Primary Clitoral Adenocarcinoma With Secondary Hypercalcemia of Malignancy in a Dog
This report describes a primary clitoral adenocarcinoma in a dog with secondary hypercalcemia of malignancy. A 10-year-old, spayed female basset hound was evaluated for a mass protruding from the vulva. The mass was excised, and a histological diagnosis of clitoral adenocarcinoma was made. No evidence of metastasis on thoracic radiographs or abdominal ultrasound was seen. Preoperative hypercalcemia resolved following excision of the mass. Cellular features were similar to an apocrine gland anal sac adenocarcinoma, and immunohistochemistry exhibited features noted with apocrine gland anal sac adenocarcinoma. No further treatment was elected by the owner. Internal iliac lymph-node metastasis was identified 4 weeks postoperatively, and hypercalcemia recurred 8 weeks postoperatively. The dog was euthanized 22 weeks postoperatively for signs related to hypercalcemia, including polyuria/polydipsia, lethargy, and weakness. A necropsy was performed and confirmed the presence of internal iliac lymph-node metastasis. The colon, rectum, and anal sacs were grossly and histologically normal. To our knowledge, this is the first reported case of clitoral neoplasia in the dog.
Introduction
Clitoral neoplasia has not been reported in the dog. In dogs, the majority of reported vaginal and vulvar tumors are benign and occur in intact females; however, malignant tumors are more common in spayed females.1–3 In humans, clitoral neoplasia is commonly grouped with other cancers of the vulva. Squamous cell carcinoma represents >90% of human vulvar cancers, 15% to 20% of which involve the clitoris.4,5 The prognosis for vulvar carcinoma in humans is strongly correlated with histological type as well as the presence and number of lymph-node metastases.6
Hypercalcemia of malignancy is a paraneoplastic syndrome that is most commonly associated with canine lymphoproliferative disorders and apocrine gland anal sac adenocarcinoma (AGASA).7,8 It is associated with the production of parathormone-related peptide (PTH-rp) by the tumor, which results in increased bone resorption and increased renal tubular resorption of calcium.7,9 Hypercalcemia has not been previously reported in association with vaginal or vulvar tumors in the dog. It also has not been reported as a paraneoplastic syndrome in women with clitoral adenocarcinoma. However, it has been reported as a rare secondary condition in men with penile carcinoma.10,11
Case Report
A 10-year-old, spayed female basset hound was presented for evaluation of a vulvar mass identified by the owner 1 week prior to presentation. The dog had a 2-week history of pollakiuria and a urinary tract infection treated with trimethoprim-sulfamethoxazole. At presentation, a 4 × 4 × 4-cm mass was identified as being intimately associated with the clitoris and protruding from the clitoral fossa [Figure 1]. The mass was spherical, firm, broad-based, highly vascular in appearance, and was creating a partial obstruction of the vaginal vestibule. The urethral orifice remained unobstructed. Rectal examination, including palpation of the anal sacs, was normal. Other abnormalities detected during physical examination included a redundant vulvar fold, mild perivulvar dermatitis, and a grade II/VI left-sided holosystolic heart murmur. Thoracic radiographs and abdominal ultrasound were unremarkable. Mild leukopenia (4.9 × 103/μL; reference range 6 to 17 × 103/μL) was identified on complete blood count. Severe hypercalcemia (>16 mg/dL; reference range 7.9 to 12.0 mg/dL) and hypophosphatemia (1.9 mg/dL; reference range 2.5 to 6.8 mg/dL) were identified. Ionized calcium concentration was elevated (2.08 mmol/L; reference range 1.12 to 1.4 mmol/L).
Surgical excision of the mass was elected. To promote calciuresis, the dog was placed on 0.9% sodium chloride (120 mL/kg per 24 hours intravenously [IV]) and furosemidea (1 mg/kg IV q 8 hours) beginning the morning of surgery; this was continued for 24 hours postoperatively. The saline infusion rate was increased (10 mL/kg per hour IV) during anesthesia. The clitoris and mass were excised with a combination of sharp dissection and electrocautery. The wall of the clitoral fossa was reconstructed with simple interrupted sutures of 4-0 polydioxanone.b Recovery from surgery was uneventful, and ionized calcium concentration decreased from 2.08 mmol/L to 1.78 mmol/L (reference range 1.12 to 1.4 mmol/L) within 24 hours.
