Chapter 2 Basic Concept
2.3 Actinic Keratoses
Actinic keratoses are proliferations of transformed, neoplastic keratinocytes that are confined to the epidermis and induced by exposure to UV radiation in sunlight.
Neoplastic(of or related to or having the properties of a neoplasm,((腫瘤)瘤化的) transformation occurs in keratinocytes that have been exposed to UV radiation and is due primarily to mutations in the p53 gene. In times, these cells proliferate in the epidermis and eventually extend into the dermis, at which point metastatic(relating to or affected by metastasis, ((癌細胞的)轉移性,變性) spread can occur.[8] Cytologic atypia is visible in early stages and is identical to that seen in metastatic lesions or in SCC in the dermis. While these cells remain confined to the epidermis, the lesions that they cause are termed actinic keratoses, but when they extend more deeply to involve the papillary and/or reticular dermis, they are termed SCC. Thus, AK and SCC are rather a progression along a spectrum but not new.[31]
2.3.1 Clinical Presentation of Actinic Keratoses
Actinic keratoses occur on sun-exposed areas such as the face, lower lip, bald scalp, neck, arms, and hands. They appear as rough, scaly papules and plaques that range from skin tone to reddish brown. The papules and plaques range in size from 1 mm to 2.5 cm or more in diameter. Most affected individuals develop multiple lesions. Because AKs develop after years of sun damage, they occur on older patients and increase in number with age. We show clinical images of AKs in chapter 5.1.
The probability that AK would evolve into SCC was estimated at 0.075-0.096%
per lesion per year.[5] Therefore, for a person with an average of 7.7 lesions of AK, the incidence of SCC would be 10.2% in 10 years.[6] Other sources give even higher estimates, with rates of 13% to 20% of all untreated AK lesions of low and moderate grade will progress to SCC in situ and invade deeper dermal tissues if left untreated over a 10-year period.[32][33]
2.3.2 Histopathologic Features of Actinic Keratoses
The diagnosis of AK is usually made on the basis of clinical characteristics while a biopsy may be required to exclude deeper involvement especially when the lesion is large, bleeding, ulcerated, erythematous, indurated, or otherwise unusual. Because many other diseases cause the same symptoms. Several rare histologic variants, including pigmented, acantholytic (皮膚棘層鬆懈的), and hyperplastic (增生性，肥 大的) types, have also been described. All these rare variants share the characteristic
of atypical keratinolytic proliferation in the epidermis. For discussion in this thesis, only classical features will be mentioned in the comparation and discussion shown in Table 2.3.2.1. However, we still show some observed images on the above-mentioned rare histologic variants in Chapter 5.
In AK, microscopic changes are confined within the epidermis and initiate in the basal layer. Along the progress of the disease, aggregates of atypical, pleomorphic (多 形的) keratinocytes at the basal cells layer would extend to the granular and cornified layers. The epidermis thus demonstrates an abnormal architecture. The dermo epidermal junction appears irregular because of small round buds at the basal cells layer that protrude slightly into the upper papillary dermis. The basal layer of AK often looks closer crowding of atypical keratinocytes than normal basal layer. Hyperkeratosis(角 質層增厚) and parakeratosis(角質層角化不完全) are present in AK, the latter overlying the abnormal cells in the epidermis. The thickness of the stratum spinosum of AK is thicker than thickness of normal the stratum spinosum, which is called irregular acanthosis. Moreover, actinic keratoses almost always occur in association with solar elastosis and superficial inflammatory infiltrate in the dermis.
On cytologic grounds alone, AK contains atypical keratinocytes with loss of polarity, with nuclear pleomorphism, with disordered maturation, and with increased numbers of mitotic figures. Many of the keratinocytes are pleomorphic also in the cellular level.[34] Fig. 2.3.2.2(a) shows that an actinic keratosis demonstrates atypical keratinocytes along the basal layer with hyperchromatic nuclei and atypical maturation compared with the Fig. 2.3.2.2(b) which is the histology of normal skin. Thus, we
focused on the epidermis (especially the basal layer) in our in vivo clinical trials. Based on previous finding, here we summarize (Table 2.3.2.1) the histopathologic features in different epidermis layers, as the diagnosis criterion of our HGM studies of AKs.
