These very common lesions are pre-skin cancers. They are also known as solar keratosis linking it with the damaging effects of solar irradiation. They are especially predominant in fair skinned individuals occurring on sun-exposed areas. It is estimated that 10-20% will transform into squamous cell carcinomas if left untreated. Some important variants include hyperplastic, pigmented, and lichenoid. The usual appearance is a scaly, erythematous lesion.
Under the microscope, there is parakeratosis overlying dysplastic epithelium, most pronounced in the basal layers of the epidermis. Extensive solar elastosis is usually present in the dermis. The diagnosis is usually straightforward although the pathologist is sometimes faced with deciding whether the lesion has progressed to a superficial squamous cell carcinoma. The general rule of thumb is protrusion of the aytpical keratinocytes into the reticular dermis with detachment of individual nests.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/
Other Diagnostic Testing
Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGIC ASSOCIATIONS CHARACTERIZATION
Reliability of Counting Actinic Keratoses Before and After Brief Consensus Discussion The VA Topical Tretinoin Chemoprevention (VATTC) Trial
Martin A. Weinstock, MD, PhD; Stephen F. Bingham, PhD; Gary W. Cole, MD; David Eilers, MD; Mark F. Naylor, MD; James Kalivas, MD; J. Richard Taylor, MD; Hayes B. Gladstone, MD; Daniel J. Piacquadio, MD; John J. DiGiovanna, MD
Arch Dermatol. 2001;137:1055-1058 Abstract quote
Objective To assess the reliability of counts of actinic keratoses (AKs) and the effect of a brief joint discussion of discrepancies on that reliability.
Design and Intervention Seven dermatologists independently counted AKs on the face and ears before and after a brief joint discussion of discrepancies.
Setting and Patients A volunteer sample of 9 patients from the ongoing VA (Department of Veterans Affairs) Topical Tretinoin Chemoprevention (VATTC) Trial. All participating individuals are veterans and have had 2 or more keratinocyte carcinomas (basal or squamous cell carcinoma) in the 5 years before enrollment in the study.
Main Outcome Measure Standard deviation of estimates of the Poisson regression parameter for the dermatologists.
Results Substantial variation was found among the dermatologists in their AK counts. The SD of the parameter estimates for the dermatologists decreased from 0.45 to 0.24 after the brief joint discussion, a 47% decrease (P = .076). The variation attributable to the dermatologists also decreased substantially (26 decrease, 94 to 12).
Conclusions Actinic keratoses are common, and there is a continuous spectrum of lesions that ranges from sun-damaged skin to squamous cell carcinoma in situ. Clinical distinguishing features may be difficult to delineate precisely. Counts of AK are commonly performed, but appear to be unreliable, even when performed by experienced dermatologists. Joint discussion of discrepancies may enhance the reliability of these counts, although substantial variation remains. Research that relied on these counts must be reevaluated in light of the marked variation among expert observers. Future studies should consider measures to assess and enhance reliability.
DISEASE ASSOCIATIONS CHARACTERIZATION PSORIASIS Are patients with psoriasis susceptible to the classic risk factors for actinic keratoses?
Paltiel O, Adler B, Herschko K, Tsukrov B, David M.
School of Public Health and the Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Arch Dermatol. 2004 Jul;140(7):805-10. Abstract quote
BACKGROUND: An increased prevalence of benign solar damage (eg, facial wrinkles) but not neoplastic lesions was observed among patients with psoriasis who were exposed to Dead Sea climatotherapy compared with controls.Objectives To compare the prevalence of actinic keratosis in psoriatic patients and controls and to assess whether known risk factors behave similarly in both groups.
DESIGN: Multicenter cross-sectional study.
SETTING: Dermatology clinics in 4 participating Israeli hospitals and at a Dead Sea clinic.
PARTICIPANTS: Adult subjects (n = 460) with plaque-type psoriasis were recruited from the Israel Psoriasis Association (volunteer sample) and from dermatology clinics (convenience sample). The control group (n = 738) consisted of nonimmunosuppressed patients attending these clinics for benign conditions unrelated to sun exposure, such as atopic or contact dermatitis.
MAIN OUTCOME MEASURES: Prevalence and distribution of actinic keratoses and odds ratios associated with skin, hair, and eye color and propensity or history of sunburn adjusted for age, ethnicity, and sun exposure.
RESULTS: Actinic keratoses were observed in 200 controls (27%) and 51 subjects (11%) (P<.001). This increased prevalence occurred in both sexes, participants aged 35 years or older, all ethnic groups, smokers, and nonsmokers. The anatomical distribution of lesions did not substantially differ between subjects and controls. In multivariate analysis, psoriasis conferred a protective effect (odds ratio, <1), as did dark skin, dark eyes, and a history of severe sunburn in childhood. However, significant interactions were observed between psoriasis and hair color as well as psoriasis and propensity to sunburn, whereby a linear association was observed for controls but not for patients with psoriasis.
CONCLUSIONS: Psoriasis confers protection against actinic keratosis. Hair color and propensity to sunburn exert differential effects among psoriatic patients and controls.
PATHOGENESIS CHARACTERIZATION GENERAL
Comparative histochemical study of Bowen's disease and actinic keratosis: preserved normal basal cells in Bowen's disease.
Ishida H, Kumakiri M, Ueda K, Lao LM, Yanagihara M, Asamoto K, Imamura Y, Noriki S, Fukuda M.
Department of Dermatology, Fukui Medical University, Yoshida-Gun, Japan.
Eur J Histochem 2001;45(2):177-90 Abstract quote
The degree of DNA-instability as revealed by immunohistochemical staining with anti-cytidine antibody after acid hydrolysis (DNA-instability test) has been recently used as a marker of malignancy.
This technique was applied to examine 17 skin tissue samples of Bowen's disease, 47 of actinic keratosis, 15 of squamous cell carcinoma, 5 of seborrheic keratosis, and 10 of normal skin. All benign neoplastic cells of seborrheic keratosis and normal epidermal cells were negative. On the other hand, all cancer cells were positive with the DNA-instability test, indicating their malignancy, but all basal cells in Bowen's disease were completely negative. Compatible with this result, the basal cells in Bowen's disease were characteristically normal as evident in other histochemical examinations. Thus, they were negative with p53 immunohistochemistry, with normal signals of chromosome 17 in situ hybridisation and argyrophilic nucleolar organiser region, and showed slightly enhanced proliferative activity as revealed by proliferating cell nuclear antigen immunohistochemistry.
Immunohistochemical staining with 34 beta E12 (monoclonal antibody against cytokeratins 1, 5, 10, and 14), which stains all normal epidermal keratinocytes including basal cells, showed that only the basal cells of Bowen's disease stained strongly and homogeneously, while all cancer cells in the upper layers of Bowen's disease and all layers of actinic keratosis were only sporadically or weakly stained. Staining with 34 beta B4 (monoclonal antibody against cytokeratin 1), which recognises the whole epidermis except for the basal layer in the normal epidermis, showed that the basal cells in the Bowen's disease were completely negative, and lower layer cells in the actinic keratosis and upper layer cells in Bowen's disease were only sporadically stained positive, although the superficial layer cells in actinic keratosis stained strongly and homogeneously.
