Chapter 29 - Tumors of the Urinary System Flashcards
Canine urinary bladder accounts for ___ % of all reported cancer in dogs.
2%
What is the most common bladder cancer in dogs and what is the most common histologic form? What is the most common location?
TCC
Intermediate to high grade papillary infiltrative
Trigone
What % of bladder TCC’s involve the urethra and prostate?
60% urethra
30% prostate
78% are T2 - invade the bladder wall
20% are T3 - invade nearby organs like prostate, uterus
What % of dogs with TCC have regional and distant metastasis at diagnosis? Overall metastatic rate at death? What % has regional and distant mets?
At diagnosis:
16% LN
14% distant
At death:
70% overall
30% LN
60% distant (50% lungs, 11% bone)
What are risk factors for the development of TCC in dogs (7)? What has been found to help reduce the risk?
Older generation flea/tick control products Lawn chemicals (ex. 2,4-D) Obesity in females Cyclophosphamide exposure Female sex Neutered status Breeds
Scottish Terriers that ate vegetables at least 3 times per week had reduced risk (OR 0.3). Carrots were most commonly used. Green leafy veggies or yellow orange veggies. NOT cruciferus.
Neoplastic cells can be present in the urine in up to ___% of dogs with TCC.
30%
Often indistinguishable from reactive epithelial cells
Urine antigen tests for TCC are ___ but not ___.
Sensitive (88%), but not specific.
Lots of false positives from RBC and WBC
What marker is used to identify urinary transitional epithelium?
Where is it expressed?
How can this marker be helpful?
This marker is expressed in more than ___% of TCCs.
Is it a sensitive or specific marker?
Uroplakin III (UPIII)
A transmembrane protein expressed in superficial transitional epithelial cells of the urinary tract
Helpful to differentiate TCC origin from other types of carcinoma
> 90%
It is a specific marker for TCC epithelium/cells
What is the most common bone metastasis site in dogs with TCC? What % has more than 1 bone lesion?
Vertebrae
35%
Majority are lytic
What are 3reasons surgery for dogs with TCC is indicated?
- To obtain tissue for dx
- To attempt to remove the tumor if the lesion is away from the trigone
- To maintain or restore urine flow
3%
Why is complete surgical excision usually not possible for dogs with TCC?
What % of dogs with TCC are able to have their tumors completely excised?
Trigone location, urethral involvement, metastasis
3%
What is the field effect and how does it apply to TCC?
Field effect of cancer - entire area, in this case lining, is thought to undergo malignant change in response to carcinogens present in the urine
In TCC, the cancer is sometimes thought to be multifocal
TCC control is usually achieved in ___ of dogs. How are MST?
75% stable, reduction in size
They can extend well over 1 year
Is there a benefit in combining chemotherapy drugs in dogs with TCC?
Has not been proven
Also, potential development of resistance to multiple drugs at the same time could limit the options for subsequent therapy
ORR, OBA, and MST of piroxicam when used as a single agent in dogs with urogenital carcinoma?
ORR - 18% (6% CR, 12% PR)
OBA - 74% (including SD in 53%)
MST 6m
*non COX selective
PR, SD, PFS, and MST of deracoxib when used as a single agent in dogs with urogenital carcinoma?
17% PR, 71% SD
PFS 4.5m
MST 10.7m
GI AE 19%
COX-2 selective*
PR, SD, PFS, and MST of firocoxib when used as a single agent in dogs with urogenital carcinoma?
20% PR, 33% SD
PFI 3.5m
MST 5m
COX-2 selective*
ORR, biological response, PFI, and MST for dogs with bladder TCC treated with mitoxantrone and piroxicam?
ORR 35%
Biological response 75%
PFI 3.5 to 6.4m
MST 10m
ORR, PFI, MST for dogs with bladder TCC when treated with carboplatin and piroxicam? What if treated with carbo alone?
ORR 38%
PFI 2.4m
MST 5.3m
If carbo alone, 0% - NADA!!!
