Skin Cancer, malignant tumors of the skin

Question 1

Non-Melanoma Skin Cancer (NMSC) risk factors:

what is the most common cause of BCC?

Other than UV radiation, what are other factors?

Answer 1

• Occurs more frequently in fair skinned individuals in geographic areas with higher UV exposure
• UV radiation is the most common cause of BCC
• Also occur after ionizing radiation, arsenic or polycyclic hydrocarbon exposure

Question 2

Basal Cell Carcinoma (BCC)

Of the subtypes, which one is the most common?

Answer 2

• Most common malignancy in the US
• An estimated 2.8 million are diagnosed annually in the US
• BCCs are rarely fatal, but can be highly disfiguring if allowed to grow.

Subtypes:

•Superficial (15%)

•Nodular (75%)**

–Micronodular

–Pigmented (6%)

• Infiltrative (5%)
• Sclerosing/ Morpheaform (3%)

Question 3

Superficial basal cell carcinoma:

Answer 3

Superficial cell carcinoma

Question 4

Nodular Basal Cell carcinoma

Answer 4

Raised papule or nodule with a central crater. In some cases, sides of crater are surfaces by telangiectatis vessels (from Goljan)

Question 5

Basal cell carcinoma

Answer 5

Desmoplastic BCC

Question 6

Pigmented BCC

Answer 6

BCC

Question 7

What are the genetic defects in BCC?

Loss of function of _____ gene, which normally blocks _______.

What is a treatment drug that inhibits smoothened?

Answer 7

• The majority of BCCs have a loss of function of PTCH1 gene which normally acts to block smoothened (SMO) a transmembrane protein.
• **Vismodegib, an inhibitor of smoothened, was approved January 2012 for the treatment of advanced BCC

Question 8

Actinic Keratosis

Intraepidermal neoplasia

It is a precursor for what type of cancer?

Answer 8

• AKs are the most common precancer affecting more than 58 million Americans
• Approximately 65 percent of all *squamous cell carcinomas and 36 percent of all basal cell carcinomas arise in lesions that previously were diagnosed as AKs

How do you treat it?

•Cryosurgery

–->Liquid nitrogen (boiling point of -196 C)

• Topical 5-fluoruracil
• Topical Imiquimod
• Topical Diclofenac
• Photodynamic therapy
• Sun protection

Question 9

Squamous Cell Carcinoma (SCC)

Much more commonly in what kind of patients?

When SCC can begins within scars, skin ulcers or other areas of chronic injury and an SCC in these situations is called a _________.

Answer 9

• Second most common cutaneous malignancy.
• Occur much more commonly in immunosuppressed pts, especially organ transplant pts
• Risk factors: UV damage, thermal injury, radiation, HPV, burn scars (Marjolin’s ulcer) and chronic injury (i.e. EB)

Question 10

SCC subtypes

Answer 10

Question 11

SCC

Answer 11

SCC

Question 13

Keratoacanthoma

Growth usually occurs rapidly, over _______.

Characterized by a crater with a ________ plug.

Answer 13

• Distribution- primarily sun-exposed skin
• Rapid growth over 6-8 weeks
• Size- 1-3 cm

•Crateriform endophytic and exophytic nodule with central keratin plug

•Complications- deep invasion without regression in 10-20%

Question 14

Invasive Squamous Cell Carcinoma (SCC)

Common in which part of the face?

Answer 14

• Hyperkeratotic papule with variable size and thickness
• Typically found on chronically sun damaged skin
• Metastasis occurs in 0.3-5%, but is more common in SCC of the lip (10-30%)

**Hyperkeratosis is thickening of the stratum corneum (the outermost layer of the epidermis), often associated with the presence of an abnormal quantity of keratin, and also usually accompanied by an increase in the granular layer.

Question 15

Skin cancer and transplant patients:

**Patients who have received an organ transplant have a higher risk than normal for developing skin cancers, in some cases up to 65 times the risk, compared with non-transplant patients.

In particular, transplant recipients have a significantly increased risk of developing squamous cell carcinomas. SCC is more likely to spread (metastatic SCC) in organ transplant recipients, and may lead to the death of the patient (from internet).

Which skin cancer is more likely to develop in the recipient of a transplant?

Which T cells are important in assessing the risk of developing a skin cancer for a transplant recipient?

Answer 15

• SCC = 65 fold risk
• BCC = 10 fold risk
• Melanoma = 3.4 fold risk (lowest)
• Kaposi’s sarcoma = **84 fold risk

What are some risk factors?

