Janet S. Winston

Sentinel node biopsy in breast cancer

AbstractBackground: Sentinel lymph node biopsy (SNB) in breast cancer may be used in place of axillary lymph node dissection (ALND) if SNB accurately stages the axilla. This study assessed the success and accuracy of axillary SNB with isosulfan blue (ISB) and technetium-99 sulfur colloid (TSC) compared to ALND. Methods: Forty-two women with T1 or T2 breast cancer underwent SNB and ALND. Sixty to 90 minutes before anesthetic induction, a mixture of 3 mL ISB and 1 mCi TSC was injected around the primary cancer or prior biopsy site. Intraoperatively, the SLN was identified using a gamma detector (Neoprobe 1000) or by visualization of the blue-stained lymph node and afferent lymphatics. The SLN was excised separately, and a level I/II ALND was completed. The histologic findings of the axillary contents and SLN were compared. Results: An axillary SLN was found in 38 of 42 (90%) cases. SLN localization rate and predictive value were the same for women who had and those who had not undergone excisional biopsy before the date of SNB. Fifteen of 42 (36%) patients had lymph node metastases. The SLN was positive in all women with axillary metastases (negative predictive value, 100%). Conclusions: If confirmed by larger series, a negative SNB may eliminate the need for ALND for select women with breast cancer.

Angiogenesis and dynamic MR imaging gadolinium enhancement of malignant and benign breast lesions

Purpose. To determine whether dynamic magnetic resonance (MR) imagingenhancement parameters are associated with vessel density of malignant andbenign breast lesions. Materials and methods. Forty-five patients with 48breast lesions underwent gadolinium-enhanced spoiled gradient-recalled echo(SPGR) MR imaging followed by excisional biopsy and Factor VIII staining andvessel density measurement in the lesions. Results. The vessel densitieswere not significantly different in 25 malignant breast lesions as comparedto 23 benign breast lesions. Among all 48 lesions, greater MR enhancementshowed an association with increased vessel density. Seventy-four percent ofall lesions with MRI enhancement amplitude greater or equal to three timespost-precontrast ratio had vessel densities greater than the median of 172as compared to 34% of lesions with enhancement amplitude less thanthree times, p = 0.02. The rate and washout of MR enhancement showedno significant association with vessel density. Conclusion. Although thereis an overall significant association between greater MRI enhancementamplitude and vessel density, MRI gadolinium enhancement of breast lesionsis not an accurate predictor of vessel density.

Intraoperative pathologic evaluation of a breast cancer sentinel lymph node biopsy as a determinant for synchronous axillary lymph node dissection.

Background: Intraoperative pathologic evaluation of a breast cancer sentinel lymph node (SLN) biopsy permits synchronous axillary lymph node dissection (ALND), but frozen section is time consuming and potentially inaccurate. This study evaluated intraoperative gross examination and touch prep analysis (TPA) of a breast cancer SLN biopsy as determinants for synchronous ALND.Methods: Intraoperative gross examination/TPA were performed on the SLN of consecutive breast cancer patients from 1997 to 2000. Patients with an intraoperative “positive” SLN underwent synchronous ALND. Intraoperative results were compared with the final pathology.Results: Thirty-seven of 150 patients had a positive SLN on final pathology. Intraoperative gross examination/TPA identified 54% (20 of 37) of these patients. All intraoperative “positive” patients underwent synchronous ALND. Of 17 “false-negative” findings, 53% (9 of 17) had micrometastatic disease. There were no “false-positive” results. Overall sensitivity and specificity were 54% and 100%, respectively.Conclusions: Gross examination/TPA are simple, rapid techniques for the intraoperative evaluation of a breast cancer SLN. As there were no false-positive results, the rationale behind SLN biopsy was preserved. These techniques permitted synchronous ALND in over half of all patients with a positive SLN. This represents a potential benefit to the patient by eliminating a second hospitalization for delayed ALND.

Downregulation of Gelsolin Correlates with the Progression to Breast Carcinoma

The actin cytoskeleton underlies several normal cellular functions and is deranged during carcinogenesis. Gelsolin, a multifunctional actin-binding protein, is downregulated in several types of tumors and its abnormal expression is one of the most common defects noted in invasive breast carcinoma (ICA). This study utilizes immunohistochemistry to examine the expression of gelsolin in 95 ICA, 59 ductal carcinoma in situ (DCIS) and 36 benign lesions, including 17 atypical ductal hyperplasia (ADH). Cytoplasmic staining was scored as positive, reduced or negative. Gelsolin expression was then correlated with patient’s age, tumor size, histologic grade and lymph node status. All unremarkable breast biopsies, 88% of ADH, 44% of DCIS and 28% of ICA were positive for gelsolin. This represents a significant difference among the groups (p=<0.0001) and the trend towards reduced gelsolin with the progression to ICA is significantly linear (p=<0.0001). For invasive carcinoma, patients older than 44 years were significantly more likely to have decreased expression of gelsolin than patients 44 years old and younger (p=0.007). Bivariate analysis showed no correlation of gelsolin expression with lymph node status (p=0.62), tumor size (p=0.10), histologic grade (p=0.42), estrogen receptor status (p=1.0) or other clinicopathologic parameters. In clinical follow-up, there were 18 breast tumor related deaths within a median follow-up time of 4.2 years. Survival analysis indicated that the level of gelsolin expression may be associated with survival (p=0.06). In summary, the frequency of gelsolin deficiency increases significantly with progression from ADH to DCIS to ICA. Additionally, gelsolin expression may be an independent marker of prognosis.

