Nancy E. Thomas

Inconsistencies in the preparation of histology slides make it difficult to perform quantitative analysis on their results. In this paper we provide two mechanisms for overcoming many of the known inconsistencies in the staining process, thereby bringing slides that were processed or stored under very different conditions into a common, normalized space to enable improved quantitative analysis.

Expression of the p16(INK4a) tumor suppressor sharply increases with age in most mammalian tissues, and contributes to an age-induced functional decline of certain self-renewing compartments. These observations have suggested that p16(INK4a) expression could be a biomarker of mammalian aging. To translate this notion to human use, we determined p16(INK4a) expression in cellular fractions of human whole blood, and found highest expression in peripheral blood T-lymphocytes (PBTL). We then measured INK4/ARF transcript expression in PBTL from two independent cohorts of healthy humans (170 donors total), and analyzed their relationship with donor characteristics. Expression of p16(INK4a), but not other INK4/ARF transcripts, appeared to exponentially increase with donor chronologic age. Importantly, p16(INK4a) expression did not independently correlate with gender or body-mass index, but was significantly associated with tobacco use and physical inactivity. In addition, p16(INK4a) expression was associated with plasma interleukin-6 concentration, a marker of human frailty. These data suggest that p16(INK4a) expression in PBTL is an easily measured, peripheral blood biomarker of molecular age.

PURPOSE: Although most hospital-based studies suggest more favorable survival with tumor-infiltrating lymphocytes (TILs) present in primary melanomas, it is uncertain whether TILs provide prognostic information beyond existing melanoma staging definitions. We addressed the issue in an international population-based study of patients with single and multiple primary melanomas. PATIENTS AND METHODS: On the basis of the Genes, Environment and Melanoma (GEM) study, we conducted follow-up of 2,845 patients diagnosed from 1998 to 2003 with 3,330 invasive primary melanomas centrally reviewed for TIL grade (absent, nonbrisk, or brisk). The odds of TIL grades associated with clinicopathologic features and survival by TIL grade were examined. RESULTS: Independent predictors (P < .05) for nonbrisk TIL grade were site, histologic subtype, and Breslow thickness, and for brisk TIL grade, they were age, site, Breslow thickness, and radial growth phase. Nonbrisk and brisk TIL grades were each associated with lower American Joint Committee on Cancer (AJCC) tumor stage compared with TIL absence (P(trend) < .001). Death as a result of melanoma was 30% less with nonbrisk TIL grade (hazard ratio [HR], 0.7; 95% CI, 0.5 to 1.0) and 50% less with brisk TIL grade (HR, 0.5; 95% CI, 0.3 to 0.9) relative to TIL absence, adjusted for age, sex, site, and AJCC tumor stage. CONCLUSION: At the population level, higher TIL grade of primary melanoma is associated with a lower risk of death as a result of melanoma independently of tumor characteristics currently used for AJCC tumor stage. We conclude that TIL grade deserves further prospective investigation to determine whether it should be included in future AJCC staging revisions.

OBJECTIVE: To compare the prognosis of patients with scalp or neck (scalp/neck) melanomas with that of patients with melanomas at other sites in a large, population-based national data set controlling for known prognostic factors. DESIGN: Retrospective cohort study using US cancer registries that constitute the Surveillance, Epidemiology, and End Results 13 Registries (SEER-13) database. PATIENTS: A total of 51 704 non-Hispanic white adults in the United States with a first invasive cutaneous melanoma reported during the period 1992 to 2003. MAIN OUTCOME MEASURES: Kaplan-Meier survival estimates were used to compare melanoma-specific survival by anatomic site at 5 and 10 years. Multivariate Cox models were used to examine the hazard ratio (HR) of melanoma-specific death associated with scalp/neck melanoma compared with melanoma of the extremities after controlling for other variables. RESULTS: The 5- and 10-year Kaplan-Meier survival probabilities for scalp/neck melanoma were 83.1% and 76.2%, respectively, compared with 92.1% and 88.7%, respectively, for melanoma of the other sites, including extremities, trunk, face, and ears (log-rank test; P < .001). In a multivariate Cox model, the patients with melanoma of the scalp/neck died of melanoma at 1.84 times (HR, 1.84; 95% confidence interval, 1.62-2.10) the rate of those with melanoma on the extremities, controlling for age, Breslow thickness, sex, and ulceration. Neither excluding cases of lentigo maligna and nodular melanoma nor controlling for lymph node involvement materially changed the HR for scalp/neck melanoma. CONCLUSIONS: A notable survival difference remained between scalp/neck melanoma and melanoma of other sites even after adjustment for important prognostic factors. This finding has implications for screening and public health recommendations, and we urge physicians, physician assistants, nurses, and nurse practitioners to examine the scalp/neck carefully during routine skin examinations. Further studies are needed to understand the biological or environmental factors leading to survival differences by anatomic site.