Andrea E. Dawson

Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6, and overexpress HER2 or EGFR

Brain metastases (BM) from breast cancer are associated with significant morbidity and mortality. In the current study, we have examined a cohort of breast cancer patients who went on to develop BM for clinical-pathologic features and predictive markers that identify this high-risk subgroup of patients at the time of diagnosis. The primary tumors from 55 patients who developed BM were used to construct a tissue microarray. The clinical and pathologic features were recorded and the tissue microarray was stained for estrogen receptor, human epidermal growth factor receptor 2, cytokeratin 5/6, and epidermal growth factor receptor by immunohistochemistry . This cohort of patients was compared against a group of 254 patients who remain free of metastases (67 mo mean follow-up), and another cohort of 40 patients who developed mixed visceral and bone metastatic disease without brain recurrence over a similar period of time. Breast cancer patients who went on to develop BM were more likely to be <50 years old (P<0.001), and the primary tumors were more likely to be estrogen receptor negative (P<0.001) and high grade (P=0.002). The primary tumors were also more likely to express cytokeratin 5/6 (P<0.001) and epidermal growth factor receptor (P=0.001), and to overexpress human epidermal growth factor receptor 2 (P=0.001). The data presented above suggest a profile for breast cancer patients at increased risk for developing BM. Predictive factors to help identify patients with metastatic breast cancer who are at an increased risk for developing central nervous system recurrence might allow for screening of this population for early detection and treatment or for the development of targeted strategies for prevention.

Loss of Breast Cancer Metastasis Suppressor 1 Protein Expression Predicts Reduced Disease-Free Survival in Subsets of Breast Cancer Patients

Purpose: This study aims to determine the effect of loss of breast cancer metastasis suppressor 1 (BRMS1) protein expression on disease-free survival in breast cancer patients stratified by estrogen receptor (ER), progesterone receptor (PR), or HER2 status, and to determine whether loss of BRMS1 protein expression correlated with genomic copy number changes. Experimental Design: A tissue microarray immunohistochemical analysis was done on tumors of 238 newly diagnosed breast cancer patients who underwent surgery at the Cleveland Clinic between January 1, 1995 and December 31, 1996, and a comparison was made with 5-year clinical follow-up data. Genomic copy number changes were determined by array-based comparative genomic hybridization in 47 breast cancer cases from this population and compared with BRMS1 staining. Results: BRMS1 protein expression was lost in nearly 25% of cases. Patients with tumors that were PR negative (P = 0.006) or HER2 positive (P = 0.039) and <50 years old at diagnosis (P = 0.02) were more likely to be BRMS1 negative. No overall correlation between BRMS1 staining and disease-free survival was observed. A significant correlation, however, was seen between loss of BRMS1 protein expression and reduced disease-free survival when stratified by either loss of ER (P = 0.008) or PR (P = 0.029) or HER2 overexpression (P = 0.026). Overall, there was poor correlation between BRMS1 protein staining and copy number status. Conclusions: These data suggest a mechanistic relationship between BRMS1 expression, hormone receptor status, and HER2 growth factor. BRMS1 staining could potentially be used in patient stratification in conjunction with other prognostic markers. Further, mechanisms other than genomic deletion account for loss of BRMS1 gene expression in breast tumors.

Use of Ethylene Vinyl Alcohol Copolymer for Tubal Sterilization by Selective Catheterization in Rabbits

