Melanoma Flashcards
What percent of skin cancer deaths occur from melanoma?
75%
What type of melanoma is most common in patients with darker skin types?
Acral lentiginous subtype
What are 3 main risk factors for melanoma?
Genetic phenotypic, gene/environmental interactions, and UVR exposure (most important for Caucasians and Hispanics)
What is the genetic mutation responsible for familial melanoma (FAMMM syndrome)?
CDKN2A
What other cancer can the CDKN2A mutations cause?
Pancreatic
What type of radiation is more important for melanoma? and why?
UVB > UVA, this penetrates to the DEJ, which is where the melanocytes are located
What is the most important clinical/cutaneous risk factor for melanoma?
Total # of melanocytic nevi>more than 5 atypical nevi > lentigines sun exposure
What are the most common types of melanoma that arise from people with many nevi?
Superficial spreading then nodular
What types of UVR exposure are important in melanoma?
Intermittant and chronic
What two mutations are mutated in 80% of melanocytic nevi and melanomas? And what pathway are they part of?
NRAS and BRAF –> part of the MAPK pathway
What is the most common mutation in BRAF?
V600E (valine to glutamine switch at 600)
What body sites are the BRAF mutated melanomas most common in?
Areas that are non-chronic sun-damaged (superficial spreading most common type of melanoma)
What are 3 genes that are more commonly involved in melanomas arising from chronically sun-damaged sites?
NRAS and C-kit CCND1/CDK4
What clinically sites in melanoma more often have mutations in CCND1/CDK4?
Acral and mucosal
What sites for melanoma more commonly have c-KIT mutations?
Mucosal, acral, and chronic sun-damaged
What is upregulated on melanomas to inhibit t-cell activation?
CTLA4
What is the “little red riding hood” sign for melanoma?
Erythema or inflammation surrounding a melanoma
What is the Garbe’s rule in melanoma?
Essentially asserts that if a patient is worried about a lesion then this should lower the threshold to bx
Most is the most common type of melanoma?
Superficial spreading
How often do superficial melanomas arise within a nevus?
50%
2nd most common melanoma in Caucasians?
Nodular
What is the difference between nodular and superficial spreading types of melanoma?
In superficial spreading, there is a longer, slower, horizontal growth phase that transitions to a rapid vertical growth phase
In nodular melanoma there is de-novo vertical growth, no horizontal growth phase
What is the most common mutation in nodular melanomas?
NRAS
What is the growth phase like for lentigo maligna melanoma?
Long horizontal growth phase precedes invasion
What % of lentigo maligna goes to LMM?
~5%
Clinical morphology of LM?
Macule, it is flat because the pathology is only in the epidermis and not dermal
What is the most common mutation in acral lentiginous melanoma?
c-KIT
What is the Hutchinson sign for nail matrix melanoma?
Extension of brown or black pigment beyond the nail bed into the nail folds.
Also melanonychia with a width greater than 3mm is a risk of nail-fold melanoma
What pathophysiologic factors occur in the vertical growth phase of melanoma?
Angiogensis, expression of VEGF, decreased responsiveness to inhibitory cytokines, ability to metastasize.
How is Breslow depth measured?
Measured in mm from top of the granular cell layer or base of superficial ulceration to the deepest point of tumor invasion
What are the different Clark levels?
1=epidermis
2=papillary dermis
3=papillary/reticular dermis interface (fills papillary dermis)
4=invasion into the reticular dermis
5=invasion into the SQ
Is prognosis worsened with ulceration?
Yes, ulceration receives a change in T-stage from “a” to “b”
- An ulceration width >3mm is associated with mitoses and risk of metastasis
What is the prognostic index in the setting of melanoma?
Mitoses (mitotic rate) x tumor thickness
What are satellite deposits and why are they important in the setting of melanoma?
