Abstract
Anal sac adenocarcinoma is uncommon in cats. We report the outcome of multi-modality therapy in two cats (surgery, definitive radiotherapy and systemic chemotherapy) and surgery alone in two cats. All received surgical excision of the primary tumour followed by radiotherapy and carboplatin chemotherapy in two cases. Both cats that underwent multimodal therapy developed distant metastatic disease and one developed recurrence of the primary tumour. One cat that underwent surgery alone with incomplete margins also developed rapid recurrence. Overall survival times were 89, 161 and 169 days. One cat that had complete surgical excision is still alive without recurrence 425 days postoperatively. Whilst the role of radiation in the local control of this disease is yet to be defined, clearly a more effective systemic therapy is required before such aggressive local treatment can be routinely recommended.
Apocrine adenocarcinoma of the anal sac is an uncommon tumour in cats and there is a paucity of information regarding treatment options and outcomes. We report the outcome of multi-modality therapy in two cats and surgical excision alone in two cats with apocrine gland carcinoma of the anal sac presented to the Small Animal Teaching Hospital (SATH) at the University of Liverpool.
Case 1
A 15-year-old neutered-male Maine Coon cat was presented for investigation of mild faecal tenesmus of 7 days duration. The cat was also in poor body condition (BCS 3/9) and a grade II/VI left apical cardiac murmur was audible. A 2 cm well-defined and firm peri-anal mass was present at the position of the right anal sac. The cat was otherwise clinically well. A fine needle aspirate (FNA) was consistent with an apocrine gland carcinoma.
Haematology and biochemistry were unremarkable other than a mild azotaemia: urine specific gravity was 1.045, indicating this was pre-renal. Total T4 was 45 (range 19–65 nmol/l) and so free T4 by equilibrium dialysis was performed, which was within normal limits at 21 (10–50 pmol/l). An echocardiogram was performed which revealed evidence of early hypertrophic cardiomyopathy. No medication was recommended.
Tumour staging included three-view, inflated thoracic radiographs and abdominal ultrasound. Thoracic radiographs were unremarkable. Abdominal ultrasound revealed a patchy echogenicity to the liver with some discrete nodules and a large, heterogeneous pancreas with some very round discrete nodules. There was also a small volume of effusion around the pancreas. A FNA of the liver and pancreas, bile cytology and culture were unremarkable. Abdominal fluid analysis revealed a low nucleated cell count, consistent with a modified transudate. No neoplastic cells were seen in any of the samples. Feline pancreatic lipase immunoreactivity (PLI) was within normal limits (1.2; 0.1–3.5 mg/l). Exploratory coeliotomy was performed to further investigate the ultrasonographic abnormalities, as there was concern that the FNA samples might have been non-representative, and that the changes seen could be related to tumour metastasis. As aggressive local tumour therapy would be inappropriate in this setting, the exploratory surgery was performed as a diagnostic/staging procedure. At surgery, no gross abnormalities were seen other than a very small amount of cranial abdominal fluid and a slight area of haemorrhage on the body wall (suspected to be due to previous needle aspiration). Biopsies were taken from the liver, pancreas, and an adjacent mesenteric lymph node. No histological abnormalities were found. After receipt of these results, the peri-anal mass was marginally excised. Complete excision was considered impossible and likely to result in significant risk of morbidity, particularly faecal incontinence. Margin excision required resection of approximately a quarter of the external anal sphincter to ensure resection of gross tumour. Closure was routine. Histology revealed an incompletely excised apocrine gland carcinoma of the anal sac.
During the week following surgery, the owner noted faecal tenesmus and the passage of very hard faecal pellets. This did not resolve despite conscious enema (Micralax) and oral lactulose. Under general anaesthetic, a warm water enema was performed. Mild distortion and stricture of the anus was reported by the attending soft tissue surgeon. This was improved following digital examination. Due to recurrent constipation, another enema was performed 5 days later. At this point there was no anal stricture and the faeces were softer. Lactulose was given orally post-enema at 5 ml PO q 8 h or as required to maintain a soft stool without diarrhoea.
