Surgical excision of anal sac apocrine gland adenocarcinomas with and without adjunctive chemotherapy in dogs: 42 cases (2005–2011)

Christopher P. Potanas Metropolitan Veterinary Hospital, 1053 S Cleveland-Massillon Rd, Akron, OH 44321.

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Sheldon Padgett Metropolitan Veterinary Hospital, 1053 S Cleveland-Massillon Rd, Akron, OH 44321.

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Rance M. Gamblin Metropolitan Veterinary Hospital, 1053 S Cleveland-Massillon Rd, Akron, OH 44321.

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Abstract

Objective—To identify variables associated with prognosis in dogs undergoing surgical excision of anal sac apocrine gland adenocarcinomas (ASACs) with and without adjunctive chemotherapy.

Design—Retrospective case series.

Animals—42 dogs with ASACs.

Procedures—Information on signalment, clinical signs, diagnostic procedures, surgical procedures, adjunctive therapies, survival time, and disease-free interval was obtained from the medical records.

Results—Survival time was significantly associated with the presence of sublumbar lymphadenopathy and sublumbar lymph node extirpation, with median survival time significantly shorter for dogs with sublumbar lymphadenopathy (hazard ratio, 2.31) than for those without and for dogs that underwent lymph node extirpation (hazard ratio, 2.31) than for those that did not. Disease-free interval was significantly associated with the presence of sublumbar lymphadenopathy, lymph node extirpation, and administration of platinum-containing chemotherapeutic agents, with median disease-free interval significantly shorter for dogs with sublumbar lymphadenopathy (hazard ratio, 2.47) than for those without, for dogs that underwent lymph node extirpation (hazard ratio, 2.47) than for those that did not, and for dogs that received platinum-containing chemotherapeutic agents (hazard ratio, 2.69) than for those that did not. Survival time and disease-free interval did not differ among groups when dogs were grouped on the basis of histopathologic margins (complete vs marginal vs incomplete excision).

Conclusions and Clinical Relevance—Results suggested that in dogs with ASAC undergoing surgical excision, the presence of sublumbar lymphadenopathy and lymph node extirpation were both negative prognostic factors. However, completeness of surgical excision was not associated with survival time or disease-free interval.

Abstract

Objective—To identify variables associated with prognosis in dogs undergoing surgical excision of anal sac apocrine gland adenocarcinomas (ASACs) with and without adjunctive chemotherapy.

Design—Retrospective case series.

Animals—42 dogs with ASACs.

Procedures—Information on signalment, clinical signs, diagnostic procedures, surgical procedures, adjunctive therapies, survival time, and disease-free interval was obtained from the medical records.

Results—Survival time was significantly associated with the presence of sublumbar lymphadenopathy and sublumbar lymph node extirpation, with median survival time significantly shorter for dogs with sublumbar lymphadenopathy (hazard ratio, 2.31) than for those without and for dogs that underwent lymph node extirpation (hazard ratio, 2.31) than for those that did not. Disease-free interval was significantly associated with the presence of sublumbar lymphadenopathy, lymph node extirpation, and administration of platinum-containing chemotherapeutic agents, with median disease-free interval significantly shorter for dogs with sublumbar lymphadenopathy (hazard ratio, 2.47) than for those without, for dogs that underwent lymph node extirpation (hazard ratio, 2.47) than for those that did not, and for dogs that received platinum-containing chemotherapeutic agents (hazard ratio, 2.69) than for those that did not. Survival time and disease-free interval did not differ among groups when dogs were grouped on the basis of histopathologic margins (complete vs marginal vs incomplete excision).

Conclusions and Clinical Relevance—Results suggested that in dogs with ASAC undergoing surgical excision, the presence of sublumbar lymphadenopathy and lymph node extirpation were both negative prognostic factors. However, completeness of surgical excision was not associated with survival time or disease-free interval.