Microsatellites separated from the main body of the tumor but in close proximity (<1cm) [Should have some normal stromal between these nests or cells and the main tumor]
- Better indicator of occult region LN mets in clinical stage I melanoma than the tumor thickness
- Recent study showed that microsatellites predict locoregional relapse but not overall survival
What is neurotropism in the setting of melanoma and what is the importance?
The tendency to adopt a circumferential arrangement around small nerves in the deep dermis and subcutaneous tissue
- Significant risk of local recurrence
- Neurotropic melanomas Neurotropism + neural transformation (spindle-shaped cells with neuroma-like patterns may invade cranial nerves and their major branches
What is the importance of lymphocyte infiltration in melanoma?
Increased ratio of width of the lymphocytic infiltrate to the width of the tumor = increased survival
Definition of micrometastases?
Diagnosed after sentinel or elective lymphadenectomy by microscopy without clinical evidence of detection.
Macrometastese are those that are palpable, visible on imaging, or those that show extracapsular invasion
What is nest discohesion in melanoma on histopathology?
Nests that fragment into individual cells
Which stain is the most specific to melanoma?
SOX10, intranuclear stain that is most specific to melanoma
Why is tyrosinase/hMB45 less specific for melanoma?
The transfer of melanosome to keratinocytes makes it so you can get staining in the keratinocytes creating false positives
What is the definition of local recurrence in melanoma?
A lesion that arises within 2cm of scar from primary excision
When should a sentinal lymph node biopsy be performed?
0.8 to <1cm can consider, if greater than 1cm it should be done
What medications can be used to treat melanomas with c-kit mutations?
Imatinib, nilotinib, dasatinib, sunitinib
What are the 2 BRAF inhibitors commonly used/available?
Vemurafenib and dabrafenib (notice the raf in name)
What lesions are associated with BRAF inhibitor treatment?
Most common lesions are: verrucous keratosis, SCC, and keratoacanthoma
What is a MEK inhibitor used in melanoma?
Trametinib
What is one reason why MEK inhibitors should be used in combo w/ BRAF inhibitors?
Decreases risk of SCC from BRAF inhibitors
Aside from melanoma, what other cutaneous neoplasms/conditions can imatinib or dasatinib be used for?
DFSP, myeloproliferative hypereosinophilic syndrome
What are some commonly used PD-1 inhibitors for melanoma?
Pembrolizumab, nivolumab
What are some PD-L1 inhibitors that are used in melanoma?
Atezolizumab, durvalumab, avelumab
What does CDKN2A encode for?
p14 and p16 - regulates Rb and p53 activity
What are the wavelengths and the penetration depths (in anatomical terms) for UVA, UVB, and UVC?
UVC= Superficial spinous layer (250nm)
UVB= Papillary dermis (300nm)
UVA= Deep dermis (350nm)
Most common body site for NRAS mutated melanomas? What types of Melanomas are these usually?
Chronically sun-damaged sites, nodular melanomas
Most common body site for c-KIT mutated melanomas? What types of Melanomas are these usually?
Chronically sun-damaged sites, mucosal and acral melanomas
Most common body site for CCND1/CDK4 mutated melanomas? What types of Melanomas are these usually?
Chronically sun-damaged sites, mucosal and acral melanomas
Most common body site for GNAQ/GNA11 mutated melanomas? What types of Melanomas are these usually?
Uveal melanoma, blue nevi, and nevus of Ota
Most common body site for BAP-1 mutated melanomas? What types of Melanomas are these usually?
Uveal melanoma, malignant cellular blue nevi (worse prognosis)
Internal malignancies like mesothelioma, renal cell carcinoma, and others
What mutations are a/w non-sun damaged areas and superficial spreading melanomas?
BRAF
What mutations are a/w chronic sun-damaged skin and nodular melanomas?
NRAS
What mutations are a/w chronic sun-damaged skin and acral/mucosal melanomas?
c-KIT, CCND1/CDK4
What mutations are a/w uveal melanoma?
