Week 8 - Squamous Cell Carcinoma and malignant melanoma

Question 1

What is cutaneous squamous cell carcinoma?

Answer 1

cSCC is the second most common skin cancer.

Approximately 20% of non-melanoma skin cancers.

Arises from malignant proliferation of epidermal keratinocytes

Increased incidence over past 20 years in the US and elsewhere

Question 2

What is the geographic variation of cSCC?

Answer 2

Age-adjusted annual incidence of cSCC in the US varies according to latitude.

Incidence is higher in Arizona than in New Hampshire”
men – 270 vs. 97 per 100,000
women – 110 vs. 32 per 100,000

Question 3

What are the clinical features of SCC?

Answer 3

Wide variety of clinical manifestations including:

• papules
• plaques
• nodules
• smooth, hyperkeratotic, or ulcerative lesions

Question 4

How do you DX SCC?

Answer 4

Skin Biopsy!

Question 5

What ages are associated with SCC?

Answer 5

Incidence increases dramatically with age – infrequent in those under 45

• But incidence is increasing significantly in young individuals.
• Over age 75, the incidence is 50 to 300 times higher than for those under 45.

Question 6

What ethnicity is associated with SCC?

Answer 6

Light-skinned, non-Hispanic white U.S. populations have the highest reported rates.

women – 150 per 100,000 individuals
men – 360 per 100,000 individuals

Most of these cSCCs tend to occur in sun-exposed areas of the skin leading to very low rate of metastasis.

U.S. blacks – 3 per 100,000 incidence

Dark-skinned Asians, and other people with skin of color have even lower reported rates.

In dark-skinned people:
cSCCs tends to arise on non sun-exposed areas (e.g. the legs and anus)
frequently associated with chronic inflammation, chronic wounds, or scarring.

Question 7

Locations of SCC?

Answer 7

cSCCs can develop on any cutaneous surface, including the head, neck, trunk, extremities, oral mucosa, periungual skin, and anogenital areas.

% of cSCC lesions in fair-skinned individuals in sites frequently exposed to the sun:  
•	Head and neck (55 %) 
•	Dorsum of hands/forearms (18 %)
•	Legs (13 %)
•	Arms (3 %)
•	Shoulder or back (4 %)
•	Chest or abdomen (4 %)
•	Other sites (3 %)	

cSCC on non-sun-exposed skin is less common overall:

Most common distribution in individuals with dark skin.

Likely due to the protective effect of epidermal melanin against the carcinogenic effects of ultraviolet light.

Common sites in black individuals:
legs and anus
areas of chronic inflammation
areas of chronic scarring (account for 20 to 40 % of cSCCs in black patients).

Question 8

What are the risk factors of SCC?

Answer 8

Genetic factors: fair skin, light-colored eyes, red hair, and Northern European origin

Environmental factors:
Epidemiologic studies support the finding that cumulative UVB sun exposure in the most recent 5 – 10 years of life increases the risk of cSCC in presence of other risk factors.

In contrast, intense intermittent sun exposure (e.g., sunburn, childhood exposure) is the most important risk factor for BCC (and melanoma).

UVA light exposure:

• Penetrates deeply into the skin
• UVA radiation is absorbed by DNA and can  DNA damage
• Unrepaired damage  series of changes that can  malignant transformation
• An estimated 45 to 60% of cSCCs have p53 tumor suppressor gene point mutations associated with damage due to UVB radiation.
• UVB radiation – more superficial skin penetration than UVA but produces more “burning” than cSCCs.

Radiation:

• Ionizing radiation for cancer treatment (used in the past for acne, tinea capitis)
• Grenz-rays (used for psoriasis and other skin diseases)
• Gamma rays – associated with development of both cSCCs and BCCs.
• Radiation risk is dose-related and higher in sites that have the most sun exposure.
• The basal layer of the epidermis is more affected by radiation than the more superficial layers, with a higher relative risk of BCC compared to cSCC

Chronic inflammation:

• Increased risk of cSCC in chronically inflamed skin that results in scars, burns, chronic ulcers, sinus tracts, or inflammatory dermatoses, such as lichen sclerosus et atrophicus.
• About 1% of cutaneous skin cancers arise in chronically inflamed skin and about 95% are cSCCs.
• The interval between the initial skin damage and appearance of a tumor varies widely, with cSCCs appearing as early as six weeks or as many as 60 years after the traumatic event.

