Chapter 19 - Melanoma Flashcards by Irene Vazquez

Most common location for melanoma

Haired skin

How well did you know this?

Not at all

Perfectly

Melanoma locations in oral cavity in descending order

Gingiva, lips, tongue, hard palate

GILTOP

How well did you know this?

Not at all

Perfectly

2 breeds in which > than ___% of melanocytic tumors experience benign behavior

> 75%

Dobies, Min Schnauzers

How well did you know this?

Not at all

Perfectly

In dogs, BRAF mutations present in ___% of melanocytomas and ___% of malignant melanomas

17% melanocytomas

6% of malignant melanomas

How well did you know this?

Not at all

Perfectly

Reduced expression of PTEN, p16, and p53 in what % of canine melanomas is suggestive of which signaling pathway potentially being activated?

PTEN - 50%
p16 - 80%
p53 - 78%

PI3K/AKT- MAPK kinase

How well did you know this?

Not at all

Perfectly

Which cell adhesion molecule is strongly expressed in OMM vs other locations?

MCAM/CD146

How well did you know this?

Not at all

Perfectly

Which tumor suppressor mi-RNA is downregulated in CMM cell lines? How did this affect survival time?

mi-RNA 203

Shorter ST

How well did you know this?

Not at all

Perfectly

Pgp expression is common in CMM. Membranous staining is present in ___% of oral vs ___% of cutaneous tumors.

Oral - 100%

Cutaneous 67%

How well did you know this?

Not at all

Perfectly

Cutaneous melanomas are often benign if they are not in a mucocutaneous location. What are the negative prognostic indicators for this location in dogs (8)?

Ki67 index ≥ 15%
MI ≥ 3/10 hpf
≥ 20% nuclear atypia
Extension beyond dermis/level of infiltration (Breslow thickness: >0.75cm = risk of recurrence/mets, >0.95cm = unfavorable outcome)
Ulceration
Distant mets
Lymphatic invasion
Degree of pigmentation

How well did you know this?

Not at all

Perfectly

What are the negative prognostic indicators identified in dogs with OMM (14)?

Ki67 index ≥ 19.5% (shorter DFI and MST)
MI ≥ 4/10 hpf
≥ 30% nuclear atypia
Co-expression of PDGFR a/b (37%, shorter DFI and MST)
Higher % of intratumoral Tregs
Stage of dz
Size of tumor
Lymphatic invasion
Distant mets
Degree of pigmentation
Female sex
Adjuvant therapy
Intralesional excision
> 12yrs of age

How well did you know this?

Not at all

Perfectly

What are the negative prognostic indicators identified in dogs with lip melanoma (7)?

Mitotic index ≥ 4/10 hpf
Ki67 index ≥ 19.5%
≥ 30% nuclear atypia
Distant mets
Degree of pigmentation
Junctional activity
Level of infiltration/deep with bone involvement

How well did you know this?

Not at all

Perfectly

What are the negative prognostic indicators identified in dogs with digital melanoma (8)?

Mitotic index ≥ 3
Ki67 index ≥ 15
≥ 20% nuclear atypia
Distant mets
Degree of pigmentation
Junctional activity
Level of infiltration/extension beyond dermis
Ulceration

How well did you know this?

Not at all

Perfectly

Overall, what prognostic indicator may have a stronger correlation with survival time compared to MI or other histologic criteria?

Ki67

How well did you know this?

Not at all

Perfectly

In dogs with MM, what locations may have a better prognosis compared to other locations? What is the MST for these location?

Lip - MST 580d (19 to 34m)

Tongue - MST > 551d

How well did you know this?

Not at all

Perfectly

Several studies have suggested that ___ does not affect remission duration, time to relapse, or MST in dogs with melanoma.

LN metastasis

How well did you know this?

Not at all

Perfectly

What 2 transcription factors haven been associated with increased risk of death in dogs with melanomas? Which one was of prognostic significance on multivariate analysis?

FOXP3, IDO (indoleamine 2,3-dioxygenase)

Increased risk of death associated with higher:

# FOXP3/HPF
% of FOXP3+ infiltrating lymphocytes
# IDO+ cells/HPF

Only #IDO+ cells/HPF prognostic on multivariate

How well did you know this?

Not at all

Perfectly

Up to ___% of dogs with OMM have bone involvement.

92%

How well did you know this?

Not at all

Perfectly

What is the metastatic rate in dogs with OMM? This is dependent on what 3 things?

80% LN, lungs

Site, size, WHO stage

How well did you know this?

Not at all

Perfectly

MST of dogs with OMM without tx?

65 days

How well did you know this?

Not at all

Perfectly

When treated with sx alone:

Overall MST range and 1-yr ST?

MST for stage I, II, and III dz?

Prognostic indicators for sx and ST (3)?