What was the major finding in a randomized phase III clinical trial comparing first line carbo vs mito in combination with piroxicam for dogs with bladder TCC? What was a negative prognostic indicator identified?
No difference in ORR or PFI
Dogs with prostatic involvement had a shorter MST compared to urethral, trigonal, or apically located tumors
What is the ORR, biological response rate and MST of dogs with bladder TCC when treated with gemcitabine and piroxicam?
ORR 26%
Biological response 76%
MST 7.6m
What is the ORR, biological response rate, PFI, and MST of dogs with bladder TCC when treated with vinblastine every 2 weeks? What % required dose reductions? DLT?
ORR 36% Biological response 86% PFI 4m MST 5m 60% required dose reductions due to neutropenia
What are localized therapies studied in dogs with TCC of the bladder?
Intravesicual mitomycin C and photodynamic therapy
What is the most serious complication seen with intravesical therapy with mitomycin?
Severe myelosuppression and marked GI upset; systemic absorption was suspected
Also severe irritation for 1 to 2 days post therapy
PDT in dogs with TCC has been evaluated with what compound? What is the photoactive metabolite when this compound is used?
5-aminolevulinic acid (ALA); converted to active protoporphyrin IX only in the bladder mucosa
In a series of 20 cats with TCC, what % of cats had a concurrent UTI? Cats in this study had a combination of surgery, chemo and piroxicam. What was the MST?
75%261 daysClinical signs, treatments, and outcome in cats with transitional cell carcinoma of the urinary bladder: 20 cases. JAVMA, 2007.
What are the 2 most common urethral tumors?
TCC and SCC
How is the response to therapy in dogs with urethral epithelial tumors when compared to bladder TCC?
Similar
What is more common in the canine kidneys, primary or metastatic tumors?
Metastatic
Primary renal tumors in dogsmake up ___ % of all canine cancers.
<2%
Most common primary renal tumor in dogs?
Renal cell carcinoma (50-65%)
Lymphoma and RCC usually occur ____.
Bilaterally
How does hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis (RCND) manifests in GSD? This condition is similar to which condition in humans?
Consists of slow growing dermal fibrosis and fibromas, concomitant renal cystadenocarcinoma, and uterine tumors if females. Results from a dominantly inherited mutation in folliculin, a tumor suppressor gene.Has a dominant patternof expression.
Birt-Hogg-Dube syndrome
Which renal tumor may occur at any age in dogs?
Nephroblastoma
What % of dogs with renal tumors have proteinuria?
50%
How can the HCT be affected in dogs with renal tumors?
Anemia, polycythemia
What 5 IHC stains have been reported to be useful in dogs with renal cell carcinomas?
c-Kit, vimentin, uromodulin, cytokeratin, Pax8 (80%)
Vimentin and cytokeratin suggest distal convoluted tumor origin
What is the tx of choice for unilateral renal tumors with no mets in dogs? MST?
Nephrectomy with removal of associated ureter
MST 16m
Unless its lymphoma, however, lymphoma is usually bilateral
What percentage of dogs with renal tumors have metastasis at the time of diagnosis and at the time of death?
Diagnosis - up to 34%
Death - up to 88%
Carcinoma - 70%
Nephroblastoma 75%
Sarcoma 88%
In dogs with renal cell carcinoma, what is the MST post nephrectomy?
1 and 2 year survival rates?
Time to recurrence or metastasis?
MST 1.5yrs
1-yr SR 43%
2-yr SR 25%
Time to recurrence/mets 8.5m post sx
use of adjuvant therapy did not improve prognosis, but 6 dogs with distant mets were treated with chemo and had an MST of 14m
What are the negative prognostic indicators for ST identified in dogs with renal cell carcinoma (10)?
