Melanoma Flashcards
1
Q
What breeds of dog is OMM most commonly diagnosed?
A
Scotties, goldens, Chows, poodles and dachshunds
2
Q
Canine OMM is most commonly found in what locations of the mouth in order of decreasing frequency
A
gingiva, lips, tongue and hard palate
3
Q
WHat are the primary factors that determine the biologic behavior of an OMM in dogs
A
Site, Size, Stage and histo parameters
4
Q
What cocktail of IHC Abs are used to diagnose melanoma
A
PNL2, tyrosinase, Melan A and S-100
5
Q
BRAF is frequently mutated in which form of human melanoma?
A
Commonly mutated in cutaneous but not in oral (also uncommon for BRAF mutations in OMMs in dogs)
6
Q
What IHC marker can more reliably predict potential malignant behavior compared to classical histology for cutaneous melanoma?
A
Ki67 (also prognostic in OMM)
7
Q
What is the MST of dogs with melanoma of the digit w/o LN or distant mets treated with digit amp?
A
~12mo, 1yr survival 42-57%, 2yr 11-13%
8
Q
What is the rate of metastasis at presentation for dogs with digital melanoma?
A
30-40%
9
Q
What do most dogs with digital melanoma die from?
A
Metastasis - regional or distant
10
Q
What are the T classifications for OMM based on WHO TNM staging
A
T1 ≤2cm T2 2-4cm T3 > 4cm
11
Q
What are the N classifications for OMM based on WHO TNM staging?
A
N0 = no regional nodes N1 = histo or cyto evidence of regional node involvement N2 = fixed nodes
12
Q
What are the WHO TNM-based stages for OMM in dogs?
A
Stage 1 = T1N0M0 2 = T2N0M0 3 = T2N1M0 or T3N0M0 4 = Any T, Any N and M1
13
Q
What is the MST for dogs with stage I OMM treated with surgery
A
511-874d
14
Q
What is the MST for dogs with stage II OMM treated with surgery
A
160-818d
15
Q
What is the MST for dogs with stage III OMM treated with surgery
A
168-207d
16
Q
What % of enlarged vs normal LN have mets from OMM?
A
70% of enlarged LN have mets 40% of normal LN have mets
17
Q
What margins are generally recommended for benign cutaneous melanomas?
A
1cm skin margins, 1 fascial plane deep
18
Q
What margins are recommended for OMM
A
2-3 cm when possible
19
Q
Dogs with incomplete histo margins from OMM are ____ times more likely to die of tumor-related causes compared with dogs with complete excision
A
3.6x
20
Q
Dogs with OMM located where in the mouth are 4.3x more likely to die of tumor-related causes
A
Caudal to PM3 (compared to those rostral to PM3)
21
Q
What is the radiosensitivity melanom
A
Generally radioresistant –> need higher dose/fx to achieve local control
22
Q
What is the overall response rate to RT for melanoma? PR vs. CR?
A
Overall 82-94% PR 25-67% CR 19-69%
23
Q
What is the PFS for dogs treated with RT for gross disease melanoma?
A
3.6-8.6mo
24
Q
What is the ORR and MST for cats with OMM treated with RT?
A
ORR = 60% (1 CR 2 PRs/5 cats) MST 146d
25
Does adding chemotherapy to RT improve outcomes for dogs with OMM?
No based on the largest study; may have a role as a chemosensitizer (low rate of recurrence 15% with cisplat or carbo)
26
For dogs treated for OMM with surgery + carbo +/- RT, what was the MST? How did RT influence this?
MST for sx/chemo/RT 440d vs. sx/chemo 387d (not stat sig), but lower rate of local recurrence for RT group (27% vs. 67%)
27
What was the difference in TTP and MST for dogs treated with RT alone vs. RT + temozolomide
PFS sig shorter for RT alone (110d vs. 205d), MST numerically different but not stat sig (RT alone 192d vs. 402d w/ chemo+RT)
28
When using the WHO TNM staging system, what is the PFS for OMM treated with 12x4Gy MWF RT protocol based on T?
T1 PFS 11.3mo T2 6.0 T3 6.7mo
29
Bony involvement has been reported in up to \_\_\_\_\_% of dogs with melanoma
92%
30
What is the ORR for dogs with measurable malignant melanoma to carbo? vs. cisplat + piroxicam
Carbo: 28% Cisplat + piroxicam: 18%
31
What happens after intradermal or intramuscular injection of a DNA vaccine (ex: melanoma vs)
APCs (dendritic cells) present the Ag on MHC
32
Collectively, the melanoma vx literature has showed what?
