The immune microenvironment of breast ductal carcinoma in situ.

The host immune response has a key role in breast cancer progression and response to therapy. However, relative to primary invasive breast cancers, the immune milieu of breast ductal carcinoma in situ (DCIS) is less understood. Here, we profile tumor infiltrating lymphocytes and expression of the immune checkpoint ligand programmed death ligand 1 (PD-L1) in 27 cases of DCIS with known estrogen receptor (ER), progesterone receptor, and human epidermal growth factor 2 (HER-2) expression using tissue microarrays. Twenty-four cases were pure DCIS and three had associated invasive ductal carcinoma. Tumors were stained by immunohistochemistry for PD-L1, as well as the lymphocyte markers CD3, CD4, CD8, FoxP3, and CD20. The expression of PD-L1 by DCIS carcinoma cells and tumor infiltrating lymphocytes was determined, and the average tumor infiltrating lymphocytes per high power field were manually scored. None of the DCIS cells expressed PD-L1, but 81% of DCIS lesions contained PD-L1+ tumor infiltrating lymphocytes. DCIS with moderate-diffuse tumor infiltrating lymphocytes was more likely to have PD-L1+ tumor infiltrating lymphocytes (P=0.004). Tumor infiltrating lymphocytes with high levels of PD-L1 expression (>50% cells) were seen only in triple-negative DCIS (P=0.0008), and PD-L1-tumor infiltrating lymphocytes were seen only in ER+/HER-2-DCIS (P=0.12). The presence of PD-L1+ tumor infiltrating lymphocytes was associated with a younger mean patient age (P=0.01). Further characterization of the DCIS immune microenvironment may identify useful targets for immune-based therapy and breast cancer prevention.

Clinicopathologic features of ductal carcinoma in situ in young women with an emphasis on molecular subtype.

Young women with ductal carcinoma in situ treated by breast-conserving therapy have a higher recurrence rate than do older women, and a younger age at diagnosis is associated with worse overall survival after recurrence. This study explores the clinical, pathologic, and immunohistochemical characteristics of ductal carcinoma in situ lesions diagnosed in women 40 years and younger with a focus on molecular subtypes to elucidate features that may contribute to the purported worse outcome for this patient population. Forty-one patients diagnosed with ductal carcinoma in situ at age 40 years and younger were identified over a 10-year period; 31 cases were used to construct tissue microarrays. The microarrays were labeled with antibodies to estrogen receptor, progesterone receptor, HER2, Ki-67, CK5/6, epidermal growth factor receptor, and p53 and subsequently classified as luminal A, luminal B, HER2, basal-like, or unclassifiable triple negative. All patients had high-grade (73.2%) or intermediate-grade (26.8%) ductal carcinoma in situ. The molecular subtype breakdown was 61.3% luminal A, 22.6% luminal B, 13% HER2, and 3.1% unclassifiable triple negative. The mean Ki-67 by subtype was 4.2%, 14%, 9.5%, and 50%, respectively. Mastectomy was performed in 33 patients (80%). Eight patients (20%) underwent excisional biopsy without subsequent mastectomy. In addition to a predominance of high-grade lesions, young patients had a high proportion of luminal B subtype, which may contribute to an increased rate of local recurrence in this population. A larger series is necessary to confirm the impact that the molecular subtypes of ductal carcinoma in situ in younger patients might have on outcome.

Neural crest transcription factor Sox10 is preferentially expressed in triple-negative and metaplastic breast carcinomas.

The transcription factor Sox10 mediates the differentiation of neural crest-derived cells, and Sox10 labeling by immunohistochemistry (IHC) is used clinically primarily to support the diagnosis of melanoma. Sox10 expression by IHC has been previously documented in benign breast myoepithelial cells but not in breast carcinomas. Here, we report the first systematic study of Sox10 expression in invasive ductal carcinomas subclassified by IHC-defined molecular subtype (100 cases), as well as in 24 cases of ductal carcinoma in situ and 44 mammary fibroepithelial neoplasms. Tissue microarrays containing 168 primary breast tumors were subjected to IHC for Sox10. The extent of nuclear Sox10 labeling was scored by percentage labeling as follows: 0 (0%), 1+ (1%-25%), 2+ (25%-50%), 3+ (50%-75%), and 4+ (>75%). Overall, 40 (40%) of 100 invasive breast carcinomas demonstrated Sox10 immunoreactivity, which was seen primarily in the basal-like, unclassified triple-negative, and metaplastic carcinomas. Sox10 labeling was seen in 66% (38/58) of the basal-like, unclassified triple-negative, and metaplastic carcinomas as compared with 5% (2/42) of the luminal A, luminal B, and Her-2 carcinomas (P < .00001). Sox10 labeling was seen in 1 (4%) of 24 cases of ductal carcinoma in situ, which was negative for estrogen receptor/progesterone receptor. No labeling was seen in the stromal component of phyllodes tumors or fibroadenomas. These findings show that breast carcinoma must be considered in the differential diagnosis of melanoma for an S100-positive, Sox10-positive metastatic malignant neoplasm. Sox10 expression in the basal-like, unclassified triple-negative, and metaplastic carcinomas types supports the concept that these neoplasms show myoepithelial differentiation.