Histologically normal human mammary epithelia with silenced p16(INK4a) overexpress COX-2, promoting a premalignant program.

Breast tissue from healthy women contains variant mammary epithelial cells (vHMEC) exhibiting p16INK4a promoter hypermethylation both in vivo and in vitro. When continuously cultured, vHMEC acquire telomeric dysfunction and produce the types of chromosomal abnormalities seen in premalignant lesions of cancer. We find that late passage vHMEC express elevated prostaglandin cyclo-oxygenase 2 (COX-2), which contributes to increased prostaglandin synthesis, angiogenic activity, and invasive ability. These data demonstrate the existence of human mammary epithelial cells with the potential to acquire multiple genomic alterations and phenotypes associated with malignant cells. Moreover, COX-2 overexpression coincides with focal areas of p16INK4a hypermethylation in vivo, creating ideal candidates as precursors to breast cancer. These putative precursors can be selectively eliminated upon exposure to COX-2 inhibitors in vitro.

Cyclooxygenase-2 expression is related to nuclear grade in ductal carcinoma in situ and is increased in its normal adjacent epithelium.

Cyclooxygenase-2 (COX-2) is emerging as an important cancer biomarker and is now an experimental target for solid tumor treatment.However, no study has exclusively focused on COX-2 expression in early lesions such as ductal carcinoma in situ (DCIS). We examined COX-2 expression by immunohistochemistry in 46 cases of women undergoing surgical resection for DCIS. We found that COX-2 expression was detected in 85% of all DCIS specimens, with increased COX-2 staining correlating with higher nuclear grade. Strikingly, COX-2 staining intensity in the normal adjacent epithelium was stronger than in the DCIS lesion itself. Our observations demonstrate that COX-2 is up-regulated in the normal adjacent epithelium and supports the hypothesis that the surrounding epithelial tissue is part of the disease process in DCIS.

Early lymph node involvement by mantle cell lymphoma limited to the germinal center: report of a case with a novel "follicular in situ" growth pattern.

Recently, several reports have described cases of "in situ" mantle cell lymphoma (MCL) in which scattered cyclin D1+ cells were present within the mantle zones of reactive-appearing lymphoid follicles. In this report, we describe an unusual histologic pattern of in situ MCL that was identified in a staging lymph node for colonic adenocarcinoma resected 4 years before a diagnosis of symptomatic MCL. Retrospective immunohistochemical studies showed scattered cyclin D1-expressing cells within otherwise reactive germinal centers but not in the surrounding mantle zones. The presence of early MCL cells limited to reactive germinal centers represents a novel "follicular in situ" growth pattern for MCL, which overlaps morphologically with reactive follicular hyperplasia and follicular lymphoma and which could have implications for MCL pathogenesis.

Flow cytometric evaluation of CD38 expression assists in distinguishing follicular hyperplasia from follicular lymphoma.

The distinction of follicular lymphoma (FL) from reactive follicular hyperplasia (FH) can be a diagnostic challenge in flow cytometry. In this study, the median fluorescent intensity (MFI) of CD38 as assessed by flow cytometry on B and T cell subpopulations in 102 lymph nodes specimens with histopathologically confirmed FL was compared with 55 cases of FH. The MFI of CD38 was highly significantly reduced in the neoplastic B cells in FL when compared with the reactive germinal center B cells in FH (P < 1.0E-16). The MFI of CD38 did not differ between the non-neoplastic B-cells in FL and nongerminal center B-cells in FH (P = 0.14) or between T-cells and non-neoplastic B-cells in FL (P = 0.63). A marginal increase in the MFI of CD38 was seen for T cells in FL compared with FH (P = 0.04). An increased difference in the MFI of CD38 was identified for T-cells compared with nongerminal center B-cells in FH (P = 0.005). No difference in CD38 expression was seen between Grades 1, 2, or 3 FL. The study also confirmed increased expression of CD10 (P < 1.0E-9), decreased CD19 (P < 1.0E-22), and CD20 (P < 1.0E-16) in FL in comparison with FH, as has been previously reported. This study identified decreased CD38 as a common finding in FL in comparison with FH and provides an additional tool to help differentiate FL from FH by flow cytometry.