1. It's safe 2. It leads to development of antityrosinase Ab and T cells 3. potentially therapeutic 4. needs to be further investigated in adjuvant, minimal disease phase II setting
33
Other than the oncept vaccine, what other vaccine has been shown to be potentially beneficial for canine OMM
CSPG4 vx MST and median DFI longer for vx group
34
What are the T classifications for digital melanoma based on WHO TNM staging
T1: \<2cm + superficial or exophytic T2 = 2-5cm with minimal invasion T3 = \>5cm or invading the SQ T4 = invading into fascia or bone
35
What are the stages of digital melanoma in dogs based on WHO TNM staging
1 = T1N0M0 2 = T2N0M0 3 = T2N1M0, T3 or T4 N0 or N1 M0 4 = Any T, any N, M1
36
What was the MST for dogs treated with digit amp + oncept based on digital melanoma stage?
stage 1 = \>952d 2 = \>1093d 3 = 321d 4 = 76d \*\* Oncept sig improved outcomes compared to historic controls\*\*
37
What was the MST for dogs treated with digit amp + oncept for digital melanoma w/ vs. w/o mets
W/mets = 105d w/o = 533d
38
What was the mOST for dogs with malignant melanomas of the haired skin treated with surgery? (Laver can Vet J 2018)
1363d
39
What were prognostic factors identified for dogs with malignant melanomas of haired skin treated with surgery? (Laver Can Vet J 2018)
MI \>20, age \>9.4
40
What was the postop rate of metastasis and local recurrence for dogs with malignant melanoma of haired skin treated with surgery? (Laver Can Vet J 2018)
Met rate 22%, local recurrence 8%
41
What was the sensitivity and specificity of identifying amelanotic OMM with cytology vs. cytology + ICC? What ICC markers were used? (Prezezdzieck Vet Clin Path 2015)
ICC for cytokeratin, vimentin and Melan A Cyto alone: sens 66.7%, spec 85.7% Cyto + ICC = both 100%
42
What was the staining pattern for RACK1 for melanomas vs melanocytomas? (Campagne Vet Path 2013)
All stained positive Melanomas all homogenous Melanocytomas all heterogenous
43
What is the sensitivity and specificity of PNL2 + Melan-A + TRP1 and TRP2 in identifying amelanotic OMM? (Smedley Vet Path 2011)
100% specific, 93.3% sensitive
44
What marker can help differentiate STS from amelanotic OMM given that 80% of STS were found to be positive for this and all OMM were negative (Smedley Vet Path 2011)
CD34
45
Decalcification of tissues can decrease staining for ____ but not ______ for melanoma IHC. (Ramos-Vara Vet Path 2011)
PNL2 and MelanA but does not affect tyrosinase
46
Tyrosinase expression was found in \_\_\_% of canine and equine melanocytic tumors and in \_\_\_\_\_% of non-melanomas. This (was/was not) correlated with tumor pigmentation. (Phillips AJVR 2012) \*\*Committee member\*\*
Tyrosinase expressed in all melanomas, no expression in non-melanomas tyrosinase expression not correlated with tumor pigmentation
47
Cytoplasmic staining of Gal3 was correlated with what in OMM? (Vargas J Comp Path 2019)
Better survival and BLC2 intensity
48
What staining pattern of Galectin-3 (Gal3) was correlated with a worse outcome in dogs with OMM? What else was associated with a worse outcome? (Vargas J Comp Path 2019)
Nuclear Gal-3 staining High nuclear atypia
49
T/F: the Clark level (anatomical level of invasion through the layers of the dermis) was found to be prognostic for cutaneous melanoma while tumor thickness was not. (Silvestri Vet Path 2018)
F - thickness was correlated with a shorter OST and DFS vs. Clark was NOT prognostic
50
Co-expression of _____ and a Ki67\> _____ were both associated with a worse prognosis in dogs with OMM (Iussich VCO 2016)
co expression of PDGFR alpha and beta Ki67 \>19.5
51
What was significantly associated with PFI and ST for dogs with OMM treated with surgery +/-adjuvant therapy (Tuohy JAVMA 2014)