BAP-1, GNAQ/GNA11 (BAP-1 worse prognosis)
How does melanoma evade immune detection?
Normally B7 on APC cells binds CD28 on T-cells and activates host response. Melanoma cells increase the expression of CTLA-4 which inhibits CD28 and downregulates host response.
- Loss of tumor-specific antigens
- Loss of MHC-1 molecules
- Secretion of immune inhibitory cytokines (Il-10 and TGF-beta)
- Inducible IL-10 producing T-regs
What is the most common mutation in superficial spreading melanoma?
BRAF
What is the most common location for superficial spreading melanoma?
Trunk (men), Legs (women)
Most common locations for nodular melanoma?
Head/neck, and back
Most common locations for Lentigo Maligna Melanoma?
Nead and neck (sun-exposed sites)
What is the epidemiology of acral lentiginous melanoma?
The raw rates are equally common among white and skin of color patients, however, among those with darker skin types this is the most common type of melanoma (they have overall lower rates of melanoma). It is most common in the 7th decade
Definition of the radial phase of melanoma?
Is the progressive centrifugal spread of melanoma, can’t metastasize, invasion of the papillary dermis only by single nested cells can be seen, unless there are mitoses then this is considered vertical phase
What are the essential histologic features reported for melanomas?
Breslow depth, Clark level, Ulceration, Satellite deposits, Lymphocyte infiltration, Lymphovascular invasion, Perineural involvement (neurotropism), Histological Subtype
What is the definition of T1 melanoma?
Size <1.00mm –> T1a= <0.8 mm w/ no ulceration T1b=>0.8mm-1mm or either size w/ ulceration
What is the definition of T2 melanoma?
1-2mm; T2a= 1-2mm w/o ulceration T2b= 1-2mm w/ ulceration
What is the definition of T3 melanoma?
2-4mm; T3a=unknown or no ulceration T3B=w/ ulceration
What is the definition of T4 melanom?
>4mm T3a=unknown or no ulceration T3B=w/ ulceration
N0 definition?
No nodal metastases
N1 definition?
1 Node + -N1a if only micrometastasis -N2b if macrometastasis
N2 definition?
2-3 nodes
- N2a if only micrometastasis
- N2b if macrometastasis
- N2c if in transit mets/satellite w/o metastatic nodes
N3 definition
4 or more metastatic nodes, matted nodes, or in-transit mets/satellites with metastatic nodes
Definition of in-transit metastases?
>2cm from the primary tumor, but not beyond the regional lymph node
Definition of satellite lesions?
Satellite lesions: within 2cm of the primary
Definition of M1 melanomas?
a=distant skin, subcutaneous, or nodal metastases w/ normal LDH b=lung metastases, LDH normal
c=all other visceral metastases or if serum LDH is elevated
d=neurologic/brain metastases (new for 8th edition)
What are the appropriate margins for melanoma excision by size?
Mis: 0.5-1cm
Breslow <1mm = 1 cm WLE
Breslow 1-2mm = 1-2 cm WLE to fascia
Breslow <2mm = 2 cm WLE to fascia
What is the definition of local recurrence?
Defined as any recurrence within 2 cm of the scar from the primary melanoma excision
- Results from the extension of the primary tumor or intralymphatic spread
- Risk is ~4%, and is increased in thicker or ulcerated tumors and those located on the head, neck or distal lower extremity
What medications can be used for c-KIT mutations?
Imatinib, nilotinib, dasatinib, sunitinib
What medications can be used for BRAF mutated melanomas?
Sorafenib, vemurafenib, and dabrafenib (notice the “raf” in the name)
Should be used with MEK inhibitors ideally to reduce resistance. (trematinib, cobimetinib, binimetinib)
Most common side effects of braf inhibitors
Vemeruafinib/dabrafinib
cutaneous: exanthematous rash - papulopustular on face, torso and arms.
- keratotic lesoins (SCC and keratoacanthoma!)