Wounds and scars:
-Sites of chronic inflammation, chronic wounds, or scars are susceptible to the development of cSCC.
-cSCC in these settings may initially present as ulcerations that fail to heal and nodules may develop as lesions progress.
Arsenic exposure – chronic arsenic
exposure by consumption of contaminated drinking water and occupational exposure is associated with cSCCs, BCCs and other cancers.

Other Risk factors:
Family history
Genetic or inherited disorders
Blood type – 14% lower in types A, AB, and B than in type O
Selenium exposure
HPV infection
Cigarette smoking

Question 9

CHEMO PROTECTION WITH ORAL RETINOIDS:

Answer 9

• Oral Vitamin A (also topically)
• Oral retinoids inhibit cSCC cell growth in vitro and may reduce development of cSCC tumors in high-risk populations, such as:
• History of multiple non-melanoma skin cancer
• Genetic disorders such as xeroderma pigmentosum
• Transplant recipients
• Exposure to high cumulative levels of PUVA therapy

Question 10

What is SCC in situ (Bowen’s disease)?

Answer 10

Typically presents as a well- demarcated, scaly patch or plaque.

Lesions often erythematous, but can also be skin-colored or pigmented.

cSCC in situ lesions tend to grow slowly, enlarging over the course of years.

Unlike the inflammatory disorders that may resemble cSCC in situ, lesions are usually asymptomatic.

Question 11

What is Erythroplasia of Queyrat?

Answer 11

cSCC in situ involving the penis.

Presents as a well-defined, velvety, red plaque

Patients may experience pain, bleeding, or pruritus.

Question 12

What is invasive cSCC?

Answer 12

Clinical appearance often correlates with the level of tumor differentiation.

Lesions of invasive cSCC are often asymptomatic, but may be painful or pruritic.

Question 13

What are well-differentiated SCC lesions?

Answer 13

Usually appear as indurated or firm, hyperkeratotic papules, plaques, or nodules.

• Lesions are usually 0.5 to 1.5 cm in diameter, although some are much larger.
• Ulceration may or may not be present.

Question 14

What are poorly-differentiated lesions?

Answer 14

• Usually fleshy, soft, granulomatous papules or nodules that lack the hyperkeratosis that is often seen in well-differentiated lesions.
• May have ulceration, hemorrhage, or areas of necrosis.

Question 15

What is Histologic perineurial invasion?

Answer 15

• Local neurologic symptoms (e.g., numbness, stinging, burning, paresthesias, paralysis, or visual changes) occur in approximately 1/3 of these patients.
• Perineural invasion is a poor prognostic sign.

Question 16

What is Oral SCC?

Answer 16

Presents as an ulcer, nodule, or indurated plaque involving the oral cavity
-Floor of the mouth and lateral or ventral tongue most common sites.
-Lesions arise in sites of:
erythroplakia (pre-malignant persistent red patches)
leukoplakia (persistent white plaques)
-Oral SCC often associated with a history of tobacco or heavy alcohol use.

Question 17

What is Keratoacanthoma?

Answer 17

Keratocytic epithelial tumors that resemble cSCC clinically and histologicaly

• Controversial whether they represent a subtype of well-differentiated cSCC or a separate entity
• Usually found on actinically-damaged skin.
• Lesions typically exhibit rapid initial growth, appearing as dome-shaped or crateriform nodules with a central keratotic core that develop within a few weeks time

Question 18

What is Verrucous carcinoma?

Answer 18

• Subtype of cSCC – well defined, exophytic, cauliflower-like growths that resemble large warts.
• Lesions are sub classified according to site:
• Oral – florid mucosal verrucous papillomatosis

Anogenital – giant condyloma acuminatum; verrucous carcinoma involving the penis, scrotum, or perianal region

Epithelioma cuniculatum – verrucous carcinoma on the plantar foot surface

May also occur in other locations.

Question 19

cSCC of the lip?

Answer 19

Primarily occurs on the lower lip

• Lesions may present as nodules, ulcers, or indurated white plaques.
• A lesion on the vermillion border is cSCC until proven otherwise!

Question 20

Sites of metastasis?

Answer 20

Most frequent site of metastasis for cSCC is the REGIONAL LYMPH NODES.