Receiving adjuvant treatment (more likely to have disease progression if they got it), presence of metastatic disease at dx, higher tumor stage (III or IV), increased tumor size (\>3cm) and sexually intact females
52
What was the median PFI and MST for dogs with OMM treated with surgery alone? (Tuohy JAVMA 2015)
PFI \>567d, MST 874d --\> dogs that have completely resected melanomas can have long PFI and MST with surgery alone
53
What was prognostic for dogs with melanomas and c-kit expression? (Newman Vet Path 2012)
MST significantly longer for melanomas with any c-kit positivity vs. those without (100% of benign melanocytiic tumors expressed kit, only 9.8% of malignant did)
54
What was the relationship found between angiogenesis/tumor vascularization and canine melanoma? (Cuitino 2012 J Comp Path)
Tumor vascularization higher in melanomas (higher microvessel density and endothelial area) than melanocytomas but not prognostic for outcome
55
What MI cutoffs are prognostic for oral/lip melanoma and cutaneous/digit melanoma in dogs? (Smedley Vet Path 2011)
Oral/lip: ≥4 = poor prognosis Cutaneous/digit: ≥ 3 = poor prognosis
56
What ki67 cutoff has been found to be prognostic for oral/lip melanoma vs. cutaneous/digit melanoma in dogs? (Smedley Vet Path 2011)
Oral/lip ≥19.5 = poor prognosis Digit/cutaneous ≥15% = poor prognosis
57
What % nuclear atypia (counted per 200 cells) has been found to be prognostic for oral/lip melanoma vs. cutaneous/digit melanoma in dogs? (Smedley Vet Path 2011)
Oral/lip ≥30% poor prog Cutaneous/digit: ≥20% poor prog
58
What change in snRNA and snoRNA was found to be similar between human and cutaneous melanoma cell lines? (Rahman VCO 2019)
Upregulation of small nuclear RNA (snRNA) U1 and decreased small nucleolar RNA (snoRNA) RA24
59
Somatic focal amplifications on chromosome _____ in canine oral melanoma was associated with ______ and a ______ prognosis (Prouteau VCO 2019)
Chromosome 30 Amelanomic phenotype, high MI and poor prognosis
60
Which cyclin was found in 70% of canine OMM and was correlated with Ki67? (Zamboni VCO 2019)
Cyclin D1
61
What is pevondedistat and what does it cause? (Wood VCO 2019)
selective inhibitor of NEDD8-activating enzyme DNA re-replication, S phase arrest, DNA damage and apoptosis
62
What did pevondedistat do to canine melanoma cell lines? ( Wood vco 2019)
Dose and time dependent reduction in cell viability - promoted apoptosis and inhibition of cell growth (some lines resistant though)
63
CD20 Tumor-infiltrating lymphocytes were found to be associated with what in canine melanocytic tumors? (Porcellato VCO 2019)
Mitotic count, cellular pleomorphism, % pigmented cells high infiltration assciated with tumor related death, presence of mets/recurrence, shorter overall DFS
64
What affect did GD3-based immunotherapy have on myeloid-derived suppressor cells in dogs with melanoma? (Hutchinson Vet Immuno 2019)
MDCS decreased significantly
65
What cytokines were found to be significantly elevated in canine melanoma compared to controls? (Hutchinson Vet Immuno 2019)
IL10, MCP1 (monocyte chemoattractant protein-1)
66
What was the effect of high-dose ascorbate on canine melanoma cell lines? (Shin VCO 2018)
All four lines reduced viability in concentration-dependent manner induced apoptosis via activation of Bax
67
Melanomas with a higher number of FoxP3/hpf had a higher/lower risk of death? (Porcellato Vet Path 2018)
Higher
68
T/F: the number of IDO positive cells/hpf in canine melanoma was found to be an independent prognostic indicator. (Porcellato Vet Path 2018)
T
69
T/F altered expression of BAP1 (deubiquitylase) can be used as a prognositic marker in both people and dogs (Jama J Comp Path 2018)
F - not good in dogs People yes (loss of nuclear BAP-1 is prognostic) - this study showed 100% of dog melanomas were positive for nuclear BAP-1 meaning it does not have same prognostic value in dogs.
