When faced with an intraduct proliferation, the first question that needs to be answered is whether the proliferation represents intraductal hyperplasia or neoplasia. Hyperplasia represents a polymorphic proliferation of basal and luminal epithelial cells. As these cell types have different morphologies, the consituent cells of usual epithelial hyperplasia will be varied in appearance.
The helpful architectural features indicating usual hyperplasia include:
1. Irregular, slit-like, collapsing secondary spaces. As the individual cells proliferating in hyperplasia have different structural and polar properties, the secondary spaces formed will be non-uniform.
2. The cells forming the collapsing bridges between the secondary spaces will stream ie. the nuclei of these cells will be stretched out along the direction of the bridge between individual spaces.
In terms of cytology, the cells of usual epithelial hyperplasia comprise a mixture of vacuolated or spindled basal cells, intermixed with epithelioid luminal cells and a range of intermediary forms.
Immunohistochemistry provides supportive evidence in cases of difficulty. Cytokeratin 5 will confirm that the majority of cells present in usual hyperplasia are basal in type, with fewer luminal type cells, expressing oestrogen receptors.
Cytokeratin 5/6 in usual epithelial hyperplasia. 
Oestrogen receptor expression in usual epithelial hyperplasia.
The immunohistochemical hallmark of hyperplasia therefore is:
Diffuse expression of high molecular weight cytokeratin.
Heterogenous expression of oestrogen receptors.
Ductal carcinoma in-situ (intraductal neoplasia) on the other hand, is almost always a proliferation of luminal epithelial cells only. It may be of low, intermediate or high nuclear grades. High grade DCIS is easy to recognise as it comprises markedly pleomorphic cells, with mitoses and prominent nuclear atypia, with or without necrosis.
Solid high nuclear grade ductal carcinoma in-situ (HGDCIS) with comedonecrosis.
Low grade DCIS comprises a monotonous proliferation of relatively uniform atypical epithelial cells. If the cells residing in a distended duct space have a monotonous appearance, think neoplasia. Low grade DCIS commonly has a cribriform (sieve-like) architecture, comprising evenly placed cells forming rigid, oval to round secondary spaces. If you observe the detailed structure of the bridges between the spaces, the cells do not stream, but are arranged in a regular fashion side by side.
Low nuclear grade cribriform ductal carcinoma in-situ (DCIS) with calcification.
As the cells in DCIS have a luminal phenotype, they will show diffuse expression of oestrogen receptors and will be negative for cytokeratin 5.
Oestrogen receptor expression in ductal carcinoma in-situ.
High molecular weight cytokeratin (CK5) in ductal carcinoma in-situ.
The immunohistochemical hallmark of intraductal neoplasia (DCIS) therefore is:
Diffuse expression of oestrogen receptors.
Negativity for high molecular weight cytokeratin*.
(*A sub-set of high grade DCIS (basal type DCIS) may express high molecular weight cytokeratin eg. cytokeratin 5 and be negative for oestrogen receptors. This is generally easy to recognise and does not enter into the differential diagnosis for usual epithelial hyperplasia).