Our findings clearly indicate that the basal cells in Bowen's disease are normal. In support of this conclusion, the same cells showed normal morphology on electron microscopy with preserved basement membrane, although the latter was often damaged in actinic keratosis.
Differential expression of proliferation- and apoptosis-related markers in lentigo maligna and solar keratosis keratinocytes.
Feinmesser M, Tsabari C, Fichman S, Hodak E, Sulkes J, Okon E.
Am J Dermatopathol. 2003 Aug;25(4):300-7 Abstract quote.
Keratinocytes influence the number, morphology, and proliferation of melanocytes. An interference in the melanocyte-keratinocyte relationship may contribute to melanoma development.
This study examined the expression of apoptotic and proliferative markers in keratinocytes in lentigo maligna to characterize the epidermis permissive to these lesions. Formalin-fixed and paraffin-embedded tissues from 25 samples of lentigo maligna, 20 samples of solar keratoses, and 5 samples each of normal sun-exposed and non-sun-exposed skin (controls) were immunostained with antibodies directed against the proapoptotic markers bax and p53, the antiapoptotic marker bcl-2, and the proliferation marker ki-67. Eight percent of the lentigo maligna samples were positive for keratinocyte expression of bcl-2, 24% were positive for p53, and 76% were positive for bax; respective findings for solar keratoses were 35%, 85%, and 90%.
Comparison with normal sun-exposed skin yielded lower rates of keratinocyte proliferation in 56% of the lentigo maligna samples, similar rates in 36%, and higher rates in 8%; for solar keratoses, proliferation was higher than controls in 60% of samples, similar in 35%, and lower in 5%. All these differences were statistically significant. These findings indicate that there are variable patterns of epidermal reaction to chronic sun exposure. The epidermis in lentigo maligna shows overall low proliferation and an apparently low apoptotic tendency.
The dysfunctional epidermis may be permissive to aberrant melanocyte proliferation in the early stages of melanoma development.
J Cutan Pathol. 2006 Feb;33(2):129-38. Abstract quote
Background: beta(1)-integrins, which localize to the basolateral surface of basal keratinocytes, are important in the differentiation control and proliferation of the epidermis. Many cutaneous diseases with perturbed differentiation, including arsenical keratosis, show altered patterns of integrin distribution and expression. Arsenic may induce arsenical keratosis through the differentiation and apoptosis aberration by integrins. The purpose of this study is to investigate the role of integrin and arsenic in the pathogenesis of arsenical keratosis.
- Methods: Twenty-five specimens obtained from 25 patients with arsenical keratosis disease were studied. Immunohistochemistry staining to beta(1), alpha(2)beta(1), or alpha(3)beta(1) integrins was performed in arsenical keratosis and clinically normal perilesional skin. Western blotting was used to assess the expression of integrin beta(1) and focal adhesion kinase (FAK) in arsenic-treated cultured keratinocytes.
- Results: A decreased expression of beta(1), alpha(2)beta(1), or alpha(3)beta(1) integrins was demonstrated in arsenical keratosis and clinical normal perilesional skin in a large proportion of arsenical keratosis cases studied. The expressions of integrin beta(1) and FAK were both decreased in arsenic-treated keratinocytes.
- Conclusions: Our results suggest that arsenic induces abnormal differentiation in arsenical keratosis via the effects of integrin expression in keratinocytes.
BETAPAPILLOMA-VIRUS Sun-Related Factors, Betapapillomavirus, and Actinic Keratoses
A Prospective Study
Arch Dermatol. 2007;143:862-868. Abstract quote
Objective To examine prospectively the relationship among sun exposure, Betapapillomavirus, and development of actinic keratoses.
Design Prospective, community-based cohort study.
Setting Township of Nambour in Southeast Queensland, Australia.
Participants A total of 291 randomly selected adults aged 36 to 86 years with the presence or absence of Betapapillomavirus DNA in eyebrow hair follicle cells known at baseline in August 1996 and with subsequently documented sun exposure histories.
Main Outcome Measures Prevalence of actinic keratoses in March 2003 after 7 years of follow-up.
Results Beyond the known determinants of multiple actinic keratoses, namely, advanced age, male sex, fair skin, and lifetime occupational sun exposure, Betapapillomavirus infection was associated with having more than 10 actinic keratoses (odds ratio, 1.8; 95% confidence interval, 0.7-4.4). However, Betapapillomavirus positivity led to a significant 13-fold increase in the risk of actinic keratoses among those 60 years or older, a nearly 6-fold increase in risk when combined with fair skin color, and a doubling in risk of actinic keratoses when combined with high sun exposure, recent or cumulative, compared with those who had neither Betapapillomavirus infection nor the respective risk factor of interest.
Conclusions Although the presence of Betapapillomavirus DNA in eyebrow hair follicle cells had only a small independent association with actinic keratoses, Betapapillomavirus infection in combination with key risk factors increased the risk of actinic keratoses, which is consistent with a potentiation by Betapapillomavirus of the effect of established causal factors.
Chromosomal aberrations in squamous cell carcinoma and solar keratoses revealed by comparative genomic hybridization.
Ashton KJ, Weinstein SR, Maguire DJ, Griffiths LR.
Genomics Research Centre, Griffith University-Gold Coast, Bundall, Queensland, Australia.
Arch Dermatol. 2003 Jul;139(7):876-82. Abstract quote
OBJECTIVE: To identify chromosomal copy numbers of frequent genetic aberrations within squamous cell carcinomas (SCCs) and solar keratoses (SKs), and provide further evidence to support or challenge current dogma concerning the relationship between these lesions.
DESIGN: Retrospective analysis of genetic aberrations in DNA from SK and SCC biopsy specimens by comparative genomic hybridization.
SETTING: University-based research laboratory in Queensland, Australia.
PATIENTS: Twenty-two biopsy specimens from patients with diagnosed SKs (n = 7), cutaneous SCCs (n = 10), or adjoining lesions (n = 5).
MAIN OUTCOME MEASURES:Identification of frequent genetic aberrations both specific to SK and SCC and shared by these lesions to investigate their clonal relationship.
RESULTS: Shared genomic imbalances were identified in SK and SCC. Frequent gains were located at chromosome arms 3q, 17q, 4p, 14q, Xq, 5p, 9q, 8q, 17p, and 20q, whereas shared regional losses were observed at 9p, 3p, 13q, 17p, 11p, 8q, and 18p. Significant loss of 18q was observed only in SCC lesions.
CONCLUSIONS: Our results demonstrate that numerous chromosomal aberrations are shared by the 2 lesions, suggesting a clonal relationship between SK and SCC. Additionally, the genomic loss of 18q may be a significant event in SK progression to SCC. Finally, the type and frequency of aberrations suggests a common mode of tumorigenesis in SCC-derived tumors.
Immunohistochemical comparison of p16 expression in actinic keratoses and squamous cell carcinomas of the skin.
Hodges A, Smoller BR.
