Proliferation patterns reflect architectural dedifferentiation: a study of nodular basal cell carcinoma

The distribution of proliferating cells in basal cell carcinoma (BCC) may be related to lesion type and architecture. Single proliferation indexes may not be representative. We aimed to establish the distribution of cell proliferation in BCC as related to architecture. We studied an unselected, consecutive series of 45 resection specimens of nodular BCC from patients in the age range of 25-95 years using MIB-1 staining and systematically reviewed the cases. These lesions included nodular (n=32) and non-nodular (n=9) BCC. Within the nodular BCC, two patterns were recognised, not related to age or gender. In small nodular patterns with well developed peripheral palisading and central parallel streaming of small, elongated nuclei, proliferation is limited to the basal palisading cells in a clustered distribution. In large nodular patterns, proliferation is absent at the basal membrane (BM) and distributed in single random cells throughout the lesion. Both patterns preclude accurate quantitation. Many lesions contained both patterns in a side-by-side, unmixed manner. These pattern differences suggest a loss of differentiation in nodular BCC. Perhaps a single mutation results in the loss of BM associated cell architecture and proliferation control related to tumor-stroma interactions. As a result, the lesion reverts to a low frequency, non-regulated proliferation, diffusely distributed throughout the lesion. The two patterns may exist side-by-side in a single lesion, further supporting the concept of polyclonality. This hypothesis explains perilesional clefting and previously reported variations in intra-lesional laminin synthesis. Based on our findings, representation of tumor cell proliferation activity by a single value is not justified. Nodular BCC exists in one of two dedifferentiation-mutation-determined patterns of cell proliferation; many lesions clearly demonstrate bi-clonality.