The histological architecture of the clitoris was effaced and expanded by a well-demarcated, unencapsulated, multilobulated neoplasm. The lobules were composed of neoplastic epithelial cells that formed nests and acinar structures that were separated by a fine, anastomosing, fibrovascular, connective-tissue stroma [Figure 2]. Individual neoplastic cells were of variable shapes and ranged from attenuated cuboidal to round or polygonal with discrete borders and eosinophilic to amphophilic cytoplasm. Nuclei were predominantly round or oval with coarse, stippled chromatin and one or two prominent nucleoli. Mitotic figures numbered 0 to 1 per 40× objective field. Complete histological margins were obtained and ranged from 0.6 to 1.3 cm in the multiple sections examined. The histological morphology was comparable to AGASA, although this mass was anatomically and histologically confined to the clitoral fossa and the clitoral vasculature. The histological diagnosis was a clitoral adenocarcinoma. Neoplastic cells stained diffusely positive for E-cadherin and pancytokeratins MNF116 and AE1/AE3, with rare neoplastic cells positive for cytokeratin (CK) 7. Neoplastic cells were negative for CK5/6, CK18, CK19, CK20, CK34BE12, and vimentin.
Two weeks postoperatively, the surgical site had healed without complication, and ionized calcium had continued to decrease (1.48 mmol/L; reference range 1.12 to 1.4 mmol/L). Four weeks postoperatively, enlarged internal iliac lymph nodes were palpated during rectal examination. The owner reported the dog to be normal at this time, and no local recurrence of the tumor was observed during examination. Ionized calcium was within the reference range (1.32 mmol/L; reference range 1.12 to 1.4 mmol/L). Fine-needle aspiration cytology of the internal iliac lymph nodes was consistent with metastatic adenocarcinoma. The owner declined further treatment but returned the dog for follow-up examinations and monitoring. Ionized calcium increased to 1.45 mmol/L at 8 weeks and >2.5 mmol/L at 16 weeks postoperatively.
The dog was euthanized 22 weeks postoperatively because of signs related to hypercalcemia, including prolonged anorexia, episodic weakness, and polyuria/polydipsia. A postmortem examination was performed, and metastasis of the clitoral adenocarcinoma to the internal iliac lymph nodes was confirmed histologically [Figure 3]. No gross evidence of tumor recurrence at the operative site was seen; however, the vulva was not examined histologically. Chronic cystitis and pyelonephritis were present, which were likely secondary to ascending urinary tract infections. No gross or histopathological evidence of tumor metastasis was identified in the liver, lungs, kidneys, ureters, urethra, colon, rectum, or anal sacs.
Discussion
The clitoris is the homolog of the male penis. It lies in the clitoral fossa, a depression in the floor of the vaginal vestibule. It is composed of paired crura, a body, and a glans. An os clitoridis is occasionally present.12 Clitoral hypertrophy may result from irritation of the clitoral fossa, hormone-dependent hypertrophy, or intersex states.13 Clitoral neoplasia has not been previously reported in the dog.
Vaginal and vulvar neoplasms account for 2.4% to 3% of all reported tumors in dogs that are between a mean age of 10.8 and 11.2 years.1,2 Most affected dogs (>90%) are intact; however, malignant tumors are more common in spayed females.2,3 The majority of reported vaginal and vulvar tumors are benign, including leiomyomas, fibromas, lipomas, and hemangiomas.1–3,14 Malignant tumors include transmissible venereal tumor, leiomyosarcoma, mast cell tumor, epidermoid carcinoma, squamous cell carcinoma, hemangiosarcoma, osteosarcoma, and adenocarcinoma.1–3 Clinical signs associated with vaginal and vulvar neoplasia include a visible mass that may protrude from the vulva, perineal swelling, vulvar discharge, vulvar bleeding, vulvar licking, tenesmus, stranguria, pollakiuria, and hematuria.1–3 Nonneoplastic differential diagnoses for vulvar masses include vaginal hyperplasia, vaginal prolapse, polyp, abscess, hematoma, os clitoridis, and clitoral hypertrophy.15
In this case, tumor cells appeared identical to those of an AGASA on light microscopy; however, no palpable masses or histological abnormalities were identified in association with the anal sacs. A choristoma (displaced embryonic nest of cells) may have been present in this dog, leading to a similar lineage of cells in the clitoral region as the apocrine glands of the anal sacs. Immunohistochemistry was consistent with a diagnosis of adenocarcinoma. Cytokeratins 5, 7, 8, and 14 and E-cadherin are commonly expressed by AGASA, and cells from the neoplasm of the clitoris of this dog were diffusely positive only for E-cadherin and focally positive for CK7.16 Due to the histological and biological correlation of this dog’s tumor to AGASA, adjunctive treatment utilizing anthracycline chemotherapy or single-agent platinum chemotherapy was recommended, based on therapeutic recommendations for women with genital carcinoma.17 Surgical excision of the metastatic iliac lymph nodes was advised, as it has been shown to improve survival in dogs with metastatic AGASA.18 Palliative-intent radiation therapy to the primary tumor site and affected lymph-node bed, either as solitary therapy or in combination with palliative-intent chemotherapy, was offered as an adjunctive or alternative treatment strategy to surgery. Additionally, palliative medical treatments, such as prednisone and bisphosphonate therapy, were discussed with the owner in an effort to reduce the clinical signs associated with hypercalcemia. All additional therapy was declined by the owner because of the anticipated aggressive biological behavior of this tumor.
