Evaluation of the Prognostic Significance of Follicular Extension in Actinic Keratoses

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aShaily Pandey, BA;  b,cStephen E. Mercer, MD, PhD; aKai Dallas, BS; b,c,dPatrick O. Emanuel, MD; b,cGary Goldenberg, MD

aMount Sinai School of Medicine, New York, New York; bDepartments of Dermatology and cPathology, Mount Sinai School of Medicine, New York, New York;dConsultant Dermatopathologist Diagnostic Medlab, Auckland, New Zealand

Disclosure: The authors report no relevant conflicts of interest.

Abstract
Objective: To determine the prognostic significance of follicular extension in actinic keratosis. Design: Retrospective, case-controlled study. Setting: Mount Sinai Dermatopathology Services. Patients/participants: Out of a randomly selected pool of 1,000 biopsies, 104 cases of actinic keratosis with follicular extension and 104 cases of actinic keratosis without follicular extension were chosen for the study (56.7% male; mean [SD] age, 67.5 [11.8] years; age range, 28–93). Main outcome measures: Presence of follicular extension and location of the actinic keratosis. Age and gender of the patient. Number of previously diagnosed squamous cell carcinomas, basal cell carcinomas, and melanomas per patient. Results: Patients with follicular extension of actinic keratosis were 1.8 times more likely to have a previous history of invasive carcinoma than patients without follicular extension. Patients with follicular extension were 11 times more likely to have a previous history of invasive melanoma than patients with actinic keratoses without follicular extension. Patients with follicular extension were more likely to be male, had an older average age, and more often presented with lesions on their leg when compared to patients with actinic keratoses lacking follicular extension. Conclusion: Patients presenting with actinic keratoses with follicular extension were more likely to have increased risk factors for skin cancer. These findings have implications for identifying patient factors predictive of progression of actinic keratosis to invasive carcinoma, providing potentially valuable patient screening guidelines.  (J Clin Aesthet Dermatol. 2012;5(4):25–28.)

Actinic (solar) keratosis (AK) is an extremely common skin neoplasm. It is reported to be the second most common diagnosis made by dermatologists in the United States.[1] According to unpublished data, it currently represents the most common diagnosis made by dermatologists in the Medicare population.[2] Actinic keratoses (AKs) contribute to 5.2 million dermatologist visits each year and treatment accounts for more than $920 million dollars of medical billings.[3] Approximately 5.2 million AKs are diagnosed annually, 62 percent of which are found on patients over the age of 65. While the annual frequency of AKs was stable between 1995 and 2003, it is expected to increase as the United States population continues to age.[3]

The incidence of AK increases with age, proximity to the equator, lighter skin color, and prolonged outdoor activity. Cumulative exposure to ultraviolet (UV) radiation is the primary etiological factor in development of this intra-epithelial neoplasm, and this has been demonstrated by both experimental and epidemiological models.[4]

Clinically, AKs present as erythematous, scaly, sometimes crusted papules and plaques on sun-exposed skin (face, scalp, neck, and upper extremities most commonly). A high percentage of these lesions may clinically be indistinguishable from squamous cell carcinoma (SCC).[4] The risk of AK progression to SCC is still debated, but most authorities now quote a rate of 10 percent per 10 years.[5] A recent study conducted through the Department of Veterans Affairs Topical Tretinoin Chemoprevention Trial suggests that AKs convert to SCCs at a rate of 0.6 percent over one year and 3.39 percent over four years.[6] AKs convert to BCCs at a rate of 0.48 percent at one year and 2.27 percent after four years.

Up to 97 percent of SCCs arise from or contain an AK.7 Another area of debate is whether AKs represent a precancerous neoplasm or a SCC in situ (SCCIS). It has been proposed that AK be renamed incipient intraepidermal squamous cell carcinoma and that classification system similar to gynecological pathology be used.[8]

Histopathologically, AKs present with atypical keratinocytes along the basal layer of the epidermis; these cells can show enlargement, hyperchromatic nuclei, lack of maturation, mitotic figures, and dyskeratosis. The dermis often shows signs of UV damage, such as atrophy and solar elastosis.