Departments of Pathology (AH, BRS) and Dermatology (BRS), University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Mod Pathol 2002 Nov;15(11):1121-5 Abstract quote
There are approximately 200,000 new cases of cutaneous squamous cell carcinoma diagnosed each year in the United States, with between 1300 and 2300 deaths per year from metastatic disease. The tumor suppressor p16, encoded by the CDKN2/INK4a locus, has been reported mutated in >/=24% of squamous cell carcinomas. Mutations of the p16 gene have also been found in actinic keratoses, the first identifiable lesion in the continuum from normal skin to squamous cell carcinoma. We hypothesized that there may be an appreciable difference in expression of p16 between normal skin, actinic keratoses, squamous cell carcinoma in situ, and invasive squamous cell carcinoma.
Ten actinic keratoses, 10 in situ squamous cell carcinomas, and 10 invasive squamous cell carcinomas were examined using the immunoperoxidase method with antigen retrieval for anti-p16(INK4a) antibody. All 10 actinic keratoses were positive for weak to moderate p16 staining in the lower third to lower half of the epidermis (especially the basal keratinocytes). This staining was significant when compared with the lack of staining seen in normal skin controls. Twenty percent of in situ squamous cell carcinomas had moderate to strong staining in only the lower half to lower two thirds of the epidermis, whereas 70% of the in situ squamous cell carcinomas exhibited full-thickness p16 staining, with no staining in the dermis. Thirty percent of invasive squamous cell carcinomas had full-thickness staining of the in situ component of the lesion, and 100% of invasive squamous cell carcinomas exhibited moderate to strong staining of the invasive component of the lesion.
These findings indicate correlation between the increased expression of p16 during the progression of skin from actinic keratosis to in situ squamous cell carcinoma to invasive squamous cell carcinoma. These data may lend further support to the view of the actinic keratosis as a precursor lesion to squamous cell carcinoma.
- J Cutan Pathol. 2006 Nov;33(11):716-720 Abstract quote
Background: Tenascin is an extracellular matrix protein frequently expressed around neoplastic and non-neoplastic lesions of the skin. Actinic keratoses (AKs) are intraepidermal neoplastic lesions of the sun-exposed skin. They are classified according to the extension of dysplasia in four stages; they also present different histological varieties.
Methods: We performed an immunohistochemical study using tenascin monoclonal antibody diluted 1 : 50 on 150 cases of AKs classified, respectively, in histotypes (38 hypertrophic, 18 atrophic, 21 bowenoid, 19 acantolytic, and 40 mixed) and in stages (27 stage I, 46 stage II, 42 stage III, and 35 stage IV; 14 in tumoral progression).
Results: Tenascin positivity was observed in all cases at the dermal level close to the epithelial lesion. The intensity of reaction increased from stage I to stage IV and, of course, also in tumoral progression. Its expression was not related to the histotypes. In very few cases, the atypical keratinocytes were positive.
Conclusions: Tenascin expression in AKs is related to the stages of dysplasia. In fact, the immunostaining intensity corresponds to the degree of the dysplasia rather than the thickness of the involved epidermis. Tenascin plays a role in neoplastic progression working as an anti-adhesive factor.
HISTOLOGICAL TYPES CHARACTERIZATION
J Cutan Pathol. 2005 Sep;32(8):546-51. Abstract quote
Diagnostic concordance of intraepithelial malignancy is generally only fair. Because the diagnosis of actinic keratosis (AK) and squamous cell carcinoma (SCC) is not uniform and because such terms are not consonant with the nomenclature of other human epithelial malignancies, nomenclature revisions have been attempted.
One hundred dermatopathologists were solicited to review 15 tissue sections representing a spectrum of varying thickness epidermal malignancy and to choose either AK or SCC as the diagnosis. Among the 77 participating dermatopathologists, intraclass correlation was high for what was perceived as AK, SCC, and their differentiation.
Development of a two-tiered diagnostic system that retains our present diagnostic capabilities, but better fits the pathobiology of superficial epidermal malignancy is suggested.
VARIANTS PIGMENTED ACTINIC KERATOSIS
S100A Protein Expression in the Distinction Between Lentigo Maligna and Pigmented Actinic Keratosis.
Ribe A, McNutt NS.
Am J Dermatopathol 2003 Apr;25(2):93-9 Abstract quote
Lentigo maligna (LM), a type of malignant melanoma in situ, and pigmented actinic keratosis (PAK) may have similar clinical appearances but are different in prognosis and treatment.
Diagnosis is established by skin biopsy. In certain cases, microscopic features may be very similar in both entities, making it difficult to determine whether the pigmented atypical cells are keratinocytes or melanocytes. Immunohistochemical markers can be useful for the identification of melanocytes in these cases. There are limitations to the use of some standard immunohistochemistry markers, however. S100 proteins are a varied group of proteins that are of special interest because of their dysregulated expression in neoplastic disorders. Their expression is changed during malignant transformation, progression, and/or metastasis in various cell lines and tumors, including melanomas.
Our study analyzed the expression of several of the S100 protein subtypes (S100A2, S100A6, and S100A8/A9 or A12) in 38 LM cases and 44 PAK cases to define their potential value in the distinction between these entities together with their role in the development of early malignant melanoma of the skin.
The results showed an upregulation of S100A2 protein in atypical keratinocytes in PAK and in normal keratinocytes adjacent to melanoma cells in LM. There was also an upregulation of S100A8/A9 or A12 protein, as detected by the antibody MAC387, in normal keratinocytes adjacent to both atypical keratinocytes and melanocytes in PAK and LM, respectively. There were statistically significant differences in the level of positive cells and in the pattern of immunoreactivity for anti-S100A2 and MAC387 in each entity, however. Moreover, the findings of our study support the notion that melanocyte-keratinocyte interactions are abnormal in both of these disease entities and may be involved in their progression.
Histologic features of actinic keratoses in solid organ transplant recipients and healthy controls
Alan S. Boyd, MD Thomas Stasko, MD Gregory S. Cameron, PhD Mark Russell, MD Lloyd E. King Jr, MD, PhD
Nashville, Tennessee, Muncie, Indiana, and Charlottesville, Virginia
J Am Acad Dermatol 2001;45:217-21 Abstract quote
Background: Squamoproliferative lesions are common in patients who are immunosuppressed, particularly in recipients of solid organ transplants. Histologic features in such biopsy specimens may differ from those of otherwise healthy patients. Actinic keratoses (AKs) in transplant recipients may possess pathologic characteristics that suggest that they arose in an immunosuppressed host.
Objective: We evaluated 30 randomly selected AKs from 25 recipients of solid organ transplants and compared their histologic features to those of 50 AKs from 45 patients who were not immunosuppressed.
Methods: Tissue samples were categorized by sex, patient age, and site of biopsy. Sixteen separate histologic criteria were evaluated in a blinded fashion in each specimen. Statistical analysis was performed between the two groups with and without controlling for the age of the patient. Results: The transplant group was significantly younger (54.8 years) than the nontransplant group (70.0) and contained more men (88%) than women (51%). AKs from transplant recipients were statistically more likely to demonstrate bacterial colonization, confluent parakeratosis, hyperkeratosis, increased mitotic activity, and verrucous changes. After controlling for age only, hyperkeratosis failed to be more prevalent in the transplant group.
Conclusion: Certain histopathologic features are more common in AKs of immunosuppressed transplant recipients and may be used to distinguish between those removed from otherwise healthy persons.
P27 and mib1 expression in actinic keratosis, Bowen disease, and squamous cell carcinoma.
Oh CW, Penneys N.
