Canine Anal Sac Adenocarcinomas

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Oncology update – canine anal sac adenocarcinomas

Author : KELLY BOWLT, MIKE STARKEY, SUE MURPHY

Categories : Vets

Date : January 20, 2014

ANAL sac adenocarcinoma (AGACA) is a locally invasive, highly metastatic tumour of the anal sac apocrine secretory epithelium (Polton, 2006), reported to comprise up to 17 per cent of canine perianal tumours (Goldschmidt and Shofer, 1992; Turek and Withrow, 2001).

Despite publications historically regarding AGACA as a tumour of older female dogs, more recent work has failed to identify any sex predilection (Goldschmidt and Shofer, 1992; Williams et al, 2003b; Polton, 2006).

Affected dogs have an average age of approximately 10 to 11 years (Turek and Withrow, 2001). English cocker spaniels, German shepherd dogs and English springer spaniels are significantly over-represented, with odds ratios of 11.5, 2.3 and 2.2 respectively (Polton, 2006; Goldschmidt and Hendrick, 2002). The incidence of AGACA in neutered dogs is higher, particularly in males (Polton, 2006).

History and clinical signs

Clinical signs of AGACA are associated with combinations of the following (Bennett et al, 2002; Hobson et al, 2006; Turek and Withrow, 2001; Brisson et al, 2004):

• primary tumour, either noticed incidentally or causing clinical signs, such as discomfort, ulceration, straining to defaecate or constipation;

• hypercalcaemia, causing polyuria/polydipsia, renal disease or lethargy; and/or

• metastasis, causing constipation, pain or neurological abnormalities.

The mass is appreciable within the anal sacs on palpation (Figure 1) and rectal examination is performed to assess the sublumbar lymph nodes. Up to half of AGACA are occult, with tumours being identified incidentally on rectal examination and with no historical signs that suggested anal sac disease (Bennett et al, 2002; Williams et al, 2003b). The majority of anal sac adenocarcinomas are unilateral, but up to 10 per cent may be bilateral (Ross, Scavelli, Matthiesen and Patnaik, 1991). A single case series exists reporting temporally spaced bilateral tumours (Bowlt, 2013).

1 / 15 Diagnosis and staging

Routine staging involves urinalysis, haematology and serum biochemistry (including serum/ionised calcium), inflated thoracic radiographs (left lateral, right lateral and ventrodorsal) and abdominal ultrasound. Additionally, CT, MRI or nuclear scintigraphy can be employed if indicated.

AGACA is associated with a high incidence of metastasis: reported rates of metastasis are 46 per cent to 100 per cent at diagnosis (Turek and Withrow, 2001; Bennett et al, 2002; Turek et al, 2003; Williams et al, 2003a, 2003b), with the regional lymph nodes (sacral, hypogastric and medial iliac nodes) being the most common site (Figures 2a and 2b).

Metastasis to other areas has also been documented, including bone (Fan et al, 2005; Brisson et al, 2004), lungs, liver and spleen (Turek and Withrow, 2001; Emms, 2005).

To achieve diagnosis, fine needle aspiration (FNA) or biopsy of the primary mass should be performed, in addition to ultrasound-guided FNA of any enlarged regional lymph nodes or other areas of gross abnormality. AGACAs are identifiable on histopathology or cytology as polyhedral epithelial cells with epithelial clustering and only subtle signs of malignancy (Figure 3; Turek and Withrow, 2001).

Hypercalcaemia of malignancy is reported in up to 25 per cent to 90 per cent of cases and is secondary to tumour secretion of parathyroid hormone-related peptide (PTHrP; Williams et al, 2003b; Ross et al, 1991; Bennett et al, 2002; Turek et al, 2003).

The World Health Organization (WHO) tumour/node/ metastasis (TMN) scheme for AGACA is a generic scheme for tumours of epidermal or dermal origin. Owen (1980; Table 1) and Polton (Polton and Brearley, 2007) proposed the proximity of AGACA to the anus, rectum and associated neurovascular structures warranted a specific clinical staging scheme. As a result, a clinical stage scheme recommendation (Table 2) and management algorithm (Figure 4) was published.

