Reliability of the histopathologic diagnosis of keratinocyte carcinomas.

OBJECTIVE: We sought to determine the interobserver reliability of the histopathologic diagnosis of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) (keratinocyte carcinomas) in the setting of a Department of Veteran Affairs multicenter chemoprevention study. METHODS: Interobserver concordance was assessed by blinded review of histopathologic slides by study dermatopathologists. RESULTS: Overall interobserver agreement between the two dermatopathogists was kappa = 0.69 (95% confidence interval [CI] 0.67-0.69). The dermatopathologists' interobserver agreement was highest for basal cell carcinoma at kappa = 0.88 (95% CI 0.84-0.91) and for a diagnostic category in the SCC-actinic keratosis spectrum at kappa = 0.80 (95% CI 0.73-0.86). The largest disagreements between the two reference dermatopathologists were regarding the categories of invasive SCC at kappa = 0.62 (95% CI 0.52-0.72), SCC in situ at kappa = 0.42 (95% CI 0.29-0.56), and actinic keratosis at kappa = 0.51 (95% CI 0.40-0.62). Agreement between the local pathologists and central reference dermatopathologists were similar to the agreement between the central dermatopathologists. The morphea subtype of basal cell carcinoma was the only reliably diagnosed subtype (kappa = 0.79, 95% CI 0.51-1.00), and tumor depth was reliably measured. LIMITATIONS: A limitation of this study was the use of only two reference dermatopathologists. CONCLUSION: Because of the impact on physician decision making and patient care, researchers and clinicians need to be aware of reliability of histopathology results, particularly pertaining to the SCC and actinic keratosis spectrum.

Predictors of squamous cell carcinoma in high-risk patients in the VATTC trial.

Invasive squamous cell carcinoma (SCC) of the skin is one of the most common cancers in the United States, with no proven means for prevention other than systemic retinoids, which have significant toxicity, and sunscreen. We sought to determine the risk factors for invasive SCC on the face or ears in a high-risk population comprising 1,131 veterans in the Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial. Participants were required to have been diagnosed with at least two keratinocyte carcinomas (KCs) in the 5 years prior to enrollment. The median duration of follow-up was 3.7 years. Twenty-three percent of the participants developed a new invasive SCC, and the cumulative risk of invasive SCC was 30% at 5 years. The following factors independently predicted for new invasive SCCs: number of invasive SCCs and number of in situ SCCs in the 5 years prior to enrollment, actinic keratoses count at enrollment, a history of ever use of topical 5-fluorouracil, and total occupational time spent outdoors. In contrast, the use of angiotensin-convering enzyme inhibitors or angiotensin receptor blockers during the study and a history of warts anywhere on the body were found to protect against new invasive SCCs. These independent predictors remained the same for all SCCs (invasive and in situ combined). The number of basal cell carcinomas in the 5 years prior to enrollment, sunburns, sun sensitivity, and recreational sun exposure were not associated with new SCCs. These findings identify key risk factors for additional SCCs in patients with multiple prior KCs, and suggest that a history of warts may be associated with reduced SCC risk.

Predictors of basal cell carcinoma in high-risk patients in the VATTC (VA Topical Tretinoin Chemoprevention) trial.

Basal cell carcinoma (BCC) is the most common cancer in the United States today, and patients who have had one are likely to have multiple carcinomas over time. Predictors of new BCCs on the face and ears among those at very high risk have not been studied in detail. We sought to do so prospectively in the context of a 6-year trial. We found that the number of BCCs in the prior 5 years was the most important predictor. Age, sun sensitivity, occupational sun exposure before the age of 30 years (but not afterward), lower educational level, history of eczema, the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and more sunscreen use in the week, but not the 6 months, before enrollment were also independent predictors, but sunburns, baseline sun exposure, and other sun-protective measures, other skin cancers, and actinic keratoses were not. None of the eczema patients had a history of topical calcineurin use. The cumulative risk of BCC was 55% at 5 years. These findings document the key risk factors in this very high-risk population, suggesting that the history of eczema may increase the risk in those at high risk and that early sun exposure is important even in this group, and underscoring the need for chemopreventive strategies.

Tretinoin and the prevention of keratinocyte carcinoma (Basal and squamous cell carcinoma of the skin): a veterans affairs randomized chemoprevention trial.