Department of Dermatology, College of Medicine, GyeongSang National University, Chinju, South Korea.
Am J Dermatopathol. 2004 Feb;26(1):22-6. Abstract quote
The histologic boundary between actinic keratosis, Bowen disease, and invasive squamous cell carcinoma is not clear in many cases. We determined nuclear expression of p27 (a protein associated with cellular quiescence) and Ki-67 (a marker of proliferation) immunohistochemically in actinic keratosis, Bowen disease, and squamous cell carcinoma to see if differential patterns of expression for p27 exist and how these might correlate with Ki-67 expression.
We determined a labeling index for p27-stained nuclei and assessed the pattern of Ki-67 expression. The student's t test was used to evaluate the p27 labeling index. The p27 labeling index was decreased in invasive aggregates of squamous cell carcinoma (76.9+/- 1.1%) when compared with those of normal epidermis (97.2+/- 2.4%), actinic keratosis (95.3 +/- 1.4%), and Bowen disease (98.0+/- 0.5%). Ki-67 was expressed in a scattered to confluent linear pattern in the basal/parabasal cell layer of normal epidermis and actinic keratosis. Keratinocytes in squamous cell carcinoma exhibited Ki-67 in the peripheral layers of the neoplasm and frequently within the tumor aggregates. Ki-67 was observed in nuclei throughout the full thickness of the epidermis in Bowen disease.
The staining pattern of Ki-67 in Bowen disease separated this entity from others under study. The combination pattern of p27 and Ki-67 staining can be used to support differentiation of actinic keratosis, Bowen disease, and squamous cell carcinoma.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES KERATINOCYTIC DYSPLASIA WITH CHEMOTHERAPY
Keratinocyte dysplasia: an usual finding after transplantation or chemotherapy.
Castano E, Rodriguez-Peralto JL, Lopez-Rios F, Gomez C, Zimmermann M, Iglesias Diez L.
Department of Dermatology, Department of Pathology, and Department of Oncology, Hospital Universitario 12 de Octubre, and Staticon International Espana, SA, Madrid, Spain.
J Cutan Pathol 2002 Nov;29(10):579-84 Abstract quote
BACKGROUND: Keratinocyte dysplasia is a histologic abnormality that has rarely been described in the first weeks after chemotherapy or transplantation. The purpose of this study was to determine the prevalence of early keratinocyte dysplasia after chemotherapy or transplant and to analyze the relationship between dysplasia and chemotherapeutic agents, transplantation or development of acute graft vs. host disease (GvHD).
METHODS: A computer search for transplant patients was performed in the Departments of Hematology, Oncology and Surgery. Only patients with a skin biopsy taken within the first days of transplantation or chemotherapeutic treatment were included in the analysis.
RESULTS: Forty-four patients were included, of these 19 were women and 25 were men. Thirty-four (77.3%) of 44 biopsies showed keratinocyte dysplasia. This dysplasia was severe in 18 cases (40.9%). Cyclophosphamide was more likely to be associated with severe keratinocyte maturation disturbances (OR = 5.51) (p < 0.01) whereas cytarabine was associated with a lower risk (OR = 0.19) (p < 0.05).
CONCLUSIONS: Severe keratinocyte dysplasia is a usual histologic finding in patients who have received chemotherapy and/or transplantation (40.9%). Cyclophosphamide is the main chemotherapeutic agent significantly associated with a higher risk of severe dysplasia (OR = 5.51). Causes other than GvHD or preconditioning treatment may be involved in the keratinocyte dysplasia, as it can be also found in transplanted patients who have not received chemotherapy and/or have not developed GvHD.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS
Standardized AgNOR Analysis in Actinic Keratosis
Giovanni Tuccari, M.D.; Giuseppe Giuffrè, M.D.; Antonino Catalano, M.D.; Maria Lentini, M.D.; Dario Batolo, M.D.
From the Department of Human Pathology, Polyclinic Pad. D (G. T., G. G., M. L., and D. B.), Department of Surgical Specialties (A. C.), University of Messina, Italy.
Am J Dermatopathol 2001;23:407-412 Abstract quote
To assess if the quantity of silver-stained nucleolar organizer region (AgNOR) proteins predicts the behavior of actinic keratosis (AK), we performed a standardized AgNOR analysis on 51 cases of AK; in addition, 10 cases of squamous cell (SCC) and 10 cases of basal cell (BCC) carcinomas and 10 normal skin samples were also studied.
AgNOR analysis was performed on formalin-fixed and paraffin-embedded sections according to the guidelines of the Committee on AgNOR Quantification (1995), evaluating the mean area (m 2 ) of AgNORs per nucleus (NORA). A highly significant P value (< 0.001) was found in the comparison among NORA values of normal skin (1.869 m 2 ; SD + 0.332), AK (3.988 m 2 ; SD + 0.914), BCC (3.044 m 2 ; SD + 0.254), and SCC (5.286 m 2 ; SD + 0.920).
In AK, a progressive increase of mean NORA values was observed moving from Stage I (3.161 m 2 ; SD + 0.600) to Stage II (3.455 m 2 ; SD + 0.562), Stage III (4.360 m 2 ; SD + 0.295), and Stage IV (5.168 m 2 ; SD + 0.694); highly significant differences ( P < 0.001) were noted when Stages I or II were compared with Stage III or Stage IV or between these latter stages.
The AgNOR quantity may identify AKs with high proliferative activity and increased tendency to develop into invasive SCC.
Acitretin treatment in (pre)malignant skin disorders of renal transplant recipients: Histologic and immunohistochemical effects.
Smit JV, De Sevaux RG, Blokx WA, Van De Kerkhof PC, Hoitsma AJ, De Jong EM.
J Am Acad Dermatol. 2004 Feb;50(2):189-96. Abstract quote
BACKGROUND: The incidence of (pre)malignant skin lesions after renal transplantation is high. Acitretin treatment appears to decrease the number of new squamous cell carcinomas and ameliorates the aspect and reduces the number of actinic keratoses. However, no histologic and immunohistochemical studies have been performed to further substantiate these observations.
METHODS: In 33 renal transplant recipients, biopsies were taken before and after 3 months of treatment with acitretin in doses up to 0.4 mg/kg/day. Histologic and immunohistochemical parameters for dysplasia, epidermal thickness, proliferation, differentiation, apoptosis, and dermal inflammation were analyzed.
RESULTS: Following acitretin treatment, a significant reduction in epidermal thickness (P =.002) and a significant increase in normal differentiation parameter K10 (P =.02) was observed. Epidermal proliferation did not change, nor did apoptosis, inflammation, keratinocytic epidermal neoplasia score, or transglutaminase staining. At baseline, in 8 actinic keratoses, a single cell expression pattern of K13 and/or K19 was found. This was associated with high levels of parameters indicative of high-risk lesions (P <.05). After acitretin treatment, an increase in K13 (P =.006) and K19 (P =.05) was found, together with a change in expression towards a focal or band-like staining pattern.
CONCLUSION: Acitretin improves the aspect of actinic keratoses via alteration of keratinization, resulting in peeling of the stratum corneum. No significant change in proliferation was found, which may explain the rapid recurrence of actinic keratoses seen after cessation of acitretin treatment.