Age <6yrs Presence of hematuria Presence of cachexia Metastasis at dx Clear cell subtype Histologic vascular invasion Fuhrman nuclear grade (grade 4 MST 87d, grade 3 MST 379d, grade 2 MST 1065d) 14-3-3o IHC protein expression COX-2 expression MI (>30 MST 120-187d HR 12, 10-30 MST 452d, <10 MST 1184d)
In a study of dogs with renal HSA treated with nephrectomy and +/- chemotherapy, the MST was ___ m.
Negative PI for ST (1)?
9.2m
Dogs with hemoabdomen had a shorter ST (2m)
What can be said about bladder tumors in humans as opposed to animals?
2/3 are superficial low grade tumors and respond well to sx
What breeds are at increased risk for developing TCC (8)?
Scotties (OR 18-21) Eskimo dogs (OR 6.5) Shelties (OR 6) Westies (OR 5.8) Keeshonds (OR 4.2) Samoyed (OR 3.4) Beagle (OR 3) Dalmatian (OR 2.4)
What is Sanguer sequencing?
Gold standard for detecting a single nucleotide substitution, but requires a 10-20% fraction of mutated allele for reliable detection - therefore low sensitivity leading to false negatives. Can be used in tissue or urine.
BRAF mutations are present in what % of dogs with urothelial and prostatic carcinoma? Overall?
Overall - 80% (20% do NOT posses the mutation)
Urothelial - 67%
Prostatic - 78%
Describe the BRAF mutation in dogs with urogenital TCC. What is the equivalent mutation in humans?
BRAF gene in chromosome 16, exon 15, codon 450 or 595
Results in a T -> A transversion that causes aa substitution of valine for glutamic acid
Humans, V600E
Sensitivity and specificity of Sanger sequencing and ddPCR for detecting BRAF mutations in tissue and urine samples from dogs with TCC?
Sanger sensitivity:
Tissue - 71%
Urine - 61% of UC, 100% of PC
ddPCR sensitivity:
Tissue: 79%
Urine: 85%
BOTH are 100% specific! ddPCR more sensitive than Sanger for both tissue and urine
Advantages of ddPCR over Sanger for BRAF mutation detection?
ddPCR much more sensitive; able to detect mutation when present at levels as low as 0.005% (1 in 10,000 alleles)
Sanger requires a 10-20% fraction of mutated allele for reliable detection - therefore low sensitivity leading to false negatives.
How does uroplakin III expression differ in dogs with TCC vs those with polyps?
Polyps = staining confined to superficial layer Carcinoma = random expression, can be patchy, and sometimes decreased in higher grade tumors
What % of dogs with bladder/prostate cancer have a concurrent UTI?
Is it more common in dogs with a specific signalment (2)?
Cats?
Overall 55%
Females 80% vs males 30%
Urethral involvement 75% vs w/o 30%
Cats 67-75%
What is the MST in dogs with TCC that have mets to the skin?
2-3m
What is the MST, recurrence rate, TTF, and median PFS in dogs with TCC treated with partial cystectomy, an NSAID and +/- chemotherapy?
MST 11.6m
Recurrence rate 76%
TTF 100d
PFS 7.8m
Dogs receiving partial cystectomy (vs full thickness) and daily piroxicam MST 2.1yr in 1 study
43% developed post-op complications with incontinence being the most common one
What is the MST in dogs with trigonal TCC treated with radical cystectomy and cutaneous ureterostomy (4 cases only)?
MST 9.3m
No major complications, but all dogs developed minor complications like bleeding and edema at ureterostomy site
What is the MST in dogs with TCC that undergo ureterocolonic anastomosis? Complications (5)?
MST 7d to 5m
Complications:
Azotemia due to intestinal recycling of urea in all dogs, hyperchloremic metabolic acidosis, pyelonephritis, hyperammonemia, neuro signs
Not recommended due to morbidity and limited ST
What % of dogs with TCC experience relief of UO with urethral stent placement?
98-100%
What % of dogs with TCC experience incontinence, UTIs, stranguria, and re-obstruction after urethral stent placement?
