Perianal tumors

Question 1

Perianal tumors represent what % of tumors in dogs and cats?

Answer 1

17% of all perianal malignancies in dogs; 2% and 0.5% (rare) of all skin and SQ tumors in dogs and cats

Question 2

List 5 dogs breeds and risk and cat breed at risk

Answer 2

English cocker spaniels, other spaniels, dachshunds, GSD and Alaskan malamutes; Siamese cats.

Question 3

Sex predilection

Answer 3

No sex predilection, neutering may be associated with increased risk in males

Question 4

Mean age in dogs? cats?

Answer 4

9-11 years in dogs (as young as 5 yo, so always check the anal sacs on PE) and 13 in cats

Question 5

List the 3 histological patterns of AGASACA?

Answer 5

95% are either classified as solid (closely packed cancer cells w/o much stroma)

tubules/rosettes (cancer cells arranged radially around a central tubule or vessel)

less commonly papillary

Question 6

What is the biological behaivour of AGASACA?

Answer 6

locally invasive disease with moderate to high risk of local recurrence after surgery and a moderate to high metastatic rate in dogs and cats

Question 7

Are AGASACA unilateral or bilateral tumor?

Bilateral incidence in dogs? cats?

Answer 7

Usually unilateral tumors

bilateral incidence is 14% for dogs and 0% for cats, includes temporarily separated

Question 8

What are the 2 reported paraneoplastic syndromes associated with AGASACA?

Answer 8

hypercalcemia (caused by tumor secretion of PTHrP) seen in 16%-53% of dogs and 11% of cats

hypertrophic osteopathy (2 dogs with pulmonary mets)

Question 9

Is metastasis common at diagnsosis? How common?

Regional LN metastasis?

Distant site metastasis and sites?

List risk factors for metastasis?

Answer 9

Common at diagnosis (26-96% in dogs, variable in cats), even when primary is small (<1cm).

Regional LN: (26-89% in dogs, 20% in cats) most commonly to the sacral and sublumbar nodes (medial and internal iliacs) and can show variable metastatic patterns (as evidenced by CT lymphography) not always following lymphatic drainage linearly from the perineum and sometimes skipping LNs.

Distant sites: (0-42%) lungs, liver, spleen and bone and less commonly “anywhere else” (including BM in 4 dogs)

Risk factors for metastasis: presence of clinical signs (vs tumor as incidental finding), marked peripheral infiltration, lymphovascular invasion (vs mitotic index and necrosis).

Question 10

Some important genes and proteins in AGASACA

Answer 10

TSG: E-cadherin (overexpression associated with increased survival), p53 (expression detected w/o clinical implications)

o COX-2: detected in all tumor samples (expression was high in 12% and moderate in 36%), but also in normal anal sacs. Neuroendocrine differentiation proteins: synaptophysin, chromogranin A, neuro-specific enolase (30% expression).

o TKR: Urie et al (BMC Vet Res, 2012) detected VEGFR-2, PDGFR-a and 13, KIT and RET mRNA in all 25 tumor samples; but IHC detection was less consistent (most expressed VEGFR2, PDGFR-a and PDGFR-13, but only 1/3 KIT).

Question 11

Two other possible anal sac tumors?

Answer 11

o Melanomas: 1 case series (n=11 dogs) by Vinayak et al (JSAP, 2017) documented moderate to aggressive unilateral tumors, with a mean size >3cm, a median mitotic index of 50/10 HPF, with metastasis to the LN (4/11) and lungs (1/11) at diagnosis, all presenting clinical signs (bleeding) and 10/11dying due to PD in only 107 days (MST).

o SCC: reports document unilateral tumors with no evidence of metastasis but do mention local recurrence.

Question 12

IHC markers for AGASACA?

Answer 12

Cytokeratin+ (CK7+/CK14-), but usually not needed for diagnosis.

Question 13

Mainstay therapy for AGASACA?

Answer 13

Surgical resection which is marginal

Question 14

Complications with anal sacculectomy?

Answer 14

rate of 5-24% (related to tumor size and % of anal circumference resected), most common are dehiscence +/- infection, rectal perforation, fistulae formation and different degrees of fecal incontinence (especially if > 50% of the sphincter muscle is resected, old/very aggressive study reports a 19% rate out of which 60% was permanent).

Question 15

What are the advantages and disadvantages for metastatic lymphadenectomy which is recommended for sublumbar and sacral LN?

Answer 15

Advantages: improve quality of life (by relieving pelvic canal obstruction and helping with hypercalcemia) and survival in some studies (Polton et al, JVIM 2007), but the opposite effect is reported in other studies (Potanas, JAVMA 2015).

Disadvantages: requires a second surgical approach (abdominal +/- pelvic osteotomy), has a complication rate of 0­12% which include severe infra-op hemorrhage which may require transfusion (LNs closely associated with aorta and caudal vena cava). Palliative RT has been proven more effective/tolerated in advanced cases.

Question 16

Role of chemotherapy in AGASACA?

Cytotoxic chemotherapy drugs?

Answer 16

Recommended due to metastasis

Cytotoxic chemotherapy: drugs with documented anti-tumor activity are carboplatin, cisplatin, actinomycin D (gross disease), mitoxantrone and melphalan (residual disease post-op).