The purpose of this study was to examine the prognostic significance of follicular extension of atypical keratinocytes in AKs and to correlate these findings with anatomical location of lesion, gender of patient, and history of prior skin cancers. Follicular extension was defined as the presence of atypical keratinocytes extending into the isthmus of the hair follicle.

Methods
Institutional Review Board (IRB) approval was received from The Mount Sinai School of Medicine Program for the Protection of Human Subjects. A retrospective analysis of AK specimens diagnosed from October 2009 to July 2010 was conducted. A total of 1,000 reported cases of AK were selected for inclusion in the study.

The exclusion criteria were concomitant findings of hypertrophic AK, pigmented AK, lichenoid AK, or the presence of another neoplasm besides AK. Furthermore, since AK is a common diagnosis, only one case per patient was chosen. Curettage specimens and superficial specimens lacking dermis were also excluded.

The selected cases were examined for extension of the AK into the hair follicle by two board-certified dermatopathologists (POE and GG), and cases positive for this finding comprised the case population. The cases of AK without follicle extension served as the control population. These control cases were reviewed to ensure that the sections contained hair follicles and that the AK did not extend into them. The exclusion criteria remained the same for both populations.

After confirming the diagnosis and categorization of the selected cases, a patient history was extracted using the dermatopathology database. Date of birth, gender, ethnicity (when available), and previous dermatopathology findings of skin cancer were recorded as well as the number of these findings. These findings included previous history of SCC, basal cell carcinoma (BCC), and melanoma. Additionally, the location of the current lesion under examination was noted as well as if this lesion was re-excised or re-evaluated at a later date. As per IRB protocol, research data was collected without any Protected Health Information. All analyses and results were de-identified and stored on a password-protected computer database. Statistical analysis was performed with SPSS (SPSS for Windows, Rel. 11.0.1. 2001. Chicago: SPSS Inc). P<0.05 was taken to confer significance.

Results
Out of the 1,000 cases examined, 104 were determined to meet the diagnostic criteria of AK with follicular extension (Figure 1 and Figure 2). An equal number of cases of AK without follicular extension were selected from the same list to represent the control population (Figure 3). The total number of patients with a history of SCC, BCC, and melanoma were tabulated for both groups (Table 1) and the odds ratio of having a history of each type of skin cancer were calculated given the presence of follicular extension versus the absence of follicular extension (Table 2). It should be noted that some patients presented with a past history of more than one type of skin cancer and of multiple skin cancers.

When compared to patients without follicular extension, patients with AK with follicular extension had a significantly increased likelihood of past history of skin cancer (p<0.043). Furthermore, there was a significantly increased likelihood of the patient having a previous history of melanoma (p<0.04). There was also an increased likelihood that patients with AKs would have past SCCs and BCCs; however, the p-values were greater than the 0.05 cut off. Odds-ratio analysis demonstrated that the cohort with follicular extension had a significantly greater percentage of males (p=0.02) and an older average age (p=0.002). Using receiver operating characteristic (ROC) analysis and Youden’s index, an optimal cut off of over age 68 was determined to significantly increase probability of presenting with an AK with follicular extension ([p<0.01] with sensitivity of 0.616 and specificity of 0.625).

Since older age and male gender were known to be independent risk factors for acquiring skin cancer, multivariate analysis was performed with a logistical regression model to determine what variables were independently useful in predicting whether a patient with AK would have follicular extension. Variables examined included age, gender, history of skin cancer (SCC, BCC, melanoma), and location of lesion (scalp, face, chest, back, arm, leg) (Table 3). Significant variables in the logistical regression model were determined using a backward stepwise regressions selection procedure with a Wald statistic to establish each variable’s significance. The presence of an AK on the leg (p=0.012) along with older age (p=0.001) and male gender (p=0.004) were found to be independent statistically significant predictors of increased likelihood of presenting with an AK with follicular extension (Table 4). None of the variables had significant interaction in predicting presence of follicular extension.

