MCT Flashcards
1
Q
What are the 3 KIT staining patterns?
A
- membrane-associated; 2. focal to stippled cytoplasmic staining with decreased membrane-associated staining; 3. diffuse cytoplasmic staining
2
Q
Which KIT staining pattern is associated with increased rate of recurrence and decreased survival?
A
diffuse cytoplasmic staining (Kiupel 2004)
3
Q
Neg prognostic factors for dogs with multiple cutaneous MCT w/surgery? (Mullins 2006)
A
incomplete excision, local recurrence, size > 3cm, CS at time of dx, adjuvant tx
4
Q
Do dogs with multiple MCT have different survival time than those with single?
A
Nope. (Murphy 2006)
5
Q
DFI for high-risk MCT tx with VBL/pred after sx +/- RT? How many alive at 3 yrs?
A
DFI 1305 days, OS not reached but 65% alive at 3 yrs. (Thamm 2008)
6
Q
OS for dogs with grade III MCT tx with VBL/pred after sx +/- RT?
A
1374d (3.8yr) (Thamm 2008)
7
Q
Does prophylactic nodal irradiation improve outcome for MCT?
A
Yes. (Thamm 2008)
But No per Poirier 2006
8
Q
What three histopath features affect survival time for SQ MCT?
A
MI >4/10 hpf, infiltrative growth pattern, presence of multinucleation. (Thompson 2011)
9
Q
In Thompson 2011, which factor for canine SQ MCT was strong predictor of survival, local recurrence, and mets in multivariable analysis?
A
MI > 4/10 hpf
10
Q
What are the criteria for high grade in the Kiupel MCT grading scheme? (4 factors)
A
- MI 7/10 hpf
- 3 multinucleated (3 or more nuclei) cells in 10 hpf
- 3 bizarre nuclei in 10 hpf
- karyomegaly
11
Q
What are the criteria for high grade in the Patnaik MCt grading scheme? (6 factors)
A
- extends into SQ and underlying tissue
- pleomorphic
- indented nuclei
- > 1 nucleoli
- 3-6 MI PER HPF (not per 10 hpf)
- areas of hemorrhage, necrosis, edema
12
Q
What factors affect PFS for grade 3 MCT? (Hume 2011)
A
tumor size and LN status in multivariate analysis (tumor size, LN, MI in univariate)
13
Q
What factors affect OS for grade 3 MCT? (Hume 2011)
A
LN status in multivariate analysis (LN status, local tumor control, LN treatment, and MI in univariate analysis)
14
Q
What is OS for dogs with for dogs with positive cytologic mets to liver and/or spleen? (Book 2011)
A
100d (3.3mo) vs. 291d (9.7mo, if no mets on cyto)
15
Q
What is FAP? How does it affect MCT prognosis? (Giuliano 2017)
A
Fibroblast activating protein - membrane serine protease expressed by activated fibroblasts, particularly tumor associated fibroblasts. Neg prognostic factor – correlated with high grade (both Patnaik and Kiupel), MI, and Ki67 expression.
16
Q
What is TIMP-1? How does it affect MCT prognosis? (Pulz 2017)
A
TIMP-1 = a tissue inhibitor of metalloproteinases.
Pos prognostic factor - increased expression showed better post-surgical survival.
17
Q
What are neg prognostic factors in dogs with stage IV de novo MCT? (Pizzoni 2018)
A
tumor diameter > 3cm, more than 2 metastatic sites, BM infiltration, lack of local control –> all multivariate analysis.
(Note: in this study, well known prog factors such as anatomic site, grade, and mutation status did NOT affect PFI and ST)
18
Q
Is c-kit mutation status different in primary vs. metastatic MCT? (Marconato 2014)
A
Nope.
19
Q
What is MST for grade 2/stage 2 MCT treated with sx + chemo vs. sx + RT + chemo?
A
Sx + chemo = 1103d (3yr)
Sx + RT + chemo = 2056d (5.6yr)
20
Q
What is DFI and MST for grade 2/stage 2 MCT treated with ALT + VBL/CCNU/pred?
A
DFI = 2120d (5.8yr) MST = 1359d (3.7yr)
21
Q
What was the % local recurrence for MCT dogs with incomplete close margins and the following tx (Kry 2012):
- re-excision
- RT
- no further tx
A
- 13%
- 8%
- 38%
Most were grade 2.