•Age, Skin type, UV radiation

• Genetic Factors
• HPV (in 65-90% of SCC)

•Level of immunosuppression:

–CD4 count

–Medications

–*Heart > Kidney > Liver

Question 16

What are some common treatments for Non-Melanoma Skin Cancer?

Answer 16

• Topical 5-fluoruracil
• Topical Imiquimod
• Cryosurgery
• Electrodessication and Curettage
• Excision
• Mohs micrographic surgery
• Radiation

Question 17

Malignant melanoma

Answer 17

A = Asymmetry

B = Border irregularity

C = Color variegation

D = Diameter greater than 6 mm

E= Evolution (or change)

Melanoma may arise within a previously existing nevus or dysplastic nevus, but approximately 70% of the time, they arise de novo. Superficial spreading melanomas typically show the ABCD’s of melanoma (Asymmetry, Border irregularity, Color variegation and Diameter greater than 6mm). Many people as look at E for evolution or change. A new tool used in diagnosing melanoma is looking for the “Ugly Duckling”, or the mole(s) that look different from their neighboring moles.

Question 18

Malignant melanoma

Relative risk

Answer 18

Melanoma facts

Question 19

Melanoma Statistics

Answer 19

Melanoma

Question 20

Malignant melanoma

Clinical features:

Affects what age groups?

Answer 20

•Affects all age groups

–**53 years = median

•Distribution

–-> Blacks-acral** (Acral melanoma is a type of skin cancer that occurs on fingers, palms, soles, and nail beds) and **mucosa

–Men- back

–Women- legs (torso in females age 15-29, perhaps due to tanning).

Question 21

Malignant melanomas

Variants:

Which one is the most common type?

Answer 21

• **Superficial spreading—–>70%
• Nodular—–>15-30%
• Lentigo maligna melanoma—–> 5%
• Acral lentiginous——> 2-10%

Question 22

What is Breslow’s depth?

Lesions with less than ______ have an excellent prognosis with infrequent metastasis.

Melanomas thicker than ____ mm have a poor prognosis with a 5-year survival of 50%.

Answer 22

The most important indicator of prognosis for all subtypes of melanoma is the Breslow depth, which is the maximal thickness of tumor invasion as measured by an ocular micrometer, from the top of the granular layer of the epidermis to the base of the neoplasm.

Breslow depth is recorded in millimeters with lesions less than 1.0 mm having an excellent prognosis with infrequent metastases and melanomas thicker than 4mm having a rather poor prognosis with a 5-year survival of approximately 50%. The most common sites of local and/or regional metastases are the draining lymph node basins and the skin between the primary site and these lymph nodes whereas the most common sites of systemic metastases are the lung, liver, brain, and gastrointestinal tract.

Question 23

What is Clark’s level?

Answer 23

Another system, called the Clark level, describes how far a melanoma has penetrated into the skin instead of actually measuring it. The Clark level of a melanoma uses a scale of I to V (with higher numbers indicating a deeper melanoma) to describe whether:

–>the cancer stays in the epidermis (Clark level I)

–>the cancer has begun to invade the upper dermis (Clark level II)

–>the cancer involves most of the upper dermis (Clark level III)

–>the cancer has reached the lower dermis (Clark level IV)

–>the cancer has invaded to the subcutis (Clark level V)

Question 24

Malignant melanoma treatment:

Answer 24

•Surgical excision

–MM in-situ: 0.5 cm with subcutaneous tissue

–MM < 1 mm: 1 cm margin to fascia

–MM > 1 mm: 1-2 cm margins to fascia with sentinel node biopsy

Question 25

Biologic events and molecular chnges in progression of melanoma.

Answer 25

Figure 2. Biologic Events and Molecular Changes in the Progression of Melanoma. At the stage of the _benign nevus_, **BRAF mutation** and activation of the mitogen-activated protein kinase (**MAPK**) pathway occur. The cytologic atypia in dysplastic nevi reflect lesions within the cyclin-dependent kinase inhibitor 2A (CDKN2A) and phosphatase and tensin homologue (PTEN) pathways. Further progression of melanoma is associated with decreased differentiation and the decreased expression of melanoma markers regulated by microphthalmia-associated transcription factor (MITF). The vertical-growth phase and metastatic melanoma are notable for striking changes in the control of cell adhesion. Changes in the expression of the melanocyte-specific gene melastatin 1 (TRPM1) correlate with metastatic propensity, but the function of this gene remains unknown. Other changes include the loss of E-cadherin and increased expression of N-cadherin, αVβ3 integrin, and matrix metalloproteinase 2 (MMP-2).