Radiotherapy commenced 24 days post-surgery. This consisted of 12 fractions of 4 Gy (48 Gy total) delivered on a Monday, Wednesday and Friday for 4 weeks using 9 MeV electrons ‘en face’ with 0.5 cm bolus material (Superflab). This delivered 85–100% dose to a depth of 3 cm. The radiation source was a linear accelerator. A field size of 10 cm × 6 cm was used, centred over the surgical site (Fig 1). A lead block was placed into the rectum for each treatment to displace and shield approximately a third of the external anal sphincter (Fig 2). The penis/prepuce was retracted from the field, and lead equivalent blocks were used to shield the urethra. After the first four treatments, the bolus thickness was increased to 1 cm to reduce dose depth and thus reduce the dose to the adjacent tissues, including the urethra. The cat required one enema in the middle of the radiation course. No acute radiation side effects occurred. The cat also received four doses of carboplatin (10 mg/kg) as adjunctive chemotherapy. One dose was given after the first radiation treatment and one after the last treatment. The next two treatments were given as planned at 3-week intervals. A full haematology, including blood film evaluation and biochemistry, was performed prior to each chemotherapy. No unwanted clinical, haematological or biochemical effects occurred.
Delivery of radiotherapy in case 1.
Lead block used to shield non-target tissues.
At 3 and 6 weeks after completing radiotherapy, the cat was defecating normally while receiving lactulose 4 ml PO q 8–12 h, and the owner considered him normal. There was alopecia in the irradiated field but the skin was healthy. There was no palpable evidence of local primary tumour recurrence. At the 6-week visit, three-view inflated thoracic radiographs were performed which revealed an approximately 5 mm wellmarginated soft tissue opacity in the left caudal lung lobe possibly due tometastatic disease. A slight generalised broncho-interstitial pattern was present, likely due to lower airway disease or possibly early metastatic disease. Abdominal ultrasound showed no changes other than those seen at initial staging. There were no respiratory signs or history of lower airway disease. At the owner's request, the fourth and final dose of carboplatin was given. Fourteen weeks after completing radiotherapy the cat presented to the referring vets with inappetence and lethargy. Thoracic radiographs were taken and sent to the SATH for analysis. A generalised broncho-interstitial/miliary pattern was seen consistent with pulmonary metastatic disease. The cat was euthanased 161 days following initial presentation. No evidence of primary tumour recurrence was found at death.
Case 2
An 11-year-old neutered-male domestic shorthair (DSH) cat was presented for investigation of treatment options for a histologically confirmed apocrine gland carcinoma of the right anal sac. The initial presenting sign was blood-spotting: the veterinarian found a 2 cm mass and attempted excision, but achieved a partial debulking and biopsy. On presentation at SATH, a 1 cm firm mass was present in the region of the right anal sac with an overlying well-healed scar. Haematology was unremarkable. Biochemistry/urinalysis revealed evidence of chronic kidney disease with elevated urea (11.1; 2.5–7.5 μmol/l) and creatinine (124; 20–120 μmol/l) and urine specific gravity of 1.026. This would be consistent with International Renal Interest Society (IRIS) stage 1 renal disease. Urine culture was negative, and blood pressure and urine protein:creatinine were normal. Blood pressure was 140 mmHg.
Three-view, inflated thoracic radiographs were unremarkable. Abdominal ultrasound was unremarkable other than mild bilateral reduction of renal corticomedullary definition. The right inguinal lymph node was slightly heterogeneous in appearance but normal in size and FNA revealed reactive hyperplasia only.
Surgery was performed to marginally excise the remaining tumour tissue. Histology revealed an incompletely excised apocrine gland carcinoma of the anal sac. Radiotherapy commenced 15 days post-surgery, and the protocol was identical to case 1 other than the field size was slightly smaller at 9 cm × 5 cm (Fig 3).
Case 2 post-surgery.
Given the renal compromise, it was elected to delay chemotherapy until after the radiation therapy had finished, and the first dose was given after the final radiation treatment. The cat also received intravenous fluid therapy from the time of admission to the time of owner collection (approximately 4 h). Haematology undertaken 1 week later was normal. The cat was due to receive 10 mg/kg carboplatin every 3 weeks, however, due to renal disease he was given a 10% dose reduction. At the time of the proposed second treatment, neutropenia was found (1.5; 3.0–12.5 × 109/l). The second chemotherapy was delayed by 1 week, at which time the neutrophil count was normal. The cat was scheduled to receive two subsequent treatments at 4-week intervals (due to the previously documented neutropenia), and the third treatment went without complication. However, 1 week before the fourth and final chemotherapy treatment, 90 days after finishing radiotherapy, the cat presented due to faecal tenesmus and constipation. Hard faeces were present on palpation and the cat was sedated for an enema. A ring of firm tissue was present around the anus on the right side between the 1 o'clock and 7 o'clock position and a moderate, left-sided perineal hernia was present. A FNA confirmed tumour recurrence. Abdominal ultrasound revealed the previously reported renal changes and an enlarged (4.0× 1.1 mm) right medial iliac lymph node. A FNA confirmed tumour metastasis to this node. Three-view, inflated thoracic radiographs revealed changes consistent with widespread pulmonary metastatic disease. The following day, the perineal hernia was repaired by internal obturator transposition and the mass was de-bulked with minimal margins for palliation. A small (approximately 3× 2 mm) section of the mass could not be removed as it was adherent to the urethra. Histology revealed recurrent tumour. The cat recovered well and was faecally continent and was discharged with 50 mg potentiated amoxicillin PO q 12 h and lactulose 4 ml PO q 8 h as required. The cat was very well at home but continued to be constipated. Another enema was performed at the referring vets but the cat was ultimately euthanased 169 days after initial presentation.