Incontinence 37-64%; severe in 26%
UTI 35%
Re-obstruction 22% at median of 90d
Stranguria 4.7%
What is the MST in dogs with TCC when treated with urethral stent?
What has been shown to prolong the MST in these dogs? MST?
MST 20d to 2.6m (therefore mostly palliative)
Tx with an NSAID for >4 weeks prior to stent and chemotherapy post stent; MST 8.3m
How is the response of hypofractionated RT combined with piroxicam and mitoxantrone when compared to medical therapy alone in dogs with urogenital carcinoma?
No improvement vs mito + NSAID alone
AE in 40%
How is the a/b ratio of bladder carcinomas?
Increased incidence of late AE is seen with total doses higher than ___Gy.
Low a/b ratio - means a higher dose per fraction is probably more important for cell kill
> 30Gy; increased incidence of ureteral fibrosis and stenosis
What is the subjective response rate, median event-free ST, and MST in dogs with urogenital carcinoma when treated with IMRT (55-58 Gy over 20 fractions)? Late AE?
ORR 60%
Median event-free survival time 10.5m
MST 1.8yrs
20% late grade 3 GI or UG toxicosis
What are some recommendations for RT protocols for dogs with urogenital carcinoma (4)?
- Position in lateral recumbency
- Use PTV of >1cm if not using IMRT
- Limit dose per fraction to <3Gy to minimize late AE
- Consider RT field size; inclusion of LN may increase risk of colitis and recta, ureteral, and urethral stricture; bladder size also influences field, so better to treat small bladders
What is the biological response rate, PFI, and MST of dogs with bladder TCC when treated with chlorambucil?
Biological response rate - 70% (SD in 67% - highest one reported)
PFI 4m
MST 7.4m
Dose 4mg/m2 PO q 24hrs
ORR, biological response rate, and MST of cisplatin and Tavocept for dogs with bladder TCC?
Only ___% developed elevated creatinine vs ___ to ___% of historical dogs treated with cisplatin.
ORR 27%
Biological response rate 91%
MST 8.4m (comparable to historical controls)
21% had elevated creatinine vs 50 to 86% previously
ORR, biological response rate, and MST of dogs with bladder TCC when treated with 5-azacytidine?
ORR 26%
Biological response rate 72%
MST 6.7m
ORR, biological response rate, PFI, and MST of dogs with bladder TCC when treated with vinorelbine?
ORR 15%
Biological response rate 78%
PFI 3m
MST 6m
Clinical response rate, PFI, MST of dogs with bladder TCC when treated with doxorubicin, piroxicam, and +/- surgery?
Biological response rate 70%
PFI 3.5m
MST 5.6m
Identified prognostic factors in dogs with TCC?
- TNM stage
- Tumor location: urethral (worse prognosis) and prostatic involvement
- Dogs receiving 3+ chemo drugs had a longer MST compared to those receiving 1-2 chemo drugs
- Daily piroxicam had a longer PFS and MST
In humans, bladder cancer is risked to what?
Cigarette smoking
What form of bladder carcinoma is similar to TCC in dogs?
The invasive form; accounts for 20% of human bladder cancers
What % of bladder TCC in cats occur away from the trigone?
55%
Overall MST in cats with bladder TCC when treated with a combination of surgery, chemotherapy, and an NSAID?
8.7m
Clinical response and mean survival time of cats with bladder TCC when treated with meloxicam? Any prognostic indicators?
Clinical response in 90%
Mean ST 10m
COX+ tumors had a shorter ST (123d) vs COX- (375d)
What % of cats with urethral stent develop incontinence and UTIs?
Incontinence - 50%
UTI - 25%
First and second most common kidney tumor in cats?
Lymphoma #1
Tubular renal cell carcinoma #2; IHC CK7, CK20, KIT, CD10
Most common renal tumor in children and humans?
Children - Wilm’s tumor (nephroblastoma)
Adults - renal cell carcinoma >90% of caricnomas
Approximately how many cats with non-lymphomatous renal tumors have metastasis at dx?
Majority