Anal sac disease is reportedly common in dogs, with approximately 12% of dogs developing conditions associated with the anal sacs, most often impaction or infection, during their lifetimes.1,2 Tumors of the perianal region also occur frequently in dogs, but reportedly 58% to 96% of all perianal tumors are benign perianal adenomas.3 By contrast, ASACs are relatively uncommon in dogs, representing only 17% of all perianal tumors and only 2% of all skin tumors.3 Other types of tumors can affect the anal sacs in dogs, but are even more rare, with squamous cell carcinoma having been reported in 5 dogs,4 papillary cystadenoma in 1,5 and malignant melanoma in 2.5,6

Anal sac apocrine gland adenocarcinomas arise from the apocrine glands located in the walls of the anal sacs, are locally invasive, and readily metastasize to distant locations. The rate of metastasis for this tumor type has been reported to range from 36% to 96%, and numerous studies1,5,7–9 have found a metastatic rate of at least 50% at the time of tumor diagnosis. Metastasis to the iliosacral lymphocenter, comprising the medial iliac, sacral, and hypogastric lymph nodes (often referred to as the sublumbar lymph nodes), is most common, but ASACs can also metastasize to the abdominal visceral organs, lungs, and bone.3 Historically, dogs with metastasis at the time of diagnosis have been thought to have a shorter survival time than those without metastasis.7,9

Dogs that develop ASACs can have a variety of clinical signs, with signs most often associated with tumor size and location (eg, visible swelling, pain, ulceration, scooting, and tenesmus). Tumor size was significantly associated with survival time in 1 study,7 and authors of another report10 recommended pursuing specific treatments on the basis of tumor size. Older reports8,9 describe ASACs in older female dogs, but more recent reports1,7,10 describe equal numbers of male and female dogs, with no association with reproductive status. Other clinical signs reported in dogs with ASACs include polyuria, polydipsia, anorexia, lethargy, and weakness of the hind limbs secondary to hypercalcemia.11 In previous studies,1,9 between 25% and 53% of dogs with ASACs had hypercalcemia. Hypercalcemia has been shown to be associated with shorter survival times in affected dogs7,9; however, the effect has been equivocal in other studies.1

Surgery remains the mainstay for treatment of dogs with ASACs. Surgical excision of the primary tumor should be coupled with extirpation of the sublumbar lymph nodes if lymphadenopathy is present. Adjunctive therapies such as chemotherapy or radiation therapy can be considered depending on whether metastases are present or absent. Multiple studies12–16 have described various primary and adjunctive therapy options for dogs with ASACs; however, inherent differences in study populations, numbers of patients evaluated, outcome measures, and long-term follow-up make it difficult to compare results or recommend particular definitive or adjunctive therapies.

The purpose of the study reported here was to identify variables associated with survival time and disease-free interval in dogs undergoing surgical excision of ASACs with and without adjunctive chemotherapy. Our hypothesis was that results of histologic examination of the margins of the excised primary mass would not be associated with survival time.

Materials and Methods

Criteria for selection of cases—Medical records of the Metropolitan Veterinary Hospital were reviewed to identify dogs that underwent perianal mass excision between April 2005 and October 2011. Dogs that underwent surgical excision of a perianal mass for which a histopathologic diagnosis of ASAC was made by a board-certified pathologist were eligible for inclusion in the study. Dogs were excluded from the study if the perianal mass was only partially excised, if the surgical procedure consisted of only an incisional biopsy, or if a histopathologic diagnosis other than ASAC was made by a board-certified pathologist.

Medical record review—Medical records were examined and information obtained included signalment (breed, age, sex, and body weight), clinical signs (including duration of signs and primary reason for evaluation), results of presurgical staging (CBC, serum biochemical analyses, urinalysis, thoracic radiography, abdominal radiography, cytologic examination, abdominal ultrasonography, and CT), date of surgery, number and types of procedures performed, size of mass, location of mass (left vs right side), histopathologic findings (including results of histologic examination of the margins of the excised primary mass), whether metastatic disease was present, recheck examination date, results of recheck diagnostic tests (CBC, serum biochemical analyses, urinalysis, thoracic radiography, abdominal radiography, abdominal ultrasonography, and rectal examination), adjunctive therapies (including date initiated, medication, dosage, and protocol), date of recurrence, date of progression, disease-free interval, survival time, and date of death. The study was ended on October 1, 2011, and the time from the initial surgery until the study end date was recorded for any patient still alive. Follow-up information was obtained from the medical record when available and consisted of in-hospital recheck examinations and reports of telephone communications with owners and referring veterinarians, when applicable.

Surgical procedure—Patients were premedicated IV with a narcotic and benzodiazepine, and anesthesia was induced with propofol and maintained with isoflurane. Morphine or bupivacaine was administered by means of epidural injection prior to the surgical procedure. When possible, primary tumors were excised with a margin of macroscopically normal tissue; however, marginal resection was often performed on the basis of standard surgical practices for this tumor type and location. Criteria used to determine the extent of excision included adherence of the mass to local structures, size of the mass, and percentage of the external anal sphincter involved. In patients with sublumbar lymphadenopathy, lymph node extirpation was performed during the same surgical session. No patients required pelvic osteotomy for lymph node extirpation.