Case 3
A 16-year-old, neutered-female DSH cat was presented for investigation of a left-sided peri-anal mass. The owner noted this 2 weeks prior to consultation and currently it was causing no clinical signs. The mass measured 0.9 cm. A FNA was consistent with apocrine gland carcinoma.
Haematology and biochemistry were unremarkable. The cat had been treated for hyperthyroidism successfully with methimazole for several months and was showing no clinical signs. An echocardiogram revealed mild hypertrophic cardiomyopathy, probably related to the hyperthyroidism. No medication was advised at this time.
Staging was performed and consisted of three-view, inflated thoracic radiographs and abdominal ultrasound. No abnormalities were identified. Surgical excision was performed, taking approximately 0.5 cm normal tissue surrounding the mass. A small amount of external sphincter was taken. Histology revealed a very narrow complete excision but cells extended to less than 1 mm of both deep and lateral margins. The owner was offered adjunctive local and systemic therapies but these were declined.
The cat presented for a routine re-examination 82 days after surgery. The owner reported that the cat had generally been well but had showed some lethargy over the preceding week. Haematology was within normal limits but biochemistry revealed markedly elevated alanine aminotransferase (ALT: 606; 7–50 U/l) and alkaline phosphatase (ALP: 410; 0–40 U/l). Clinical examination was unremarkable other than a 1.0 cm × 0.8 cm firm, well-defined mass in the region of the previously diagnosed anal sac mass. A FNA confirmed recurrence of the apocrine carcinoma. The owner requested no further diagnostics or treatment and the cat was euthanased 7 days later when faecal tenesmus, including blood-spotting, occurred. Overall survival was 89 days.
Case 4
A 12-year-old, neutered-male DSH cat presented for investigation of a left-sided per-anal mass noted by the owners 2 weeks prior to presentation. There were no clinical signs attributed to the mass. The mass measured approximately 1 cm. A fine needle aspiration was not performed. A grade II/VI left-sided systolic murmur was noted.
Haematology was unremarkable and biochemistry revealed an elevated ALT (142; 750 U/l). Total T4 was measured and was elevated (150; 19–65 nmol/l) consistent with hyperthyroidism.
Staging was performed and consisted of three-view, inflated thoracic radiographs and abdominal ultrasound. No abnormalities were identified. Surgical excision was performed taking approximately 0.5 cm of normal tissue surrounding the mass and a small amount of external sphincter. Histology revealed a complete excision with no neoplastic cells near the deep or lateral margins. Tumour emboli were, however, seen within thin-walled vessels presumed to be lymphatics. The owner was offered adjunctive systemic chemotherapy but this was declined.
Currently, is alive and the cat ell with no evidence of primary tumour recurrence 425 days post-surgery as deemed by rectal examination at the referring veterinarian. No further imaging has been performed.
Discussion
Anal sac gland carcinoma is an uncommon and aggressive malignant tumour that arises from the apocrine glandular tissue of the anal sacs. 1 It has been well characterised in dogs but rarely reported in cats. To the authors' knowledge there are only five isolated case reports and one pathology-based publication (Table 1).1–6 A further case was reported in 1974, 7 however, this was subsequently believed to be a misdiagnosis, and in fact the tumour was a poorly differentiated sebaceous gland neoplasm. 8 Only surgery and chemotherapy have been described as treatment options in these cats to date. The limited available feline data suggests that these tumours have a high rate of local recurrence after surgery, and are potentially metastatic1,4,6 resulting in poor survival times with a median survival of 3 months. 1
Summary of previous cases of apocrine gland carcinoma in the literature.
