Diagnosis and management of canine anal sac adenocarcinomas

The main perianal tumours observed in dogs are perianal sebaceous adenoma, perianal sebaceous adenocarcinoma and apocrine gland anal sac adenocarcinoma (AGASAC). Other tumours arising from the anal sac include squamous cell carcinoma and malignant melanoma. This last article in the author’s series on canine gastrointestinal tumours will focus on canine AGASAC.

Anal sac adenocarcinomas represent 17 percent of all perianal tumours in dogs, and certain breeds, especially spaniels such as the English Cocker Spaniel, are predisposed (Polton et al., 2006). Tumours arise from the apocrine sweat glands of the anal sac, which produce secretions that drain into the lumen of the anal sac. Histologically, there are three main classifications of AGASACs based on histological pattern, and these subtypes may hold prognostic significance. The three patterns are solid, papillary, and tubules, rosettes and pseudorosettes. Expression of VEGFR-2, PDGFR-α, PDGFR-ß and KIT have been documented in canine AGASACs, which may drive tumorigenesis, making them attractive targets for treatment with drugs such as tyrosine kinase inhibitors (Urie et al., 2012).

Clinical signs

Most dogs with AGASACs present due to the mass effect of the primary tumour (Figure 1), which can cause signs such as perianal discomfort, tenesmus, excessive licking, bleeding or change in faecal shape. However, tenesmus or change in faecal shape may sometimes be attributed to obstruction of the pelvic canal by enlarged sublumbar lymph nodes (LNs). As discussed below, some dogs with AGASACs are hypercalcaemic. Therefore, they may also demonstrate clinical signs such as polyuria, polydipsia, lethargy and vomiting. Pain or lameness may be observed secondary to bone metastasis or bony invasion of metastatic LNs into the lumbar/sacral vertebrae.

Most dogs present with one anal sac affected, but bilateral AGASACs have been reported. In almost half of AGASAC cases, the tumour is detected incidentally, highlighting the importance of incorporating palpation of the anal sacs and a rectal examination into routine physical examinations and health checks (Ross et al., 1991; Williams et al., 2003).

Diagnosis and further investigations

A minimum database including haematology, biochemistry and urinalysis should be obtained in any dog where AGASAC is suspected. Ionised calcium should also be assessed as paraneoplastic hypercalcaemia is observed in up to half of cases (Liptak and Turek, 2020). This, however, occurs secondary to tumour production of parathyroid hormone-related peptide (PTHrP).

A minimum database including haematology, biochemistry and urinalysis should be obtained in any dog where AGASAC is suspected

A definitive diagnosis should be made on the basis of cytology or histopathology. In most cases, AGASAC is easily diagnosed via fine needle aspirate cytology of the primary mass. Anal sac adenocarcinoma has a typical “neuroendocrine” cytological appearance, with bare nuclei a common feature. Despite being a malignant neoplasia, cytological criteria of malignancy may be mild or absent. If cytology is inconclusive, then biopsy for histopathology can be considered, although this is rarely required.

Staging

Staging is important for canine AGASACs as the metastatic rate is moderate. Overall, metastasis is reported in 26 to 96 percent of dogs at diagnosis, with up to 89 percent having regional LN metastasis and up to 42 percent having distant (mostly pulmonary) metastasis (Liptak and Turek, 2020). Metastasis can even be present with small (under 1cm) primary tumours. The most common sites of regional metastasis include the medial iliac, internal iliac and sacral LNs. Distant metastases are most commonly to the lungs, but other locations include the liver, spleen and bone. A clinical staging system (Table 1), accounting for primary tumour size, the presence/absence of LN or distant metastasis, and metastatic LN size, has been proposed, and may have prognostic significance (Polton and Brearley, 2007).

Any enlarged lymph nodes should be sampled to differentiate between reactive versus metastatic nodes, as this will guide treatment decisions

The best imaging modality for staging is computed tomography (CT) of the thorax and abdomen (Figure 2) as, compared to radiographs and ultrasound, this is most sensitive for the detection of small pulmonary nodules and the assessment of caudal abdominal LNs (Palladino et al., 2016; Pollard et al., 2017). Additionally, CT will more thoroughly screen for bone metastasis. Alternatively, inflated three-view thoracic radiographs and abdominal ultrasound can be considered; however, LNs within the pelvic canal are unlikely to be visualised with ultrasound. Any enlarged LNs should be sampled to differentiate between reactive versus metastatic nodes, as this will guide treatment decisions.