Overall MST 150-320d (5-10m)

Overall 1-yr ST <35%

Stage I - 17 to 18m MST
Stage II - 5 to 6m MST
Stage III - 3m MST

Size, stage, ability of 1st sx to achieve local control

T1 MST 511d (1.5yr)
T2+ or LN mets MST 160d (5m)

How well did you know this?

Not at all

Perfectly

What is the MST in dogs with digital melanoma w/o metastasis when treated with amputation alone?
What are the 1 and 2 yr survival rates?

~12 months
1-yr SR 40-60% (42-57%)
2-yr SR 11-13%

How well did you know this?

Not at all

Perfectly

Melanomas in the footpad have a similar prognosis/behavior to melanomas in which location?

Digital

How well did you know this?

Not at all

Perfectly

What is the overall MST and PFS in dogs with anal sac melanoma treated with a combination of therapies?

MST 107d (3.5m)
PFS 92.5d (3m)

How well did you know this?

Not at all

Perfectly

MST most recently of dogs with stage I dz treated with a combination of sx, RT, and/or chemo?

12-14m

How well did you know this?

Not at all

Perfectly

What is stage III melanoma?

Any T, N1, M0 or T3, N0, M0

What % of dogs with OMM have LN mets when lymphadenopathy is present? When lymph nodes palpate normally?

Enlarged LN - 70% have mets | Normal LN - 40% have mets

What combination of IHC markers are useful helpful when trying to differentiate amelanotic from a STS (4)? What is the sensitivity and specificity of this combination? What other markers can be used and what other histologic characteristic can be used to dx melanoma?

Melan A, S100, PNL2, tyrosinase (TRP1/2) 93% sensitive and 100% specific Others: vimentin, NSE, MITF Presence of junctional activity = proliferation of neoplastic cells at the dermoepithelial junction

What IHC marker can be used to differentiate a malignant melanoma from a melanocytoma and how does the expression of this marker differs between them?

RACK1 (receptor for activated C kinase 1) Malignant melanomas stain homogeneously and benign ones heterogeneously Correlates with cell and nuclear size

What ICC stain has been shown to be 100% sensitive and specific for the diagnosis of amelanotic melanoma? How does this differ when compared to routine cytology stains?

Melan A Routine cytology: 67% sensitive, 86% specific

When evaluating histopathology LN samples in dogs with melanoma, the addition of Melan A has been reported to change the final diagnosis in what % of samples?

47% 14 from metastatic to reactive 1 from reactive to metastatic

What is the reported range of complete agreement between cytology and histopathology for the diagnosis of metastatic LN in dogs with melanoma?

30- 50% POOR

Margins for cutaneous melanoma excision?

1cm skin margins, 1 fascial plane deep

What is the risk of death in dogs with OMM that have incompletely excised tumors (dirty margins) and in those with tumors caudal to PM3?

Incomplete margins - 3.6x more likely to die | Caudal to PM3 - 4.3x more likely to die

What is the local RR post mandibulectomy and maxillectomy? Overall RR?

Overall 28% Mandibulectomy 20% Maxillectomy 48%

In a study of 151 dogs with OMM that were treated with sx and -/+ systemic therapy, what prognostic indicators for MST were identified on multivariate analysis?

Age of 12 yrs <12 yrs 433d >12 yrs 224d Tumor size T1: <2cm 630d (1.7yr) T2: 2-4cm 240d (8m) T3: >4cm 173d (6m) Type of excision - Intralesional 117d - Marginal 346d - Radical 354d

What are the reported ranges for overall RR, CR, and PR in dogs with OMM when treated with RT?

ORR 82-100% CR 50-70% PR 25-30%

What is the reported overall PFS and MST in dogs with OMM when treated with RT? 1 and 2 yr SR?

PFS 5-8m MST 5-12m 1-yr SR 35-50% 2-yr SR 20%

What is the reported recurrence rate in dogs with OMM when treated with RT in the microscopic vs gross dz setting?

Microscopic 25% | Gross 45%

In a study of dogs with OMM tx with RT and cisplatin or carbo 1 hour prior to RT, what was the median time to tumor metastasis?

10.2m

In a study of dogs with OMM tx with RT +/- chemotherapy, what was the difference in MST in dogs tx with chemo vs no chemo?

MST with chemo 290d MST w/o chemo 310d NOT statistically significant

What has been shown to affect prognosis in dogs with OMM treated with different forms of RT (4)? These dogs were also +/- treated with sx and chemo

- Stage; stage III dz tx with orthovoltage and stage I dz vs higher stage (shorter MST) - Bone involvement (shorter TTP and MST) - Tumor volume/size (>5cm3 shorter MST) - High VEGF (shorter TTP and MST)

What % of dogs with OMM is reported to develop oronasal fistulas and bone necrosis when tx with RT?

5.4% oronasal fistula | 7-8% bone necrosis

When combining chemotherapy with RT for the treatment of OMM, what drug has been shown to be effective and how did it affect prognosis?

