AssessmentsSkin cancer: Pathology review
USMLE® Step 1 style questions USMLE
A 55-year-old woman is brought to the emergency department by her partner following generalized tonic-clonic seizure activity. Her partner states that the patient has generally been in good health, but states that she has mentioned right-sided weakness over the past week. She has no significant past medical history. Temperature is 37.0°C (98.6°F), pulse is 96/min, respirations are 22/min, and blood pressure is 125/85 mmHg. Physical examination reveals a stuporous woman who is unable to speak coherently. Physical examination reveals mild right-sided weakness. A hyperpigmented lesion is noted on the dorsum of the right hand with irregular borders measuring 8-mm in diameter. Noncontrast CT of the brain is shown:
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After confirming the diagnosis, a decision is made to start this patient on vemurafenib. Which of the following is the most likely mechanism of action of this drug?
Content Reviewers:Antonella Melani, MD, Scott Caterine, BSc (Hons.), MSc, MB, BCh, BAO (Hons.)
62 year old William comes to the dermatology clinic for a routine skin examination. He has been working as a farmer since the age of 20 and rarely wears a hat or sunscreen. Physical examination reveals a pink, pearly lesion with surrounding telangiectasias on his right upper lip. Right after him, 47 year old Shelby comes in because of a large mole on her right shoulder that has recently grown in size. She is light skinned and has many freckles. Physical examination shows an asymmetric lesion, 8 millimeters in diameter, with irregular borders and variegated brown to black pigmentation.
Based on the initial presentation, both William and Shelby seem to have some form of skin cancer. Okay, first, let’s talk about physiology real quick. Normally, the skin is divided into three main layers, the epidermis, dermis, and hypodermis. The hypodermis is made of fat and connective tissue that anchors the skin to the underlying muscle. Above the hypodermis is the dermis, containing hair follicles, nerve endings, glands, blood vessels and lymphatics. And above the dermis is the epidermis, which contains 5 layers of developing keratinocytes. Keratinocytes start their life at the lowest layer of the epidermis, so the stratum basale or basal layer. As keratinocytes in the stratum basale mature, they migrate into the next layers of the epidermis, called the stratum spinosum, stratum granulosum, stratum lucidum, and finally, the stratum corneum, which is the uppermost and thickest epidermal layer.
Now, the stratum basale also contains the melanocytes, which produce a pigment called melanin from tyrosine. Melanin is then taken up by surrounding keratinocytes, and it contributes to the color of our skin, hair, and eyes. Now, what’s high yield is that melanin acts as a natural sunscreen that absorbs and dissipates, or scatters, UV radiation from the sun or other sources such as tanning booths, preventing it from penetrating the skin.
Now, this is important because UV radiation can damage the DNA of keratinocytes. This occurs mostly through the formation of pyrimidine dimers. Fortunately, most pyrimidine dimers are recognized and repaired by nucleotide excision repair enzymes, which can remove the damaged strand on both sides of the pyrimidine dimer. Now, what’s high yield is that sometimes the repair process doesn’t work and may leave transcriptional errors and mutations. These errors can occur in proto-oncogenes and tumor suppressor genes, increasing the risk of skin cancer. All right, so UV radiation exposure is definitely the number one risk factor for skin cancer, which is why most cases of skin cancer occur on sun-exposed skin regions, particularly the face, ears, neck, and hands. In general, fair skinned individuals are considered to be at a higher risk of developing skin cancer, and the risk increases with sun exposure over time. Other risk factors that affect the protection and repair mechanisms of the skin can also increase the risk of cancer and this include diseases like albinism and xeroderma pigmentosum. Albinism is caused by an autosomal recessive gene mutation encoding any one of the enzymes needed to produce melanin, typically tyrosinase. The result is a dysfunctional or deficient enzyme that drastically decreases the amount of melanin that’s made within normal melanocytes. As a result, there’s reduced or obliterated pigmentation of the skin, hair, and eyes, as well as increased risk of skin cancer. On the other hand, xeroderma pigmentosum is a rare inherited autosomal recessive disorder in which nucleotide excision repair enzymes are defective and cannot repair pyrimidine dimers. Individuals affected by xeroderma pigmentosum are at much higher risk of developing skin cancer. In addition, they can present dry skin, extreme sensitivity to light, and hyperpigmentation in sun exposed areas.