Treatment

Surgery

Surgery is the main treatment method for canine AGASAC and should include excision of the primary tumour and any metastatic LNs; extirpation of metastatic LNs has been shown to significantly improve survival time (Polton and Brearley, 2007). Due to the challenging location of AGASAC, excision is always marginal and incomplete histological margins are common. The risk of complications following anal sacculectomy is low to moderate, reported as between 5 and 24 percent in more recent studies (Liptak and Turek, 2020). Possible complications include transient faecal incontinence, wound infection or dehiscence, rectal perforation or fistula formation. If paraneoplastic hypercalcaemia is moderate to marked, medical management prior to surgery is indicated due to the increased risk of renal injury.

Adjuvant therapy

Regarding adjuvant therapies, the roles of radiation therapy (RT) or chemotherapy are controversial and not well defined. Historically, chemotherapy was often administered following surgery due to the moderate metastatic rate of AGASAC. However, multiple studies assessing the efficacy of adjuvant chemotherapy have shown no benefit compared to surgery alone (Williams et al., 2003; Wouda et al., 2016; Potanas et al., 2015). Similarly, the role of adjuvant RT is unclear. One study demonstrated that RT following surgery did not improve the survival time of a small group of 15 dogs (Williams et al., 2003). A recent study, however, potentially suggests that adjuvant RT may reduce the risk of locoregional failure following surgery (Williams et al., 2022). Additional studies are required to further understand the role of adjuvant RT in the management of canine AGASAC.

Chemotherapy

Chemotherapy, targeted therapy, RT or combinations of these treatment modalities can be considered in cases where surgical management is not possible or not elected by the owner, or in cases of stage IV disease. The two main chemotherapy drugs with demonstrated efficacy in the gross disease setting include carboplatin (33 percent partial response rate) and actinomycin-D (50 percent partial response rate), although it should be noted that these figures come from very small study populations (Bennett et al., 2002; Hammer et al., 1994). Targeted therapy with toceranib phosphate (Palladia) is perhaps a more promising medical option for the management of gross disease, with clinical benefit seen in 69 to 88 percent of cases (Heaton et al., 2020; London et al., 2012); around 20 to 25 percent of dogs will demonstrate a partial response with 60 to 70 percent achieving stable disease. A clinical benefit is also observed in the majority of stage IV patients, despite no partial or complete responses being observed in one study (Elliott, 2019). Toceranib inhibits a number of targets including VEGFR-2, PDGFR-ß, KIT, FLT3 and CSF1R, a number of which are known to be expressed in canine AGASAC as discussed earlier (Urie et al., 2012). Regarding RT, in the gross disease setting response rates of up to 75 percent have been reported, and resolution of hypercalcaemia has been reported in 31 percent of cases (McDonald et al., 2012). A variety of protocols, both definitive-intent and palliative-intent, have been described and can be tailored to patient and client needs. In some specific situations, such as stage IIIb disease, RT may be superior to surgery (Meier et al., 2017).

If disease recurs then repeat surgical excision of the primary mass and/or regional lymph nodes can be considered and has been shown to improve survival (Wouda et al., 2016; Hobson et al., 2006; Potanas et al., 2015). If a second surgery is not elected, then medical management or RT as described above can be used.

Prognosis and follow-up

The prognosis for canine AGASAC can be good as, generally, it is a slowly progressive tumour. Overall median survival times (MST) for canine AGASAC range from 386 to 960 days with one- and two-year survival rates of 65 percent and 29 percent respectively; local recurrence, regional (LN) recurrence or distant metastatic rates vary widely but are up to 45 percent, 70 percent and 20 percent respectively (Liptak and Turek, 2020). Even with the presence of LN or distant metastasis at diagnosis, MST can still be over one year. Negative prognostic factors reported for canine AGASAC include presence of clinical signs, tumour stage (including primary tumour size, LN status, metastatic LN size, presence/absence of distant metastasis), lack of surgical treatment, solid histological subtype and reduced E-cadherin expression. Hypercalcaemia is occasionally reported as a negative prognostic factor, but the evidence is contradictory.

Due to the moderate risk of locoregional recurrence and/or distant metastasis, regular follow-up after treatment is indicated; disease progression often occurs many months, and sometimes years, after treatment so monitoring periods may need to be prolonged. Ideally, serial restaging via thoracic and abdominal CT (versus radiographs/ultrasound) should be performed every three months for the first 12 to 18 months after which the monitoring interval could be extended to every four to six months. In-between restaging, regular (monthly) rectal exams should be performed to assess for local recurrence or sublumbar lymphadenopathy.