Discussion
Analysis via odds ratio showed that patients with AK with follicular extension were more likely to have a previous history of skin cancer, specifically melanoma. Further examination of these results using linear regression revealed that the difference between the two populations was chiefly determined by variance in age, gender, and if the lesion was on the leg.

Two variables that were found to be significant, age and gender, are well known to be risk factors for sun-induced skin cancer. Older male individuals are more likely than female individuals to get skin cancer and thus these patients who present with follicular extension should be treated more aggressively. Furthermore, the odds ratio analysis revealed that patients with follicular extension are more likely to have been diagnosed with skin cancer in the past. Since they are also at greater risk of developing new cancerous lesions, these patients should be followed closely to ensure that their current lesions do not progress to cancer and to allow the dermatologist to treat any new lesions at earlier stages.

The leg is an uncommon location to find an AK, which is most commonly found on the scalp and face.9 Additionally, within one year, two of the patients in the case cohort had a diagnosis of SCC arising from AK in the same location as the lesion, as opposed to none of the patients in the control cohort. This finding is supported by two small case studies examining the histological characteristics of patients with recurrent and treatment non-responsive proliferative AKs.[10,11] Among these studies, 6 out of 7 cases featured AKs with follicular extension and had a concomitant SCC or BCC, which in some cases were infiltrative.[10,11] Thus, these studies also highlight the need for added therapeutic urgency in treating the lesions of patients who have AKs with follicular extension as they can rapidly progress from precancerous to cancerous lesions. One limitation of the current study is the short follow up of this retrospective analysis.

The increased likelihood of previous history of skin cancer among patients with AKs with follicular extension demonstrates a trend toward significance. Furthermore, the difference found in age and gender among the two populations correlates with increased risk for skin cancer. Therefore, the authors believe that more aggressive treatment is recommended for these patients. Understanding the prognostic significance of follicular extension in AK allows physicians to choose more appropriate therapies on an individual basis and provides insurance justification for more frequent follow up. There were no patients in the control population who had a similar diagnosis within one year.

References
1.    Fleischer AB Jr, Herbert CR, Feldman SR, O’rien F. Diagnosis of skin disease by nondermatologists. Am J Manag Care. 2000;6:1149–1156.
2.    Feldman SR, Fleischer AB Jr, et al. Most common dermatologic problems identified by internists, 1990–1994. Arch Intern Med. 1998;158(7):726–730.
3.    Warino L, Tusa M, Camacho F, et al. Frequency and cost of actinic keratosis treatment. Dermatol Surg. 2006;32(8): 1045–1049.
4.    Rossi R, Mori M, Lotti T. Actinic keratosis. Int J Dermatol. 2007;46(9):895–904.
5.    Cockerell CJ, Wharton JR. New histopathological classification of actinic keratosis (incipient intraepidermal squamous cell carcinoma). J Drugs Dermatol. 2005;4(4):462.
6.    Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009;115(11):2523–2530.
7.    Hurwitz RM, Monger LE. Solar keratosis: an evolving squamous cell carcinoma. Benign or malignant? Dermatol Surg. 1995;21(2):184.
8.    Cassarino DS, Derienzo DP, Barr RJ. Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification. J Cutan Pathol. 2006;33(4):261–279.
9.    Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol. 2000;42(1 Pt 2):4–7.
10.    Goldberg LH, Chang JR, Baer SC, Schmidt JD. Proliferative actinic keratoses: three representative cases. Dermatol Surg. 2000;26(1):65–69.
11.    Goldberg LH, Joseph AK, Tschen JA. Proliferative actinic keratosis. Int J Dermatol. 1994;33(5):341–345.

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