Patients received injectable narcotics for pain control after surgery and were prescribed tramadol hydrochloride, amoxicillin–clavulanic acid, and either a fentanyl patch or NSAID at the time of hospital discharge. Recheck examinations were scheduled for 10 to 14 days after discharge from the hospital.

Statistical analysis—Survival time was calculated as the time from the initial surgical procedure to the date of death, as confirmed in the medical record or by telephone communication with the owner or referring veterinarian. Dogs still alive at the time of the study were censored at the date of final follow-up. Disease-free interval was calculated as the time from the initial surgical procedure to the date when a diagnosis of disease progression or recurrence was made. Dogs that were alive and had not developed disease progression at the time of the study were censored at the date of final follow-up. Survival time and disease-free interval were analyzed by means of the Kaplan-Meier method and log rank test for equality over strata, with values of P ≤ 0.05 considered significant. Unadjusted Cox regression analyses were performed, and hazard ratios and their 95% CI were calculated. Proportional hazards assumptions were tested and found to hold for all models. All analyses were performed with standard software.a

Results

Forty-two dogs met the criteria for inclusion in the study. Mean ± SD age at the time of surgery was 10.36 ± 2.05 years (range, 7.16 to 16.22 years), and mean weight was 27.0 ± 11.7 kg (59.4 ± 25.7 lb; range, 7.0 to 50.9 kg [15.4 to 112.0 lb]). Twenty-one (50%) dogs were female, all of which were spayed. The remaining 21 (50%) dogs were male, all of which were castrated. Mixed-breed dogs were the most common (n = 12), followed by German Shepherd Dogs (7), Labrador Retrievers (3), Golden Retrievers (2), Siberian Huskies (2), Shetland Sheepdogs (2), and 1 each of English Bulldog, Beauceron, Dachshund, Bassett Hound, Cairn Terrier, Bullmastiff, Tibetan Terrier, Belgian Sheepdog, Boxer, Brittany Spaniel, Cavalier King Charles Spaniel, English Setter, Shih Tzu, and Portuguese Water Dog. Age (P = 0.45 and 0.67, respectively), body weight (P = 0.87 and 0.17, respectively), and sex (P = 0.18 and 0.84, respectively) were not significantly associated with survival time or disease-free interval.

Mean ± SD duration of clinical signs, calculated on the basis of time from the onset of clinical signs or the diagnosis of a perianal mass until initial evaluation, was 44.79 ± 63.04 days (range, 3 to 365 days). Clinical signs were reported in 40 dogs and consisted of perianal swelling (n = 23 [57.5%]), polydipsia (16 [40%]), polyuria (12 [30%]), tenesmus (11 [27.5%]), hind limb weakness (9 [22.5%]), decreased appetite (7 [17.5%]), vomiting (4 [10%]), and lethargy (2 [5%]). Four dogs with perianal swelling had bleeding from the mass, and 2 dogs reportedly were scooting. A perianal mass was discovered or confirmed in all dogs at the time of initial evaluation.

Of the 42 dogs in the study, 29 (69%) underwent fine-needle aspiration of the mass prior to or at the time of initial evaluation. For all 29 dogs, results of cytologic examination of fine-needle aspirates were consistent with ASAC.

Preoperative CBCs and serum biochemical analyses were performed in 40 dogs. No variables significantly related to survival time or disease-free interval were identified. Hypercalcemia was documented before surgery in 8 of 40 (20%) dogs, and hypophosphatemia was documented in 4 (10%). Three of the 4 dogs with hypophosphatemia also had hypercalcemia prior to surgery. Five of the 8 dogs with hypercalcemia prior to surgery had calcium concentrations measured after surgery. In all 5, serum calcium concentration was within reference limits following tumor excision. Most dogs did not undergo postoperative diagnostic testing; therefore, we did not test whether postoperative clinicopathologic variables were associated with survival time or disease-free interval.