Keratinocyte carcinoma (KC) is the most common cancer in the United States, with no proven means for prevention other than systemic retinoids, which have significant toxicity, and sunscreen. Topical tretinoin has been used for KC chemoprevention, although this use is unproven. Hence, we conducted the randomized Veterans Affairs Topical Tretinoin Chemoprevention Trial of high-dose topical tretinoin for KC prevention. We randomized 1,131 patients to topical 0.1% tretinoin or a matching vehicle control for 1.5-5.5 years. The primary outcomes were time to development of new basal cell carcinoma (BCC) and new invasive squamous cell carcinoma (SCC) on the face or ears. The effects were not significant (P=0.3 for BCC and P=0.4 for SCC). The proportions of the tretinoin and control groups who developed a BCC at 5 years were 53 and 54% and an invasive SCC at 5 years were 28 and 31%. These differences (95% confidence intervals) were: for BCC, 1.0% (-6.5, 8.6%); for SCC, 3.6% (-3.1, 10.3%). No differences were observed in any cancer-related end points or in actinic keratosis counts. The only quality of life difference was worse symptoms in the tretinoin group at 12 months after randomization. This trial in high-risk patients demonstrates that high-dose topical tretinoin is ineffective at reducing risk of KCs.

Actinic keratoses: Natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial.

BACKGROUND: Actinic keratoses (AKs) are established as direct precursors of squamous cell carcinoma (SCC), but there is significant controversy regarding the rate at which AKs progress to SCC. The authors of this report studied a high-risk population to estimate the risk of progression of AK to SCC and to basal cell carcinoma (BCC) and the risk of spontaneous regression of untreated AKs. METHODS: Data were obtained from participants in the Department of Veterans Affairs Topical Tretinoin Chemoprevention Trial. Participants were examined every 6 months for up to 6 years. At each examination, the locations on the face and ears of clinically diagnosed AKs and lesions scheduled for biopsy were marked, and high-resolution digital photographs were taken. These photographs were used later to map and track the presence, absence, or biopsy of each AK across visits. RESULTS: In total, 7784 AKs were identified on the face and ears of 169 participants. The risk of progression of AK to primary SCC (invasive or in situ) was 0.60% at 1 year and 2.57% at 4 years. Approximately 65% of all primary SCCs and 36% of all primary BCCs diagnosed in the study cohort arose in lesions that previously were diagnosed clinically as AKs. The majority of AKs (55%) that were followed clinically were not present at the 1-year follow-up, and the majority (70%) were not present at the 5-year follow-up. CONCLUSIONS: In the current study, the authors quantified the malignant potential of clinically diagnosed AKs for both SCC and BCC, although many did not persist, and the results suggested that AKs may play a greater role in the overall burden of keratinocyte carcinomas than previously documented.

Topical tretinoin therapy and all-cause mortality.

OBJECTIVE: To evaluate the relation of topical tretinoin, a commonly used retinoid cream, with all-cause mortality in the Veterans Affairs Topical Tretinoin Chemoprevention Trial (VATTC). The planned outcome of this trial was risk of keratinocyte carcinoma, and systemic administration of certain retinoid compounds has been shown to reduce risk of this cancer but has also been associated with increased mortality risk among smokers. DESIGN: The VATTC Trial was a blinded randomized chemoprevention trial, with 2- to 6-year follow-up. Oversight was provided by multiple independent committees. SETTING: US Department of Veterans Affairs medical centers. Patients A total of 1131 veterans were randomized. Their mean age was 71 years. Patients with a very high estimated short-term risk of death were excluded. Interventions Application of tretinoin, 0.1%, or vehicle control cream twice daily to the face and ears. MAIN OUTCOME MEASURES: Death, which was not contemplated as an end point in the original study design. RESULTS: The intervention was terminated 6 months early because of an excessive number of deaths in the tretinoin-treated group. Post hoc analysis of this difference revealed minor imbalances in age, comorbidity, and smoking status, all of which were important predictors of death. After adjusting for these imbalances, the difference in mortality between the randomized groups remained statistically significant. CONCLUSIONS: We observed an association of topical tretinoin therapy with death, but we do not infer a causal association that current evidence suggests is unlikely.