70
What % of feline non-ocular amelanotic melanomas stained positively for Melan A? What about S100? (Sabattini BMC 2018)
48% for Melan A; 95% for S100
71
What was associated with a poor outcome in cats with non-ocular melanocytic tumors? (Sabattini BMC 2018)
Tumor histotype (spindle, balloon and signet ring cell) and treatment
72
What was significantly higher in feline melanomas that were spindle histotype, in tumours lacking junctional activity and in poorly-pigmented tumours? (Sabattini BMC 2018)
mi and Ki67
73
Canine primary OMM cells expressed what two markers indicating a shift to mesenchymal phenotype/EMT? (Shmid VCO 2019)
MMP2 and vimentin
74
What is IQGAP1 and how does it related to melanoma? (Lee Plosone 2017)
Signaling scaffold that regulates oncogenic ERK1/2 MAPK signaling in human ras and raf driven cancers
IQGAP1 expressed in human and canine melanoma cell lines
Deletion of IQGAP1 = reduced MAPK activation; blocking peptides reduced proliferation in vitro
75
**Altered expression of what MMPs correlated with clinicopathologic features in canine oral cancers? What markers were associated with early stage oral tumors? (Pisamai Res Vet Sci 2017)**
**MMPs 7 &2 correlated with path**
**TIMP1 and MMP14 associated with early stage tumors**
76
**Early stage OMM had notable MMP\_\_\_\_ expression vs. late-stage OMM had MMP ____ expression (Pisamai Res Vet Sci 2017)**
**Early: MMP14**
**Late: MMP7**
77
What is bortezomib? (Ito Vet J 2013)
Boric acid analog that inhibits 26s proteasome - may inhibit NFkB signaling by preventing degredation of the IKappaB inhibitor
Approved for use in MM and mantle LSA in humans
78
What was the effect of Bortezomib in canine malignant melanoma cell lines? (Ito Vet J 2013)
Potent growth inhibition
IKappaB levels increased
79
Was MDR1-P-glycoprotein expression higher in canine cutaneous or oral melanoma? (Finotello VCO 2017)
Higher in OMM (100%) vs. cutaneous (66.6%
PgP may be one reason for chemo resistance in OMM
80
What was the objective tumor response rate for a canine-chimerized anti-PDL1 mAb (c4G12) used in OMM or undifferentiated sarcoma? (Maekawa Sci Rep 2017)
OMM: 14% (1/7)
Anaplastic sarcoma 50%
81
What canine tumor types were found to express PDL1 (cell lines used) (Maekawa PLOS one 2016)
OMM, OSA, HSA, Grade III MCT, mammary adenocarcinoma, prostatic carcinoma
82
How does PDL1 aid in development of cancers? What has blocking it been shown to do in vitro (primarily with OMM cell lines)? (Maekawa PLOS + Nemoto Vet immuno 2018)
PD1 = costimulatory receptor with immunosuppressive activity - inhibits function of cytotoxic tell cells --\> dysfunction of tumor specific lymphs --\> immune evasion
Blocking shows increased IFN-gamma levels (produced by T cells)
83
What was the effect of celecocib on canine melanoma cell lines? (Seo 2014)
anti-tumor effect on two cell lines via G1-S cell cycle arrest
84
T/F: Wnt/B catenin signaling is common in canine malignant melanoma? (Chon 2013)
F - rare in OMM and melanoma cell lines
another study (Han 2013) did show loss of membrane e-cadherin/b catenin complex in both skin and oral melanomas, so b-catenin may be involved still
85
What 4 genes had increased expression in canine uveal melanomas that metastasized? (also found in human uveal melanomas that met) (Malho JSAP 2013)
HTR2B, FXR1, LTA4H, CDH1
86
COX-2 expression was highest in canine melanomas with what characteristics? (Martinez Vet Path 2011)
Moderate to high in 88% of OMM and in 73% of tumors with MI ≥3
Low to absent in 75% of cutaneous melanomas and 81% of melanomas with MI \< 3
\*\*correlated with survival at 1 yr - high cox2 = 16.7% alive vs. no cox-2 100% alive\*\*
87
Which MMP was overexpressed in malignant melanoma compared to melanocytoma? (Docampo AJVR 2011)
MMP 9 (no sig differences in MMP-2 and MTI-MMP)
88
What is Fascin-1 and what was its relationship with canine melanoma? (Yamada VCO 2011)
actin bundling protein - increased expression correlates with aggressive behavior in human melanoma
High staining correlated with significant decrease in survival for canine melanomas (melanomas also had higher staining (98%) than melanocytomas (59%)
89
What is CSPG4 and how has it been used in the treatment of dogs with OMM? (Piras VCO 2017, Riccardo 2014)
Human chondroitin sulfate proteoglycan-4 used for electrovaccination in dogs
Possible survival benefit (longer DFI and OS in 2014 study and longer DFI and OS in dogs \<20kg in 2017 study); lower rate of pulm mets in 2017 study for vx dogs (40%) vs. unvx dogs (80%)
90
What was the clinical response rate to the oncept vaccine in UK dogs with macroscopic melanoma? (Verganti JSAP 2017)
8/13 (61.5%) but half had other treatment too (variety of chemo/RT)
91
What was the PFS and MST for dogs with OMM treated with a combination of surgery + Oncept? (Treggiari J Vet Med Sci 2016). What % of dogs in this study didn't finish the induction phase due to progressive disease?