Differential Expression of High-Affinity Melatonin Receptors (MT1) in Normal and Malignant Human Breast Tissue

Melatonin is a pineal hormone that strongly inhibits the growth of breast cancer cells in vitro and in vivo. We report thefirst use of immunohistochemical analysis to determine the distribution of the high-affinity melatonin receptor subtype, MTI, in human breast tissue, the hypothalamic suprachiasmatic nucleus, and skin. The MT1 antibody, which is specific for the cytoplasmic portion of the receptor, produced cytoplasmic staining in normal-appearing breast epithelial cells and ductal carcinoma cells; stromal cells, myoepithelial cells, and adipocytes were nonreactive. The majority of nonneoplastic samples (13/19 [68%]) were negative to weakly positive, while moderate to strong reactivity was seen in most cancer samples (49/65 [75%]). Thus, although MT1 receptors were detectable in normal and malignant breast epithelium, high receptor levels occurred more frequently in tumor cells (P < .001), and tumors with moderate or strong reactivity were more likely to be high nuclear grade (P < .045). These findings may have implications for the use of melatonin in breast cancer therapy.

Down-regulation of gelsolin expression in human breast ductal carcinoma in situ with and without invasion

Expression of gelsolin, an actin filament regulatory protein, in human breast ductal carcinoma in situ (DCIS) was analyzed by immunohistochemistry using a monoclonal antibody. Formalin‐fixed paraffin‐embedded tissues from 59 pure DCIS specimens and 33 DCIS specimens with associated invasive components were evaluated for gelsolin reactivity and compared to eight normal breast cases and 76 invasive breast cancers. The proportion of cases exhibiting negative/low expression of gelsolin in the epithelium was as follows – normal, 0%; pure DCIS, 56%; DCIS associated with invasion, 58% in the DCIS component and 66% in the invasive component; invasive carcinoma, 70%. These data demonstrate that down‐regulation of gelsolin expression in breast epithelium frequently parallels progression to malignancy. Testing gelsolin expression (normal vs. negative/low levels) in the DCIS lesions for associations with patient age or any of the following histopathologic parameters revealed no significant (95% probability level) correlations – tumor size; pathologic (Van Nuys system) grade; nuclear grade; necrosis; presence of histologic calcifications; presence or type of adjacent benign lesions; architectural histologic pattern; and mammographic extent. Gelsolin loss was more commonly associated with mammographic soft tissue lesions as compared to calcified lesions (P = 0.009). A positive trend of borderline significance (P = 0.06) found in the DCIS with invasion group was a correlation between down‐regulated gelsolin expression in the DCIS component and size (< versus ≥ 15 mm) of the invasive tumor. In conclusion, reduced gelsolin protein is detectable in at least half of breast lesions which have progressed to DCIS. The trend between increasing gelsolin loss and malignant progression from normal epithelium to DCIS to invasive breast cancer (P < 0.0001) suggests additional investigation is needed to determine the potential of altered gelsolin expression as a marker for prognosis and for therapeutic interventions in breast cancer.

Concordance with breast cancer pathology reporting practice guidelines.

BACKGROUND Accurate pathology reporting is important for treatment of breast cancer. The College of American Pathologists (CAP) distributed guidelines for reporting cancer specimens in 1998. The aim of this study was to determine community-wide concordance with CAP breast cancer reporting guidelines. STUDY DESIGN Pathology reporting of stage I and II breast cancers was examined for adherence to CAP guidelines. Pathology reports were reviewed from 100 consecutive cases of invasive breast cancers referred to Roswell Park Cancer Institute in 1998 to 1999 from community hospitals after excisional breast biopsy and 20 consecutive cases with excisional biopsy at RPCI. Adherence to CAP guidelines for clinically relevant items was determined from the original pathology report in each case. RESULTS One hundred one cases met the inclusion criteria. Most reports did not include at least one of the guideline required elements. Surgical margins were inked in only 77%, and the margins oriented in only 25% of patients. Many specimens were not oriented by the surgeon. Grade was reported in most cases, but the Bloom Scarf Richardson grade was reported in only 6%. The presence or absence of lymphovascular invasion, and of coexisting in situ disease, was reported in 57% and 71%, respectively. The extent and type of in situ disease was reported in 47% and 49%, respectively. CONCLUSIONS Breast cancer pathology reporting varies widely. Key elements that affect treatment are often omitted. These include gross description and size, orientation and involvement of surgical margins, and description of histologic features, including Bloom Scarf Richardson reporting of grade and the extent of an in situ component. Passive distribution of CAP practice guidelines might be insufficient to accomplish community-wide quality improvement in breast pathology reporting.