Acitretin treatment of premalignant and malignant skin disorders in renal transplant recipients: clinical effects of a randomized trial comparing two doses of acitretin.
de Sevaux RG, Smit JV, de Jong EM, van de Kerkhof PC, Hoitsma AJ.
Department of Nephrology, University Medical Center, Nijmegen, The Netherlands.
J Am Acad Dermatol. 2003 Sep;49(3):407-12 Abstract quote.
INTRODUCTION: After renal transplantation, the incidence of premalignant and malignant skin lesions is high. Treatment with acitretin improves the number and aspect of actinic keratoses and appears to reduce the incidence of squamous cell carcinomas, but treatment is hampered by frequent side effects. No optimal long-term dosing advice is available.
METHODS: A total of 26 long-term renal transplant recipients were randomized to 1-year treatment with acitretin, either 0.4 mg/kg/d throughout the whole year or 0.4 mg/kg/d during the first 3 months followed by 0.2 mg/kg/d for the remaining 9 months. At 9 different time points, the number of actinic keratoses and tumors was counted, and erythema and thickness of the lesions, and severity of side effects were scored. Patient's judgment was recorded using visual analog scores.
RESULTS: In both groups, the number of actinic keratoses decreased by nearly 50%, but the number of new malignant tumors during the study year was similar to the number of tumors in the year before the study. Thickness of the keratoses decreased significantly in both groups. Acitretin dose had to be reduced in most patients because of the frequent occurrence of mucocutaneous side effects, such as cheilitis, excessive peeling of the skin, and hair disorders. In the 14 patients randomized to continuous treatment with a dose of 0.4 mg/kg/d, this dose could be maintained in 3 of 14 patients only. Temporary interruption of acitretin therapy was necessary in 7 of 26 patients. Patients' contentment about the aspect of their skin increased significantly, with no differences between groups.
CONCLUSIONS: Acitretin therapy decreased the number of actinic keratoses in renal transplant recipients at a low maintenance dose of 0.2 mg/kg/d and significantly decreased the degree of thickness of the lesions. However, the incidence of new skin malignancies remained unchanged. Despite the high incidence of mucocutaneous side effects, patient's contentment with the aspect of their skin increased significantly.
Assessment of adapalene gel for the treatment of actinic keratoses and lentigines: a randomized trial.
Kang S, Goldfarb MT, Weiss JS, Metz RD, Hamilton TA, Voorhees JJ, Griffiths CE.
University of Michigan School of Medicine, Department of Dermatology, Ann Arbor, USA.
J Am Acad Dermatol. 2003 Jul;49(1):83-90. Abstract quote
BACKGROUND: Adapalene is a synthetic retinoid with an established clinical efficacy against acne and good local tolerability. Its effectiveness in the treatment of photodamaged skin has not been studied.
OBJECTIVE: We sought to determine the safety and efficacy of adapalene gel in the treatment of actinic keratoses and solar lentigines.
METHODS: In a prospective, 2-center, randomized, controlled, investigator-masked, parallel-group study, 90 patients with actinic keratoses and solar lentigines were treated daily with either adapalene gel (0.1% or 0.3%) or its vehicle gel for 4 weeks, followed by twice-daily applications, if tolerated, for up to 9 months.
RESULTS: Of the 90 Caucasian patients (69 male, 21 female; mean age 63.1 years) who were enrolled into the study, 83 patients completed 9 months of treatment. With adapalene gel 0.1% and 0.3%, the mean number of actinic keratoses was reduced by 0.5 +/- 0.9 (mean +/- SE) and 2.5 +/- 0.9, respectively. Whereas, with the vehicle gel, there was an increase of 1.5 +/- 1.3 (P <.05). After 1 month of treatment, the patients who received adapalene had significant lightening of solar lentigines as compared with the patients who were treated with vehicle gel (P <.05). After 9 months, 57% and 59% of the patients had lighter lesions in the adapalene 0.1% and 0.3% groups, respectively, in comparison with only 36% in the vehicle group (P <.05). Histologic evaluations revealed improved cellular atypia and reduced epidermal melanin in adapalene-, as compared with vehicle-treated group. The differences, however, were not statistically significant. A retrospective evaluation of paired clinical photographs (before and after 9-month treatment) by 2 dermatologists who were treatment-blinded revealed significant improvement in wrinkles and other clinical features of photoaged skin with adapalene as compared with its vehicle.
CONCLUSION: Adapalene gel 0.1% and 0.3% were well tolerated and improved actinic keratoses, solar lentigines, and other features of photodamaged skin.
- Effect of a 1-week treatment with 0.5% topical Fluorouracil on occurrence of actinic keratosis after cryosurgery: a randomized, vehicle-controlled clinical trial.
Jorizzo J, Weiss J, Furst K, VandePol C, Levy SF.
Wake Forest University School of Medicine, Winston-Salem, NC.
Arch Dermatol. 2004 Jul;140(7):813-6. Abstract quote
BACKGROUND: No long-term randomized controlled clinical trial has compared the efficacy of cryosurgery alone vs cryosurgery following fluorouracil applications for the treatment of actinic keratosis.
OBJECTIVE: To determine the 6-month outcome of a 1-week course of 0.5% fluorouracil followed by cryosurgery.
DESIGN: Prospective, multicenter, randomized, double-blind, vehicle-controlled clinical trial performed in community and academic outpatient clinics.Patients A total of 144 patients with 5 or more visible or palpable actinic keratoses on the face.Interventions Topical 0.5% fluorouracil or vehicle once daily for 7 days. At the 4-week follow-up visit, residual lesions were treated with cryosurgery.Main Outcome Measure Reduction in facial actinic keratoses from baseline to 4 weeks and 6 months.
RESULTS: At 4 weeks, mean actinic keratosis lesion count was reduced by 62.4% in the 0.5% fluorouracil group vs 28.8% in the vehicle group (P<.001), and complete clearance was achieved in 16.7% of patients in the 0.5% fluorouracil group vs 0% of those in the vehicle group (P<.001). At 6 months, mean lesion count was reduced by 67.0% in the 0.5% fluorouracil plus cryosurgery group vs 45.6% in the vehicle plus cryosurgery group (P =.01), and significantly more patients in the 0.5% fluorouracil plus cryosurgery group than in the vehicle plus cryosurgery group had complete clearance (30% vs 7.7%; P<.001).
CONCLUSIONS: A 1-week course of topical 0.5% fluorouracil before cryosurgery is significantly more effective in reducing patients' numbers of actinic keratosis lesions 6 months after treatment than cryosurgery alone. The high occurrence rate of actinic keratosis lesions at 6 months suggests a need for follow-up.
IMIQUIMOD 5% TOPICAL
- Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials.
Korman N, Moy R, Ling M, Matheson R, Smith S, McKane S, Lee JH.
Department of Dermatology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio, USA.
Arch Dermatol. 2005 Apr;141(4):467-73. Abstract quote
OBJECTIVE: To evaluate the efficacy and safety of 5% imiquimod cream compared with vehicle in the treatment of actinic keratosis (AK).
DESIGN: Two phase 3 randomized, double-blind, parallel-group, vehicle-controlled studies.
SETTING: Twenty-six ambulatory care offices, including dermatologists in private practice or research centers.