22
Q
What was the MST for MCT dogs with incomplete close margins and the following tx (Kry 2012):
- re-excision
- RT
- no further tx
A
- 2930d (8yr)
- 2194d (6yr)
- 710d (2yr)
Most were grade 2.
23
Q
What are the recommended surgical margins for MCT (Simpson 2004)?
A
2cm margins, 1 fascial plane deep
(100% were completely excised with 2cm margins)
However, more recent recommendations are 3cm and 1 fascial plane for high grade especially.
24
Q
What stains are expected to be positive in agranular MCT?
A
CD117, avidin peroxidase, Kpl antibody
Also express CD18, CD45
(poor staining with H&E, toluidine blue, alcian blue, Giemsa –> these are better for well-differentiated)
25
What tumors have been shown to express PD-L1 (Shosu 2016)
frequently expressed in malignant melanoma, mammary gland tumor, MCT, and LSA
(less frequent in STS and HSA)
26
Where do the c-kit genetic mutations occur in canine MCT?
either juxtamembrane domain (exons 11 and 12) or extracellular domain (exons 8 and 9)
27
What cell cycle control mutations have been identified in MCT?
p21, p27, CDK inhibitor mutations
28
What is the prevalence of c-kit mutation in dog/cat grade 2/3 MCT that failed surgical resection or was unresectable?
dog - 26%, cat - 68%
29
What will c-kit analysis look like if mutation present?
All samples have wild-type gene spike, if mutated there will be a second spike.
30
What percent of MCT dogs had GI ulceration at necropsy?
35-83%
31
What was MST for high/low grade MCT on Kiupel scale?
high: 4 months, low: > 2 years
32
What was the agreement on grading using Patnaik scale (reported in Kiupel paper)?
Grade 3 - 75%; grade 1-2 - 63%
33
What was cytologic grading agreement with Patnaik/Kiupel (Camus 2016)?
62% agreement with Patnaik, 97% agreement with Kiupel
34
What was Sn/Sp of Camus 2016 MCT cytologic grading?
88% Sn/94% Sp
35
Dysregulation of what miRNA has been correlated with aggressive MCT phenotype and metastatic behavior?
miR-9 (Fenger 2014)
36
What are the markers of proliferation for MCT?
Ki67 - nuclear protein that correlates w/proliferation; AgNOR - nuclear organizer region correlating with cell division; PCNA - proliferating cell nuclear antigen; MI
37
How do VEGF and microvessel density (MVD) correlate with MCT grade?
higher VEGF and MVD correlate with grade 3 (Patruno 2009)
38
What % of oral/perioral MCT have RLN mets at dx? (Hillman 2010)
60%
MST w/LN mets: 14 mo
MST no mets: not reached
39
Are inguinal MCT more aggressive?
No (according to two studies) but if you separate preputial/scrotal those are more aggressive.
40
What was 5yr survival for SQ MCT? (Thompson 2011)
86% 5yr survival
41
What is prognosis for conjunctival MCT? (Fife 2011)
Good px, 60% were disease free at 21 months.
| 30% grade 1, 55% grade 2, 15% grade 3 - all tx with surgery and most had incomplete margins
42
What is WHO staging scheme for MCT?
```
0 - 1 tumor incompletely excised
1 - 1 tumor w/out RLN
2 - 1 tumor in dermis with RLN
3 - multiple tumors or large/infiltrating tumor w/ or w/out RLN (the multiple tumors part is controversial)
4 - any tumor with distant mets
```
43
Should you sample ultrasonographically normal liver/spleen? Justify answer with literature.
Yes per:
- Stefanello 2009 - majority of dogs with infiltration and normal appearing liver/spleen
- Book 2011 - infiltration MST was 100 days, no infiltration was 290 days; cytology agreement with AUS - 63% spleen, 71% liver
44
What is rate of BM infiltration in canine cutaneous MCT?
3% initial staging, 5% overall
45
In Pizzoni VCO 2018, what was % BM infiltration for stage IV dogs?
20%! (and only 11% of dogs with BM infiltration had circulating mast cells)
46
What was MST for stage IV MCT in Pizzoni 2018?
110 days
47
What is electrochemotherapy? What was recurrence rate after electrochemotherapy with cisplatin for MCT (Spugnini 2011)?
Tumor bed infusion with cisplatin and then electrical pulses. 16% recurrence rate in Spugnini study; median time to recurrence was 3 years.
