A deeper understanding of the variance of epidermal cell proliferation may eventually increase the reproducibility of diagnostic classification. A prospective study of 46 consecutive, unselected biopsies from benign (keratoacanthoma n=14), premalignant (actinic keratosis n=15 and Bowen disease n=10) and malignant (squamous cell carcinoma n=7) skin lesions was studied to assess the presence and extent of differences in expression of the proliferation marker Ki-67 using a monoclonal antibody directed against a c-DNA defined subsegment (MIB-1) and a noncross-linking, proprietary fixative BoonFix. MIB-1 was expressed in the adjacent, non-affected skin in a scattered to confluent linear pattern in the basal/suprabasal cell layer. In actinic keratosis, MIB-1 expression, in addition to basal/suprabasal layers, extended to mid-zones of the epidermis. An interesting feature in actinic keratosis as well as in Bowen disease was the expression of MIB-1 in the epithelium lining the hair follicles. In Bowen disease, MIB-1 was observed throughout the full thickness of the epidermis, unequivocally separating this entity from others under study. In invasive squamous cell carcinoma, MIB-1 expression was not consistent between and within cases. MIB-1 positivity was variably found in all layers of the epidermis, but showed a chaotic and haphazard pattern with total loss of polarity. Keratoacanthoma cases showed highly variable MIB-1 expression, ranging from no expression to expression in both basal/suprabasal and mid-zone layers of the epidermis. These results warrant further study of modulation of cell proliferation in actinic keratosis.

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.