Pathophysiology
Summary
Actinic keratosis, also known as solar keratosis, is primarily associated with cumulative UV light exposure. It typically affects the stratum corneum—the skin's most superficial layer, composed of dead, denucleated keratinocytes—and the stratum basale, which houses keratinocyte stem cells. A hallmark of actinic keratosis is the hyperplastic keratinocytes with cytologic atypia in the basal layer, though importantly, these does not invade the dermis. The basement membrane acts as a boundary between the epidermis and dermis, with the latter's projections, or papillae, extending into the epidermal layer.
Actinic keratosis and squamous cell carcinoma (SCC) share a strong association with mutations in the p53 tumor suppressor gene. UVB exposure in particular can induce DNA damage to the p53 gene, leading to unregulated keratinocyte proliferation. Clinically, actinic keratosis manifests as hyperkeratosis, causing the stratum corneum to thicken and form rough, raised lesions typically < 2 cm in size. These lesions have a whitish-brown scaly appearance, a result of parakeratosis, or abnormal retention of keratinocyte nuclei within the stratum corneum. A key histological feature is solar elastosis, thick deposits of damaged elastic tissue in the dermis due to UV damage. Older patients are the most likely to develop these lesions in sun-exposed areas such as the face, scalp, ears, and hands. A significant risk factor for actinic keratosis is hypopigmented skin, which lacks melanin's protective effect against UV light. Actinic keratosis can progress to SCC, with nearly half of SCC cases originating from actinic keratosis lesions.
Squamous cell carcinoma (SCC) is a malignant neoplasm of keratinocytes. It shares several risk factors with actinic keratosis, including cumulative UV exposure, fair skin, and TP53 mutations. SCC is more prevalent in older individuals, but other factors including chronic skin inflammation or scarring, arsenic exposure, and immunosuppression are also risk factors. Bowen's disease, or squamous carcinoma in situ, represents SCC that involves the entire epidermis but does not extend beyond the intact basement membrane into the dermis. In contrast, when dysplastic keratinocytes spread through the basement membrane, it progresses to invasive SCC. Histologically, SCC displays keratin pearls, concentric rings of eosinophilic keratin produced by the abnormal squamous cells. Regional lymph nodes are the most common site of metastasis in SCC.
Basal cell carcinoma (BCC) is the most common skin cancer globally and is also linked to age, UV light exposure, and fair skin complexion. However, the most significant risk factors for BCC are sunburns in childhood and childhood sun exposure. BCC is associated with inactivating mutations of the patched-1 (PTCH1) tumor suppressor gene, which subsequently activates the sonic hedgehog regulatory pathway, leading to unchecked cell proliferation.
Nodular BCC lesions features nodules and cords of palisading basophilic cells with a mucinous stroma in the dermis, often with central areas of pigmented erosion or ulceration. These nodules present as flesh-colored ‘pearly’ nodules with raised edges, commonly accompanied by telangiectasias. Nodules in BCC often occur on the upper lip, in contrast to the lower lip preference of SCC. Superficial BCC features round buds of cancer cells in the dermal papillae and epidermis covered by a scaly, erythematous papule or plaque. While BCC rarely metastasizes, it can invade surrounding structures, including cartilage and bone.
Lastly, xeroderma pigmentosum is an autosomal recessive condition that heightens the risk for skin cancers, including SCC, BCC, and melanoma. Xeroderma pigmentosum results from mutations in nucleotide excision repair renders, a mechanism that normally corrects DNA damage from UV radiation, such as the formation of pyrimidine dimers, resulting in extensive DNA damage when exposed to UV light.
Lesson Outline
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FAQs
Actinic keratosis, or solar keratosis, is a skin condition characterized by small, raised, rough papules with a whitish-brown scaly appearance. It primarily affects older patients in sun-exposed areas like the face, scalp, ears, and hands. The most significant risk factor for actinic keratosis is UV light exposure, especially in individuals with hypopigmented skin. UV exposure can lead to DNA damage in the p53 gene, promoting unregulated keratinocyte proliferation. This results in hyperkeratosis and the formation of these rough lesions. Over time, actinic keratosis holds the potential to transform malignantly into squamous cell carcinoma.
Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are both skin cancers, but they have distinct risk factors and clinical presentations. SCC is associated with cumulative UV exposure, fair skin, TP53 mutations, and areas of chronic skin inflammation or scarring. It commonly develops in sun-exposed areas like the head, neck, hands, and notably the lower lip. BCC, the most prevalent skin cancer globally, is linked to brief, intense sun exposure, such as sunburns during childhood. It's commonly associated with mutations in the patched-1 (PTCH1) tumor suppressor gene. BCC typically arises in sun-exposed areas like the lateral canthal folds and the upper lip, contrasting with SCC's predilection for the lower lip.
Basal cell carcinoma (BCC) presents histologically with nodules and cords of palisading basophilic cells accompanied by a mucinous stroma in the dermis. These nodules often exhibit nuclear palisading on their edges. Clinically, nodular BCC manifests as flesh-colored ‘pearly' nodules with raised, or rolled, edges, commonly accompanied by telangiectasias, BCC can also have central areas of pigmented erosion or ulceration. While BCC rarely metastasizes, it can invade surrounding structures like cartilage and bone.
Xeroderma pigmentosum is an autosomal recessive genetic condition that heightens the risk for skin cancers, including squamous cell carcinoma, basal cell carcinoma, and melanoma. Patients with this condition are unable to perform nucleotide excision repair, a process that typically corrects UV radiation-induced DNA damage. UV radiation can cause the formation of pyrimidine dimers, which are crosslinks between thymidine bases. In the absence of nucleotide excision repair, these patients accumulate extensive DNA damage upon UV light exposure, predisposing them to various skin cancers.
The p53 tumor suppressor gene plays a crucial role in actinic keratosis and squamous cell carcinoma (SCC). UV exposure, especially UVB, can lead to DNA damage in the p53 gene, resulting in unregulated keratinocyte proliferation. Actinic keratosis, a precursor to SCC, is strongly associated with mutations in the p53 gene. When these mutations persist, they can lead to the development of SCC. The p53 gene's primary function is to regulate the cell cycle and prevent cancer. When mutated, it can pave the way for malignant transformations in the skin.
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