48
What was CR rate for electrochemotherapy with IL-12 gene electrotransfer? (Cemazar VCO 2017)
72%
(78% of patients had detectable serum IFN-gamma and/or IL-12)
Interleukin 12 (IL-12) is produced by activated antigen-presenting cells (dendritic cells, macrophages). It promotes the development of Th1 responses and is a powerful inducer of IFNγ production by T and NK cells.
49
What is MCT RR to VBL/CCNU? (Cooper 2009)
60% - 1yr duration
| 65% of patients in study had macroscopic dz but grade unknown.
50
What is PFS for macroscopic and microscopic MCT treated with VBL/CTX/pred? (Camps-Palau 2007)
macroscopic PFS 74 days (2.5mo)
microscopic PFS 865 days (2.4yr)
(grade?)
51
What receptors are inhibited by Palladia?
KIT, VEGFR2, PDGFRbeta
52
What was the RR for macroscopic MCT to Palladia? (London 2009)
40%
| vs. 8% placebo
53
What was duration of response for macroscopic MCT to Palladia? PFS? (London 2009)
response - 3 months
| PFS - 4.5 months
54
What % of MCT had KIT mutation? (London 2009)
20-40%
55
What did London 2009 report as likelihood for MCT with c-kit mutation to respond to Palladia?
2x more likely to respond vs. wild-type c-kit
(68% vs. 37%)
This has NOT necessarily been corroborated by other studies (see Weishaar 2018)
56
What is MST for MCT tx with masitinib - c-kit mutated vs. wild-type? (Hahn 2008)
c-kit mutation: MST not reached
normal c-kit: 253d (8.4mo)
(recurrent or nonresectable tumors evaluated)
57
What was overall PFS for MCT tx with masitinib (Hahn 2008)?
PFS 118d (4mo); first-line therapy PFS 253 days (8.4mo)
58
Overall RR of MCT to masitinib? (Smrkovski 2013)
50%
| Although Grant 2016 reported 82.1% response rate
59
Does imatinib have efficacy against canine MCT? (Isotani 2008)
Yes - objective responses in both c-kit mutant and wild-type.
No PK studies have been done in dogs, though.
60
What is MTD of VBL when combined with EOD toceranib? (Robat 2012)
1.6 mg/m2
| BUT toceranib was at 3.25 mg/kg EOD in this study
61
What was ORR of toceranib combined with hypofractionated RT for MCT? (Carlsten 2012)
ORR 76.4% (58.8% CR and 17.6% PR)
62
What was MST of toceranib combined with hypofractionated RT for MCT? (Carlsten 2012)
MST not reached, median follow-up 374d, median PFI 316d (10.5mo)
63
What is RR to hydroxyurea for MCT? (Rassnick 2010)
28%
64
In cats with splenic MCT, what is MST with splenectomy vs. no surgery? (Evans 2017)
```
Splenectomy 856d (2.3yr), no surgery 342d (0.9yr)
Role of chemo remains unknown
```
65
What was % benefit to Palladia for cats with MCT amd median duration of benefit? (Berger 2017)
80%; median duration 36 weeks (9 months)
50 cats with cutaneous (22), splenic/hepatic/visceral (10), GI (17), other (1)
66
ORR to CCNU in cats with MCT? Duration of response? Dose? Toxicity? (Rassnick 2008)
ORR 50% (median duration 168d - 5.6mo)
Dose 50-60 mg/m2
Toxicity neutropenia, thrombocytopenia
67
What % of nodes palpate normal but have MCT mets? (Ferrari 2018)
50%
This increased to 65% if you included pre-metastatic status (HN1)
Justifies prophylactic nodal removal or sampling at a minimum - they did not compare to cyto in this study.
68
Prognosis of intramuscular MCT?
Favorable according to Robinson 2017. All 6 dogs that had had surgery were alive at follow-up with a minimum elapsed time of 7 months; 3 had adjunct chemo.
69
ORR of chlorambucil and pred for MCT? (Taylor 2009)
38% but this is a crap study.
70
Criteria for the MCT RNL metastasis classification system? (Weishaar 2014)
HN0 - none to rare mast cells (non-metastatic)
HN1 - more than 3 mast cells in 4hpf (pre-metastatic)
HN2 - aggregates (early metastasis)
HN3 - disruption or effacement of normal nodal architecture (over metastasis)
71
MST for HN0/1 vs. HN2/3?