• Other potential sites for metastasis include the lungs, liver, brain, skin, or bone.
• Metastases to the skin can present with erythematous papules or nodules that resemble primary lesions of cutaneous cancers.

Question 21

Dx of SCC?

Answer 21

Histopathologic examination is necessary to confirm the diagnosis even with strong clinical findings. 
Also assesses for: 
-perineural invasion
-tumor depth and
-tumor differentiation

All are important for tumor staging and prognosis!

Full thickness excisional or punch biopsies are essential for lesions that are papular, nodular, or otherwise suspicious for invasive cSCC.

Shave biopsies may be performed in patients with lesions that are suggestive of in situ cSCC (best determined by a dermatologist).

Question 22

TREATMENT OPTIONS FOR LOCALIZED cSCC? – (similar to the Tx of BCC)

Answer 22

• Cryotherapy
• Electrosurgery (e.g. ED & C)
• Topical (5-fluorouracil, imiquimod)
• Radiation therapy
• Surgical excision
• Mohs surgery

All of the above therapies are highly effective in properly selected patients.

Question 23

SUMMARY OF TREATMENT FOR cSCCs

Answer 23

Early diagnosis and definitive treatment provide the best opportunity to cure cSCCs.

In contrast to BCCs which only rarely metastasize (0.003%), 5-10 percent of cSCCs spread to regional lymph nodes or more distant sites  a relatively poor outcome.

The optimal approach considers the following:

• the form and location of the cSCC
• the likelihood of the lesion recurring or metastasizing
• cosmetic factors
• the expertise and resources of the treating physician.

Special attention must be directed toward the preservation of form and function without sacrificing the opportunity for cure with lesions situated on or near cosmetically sensitive areas (e.g., eyelids, lips, ears, nose, genitals, fingers).

Question 24

FEATURES OF cSCC LESIONS THAT CORRELATE WITH LOW RISK FOR RECURRENCE AND REGIONAL OR DISTANT METASTASES

Answer 24

• Small size
• Do not invade into the subcutaneous issue
• Arise from actinic keratoses or as a consequence of sun exposure
• Do not have any other high-risk features

Question 25

What is MALIGNANT MELANOMA?

Answer 25

Most common fatal form of skin cancer

5th most common cancer in men, 7th in women in US.

5-year survival rates – varies with stage at diagnosis

Survival declines steadily as the tumor thickness and disease stage increase.

Thin stage I lesions – prolonged disease-free survival and even cure.
Thicker, later stage lesions (e.g. >2.0 mm) – more likely to die from metastasis.

Question 26

What is the incidence of malignant melanoma?

Answer 26

Increasing faster than any other potentially preventable cancer in US

1985 data – US lifetime risk
1 in 150 for men
1 in 600 for women

2004 and 2006 data – US lifetime probability:
1 in 37 for men
1 in 56 for women.

2011 estimates:
70,230 invasive mms diagnosed in US
Mms could claim 8790 lives.

Question 27

What are the RISKS of malignant melanoma?

Answer 27

1. Genetic:
   - Familial – approx. 10 % of melanomas
   - Considerable genetic heterogeneity among different families suggesting involvement of multiple genes.
   - Phenotypic traits – less skin pigmentation, hair color (red or blond), high-density freckling, and light eye color (green, hazel, blue) are associated with increased risk.
2. Atypical nevi:
   Individuals with atypical nevi have a 3 to 20-fold elevated risk of developing malignant melanoma compared to the general population.

Approximately 10 to 20 % of diagnosed melanomas arise within atypical nevi.

3. High nevus count:
   Strong association between high nevus counts (more than 25) and melanoma.

More strongly associated with melanoma developing on the legs or trunk, compared to other sites.

4. Environmental – Sun or ultraviolet exposure:

Clinical/epidemiologic evidence – higher rates of MMs in adults with extensive or repeated intense sunlight exposure.

Case control studies found the strongest association for intermittent exposure and sunburn in childhood or adolescence.

Increased risk with UV exposure from tanning beds, especially with use before the age of 35.

Socioeconomic – less affluent groups have more advanced disease and poorer survival

Question 28

What are the growth phases of melanoma?

