Ramesh K. Sivacolundhu, BSc, BVMS, MVS, FANZCVS (Small Animal Surgery)
Director of Department of Surgery and Oncology, Vet24, Balcatta, WA, Australia
Anal sac adenocarcinoma (ASAC) is a malignant tumor arising from the apocrine glands in the wall of the anal sac. It accounts for about 17% of all perianal tumors in the dog. Females were previously thought to have been predisposed, but more recent studies have shown an approximately equal sex distribution. It occurs in older dogs (mean 10 to 11 years old, range 3 to 17 years old). There is little information on breed predisposition, although German shepherd dogs, English cocker spaniels, dachshunds, Alaskan malamutes and English springer spaniels may be predisposed.1
Biological Behavior
ASAC is both locally invasive and highly metastatic. It has a 20 to 50% local recurrence rate with surgery alone and a median time to local recurrence of 10 months. It most commonly metastasizes to the regional lymph nodes. The lymph nodes responsible for drainage of the pelvic canal and perineal region are those of the iliosacral mpho centre. This centre is composed of the medial iliac, hypogastric and sacral lymph nodes. The medial iliac lymph nodes are the largest, lying between the caudal circumflex and external iliac arteries, adjacent to the aorta and caudal vena cava, ventral to the fifth and sixth lumbar vertebrae. The hypogastric lymph nodes are smaller, often paired and lie within the angle between the internal iliac and median sacral arteries, ventral to the sixth or seventh lumbar vertebrae. The sacral lymph nodes are the most caudally located and lie ventral to the sacrum, alongside the median sacral arteries. Of this lymphocentre, metastases most commonly occur in the sacral lymph nodes and least commonly in the medial iliac lymph nodes. Sole involvement of the hypogastric and medial iliac lymph nodes is not generally seen.1
ASAC may metastasise to the lung, liver, spleen, bone and less commonly to the mediastinum, heart, pancreas, adrenal gland and kidney.
Clinical Signs and Hypercalcemia
Clinical signs are not seen in a significant number of cases, with the problem being an incidental finding in 39% of cases in 1 study.2 When clinical signs are present, they are referable to perianal irritation, paraneoplastic hypercalcemia, or physical obstruction of the anus or rectum by the primary mass or regional lymph nodes.
Paraneoplastic hypercalcemia may be seen in about 25% of cases, although not all cases are symptomatic. Production of a parathyroid hormone related peptide by the tumor is a common cause of the hypercalcemia. Hypercalcemia often resolves with tumor removal, and recurs with recurrence of the tumor. Hypercalcemia is often considered a medical emergency and clinical signs that may be seen with hypercalcemia include weakness, vomiting, twitching or shaking, muscle wasting or polyuria/polydipsia.
Diagnostic Tests and Staging
A CBC, biochemical panel and urinalysis should be performed as a part of a minimum database. Three- view thoracic radiographs or thoracic computer tomography (CT) scans should be performed to check for pulmonary metastatic disease. Cytology of a fine-needle aspirate of the primary tumor may be considered. A small number of cases may have a different tumor present, such as squamous cell carcinoma. Computer-assisted nuclear morphometry has been used as an auxiliary tool to differentiate anal sac adenocarcinomas from adenomas.
Abdominal imaging should be performed, particularly to image the regional lymph nodes. This may be achieved using abdominal ultrasound, magnetic resonance imaging (MRI) or computed tomography (CT).
For abdominal ultrasonography a general anesthetic is not usually required and sonographic features of normal and abnormal medial iliac lymph nodes have been previously described. Features of abnormal lymph nodes include increased size, more numerous nodes, rounded shape and decreased and heterogenous echogenicity. There is considerable overlap in the appearance of lymph nodes affected by benign and malignant disease, necessitating use of cytology or histopathology.1
In humans, MRI and CT are standard screening tests for anal and rectal cancer, and are more sensitive than abdominal ultrasound for detecting abdominal lymphadenopathy. Abnormal nodes on MRI are identified by increased numbers and/or size, if they have a rounded shape, have altered or heterogenous signal intensity, or if they demonstrate a heterogenous contrast enhancement pattern. MRI has been found in dogs to be more sensitive in identifying abnormal pelvic lymph nodes with ASAC due to its ability to image the sacral nodes.1
CT in dogs with ASAC was able to identify more pelvic lymph nodes and more normal pelvic lymph nodes, but did not identify more abnormal lymph nodes than abdominal ultrasound.