Williams et al JAVMA, 2003: n=113 dogs, MST=500 days with surgery alone vs MST=540 days with surgery + chemotherapy (cisplatin, carbo, mito and doxo). No significant difference.

Wouda et al, VCO, 2016: n=75 dogs, OS=581 and TTP=402 days with surgery alone vs OS=723 and TTP=384 days with surgery + carbo chemotherapy. No statistical difference.

Potanas et al, JAVMA, 2015: n=42 dogs, DF1=470 days with surgery alone vs surgery + DP7=226 days with chemotherapy (mostly carboplatin), similar MST. More advanced disease on chemo group

Question 17

Role of RTKi?

Answer 17

RTKi (Palladia): modest tumors responses have been reported.

London et al, VCO, 2012: n=32 AGASACAs, clinical benefit=88%, with 25% PRs (8) and 63% SD (20), lasting 10-47 weeks, resolution of hypercalcemia was also reported.

Elliot, JAVMA, 2019: n=15 dogs with advanced stage AGASACA; noted CRs=0, PRs=0, SD=13 and PD=2, but also improvement of clinical signs (tenesmus, cough) in 5/10 dogs, PFI=354, ST=356 days.

Question 18

Side effects associated with curative intent radiation therapy for AGASACA

Answer 18

late side effects, such as rectal stricture or perforation or chronic colitis; but also transient acute side effects such as severe moist desquamation and colitis.

<3Gy fractions and IMRT have been shown to decrease the chances of these adverse events observed in older studies.

Question 19

What is the DFI after surgery with or without adjuvant therapy for AGASACA?

Answer 19

DFI after surgery with or w/o adjuvant therapy is 262-443 days (9-15 mo).

Question 20

What is the overall MST for AGASACA and the 1- and 2- year survival rate?

Tumor related death?

Answer 20

Overall MST=386-960 days (1.0-2.6 yr)

1- and 2-year survival rates of 65% and 29%, with 41-81% tumor-related death rate

Question 21

List the 8 prognostic factors for AGASACA?

Answer 21

Clinical stage

Metastasis

Primary tumor size

Clinical signs

Treatment modality

Histology

E-cadherin expression

Hypercalcemia

Question 22

How is clinical stage a prognostic factor for AGASACA?

Answer 22

Dogs with no metastasis and small tumors (<2.5cm) treated with surgery have a good outcome. e.g., Polton et al, MST—-not reached, tumor-related death rate=only 9%.

Question 23

How is metastasis a prognostic factor for AGASACA?

MST for dogs with LN mets, distant mets, no mets?

Answer 23

Presence of regional LN or distant metastasis is associated with a worse prognosis and 2.3x higher risk of tumor-related death. e.g., MST-293-448 days (10-15 mo) with LN mets and 71-356 days (2.4-12 mo) with distant mets treated with different modalities vs MST-529-1205 (1.4-3.3 yr) w/o metastasis.

Question 24

How is primary tumor size a prognostic factor for AGASACA?

Answer 24

Prognostic for survival, nut the threshold varies across studies. e.g., Williams et al, MST-584 days for <10cm vs 292 days for >10cm; Polton et al, MST=1205 days for <2.5cm vs 722 days for >2.5cm; Turek et al, DFI=518 and MST=773 days for <4cm vs DFI=251 and M ST=433 days for >4cm.

Question 25

How are clinical signs a prognostic factor for AGASACA?

Answer 25

RR was higher and DFI and MST were shorter in dogs with clinical signs vs those diagnosed incidentally.

Question 26

How is treatment modality a prognostic factor for AGASACA?

Answer 26

Dogs treated with surgery had a better outcome (MST=548 days) vs dogs w/o surgery (MST-402 days) vs advanced cases with chemo alone (MST=202 days).

Question 27

How is histology a prognostic factor for AGASACA?

Answer 27

Solid pattern (vs other patterns), increased peripheral infiltration of surrounding tissues, necrosis and lymphovascular invasion were associated with a shorter DFI and MST.

Question 28

How is E-cadherin expression prognostic factor for AGASACA?

Answer 28

positive prognosis, MST=1168 days with >75% expression vs MST-448 days with <75%.

Question 29

How is hypercalcemia a prognostic factor for AGASACA?

Answer 29

Hypercalcemia: negative prognosis. MST-256 (8.5 mo) with hypercalcemia vs MST=584 days (1.6 yr) w/o. Recurrence of hypercalcemia is usually a sign of recurrence or metastatic progression

Question 30

What is the prognosis for anal sac melanomas?

PFS and MST

Answer 30

Guarded to poor. PFI=3 months and MST=3.5 months after variable combination therapy (surgery, RT, chemo, immunotherapy) and 10/11 dying due to PD on Vinayak et al study.

Question 31

What is the prognosis for anal sac SCC?

MST?

Answer 31

reported MST-0-7 months from diagnosis and recurrence noted in 4/5 dogs in 1-5 months after surgery.

Question 32

What is the prognosis for cats with AGASACA?

MST with surgery +/- chemo?

Negative prognostic factors?

Answer 32

MST=260 days in 30 cats treated with surgery +/- chemotherapy with a 1-, 2- and 3-year survival rate of 42, 27 and 18% and a tumor related death rate of 53%.

Increased nuclear pleomorphism and local recurrence; thus, curative intent post-surgical RT may have a role and has been well tolerated.