Answer 28

Horizontal (“radial“) phase

• Most MMs arise as superficial tumors that are confined to the epidermis, where they remain for several years.
• During the “radial” growth phase the melanoma is almost always curable by surgical excision alone.
• Even some superficially invasive malignant melanomas (“microinvasive radial growth phase“) remain highly curable with excision alone.

“Vertical” growth phase:

• Lesions that infiltrate deep into the dermis and have metastatic potential.
• Can arise de novo or from a radial growth phase MM.
• Some MMs take decades to reach vertical growth phase.
• Others grow vertically very early!
• Nodular melanomas have no identifiable radial growth phase and enter the vertical growth phase almost from their inception.
• The probability of metastases with an invasive, vertical growth phase melanoma may be predicted by measuring the depth of invasion of the vertical growth phase nodule below the granular cell layer of the overlying epidermis.

Question 29

What are the 4 MAJOR SUBTYPES OF MALIGNANT MELANOMAS?

Answer 29

Three types beginin situand sometimes invade.
The fourth (nodular) is initially invasive. 

Four distinct histologic patterns in descending order of frequency:

• Superficial spreading
• Nodular
• Acral lentiginous
• Lentigo maligna

Question 30

What is superficial spreading melanoma?

Answer 30

Most common type – up to 70 % of cases.

Most often in young people.

Grows slowly along the top layer of the skin for a fairly long time before penetrating more deeply.

Over 60% are diagnosed as thin, highly curable tumors of less than 1 mm thickness.

First appear as an asymmetrical, flat or slightly raised discolored patch with irregular borders.

The color varies – areas of tan, brown, black, red, blue or white.

Size range – few mms. to several cms.

Can occur in a previously benign mole!

Can be found almost anywhere on the body, but are most likely to occur on:
trunk in men
legs in women
upper back in both.

Question 31

What is nodular melanoma?

Answer 31

Most aggressive MM

Second most common type, accounting for up to 37% of all melanomas.

Most difficult to diagnose at an early stage – typically not recognized until it becomes a “bump”

THE BAD NEWS – at least half of these lesions are greater than 2 mm in thickness when diagnosed!

Usually pedunculated or polypoid black nodules, some times blue, gray, white, brown, tan, red or skin tone.

Amelanotic variants occur as well.

Most frequent locations are the trunk, legs, and arms, mainly of elderly people, as well as the scalp in men.

Question 32

What is Lentigo maligna melanoma?

Answer 32

Similar to the superficial spreading type – also remain close to the skin surface for quite a while.

Found most often in the elderly, on chronically sun-exposed, damaged skin on the face, ears, arms and upper trunk.

Usually appears as a flat or mildly elevated mottled tan, brown or dark brown lesion

Gradually enlarge and develop darker, asymmetric foci, color variegation, and raised areas that signify the onset of vertical growth.

The great majority are diagnosed at less than 1 mm of thickness!

Account for 5-15% of all melanomas, but the incidence is rising in the US.

Most common form of melanoma in Hawaii.

Question 33

What is Acral lentiginous melanoma?

Acral = peripheral

Answer 33

+/- 6% of all melanomas

Most common type of malignant melanoma among Asians and in African-Americans (at lower risk for more sun-related melanoma subtypes).

Least common type in Caucasians.

Most commonly on palmar, plantar, and subungual surfaces.

Dark brown to black, irregularly pigmented macules or patches.
Spread superficially before penetrating more deeply.

CAUTION!
If a lesion becomes:
-raised
-develops ulceration
->5 mm in diameter 
the likelihood of invasion should be considered.

Can often advance more quickly than superficial spreading melanoma and lentigo maligna melanoma

Question 34

What is the PROGNOSIS for MM?

Answer 34

Most important prognostic factors for patients with localized melanoma of any subtype are:*

• tumor thickness
• mitotic rate
• ulceration

*Staging system of the American Joint Committee on Cancer (AJCC), 2010 edition

NOTE:
Tumor thickness is the single most important determinant of prognosis.

Survival rates decline as tumor thickness increases.

Question 35

Tumor staging:

Answer 35

AJCC data from 27,000 patients with stage I and II disease used tumor thickness and follow-up information to calculate ten year survival rates:

T1: ≤1 mm; 92%
T2: 1.01 - 2.00 mm; 80%
T3: 2.01 - 4.00 mm; 63%
T4: >4 mm; 50%

BOTTOM LINE - early detection of MMs is crucial to improve patient outcome and save lives.