Table 2.3.2.1 Histopathologic features of AK for diagnosis criterion of H&E and HGM images.
Fig. 2.3.2.2[35] (a) Histology (H&E) of AK. (b) Histology (H&E) of normal skin. Scale bar=20 μm. Copyright: J.
Lanoue, C. Chen, G. Goldenberg, “Actinic keratosis as a marker of field cancerization in excision specimens of cutaneous malignancies.” Cutis. 2016, 2016, 97:6 (415-420) with permission from Wolters Kluwer health, Inc.
2.3.3 Comparing AK and Normal Tissues with H&E Examination
Here we show some H&E examination images of AKs, with corresponding features in Table 2.3.2.1. This discussion will assist to form our judgement standard.
Fig. 2.3.3.1 (a)[36] Histology (H&E) of Bowenoid AK in the stratum corneum: parakeratosis/hyperkeratosis in the arrows. Copyright: own work in Wikimedia commons, Nephron. With permission from owner Nephoron. (b)[37]
Histology (H&E) of normal skin in the stratum corneum. Scale bar=20 μm. Copyright: A. Day, S. M. Holland, J. P.
Scurry, “Normal vulvar histology: variation by site.” Journal of Lower Genital Tract Disease, 2016, 20:1 (64-69) with permission from Wolters Kluwer health, Inc.
Fig. 2.3.3.1 shows the parakeratosis and hyperkeratosis, in comparison with the normal stratum corneum. From Fig. 2.3.2.2 (b), the thickness of the stratum corneum is one or two cell layers and the nuclei is disappeared. But in Fig. 2.3.3.1(a) keratinization is not complete in the labeled arrow “parakeratosis” due to the retention of nuclei. In the labeled arrow “hyperkeratosis” region, the thickness of the stratum corneum is thicker than the normal one due to proliferation of keratinocytes.
Fig. 2.3.3.2 Histology (H&E) of AK. Scale bar=20 μm. It is marked the different situations in the stratum spinosum and the stratum basale. Copyright: J. Lanoue, C. Chen, G. Goldenberg, “Actinic keratosis as a marker of field cancerization in excision specimens of cutaneous malignancies.” Cutis. 2016, 2016 ,97:6 (415-420) with permission from Wolters Kluwer health, Inc.
Fig. 2.3.3.2 shows the irregular acanthosis in the labeled location, where the thickness of the stratum spinosum is thicker than the thickness of the normal stratum spinosum in Fig. 2.3.2.2(b) and these cells are irregular. In Fig. 2.3.3.2, the circles show abnormal architecture in the stratum basale. These cells are in disordered array. Fig.
2.3.3.2 also shows the pleomorphism of cells and nuclei in the stratum spinosum and in the stratum basale. The shape of cells is not oval and cells vary in different size. In the stratum basale, Fig. 2.3.3.2 shows crowding of keratinocytes, where the cells are closer to each other than cells in Fig. 2.3.2.2(b). In the dermis, Fig. 2.3.3.2 shows the solar elastosis, where the elastosis fiber is purple. The normal collagen fiber is pink in the H&E section in Fig. 2.3.2.2(b). If the connective tissue is purple in H&E section, it means that solar elastosis happens. For all these histopathologic features of AK for diagnosis, the features in the stratum basale are the most important because the pathological changes started in the stratum basale in mild AK cases. The stratum corneum and the stratum spinosum are normal sometimes. For diagnosis in reality, the morphology of the stratum basale is also the main standard for pathologist.
2.3.4 Treatment
A variety of treatment options exist for AK, and the method most suitable varies depending on the size, location, and growth of the lesions, as well as on personal
preference. The most common treatment options are cryotherapy with liquid nitrogen, fluorouracil, and curettage. In our in vivo trails, we used cryotherapy to treat patients.
This treatment requires no anesthetic, and patients tolerate it well despite posttreatment swelling and blistering. The recurrence rate of AKs with this method, while unknown, appears to be low and has been estimated to be as low as 1.2%.[38]