Now, skin cancer can be classified based on the type of skin cell that’s involved. The most common type of skin cancer is basal cell carcinoma, which involves cells in the stratum basale. Most cases occur in middle aged or elderly individuals, and typically appear as well circumscribed, pink, pearly, and waxy elevations of skin with small, dilated blood vessels running over it, also known as telangiectasias. In addition, these lesions can frequently develop central ulceration or crusting. Less commonly, they can appear as non-healing ulcers with infiltrating growth or as scaling plaques. The high yield classic location of a basal cell carcinoma is the upper lip, but are also found on the face and trunk. Basal cell carcinomas tend to be slow growing tumors that rarely metastasize to distant regions of the body, but can be locally invasive, invading into the basement membrane and spreading through the skin and surrounding structures. Diagnosis is based predominantly on clinical examination, although an excisional skin biopsy can be performed both to confirm diagnosis and for treatment. Upon skin biopsy, the classical finding are nests of basaloid cells with peripheral palisading nuclei. Now, the first line treatment is surgical excision, while nonsurgical candidates can get topical therapies such as imiquimod or 5-fluorouracil, curettage, photodynamic therapy, or radiation therapy.
Moving on, the second most common type of skin cancer is squamous cell carcinoma, which has a peak incidence at age 60. Risk factors include not only sun exposure, but also immunosuppression, chronic non-healing wounds, and arsenic exposure. Squamous cell carcinoma typically develops on surfaces exposed to the sun such as cutaneous surface, including the face, ears and hands. There are three stages of squamous cell carcinoma. First, there’s actinic keratosis, which is a precancerous lesion that can appear on sun exposed skin areas as small, erythematous or brownish papules or scaly plaques. The key here is that the lesion typically has a rough, sandpaper-like texture, along with central scaling. On skin biopsy, there are atypical keratinocytes that involve partial thickness of the epidermis only, while sparing the dermis. For treatment, topical chemotherapeutic agents like 5-fluorouracil can be given, as well as surgery, cryotherapy, or photodynamic therapy. After being treated, individuals should undergo frequent monitoring as a small percentage of actinic keratosis can go on to become squamous cell carcinomas.
Next, there’s Bowen disease, which is also called squamous cell carcinoma in situ, because it’s a cancerous lesion, but it does not extend into the dermis. It usually appears as small, erythematous, scaly, and well circumscribed elevations of the skin. They can often be confused for actinic keratosis, but they are typically more red and scaly, and can be tender and bleed. On skin biopsy, Bowen disease presents atypical keratinocytes that involve the full thickness of the epidermis without infiltration into the dermis. Treatment options are the same as those for actinic keratosis, followed by frequent monitoring for progression as well.
Finally, invasive squamous cell carcinoma can break through the basement membrane, extend into the dermis, and it may even reach the hypodermis. Now, squamous cell carcinoma rarely metastasizes, but it is more likely to do so than basal cell carcinoma. Another high yield contrast is that basal cell carcinoma typically appears on the upper lip, while squamous cell carcinoma typically appears on the lower lip. As for its clinical appearance, squamous cell carcinoma can appear as a firm, red, and well circumscribed elevation of the skin. As the lesion grows, the center may become necrotic and can eventually turn into an ulcer. In addition, some lesions may be painful or pruritic. The diagnosis is clinical, followed by excisional skin biopsy performed both to confirm diagnosis and for treatment. On skin biopsy, invasive squamous cell carcinomas have atypical keratinocytes that involve the full thickness of the epidermis, and penetrate the basement membrane into the dermis and deeper tissues. Another classic histologic finding to keep in mind is the formation of keratin pearls, which are deposits of keratin that are surrounded by concentric layers of atypical keratinocytes. First line treatment is surgical excision, but radiation, chemotherapy, or immunotherapy may also be options. And again, after getting successful treatment, individuals should be followed up.
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