PURPOSE To assess the efficacy of ethylene vinyl alcohol copolymer (Uryx) in nonsurgically occluding the fallopian tube and achieving tubal sterilization in the rabbit model. MATERIALS AND METHODS Ten mature virgin female New England rabbits underwent transvaginal selective bilateral fallopian tube cannulation with use of a coaxial catheter system under general anesthesia. Selective salpingography was performed bilaterally to assess patency of the fallopian tubes. Ethylene vinyl alcohol copolymer was injected unilaterally through a microcatheter to completely fill the middle portion of the tube. Three to seven days after injection, each animal was bred. Conception was determined by ultrasonography (US) 7-19 days after effective breeding. If pregnant, the rabbit was killed. Otherwise, it was permitted to rebreed until pregnancy was achieved. Histologic specimens of the fallopian tubes were prepared and analyzed. RESULTS Patency of the fallopian tubes was demonstrated bilaterally in all animals by the free spillage of contrast material into the peritoneum. The delivery of ethylene vinyl alcohol copolymer into the fallopian tubes was successful in all animals but one, in which most of the plug almost immediately extruded into the uterus. Pregnancy was detected by US in the untreated fallopian tube in the nine rabbits that were receptive to breeding. No pregnancies were detected in the injected side. Histologic analysis demonstrated variable degrees of occlusion, fibrosis, and inflammation, with the majority of specimens demonstrating mild to moderate inflammation and moderate to marked fibrosis. CONCLUSION Ethylene vinyl alcohol copolymer can reliably be placed nonsurgically via the transvaginal approach into the fallopian tubes with use of a coaxial catheter system. Ethylene vinyl alcohol copolymer appears to result in less fibrosis than previously investigated agents and demonstrates a 100% early sterilization rate in the rabbit model.

Mammary ductoscopy and ductal washings for the evaluation of patients with pathologic nipple discharge.

Abstract:  The majority of breast diseases result from lesions of the ductal epithelium. Mammary ductoscopy allows for visualization of intraductal abnormalities, and ductoscopic lavage provides thousands of cells for analysis. We reviewed our experience of 89 cases of patients with pathologic nipple discharge (PND) undergoing ductoscopy‐directed duct excision and collection of ductal washings. Patients undergoing ductoscopy‐directed duct excision with ductal washings had an 88% abnormal pathology rate. Most abnormalities were benign (71% papillomas), but the atypia rate for this group was 62%. The combination of visualization and pathologic analysis of washings provided the highest predictive value for the diagnosis of papilloma. Cellular yields for this technique were excellent with most specimens yielding >5,000 epithelial cells per high powered field and with evaluable ductal cells in 82% of specimens. Mammary ductoscopy offers the advantage of a high lesion localization rates with intraoperative guidance. The most accurate tool was the combination of ductal washings and ductoscopic visualization, but preoperative use of these techniques is not helpful in most cases. Greater than 90% of patients with PND are found to have a lesion on pathologic examination when using this technique for directed duct excision. Of interest, ductal washings obtained from symptomatic patients with benign diseases are often atypical.

Breast carcinoma detection in women age 35 years and younger

BACKGROUND Delays in breast carcinoma diagnosis may occur in young women due to a low index of suspicion. Fine-needle aspiration (FNA) is an ideal method for evaluating breast lesions in younger women. Mammographic and FNA findings, including nuclear grade, were studied to determine both the utility of FNA and the presence of unique cytologic features in women age < or = 35 years with breast carcinoma. METHODS The cytopathology files were searched from 1984 to 1996 for FNA in women age < or = 35 years with breast carcinoma. The cytologic, mammographic, and clinical findings were reviewed in the 68 FNAs identified. A nuclear grade was assigned to each FNA. RESULTS Thirteen patients were age < 30 years and 55 were age 31-35 years (range, 22-35 years; average, 31 years). The clinical and mammographic findings were carcinoma in 45 patients (66%) and fibroadenoma/benign in 23 patients (34%). FNA diagnoses were malignant/suspicious (86%), atypical (12%), and negative (1.4%). In 23 patients with unsuspected carcinoma, the FNA diagnosed or suggested malignancy in 22 of 23 patients (96%). The cytologic findings on review were variable. Many FNAs were cellular, with enlarged nuclei and prominent nucleoli. The FNAs predominantly were nuclear Grade 2 (47%) and 3 (47%); only 4 tumors were nuclear Grade 1 (6%). CONCLUSIONS By detecting breast carcinoma in 23 patients with unsuspected carcinoma, this study demonstrates how breast FNA in young women can help avoid delays in diagnosis. The cytologic findings are striking for an increased incidence of high grade tumors.