As many as 79% of cases have been reported to have evidence of gross metastases at the time of presentation.
Treatment
Treatment should include surgical removal of the primary tumor if possible, although it is associated with a 20 to 50% rate of local recurrence. Excision usually involves a marginal excision, and 180 degrees of the external anal sphincter may be removed with a good expectation for animals to maintain or regain faecal continence. In a small series of 4 cases with bilateral ASAC, 2 cases had the second side surgically removed following diagnosis and neither case experience faecal incontinence. Surgical removal of the primary tumor may be difficult or life-threatening if the tumor is large and fixed.
Electrochemotherapy has been reported following incomplete resection of an ASAC and the dog was still in remission 18 months later.
Follow-up radiation has also been used, on the primary tumor site and/or the regional lymph node pool. Efficacy of radiation is unknown and side-effects are common with the majority of cases experiencing severe acute moist desquamation, acute colitis, acute tenesmus and perineal discomfort. Fifty-three percent of cases experience clinically-relevant chronic complications related to radiation therapy including chronic tenesmus (4/15), rectal stricture (2/15), chronic diarrhea (4/15), and faecal incontinence (1/15).3 In a series of 16 cases that received pelvic radiation (bilateral opposed beams), colitis was a major late effect in 9/16 cases. Colitis was severe in 5 cases, moderate in 1 and mild in 3 cases. All cases with severe colitis experienced 3 Gy or 3.3 Gy fractions, and 80% received radiation potentiators (OPLA-Pt). Late effects are generally irreversible and are sometimes progressive.
Late effects that may been seen include chronic colitis, enteritis, proctitis, gastrointestinal perforation, gastrointestinal stricture, fibrosis of the urinary bladder, myelopathy and bone necrosis. Risk of late effects is minimized by using smaller doses and avoiding radiationpotentiators.4 The longest median survival time was reported in this series of cases which were treated with a combination of surgery, radiation and chemotherapy.3
Hypofractionated radiation therapy was reported for 77 cases with advanced ASAC.5 Radiation toxicities were mild and infrequent. Thirty-eight percent of cases had a partial remission and there was improvement or resolution of clinical signs in 63% of cases. If hypercalcemia was present, 31% resolved with radiation alone and an additional 46% resolved with radiation and prednisolone ± bisphosphonates. The median survival time reported was 329 days (range 25–448 days). These cases had a variety of chemotherapy agents at different time points.