Preoperative diagnostic imaging for staging purposes included thoracic radiography, abdominal radiography, abdominal ultrasonography, and CT. Thoracic radiography was performed in 39 of the 42 (92.9%) dogs; only 1 of the 39 (2.6%) dogs had signs of thoracic metastasis. Abdominal radiography was performed in 15 of the 42 (35.7%) dogs; 8 of the 15 dogs had signs consistent with sublumbar lymphadenopathy. Of the 8 dogs with radiographic signs consistent with sublumbar lymphadenopathy, 5 underwent abdominal ultrasonography and 1 underwent CT. All 6 dogs were confirmed to have sublumbar lymphadenopathy on advanced imaging. Abdominal ultrasonography was performed in 30 of the 42 (71.4%) dogs, and 13 of the 30 (43.3%) dogs had sublumbar lymphadenopathy. Overall, 16 of the 42 (38.1%) dogs had evidence of sublumbar lymphadenopathy prior to surgery.

Twenty-two of the 42 (52.4%) dogs had right-sided masses, and 20 (47.6%) had left-sided masses. Three (7.1%) dogs had smaller contralateral tumors. All dogs underwent surgical removal of the primary ASAC tumor. Tumor length was measured ex vivo after surgical resection. Mean ± SD tumor length was 4.39 ± 1.83 cm (range, 1.2 to 8.5 cm). Results of histologic evaluation of the tumor margins were available for 39 of the 42 (92.9%) dogs. Seventeen of the 39 (43.6%) had complete excision of the tumor (no tumor cells detected within 1 cm of the tissue margins), 8 (20.5%) had marginal excision of the tumor (tumor cells within 1 cm of but not extending to the tissue margins), and 14 (35.9%) had incomplete excision of the tumor (tumor cells extended to the tissue margins).

Twenty-two of the 42 (52.4%) dogs had additional surgical procedures performed at the time of initial tumor excision. Twenty-seven additional surgical procedures were performed, including sublumbar lymph node extirpation (n = 16), dermal mass excision (4), contralateral anal sac excision (4), liver lobectomy (2), and liver lobe biopsy (1). All extirpated lymph nodes had histopathologic abnormalities consistent with metastatic anal sac adenocarcinoma. The dermal masses that were excised consisted of a hemangioma, mast cell tumor, squamous cell carcinoma, and preputial metastatic anal sac adenocarcinoma. Histopathologic diagnoses in the 2 dogs that underwent liver lobectomy were hepatocellular carcinoma and nodular regeneration. One of the 4 dogs that underwent contralateral anal sac excision had anal sacculitis; the other 3 had ASACs.

Two dogs had recurrence of ASAC at the primary surgical site. These dogs underwent surgical removal of the recurrent mass 1 month and 1 year after the initial surgical removal. Incomplete excision of the primary tumor was documented for both dogs that developed tumor recurrence. Both of these dogs were still alive at the time of the study, 381 and 736 days, respectively, after the initial surgical excision.

Postoperative chemotherapy was recommended for all 42 dogs, but was administered to only 21 (50%). Chemotherapy was initiated a minimum of 14 days after surgery. Eleven of the 21 (52.4%) dogs that received adjunctive chemotherapy had sublumbar lymph node metastases at the time of primary tumor excision. Nine of the 21 (42.9%) had incomplete excision of the primary tumor, 6 (28.6%) had marginal excision, and 6 (28.6%) had complete excision. First-line chemotherapy treatments consisted of carboplatin (n = 12), chlorambucil (4), prednisone (2), cisplatin (1), toceranib phosphate (1), and doxorubicin (1). Two dogs that received carboplatin were subsequently treated with toceranib because of disease progression. One dog that received carboplatin also received a course of external-beam irradiation.

Eight dogs were still alive at the time of the study; the remaining 34 dogs died or were euthanized for reasons related to tumor progression. No dogs were lost to follow-up. Mean ± SD survival time was 531.5 ± 391.6 days (range, 119 to 1,699 days; median, 404 days; interquartile [25th to 75th percentile] range, 269 to 651 days). Twenty-six (61.9%) dogs had disease progression or recurrence. Mean ± SD disease-free interval was 399.8 ± 401.1 days (range, 56 to 1,336 days; median, 261.5 days; interquartile range, 132 to 470 days).

No significant differences in survival time or disease-free interval were found between dogs with versus without any of the reported clinical signs, between dogs with tumor length < 4.2 cm versus > 4.2 cm (P = 0.6 and 0.61, respectively), among dogs grouped on the basis of histopathologic margin (P = 0.95 and 0.28, respectively), or between dogs that did or did not have an additional surgical procedure other than sublumbar lymph node extirpation (P = 0.16 and 0.87, respectively). Neither hypercalcemia nor hypophosphatemia was found to be a significant independent prognostic variable for survival time or disease-free interval. Finally, dogs that received a platinum-containing chemotherapeutic agent (carboplatin or cisplatin) did not have significantly (P = 0.16) different survival times, compared with dogs that did not.

