Chapter 124 Cutaneous melanoma

Question 1

Invasive melanoma of the skin is the______ most frequent site for cancer to occur in men and the _______ most frequent site in women, representing approximately 5% of all newly diagnosed cancers

The mean age of diagnosis is relatively young at _______, which is 10–15 years earlier than the mean age of diagnosis in the more common tumors of the _____, ______, colon, and prostate

Answer 1

fifth
sixth

52 years
breast, lung

Question 2

periodic, intense sun exposure (particularly during the critical time period of _____ and _______) rather than long, continued, heavy sun exposure is most important in melanoma causation, termed the_________________

Answer 2

childhood and adolescence

intermittent exposure hypothesis

Question 3

Data from the behavior risk factor surveillance system of the Centers for Disease Control and Prevention show that nearly 32% of all adults aged ≥18 years, __% between 18 and 29 years of age, and more than __% of children report having had at least one annual sunburn defined as ______________________

Answer 3

58%
40%
red skin for more than 12 hours.

Question 4

Melanoma incidence and mortality among Caucasians correlate inversely with latitude of residence and dose of UV radiation, termed the _________. The highest rates are __________.

In men, the ___, particularly the ______, is the most common site for melanoma. In women, the _______, followed by the ___, are the most common sites

Answer 4

latitude gradient
nearest the equator

trunk
upper back
lower legs
trunk

Question 5

Adults with more than _____ clinically typical-appearing nevi, children with more than _____ typical-appearing nevi, and any patient with atypical nevi are at risk.

Many series define large congenital nevi as greater than ____ in diameter in adulthood, and lifetime risks for developing melanoma are generally accepted to be in the_____% range

Answer 5

100
50

20 cm
5%–10%

Question 6

Patients with large congenital nevi located on the ______ (____, ____, ____regions) or in conjunction with multiple satellite lesions are at risk for neurocutaneous melanosis

Answer 6

posterior axis

paraspinal, head, and neck

Question 7

Germline mutations in the _________ tumor suppressor gene,__________________, account for approximately 40% of hereditary melanoma cases (≥3 melanomas in one lineage)

Answer 7

chromosome 9p21

cyclin-dependent kinase inhibitor 2A (CDKN2A)

Question 8

____ has a much higher basal kinase activity than either_____ or _____ and somatic mutations in ___ occur with moderate to higher frequency in melanoma and_____, _____, and papillary thyroid carcinomas, implicating activating oncogenic mutations of _____ as critical promoters of malignancy

Answer 8

B-raf
A-raf or C-raf,
B-raf 
colorectal, ovarian
B-raf

Question 9

The _______ is a transcription factor that appears to be a master regulator of melanocyte differentiation, and amplification of this gene appears to contribute to a novel carcinogenic mechanism known as __________

The _________________ has also been shown to be mutated or amplified in a subset of melanomas predominantly from ______ & _______

Answer 9

Mitf protein
lineage addiction

KIT tyrosinse kinase receptor
acral and mucosal sites

Question 10

mutations in the _____________________ were shown to strongly contribute to the red hair/fair skin phenotype

The XP genes are involved in excising DNA photoproducts in a reparative program termed _______________

Carriers of the breast cancer susceptibility gene, ______, appear to harbor an increased risk for melanoma (2.58-fold)

Answer 10

melanocortin-1-receptor (MC1R)

nucleotide excision repair

BRCA2

Question 11

The radial growth phase consists of primarily _________ proliferation of melanoma cells, but also invasion of the __________ by small numbers of cells that have gained a growth advantage.
Radial growth phase cells are characterized by the presence of _______

The vertical growth phase is signaled by the property of ____________, resulting in the formation of expansile nests or nodules of cells
________, a molecule that interacts with fibroblasts, macrophages, and endothelial cells

Answer 11

intraepidermal
papillary dermis
E-cadherin

aggregative growth
N-cadherin

Question 12

In the first pathway, melanomas, particularly superficial spreading melanomas (SSMs), at least in some cases, develop in association with ___________

A second pathway of melanoma development is exemplified by_______________. This form of melanoma results from _______________ and a corresponding cumulative insult to the DNA of melanocytes