In dogs, where this disease is much more common, invasive behaviour is frequent and there is a high rate of primary tumour recurrence post-surgery.9,10 Radiotherapy is an accepted treatment option for these tumours when incomplete resection is noted. 9 In the dog, these tumours are also highly metastatic, particularly to regional nodes but also to distant sites including the lungs.9–11 Chemotherapy, such as the platinum agent carboplatin, whilst still relatively unproven, is widely used.9,10 Dogs that receive multi-modality treatment seem to have the longest survival times. 12
The limited data in cats suggests a high rate of local recurrence following surgery, and a high metastatic potential. For this reason, a multi-modality approach was used to try to achieve superior tumour control rates and overall survival times.
Surgery is an important part of the treatment of most solid tumours. Surgery reduces tumour burden to microscopic disease, enhancing the efficacy of adjuvant therapies such as radiation and chemotherapy, which are much more effective in the face of minimal residual disease. Surgery was generally well tolerated, however, postoperative constipation in case 1 due to anal distortion and slight stricture formation occurred requiring subsequent management.
A recent case report described a partial response to carboplatin in a cat with measureable anal sac carcinoma. 4 Chemotherapy is, ideally, given when there is only microscopic/minimum-residual disease, as growth fraction and chemosensitivity should be maximal in this setting, and thus it was anticipated that carboplatin given as adjuvant chemotherapy post-surgery would be more beneficial. Unfortunately, despite treatment both cats that received the drug developed suspected metastatic disease, and one cat had local recurrence. A larger number of cats would have to be treated to confirm whether there is a benefit to adjuvant carboplatin in cats with this tumour type. Although carboplatin is not nephrotoxic, it is renally excreted and should be used in caution in the presence of renal disease. In case 2, early stage renal disease was present but it was deemed that the potential benefits would outweigh any risks of precipitating a renal crisis. Fluid therapy was given at each treatment and biochemistry rigorously monitored. There is increasing evidence that, in cats, an individualised prescription strategy for carboplatin administration based on a targeted area under the curve (AUC) and determination of glomerular filtration rate (GFR) might be beneficial.13–15 Ideally, this should have been performed in the cats described here, particularly in case 2. However, while dose adjustment might have reduced potential toxicity, it would have no positive impact on efficacy.
Radiation therapy was performed in two cases and was well tolerated in both. Acute side effects were minimal. This contrasts to dogs where acute side effects of peri-anal radiation can be marked, and include moist desquamation of the skin and proctitis. In case 2 there was clearly a failure of radiation therapy as primary tumour recurrence occurred quickly after finishing treatment. The fact that this cat had two surgeries prior to radiation and the exact location and extent of the original tumour were unknown may have increased the risk of radiation failure or a geographic miss (tumour recurring outside the radiation field). It is recognised that radiation planning based on scars and recurrent masses may result in failure to include adequate margins. 16 However, tumour recurred right in the centre of the radiation field, making geographic miss or planning failure an unlikely cause. The development of nodal metastases after perineal radiation in case 2 suggests that larger field pelvic/ perineal irradiation may be more appropriate. However, in dogs, pelvic irradiation is associated with a greater frequency of significant radiation side effects, 17 particularly with fraction sizes over 3 Gy. 18 Currently, the recommended fractionation and dosing is unknown and further work is required to determine the optimal radiotherapy protocol for feline anal sac carcinomas. It is also possible that the tumour is inherently radiation resistant. Case 1 died of presumed metastatic disease, with no evidence of primary tumour recurrence, which may have been prevented by radiation therapy. Clearly, a superior systemic therapy must also be found to delay the onset of metastatic disease if this is to provide a meaningful survival advantage. Further study is warranted to evaluate the role of radiation in preventing local recurrence of these tumours in cats.
The perineal hernia in cat 2 was presumed to be due to repetitive straining caused by local tumour recurrence, rather than a complication of the initial surgery or radiation. However, regional scarring due to surgery and/or fibrosis due to adjunctive radiation, either alone or in combination with tumour recurrence, may have been involved in the pathogenesis.
In conclusion, this report supports the notion that apocrine gland carcinomas of the anal sac in cats are aggressive tumours with a propensity to recur locally and metastasise. They seem to be relatively resistant to standard oncological therapy and carry a very poor prognosis despite aggressive treatment. Complete histological excision of the primary tumour may provide a more favourable outcome and lymphatic tumour emboli do not necessarily correlate with a poor outcome. Whilst the role of radiation in these tumours is still yet to be defined, clearly a more effective systemic therapy is warranted to justify such aggressive local treatment.
Footnotes
Acknowledgements
The authors would like to thank the veterinarians that referred the cases described. They would also like to thank the committed owners of the patients, Alistair Freeman and Rachel Burrow for performing the surgeries and taking care of the cats postoperatively, and Tracy Graham and Josephine Jones for helping to plan and deliver the radiotherapy.