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Background: CDKN2A, CDK4, and POT1 are well-established melanoma-susceptibility genes., Objective: We evaluated melanoma histopathology for individuals with germline mutations of CDKN2A, CDK4, and POT1., Methods: We assessed histopathology for melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) from the United States, Italy, and Spain. Comparisons between mutation carriers and noncarriers (no mutation) were adjusted for age, sex, Breslow depth, and correlations among individuals within the same family., Results: Histologic slides were evaluated for 290 melanomas (139 from 132 noncarriers, 122 from 68 CDKN2A carriers, 10 from 6 CDK4 carriers, and 19 from 16 POT1 carriers). Superficial spreading was the predominant subtype for all groups. Spitzoid morphology (>25% of tumor) was observed in 10 of 15 invasive melanomas (67%) from POT1 carriers (P < .0001 vs noncarriers). This finding was independently confirmed by 3 expert melanoma dermatopathologists in 9 of 15 invasive melanomas (60%). In situ and invasive melanomas from CDKN2A and CDK4 carriers were histologically similar to melanomas from noncarriers., Limitations: Limited sample sizes for rare melanoma-susceptibility syndromes (CDK4, POT1)., Conclusion: Spitzoid morphology was associated with POT1 mutations suggesting that telomere dysfunction (POT1 mutations) may contribute to spitzoid differentiation in melanocytic tumors., (Published by Elsevier Inc.)

Importance: This study proposes an alternative tumor staging system for cutaneous squamous cell carcinoma (CSCC) that more precisely defines the small subset of tumors with a high risk of metastasis and death., Objective: To identify risk factors for poor outcomes in CSCC and evaluate the 2010 American Joint Committee on Cancer (AJCC) tumor (T) staging system's ability to stratify occurrence of these outcomes., Design: Retrospective cohort study., Setting: A single academic hospital., Participants: Study participants were identified via a pathology and dermatopathology database search for patients diagnosed as having high-risk CSCC., Results: Two hundred fifty-six primary high-risk CSCCs were included. Outcomes for AJCC tumor stages T2 to T4 were statistically indistinguishable because only 4 cases (<2% of the cohort) were AJCC stages T3 or T4, which require bone invasion. Subsequently, the bulk of poor outcomes (83% of nodal metastases, 92% of deaths from CSCC) occurred in AJCC stage T2 cases. An alternative tumor staging system was developed with the aim of better stratifying this stage T2 group. Four risk factors were found to be statistically independent prognostic factors for at least 2 outcomes of interest in multivariate modeling. These factors (poor differentiation, perineural invasion, tumor diameter ≥2 cm, invasion beyond subcutaneous fat) were incorporated in the alternative staging with 0 factors indicating T1, 1 factor indicating T2a; 2 to 3 factors, T2b; and 4 factors or bone invasion, T3. Stages T2a and T2b significantly differed in incidences of all 4 end points. Stage T2b tumors comprised only 19% of the cohort but accounted for 72% of nodal metastases and 83% of deaths from CSCC., Conclusions and Relevance: The proposed alternative tumor staging system offers improved prognostic discrimination via stratification of stage T2 tumors. Validation in other cohorts is needed. Meanwhile, stage T2b tumors are responsible for most poor outcomes and may be a focus of high-risk CSCC study.

Purpose: Most patients with melanoma have microscopically thin (< or = 1 mm) primary lesions and are cured with excision. However, some develop metastatic disease that is often fatal. We evaluated established prognostic factors to develop classification schemes with better discrimination than current American Joint Committee on Cancer (AJCC) staging., Patients and Methods: We studied patients with thin melanomas from the US population-based Surveillance, Epidemiology, and End Results (SEER) cancer registry (1988 to 2001; n = 26,291) and those seen by the University of Pennsylvania's Pigmented Lesion Group (PLG; 1972 to 2001; n = 2,389; Philadelphia, PA). AJCC prognostic factors were thickness, anatomic level, ulceration, site, sex, and age; PLG prognostic factors also included a set of biologically based candidate prognostic factors. Recursive partitioning was used to develop a SEER-based classification tree that was validated using PLG data. Next, a new PLG-based classification tree was developed using the expanded set of prognostic factors., Results: The SEER-based classification tree identified additional criteria to explain survival heterogeneity among patients with thin, nonulcerated lesions; 10-year survival rates ranged from 89.1% to 99%. The new PLG-based tree identified groups using level, tumor cell mitotic rate, and sex. With survival rates from 83.4% to 100%, it had better discrimination., Conclusion: Prognostication and related clinical decision making in the majority of patients with melanoma can be improved now using the validated, SEER-based classification. Tumor cell mitotic rate should be incorporated into the next iteration of AJCC staging.