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Withrow > Chapter 19 - Melanoma > Flashcards

Chapter 19 - Melanoma Flashcards

1
Q

Most common location for melanoma

A

Haired skin

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2
Q

Melanoma locations in oral cavity in descending order

A

Gingiva, lips, tongue, hard palate

GILTOP

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3
Q

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

A

> 75%

Dobies, Min Schnauzers

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4
Q

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

A

17% melanocytomas

6% of malignant melanomas

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5
Q

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

A

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

PI3K/AKT- MAPK kinase

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6
Q

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

A

MCAM/CD146

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7
Q

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

A

mi-RNA 203

Shorter ST

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8
Q

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

A

Oral - 100%

Cutaneous 67%

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9
Q

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)?

A
  • 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
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10
Q

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

A
  • 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
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11
Q

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

A
  • 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
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12
Q

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

A
  • Mitotic index ≥ 3
  • Ki67 index ≥ 15
  • ≥ 20% nuclear atypia
  • Distant mets
  • Degree of pigmentation
  • Junctional activity
  • Level of infiltration/extension beyond dermis
  • Ulceration
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13
Q

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

A

Ki67

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14
Q

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

A

Lip - MST 580d (19 to 34m)

Tongue - MST > 551d

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15
Q

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

A

LN metastasis

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16
Q

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?

A

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

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17
Q

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

A

92%

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18
Q

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

A

80% LN, lungs

Site, size, WHO stage

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19
Q

MST of dogs with OMM without tx?

A

65 days

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20
Q

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)?

A

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)

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21
Q

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?

A

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

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22
Q

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

A

Digital

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23
Q

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

A 
MST 107d (3.5m)
PFS 92.5d (3m)
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24
Q

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

A

12-14m

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25
Q

What is stage III melanoma?

A

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

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26
Q

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

A

Enlarged LN - 70% have mets

Normal LN - 40% have mets

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27
Q

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?

A

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

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28
Q

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?

A

RACK1 (receptor for activated C kinase 1)

Malignant melanomas stain homogeneously and benign ones heterogeneously

Correlates with cell and nuclear size

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29
Q

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?

A

Melan A

Routine cytology: 67% sensitive, 86% specific

30
Q

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?

A

47%

14 from metastatic to reactive
1 from reactive to metastatic

31
Q

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

A

30- 50%

POOR

32
Q

Margins for cutaneous melanoma excision?

A

1cm skin margins, 1 fascial plane deep

33
Q

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?

A

Incomplete margins - 3.6x more likely to die

Caudal to PM3 - 4.3x more likely to die

34
Q

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

A

Overall 28%
Mandibulectomy 20%
Maxillectomy 48%

35
Q

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?

A

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
36
Q

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

A

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

37
Q

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

A

PFS 5-8m

MST 5-12m

1-yr SR 35-50%

2-yr SR 20%

38
Q

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

A

Microscopic 25%

Gross 45%

39
Q

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?

40
Q

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?

A

MST with chemo 290d
MST w/o chemo 310d

NOT statistically significant

41
Q

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

A
  • 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)
42
Q

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

A

5.4% oronasal fistula

7-8% bone necrosis

43
Q

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

A

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

44
Q

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

45
Q

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?

A

VEGF; shorter TTP and MST

46
Q

Most common RT induced neoplasia?

47
Q

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

48
Q

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)?

A

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

49
Q

What % of canine melanocytic tumors express COX-2?

50
Q

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

A

Cisplatin and piroxicam; 18% CR

51
Q

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?

A 
Exon 11, C -> T mutation
10% of dogs with MM
Strongly positive in 56%
Weakly positive in 44%
Significantly associated with dz recurrence
52
Q

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

A

-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

53
Q

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?

A 
PFS 160d (5.3m)
DFI 222d  (7.3m)
MST 335-455d  (11-15m)

One study -> increased MST compared to historical controls

54
Q

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

A

> 170d (5.7m)

55
Q

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?

A

Adequate locoregional control > 1075d (36m)

Inadequate locoregional control 550d (18m)

56
Q

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

A

Murine tyrosinase + GM-CSF; MST > 900d

57
Q

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

A

PD-L1

Also in OSA, HSA, MCT, CMT, prostatic ACA

58
Q

What is the most common location for feline MM?

A

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

59
Q

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

60
Q

Cats with malignant melanoma in what location are significantly younger?

A

Auricular; <8yrs

61
Q

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

A 
Oral 120d (4m)
Cutaneous 180d (6m)
Auricular - MST not reached
62
Q

What is the most common location for feline cutaneous MM?

63
Q

What is the most common location for feline oral MM?

64
Q

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

A

Oral; especially anorexia

65
Q

What is the most common location for feline amelanotic melanomas?

66
Q

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

A

Amelanotic melanoma - negative prognosis

Surgical therapy - longer MST

67
Q

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

68
Q

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

A

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

Incidence of AE higher in dogs

69
Q

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

A
  • Rostral tumors
  • Smaller size
  • Lack of bone lysis
  • Use of post op RT for microscopic dz
70
Q

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

A
  • 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
71
Q

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

A

60% ORR

MST 146 days(4.8m)

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