Table 1—

Results of univariate analysis of factors potentially associated with survival time and disease-free interval in 42 dogs that underwent surgical excision of ASACs with or without adjunctive chemotherapy.

 Survival timeDisease-free interval
VariableHR (95% CI)P valueHR (95% CI)P value
Female0.62 (0.31–1.26)0.180.92 (0.43–2.00)0.84
Age ≥ 10 y0.77 (0.39–1.53)0.450.85 (0.39–1.86)0.68
Weight ≥ 30 kg (66 lb)1.06 (0.53–2.11)0.881.72 (0.78–3.77)0.17
Sublumbar lymphadenopathy2.31 (1.09–4.92)0.032.47 (1.10–5.53)0.02
Sublumbar lymph node extirpation2.31 (1.09–4.92)0.032.47 (1.10–5.53)0.02
Treatment with carboplatin or cisplatin1.75 (0.80–3.83)0.162.69 (1.20–6.00)0.01
Additional surgical procedures0.61 (0.30–1.22)0.161.07 (0.46–2.47)0.87
Calcium ≥ 12.0 mg/dL1.20 (0.51–2.82)0.681.18 (0.44–3.15)0.74
Decreased appetite0.88 (0.36–2.17)0.780.47 (0.14–1.56)0.20
Polyuria1.29 (0.60–2.77)0.510.72 (0.29–1.80)0.48
Polydipsia1.12 (0.55–2.28)0.740.54 (0.23–1.30)0.16
Swelling1.32 (0.65–2.70)0.441.25 (0.55–2.81)0.59
Tenesmus1.52 (0.71–3.25)0.281.26 (0.53–3.03)0.60
Hind limb weakness1.48 (0.67–3.25)0.330.80 (0.30–2.15)0.66
Tumor length ≥ 4.2 cm1.22 (0.59–2.53)0.601.23 (0.55–2.78)0.61

HR = Hazard ratio.

Factors found to be significantly associated with survival time were the presence of sublumbar lymphadenopathy and lymph node extirpation (Table 1). Dogs with sublumbar lymphadenopathy (n = 16) had a significantly (P = 0.03) shorter median survival time (422 days), compared with dogs without lymphadenopathy (n = 26) prior to surgery (529 days; Figure 1). Dogs with sublumbar lymphadenopathy prior to surgery had an increased risk for death (hazard ratio, 2.31; 95% CI, 1.09 to 4.92), compared with dogs without lymphadenopathy. Dogs that underwent lymph node extirpation (n = 16) had a significantly (P = 0.03) shorter median survival time (422 days), compared with dogs without sublumbar lymphadenopathy that did not undergo lymph node extirpation (529 days; Figure 2). Similarly, dogs that underwent lymph node extirpation had an increased risk for death (hazard ratio, 2.31; 95% CI, 1.09 to 4.92), compared with dogs without lymphadenopathy that did not undergo lymph node extirpation. Two dogs underwent a second lymph node extirpation procedure 102 and 179 days after the initial surgery. Survival times for these 2 dogs were 236 and 317 days, respectively.

Figure 1—
Figure 1—

Kaplan-Meier curves of survival time for 42 dogs that underwent surgical excision of ASACs with or without adjunctive chemotherapy and did (n = 16; dashed line) or did not (26; solid line) have sublumbar lymphadenopathy at the time of surgery. Hash marks indicate censored dogs.

Citation: Journal of the American Veterinary Medical Association 246, 8; 10.2460/javma.246.8.877

Figure 2—
Figure 2—

Kaplan-Meier curves of survival time for 42 dogs that underwent surgical excision of ASACs with or without adjunctive chemotherapy and did (n = 16; dashed line) or did not (26; solid line) undergo sublumbar lymph node extirpation.