PATIENTS: Four hundred ninety-two patients, 18 years and older, with 4 to 8 AK lesions in a 25-cm(2) treatment area on the face or the balding scalp were randomized; an additional 162 patients underwent screening but were ineligible.
INTERVENTIONS: Patients applied 5% imiquimod (Aldara) or vehicle cream to the treatment area once daily, 3 times per week, for 16 weeks, followed by an 8-week posttreatment period.
MAIN OUTCOME MEASUREMENTS: Complete clearance rate (proportion of patients at the 8-week posttreatment visit with no clinically visible AK lesions in the treatment area), partial clearance rate (proportion of patients at the 8-week posttreatment visit with a >/=75% reduction in the number of baseline AK lesions in the treatment area), and frequency and severity of adverse events and local skin reactions were measured.
RESULTS: Complete and partial clearance rates for imiquimod-treated patients (48.3% and 64.0%, respectively) were clinically and statistically significantly higher than for vehicle-treated patients (7.2% and 13.6%, respectively). The median percentage reduction of baseline lesions was 86.6% for the imiquimod-treated group and 14.3% for the vehicle-treated group.
CONCLUSION: The 5% imiquimod cream dosed 3 times weekly for 16 weeks is safe and effective for the treatment of AK.
Imiquimod 5% cream for the treatment of actinic keratosis: results from a phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology.
Szeimies RM, Gerritsen MJ, Gupta G, Ortonne JP, Serresi S, Bichel J, Lee JH, Fox TL, Alomar A.
Klinikum der Universitat Regensburg, Klinik und Poliklinik fur Dermatologie, Regensburg, Germany.
J Am Acad Dermatol. 2004 Oct;51(4):547-55. Abstract quote
BACKGROUND: Increasing evidence suggests imiquimod may be a safe therapeutic option for the treatment of actinic keratosis (AK). The diagnosis and assessment of most AK lesions is made clinically, without histologic confirmation.
OBJECTIVE: A phase III, randomized, double-blind, parallel group, vehicle-controlled study evaluated the efficacy of imiquimod 5% cream compared with vehicle in the treatment of AK lesions on the face and balding scalp including pretreatment and posttreatment biopsy specimens.
METHODS: A total of 286 patients at 18 centers in 6 European countries with histologically confirmed AK were randomized to either imiquimod 5% cream or vehicle cream. Study cream was applied once per day, 3 days per week, for 16 weeks. Clearance of AK lesions was clinically and histologically assessed at an 8-week posttreatment visit.
RESULTS: The complete clearance rate for the imiquimod group was 57.1% versus 2.2% for the vehicle group (P <.001). The partial clearance rate (> or =75% reduction in baseline lesions) for the imiquimod group was 72.1% versus 4.3% for the vehicle group (P <.001). The most common side effects were erythema, scabbing/crusting, and erosions/ulceration. For the imiquimod group the incidence of severe erythema, scabbing/crusting, or erosions/ulceration was 30.6%, 29.9%, and 10.2%, respectively.
CONCLUSION: Imiquimod 5% cream used 3 times per week for 16 weeks is an effective treatment for AK. Clinical clearance was established by both clinical observation and histologic analysis.
Topical 5% imiquimod for the therapy of actinic cheilitis.
Smith KJ, Germain M, Yeager J, Skelton H.
Department of Dermatology, University of Alabama at Birmingham, 35294, USA.
J Am Acad Dermatol 2002 Oct;47(4):497-501 Abstract quote
BACKGROUND: Tissue-destructive and more selective cytotoxic therapies are the main methods used to treat actinic cheilitis. A topical immune stimulant, 5% imiquimod cream, has recently been used for treatment of cutaneous epithelial malignancies including squamous cell carcinoma in situ and basal cell carcinoma.
OBJECTIVE: Our aim was to review the results in patients who had been treated for actinic cheilitis with imiquimod cream.
METHODS: A review identified 15 patients with biopsy-proven actinic cheilitis who had been treated with topical imiquimod 3 times weekly for 4 to 6 weeks. All patients with histories consistent with facial herpes simplex or documented prior facial herpes simplex eruptions were treated with oral valcyclovir, 1 g/d, during imiquimod therapy.
RESULTS: All 15 patients showed clinical clearing of their actinic cheilitis at 4 weeks after discontinuation of the topical imiquimod. Sixty percent of the patients experienced a moderate to marked increased local reaction consisting of increased erythema, induration, and erosions or ulcerations, which in some cases continued through the period of therapy.
CONCLUSION: Imiquimod appears to have a role in the treatment of actinic cheilitis. However, the dose and duration of therapy, as well as the long-term efficacy, need to be established; and local reactions are to be expected and may not improve during therapy.
Cycle therapy of actinic keratoses of the face and scalp with 5% topical imiquimod cream: An open-label trial.
Salasche SJ, Levine N, Morrison L.
University of Arizona Health Sciences Center, Tucson 85724, USA.
J Am Acad Dermatol 2002 Oct;47(4):571-7 Abstract quote
BACKGROUND: Preliminary studies indicate that topically applied immune response modifiers may be an effective and safe method of treating actinic keratoses (AKs).
OBJECTIVE: Our aim was to study the potential efficacy of topical 5% imiquimod cream in the treatment of facial or scalp AKs and improve the safety profile by using a novel "cycle" dosing regimen.
METHODS: This pilot study is an open-label trial that included 25 patients who had between 5 and 20 discrete AKs within a cosmetic unit of the forehead, scalp, or cheek. Treatment consisted of once-daily application of 5% imiquimod cream, 3 times a week for 4 weeks. to the entire cosmetic unit, followed by a rest period of 4 weeks. The cycle was repeated if any AKs remained after a complete 8-week cycle. A maximum of 3 cycles was permitted (24 weeks). Thirty-three sites in 25 patients were evaluated.
RESULTS: Compliance was excellent with a very tolerable safety profile. Complete clearing of all AKs was noted in 82% (27/33) of anatomic sites in 25 study subjects. Almost half the sites (15/33) were clear at the end of the first cycle. A "therapeutic interval" was noted during the rest period wherein clinical inflammation subsided but AKs continued to clear. An added effect was the uncovering and clinical appearance and subsequent eradication of incipient (subclinical) AKs in the treatment area.
CONCLUSION: There was excellent compliance with the cycle therapy regimen. The observations and hypotheses made in this pilot study will be tested in controlled, randomized trials with larger study populations. The identification of a therapeutic interval may prove to be beneficial in formulating individualized dosing regimens.
Topical treatment of actinic keratoses with 3.0% diclofenac in 2.5% hyaluronan gel.
Rivers JK, Arlette J, Shear N, Guenther L, Carey W, Poulin Y.
Division of Dermatology, University of British Columbia and the Vancouver General Hospital, Faculty of Medicine, 835 West 10th Avenue, Vancouver, BC V5Z 4E8, Canada.
Br J Dermatol 2002 Jan;146(1):94-100 Abstract quote
BACKGROUND: Actinic keratoses (AKs) are premalignant skin lesions, which, if left untreated, can develop into squamous cell carcinoma. Current treatments for AKs are destructive and are often associated with significant adverse events. The development of an effective and well-tolerated topical treatment for AK is desirable.