Temozolamide: 60mg/m2 x 5 days then q1 month RT: 6 Gy x 5 Dogs tx with TMZ had a longer TTP vs RT alone; 205d vs 110d No difference in ORR or MST

Dogs with OMM of what tumor volume are more likely to achieve a CR and longer MST when treated with RT?

<5cm3

Dogs with OMM have elevated ____ plasma values when compared to normal dogs. What are 2 ways this can affect prognosis in dogs when treated with RT?

VEGF; shorter TTP and MST

Most common RT induced neoplasia?

Sarcomas

ORR of carboplatin in the gross dz setting for canine melanoma? Most common response seen?

28%, PR

What is the PFS, MST, recurrence rate, and metastatic rate in dogs with malignant melanoma that have adequate loco-regional control when treated with carboplatin (microscopic dz setting)?

PFS 260d (8.7m) MST 440d (1.2yr) RR 41% MR 41%

What % of canine melanocytic tumors express COX-2?

68%

What systemic therapy combination has been reported to induce a CR in 2 dogs with melanoma?

Cisplatin and piroxicam; 18% CR

A mutation in the KIT gene has been detected in exon ___ in ___% of dogs with MM. All samples were KIT+ on IHC, but what was the difference in staining? How does the mutation affect prognosis?

``` Exon 11, C -> T mutation 10% of dogs with MM Strongly positive in 56% Weakly positive in 44% Significantly associated with dz recurrence ```

What drugs have been shown to be efficacious against CMM cell lines or mic in vitro?

-CTX + piroxicam; both drugs alone or in combo suppressed growth and significantly decreased MVD and VEGF levels -Rapamycin + AZD6244 (MEK1/2 inhibitor) - cytotoxicity -Bosutinib - TKI of Src and Abl kinases; induced cell death and promoted autophagy -Bortezomib - proteasome inhibitor; inhibited cell growth through NF-Kb inhibition KPT-335 - selective inhibitor of nuclear exportin 1; inhibits proliferation, induces apoptosis, upregulates mRNA for p53 and p21 -BIO - serine/threonine kinase inhibitor specific for GSK-3B; enhanced B-catenin -High-dose ascorbate - activation of Bax and apoptosis

What is the overall PFS, DFI and MST in dogs with malignant melanoma that have adequate loco-regional control (either via sx or RT) when treated with the Oncept melanoma vaccine? How can the vaccine affect prognosis?

``` PFS 160d (5.3m) DFI 222d (7.3m) MST 335-455d (11-15m) ``` One study -> increased MST compared to historical controls

3 dogs with stage IV melanoma have been reported to survive for longer than ___ days when treated with the Oncept melanoma vaccine

> 170d (5.7m)

What is the overall MST in dogs with stage I-III OMM and either adequate or inadequate locoregional control when treated with all available xenogenic vaccines?

Adequate locoregional control > 1075d (36m) | Inadequate locoregional control 550d (18m)

What xenogenic vaccine has been reported to provide the longest MST in dogs with stage II-IV OMM?

Murine tyrosinase + GM-CSF; MST > 900d

Expression of ___ by tumor infiltrating lymphocytes has been documented in dogs with OMM. In what other tumors has this been documented (5)?

PD-L1 Also in OSA, HSA, MCT, CMT, prostatic ACA

What is the most common location for feline MM?

Eye; ocular melanoma is the most common intraocular tumor in cats

What is the overall metastatic rate in cats with malignant melanoma (excluding ocular)?

30.7%

Cats with malignant melanoma in what location are significantly younger?

Auricular; <8yrs

What is the MST in cats with oral, cutaneous, and auricular malignant melanoma when treated with various therapies?

``` Oral 120d (4m) Cutaneous 180d (6m) Auricular - MST not reached ```

What is the most common location for feline cutaneous MM?

Head

What is the most common location for feline oral MM?

Lip

What tumor location is more commonly associated with clinical signs in cats with MM?

Oral; especially anorexia

What is the most common location for feline amelanotic melanomas?

Oral

What are 2 identified prognostic indicators in cats with MM and how do they affect prognosis?

Amelanotic melanoma - negative prognosis | Surgical therapy - longer MST

What is the reported MST in cats with OMM when treated with RT and +/- chemo?

150d (5m)

What % of cats treated with the Oncept vaccine develop adverse events? Is the incidence higher or lower in dogs?

12% - pain on administration, brief muscle fasciculation, transient inappetence, depression, nausea, mild increase in pigmentation at injection site Incidence of AE higher in dogs

What are positive some prognostic factors associated with ST in dogs with OMM (5)?

- Rostral tumors - Smaller size - Lack of bone lysis - Use of post op RT for microscopic dz

Negative prognostic factors for ST in dogs with melanoma (8)?

- Non rostral location - Location (tongue/lip vs maxilla and hard palate) - T2-T3 size - Bone lysis - Macroscopic dz presen - Nuclear atypia - MI index - # of prognostic factors/px

What is the reported ORR and MST of hypofractionated RT in cats with OMM?

60% ORR | MST 146 days (4.8m)