D2-40/p63 defined lymph vessel invasion has additional prognostic value in highly proliferating operable node negative breast cancer patients

Abstract

Phosphohistone H3 assessed proliferation has strong prognostic value. Lymph vessel invasion by D2-40 is also prognostic, but D2-40 þ myoepithelial expression in small ducts completely filled by solid-pattern ductal carcinoma in situ can mimic lymphovascular invasion. As myoepithelial cells are also p63 positive, we have investigated whether lymph vessel invasion identified by combined D2-40/p63 is stronger prognostically than by D2-40 alone, and whether it has independent prognostic value to phosphohistone H3. In 240 operable T 1-2 N 0 M 0 node negative invasive breast cancer patients o71 years, phosphohistone H3 was determined by quantitative immunohistochemistry and lymph vessel invasion by D2-40/p63 double immunostaining. Correlation analysis between the clinico-pathologic factors and lymph vessel invasion, and univariate and multivariate prognostic survival analysis were performed. With median 117 (range: 12-192) months follow-up, 36 patients (15%) developed and 28 (12%) died of distant metastases. Ten of the 61 patients (16%) with cancer cells surrounded by D2-40 were p63 positive and none of these 'false lymph vessel invasion' recurred. D2-40 þ / p63À lymph vessel invasion occurred in 51/239 (21%) cases and correlated with grade, mitotic activity index, phosphohistone H3, ER, cytokeratin14, and HER2. D2-40 þ /p63À lymph vessel invasion was strongly prognostic, but far more in women Z55 than those o55 years (Po0.0001 and 0.04). With multivariate analysis, phosphohistone H3 proliferation was the strongest single prognosticator. Lymph vessel invasion had additional prognostic value to phosphohistone H3 only in women Z55. This group of patients, without/with lymph vessel invasion, had 10-year survival rates of 83 and 50%, respectively (hazard ratio-lymph vessel invasion ¼ 3.0, P ¼ 0.04; hazard ratio-phosphohistone H3 ¼ 6.9, P ¼ 0.002). Where age was o55 years, only phosphohistone H3 had independent prognostic value. Combinations of other features had no additional value. In conclusion, T 1-2 N 0 M 0 invasive breast cancer patients Z55 years with phosphohistone H3Z13, D2-40 þ /p63À defined lymph vessel invasion identifies a subgroup with a high risk of distant metastases.

Peritumoral apparent diffusion coefficients for prediction of lymphovascular invasion in clinically node-negative invasive breast cancer

“…LVI was reported to associate with tumours with a high cell proliferation level or high Ki-67 labelling index [27], which are likely to have lower ADC values. On the other hand, peritumoral maximum-ADC values would become higher with lymph oedema caused by LVI [19].…”

High lymphatic vessel density and presence of lymphovascular invasion both predict poor prognosis in breast cancer

“…A total of 4215 breast cancer patients, aging from 23 to 90 (except one study did not indicate the age [13]), were adopted in this study. Different antibodies, including LYVE-1 in one study, podoplanin in four studies, and D2–40 in 14 studies, were used to label the lymphatic vessels.…”

“…At present, lymphatic vessels can be distinguished from blood vessels or retraction artifacts. Thus, using immunohistochemical staining, many studies have updated the investigation of the prognostic value of lymphovascular invasion [13, 14]. …”

Prognostic comparison of the proliferation markers mitotic activity index, phosphohistone H3, Ki67, steroid receptors, HER2, high molecular weight cytokeratins and classical prognostic factors in T 1-2 N 0 M 0 breast cancer

“…Cytokeratin 5/6 (Clone D5/16 B4, Dako, Glostrup, Denmark) at a dilution of 1/100 and cytokeratin 14 (Clone LL002, Novocastra, Wetzlar, Germany) at a dilution of 1/40 were used. For lymph vessel invasion, the same protocol was used as described before [16]. Briefly, the sections were incubated with a primary antibody cocktail of p63 (Dako, Glostrup, Denmark, clone 4A4) and D2-40 (Dako, clone D2-40).…”