Answer 12

melanocytic nevi

lentigo maligna melanoma (LMM)
cumulative sun exposure

Question 13

SSM
most frequently the ______ of women, and the _______ of men

subtype of melanoma most commonly associated with __________

Answer 13

lower extremity
upper back

preexisting nevi

Question 14

NM
The _____ is the most common site. NM is remarkable for ______,

pigmented lesions may be mistaken for _________ or _________

Answer 14

trunk
rapid evolution (often arising over several weeks to months)

blue nevi or pigmented basal cell carcinoma

Question 15

LM and LMM
pathogenesis is thought to be related to ________________

LMM is frequently larger than LM and may continue to be ______ in early lesions, although a _____ is often seen within the macule later

higher rates of extensive _________ growth, resulting in higher recurrence rates with standard recommended margins and failure to ____________________
highest rate of association with _____________

Answer 15

cumulative sun exposure

macular
nodular portion

subclinical lateral
completely excise the lesion
desmoplastic melanoma

Question 16

ALM
represents the most common form in _____________

most common site for ALM is the , with the _____ & _____ locations following

ALM is not thought to be associated with ___________

Subungual melanoma, considered a variant of ALM, generally arises from the _________, most commonly on the _____ or ________
________ sign, the finding of pigmentation on the proximal nail fold, may be noted with subungual melanoma

Answer 16

darker-pigmented individuals

sole
palm and subungual

sun exposure

nail matrix
great toe or thumb
Hutchinson sign

Question 17

Desmoplastic Me
firm, sclerotic, or indurated quality, and one- half are amelanotic.
Approximately half of the lesions arise in association with the _____________.
may be associated with a higher rate of ____________ due to a propensity to infiltrate _______________ and failure to appreciate occult growth, which may be deeply invasive at diagnosis

Answer 17

LM histologic subtype
local recurrence
perineurally with neurotropism

Question 18

Mucosal Me
With the exception of the __________, patients present most often with delayed detection and a deeply pigmented, irregular lesion, but due to its location, may also present with _____________ lesion

Answer 18

conjunctiva

bleeding or a mass

Question 19

Nevoid Me
correspond to a tan papule or nodule, more often ____ in diameter on a _______

Spitzoid Me
large lesions, greater than ___ in diameter; lesions with a thick invasive component, well over ______; lesions with numerous mitoses, many atypical, and lesions that have clinically concerning course such as ______ or _______

Answer 19

> 1 cm
young adult

1 cm
2 mm
rapid growth in size or satellitosis

Question 20

Pregnant women with melanoma should be offered the same surgical treatments, including sentinel lymph node biopsy (SLNB) (usually with _________) as non- pregnant patients;

Melanoma in childhood and adolescence is rare. Of all newly diagnosed melanomas, ____% occur in patients younger than 20 years of age, and only ___% occur in prepubertal children

Answer 20

omission of blue dye

1%–4%
0.3%–0.4%

Question 21

A stands for asymmetry (_______________); B for border (____, ____, ____, ____, or poorly defined borders as opposed to smooth and straight edges); C for color (having_____________); and D for diameter (i.e., _________, approximately the size of a pencil eraser).

Answer 21

one half is not identical to the other half
irregular, notched, scalloped, ragged
varying shades from one area to another
greater than 6 mm

Question 22

persistent ________ is also an earlier (albeit nonspecific) symptom; ____, ______, ______ generally signify a more advanced primary lesion

Answer 22

lesional itching

ulceration, bleeding, and tenderness

Question 23

Histopath
__________, referring to cellular enlargement, nuclear enlargement, nuclear pleomorphism, hyperchromasia of nuclei, nucleolar variability, and the presence of mitoses especially deep in the dermis, is considered necessary for a diagnosis of melanoma.
The major architectural features of melanoma include______, ________ (i.e., cells at the edge of the lesion tend to be small, single, and scattered), and large size (______).

Answer 23

Cytologic atypia
asymmetry, poor circumscription
>5–6 mm

Question 24

Histopath

SSM
characterized by a population of melanocytes appearing __________

LM and LMM
atypical melanocytes singly and in nests, predominantly confined to the _______ of the epidermis, which become confluent without _________,

Answer 24

uniformly atypical
(“pagetoid” distribution of large melanocytes)

basal layer
pagetoid spread

Question 25

Histopath ALM characteristic lentiginous pattern of most cells being single and located near the ________ NM demonstrates little tendency for intraepidermal growth; instead, there is a _______________