Citation: Journal of the American Veterinary Medical Association 246, 8; 10.2460/javma.246.8.877

Factors found to be significantly associated with disease-free interval were the presence of sublumbar lymphadenopathy, lymph node extirpation, and administration of a platinum-containing chemotherapeutic agent. Dogs with sublumbar lymphadenopathy prior to surgery had a significantly (P = 0.02) shorter median disease-free interval (197 days), compared with dogs without lymphadenopathy (529 days; Figure 3). Dogs with sublumbar lymphadenopathy prior to surgery had an increased risk for disease progression (hazard ratio, 2.47; 95% CI, 1.10 to 5.53), compared with dogs without lymphadenopathy. Dogs that underwent lymph node extirpation had a significantly (P = 0.02) shorter median disease-free interval (197 days), compared with dogs without sublumbar lymphadenopathy that did not undergo lymph node extirpation (529 days; Figure 4). Dogs that underwent lymph node extirpation had an increased risk for disease progression (hazard ratio, 2.47; 95% CI, 1.10 to 5.53), compared with dogs without lymphadenopathy that did not undergo lymph node extirpation. Dogs that received platinum-containing chemotherapeutic agents had a significantly (P = 0.01) shorter median disease-free interval (226 days), compared with dogs that did not (470 days; Figure 5). Dogs that received platinum-containing chemotherapeutic agents had an increased risk for disease progression (hazard ratio, 2.69; 95% CI, 1.20 to 6.00), compared with dogs that did not.

Figure 3—
Figure 3—

Kaplan-Meier curves of disease-free interval for 42 dogs that underwent surgical excision of ASACs with or without adjunctive chemotherapy and did (n = 16; dashed line) or did not (26; solid line) have sublumbar lymphadenopathy at the time of surgery.

Citation: Journal of the American Veterinary Medical Association 246, 8; 10.2460/javma.246.8.877

Figure 4—
Figure 4—

Kaplan-Meier curves of disease-free interval for 42 dogs that underwent surgical excision of ASACs with or without adjunctive chemotherapy and did (n = 16; dashed line) or did not (26; solid line) undergo sublumbar lymph node extirpation.

Citation: Journal of the American Veterinary Medical Association 246, 8; 10.2460/javma.246.8.877

Figure 5—
Figure 5—

Kaplan-Meier curves of disease-free interval for 42 dogs that underwent surgical excision of ASACs and did (n = 13; dashed line) or did not (29; solid line) receive postoperative treatment with a platinum-containing chemotherapeutic agent (carboplatin or cisplatin).

Citation: Journal of the American Veterinary Medical Association 246, 8; 10.2460/javma.246.8.877

Variables significantly associated with survival time or disease-free interval in univariate analyses were evaluated in multivariate models, but multivariate modeling could not be performed because of high correlations among variables.

Surgical complications related to tumor excision were minimal. One dog developed a dehiscence of the pararectal incision, 1 dog developed a marked reaction to the suture materials, and 1 dog had fecal incontinence that improved over time. The dehiscence was revised surgically, and the dog was treated with antimicrobials; the incision subsequently healed appropriately. For the dog with a suture reaction, affected tissues were excised. On histologic evaluation, there was no evidence of ASAC recurrence, and the incision subsequently healed appropriately. The dog with fecal incontinence was euthanized owing to disease progression; however, survival time was 1,434 days and disease-free interval was 1,336 days. No surgical complications were reported in relation to sublumbar lymph node extirpation.

Discussion

Results of the present study suggested that in dogs with ASAC undergoing surgical excision, the presence of sublumbar lymphadenopathy and lymph node extirpation were both negative prognostic factors. However, completeness of surgical excision was not associated with survival time or disease-free interval in this study.

Half of the dogs in the present study were female, which is similar to recently reported rates of 41.8% to 54%.1,5,7,10 In contrast, in studies8,9,17,18 published prior to 1992, 79% to 100% of dogs were female. All 42 dogs in the present study were spayed or neutered, suggesting that ASACs may not require hormonal influences to develop. This varied slightly from the findings of Polton et al,19 who reported that neutered males had an increased risk, compared with sexually intact dogs, for the development of ASACs in a large population of dogs in Britain. Age (mean, 10.4 years), body weight (mean, 27 kg), and breeds in the present study were consistent with those in earlier studies.1,5,7,9,10 Similar to Williams et al,7 the present study found an ASAC in a dog as young as 7.2 years of age.

Clinical signs reported in the present study were similar to those reported previously,1,8,9 and support the contention that tumor visualization may not be the primary reason for initial evaluation of dogs with ASACs. Only 23 of 40 (57.5%) dogs had a visible perianal swelling, and only 24 (60%) had multiple clinical signs.