Question 26

**BRAF** mutations in malignant melanoma How does **Vemurafenib** works?

Answer 26

**Vemurafenib** is an orally available, selective **BRAF** (V-raf murine sarcoma viral oncogene homolog B1) inhibitor that is approved by the FDA for patients with unresectable or metastatic melanoma that tests positive for the BRAF V600E mutation. Because improvement with BRAF inhibitors is often temporary, newer approaches such as combination with a MEK inhibitor is currently under investigation.

Question 27

Targeted treatment for Melanoma ## Footnote BRAF inhibitors are\_\_\_\_\_\_\_ and \_\_\_\_\_\_\_\_\_.

Answer 27

For BRAF: * **Vemurafenib** (Zelboraf) and **dabrafenib** (Tafinlar) * Helpful in targeting melanomas with a mutation in BRAF (50% melanomas) that signals melanoma cells to grow and divide quickly. * 4 tablets PO BID

Question 28

Targeted treatment for Melanoma ## Footnote For inhibiting MEK there is \_\_\_\_\_\_\_\_\_\_.

Answer 28

* **Trametinib** (Mekinist) and **cobimetinib** (Cotellic) * Often used in combination with BRAF Inhibitors * Dosed 2 mg PO QD The MEK gene is in the same signaling pathway inside cells as the BRAF gene, so drugs that block MEK proteins can also help treat melanomas with BRAF gene changes. MEK inhibitors **trametinib (Mekinist)** and **cobimetinib (Cotellic)** have been shown to shrink some melanomas with BRAF changes. When used by themselves, these drugs don’t seem to shrink as many melanomas as the BRAF inhibitors. A more common approach is to **combine** a MEK inhibitor with a BRAF inhibitor. This seems to shrink tumors for longer periods of time than using either type of drug alone. Some side effects (such as the development of other skin cancers) are actually less common with the combination.

Question 29

Targeted treatment for melanomas c-KIT inhibitors:

Answer 29

•**Imatinib** (Gleevec) and **Nilotinib** (Tasigna)

Question 30

_Immunotherapy_ for Melanoma CHECKPOINT INHIBITORS ## Footnote PD-1 inhibitors are\_\_\_\_ and \_\_\_\_\_

Answer 30

PD-1 inhibitors ## Footnote * **Pembrolizumab** (Keytruda) * **Nivolumab** (Opdivo) * By blocking Programmed death receptor on T cells, the immune response is boosted against melanoma cells * Given IV Q2-3 weeks *--\>Programmed death inhibitors (PD1 Inhibitors) Many tumor cells express PD-L1, an immunosuppressive PD-1 ligand; inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell antitumor activity. This is known as immune checkpoint blockade. Nivolumab (Opdivo) and pembrolizumab (Keytruda) treat melanoma, non-small-cell lung cancer, and renal-cell cancer.*

Question 31

Immunotherapy for melanoma ## Footnote **CTLA-1 inhibitor is \_\_\_\_\_\_\_\_\_\_\_.**

Answer 31

**•Ipilimumab** (Yervoy) * Blocks CTLA-4 receptor on T cells thereby allowing a stronger immune response against melanoma * Given IV Q3 weeks x 4. **Ipilimumab** (Yervoy) is a human monoclonal antibody that blocks the activity of cytotoxic T-lymphocyte antigen 4 (CTLA-4), blocking the function of CTLA-4 as a down regulator of T-cell activation. It is approved for the treatment of unresectable or metastatic melanoma and supported by two prospective, randomized, international trials, one each in previously untreated and treated patients.

Question 32

Malignant melanoma and tanning

Answer 32

Prevention:

Question 33

What is SPF?

Answer 33

When to use sun blocker?

Question 34

How much sunblocker to apply?

Answer 34

The sun exposure vs. Vit D dilemma

Question 35

Kaposi's Sarcoma ## Footnote Triggered by\_\_\_\_\_\_\_. Which type is rapidly fatal? Which one is due to chronic immunosupression?

Answer 35

* Endothelial cell malignancy triggered by **HHV-8** * Usually appears on skin or **mucosal surfaces (mouth)**, but can also develop in \*\***lymph nodes, lungs, or digestive tract.** * **Classic (Mediterranean)** –Occurs primarily in elderly men of Eastern European descent •**Lymphadenopathic (Endemic, African)** –Aggressive form primarily in equatorial Africa –Affects young men and is **rapidly fatal** **•Iatrogenic (Transplant-related)** –Due to _chronic immunosuppression_ **•AIDS – Associated (Epidemic)** –Incidence is declining with better anti-retroviral therapy against HIV

Question 36

**Kaposi sarcoma treatment**

Answer 36