contains scent-like glands; hence, it is unclear whether the clitoral mass in the dog of the present report originated from adjacent vestibular glands or from another cell population within the clitoris. In the human medical literature, clitoral neoplasms are grouped with other cancers of the vulva, of which > 90% are squamous cell carcinomas and 15% to 20% of those involve the clitoris.2 Similar to other animals, vulvar malignancies in humans are rare and can be primary or metastatic.12 A previous study in humans by Dehner et al12 revealed that among 262 primary and secondary vulvar malignancies evaluated, only 2% were primary adenocarcinomas and 8% were metastases. Of the 22 metastatic cases in that study, 73% were derived from the genital tract (most commonly the cervix with fewer cases involving the endometrium, ovaries, or vagina) and 18% were derived from the urinary tract.12 Primary vulvar adenocarcinomas have been reported to originate from Bartholin (vestibular) glands or vulvar apocrine glands, or can develop as a result of Paget disease (which accounts for < 1% of all vulvar cancers in humans).12
In dogs, vaginal and vulvar neoplasms are rare, comprising 2.4% to 3% of all reported tumors.2 Among dogs, malignant tumors of the vagina and vulva are more common in spayed females than in sexually intact females.2 Other malignant tumors of the vagina and vulva include mast cell tumor, vestibular carcinoma, transitional cell carcinoma, transmissible venereal tumor, and leiomyosarcoma. Benign tumors include leiomyoma, fibroma, lipoma, and hemangioma.4 These are not comprehensive lists, and tumors of the vulva are generally considered to be similar to those that develop in the skin. Carcinomas that affect the vagina or vulva are squamous cell carcinoma and vestibular carcinoma.13 Vulvar squamous cell carcinoma in sheep, goats, and cattle that are exposed to high levels of solar irradiation has been described.13 Vestibular carcinoma in dogs has been reported, and most of those tumors are urothelial in origin.13 Vestibular adenocarcinoma is extremely rare but has been identified in a cow.13
Although uncommon, clitoral adenocarcinoma should be considered a differential diagnosis for vulvar masses with neuroendocrine-like differentiation on cytologic and histologic examination. The clinical signs in dogs with clitoral adenocarcinoma are often similar to those in dogs with apocrine gland anal sac adenocarcinoma; however, it is important to distinguish between these 2 entities to determine appropriate treatment options and prognosis.
References
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