Hypercalcemia of malignancy has been well defined in dogs with ASACs. In a 2009 study20 of 109 dogs with ionized hypercalcemia, 3.7% of the dogs overall and 6% of the dogs with neoplasia had ASACs. These tumors were the second most common neoplasm behind lymphosarcoma.20 In the present study, 8 of 40 (20%) dogs had hypercalcemia, and historically, 25% to 53% of dogs with ASACs have been reported to have hypercalcemia.1,5,7,9 Previous reports conflict as to whether hypercalcemia affects survival time. Williams et al7 and Ross et al9 both reported hypercalcemia to negatively impact survival time, whereas Bennett et al1 and Emms5 reported no difference in survival time between hypercalcemic and normocalcemic dogs. Similar to the latter studies,1.5 we did not find hypercalcemia to negatively impact survival time or disease-free interval in the present study. Also, 5 of the dogs in the present study with hypercalcemia that underwent follow-up diagnostic testing had normocalcemia after surgery. Ross et al9 reported that 7 of 8 hypercalcemic patients returned to normocalcemia after surgical removal of the ASAC tumor as well.

Tumor size has been evaluated in several studies for an association with survival time for dogs with ASACs. In the present study, when tumor size was dichotomized (length < 4.2 cm vs > 4.2 cm), we did not find significant differences in survival time or disease-free interval between groups. Williams et al7 found that dogs with ASACs > 10 cm2 in area had significantly shorter survival times, and Polton et al10 found that dogs with tumors > 2.5 cm in length had significantly shorter survival time. These discrepancies likely reflect not only differences in how tumors were measured but also variances in surgical technique and adjunctive therapies. Tumor size has not been shown to be associated with the likelihood of metastasis or hypercalcemia; however, it contributes to the amount of external anal sphincter resected and the possibility of local disease recurrence.

To the authors' knowledge, associations between histopathologic margins (ie, complete vs marginal vs incomplete excision) and survival time or disease-free interval in dogs with ASACs have not been evaluated previously. Results of histopathologic examination of tumor margins were available for 39 of 42 (92.8%) patients in the present study, and we did not find any significant differences in survival time or disease-free interval among groups when dogs were grouped on the basis of histopathologic margins. On the basis of these findings, we recommend that histopathologic margins not be used to determine whether dogs should receive postoperative adjunctive chemotherapy and that all ASACs should be considered to have metastatic potential, independent of the completeness of surgical excision. On the other hand, we believe that our findings suggest that surgical removal should be performed (in conjunction with lymph node extirpation if sublumbar lymphadenopathy is present) even if tumor size or location is such that complete incision may not be possible.

Prevalence of sublumbar lymphadenopathy and of metastasis to the sublumbar lymph nodes differ among studies, likely because of variations in the method or definition used to determine metastasis. Infrequently, results of cytologic examination of lymph node aspirates have been reported, but abdominal radiography, lymph node palpation, abdominal ultrasonography, and histologic examination of biopsy specimens have all been used to identify metastases. In the present study, sublumbar lymphadenopathy was identified by means of abdominal radiography, ultrasonography, or CT in 16 dogs. All 16 underwent lymph node extirpation, and all lymph nodes had histologic evidence of metastatic ASAC.

There were significant differences in survival time (422 vs 529 days) and disease-free interval (197 vs 529 days) between dogs with and without sublumbar lymphadenopathy in the present study. Similarly, Polton et al10 found a correlation between tumor stage and overall survival time and reported that dogs with lymph node metastases had a shorter survival time, compared with dogs without lymph node metastases. In contrast, other studies5,7 have not found lymphadenopathy to be prognostic for survival time.

In the present study, ultrasonography was found to be useful in identifying sublumbar lymphadenopathy. Ultrasonography provides information regarding lymph node size and location, but intrapelvic lymph nodes may be difficult to image because of obstruction by the pelvis. In a previous study,21 advanced imaging techniques provided a viable tool for monitoring progression and recurrence of disease. In that study,21 significantly more lymph nodes were found in dogs with lymphosarcoma or ASAC than in control dogs or dogs with lymphosarcoma in remission.

In the present study, dogs that underwent lymph node extirpation had significantly shorter median survival time and median disease-free interval than did dogs that did not. This was not unexpected, in that dogs that underwent lymph node extirpation already had progressive disease. It could be argued that any dog with an ASAC should have the sublumbar lymph nodes removed for disease staging purposes and to improve the response to chemotherapy or radiation therapy. However, additional studies are needed to determine whether lymph node extirpation has beneficial effects in dogs with and without sublumbar lymphadenopathy. It has been shown in small case studies16,b that dogs undergoing lymph node extirpation can have a prolonged survival time and that even incomplete tumor resection can help to control hypercalcemia. Median survival time for dogs with lymph node extirpation in the present study was longer than that for dogs that did not receive surgery as part of their treatment in the study by Williams et al7 (402 days).