Treatment

Before surgery, treatment for hypercalcaemia must be provided to reduce the risk of renal damage and resultant anaesthetic risk and prognosis. Options for treatment include intravenous fluid therapy, furosemide, salmon calcitonin, bisphosphonates or glucocorticoids (Boag, 2007; Fan et al, 2005). Additionally, removal of the primary tumour and metastatic lymph nodes results in reversal of hypercalcaemia (Turek and Withrow, 2001; Hobson et al, 2001).

Complete surgical resection of the AGACA is desirable where size of the mass permits and offers improved survival compared with chemotherapy/radiotherapy alone (Williams, et al, 2003). It is often difficult to define a clear margin intraoperatively due to the neighbouring rectum, and postoperative faecal incontinence is not uncommon, depending on the volume of tissue removed.

2 / 15 Enlarged abdominal lymph nodes should also be removed (Turek and Withrow, 2001) or, if cystic, they can be omentalised (Hoelzler et al, 2001). Postoperative radiation therapy and chemotherapy has been described (Turek et al, 2003).

A study (Williams et al, 2003a) showed the medial survival for dogs with AGACA is 544 days, with surgical treatment offering an increased survival compared with medical treatment (median 584 days compared with median 212 days respectively).

The median survival times following surgery alone are six to 11 months, with 20 per cent to 50 per cent of patients suffering from local recurrence (Ross et al, 1991; White and Gorman, 1987).

Because of the high metastatic rate to regional lymph nodes, sublumbar lymphadenectomy has been recommended, offering median survival times of 20.6 months with surgical treatment alone (Figures 5a and 5b; Hobson et al, 2006). Lymphadenectomy can be repeated as often as required as the disease progresses and one dog is reported to have undergone five sequential such surgeries, and was still living 54 months after the initial surgery (Hobson et al, 2006).

Platinum chemotherapeutic agents have been utilised in the treatment of AGACA (with and without surgical intervention), resulting in a median survival of six months (Bennett et al, 2002). While this initially appears to be little improvement over surgery alone, 35 per cent of the dogs in this study received chemotherapy alone, presumably because of advanced disease or owner preference, yielding a median survival in this group of 8.7 months.

Platinum chemother-apeutic drugs are considered to offer the most potential benefit in patients with metastasis beyond regional lymph nodes (Bennett et al, 2002), but this correlation was not identified with the use of cytoreductive surgery followed by melphalan (Emms, 2005). Mostly, carboplatin is used because it can be given without saline diuresis, which is imperative for the administration of nephrotoxic cisplatin (Dernell, 2007).

In some studies, there is no statistical association with chemotherapy and outcome (Polton and Brearley, 2007; Williams et al, 2003a and 2003b) and this has been proposed to be due to tumour heterogeneity, incomplete or short-lived responses, and chemotherapy-related adverse effects (Polton and Brearley, 2007). However, Polton advises caution in this observation because incomplete responses can be greatly significant in individual patients where neoadjuvant treatment results in reduction in tumour size to the extent that surgery is possible or obstipation is relieved.

The greatest benefit following the use of chemotherapy is seen in stage 3b patients (Polton and Brearley, 2007).

Palliative care alone (piroxicam, prednisolone, furosemide, stool softeners and intravenous fluid therapy) has been described in 10 dogs (Bennett et al, 2002), resulting in a survival of between two days and nine months.

3 / 15 Where surgery, mitoxantrone and radiation of the primary tumour and regional lymph nodes is used, median survival can be up to 956 days (Turek et al, 2003). To the authors’ knowledge, there are no studies investigating the efficacy of radiation therapy alone in the treatment of this disease.

