BRAF, NRAS and HRAS mutations in spitzoid tumours and their possible pathogenetic significance.

BACKGROUND: The relationships between so-called spitzoid tumours have proven difficult to understand. OBJECTIVES: To address three questions: does spitzoid tumour morphological similarity reflect molecular similarity? Does Spitz naevus progress into spitzoid melanoma? Are ambiguous spitzoid tumours genuine entities? METHODS: BRAF, NRAS and HRAS mutations were analysed using single-strand conformational polymorphism analysis and sequencing. RESULTS: Both Spitz naevi and spitzoid melanoma had a lower combined BRAF and NRAS mutation frequency compared with common acquired naevi (P = 0.0001) and common forms of melanoma (P = 0.0072), respectively. To look for evidence of progression from Spitz naevi to spitzoid melanoma, HRAS was analysed in 21 spitzoid melanomas, with no mutations identified. The binomial probability of this was 0.03 based on an assumption of a 15% mutation frequency in Spitz naevi with unbiased progression. Under these assumptions, HRAS mutations must be rare/absent in spitzoid melanoma. Thus, Spitz naevi seem unlikely to progress into spitzoid melanoma, implying that ambiguous spitzoid tumours cannot be intermediate degrees of progression. In addition, the data suggest that HRAS mutation is a potential marker of benign behaviour, in support of which none of three HRAS mutant spitzoid cases metastasized. CONCLUSIONS: First, the morphological similarity of spitzoid tumours reflects an underlying molecular similarity, namely a relative lack of dependence on BRAF/NRAS mutations. Second, Spitz naevi do not appear to progress into spitzoid melanoma, and consequently ambiguous spitzoid tumours are likely to be unclassifiable Spitz naevi or spitzoid melanoma rather than genuine entities. Third, HRAS mutation may be a marker of Spitz naevus, raising the possibility that other molecular markers for discriminating Spitz naevi from spitzoid melanoma can be discovered.

Understanding spitzoid tumours: new insights from molecular pathology.

Spitzoid tumours are a morphologically diverse group of lesions that share histological similarity to the Spitz naevus, a benign melanocytic skin tumour. Distinguishing classic Spitz naevi from cutaneous malignant melanoma is usually achievable on standard histology sections, but occasionally equivocal lesions are encountered that show features intermediate between these two entities and consequently generate considerable clinical and histopathological concern. The nomenclature and diagnostic criteria for spitzoid lesions are not standardized and this article begins by considering the adverse effect this has on our understanding of spitzoid tumour biology. Investigations of some of the hallmark features of cancer and neoplasia in spitzoid tumours are described, and the contribution of these studies to our understanding of spitzoid tumour biology is considered, along with their potential diagnostic utility. These studies compare spitzoid tumours with better-characterized melanocytic lesions, and from such comparisons assumptions concerning the biological nature of different spitzoid tumours can be made. In contrast, investigations of the mitogen-activated protein kinase (MAPK) pathway and DNA gains and losses have suggested that Spitz naevi may be genetically distinct from other melanocytic tumours. The studies that led to this conclusion are reviewed, as well as subsequent work examining whether the same applies to all spitzoid tumours. Possible explanations for the considerable inconsistencies within some of these data are explored. Finally, potential pathways of tumour progression within spitzoid lesions are considered, with an emphasis placed upon insights gained from investigations of MAPK genes and DNA gains and losses.

Long-term follow-up of patients following negative colposcopy: a new gold standard and its implications for cervical screening.

From 1189 colposcopy referrals in 1997 at a single cervical screening centre, 88 women who had no biopsy taken at colposcopy (negative colposcopy) were identified. We followed up these women for a maximum of 4 years and calculated the positive predictive value (PPV) of a single smear before and after follow-up. Using slide review we attempted to correlate the grade of smear leading to colposcopy referral with final outcome. Our results showed that long-term follow-up alters the PPV of cervical cytology. Analysis showed a strong correlation between the review grade of the referring smear and the final outcome after follow-up. From these results we suggest an evidence-based protocol for cervical screening follow-up after negative colposcopy.