Prostate-derived Ets transcription factor (PDEF) downregulates survivin expression and inhibits breast cancer cell growth in vitro and xenograft tumor formation in vivo

Previous studies using immunohistochemistry suggest that loss of the expression of the prostate-derived Ets transcription factor (PDEF) is a strong indicator for cancer cell malignancy. However, the underlying mechanism for this has not been well elucidated. We determined the role of PDEF in breast cancer cell growth and tumor formation using a series of experiments including Western blotting, promoter-luciferase reporter assay, RNA interference technology and a mouse xenograft model. We also determined the relationship between PDEF expression in human breast tumor specimen and cancer patient survivability. These studies revealed that PDEF expression is inversely associated with survivin expression and breast cancer cell xenograft tumor formation. PDEF-specific shRNA-mediated silencing of PDEF expression resulted in the upregulation of survivin expression in MCF-7 cells, which was associated with increased cell growth and resistance to drug-induced DNA fragmentation (apoptosis). In contrast, survivin-specific siRNA-mediated silencing of survivin expression decreased MCF-7 cell growth. Ectopic expression of PDEF inhibited both survivin promoter activity and endogenous survivin expression. Importantly, shRNA-mediated silencing of PDEF expression in MCF-7 breast cancer cells enhanced survivin expression and xenograft tumor formation in vivo. Furthermore, loss of PDEF expression in breast cancer tissues tends to be associated with unfavorable prognosis. These studies provide new information for the role of PDEF and survivin in breast cancer cell growth and tumor formation.

Clinical presentation and treatment of non-Hodgkin's lymphoma of the thyroid gland.

Background: Non-Hodgkin’s lymphoma (NHL) of the thyroid is a rare malignancy. The traditional approach to curative treatment of localized (stages I and II) NHL of the thyroid gland is surgical resection. The recent success of multimodality chemoradiotherapy suggests that surgery should be reserved for providing a tissue diagnosis or relief from acute airway obstruction. It is questionable whether this has made an impact on treatment approaches.Methods: Retrospective chart review was conducted for all cases of localized NHL of the thyroid gland treated at Roswell Park Cancer Institute between January 1970 and January 1999.Results: Ten patients (8 women, 2 men) with a mean age of 56.8 years were identified. Nine patients (90%) presented with a neck mass; seven patients (70%) had a history of Hashimoto’s disease. Nine patients (90%) had extensive investigations to rule out extrathyroidal disease. All patients were treated with either a total thyroidectomy (eight patients) or a thyroid lobectomy (two patients). Nine (90%) were initially treated outside of Roswell Park Cancer Institute and referred secondarily for consideration of further therapy. Adjuvant therapy consisting of cyclophosphamide-based chemoradiotherapy was administered to nine patients. Overall survival was 80% at a mean follow-up of 8.6 years with a disease-specific survival rate of 100%.Conclusions: A review of the literature suggests that fine needle aspiration (FNA) with flow cytometry and immunohistochemistry can be used to accurately diagnose NHL of the thyroid gland. Open biopsy should be reserved for cases where this technique is not available or where the diagnosis can not be confirmed by FNA alone. Extrathyroidal NHL should be ruled out by chest x-ray, CT scan of the abdomen, and bone marrow biopsy. Further review suggests that the most efficacious therapy is systemic chemotherapy in combination with radiation for local control. Debulking surgery should be used only to provide relief from acute airway obstruction.

Altered expression and localization of PKC eta in human breast tumors

Protein kinase C (PKC) eta is a PKC isoform whose upregulation is associated with differentiation in many epithelial tissues, including the rat mammary gland. The purpose of this study was to examine whether PKC eta is altered, in expression or localization, in human breast cancer. Paraffin sections of 49 in situ breast lesions, 29 invasive breast tumors, and nine normal breast biopsies were examined for PKC eta expression by immunohisto chemistry. Adjacent regions of normal epithelium, and in situ lesions that were present adjacent to invasive lesions were also analyzed. In normal epithelium, regardlessof the presence of adjacent in situ or invasive lesions, PKC eta was present in the cytoplasm of the luminal epithelium, and increased inareas of normal lobular development, similar to normal rat mammary gland. PKC eta staining intensity was homogeneous in normal lobules, but heterogeneous in in situ and invasive lesions, being focally increased in cells with aberrant nuclear morphology. In situ lesions were similar to adjacent normal epithelium in average staining intensity, regardless of whether invasion was also present. However, the invasive lesions themselves were significantly decreased in staining intensity compared to adjacent in situ lesions. In addition, 75% of invasive breast cancer lesions showed decreased staining relative to adjacent normal epithelium, compared to 37% of in situ lesions. The invasive tumors which possessed high PKC eta staining were associated with positive lymph node status. These results demonstrate that quantitative and qualitative alterations in PKC eta occur in human breast cancers.