Page 493 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 23 Cancer of the Gastrointestinal Tract 471

sites. 564,568,599–602,605,606,610,616 Metastasis can be present even from the anal sac in nine dogs, all with unilateral disease. 561–563
when the primary tumor is small (<1 cm). 607 The medial iliac and Four of these dogs were clinically staged and none had evidence of
regional LN or distant metastasis. Tumors recurred in four of five
internal iliac LNs (collectively called sublumbar LNs) and sacral
VetBooks.ir LNs are the most common sites of metastasis, 564,599–601,605,606,609 dogs after surgical excision. 561–563
The biologic behavior of feline AGASAC has not been clearly
whereas distant sites include lungs, liver, spleen, bone, and, less
commonly, heart, adrenal glands, stomach, omentum, pancreas, defined. Most reports suggest that it is a locally invasive disease
kidneys, urinary bladder, and the mediastinum. 564,568,599–604 associated with a moderate-to-high risk of tumor recurrence after
AGASAC micrometastases were detected incidentally in the bone surgery. 565–567 The rate of metastasis is variable between stud-
marrow in one of four dogs in one study. 623 Tumor behavior can ies. 565–567 Metastasis to the regional LNs was suspected at the time
vary, because some dogs with large primary tumors may present of diagnosis in 20% of surgically treated cats with AGASAC. 566
without metastatic disease, whereas others may have a small pri- Metastatic sites include regional LNs, liver, diaphragm, and
mary tumor that has already metastasized. 607 In one study, dogs lungs. 565,567 Paraneoplastic hypercalcemia is relatively rare in cats
with clinical signs were more likely to have LN metastasis at with AGASAC, being reported in 11% of cats in one series. 565,566
diagnosis compared with dogs whose tumors were detected inci- Bilateral tumors have not been reported.
dentally. 607 Histologic features including marked peripheral infil-
tration into surrounding tissue (neoplastic aggregates separated History and Clinical Signs
from the main tumor nodule), lymphovascular invasion, and solid
pattern of cell arrangement were also associated with nodal metas- Clinical signs in dogs with AGASAC are often referable to either
tasis at diagnosis, whereas mitotic index and presence of necrosis the presence of the primary mass (perianal discomfort, swell-
were not. 607 In another study, E-cadherin, a protein that medi- ing [Fig. 23.31A], discharge, bleeding, scooting, perianal lick-
ates adhesion and communication between cells and the extracel- ing), obstruction of the pelvic canal by LN metastasis (tenesmus,
lular matrix, was evaluated as a prognostic marker in dogs with abnormal stool shape, constipation, lethargy, anorexia), or to
AGASAC. 624 A positive relationship between survival and the hypercalcemia (polyuria, polydipsia, hyporexia, lethargy, vomit-
proportion of cells expressing E-cadherin immunoreactivity was ing). 599,600,607 The primary tumor is an incidental finding on
observed, suggesting that loss of E-cadherin expression may play a physical examination in up to 47% of reported dogs. 600,603 Rarely,
role in tumor progression. 624 p53 expression has been detected via dogs present with pain or lameness as a result of bone metastasis
IHC in a low-to-moderate proportion of AGASAC samples; how- or direct extension of metastatic LNs into the lumbar or sacral
ever, no clinical implications have come from these findings. 579 A vertebrae. In one study, presence of clinical signs was associated
genetic analysis study in English cocker spaniels showed a higher with the size of the primary tumor. 616
frequency of AGASAC in dogs with the major histocompatibility Dogs with anal sac melanoma or SCC present with clini-
complex DLA–DBQ1 allele, suggesting that a genetic factor may cal signs related to the primary tumor. 561–563 Common signs
play a role in tumor development in this breed. 625 COX-2 expres- include hemorrhagic discharge and perineal licking. 561–563 Tenes-
sion also has been evaluated in AGASAC. 626 All tumor samples mus and constipation may be less common than in dogs with
evaluated in one study showed positive immunoreactivity, as did AGASAC. 561–563 In one study, all dogs with anal sac melanoma
ductal cells in normal anal sacs. 626 Neuroendocrine differentia- presented with clinical signs; none of the tumors were detected
tion, suggested by expression of markers including synaptophysin, incidentally. 560 Of nine dogs with anal sac SCC, one dog was
chromogranin A, and neuron-specific enolase, was detected via diagnosed incidentally. 561–563
IHC in 30% of AGASAC. 608,627 In cats with AGASAC, the most common clinical sign is peri-
To further dissect the molecular basis of AGASAC and its neal ulceration or discharge and this is present in up to 85% of
reported sensitivity to the tyrosine kinase inhibitor toceranib cats (see Fig. 23.31B). 566 Other clinical signs include tenesmus,
phosphate (Palladia), expression of key toceranib targets has been constipation, scooting, and excessive grooming of the perineal
evaluated. 628,629 In one study, mRNA for vascular endothelial area. 565–567 Lethargy and/or hyporexia may be secondary to severe
growth factor receptor (VEGFR)-2, platelet-derived growth fac- constipation. Not all cats present with clinical signs, and tumors
tor receptor (PDGFR)-α and -ß, and KIT was detected in all 24 can be detected incidentally during a routine physical examina-
tumors evaluated, but protein expression assessed by IHC was less tion, although this is rare. 565 It is not uncommon for an AGASAC
consistent. 629 Protein expression of VEGFR-2 and PDGFR-α to be misdiagnosed as an anal sac abscess based on the presence of
was present in most tumors; however, only one third expressed ulceration and discharge in the perineal region. 565,566
KIT. PDGFR-ß was strongly expressed in stroma. 629 Interestingly,
RET expression was observed at both the mRNA and phosphory- Diagnostic Techniques and Workup
lated protein levels. 629 Phosphorylation of other receptor tyrosine
kinases, including EGFR, Dtk/TYRO3, ROR-1, ROR-2, Tie- Because dogs with AGASAC may present with signs unrelated
1, insulin-R, and RON, was observed in more than half of the to perianal disease (i.e., polyuria and polydipsia due to hyper-
tumors, suggesting that these may also have a role in AGASAC calcemia), assessment of animals with suspicious clinical signs
tumorigenesis. 629 requires a careful rectal examination, including palpation of
A case series of 11 dogs with anal sac melanoma suggests a both anal sacs and evaluation for possible regional lymphadeno-
moderate to aggressive biologic behavior. 560 Primary tumors were megaly. Although a definitive diagnosis requires either an FNA
unilateral in all cases with a mean diameter of 3.4 cm. At the time or biopsy, the likelihood of AGASAC is high in animals with a firm
of diagnosis, four of eight dogs had confirmed or suspected sub- and discrete mass in the anal sac. AGASAC has a characteristic
lumbar LN metastasis, and 1 of 11 dogs had pulmonary metasta- “neuroendocrine” cytologic appearance consisting of polyhedral
sis. 560 The median mitotic index of the primary tumors was 50 per to roundish epithelial cells with uniform round nuclei and light
10 high-power fields. Ten of 11 dogs died due to tumor progres- blue-gray, slightly granular cytoplasm (see Fig. 7.18). Cytologic
sion. 560 Squamous cell carcinoma has also been reported arising criteria of malignancy are often subtle or absent. FNA cytology