OBJECTIVES: To evaluate the efficacy and safety of 3.0% diclofenac in 2.5% hyaluronan gel as a treatment for AK.
METHODS: This was a multicentre, double-blind, placebo-controlled study in which 195 patients with at least five AKs in up to three designated treatment blocks were randomized to four treatment groups. Patients randomized into the active treatment groups A30 (n = 49) and A60 (n = 48) received topical treatment with 3.0% diclofenac in 2.5% hyaluronan gel 0.5 g twice daily for 30 or 60 days, respectively. Patients in the placebo (vehicle gel) groups V30 (n = 49) and V60 (n = 49) received topical treatment with 2.5% hyaluronan gel 0.5 g twice daily for 30 or 60 days, respectively. Treatment efficacy was assessed by target and cumulative lesion number scores (TLNS and CLNS, respectively) and lesion total thickness score (TTS). Investigator and patient global improvement indices (IGII and PGII) were also used to rate overall improvement.
RESULTS: Compared with placebo, significantly more patients given active treatment for 60 days had TLNS = 0 (33% vs. 10%, P < 0.05; an improvement of 64% compared with 34% with placebo), CLNS = 0 (31% vs. 8%, P < 0.05; an improvement of 54% compared with 23% with placebo) and TTS = 0 (25% vs. 6%, P < 0.05; an improvement of 59% compared with 31% with placebo). The IGII and PGII scores were also significantly better when active treatment was compared with placebo (P < 0.05). Both treatments were generally well tolerated and the incidence of the most common adverse events was similar between groups.
CONCLUSIONS: Treatment with 3.0% diclofenac in 2.5% hyaluronan gel was effective when used for 60 days and was well tolerated in patients with AK.
Photodynamic therapy with aminolevulinic acid topical solution and visible blue light in the treatment of multiple actinic keratoses of the face and scalp: investigator-blinded, phase 3, multicenter trials.
Piacquadio DJ, Chen DM, Farber HF, Fowler JF Jr, Glazer SD, Goodman JJ, Hruza LL, Jeffes EW, Ling MR, Phillips TJ, Rallis TM, Scher RK, Taylor CR, Weinstein GD.
Division of Dermatology, Department of Medicine, University of California, San Diego, USA.
Arch Dermatol. 2004 Jan;140(1):41-6. Abstract quote
OBJECTIVE: To determine the safety and efficacy of photodynamic therapy (PDT) using 20% wt/vol aminolevulinic acid hydrochloride (hereinafter "ALA") and visible blue light for the treatment of multiple actinic keratoses of the face and scalp.
DESIGN: Randomized, placebo-controlled, uneven parallel-group study.
INTERVENTIONS: Patients (N = 243) were randomized to receive vehicle or ALA followed within 14 to 18 hours by PDT. Follow-up visits occurred 24 hours and 1, 4, 8, and 12 weeks following PDT. Target lesions remaining at week 8 were re-treated.
MAIN OUTCOME MEASURE: Clinical response based on lesion clearing by week 8.
RESULTS: Most patients in both groups had 4 to 7 lesions. Complete response rates for patients with 75% or more of the treated lesions clearing at weeks 8 and 12 were 77% (128/166) and 89% (133/149), respectively, for the drug group and 18% (10/55) and 13% (7/52), respectively, for the vehicle group (P<.001, Cochran-Mantel-Haenszel general association test). The 95% confidence interval for the difference in response rates at week 8 was 46.9% to 71.0% and at week 12, 65.3% to 86.3%. The week 12 response rate includes 30% of patients who received a second treatment. Most patients experienced erythema and edema at the treated sites, which resolved or improved within 1 to 4 weeks after therapy, and stinging or burning during light treatment, which decreased or resolved by 24 hours after light treatment.
CONCLUSION: Findings indicate that topical ALA PDT is an effective and safe treatment for multiple actinic keratoses of the face and scalp.
A trial of short incubation, broad-area photodynamic therapy for facial actinic keratoses and diffuse photodamage.
Touma D, Yaar M, Whitehead S, Konnikov N, Gilchrest BA.
Department of Dermatology, Boston University School of Medicine, Boston, MA 02118-2394, USA.
Arch Dermatol. 2004 Jan;140(1):33-40. Abstract quote
BACKGROUND: There is no completely satisfactory treatment for multiple actinic keratoses (AKs).
OBJECTIVE: To evaluate the efficacy of short incubation, broad-area application of delta-aminolevulinic acid followed by exposure to activating light-photodynamic therapy (delta-ALA/PDT) for treatment of AKs and background photodamage. The benefit of pretreatment with 40% urea cream to enhance penetration and the use of topical 3% lidocaine hydrochloride to decrease discomfort were also evaluated.
METHODS: Eighteen patients with at least 4 nonhypertrophic facial AKs and mild to moderate diffuse facial photodamage were enrolled in the study. For 7 days, 40% urea cream or vehicle was applied to half of the treatment area, and then delta-ALA was applied to the entire area for 1, 2, or 3 hours. Lidocaine hydrochloride (3%) or vehicle cream was also applied to the entire area 45 minutes before exposure to 10 J/cm(2) of blue light. Pain,phototoxic reactions, AK counts, and photodamage improvement were evaluated 1 day, 1 week, and 1 month after treatment in all patients and after 5 months in 10 patients.
RESULTS: All patients experienced mild to moderate discomfort during treatment and moderate phototoxic effects for 1 week. At 1 and 5 months there was significant reduction in AKs in all groups and significant improvement of several photodamage parameters. Different delta-ALA application times and pretreatment with urea cream or lidocaine had no significant effect on the results.
CONCLUSIONS: This delta-ALA/PDT protocol is safe and effective for AK treatment as well as for improving photodamage. Further studies with a larger cohort, longer follow-up, and histologic confirmation of the clinical data would be of value.
Photodynamic therapy with topical methyl aminolevulinate for actinic keratosis: results of a prospective randomized multicenter trial.
Pariser DM, Lowe NJ, Stewart DM, Jarratt MT, Lucky AW, Pariser RJ, Yamauchi PS.
Division of Dermatology, Eastern Virginia Medical School, and Virginia Clinical Research Inc., Norfolk, VA, USA.
J Am Acad Dermatol 2003 Feb;48(2):227-32 Abstract quote
BACKGROUND: Photodynamic therapy (PDT) is a promising new treatment modality for actinic keratoses. Methyl aminolevulinate (MAL) (Metvix, PhotoCure, Oslo, Norway) leads to selective accumulation of photoactive porphyrins in premalignant skin lesions and makes the lesions susceptible to phototoxic effects on illumination with red light.
OBJECTIVE: This multicenter, randomized, double-blind study compared complete response rates, cosmetic outcome, and patient satisfaction for PDT with cream containing 160 mg/g MAL or placebo cream in the treatment of actinic keratoses.
METHODS: After application of the cream under occlusion for 3 hours, the lesions were illuminated by noncoherent red light (570-670 nm, light dose 75 J/cm(2)). Treatment was repeated after 1 week and response was assessed 3 months later. A total of 80 patients were randomized into the study, 42 in the active and 38 in the placebo group.
RESULTS: Complete lesion response rate was higher after MAL PDT than placebo, 89% versus 38% per protocol analysis (P =.001). An excellent or good cosmetic outcome was reported in more than 90% of patients treated with MAL.