Prognosis

When assessing median survival based on clinical stage, patients with higher stage disease have reduced survival compared to patients with lower stage disease (Polton and Brearley, 2007). The survival data provided in this paper is from a retrospective and prospective referral population, and animals received a combination of treatments, including carboplatin, surgery, hypofractionated radiation or combinations.

There is conflicting evidence regarding the prognostic significance of hypercalcaemia with AGACA (Ross et al, 1991; Bennett et al, 2002; Williams et al, 2003; Turek et al, 2003), but return of hypercalcaemia is considered to be indicative of recurrence or metastasis (Hobson et al, 2006).

Negative prognostic indicators for survival include (Williams et al, 2003; Polton and Brearley, 2007; Polton et al, 2007):

• masses (primary or metastatic) greater than 10cm2;

• lack of surgical treatment;

• lack of any therapy;

• presence of distant metastases;

• presence of lymph node metastases; and

• expression of E-cadherin in fewer than 75 per cent of the cells (median survival 448 days versus 1,168 days in tumours expressing E-cadherin in greater than 75 per cent of the cells).

The most common cause of death in animals with AGACA is euthanasia because of debilitation, relapse of disease or an inability to defaecate or urinate (Bennett et al, 2002).

Comparative aspects

No comparable tumours exist in humans, although AGACA has been reported in cats (Mellanby et al, 2002).

Summary of AGACA

4 / 15 • English cocker spaniels, German shepherd dogs and English springer spaniels are significantly over-represented.

• Up to 50 per cent of AGACA are identified incidentally.

• Forty-six per cent to 100 per cent metastatic rate, most commonly to the regional lymph nodes.

• Twenty-five per cent to 90 per cent of patients demonstrate hypercalcaemia.

• Surgery (removal of the primary tumour with metastatic lymphadenecomy) is the treatment of choice, with 20 per cent to 50 per cent of patients suffering local recurrence.

• Adjuvant and neoadjuvant chemotherapy and radiation therapy is also commonly used.

• Median survival for dogs with AGACA is 544 days, with dogs undergoing surgical treatment surviving longer than those undergoing medical treatment.

References

Bennett P, DeNicola D, Bonney P, Glickman N and Knapp D (2002). Canine anal sac adenocarcinomas: clinical presentation and response to therapy, Journal of Veterinary Internal Medicine 16(1): 100-104. Brisson B, Whiteside D. and Holmberg D (2004). Metastatic anal sac adenocarcinoma in a dog presenting for acute paralysis, Canadian Veterinary Journal 45(8): 678-681. Boag A (2007). Electrolyte and acidbase balance. In King L and Boag A, BSAVA Manual of Canine and Feline Emergency and Critical Care (2nd edn), BSAVA, Gloucester: 50-51. Bowlt K L, Friend E J, Delisser P, Murphy S and Polton G (2013). Four cases of staged bilateral anal sac adenocarcinoma in the dog, Journal of Small Animal Practice. In press. Dernell W E (2007). Tumours of the skeletal system. In Withrow S V (ed) Small Animal Clinical Oncology, Saunders Elsevier, Missouri: 540-582. Emms S (2005). Anal sac tumours of the dog and their response to cytoreductive surgery and chemotherapy, Australian Veterinary Journal 83(6): 340-343. Fan T, de Lorimier L, Charney S and Hintermeister J (2005). Evaluation of intravenous pamidronate administration in 33 cancer-bearing dogs with primary or secondary bone involvement, Journal of Veterinary Internal Medicine 19(1): 74-80. Goldschmidt M and Hendrick M (2002). Tumours of the skin and soft tissues. In Meuten D (ed) Tumours in Domestic Animals (4th edn) Ames, Iowa: 45-118. Goldschmidt M and Shofer F (1992). Anal sac gland tumours. In Skin Tumours of the Dog and Cat, Pergamon Press, Oxford: 103-108. Hobson H, Brown M and Rogers K (2006). Surgery of metastatic anal adenocarcinoma in five dogs, Veterinary Surgery 35(3): 267-270. Hoelzler M, Bellah J and Donofro M. (2001). Omentalisation of cystic sublumbar lymph