- verrucous keratosis (MOST COMMON) benign
- photosensitivity, alopecia, plantar hyperkeratosis
non cutaneous: arthralgias, nausea, dirarrhea, fatigue, QT PROLONGATION and RETINAL VEIN THROMBOSIS
Most common and most serious SE’s for MEK inhibitors?
GI S/E most common, rash also very common (~57%), hypoalbuminemia, dysgeusia, xerostomia. CARDIOMYOPATHY, interstitial lung dz, RETINAL VEIN OCCLUSION.
What are the main dermatologic applications of the tyrosine kinase inhibitors Imatinib/dasatinib?
Melanoma (c-kit), myeloproliferative hypereosinophilic syndrome, and DFSP.
What are the most common cutaneous SE’s with tyrosine kinase inhibitors imatinib and dasatinib?
Cutaneous: rash (maculopapular, nonspecific), hypopigmented/depigmentation (due to inhibition of c-KIT which is involved in melanocyte activation), lichenoid eruptions (oral and mucosal), photosensitivity
Most common SE’s of ipilimumab and tremelimumab?
Cutaneous: rash –> maculopapular or eczematous on trunk/extremities. pruritus, alopecia and hypopigmentation
Noncutaneous: GI (most severe) and common–> diarrhea, constipation, and bloating. Can be severe (life-threatening colitis w/ bowel perforation)
Uncommon: hypothyroidism, transaminitis, hepatitis, and hypopituitarism.
Explain how PD-1 inhibitors work?
PD-1 is normally expressed on activated T cells. This binds to PD1-L1/L2 (expressed on tumor cells) –>deactivation of T-cells –>loss of immune responses.
Monoclonal antibodies target PD-1–> prevents T cells deactivation which increases the immune-mediated tumoricidal activity
SE associated with PD-1 inhibitors?
Cutaneous: non-sepcific rash
Noncutaneous: fatigue, pruritis, pnemonitis, colitis, hepatitis, nephritis, reanl dysfunction, and thyroid dysfunction.
What are the PD-L1 inhibitors and some primary uses for these?
Atezolizumab (urothelial carcinoma/nsclc), durvalumab (urotherlial carcinoma and unresectable nsclc) , avelumab (metastitic merkel-cell carcinoma)
What is a “BAPoma”?
Epithelial Spitzoid nevus, associated with BAP-1 loss
What is the immunohistologic staining of desmoplastic melanomas?
Melan-A/HMB-45 negative, S100 +, SOX-10 +
What size of margins should be taken in an excisional biopsy of a pigmented lesion?
Somewhat controversial, if you feel strongly that it is Mis, can consider a full margin, but usually recommended 2mm margins and then re-excise if positive
What are the general histologic features that would suggest melanoma?
Asymmetry, poor circumscription, irregularly sized and shaped junctional nests with discohesion, lentiginous/confluent growth along DEJ more than nests, pagetoid scatter “epidermal consumption”, which is where melanoma effaces epidermis which leads to epidermal thinning and ulceration, an extension to the adnexal epithelium, lack of maturation of dermal component, dermal mitoses, cytologic atypia (irregular large nuclei, w/ prominent red nucleoli)
What is the staging definitions for IA-IIC?
All are N0/M0
IA = T1a
IB = T1b/T2a
IIA= T2b/T3a
IIB= T3b/T4a
IIC= T4b
What is the definition of melanoma overall stages of IIIA-C?
For the III’s, it can be any T, M0, the differences come down to the N’s and higher combinations of T’s
IIIA = N1a/N2a and T1a-4a
IIIB = N1a/N2a if T4b or T1-4a N1b-N2b-c
IIIC = T4b N1B-N2c or any T + N3
What is the definition of stage IV melanoma?
IV = any M1, as soon as there is metastasis = IV
What mutations are commonly seen in Spitz nevi that are not often seen in melanomas?
H-ras mutations
What two genes are most commonly mutated in melanoma?
BRAF and NRAS