Does Identifying Whether Pseudoangiomatous Stromal Hyperplasia (PASH) Is Focal or Diffuse on Core Biopsy Correlate With a PASH Nodule on Excision

Aims. Pseudoangiomatous stromal hyperplasia (PASH) diagnosed on core needle biopsy is generally excised. As a consequence, PASH as an incidental finding, may lead to unnecessary excisions. This study categorized PASH in biopsies as diffuse versus focal to determine if this correlates with the presence of a mass. Methods. In a 10-year period, 253 biopsies were identified and 159 met inclusion criteria. Of these, 47 biopsies had excisions. Biopsies and excisions were classified as diffuse, involving 2 adjacent lobules, or focal PASH in a single lobule or noncontiguous lobules. The diffuse or focal category on biopsy was correlated to the category on excision. Fibroadenomas with PASH were defined as concordant with diffuse PASH on biopsy. The category was correlated to the presence/absence of a mass determined from radiographic/clinical data for the 159 biopsies. Results. The biopsies were classified as diffuse (105, 66%) and focal (54, 34%). A total of 67% of biopsies with focal PASH showed either focal or no PASH on excision. Diffuse PASH on biopsy, had diffuse PASH in 93% of excisions. Concordance of this classification between biopsy and excision, using a Fisher’s exact test (2-tailed P value is <.0001), is statistically significant. A mass was present in 102/105 (97%) of biopsies with diffuse PASH. In biopsies with focal PASH, 78% had a mass lesion. Conclusions. Classification of diffuse versus focal PASH on biopsy was concordant with findings on excision. We found that diffuse PASH on biopsy showed strong correlation with a mass lesion. Quantifying PASH may assist with clinical-pathologic correlation and reduce unnecessary excisions.

Using novel protein antibodies on tissue microarrays (TMAs) for breast cancer prognostication

9629 Background: Estrogen receptor (ER) and progesterone receptor (PR) are important prognostic and predictive factors for breast cancer patients (pts). Murine monoclonal antibodies (MuAb) are currently used in immunohistochemistry (IHC) assays to determine ER/PR status. Rabbit monoclonal antibodies (RAb) may have greater affinity for human antigens than MuAb. We compared the concordance of MuAb- and RAb-based IHC assays of ER and PR and the prognostic value of these and other factors in pts with Stage I-III breast cancer. METHODS TMAs were produced from formalin-fixed paraffin-embedded tissue sections of primary breast cancer pts. IHC assays were performed for the following: ER/PR status using RAb SP1CLONE (Labvision™) and using MuAb (Ventana™), fascin (a tumor cell motility protein) using clone 55K-2 (DAKO/M3567™), cytokeratin 5/6 (CK5/6) using clone D5/164B (Roche Biomed/1273396™), and HER2 using CB11. These were correlated with stage, progression-free (PFS) and overall survival (OS). ER/PR positivity was defined as ≥5% estimated proportion of positive-staining tumor cells. RESULTS 199 pts were evaluable for ER/PR. The concordance rate for RAb- and MuAb- assessed ER status was 90% (180/199). The level of agreement for RAb- and MuAb- assessed PR status was 81% (162/199). ER/PR positivity by RAb correlated with each other, HER2 negativity and earlier stage. In 159 pts with evaluable follow up, pts with ER positivity by RAb had better 5-year PFS (p<.001) and OS (p=.03), similar to ER positivity by MuAb. Pts with PR positivity by RAb had superior 5-year PFS (p=.001) and OS (p=.04) and correlated better with survival than PR positivity by MuAb. Fascin was expressed in 34 pts. Using univariate analysis, fascin expression correlated with higher stage, negative ER/PR, shorter PFS and OS. CK5/6 positivity did not correlate with any variable, except ER/PR positivity by RAb. After multivariate analysis, significant factors for PFS were stage, HER2, and PR by RAb, and for OS were stage, HER2, and fascin positivity. CONCLUSION 1) The RAb for PR may be superior to the MuAb in predicting prognosis. 2) Fascin deserves further investigation as a prognostic factor. No significant financial relationships to disclose.