HN0/1 = 1824 days (5yr)
HN2/3 = 804 days (2.2yr)
High grade more likely to met (duh).
72
What % of MCT were changed to incomplete margins using tangential sectioning instead of radial? (Dores 2018)
Low grade MCT 23% change in tumor free margin status with radial to tangential
73
In evaluating histologically tumor free margins, what margin prevented recurrence of high grade tumors? (Donnelly 2015)
No "safe" margin was identified, no association between HTFM and LR. 36% recurred.
74
In Donnelly 2015, what % of low grade MCT had histologic margins less than 3 mm and how many recurred?
29% had <3mm, none recurred.
| Only 3.9% low grade MCT recurred total in this study.
75
What was RR of macroscopic MCT to toceranib vs. VBL in a prospective study? (Weishaar 2018)
46% TOC, 30% VBL
76
What was MST and PFS of macroscopic MCT to toceranib vs. VBL in a prospective study? (Weishaar 2018)
VBL - MST 241.5d (8mo); PFS was 78d (2.6mo)
| TOC - 159d (5.3mo); PFS was 95.5d (3.2mo)
77
Did c-kit mutation predict treatment response to TOC or VBL in recent prospective study? (Weishaar 2018)
Nope.
78
Did kit cytoplastmic staining affect prognosis in cats? What MI cut-off was prognostic? (Sabattani 2013)
Yes - risk factors associated with survival were MI >5/10hpf and cytoplastmic kit staining. In 67% of cats, multiple nodules from same cat had different mutational status.
79
What is MST of GI MCT in cats? (Barrett 2018)
531d (1.5yr)
26% of cats actually died from a different cause. GI MCT may be better prognosis than previously reported).
Surgery and medical tx (including pred) both associated with prolonged survival. May need no more than pred.
80
In Weishaar 2018 multivariate analysis, what factors affected PFS? OS?
PFS - grade and KIT localization
| OS - KIT localization
81
Ki67 as prognosticator - cut-off? (Vascellari 2012)
10.6
| >10/6 -- 8x higher risk of mortality
82
Response of MCT to glucocorticoids? (Horta 2018)
63% PR, no CR
83
Multivariate analysis of glucocorticoids and MCT - response to GCs correlates with what? (Horta 2018)
tumor recurrence/related death, clinical stage, MI
84
What % of MCT located on muzzle present with RLN mets? What is MST for RLN mets?
50-60%, 14 months
85
T/F: The presence of c-kit activating mutation is associated with higher rate of local recurrence, metastasis, and death from MCT.
True
86
What % of incompletely excised low/intermediate grade MCT recur?
20-30%
87
Which is/are not neg prog factor(s) for MCT?
1. diploid tumor
2. high Ki67
3. male dog
4. systemic signs
5. Shar Pei breed
diploid tumor and male dog
88
Incidence of BM involvement in MCT for cutaneous? visceral?
cutaneous - 2.8%, visceral 56% (different than recent study)
89
What % of treated vs. placebo dogs were alive at 2yrs in masitinib study?
40% vs. 15%
90
RR with VBL/TOC?
71%
91
What exons are feline cKIT mutations located on?
8 and 9
92
What surgical margins are recommended for feline GI MCT?
5-10cm
93
What were prognostic factors for feline splenic MCT according to Evans 2018? According to historical data?
Evans - none were significant.
| Historically - anorexia, significant weight loss, male gender
94
What 5 features of canine MCT histopath correlated with worse outcome? (Sabattini 2010)
multiplicity of lesions, pleomorphic phenotype, KIT score, mitotic indices, Ki67 indices
95
Ki67 cutoff that predicts MCT grade and survival?
1.8 (Maglennon VCO 2008)
96
Turnover of ____ appears to play an important role in canine MCT pathogenesis. (Arendt PLoS Genetics 2015)
hyaluronan
97
Does imatinib have clinically activity against MCT in dogs? (Isotani JVIM 2008)
Yes, dose at 10 mg/kg daily. Authors recommended checking for exon 11 mutation within c-kit.
98
In Schultheiss 2011, there was no recurrence of tumors with >/= ___ mm lateral and >/= ___ mm deep margins. (this was only MCT)
10mm lateral
| 4mm deep
99
In Scarpa 2012 (evaluation of histologic margins of multiple tumor types), what conclusion was made about follow-up? (This included MCT, STS, and carcinomas)
Should follow for at least 2 years, late tumor recurrence was noted in this study.