Although most melanomas are detected by patients themselves, clinician detection is associated with thinner, more curable tumors.

Question 36

What are the diagnostic checklists?

Answer 36

Two useful checklists have been developed to help clinicians and the lay public identify skin lesions that need further evaluation.

Question 37

What is the revised glascow seven-point checklist?

Answer 37

This seven-point checklist is another set of criteria for referral or biopsy that was developed from a retrospective review of patients with melanoma and subsequently revised.

It is used more commonly in Europe than in the United States.

 It includes three major and four minor features:
Major:
Change in size/new lesion
Change in shape 
Change in color 

Minor: 
Diameter ≥7mm
Inflammation 
Crusting or bleeding
Sensory change

Question 38

DIFFERENTIAL DIAGNOSIS of MM?

Answer 38

Common melanocytic nevus
Atypical melanocytic nevus 
Traumatized nevus
Blue nevus 
Lentigo (ink spot)
Spitz nevus 
Melanonychia striata 
Pigmented basal cell carcinoma
Pigmented actinic keratosis
Seborrheic keratosis 
Pyogenic granuloma
Cherry hemangioma
Dermatofibroma
Keratoacanthoma 
Subungual hematoma
Etc.

Question 39

MANAGEMENT OF PATIENTS WITH SUSPICIOUS SKIN LESIONS

Answer 39

Indications for Referral:
Primary care clinicians should have a relatively low threshold for referral to a dermatologist to determine whether biopsy is indicated – when a lesion is identified that is not clearly benign.

Guidelines published in 2010 by the British Association of Dermatologists suggest the following indications for referral:
1. A new mole appearing after the onset of puberty which is changing in shape, color, or size
2. A long-standing mole which is changing in shape, color, or size
3. Any mole which has three or more colors or has lost its symmetry
4. Any new persistent skin lesion especially if:
growing
if pigmented
appears vascular
unclear diagnosis
5. A mole which is itching or bleeding
6. A new pigmented line in a nail especially where there is associated damage to the nail
7. A lesion growing under a nail

Question 40

Biopsyto R/O Malignant Melanoma:

Answer 40

Excisional Biopsy:
Best method – create 1 to 3 mm margins of normal skin and a layer of the subcutaneous fat

This “narrow-margin” excision allows assessment of the entire lesion without compromising results of subsequent wider margin surgery.

Attempt to follow Langer’s lines:
facilitates subsequent wider excision and closure when needed
minimizes the need for skin grafting.

Punch Biopsy:
Generally adequate to make the diagnosis
CAUTION - might fail to accurately assess tumor thickness if the thickest portion of the lesion is not sampled!

Question 41

What would you NOT do Superficial Shave Bx for malignant melanoma?

Answer 41

Superficial Shave Bx – never appropriate for the following reasons:
The lesion is likely to be inadequately excised, leaving residual tumor at both the radial and deep margins.

Underestimates tumor thickness, which is a critical treatment and prognostic factor

Fibrosis and scarring at the base of the biopsy site may obscure residual melanoma when a subsequent larger excision is made, making it impossible for a pathologist to identify tumor and accurately measure its thickness.

Question 42

WIDE LOCAL EXCISION (down to the deep fascia):

Answer 42

Historically considered the definitive “initial” surgical treatment for primary cutaneous melanomas.

The thicker the lesion, the wider the margin of normal tissue that should be resected.

BUT multiple clinical trials showed that a narrower margin of normal tissue removed from around the lesion does not alter the recurrence rate!

Useful info to provide to the pathologist:
ABCDE findings
clinical images (especially for incisional or punch biopsies
anatomic location
type of bx performed
intent (excisional or incisional)
size of the lesion
marking suspicious foci

Question 43

Mohs Micrographic Surgery for Melanomas:

Answer 43

STANDARD - because of the potential of metastasis and possible death, any biopsy that comes back positive for melanoma needs to be referred for additional surgery via Mohs procedure!

This ensures complete removal of the cancer by verifying clean wound margins.

If the lesion has metastasized, removal of the lesion is followed (with or without Mohs) by inspection of appropriate lymph nodes via radioactive colored dye injected into the lesion area to determine if further medical treatment is necessary.