Actinic Keratosis Pathology

Updated: Sep 24, 2015
  • Author: Neil M Coleman, MD; Chief Editor: Jon A Reed, MD, MS  more...
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Overview

Overview

Actinic keratosis is an erythematous scaly papule or plaque that develops on sun-damaged skin as a result of chronic exposure to ultraviolet radiation, typically in elderly patients with lighter skin types. This condition is related to squamous cell carcinoma of the skin and is often described as a precursor or early form of squamous cell carcinoma in situ, although most actinic keratoses will not progress to invasive squamous cell carcinoma.

The primary histologic feature is atypia or dysplasia of the keratinocytes in the basal layers of the epidermis (see an example in the image below). This is often accompanied by parakeratosis, thinning of the granular layer, buds of atypical epidermis extending toward the papillary dermis, dermal solar elastosis, and inflammation.

The epidermis show mild hyperkeratosis with dyspla The epidermis show mild hyperkeratosis with dysplasia of the basal keratinocytes and formation of small buds extending into the papillary dermis. There is prominent solar elastosis in the superficial dermis. The dysplastic changes primarily affect the epidermis between follicles. (Hematoxylin & eosin, 5× magnification.)

Actinic keratoses are extremely common, and the populations most at risk are older individuals with chronic sun-exposure and light skin. Millions of office visits to dermatologists each year are related to actinic keratosis. [1] One early estimate of the prevalence of actinic keratosis in the United States was 39.5 million. [2] Factors leading to an increased incidence of actinic keratosis include cumulative ultraviolet radiation exposure, increasing age, childhood sun exposure, male sex, and residing in latitudes close to the equator. [3]

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Etiology

Chronic exposure to ultraviolet light (UV) or sunlight is one of the most important factors in the development of actinic keratoses. Both UVB (290-320 nm) and UVA (320-400 nm) likely play a role in the development of these conditions. [4, 5] UV radiation acts as an initiator and promoter of carcinogenesis in actinic keratosis and squamous cell carcinoma. Overexposure to UV in normal skin will induce p53-dependent apoptosis, which may serve to protect the skin from damaged cells. These individual apoptotic keratinocytes are often referred to as "sunburn" cells and are seen histologically in the epidermis of skin overexposed to sunlight or UV radiation.

UV-induced mutations of the tumor suppressor gene TP53 are of major importance in the development of actinic keratosis. Basal keratinocytes with mutated TP53 may not respond normally to UV-induced apoptosis, allowing further proliferation and development of new genetic abnormalities. [6, 7, 8, 9]

Immunosuppression can also contribute to the development of actinic keratosis. Solid organ transplant patients are at increased risk for actinic keratosis and squamous cell carcinoma. Some drugs may act as photosensitizers, increasing susceptibility to UV radiation, whereas others may increase the risk for squamous cell carcinoma regardless of exposure to UV radiation. [10] However, it has been proposed that some medications actually reduce the risk for actinic keratosis; regular users of nonsteroidal anti-inflammatory drugs (NSAIDs) may appear to have reduced counts of actinic keratosis. [11]

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Clinical Features

Areas of skin that are heavily exposed to ultraviolet (UV) light are the most common locations for actinic keratoses. These common areas include the upper limbs, face, forehead, ears, and neck. Actinic keratoses that develop on the lips are referred to as actinic cheilitis. [12]

The clinical appearance of an actinic keratosis is that of a small (several millimeters), red scaly papule or plaque, with induration and thickening of the epidermis. There may be associated erythema. Often, more than one actinic keratosis will be present, and the lesion may show signs of secondary trauma from excoriation or chronic rubbing. A cylindrical hyperkeratotic cutaneous horn may develop in some cases. [13]

Tumor staging does not apply to actinic keratosis. Squamous cell carcinomas that arise in association with actinic keratosis typically have a low risk for metastasis. [14, 15]

Differential diagnosis

Consider the following conditions when evaluating a patient with suspected actinic keratosis pathology:

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Gross and Microscopic Features

Hyperkeratosis may be apparent grossly in the typical shave biopsy specimen.