Answer 25

dermal- epidermal junction dermal mass of atypical melanocytes

Question 26

Immunohisto _______ is expressed by almost all melanomas; but also by melanocytic nevi, Langerhans cells, and cutaneous neural tumors. _______ is a monoclonal antibody with high specificity for melanoma cells, although it is frequently negative in DM; DMs commonly exhibit _____ and S100 positivity _____ is broadly expressed in benign and malignant melanocytic lesions but not in most DMs __________________ may be useful, especially in amelanotic melanomas, as it is a marker in the nucleus, whereas all other markers are intracytoplasmic

Answer 26

S100 protein HMB-45 vimentin Melan-A microphthalmia-associated transcription factor (Mitf)

Question 27

The single most important prognostic factor for survival and clinical management in localized stage I and II cutaneous melanoma is __________ Ulceration correlates with tumor thickness; it occurs infrequently in thin melanomas (________________) and frequently in thick melanomas (____________________) Among patients with clinically localized melanoma, a _______________________ may be the second most powerful predictor of survival, after tumor thickness

Answer 27

tumor thickness 6% for melanomas <1 mm 63% for melanomas >4 mm mitotic rate of 1/mm2 or greater

Question 28

Patients with any satellite metastases, including microsatellite metastases, are considered to have _______ disease even in the absence of nodal metastases (_____, satellite metastases without nodal metastases) ___________________ status, however, is a predictor of melanoma outcome

Answer 28

stage III N2c Sentinel lymph node

Question 29

_____ more than 60 years of age have the highest mortality rates from melanoma ______ have better survival rates than men, even after adjustment for tumor thickness and anatomic site. anatomic site is ______ (strong or not strong?) independent prognostic factor in melanoma

Answer 29

Males women not a strong

Question 30

The _________________ involved, independent of size, is the most significant risk factor in patients with stage III melanoma. The second most important risk factor is_______, stratified into micrometastatic disease as determined by SLNB, or macrometastatic disease (i.e., clini- cally palpable nodes) In clinically node-negative stage I or II patients, ________ is the most significant prognostic factor with respect to disease-free and disease- specific survival

Answer 30

number of lymph nodes tumor burden SLN status

Question 31

______, both clinical and microscopic, metastases around a primary melanoma and ______________ between the primary and its nodal basin represent intralymphatic metastases (N2c or N3) and portend the worst prognosis for regional metastases (stage IIIC disease) with a 5-year survival rate less than 50%.

Answer 31

Satellite | in-transit metastases

Question 32

Elevated ________________ levels are associated with a worse prognosis, regardless of the site of metastatic disease

Answer 32

serum lactate dehydrogenase (LDH)

Question 33

Stage I and II the 5–10-year survival for patients with localized thin primary melanoma ____mm in Breslow depth is more than ___% Stage III The general overall 5-year survival range of ______% is wide, primarily related to several variables such as: the _______________ (most important), tumor burden within a lymph node (microscopic vs. macroscopic), age, and ulceration status, Breslow thickness, and mitotic rate of the primary melanoma

Answer 33

<1 mm 90% 38%–78% number of positive lymph nodes

Question 34

Stage IV The most common visceral sites are the ____(18%–36%), ____ (14%–20%), ____ (12%–20%), bone (11%–17%), and gastrointestinal tract (1%–7%). Once metastases to distant sites have been detected, median survival is approximately _____,

Answer 34

lungs liver brain 6–8 months

Question 35

Metastatic melanoma of unknown primary Approximately 60% of these involve the _______, the remaining involve distant sites typically the skin/subcutaneous tissue, and less commonly lung, brain, or gast''''''rointestinal tract

Answer 35

lymph nodes

Question 36

An ________ should be obtained in the____________________________ with a strong appreciation that the clinically most suspicious area may not always correlate with the thickest portion of the lesion

Answer 36

incisional biopsy | most elevated or darkest area of the lesion,

Question 37

Excisional biopsy performed after incisional biopsy of melanoma with ____% of the lesion remaining resulted in significant upstaging in 21% of patients, and change in SLNB consideration in 10% of patients in one large study.

Answer 37

≥50

Question 38

Eval for distant mets If a palpable lymph node or a dermal/sub- cutaneous nodule in the regional area of the primary is found, _________________ may be utilized to make a histological diagnosis. An _________________ of the lymph node should be performed if fine needle aspiration is inconclusive or not feasible. Noninvasive imaging, most commonly with ____________________, is perhaps the most sensitive noninvasive method to detect small nodal metastases.