While hypercalcemia of malignancy is commonly associated with canine lymphoproliferative disorders and AGASA, it has also been reported with a variety of other tumors, including other types of carcinomas, thymoma, multiple myeloma, malignant melanoma, bone tumors, primary lung tumors, and pheochromocytomas.7,8,19 In this dog, a PTH-rp was not determined preoperatively because of the high likelihood of tumor-related hypercalcemia after staging. The return to normocalcemia postoperatively is consistent with the behavior of hypercalcemia secondary to PTH-rp release from AGASA, in which calcium returned to normal in seven of eight dogs postoperatively.20 The PTH-rp concentration has also been shown to decrease significantly following treatment for AGASA.7 Because this dog experienced resolution of hypercalcemia after surgical removal of the clitoral tumor, and hypercalcemia did not recur until internal iliac lymphnode metastasis developed, we believe that the clitoral mass represented the primary and functional neoplastic lesion in this dog. We considered the development of tumor metastasis combined with the recurrence of hypercalcemia at 8 weeks postoperatively to be indicative of hypercalcemia of malignancy; however, a PTH-rp was not performed at that time (because of financial constraints of the owner).
Negative prognostic indicators for canine AGASA include the presence of hypercalcemia, local lymph-node metastasis, and tumor size.20–22 The median postoperative survival time for hypercalcemic dogs with AGASA is significantly shorter than that for dogs that are normocalcemic at the time of diagnosis.20,21 In this solitary case report, it is not possible to determine the significance of hypercalcemia as a predictor of survival for dogs with clitoral adenocarcinoma. Interestingly, hypercalcemia secondary to penile carcinoma in men has been reported to be responsive to chemotherapy, with normalization of ionized calcium to be associated with disease remission.10
Conclusion
Clitoral adenocarcinoma should be considered as a differential diagnosis for clitoral enlargement in the dog. To our knowledge, this is the first reported case of clitoral neoplasia in the dog. This is also the first report of hypercalcemia associated with a tumor of the vulva. The findings in this case suggest that clitoral adenocarcinoma may exhibit aggressive biological behavior similar to that of an AGASA. While surgical excision appeared to control the tumor locally, metastasis and recurrent hypercalcemia were identified early in the course of disease. The effect that additional therapy, such as chemotherapy or excision of the metastatic iliac lymph nodes, may have had on survival remains unknown.
Salix; Intervet, Millsboro, DE 19966
PDS II; Ethicon, Somerville, NJ 08876
Citation: Journal of the American Animal Hospital Association 46, 3; 10.5326/0460193
Citation: Journal of the American Animal Hospital Association 46, 3; 10.5326/0460193
Citation: Journal of the American Animal Hospital Association 46, 3; 10.5326/0460193
Intraoperative photograph of the primary clitoral adenocarcinoma described in this report. The dog is in dorsal recumbency. The clitoris is identified (asterisk).
Adenocarcinoma of the clitoris in a dog. An unencapsulated proliferation of neoplastic apocrine-type glands is seen. Nests and acinar arrangements of neoplastic cells are separated by an intervening, fine, anastomosing, fibrovascular, connective-tissue stroma (Hematoxylin and eosin stain, bar=50 μm).
Postmortem photograph of enlarged, metastatic, iliac lymph nodes secondary to a clitoral adenocarcinoma. Cranial is to the right. The lymph nodes are located at the trifurcation of the aorta.