Histologically, actinic keratoses show dysplastic changes of the basilar layers of the epidermis, typically associated with parakeratosis, and some degree of dermal solar elastosis. The dysplastic changes may include nuclear enlargement and pleomorphism, nuclear hyperchromatism, increased or atypical mitoses, as well as cytoplasmic pallor. Buds of dysplastic epidermis may extend toward the papillary dermis. In some cases, these buds may be difficult to distinguish from superficially invasive squamous cell carcinoma, especially in a superficial shave biopsy. The dysplastic epidermal changes typically spare the cutaneous appendages. There may be hyperpigmentation of the epidermis, trauma-related changes (ulceration, lichen simplex chronicus), as well as an inflammatory response. [16, 17, 18] See the following images.

The epidermis show mild hyperkeratosis with dyspla The epidermis show mild hyperkeratosis with dysplasia of the basal keratinocytes and formation of small buds extending into the papillary dermis. There is prominent solar elastosis in the superficial dermis. The dysplastic changes primarily affect the epidermis between follicles. (Hematoxylin & eosin, 5× magnification.)
The basal keratinocytes show dysplastic changes, i The basal keratinocytes show dysplastic changes, including nuclear enlargement, hyperchromasia, increased cytoplasm, and form small buds that extend into the papillary dermis. There is subtle hyperkeratosis of the stratum corneum. (Hematoxylin & eosin, 10× magnification.)

Variants or subtypes of actinic keratosis that have been described include pigmented, hypertrophic, atrophic, lichenoid, proliferative, acantholytic, and Bowenoid. [16, 17, 18] Pigmented actinic keratosis may show heavy melanin pigmentation of the basal layer keratinocytes, and clinically and histologically these may mimic a melanocytic proliferation, as seen in the following image. [19]

Acantholysis is present in this actinic keratosis. Acantholysis is present in this actinic keratosis. The degree of acantholysis can vary. Such a lesion may show histologic overlap with Grover disease and Darier disease. (Hematoxylin & eosin, 10× magnification.)

The dorsal hand is a common place for hypertrophic actinic keratosis. Such lesions often show changes of lichen simplex chronicus due to chronic irritation and rubbing of the lesion (see the first image below). [20] Lichenoid actinic keratosis will show some degree of interface change with associated lymphocytic infiltrate within the superficial dermis (see the second image below). Changes of lichen simplex chronicus accompany many atypical squamoproliferative lesions, such as hypertrophic actinic keratosis and squamous cell carcinoma. Beware of a superficially sampled lesion, especially on sites such as the dorsal hand or forearm.

A hypertrophic/hyperplastic actinic keratosis from A hypertrophic/hyperplastic actinic keratosis from the dorsal hand. It is not uncommon to see changes of lichen simplex chronicus, in addition to the dysplastic epidermal changes. (Hematoxylin & eosin, 5× magnification.)
This lichenoid actinic keratosis showed interface This lichenoid actinic keratosis showed interface changes, including apoptotic basal keratinocytes and a bandlike infiltrate of lymphocytes in the superficial dermis. (Hematoxylin & eosin, 10× magnification.)

Acantholytic actinic keratosis may mimic other conditions associated with acantholysis, such as Grover disease, Darier disease, and warty dyskeratoma, as well as seborrheic keratosis with acantholysis (see the image below).

Acantholysis is present in this actinic keratosis. Acantholysis is present in this actinic keratosis. The degree of acantholysis can vary. Such a lesion may show histologic overlap with Grover disease and Darier disease. (Hematoxylin & eosin, 10× magnification.)

There is a histologic spectrum between actinic keratosis and squamous cell carcinoma, and the line between the actinic keratosis and squamous cell carcinoma in situ can sometimes be arbitrary. Some authors have proposed a revision in nomenclature to address this issue, suggesting the term keratinocytic intraepidermal neoplasia or keratinocytic intraepidermal malignant neoplasia (KIN), using a 3-tiered grading system. [21, 22] The term actinic keratosis, however, is still commonly used in clinical practice.

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Immunohistochemistry

Immunohistochemistry or special stains typically play a very limited role in the routine diagnosis of actinic keratosis. The histologic changes alone in most cases are sufficient to render the diagnosis.

