Rosen's Breast Pathology, 4e

373

Ductal Carcinoma In Situ

A

B

FIG. 11.55.  DCIS, estrogen receptor. A,B: Strong and diffuse nuclear immunoreactivity for ER (B) in solid DCIS with intermediate-grade nuclei and central necrosis. Nuclear reactivity has been lost in the dying cells around the necrotic center.

Samples of ER-negative comedo DCIS had a high prolifera- tive rate prior to transplantation, and this was maintained but did not increase when xenografts were exposed to es- trogen. On the other hand, noncomedo, ER-positive DCIS exhibited increased proliferation after exposure to estrogens, although the proliferative levels did not reach those of the comedo DCIS. These results suggest that ER-negative DCIS is estrogen independent and that antiestrogen therapy may not be beneficial for patients with these lesions. Hormone receptor expression in DCIS may be a signifi- cant factor for local recurrence after breast conservation treatment. Roka et al. 181 reported that DCIS with high nuclear grade and absence of ER had a significantly higher recurrence rate. However, not all high-grade DCIS lack ER expression. Collins and Schnitt 182 found that 14 (12%) of 114 ER-positive DCIS had high nuclear grade and overexpressed HER2 pro- tein. Concurrent ER and HER2 expression was not found in any of the 74 examples of low- and intermediate-grade DCIS, all of which expressed ER and lacked HER2 overexpression. In general, approximately 75% of DCIS cases show posi- tive nuclear immunoreactivity for ER (ranging from 1% to 100% cells), and a somewhat lower frequency are positive for PR. However, determination of “positivity” of ER and PR in DCIS can be problematic. 183 There are three main scoring methods for ER and PR immunoreactivity. One is the simple percentage method , that is, simple proportion of cells staining without regard to intensity. A second is the histochemical “H” method , that is, the sum of the percentage of cells with three degrees of staining of cells resulting in a range of 0 to 300. The third, Allred method , produces an intensity score between 1 and 3, and a percentage of cells staining compartmentalized in a nonlinear manner using scores between 1 and 5, to yield a final score of between 2 and 8. The Allred and “H” scor- ing methodologies include assessment of staining intensity, whereas the simple percentage method does not. Optimally, a scoring method utilizing both proportion and intensity of ER staining should be used for DCIS, if only because there is

evidence for the value of such assessment in invasive breast cancer. Excellent interobserver agreement has been reported in the use of “H” score for the assessment of ER and PR in in- vasive breast carcinoma since it provides a “continuous mea- sure of tumor hormone-receptor content” as opposed to the Allred system that has a “limited dynamic range.” 184 The UK breast-screening guidelines recommend the use of less than 5% cells staining for DCIS and the use of the Allred score for invasive cancers. 185 A cutoff point of Allred score 3 for positivity has been used in a study of various phe- notypes of DCIS. Baqai and Shousha 186 reviewed 56 cases of pure DCIS. ER positivity was defined as more than 10% of cells showing dark brown nuclear staining (Allred score greater than 4, “H” score of greater than 20). Eighty-eight percent of high-grade DCIS were ER negative. Data from the Sloane Project (named after the late Professor John Sloane of the Royal Liverpool Infirmaray who had a special inter- est in the pathology of DCIS) show that intermediate and low-grade DCIS are almost invariably ER positive, whereas high-grade DCIS is positive in 69% of cases. 185 Oncogenes HER2: Immunohistochemical studies have demonstrated membrane immunoreactivity for the HER2 (HER2) onco- gene in 42% to 61% of DCIS. 187–191 (Fig. 11.56). HER2 gene amplification has been reported in 40% to 48% of DCIS specimens isolated by microdissection and studied by the polymerase chain reaction (PCR). 192,193 Ho et al. 193 found significantly higher frequencies of HER2 amplification in comedo than in noncomedo DCIS (69% vs. 18%) and in le- sions with high rather than low nuclear grade (63% vs. 14%). Expression of HER2 occurs in 85% to 100% of comedocar- cinomas and is associated with the pleomorphic nuclear ­cytology in these lesions. 187,191,194 Most investigators have not detected HER2 in small cell micropapillary and cribriform DCIS. 187,191,195 Using