5 / 15 node metastases for long-term palliation of tenesmus and dysuria in a dog with anal sac adenocarcinoma, Journal of American Veterinary Medical Association, 219(12): 1,729-1,731. Mellanby R, Foale R, Friend E, Woodger N, Herrtage M and Dobson J (2002). Anal sac adenocarcinoma in a Siamese cat, Journal of Feline Medicine and Surgery, 4(4): 205-207. Owen L (1980). TMN Classification of Tumours in Domestic Animals. World Health Organisation, Geneva, Switzerland. Polton G A, Mowat V, Lee H C, McKee K A and Scase T J (2006). Breed, gender and neutering status of British dogs with anal sac gland carcinoma, Veterinary and Comparative Oncology 4(3): 125-131. Polton G and Brearley M J (2007). Clinical stage, therapy and prognosis in canine anal sac gland carcinoma, Journal of Veterinary Internal Medicine 21(2): 274-280. Polton G A, Brearley M J, Green L M and Scase T J (2007). Expression of e-cadherin in canine anal sac gland carcinoma and its association with survival, Veterinary and Comparative Oncology 5(4): 232-238. Ross J, Scavelli T, Matthiesen D and Patnaik A (1991). Adenocarcinoma of the apocrine glands of the anal sac in dogs: a review of 32 cases, Journal of the American Animal Hospital Association 27(3): 349-355. Turek M and Withrow S (2001). Perianal tumours. In Withrow S and Vail D, Small Animal Clinical Oncology, Saunders Elsevier, Missouri: 503-510. Turek M, Forrest L, Adams W, Helfand S and Vail D (2003). Postoperative radiotherapy and mitoxantrone for anal sac adenocarcinoma in the dog: 15 cases (1991-2001), Veterinary Comparative Oncology 1(2): 94-104. White R and Gorman N (1987). The clinical diagnosis and management of rectal and pararectal tumours in the dog, The Journal of Small Animal Practice 28(2): 87-107. Williams L, Gliatto J, Dodge R, Johnson J, Gamblin R, Thamm D et al (2003a). Carcinoma of the apocrine glands of the anal sac in dogs, Journal of American Veterinary Medical Association 223(6): 825-831. Williams L, Gliatto J et al (2003b). Carcinoma of the apocrine glands of the anal sac in dogs: 113 cases (1985-1995), Journal of the American Veterinary Medical Association 223(6): 825-831.

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Figure 1. Gross appearance of an anal sac adenocarcinoma.

PHOTO: Daniela Murgia, AHT.

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Figure 2a (above). Left lateral abdominal radiograph of an 11-year-old male neutered collie with a large metastatic medial iliac lymph node from an anal sac adenocarcinoma.

PHOTO: Ruth Dennis, AHT.

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Figure 2b (below). Ultrasonographic image of the metastatic medial iliac lymph node in the dog in Figure 2a.

PHOTO: Ruth Dennis, AHT.

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Figure 3. Histopathological section of an anal sac adenocarcinoma, x10, H&E.

PHOTO: Jennifer Stewart, AHT.

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Figure 4. Management algorithm for canine patients with canine anal sac gland carcinoma (taken from Polton and Brearley, 2007, with permission).

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Figure 5a. Intraoperative photograph of removal of a small left anal sac adenocarcinoma in a five- year-old neutered male dog.

PHOTO: Silke Stein, AHT.

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Figure 5b. Intraoperative photograph of removal of a metastatic medial iliac lymph node in a nine- year-old dog with an anal sac adenocarcinoma.

PHOTO: Silke Stein, AHT.

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Table 1. WHO TMN classification for canine tumours of epidermal or dermal origin (not lymphoma or mastocytoma; Owen, 1980)

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Table 2. Clinical stage scheme recommendation for AGACA (Polton and Brearley, 2007)

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