100
Do ferret MCTs express KIT?
Yes, 100% showed expression. 1/3 showed KIT pattern 1 and the remaining KIT pattern III. (Vilalta Journal of Comp Path 2016)
101
What two features were significantly associated with survival in evaluation of feline GI MCT? (Sabattini 2016)
tumor degree of differentiation and MI > 2
| cytoplasmic KIT pattern was associated with lesser differentiation
102
What is the ORR to pred and VBL in macroscopic MCT? (Thamm/Vail 2008)
47%
103
```
What is the response rate of measurable MCT to the following:
CCNU
Calcitriol
Hydroxyurea
Chlorambucil/pred
```
CCNU - 44% (source?)
Calcitriol - 40%
Chlorambucil/pred - 38% (bad study)
Hydroxyurea - 28% (bad study)
104
Where were the majority of feline c-kit mutations identified? Were these mutations correlated with biologic behavior? (Sabattini 2013)
exon 9 - 71%
(exon 8, 19%; exon 9, 71%; exon 11, 10%)
Not correlated with behavior
105
What is the typical behavior of a canine conjunctival MCT?
Benign
106
How did micellar paclitaxel compare to CCNU for MCT? (Vail 2012)
CORR (confirmed ORR) was 7% for paclitaxel and 1% for CCNU
107
How did hepatotoxicity with micellar paclitaxel compare to CCNU? (Vail 2012)
CCNU - 33%
| paclitaxel - 2%
108
What was the response rate of MCT to Vinorelbine? Toxicity? (Grant 2008)
13% response
54% neutropenia, 46% GI dox
(dose 1 tx at 15 mg/m2)
109
What are the response rates of MCT to the following?
- Chlorambucil/pred
- Lomustine
- VBL/pred
- VBL/CCNU
- VBL/CCNU/pred
- Palladia
- Masitinib
- VBL/Palladia
- Chlorambucil/pred: 38%
- Lomustine: 42%
- VBL/pred: 47%
- VBL/CCNU: 57%
- VBL/CCNU/pred: 65%
- Palladia: 42%
- Masitinib: 50% (82% ORR in Grant 2016, 2/3 had pred)
- VBL/Palladia: 71%
110
What does masitinib target?
c-kit, PDGFRa/B, lyn, FGFR receptor 3, focal adhesion kinase pathway
111
What was the accuracy of using margins to predict MCT recurrence? STS? Carcinoma? (Scarpa 2012)
MCT - 76%
STS - 87%
Carcinoma - 94%
112
What is the dose of masitinib? (Hahn 2010)
12.5 m/kg
113
What was the confirmed ORR, biologic response rate, and 5 week PFS in dogs with grade 2 or 3 MCT treated with Paccal Vet? (Vail JVIM 2012)
CORR: 7%, BORR: 23%, 6 week PFS: 68%
114
Which KIT exon is most commonly mutated in canine MCT?
exon 11
115
What are the four members of the ErbB family of RTKs?
1. ErbB-1 (aka EGFR/HER1)
2. ErbB-2 (aka HER2/neu)
3. ErbB-3 (aka HER3)
4. ErbB-4 (aka HER4)
116
What is the MOA of gefitinib and erlotinib?
bind to ATP-binding pocket of INTRAcellular kinase domain of EGFR - prevents autophosphorylation and downstream signaling
117
What are MOR to EGFR inhibitors?
1. secondary mutation of EGFR that prevents drug binding
| 2. activation of downstream signals (i.e. amplification of Met)
118
What is the MOA of cetuximab and panitumumab? What is the molecular predictor of response of these in colorectal cancer?
- Bind to extracellular domain of EGFR, inhibits activation and receptor dimerization
- absence of K-RAS mutation
119
What % of dogs with macroscopic MCT have elevated histamine?
75%
120
What does electrochemotherapy do to cell membranes? (Lowe 2016)
temporary permeabilization and increased porosity
121
T/F: Dogs with MCT that were treated with electrochemotherapy intra-operatively had the longest DFA, as compared to dogs treated in gross disease setting or post-operatively. (Lowe 2016)
True
122
What are the most commonly used agents for electrochemotherapy in canine MCT?
bleomycin, cisplatin