Answer 38

fine needle aspiration excisional biopsy ultrasound or computerized or PET

Question 39

For microscopic mets _____ is the best baseline staging test for detection of occult nodal metastasis in the subset of melanoma patients where it is indicated, and is the only staging test with both relatively high sensitivity and specificity In current practice,______________________, often with vital blue dye, allows for detection of the SLN >95% of the time in skilled hands. Ideally, the procedure should be performed at the same time as ____________________ of the primary melanoma for greatest accuracy

Answer 39

SLNB technetium-99-labeled radio-colloid solution wide local excision (WLE)

Question 40

The seventh edition of the AJCC melanoma staging system now accepts as positive any________________________________ that are clearly visualized by immunohistochemistry with melanoma markers, even if these metastatic deposits are not visible on H&E staining Sentinel lymph node status was demonstrated to be a powerful predictor of survival as those with a negative SLN had a 5-year survival of ___%, versus ____% 5-year survival for those with a positive SLN

Answer 40

sentinel lymph node containing metastatic foci 90. 2% 72. 3%

Question 41

Eval for distant mets Current NCCN guidelines recommend no additional workup in Stage 0 and 1A, ________ in stage 1B and II, ____________for stage III, and ____________for stage IV. Even for stage III and IV, further imaging with ____, ____, or ____ is recommended to be performed as clinically indicated

Answer 41

optional CXR optional CXR and LDH CXR and/or chest CT plus LDH CT, MRI, or PET

Question 42

Tx for Primary Melanoma The standard of therapy for primary cutaneous melanoma is _____ Current recommended clinical margins around the residual lesion or biopsy scar for melanoma in situ, non-LM pattern, is _____cm, for melanoma <1 mm Breslow depth __cm margin, for melanoma 1–2-mm thick ___cm as anatomically possible, and for melanoma >2-mm thick ___cm (with pathologic confirmation of clear peripheral margins for all) ___________________ remains the “gold standard” for histologic evaluation of surgical margin assessment of melanocytic lesions and

Answer 42

WLE 0.5–1 cm 1-cm 1–2 cm 2 cm Formalin fixed permanent section histology

Question 43

Macrometastatic nodal disease The current standard of therapy for microscopic or macroscopic melanoma in lymph nodes is________________ of the involved regional Micrometastatic nodal disease Therefore a _____ should be followed by a ________ for both prognostic and therapeutic benefit. From a prognostic standpoint, among node-positive patients with melanoma, the presence of a positive non-SLN is a significant poor prognostic sign

Answer 43

``` complete lymph node dissection (CLND) ``` positive SLNB CLND

Question 44

High-dose ________________ is the only adjuvant therapy approved by the U.S. FDA) that has been shown to improve disease-free survival for stage IIB–III melanoma.

Answer 44

interferon-α 2b (IFN-α 2b) The high-dose regimen consists of 20 million units per square meter of body surface area per day given intravenously 5 days a week for 4 weeks (induction phase), followed by 10 million units per square meter per day given subcutaneously 3 times a week for 48 weeks (maintenance phase)

Question 45

Satellite or in transit mets Tx However, if multiple lesions make surgery unreasonable, ________________ may be considered for locoregional disease control limited to an extremity _________________ is a, simpler, less-invasive technique. Early studies of ILI with _______ and ________ demonstrate comparable efficacy to ILP with melphalan

Answer 45

isolated limb perfusion (ILP) Isolated limb infusion (ILI) melphalan and actinomycin D

Question 46

Distant / disseminated mets Tx The treatment of stage IV melanoma must take into account that the average survival is _____mos and that no systemic therapies have been shown to significantly increase survival in randomized controlled trials The alkylating agent ________ is the only FDA-approved chemotherapy for metastatic melanoma. Response rates are in the 10%–20% range, with median response duration _______ mos ______________ is an alkylating agent with the same active metabolite as DTIC, but it is able to cross the blood-brain barrier and can be absorbed orally High-dose bolus _____ is the only FDA-approved immunologic treatment of metastatic melanoma that may produce rare but durable complete responses

Answer 46

6–8 months dacarbazine (DTIC) 4 to 6 months Temozolomide (TMZ) IL-2

Question 47

Current NCCN and national melanoma center guidelines call for at least annual follow-up visits for life, with follow-up intervals generally ranging from__________ for 1–3 years after diagnosis and ______ thereafter, depending primarily on stage of disease

Answer 47

every 3 to 6 months | annually