Lymph node metastases of melanoma: challenges for BRAF mutation detection

• Published in: Human pathology Vol. 46; no. 1; pp. 113 - 119
• Main Authors: Chen, Guoli, MD, PhD, Dudley, Jonathan, MD, Tseng, Li-Hui, MD, PhD, Smith, Kirstin, BS, Gurda, Grzegorz T., MD, PhD, Gocke, Christopher D., MD, Eshleman, James R., MD, PhD, Lin, Ming-Tseh, MD, PhD
• Format: Journal Article
• Language: English
• Published: United States 01.01.2015
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Allelic Imbalance; Biopsy; Child; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Humans; Lymph Nodes - enzymology; Lymph Nodes - pathology; Lymphatic Metastasis; Male; Melanoma - enzymology; Melanoma - genetics; Melanoma - secondary; Middle Aged; Mutation; Pathology; Phenotype; Predictive Value of Tests; Prognosis; Proto-Oncogene Proteins B-raf - genetics; Retrospective Studies; Risk Factors; Skin Neoplasms - enzymology; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Young Adult; Mutant allele-specific imbalance; BRAF; Lymph node; Melanoma; Tumor cellularity
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2014.09.014

Summary Detection of B-Raf proto-oncogene, serine/threonine kinase ( BRAF ) mutations is required to predict response to BRAF or mitogen-activated protein kinase kinase 1 and 2 inhibitors in metastatic melanoma. Lymph node (LN) specimens carrying melanoma cells intermingled with abundant lymphocytes often contain low tumor cellularity. This study is aimed to examine challenges in the clinical detection of BRAF mutations in LN specimens with metastatic melanoma and to illustrate characteristic features of p.V600E and non-p.V600E mutations. In this retrospective study for quality assessment of the pyrosequencing assay, we compared characteristics of 53 LN and 135 non-LN formalin-fixed, paraffin-embedded specimens with metastatic melanoma submitted for BRAF mutation detection over a 40-month period. LN specimens showed a significantly higher incidence of p.V600E mutations than non-LN specimens (49% versus 22%, P < .01) but a significantly lower tumor cellularity, particularly in the case of subcapsular or infiltrative metastases. Mutant allele-specific imbalance of the p.V600E mutation was predominantly present in specimens with distant organ metastases (79% versus 27% in LN metastases versus 13% in primary cutaneous tumors or adjacent soft tissue, P < .001). p.V600K was detected in 23% of men older than 60 years old, compared with 6% in women older than 60 years old and 2% in both men and women younger than 60 years old ( P < .001). LN specimens with low tumor cellularity due to numerous adjacent lymphocytes may pose a challenge to clinical detection of BRAF mutations of melanoma. The higher incidence of p.V600E mutations in LNs may prompt further studies to elucidate if the p.V600E mutation in primary tumors is associated with a higher risk of LN metastasis.