Surgical removal of enlarged regional lymph nodes may be of benefit, with dogs that have had nodal extirpation prior to adjuvant therapy having longer median survival times (906 vs. 568 days).3 Surgical removal is palliative and is associated with increased morbidity and risk of mortality.6 Prolonged survival can be achieved with multiple sequential lymph adenectomies with 1 reported case having 5 sequential lymphadenectomies and still being alive 54 months after the initial surgery.7
Use of chemotherapy is controversial. This is a highly metastatic cancer, so it is reasonable to consider chemotherapy. Although some efficacy of carboplatin has been shown (33% partial response with gross disease)6, no study has demonstrated a survival advantage with chemotherapy. Use of metronomic chemotherapy and/or toceranib may show some promise.8,9 Toceranib is a receptor tyrosine kinase (RTK) inhibitor that blocks the activity of VEGFR2, PDGFRα and ß, FLT-3, KIT and CSFR1. RTKs are transmembranous cellular proteins that are involved in intracellular signaling. They are important for cell cycling, apoptosis and angiogenesis. Several RTKs are expressed in ASAC including VEGFR2 (19/24 primary tumors, 6/10 metastatic tumors), PDGFRα (all ASAC samples), KIT (8/24 primary tumors, 3/10 metastatic tumors), and PDGFRß (only expressed in afew tumor samples, but present in stroma of all tumor specimens). Toceranib used in the face of gross disease wasassociated with a 25% partial response rate and an additional 62.5% of cases hadstable disease.4
Prognostic Factors
Negative prognostic factorspreviously reported for this disease include lack of surgery, lack oftreatment, increased tumor size, hypercalcaemia, presence of distantmetastases, clinical stage, decreased E-cadherin expression (a transmembraneprotein that mediates cellular adhesion), histological pattern (solid patternworse than rosette or tubular patterns), and cytologic nuclear morphometry (meannuclear area, perimeter and diameter, and nuclear roundness). Regional metastases may or may not be associated with a worse prognosis.2,6,8,10,11 Median survival times in more recent articles are around 422 to 703 days.8,10,12 The longest median survival reported in a reasonable number of cases (15) was 956 days.3
References
1. Anderson CL, MacKay CS, Roberts GD, Fidel J. Comparison of abdominal ultrasound and magnetic resonance imaging for detection of abdominal lymphadenopathy in dogs with metastatic apocrine glandadenocarcinoma of the anal sac. Vet Comp Oncol. 2013;13(2):98–105.
2. Williams LE, Gliatto JM, Dodge RK, Johnson JL, Gamblin RM, Thamm DH, et al. Carcinoma of the apocrine glands of the anal sac in dogs: 113 cases (1985–1995). J Am Vet Med Assoc.2003;223(6):825–831.
3. Turek MM, Forrest LJ, Adams WM, HelfandSC, Vail DM. Postoperative radiotherapy and mitoxantrone for anal sacadenocarcinoma in the dog: 15 cases (1991–2001). Vet Comp Oncol. 2003;1(2):94–104.
4. Anderson CR, McNiel EA, Gillette EL,Powers BE, LaRue SM. Late complications of pelvic irradiation in 16 dogs. Vet Radiol Ultrasound. 2002;43(2):187–192.
5. McQuown B, Keyerleber MA, Rosen K, McEntee MC, Burgess KE. Treatment of advanced canine anal sac adenocarcinomawith hypofractionated radiation therapy: 77 cases (1999–2013). Vet Comp Oncol. 2016.
6. Bennett PF, DeNicola DB, Bonney P, Glickman NW, Knapp DW. Canine anal sac adenocarcinomas: clinical presentationand response to therapy. J Vet Intern Med. 2002;16(1):100–104.
7. Hobson HP, Brown MR, Rogers KS. Surgery of metastatic anal sac adenocarcinoma in five dogs. Vet Surg. 2006;35(3):267–270.
8. Emms SG. Anal sac tumours of the dogand their response to cytoreductive surgery and chemotherapy. Aust Vet J. 2005;83(6):340–343.
9. Urie BK, Russell DS, Kisseberth WC, London CA. Evaluation of expression and function of vascular endothelial growth factor receptor 2, platelet derived growth factor receptors-alpha and -beta,KIT, and RET in canine apocrine gland anal sac adenocarcinoma and thyroidcarcinoma. BMC Vet Res. 2012;8:67.
10. Wouda RM, Borrego J, Keuler NS, Stein T. Evaluation of adjuvant carboplatin chemotherapy in the management of surgicallyexcised anal sac apocrine gland adenocarcinoma in dogs. Vet Comp Oncol. 2016;14(1):67–80.
11. Polton GA, Brearley MJ. Clinical stage, therapy, and prognosis in canine anal sac gland carcinoma. J Vet Intern Med. 2007;21(2):274–280.
12. Potanas CP, Padgett S, Gamblin RM. Surgical excision of anal sac apocrine gland adenocarcinomas with and without adjunctive chemotherapy in dogs: 42 cases (2005–2011). J Am Vet Med Assoc. 2015;246(8):877–884.