Skin cancer: Pathology review

Definitions & Key takeaways

Skin cancer is a type of cancer that develops in the cells of the skin. Three main types of skin cancer are basal cell carcinoma (the most common), squamous cell carcinoma (the second most common), and the least common but most deadly, melanoma. Risk factors for skin cancer include exposure to UV radiation, a history of sunburns, fair skin, and a weakened immune system. Diagnosis is made with a tissue biopsy and treatments can include physically removing cells with a high risk of developing into skin cancer. Tumor cells are also commonly removed and treated with radiation, chemotherapy, or immunotherapy.

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Case study0:00–0:48

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.

Physiology0:48–2:17

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.

Pathophysiology2:17–4:28

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.

Basal cell carcinoma4:28–6:00

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.

Squamous cell carcinoma6:00–9:33

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.Okay, now, for your exams, you may need to differentiate between squamous cell carcinoma and keratoacanthoma, which can have a similar appearance.

Keratoacanthoma9:33–10:13

Keratoacanthoma is a benign skin tumor that originates from the hair follicle. The classic test question will describe a middle aged or elderly individual presenting with an erythematous, dome shaped nodule with a keratin filled center.
The best distinction between the two is the fact that keratoacanthomas grow very rapidly, and can reach 1-2 cm in diameter within a few weeks or months.
They can also regress spontaneously into an atrophic scar without treatment.Finally, the most aggressive form of skin cancer is melanoma, which involves melanocytes.

Melanoma10:13–13:32

Unlike basal and squamous cell carcinomas, melanoma has a high risk of metastasis, and is the most common cause of death from skin cancer.
Risk factors for melanoma, in addition to sunlight, include a family history of melanoma, and having many or atypical nevi or moles.
In addition, a large amount of melanomas are driven by an activating mutation in the BRAF V600E gene coding for BRAF kinase, which is a proto-oncogene resulting in uncontrolled growth signals.
Another common mutation which leads to formation of melanomas is in the tumor suppressor gene CDKN2A. Now, once a melanoma arises, it is characterized by two growth phases.
The first one is the horizontal or radial growth phase, where the melanoma grows horizontally within the epidermis and superficial dermis, and has a low risk of metastasis.
The second phase is the vertical growth phase, where the melanoma grows vertically and invades the dermis, which increases the risk of metastasizing to distant sites through blood or lymph nodes.
Now, the depth of invasion is known as Breslow thickness, and it is the single most important prognostic factor for predicting metastasis.
In other words, the depth of the tumor correlates with the risk of metastasis. Okay, melanomas can be classified into four major subtypes.
The most common one is superficial spreading melanoma, in which the horizontal growth phase is prolonged and, therefore, the prognosis is good.
The second most common is nodular melanoma, which presents as a nodule or lump and has an early vertical growth phase. As a result, this has the worst prognosis of all melanomas.
Next, there is lentigo maligna melanoma, which has horizontal growth that is relatively slow and lentiginous, so the prognosis is good.
And the last subtype is acral lentiginous melanoma, which arises on the palms, soles or nail beds, and it most often affects darker skinned individuals.Now, a good way to check and monitor for worrisome nevi and melanoma is to use the mnemonic ABCDE.
Malignant lesions are typically Asymmetrically shaped, Borders are irregular or notched, there are Color variations within the same lesion, the Diameter can become larger than 6mm, and the lesion rapidly Evolves over time and can cause skin elevation.
Definitive diagnosis and treatment are done with a complete full thickness excisional biopsy of the suspicious lesion with appropriate margins.
Upon immunohistochemistry, melanomas will stain positive for S100, which is a marker specific for melanocytes. If diagnosis of melanoma is confirmed, it is usually followed up with a wide surgical excision of the surrounding normal tissue to reduce the risk of recurrence.
Finally, metastatic melanomas that are positive for the BRAF V600E mutation may benefit from drug therapy with vemurafenib, which is a BRAF kinase inhibitor.All right, as a quick recap, the most important risk factor for skin cancer is long term exposure to UV radiation.

Review13:32–15:35

Basal cell carcinoma is the most common type of skin cancer. It originates from cells in the stratum basale and is frequently found on the upper lip.
It rarely metastasizes, but can be locally invasive. The second most common skin cancer is squamous cell carcinomas, which can have different stages.
The first one is actinic keratosis, which is a precancerous lesion with partial thickness of the epidermis. Next, Bowen disease is squamous carcinoma in situ, meaning that it is a cancerous lesion that involves the full thickness of the epidermis, but doesn’t invade the basal membrane or dermis.
Finally, there’s invasive squamous cell carcinoma, which breaks through the basal membrane and into the dermis. It is most commonly located on the lower lip, and can spread to lymph nodes, but rarely metastasizes.
Biopsy frequently shows keratin pearls. Keratoacanthoma is similar to squamous cell carcinoma, but originates from hair follicles, and presents as a rapidly growing dome shaped nodule with a keratin filled center.
Finally, the most aggressive form of skin cancer is melanoma, and is often driven by the V600E mutation in the BRAF gene.
Melanoma has a horizontal and a vertical growth phase. The vertical Breslow thickness is the single most important risk factor for predicting the risk for metastasis.
The worrisome signs of melanoma can be remembered using the mnemonic A B C D E. A is for asymmetry of the lesion, B for borders that are irregular, C for color variations, D for a diameter greater than 6mm, and E for evolution of the lesion over time.
Melanoma can be classified into superficial spreading, nodular, lentigo maligna, and acral lentiginous. Okay, back to our cases.
William presented with a pink, pearly lesion with surrounding telangiectasias on his right upper lip, which is classic for basal cell carcinoma.

Summary15:35–16:19

This was confirmed with a skin biopsy, which showed nests of cells with palisading nuclei. On the other hand, Shelby came in with a suspicious mole that was asymmetrically shaped, with irregular borders, varying coloration, diameter larger than 6 millimeters, and rapidly evolving over time.
These features point towards melanoma, which was confirmed with a full thickness excisional biopsy. Additional clues include William’s outdoor occupation and Shelby’s fair skin color, which are all risk factors for skin cancer.