PFS 160d, MST 335d
20% didn't finish
92
What was the MST of of dogs with stage II/III OMM with no gross disease treated with the oncept vaccine? How did this compare to historic controls? (Grosenbaugh AJVR 2011)
MST not reached for vx group vs. 324d for controls
MST may be longer compared to Treggiari 2016 paper due to different population or poor locoregional control in the 2016 paper)
93
What was the rate of AEs to the oncept vx in cats? (Sarbu JFMS 2015)
11.4% (all grade 1-2)
pain on admin, brief mm fasiciulation, transient inappetence, depression, nausea, mild increase in pigmentation at injection site
94
What was found in the Ottnod VCO 2013 paper about the oncept vaccine and canine OMM?
No difference in PFS or MST in vx vs. nonvx; nonvx had better DFI than vx
these dogs were treated with a mix of surgery or surgery + RT in addition to the melanoma vx
95
What is NHS-IL12 and what were the AEs in dogs treated with it for malignant melanoma? (Paoloni PLOS 2015) \*\*Committee member\*\*
NHS-IL12 = immunocytokine consisting of antibody targeting necrotic tumor regions linked to IL-12 (IL12 given by itself usually causes unacceptable tox)
AEs of NHS-IL12 = thrombocytopenia, liver enzyme elevation, fever and vasculitis --\> narrow therapeutic window found
96
What were the findings of the oncept phase I trial (Bergman clin cancer res 2003)
1 dog with lung mets had CR for 329d
2 stage IV had longer term survival (421 and 588+)
2 dogs with local control stage 2 and 3 had long term survival (501 and 496)
overall MST = 389d
97
What is liporaxel and what was its effect on canine melanoma in vitro and in a mouse xenograft model? (Yang VCO 2019)
oral paclitaxel
in vitro - antiproliferative effect + mediated cell cycle arrest
mouse model - decreased tumor size by ~30% compared to controls
98
What was the effect of metronomic cytoxan + piroxicam on canine OMM in a mouse xenograft model? (Choisunirachon 2015)
combination significantly lowered microvessel density and VEGF levels --\> ctx or piroxicam alone did not
99
What was the MST for dogs with OMM treated with surgery alone vs. surgery + adjuvant therapy (chemo, vaccine) (Boston JAVMA 2014)
Surgery alone 335d, adjuvant 352d - not stat different
100
What was the result of carboplatin chemotherapy for dogs with malignant melanoma with or without surgery? (Brockley New Zealand Vet J 2013)
No benefit in locoregional control in sx + chemo group
gross disease 3/11 responded (27%), those that did respond had a survival benefit (987d vs. 147d)
Take home: carbo not very effective for OMM
101
What was the ORR to carboplatin for dogs with malignant melanoma (Rassnick JAVMA 2001)
28%
102
Was there a benefit to adding temozolomide to RT (6Gy x5) for treatment of dogs with measurable melanoma? (Cancedda VCO 2016)
Yes - not different response rate but median time to progression longer for temozolomide group (205d vs. 110d) and MST numerically (but not stat sig) for temozolomide group (401d vs. 192)
103
What was the local response to RT in dogs with OMM and the median time to first event (progression) and MST? (Proulx VRU 2003)
Response: CR 51%, PR 31%, 16% SD, 1% PD
Metian time to first event: 5mo
MST 7mo - best for dogs without risk factors
104
T/F - The addition ofcarboplatin has been shown to benefit dogs with OMM treated with RT compared to dogs treated with RT alone.
False - none of the RT studies have found a benefit in adding carbo
105
What is the most common site for ocular melanoma in the dog?
Limbal (20-50% of ocular melanomas)
106
How do uveal melanomas behave in dogs vs. cats?
typically low metastatic rate in dogs, only treat w/ enuc if causing problems (ex. glaucoma or uveitis)
Cats: anterior uveal melanoma = most common ocular tumor in cats, higher met rate (60%)
107
What was the response to synthetic microRNA-205 given to dogs via intratumoral injection for malignant melanoma? (Yoshikawa VOC 2019)
5 CR, 3 SD and 2 PD
108
Gene expression analysis of ocular melanomas in cats showed significant upregulation of _____ and down regulation of \_\_\_\_
up: KIT and LTA4H
down: BRAF (and others that I am never going to remember)
109
What % of LN diagnosis changed when comparing cyto and histo for regional LN staging in dogs with melanoma? (Grimes vet path 2017)
47% (15 cases, 14 of which were considered metastatic and changed to negative)
take home: agreement b/w cyto and histo for LN is poor
