Breslow Density Is a Novel Prognostic Feature That Adds Value to Melanoma Staging.

Histomorphologic prognostic biomarkers that can be measured using only an hematoxylin and eosin stain are very attractive because they are simple and cheap. We conceived an entirely novel biomarker of this type, the Breslow density (BD), which measures invasive melanoma cell density at the site where Breslow thickness (BT) is measured. This study assessed BD's prognostic value. In this study, BD was measured in 1329 melanoma patients. Measurement accuracy and precision was assessed using intraclass correlation coefficient (ICC). Survival was assessed with a primary end-point of melanoma-specific survival (MSS) and also overall survival and metastasis-free survival. We found that BD measurement was accurate compared with gold standard image analysis (ICC, 0.84). Precision was excellent for 3 observers with different experience (ICC, 0.93) and for an observer using only written instructions (ICC, 0.93). BD was a highly significant predictor in multivariable analysis for overall survival, MSS, and metastasis-free survival (each, P<0.001) and it explained MSS better than BT, but BT and BD together had best explanatory capability. A BD cut point of ≥65% was trained in 970 melanomas and validated in 359. This cut point showed promise as a novel way to upstage melanoma from T stage "a" to "b." BD was combined with BT to create a targeted burden score. This was a validated as an adjunct to American Joint Committee on Cancer stage. In summary, BD can be measured accurately and precisely. It demonstrated independent prognostic value and explained MSS better than BT alone. Notably, we demonstrated ways that BD could be used with American Joint Committee on Cancer version 8 staging.

A Novel Numerical Scoring System for Melanoma Tumor-infiltrating Lymphocytes Has Better Prognostic Value Than Standard Scoring.

The purpose of this study was to evaluate the prognostic value of tumor-infiltrating lymphocytes (TILs) in melanoma and to determine whether a simpler numerical scoring system would be more effective. In total, 655 patients presenting to a UK teaching hospital with primary invasive melanoma were analyzed. TILs were rescored using the standard Clark's method and univariable and multivariable analyses of the effect of TILs on overall survival (OS), disease-specific survival (DSS), and metastasis-free survival (MFS) was assessed using Cox regression. In total, 30 (5%) melanomas showed absent, 464 (71%) nonbrisk, and 161 (24%) brisk TILs. There was a statistically significant relationship between TILs and Breslow thickness, age, melanoma type, mitotic rate, and histologic regression. TIL grade was a significant predictor of MFS in multivariable analysis (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.25-0.77) but was not significant for OS or DSS. By contrast, when a simple numerical TIL percentage score was used this was a strong predictor of OS (HR, 0.55; 95% CI, 0.38-0.78), DSS (HR, 0.25; 95% CI, 0.14-0.44), and MFS (HR, 0.32; 95% CI, 0.21-0.51) in multivariable analysis. The percentage TIL score was also significant when adjusted for the prognostic gold standard, American Joint Committee on Cancer stage: OS (HR, 0.66; 95% CI, 0.46-0.95), DSS (HR, 0.33; 95% CI, 0.19-0.60), and MFS (HR, 0.41; 95% CI, 0.26-0.65). The TIL percentage score was subsequently validated in new cases. In summary, this study strongly confirms that higher amounts of TILs are associated with better prognosis and in addition demonstrates the value of a simplified numerical TIL scoring system.

Breslow density is a novel prognostic feature in cutaneous malignant melanoma.

AIMS: In 1970, Breslow described his eponymously named thickness measurement. No-one has sought to enhance the Breslow thickness (BT). The aim of this study was to demonstrate a proof of concept that the density of melanoma cells at the position where the BT is measured is a morphological prognostic biomarker, which we name the Breslow density (BD). The hypothesis was that the BD has prognostic value for overall survival (OS) and is independent of the BT. METHODS AND RESULTS: We analysed 100 cutaneous melanomas, and followed REMARK guidelines. The BD was the estimated percentage dermal area occupied by melanoma cells in a specified location. The BT and BD had a strong correlation (P = 2.1 × 10-11 ) but, despite this, they were independent prognostic factors for OS in Cox regression [BD hazard ratio (HR) 1.03, P = 0.001849; and BT HR 1.09, P = 0.000146]. This was corroborated by an independent effect on melanoma-specific survival. We assessed whether the BT and BD could be combined into a Breslow score. A prognostic index based on Cox regression coefficients was used, and this showed a marginal improvement in predicted 5-year survival as compared with the BT alone (area under the curve of 94.8% versus 96.7%). CONCLUSIONS: We show a proof of concept that the BD represents a novel morphological prognostic biomarker that is independent of the BT, and that there is potential to combine these into a Breslow score. Larger studies are needed to validate the BD, but the simplicity of this biomarker makes it a strong candidate for translation to clinical practice.

Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis.

BACKGROUND: Cardiac transthyretin (ATTR) amyloidosis is a progressive and fatal cardiomyopathy for which several promising therapies are in development. The diagnosis is frequently delayed or missed because of the limited specificity of echocardiography and the traditional requirement for histological confirmation. It has long been recognized that technetium-labeled bone scintigraphy tracers can localize to myocardial amyloid deposits, and use of this imaging modality for the diagnosis of cardiac ATTR amyloidosis has lately been revisited. We conducted a multicenter study to ascertain the diagnostic value of bone scintigraphy in this disease. METHODS AND RESULTS: Results of bone scintigraphy and biochemical investigations were analyzed from 1217 patients with suspected cardiac amyloidosis referred for evaluation in specialist centers. Of 857 patients with histologically proven amyloid (374 with endomyocardial biopsies) and 360 patients subsequently confirmed to have nonamyloid cardiomyopathies, myocardial radiotracer uptake on bone scintigraphy was >99% sensitive and 86% specific for cardiac ATTR amyloid, with false positives almost exclusively from uptake in patients with cardiac AL amyloidosis. Importantly, the combined findings of grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy and the absence of a monoclonal protein in serum or urine had a specificity and positive predictive value for cardiac ATTR amyloidosis of 100% (positive predictive value confidence interval, 98.0-100). CONCLUSIONS: Bone scintigraphy enables the diagnosis of cardiac ATTR amyloidosis to be made reliably without the need for histology in patients who do not have a monoclonal gammopathy. We propose noninvasive diagnostic criteria for cardiac ATTR amyloidosis that are applicable to the majority of patients with this disease.