CONCLUSION: In this small study, PDT using topical MAL was a safe and effective treatment for actinic keratoses with excellent cosmetic outcome. It is a promising treatment that could benefit from further study.
Photodynamic therapy of actinic keratoses with topical aminolevulinic acid hydrochloride and fluorescent blue light Edward W. Jeffes, MD, PhD
Jerry L. McCullough, PhD
Gerald D. Weinstein, MD
Ross Kaplan, MD
Scott D. Glazer, MD
J. Richard Taylor, MD
Irvine and Long Beach, California, Miami, Florida, and Buffalo Grove, Illinois Sections
J Am Acad Dermatol 2001;45:96-104. Abstract quote
Background: Aminolevulinic acid hydrochloride (ALA, Levulan) applied topically to actinic keratoses (AKs) leads to accumulation of the photosensitizer protoporphyrin IX, which, when activated by exposure to light, eradicates AKs.
Objective: We examined the safety and efficacy of photodynamic therapy using topical 20% ALA in a solution formulation and varying blue light doses to treat multiple AKs on the face and scalp.
Method: This is a multicenter, investigator-blinded, randomized, vehicle-controlled study.
Results: Thirty-six patients with clinically typical AKs were treated with 20% ALA; 14 to 18 hours later, they were irradiated with a nonlaser fluorescent blue light source. With the optimal light dose of 10 J/cm2, 88% of the AKs completely cleared 8 weeks after a single photodynamic treatment, compared with 6% after treatment with vehicle and light.
Conclusion: Topical ALA PDT using a nonlaser, blue light source is an effective treatment for multiple AKs.
Photodynamic therapy using topical methyl 5-aminolevulinate compared with cryotherapy for actinic keratosis: A prospective, randomized study.
Szeimies RM, Karrer S, Radakovic-Fijan S, Tanew A, Calzavara-Pinton PG, Zane C, Sidoroff A, Hempel M, Ulrich J, Proebstle T, Meffert H, Mulder M, Salomon D, Dittmar HC, Bauer JW, Kernland K, Braathen L.
Department of Dermatology, University of Regensburg, Germany.
J Am Acad Dermatol 2002 Aug;47(2):258-62 Abstract quote
BACKGROUND: Actinic keratoses (AKs) are the most common premalignant tumors. Without treatment, a significant number of patients with AK will experience squamous cell carcinoma. Photodynamic therapy (PDT) using the new highly selective photosensitizer methyl 5-aminolevulinate is a promising new treatment modality for AK.
OBJECTIVE: We investigated the complete response rates, cosmetic outcome, and patient satisfaction after photodynamic therapy (PDT) using methyl 5-aminolevulinate (Metvix) versus cryotherapy in the treatment of AKs.
METHODS: Patients were randomized to receive either cryotherapy with liquid nitrogen spray or PDT using methyl 5-aminolevulinate cream 160 mg/g, 3 hours application time, and red light (75 J/cm(2)).
RESULTS: Efficacy results from 193 patients with 699 lesions (92% face/scalp and 93% thin/moderately thick) were analyzed. Overall complete response rates after 3 months were 69% for PDT and 75% for cryotherapy. Both treatments gave higher response rates in thin lesions (PDT 75%, cryotherapy 80%). PDT gave better cosmetic results and higher patient satisfaction than cryotherapy.
CONCLUSION: PDT using methyl 5-aminolevulinate is an attractive treatment option for patients with AK, with a response rate similar to that of cryotherapy, but with superior cosmetic results and high patient satisfaction.
A randomized controlled trial to assess sunscreen application and Beta carotene supplementation in the prevention of solar keratoses.
Darlington S, Williams G, Neale R, Frost C, Green A.
Comprehensive Cancer Research Center, Population and Clinical Sciences Division, Queensland Institute of Medical Research, and the School of Population Health, University of Queensland, Australia.
Arch Dermatol 2003 Apr;139(4):451-5 Abstract quote
BACKGROUND: Solar keratoses (SKs) are among the strongest determinants of skin cancer, but little is known about the success of measures to control these common skin tumors.
OBJECTIVE: To determine whether daily sunscreen application and/or beta carotene supplementation retards the rate of occurrence of SKs in adults in the medium term.
DESIGN: Randomized controlled trial conducted between February 1992 and August 1996.
SETTING: General community of the subtropical township of Nambour, Australia (latitude, 26 degrees south).
PARTICIPANTS: A total of 1621 adults aged 25 to 74 years.Interventions Participants were randomized to daily use of sunscreen (application of a high-protection sunscreen to their head, neck, arms, and hands every morning) or application of sunscreen at their usual discretionary rate. They were also randomly assigned to take either one 30-mg tablet of beta carotene or one placebo tablet each day.Main Outcome Measure Change in the prevalent number of SKs in the intervention group relative to change in the control group.
RESULTS: The ratio of SK counts in 1994 relative to 1992 was lower in people randomized to daily sunscreen use (1.20; 95% confidence interval, 1.04-1.39) than in those randomized to discretionary sunscreen use (1.57; 95% confidence interval, 1.35-1.84). This 24% reduction is equivalent to the prevention of an average of 1 additional SK per person over that time. A reduction in the rate of change of SK prevalence was also seen in the sunscreen intervention group relative to the discretionary sunscreen group between 1994 and 1996, but it was not significant. No effect on the rate of change of prevalent SK counts was seen among those taking beta carotene supplements relative to those taking placebo tablets.
CONCLUSIONS: Daily application of sunscreen retarded the rate of SK acquisition among adults in a subtropical environment, while a beta carotene supplementation of 30 mg/d had no influence on the occurrence of SKs.
Arch Dermatol. 2006 Apr;142(4):455-9. Abstract quote
OBJECTIVE: To compare differences in biopsy techniques of actinic keratoses between dermatologists and plastic surgeons.
DESIGN: Blinded, comparative, retrospective study.
SETTING: Dermatopathology laboratory at a major academic medical center with referral of outside cases.Intervention We reexamined the histopathologic slides of 405 actinic keratosis biopsy specimens obtained by plastic surgeons and dermatologists from January 1, 1992, through May 31, 2002. We were specifically interested in the type of biopsy technique (shave, punch, or excisional biopsy) used for the surgical management of actinic keratoses by both groups of physicians. We also recorded the clinical diagnoses rendered on the dermatopathology request form and compared them with the histopathologic diagnoses.
RESULTS: Excisional biopsies were performed by plastic surgeons in 50.0% of the cases, compared with only 1.4% by dermatologists. In contrast, shave biopsies of actinic keratoses were performed by plastic surgeons in only 32.4% of the cases, compared with 89.4% by dermatologists. Only 1 (0.5%) of the 198 dermatopathology request forms submitted by the plastic surgeons mentioned actinic keratosis, compared with 82 (39.6%) of 207 histopathologic evaluation requests submitted by dermatologists.
CONCLUSIONS: The predominance of excisional biopsies of actinic keratoses by plastic surgeons may be related to a different ability in the clinical recognition of actinic keratoses compared with that of dermatologists. The surgical approach of dermatologists to shave diagnostically uncertain cutaneous lesions is less invasive than that of plastic surgeons and is more likely to achieve a better cosmetic outcome.
Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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