Rosen's Breast Pathology, 4e

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Ductal Carcinoma In Situ

distinguished from HER2 ( + ) high-grade DCIS in routine H&E sections. Livasy et al. 202 studied 245 examples of pure DCIS and found that 19 (7.7%) qualified as basal like: (ER [−], HER2 [−], and EGFR or CK5/6 [ + ]). This small subset of DCIS displayed a variety of characteristics typically asso- ciated with HER2 ( + ) DCIS, including a high Ki67 index, expression of p53, and comedo histology. Thike et al. 203 ex- amined the DCIS component in 241 triple-negative invasive carcinomas and found that 151 (62.6%) DCIS were of high nuclear grade, and 236 (97.9%) were also triple negative. The basal phenotype, defined by immunoreactivity for CK14, EGFR, and 34βE12, was expressed in 68% in the in situ and invasive components of the same case. The authors con- cluded that triple-negative DCIS is the likely precursor of the corresponding invasive counterpart and that basal-like expression is maintained in the majority of invasive cancers associated with basal-like in situ disease. p53: Investigators employing a monoclonal antibody to wild and mutant forms of the p53 protein have reported nuclear reactivity in 10%, 204 18.5%, 205 19.2%, 195 25.2%, 206 and 37% 207 of DCIS examined (Fig. 11.57). In some stud- ies, expression of p53 was significantly associated with large or pleomorphic cell type, intraductal necrosis, and comedo DCIS, 195,198,204–206 but others did not find a significant corre- lation between grade or histologic subtype and p53 expres- sion 207 or p53 mutations. 193 Nuclear p53 was found only rarely in small cell DCIS. 206 No p53 reactivity was found in 17 cystic papillary carcinomas studied by O’Malley et al. 204 When present, p53 mutations have been identical in most instances where intraductal and invasive carcinoma samples from a single tumor have been examined. 208 In one study, no p53 mutations were identified in microdissected hyperplastic lesions from patients who had p53 mutations in coexisting intraductal and invasive duct carcinoma. 208 Carcinomas expressing p53 tend to be ER and PR nega- tive, 198,206 and they show evidence of a higher than median

proliferative rate manifested by a relatively high MIB1 la- beling index. 198 Molecular analysis using direct sequencing of PCR products revealed mutant p53 protein accumulation in comedo DCIS. 151 There was not a significant trend for coexpression of p53 and HER2 in any subset of carcinoma, despite the independent association of p53 and HER2 with large cell or comedo DCIS in some studies. 189,193,206,209 Other Markers The nm23 gene product is associatedwith lowmetastatic poten- tial in some cell culture systems and in invasive human breast carcinomas. 210 Cytoplasmic immunoreactivity for nm23 is found in normal breast epithelium and in most noninvasive carcinomas. 211 Strong staining was found in LCIS. Comedo- carcinomas without associated invasion exhibited more in- tense nm23 reactivity than comedocarcinomas with invasion, a difference not observed when noncomedo intraductal and invasive carcinoma were compared. 211 These observations suggest that reduced nm23 expression in comedo DCIS may be a marker for the acquisition of invasive characteristics. The relationship of growth factors and their receptors to the morphology and prognosis of DCIS has not been exten- sively explored. As noted earlier, EGFR expression has been associated with the basal-like phenotype DCIS (Fig. 11.58). E-cadherin is a cell–cell adhesion molecule expressed by epithelial cells. Loss of expression resulting frommutations in the E-cadherin gene has been associated with invasive lobular carcinoma and LCIS. E-cadherin expression may be reduced in DCIS, but it is rarely absent. Vos et al. 212 studied 150 ex- amples of DCIS and detected E-cadherin in all cases with re- duced expression in 11%. In one study, there was significantly less expression in high-grade than in low-grade lesions. 213 Bankfalvi et al. 214 also reported reduced E-cadherin reactivity in high-grade DCIS and confirmed the absence of E-cadherin expression in lobular carcinomas. The reduced cell–cell adhe- sion in high-grade DCIS may contribute to the relatively high frequency of microinvasion observed in these lesions.

FIG. 11.57.  DCIS, p53. Nuclear immunoreactivity is ­evident in almost all neoplastic cells in this DCIS with intermediate nuclear grade.

FIG. 11.58.  DCIS, EGFR. Membrane immunoreactivity for EGFR forms slender beaded lines between cells in this DCIS. Background cytoplasmic staining is also evident.