With some pigmented actinic keratoses, especially on atrophic sun-damaged skin, melanocytic markers (S100, Melan-A/Mart-1, MiTF, tyrosinase) may be useful to rule out an atypical lentiginous melanocytic proliferation in cases in which it is difficult to sort out atypical keratinocytes from atypical melanocytes. Care should be taken in interpretation of these stains, as some pigmented actinic keratoses may show increased labeling with Melan-A/Mart-1 in keratinocytes, leading to an over diagnosis of melanoma in situ. [23] In addition, Melan-A-positive "pseudomelanocytic nests" have been described in a lichenoid dermatitis on sun-damaged skin, which may mimic melanoma in situ histologically; correlation with the clinical presentation (and perhaps additional biopsy) is often necessary. [24, 25, 26]

Different patterns of staining with MIB-1 and p53 have been shown with actinic keratosis and Bowen disease. P53 and MIB-1 stain the lower portions of the epidermis and the basal layer of the epidermis in actinic keratosis, whereas in Bowen lesions, the staining occurs throughout the epidermis, with lack of staining in the basal layer. [27, 28] Diffuse epidermal expression of p16INK4a may also help distinguish Bowen disease/squamous cell carcinoma in situ from actinic keratoses, in which staining is rare and typically limited to the basal layer. [29, 30]

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Molecular and Genetic Alterations

Ultraviolet (UV) radiation induces abnormalities that initiate and promote the development of actinic keratosis. Many of the same genetic alterations are found in cutaneous squamous cell carcinoma as well as other malignancies. The interplay of alterations in cell cycle regulators, signal transduction pathways, and other genetic alterations in the development and progression of actinic keratoses to squamous cell carcinoma is a subject of great interest and active research.

Mutations in TP53 appear to play a crucial role in the development of actinic keratosis. [7, 31] When exposed to UVB light, mice with severe combined immune deficiency (SCID) with transplanted human skin will develop actinic keratoses associated with specific TP53 mutations. [32] UVB light has also been shown to downregulate the tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) in actinic keratosis, via an ERK (extracellular signal-regulated kinase)/AKT–dependent mechanism. [33]

The immunosuppressive cyclosporin may also affect the PTEN/AKT pathway in the development of actinic keratosis. [34] Overexpression of matrix metalloproteinase-1 (MMP-1) is also associated with early development of actinic keratosis and metalloproteinases may also play a role in mediating the epidermal growth factor receptor (EGFR)/ERK/AKT/cyclin D1 pathways and cell cycle progression induced by UVB radiation. [35, 36]

Actinic keratosis has been shown to have higher frequency of loss of heterozygosity on several chromosome arms. [37] Upregulation of p53, bcl-2, and cyclin D protein expression as well as activated ras genes have been shown in actinic keratosis. [38, 39, 40, 41] MYC numeric aberrations have been detected in one third and EGFR to one half of actinic keratoses. [42, 43]

Other proteins identified as having overexpression in actinic keratoses include p63, survivin, and telomerase reverse transcriptase (TERT). [44] Gene expression profiling of actinic keratosis and squamous cell carcinoma have shown similar patterns of gene expression, when compared with non–sun-exposed and sun-exposed skin. [45]

A study indicated that the mitogen activated protein kinase pathway may be pivotal to the transition from actinic keratoses to cutaneous squamous cell carcinoma and that this may represent a potential target for cutaneous squamous cell carcinoma prevention. [46]

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Prognosis

Although the majority of cutaneous squamous cell carcinomas arise from or in association with actinic keratosis, the risk of progression of actinic keratosis to squamous cell carcinoma is low. No reliable histologic criteria have been established that predict which actinic keratoses will progress to squamous cell carcinoma in situ or invasive squamous cell carcinoma. Published estimates have ranged from 0.025% and 20% per year/per lesion, although few longitudinal studies have been performed. [3]

A longitudinal study that sought to quantify risk of progression in actinic keratoses of the face and ears in a high-risk, predominantly male population of patients in the United States found that the risk of progression from actinic keratosis to squamous cell carcinoma (either in situ or invasive) was 0.60% at 1 year and 2.57% at 4 years of follow-up. [47] For progression from actinic keratosis to primary invasive squamous cell carcinoma, the risk was 0.39% at 1 year and 1.97% at 4 years of follow-up.

This same study found that the majority of clinically diagnosed actinic keratoses were not found at 1-year (55%) and 5-year (70%) follow-up intervals. [47] An Australian study with longitudinal follow-up estimated the risk of progression from actinic keratosis to squamous cell carcinoma in 1 year at less than 1 in 1000. [48]

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