There has been great difficulty in establishing the value of postoperative chemotherapy in dogs with ASACs, largely because of a lack of standardization of staging and treatment protocols. In the present study, we did not find a significant difference in survival time between dogs that received a platinum-containing chemotherapeutic agent (carboplatin or cisplatin) and those that did not. We did find that these patients had a significantly shorter disease-free interval; however, we believe that this was likely due to differences between dogs that did and did not receive chemotherapy. It is our standard practice to offer postoperative chemotherapy for all dogs that have had an ASAC removed, but owner-related factors (eg, financial considerations and the desire to pursue adjunctive therapies) affect which dogs actually receive chemotherapy. Owners of dogs with more advanced disease, metastatic disease, or incomplete mass excision may be more willing to pursue adjunctive therapies, and this may account for the shorter disease-free interval. Williams et al7 reported a median survival time of 202 days for patients that underwent chemotherapy but did not have a surgical procedure as part of their treatment. That study7 and the present study highlight the benefit of surgical cytoreduction in dogs with ASACs. Emms5 found an apparent benefit of melphalan chemotherapy in dogs with and without lymph node metastases; however, survival times were not significantly (20 vs 29.3 months) different between groups. There was no significant difference in survival time between dogs that received carboplatin and dogs that did not in the study by Polton et al.10 However, a recent study14 that included 32 dogs with ASACs reported that adjunctive therapy with toceranib may have been beneficial. The longest survival time for a group of dogs with ASACs was reported for 15 dogs that received external beam radiation and mitoxantrone.12 These 15 dogs had a median survival time of 956 days and a disease-free interval of 287 days.12

The most important limitations of the present study were the lack of standardized protocols for disease staging, postoperative treatment, and follow-up. Lack of standardization may lead to selection bias for patients with larger tumors and incomplete excisions. A prospective study controlling for tumor stage and therapeutic approach would be beneficial to better assess the benefits of particular treatments. A lower number of patients may have been considered hypercalcemic, compared with what we reported, if total body calcium concentration had been used. Messinger et al20 found that when serum total calcium concentrations were compared among various disease groups, dogs with anal sac adenocarcinoma had significantly higher ionized calcium concentrations. The use of ionized calcium concentration may alter the clinical picture for hypercalcemic patients related to survival time, disease-free interval, and associated comorbidities.

The fact that multiple pathologists evaluated histopathologic margins, along with the lack of consistency in postoperative diagnostic testing, may have limited data interpretation in the present study. Animals that were hypercalcemic were confirmed to have values within reference limits after surgery; however, not all dogs had postoperative blood work performed. Postoperative abdominal ultrasonography was performed in patients that had clinical signs or physical examination findings consistent with disease progression or recurrence. Lymph node size has been associated with survival times,10 and abdominal ultrasonography is useful for monitoring disease progression. Thus, a more standardized follow-up protocol that included routine abdominal ultrasonography may have provided more information about disease progression overall. In addition, no dogs in the present study underwent necropsy, so the rate of disease progression and number of metastatic sites may have been underestimated. Finally, the low number of dogs in the study and correlations among factors found to be significant in univariate analyses precluded multivariate analyses. A larger patient population may have resulted in different findings.

The present study highlights the importance of diagnostic staging and standardized postoperative follow-up and assessment. Significant differences in survival time and disease-free interval were found between dogs with and without metastasis to the sublumbar lymph nodes. Survival times in the present study compared favorably with those described in more recent reports and in older reports of dogs with ASACs in general. The fact that all dogs underwent surgery suggests the beneficial role of surgical excision in the management of ASACs. Prospective studies are needed to determine what adjunctive therapies, alone or in combination, will be the most advantageous in dogs with ASACs. Prospective studies are also necessary to evaluate preoperative variables that may influence survival time and disease-free interval.

ABBREVIATIONS

ASAC

Anal sac apocrine gland adenocarcinoma

CI

Confidence interval

a.

SAS, version 9.2, SAS Institute Inc, Cary, NC.

b.

Jeffery N, Phillips SM, Brearley MJ. Surgical management of metastases from anal sac apocrine gland adenocarcinoma of dogs (abstr). J Small Anim Pract 2000;41:390.

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