What features do patients notice that help to distinguish between benign pigmented lesions and melanomas?: the ABCD(E) rule versus the seven-point checklist

The ABCD(E) rule and the seven-point checklist are diagnostic aids that have proven to be useful in the hands of physicians; however, little is known of their value to patients with respect to aiding self-detection. The objective of this study was to investigate features that patients notice when identifying melanomas and to explore how well these features correspond to the ABCD(E) rule and the seven-point checklist. A retrospective, modified, case-control study involving patient interviews was performed. All interviews were conducted through the private consulting rooms of a Melbourne dermatologist (JWK) and a Newcastle plastic surgeon (CH) prior to the result of pathology being known to the patients and the interviewers. Sixty-seven patients with benign pigmented skin lesions and 46 patients with melanomas were included. Using a logistic regression model, the change in size/new lesion and change in colour (major criteria, seven-point checklist) were most useful in differentiating between melanomas and benign pigmented lesions in the hands of patients [odds ratio (OR), 4.74; 95% confidence interval (CI), 1.85-12.19; P=0.001; OR, 4.27; 95% CI, 1.62-11.26; P=0.003, respectively). The ABCD(E) rule failed to discriminate between melanoma and other benign pigmented skin lesions. It can be concluded that, of the patients' observations, changes in size or colour were most important in distinguishing between benign pigmented lesions and melanomas. Such features therefore deserve emphasis in public education campaigns. Medical professionals should also remember to seek a history of change in assessing pigmented skin lesions.     

Genotype-phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency

Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non-missense, including 20 stop-gain, 11 affecting splicing, five large deletions, four in-frame indels, and three promoter variants. Within the 177 unrelated patients, 35 were homozygous and 142 compound heterozygous (77 for two missense, 48 for one missense and one non-missense, and 17 for two non-missense variants); the two most frequent mutations were p.R510Q in 23% and p.R486W in 9% of mutated alleles. Fifty-five (21%) patients were found to have at least one previously unreported variant with 45 newly described mutations. Patients with two non-missense mutations had lower hemoglobin levels, higher numbers of lifetime transfusions, and higher rates of complications including iron overload, extramedullary hematopoiesis, and pulmonary hypertension. Rare severe complications, including lower extremity ulcerations and hepatic failure, were seen more frequently in patients with non-missense mutations or with missense mutations characterized by severe protein instability. The PKLR genotype did not correlate with the frequency of complications in utero or in the newborn period. With ICCs ranging from 0.4 to 0.61, about the same degree of clinical similarity exists within siblings as it does between siblings, in terms of hemoglobin, total bilirubin, splenectomy status, and cholecystectomy status. Pregnancy outcomes were similar across genotypes in PK deficient women. This report confirms the wide genetic heterogeneity of PK deficiency.     

A BRCA1/2 mutation,high breast density and prominent pushing margins of a tumor independently contribute to a frequent false-negative mammography

Female BRCA1/2 mutation carriers develop in up to 50% breast cancer (BC) before age 50 years. We investigated whether the specific histologic features of BRCA1/2-associated breast cancer influence imaging. We correlated the mammographic results with the histology of 34 BC in BRCA1/2 mutation carriers and 34 sporadic cancers in patients, matched for age and year of diagnosis. Mammography was significantly more frequently false-negative in carriers than controls (62% vs. 29% p = 0.01), despite comparable tumor size (mean solidus in circle 1.51 vs. 1.75) and breast density (high 41% vs. 53%). The image in carriers was significantly less as spiculated mass (6 vs. 18 p = 0.01). Cancers of BRCA1/2 mutation carriers had frequently higher mitotic counts (p < 0.0001) and prominent pushing margins around the tumor (p = 0.08) (p = 0.05 for 32 BRCA1). We also observed that prominent "pushing margins" correlated significantly with a false-negative mammography (p = 0.005) and with a mammographic image of a smooth, not a spiculated, mass (p = 0.01). False-negative mammography correlated independently with: BRCA1/2 mutation (p = 0.02), prominent pushing margins (p = 0.03) and high breast density (p = 0.01). MRI was carried out in 12 carriers, had 100% sensitivity and detected 5 cancers, still occult at physical examination and mammography. A BRCA1/2 mutation and high breast density at mammography contribute independently to false-negative mammography results. In mutation carriers any mammographic mass must be regarded with suspicion. Pushing margins of the tumor partly explain these results. For early BC detection in mutation carriers additional methods like MRI may be needed. This may not be necessary in other young women with breast symptoms.